Cysteine covalent modifiers of AKT1 and uses thereof

Provided herein are covalent modifiers of AKT1 of Formula (I), (I-A), (II), (II-A), (III), (II-A), or (III-B), and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides methods of modulating AKT1 using a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and pharmaceutical compositions thereof.

1. 11. A compound represented by the structure of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from: hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; and C3-8 carbocycle and 4- to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —N(R10)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl; A1 and A2 are each independently selected from (i), (ii), and (iii): (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN; (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and (iii) 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2(R11)2, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN; and C3-10 carbocycle and 4- to 10-membered heterocycle any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, —N(R11), and —CN; R3 is independently selected at each instance from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, and —CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, —O, ═S, ═N(R13), and —CN; R4 is independently selected at each instance from: halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, —O, —S, ═N(R14), and —CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, —N(R14), and —CN; L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from (a) and (b): (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(N15)—, N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, N(R15)S(O)2N(R15)—, —S(O)(N(R15)N(R15)—, N(R15) N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, —O, ═S, and —CN; wherein L1, L2, L3, and L4 are each optionally absent; wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent; Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; and 3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, —S, ═N(R16), and —CN; Ring D is selected from: R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN; A3 is cysteine susceptible electrophile; R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl; m is selected from 0, 1, 2, and 3; n is selected from 0, 1, 2, and 3; q is selected from 1, 2, and 3; and p is selected from 0, 1, 2, 3, 4, and 5.

CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation application of International Patent Application No. PCT/US2024/051051, filed Oct. 11, 2024, which claims the benefit of U.S. Provisional Application No. 63/590,256 filed on Oct. 13, 2023, U.S. Provisional Application No. 63/562,578 filed on Mar. 7, 2024, and U.S. Provisional Application No. 63/686,523 filed on Aug. 23, 2024, the entirety of each is incorporated herein by reference.


SEQUENCE LISTING
The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 30, 2025, is named 61402-712_301_SL.xml and is 5,556 bytes in size.
BACKGROUND OF THE INVENTION
The AKT or Protein Kinase B (PKB) family of serine/threonine protein kinases is comprised of 3 highly homologous members, AKT1, AKT2 and AKT3. The family of AKT proteins are involved in signal transduction pathways that regulate cellular processes including apoptosis, proliferation, differentiation, and metabolism. The AKT1 pathway is the most frequently dysregulated signaling pathways in human cancers. Enhanced activation of all the isoforms can be implicated in tumor development and progression, and has been demonstrated in breast, ovarian, pancreatic, and prostate cancers among others (Song et al., 2019). In cancer cells, AKT1 is involved in proliferation and growth, promoting tumor initiation, and suppressing apoptosis, whereas AKT2 regulates cytoskeleton dynamics, favoring local tissue invasion and metastasis. The role of AKT3 hyperactivation in cancer is hypothesized to be involved with possible stimulation of cell proliferation (Hinz et al., Cell Commun Signal 2019, 17 (1), 154; Pascual et al., Ann. Oncol. 2019, 30 (7), 1051-1060). Expression of these AKT family members is altered in many human malignant carcinomas including gastric, breast, prostate, ovarian, and pancreatic. AKT family members are rarely mutated however, the most common mutation is AKT1 E17K which has been reported in 6-8% of breast cancers, 2-6% of colorectal cancers, and in 6% of meningiomas, in humans (Yu et al., PLOS One 2015, 10 (10), No. e0140479). Thus, there is a need to develop new treatments for the modulation of AKT1 and mutants thereof.
SUMMARY OF THE INVENTION
In one aspect, the present disclosure provides compounds represented by the Formula (I):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 is selected from:
        
            hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN;
            C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; and
            C3-8 carbocycle and 4- to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —N(R10)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl;
        
        
        A1 and A2 are each independently selected from (i), (ii), and (iii):
        
            (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
            (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            
            
            (iii) 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, —N(R11), and —CN;
                C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
                
                    halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN;
                    C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN; and
                    C3-10 carbocycle and 4- to 10-membered heterocycle any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN;
                
                
            
            
        
        
        R3 is independently selected at each instance from:
        
            halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, ═O, ═S, ═N(R13), and —CN;
        
        
        R4 is independently selected at each instance from:
        
            halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN;
        
        
        L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from (a) and (b):
        
            (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
            (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN;
            wherein L1, L2, L3, and L4 are each optionally absent;
            wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent;
        
        
        Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; and
            3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
        
        
        Ring D is selected from:
    
    






    
    
        R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN;
        A3 is cysteine susceptible electrophile;
        R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from:
        
            hydrogen,
            C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
            C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl;
        
        
        m is selected from 0, 1, 2, and 3;
        n is selected from 0, 1, 2, and 3;
        q is selected from 1, 2, and 3; and
        p is selected from 0, 1, 2, 3, 4, and 5.
    
    


In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides a method of modulating activity of wild-type AKT1 comprising, administering to a subject in need thereof a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides a method of modulating activity of mutant AKT1 comprising, administering to a subject in need thereof a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides a method of selectively modulating activity of wild-type AKT1 over wild-type AKT2 comprising administering to a subject in need thereof a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B) and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides a method of selectively modulating activity of a mutant AKT1 over wild-type AKT2 comprising administering to a subject in need thereof a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B) and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B) and a pharmaceutically acceptable excipient. In some embodiments, the cancer is selected from breast cancer, colorectal cancer, and meningioma. In some embodiments, the administration modulates activity of a mutant AKT1. In some embodiments, the mutant AKT1 is AKT1 E17K. In some embodiments, the administration modulates activity of wild-type AKT1.
In another aspect, the present disclosure provides an AKT1 protein covalently bound to a compound, wherein the compound is covalently bound to a cysteine residue of the AKT1 protein. In some embodiments, the compound is an exogenous AKT1 modulator. In some embodiments, the compound is an exogenous AKT1 inhibitor. In some embodiments, the exogenous AKT1 inhibitor is a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the AKT1 protein comprises a E17K mutation, a E40K mutation, or a E49K mutation. In some embodiments, the cysteine residue is selected from C296 and C310. In some embodiments, the cysteine residue is C296. In some embodiments, the AKT1 protein is in vivo. In some embodiments, the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the compound. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein. In some embodiments, the covalent bond between the compound and the cysteine residue is an irreversible covalent bond. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and a cysteine susceptible electrophile on the compound, wherein the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and a cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forms a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the AKT1 protein comprises a E17K mutation. In some embodiments, the cysteine residue is selected from C296 and C310. In some embodiments, the cysteine residue is C296. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides a method of covalently modifying an AKT1 protein, comprising contacting the AKT1 protein with an exogenous AKT1 modulator, wherein the AKT1 modulator comprises a cysteine susceptible electrophile thereby forming a covalent AKT1 adduct. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the AKT1 modulator is an AKT1 inhibitor. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group.
In another aspect, the present disclosure provides a method of attenuating AKT1 activity, comprising contacting AKT1 protein with an AKT1 inhibitor, wherein the AKT1 inhibitor comprises a cysteine susceptible electrophile. In some embodiments, the contacting is in vitro. In some embodiments, following the contacting, the AKT1 activity is attenuated by 50% or more relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by 70% or more relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the exogenous AKT1 inhibitor is a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B).
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.



BRIEF DESCRIPTION OF THE DRAWINGS
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
FIGS. 1A-1C provide diagrams of the crystal structure for the Compound 13/AKT1 WT co-crystallization complex. FIG. 1A provides a 2-D diagram from the crystal structure of Compound 13/AKT1 WT with the AKT1 WT rendered in a cartoon model and Compound 13 with the AKT1 WT cysteine residue C296 rendered in stick model. FIG. 1B provides a 2-D diagram close-up from the crystal structure of Compound 13/AKT1 WT with Compound 13 depicted by a thicker stick model and the residues of AKT1 WT depicted by a thinner stick model. FIG. 1C provides a 2-D diagram close-up from the crystal structure of Compound 13/AKT1 WT detailing the interactions between the residues of AKT1 WT and Compound 13, specifically showing the covalent bond between C296 cysteine residue of AKT1 WT and Compound 13 (contains SEQ ID NO: 4).
FIGS. 2A-2C provide diagrams of the crystal structure for the Compound 13/AKT E17K co-crystallization complex. FIG. 2A provides a 2-D diagram from the crystal structure of Compound 13/AKT E17K with the AKT E17K rendered in a cartoon model and Compound 13 with the AKT E17K cysteine residue C296 rendered in stick model. FIG. 2B provides a 2-D diagram close-up from the crystal structure of Compound 13/AKT E17K with Compound 13 depicted by a thicker stick model and the residues of AKT E17K depicted by a thinner stick model. FIG. 2C provides a 2-D diagram close-up from the crystal structure of Compound 13/AKT E17K detailing the interactions between the residues of AKT E17K and Compound 13, specifically showing the covalent bond between C296 cysteine residue of AKT E17K and Compound 13 (contains SEQ ID NO: 4).



DETAILED DESCRIPTION OF THE INVENTION
The AKT or Protein Kinase B (PKB) family of serine/threonine protein kinases regulate a myriad of key cellular functions, including apoptosis, proliferation, differentiation, and metabolism. The AKT family is comprised of 3 highly homologous members, AKT1, AKT2 and AKT3, and each member possesses a unique tissue distribution and may perform a unique set of biological functions. Aberrant expression and/or activation of all AKT isoforms has been implicated in tumor development, including breast, ovarian, pancreatic, and prostate cancers among others.
Inhibitors of AKT proteins have been developed for the treatment of cancer, including the two major classes of small-molecule AKT inhibitors being investigated in the clinic: allosteric and ATP-competitive inhibitors. First, allosteric inhibitors (such as miransertib (ARQ 092) and MK-2206) interfere with PH-domain mediated membrane recruitment (the first step in AKT activation) and inhibit AKT kinase activation and AKT phosphorylation. Second, ATP-competitive inhibitors of AKT (such as ipatasertib and capivasertib) bind to the active kinase, in which the PH-domain has shifted from the kinase domain and exposed the ATP-binding pocket site, thus inhibiting ATP binding.
Provided herein are compounds for modulating (e.g., inhibiting) AKT1 function, as well as methods and compositions for using compounds of the present disclosure in the treatment of cancer. In some embodiments, the compounds selectively inhibit (e.g., 2×, 5×, 10×, 50×, 100×, etc.) an AKT1 protein over an AKT2 and/or AKT3 protein.
Definitions
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.
As used in the specification and claims, the singular form “a,” “an,” and “the” includes plural references unless the context clearly dictates otherwise.
“Alkyl” refers to a straight or branched hydrocarbon chain monovalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to twelve carbon atoms (i.e., C1-12 alkyl). The alkyl is attached to the remainder of the molecule through a single bond. An alkyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkyl comprises one to twelve carbon atoms (i.e., C1-12 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-2 alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-5 alkyl). For example, the alkyl group may be attached to the rest of the molecule by a single bond, such as, methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl), and the like.
“Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-12 alkenyl). An alkenyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-6 alkenyl). In other embodiments, an alkenyl comprises two to four carbon atoms (i.e., C2-4 alkenyl). The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.
“Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-12 alkynyl). An alkylnyl chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-6 alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
“Alkylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, (methyl)ethylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. An alkylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkylene comprises one to ten carbon atoms (i.e., C1-10 alkylene). In certain embodiments, an alkylene comprises one to eight carbon atoms (i.e., C1-8 alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-2 alkylene). In other embodiments, an alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (i.e., C5-8 alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-5 alkylene).
“Alkenylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. An alkenylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkenylene comprises two to ten carbon atoms (i.e., C2-10 alkenylene). In certain embodiments, an alkenylene comprises two to eight carbon atoms (i.e., C2-8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (i.e., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-5 alkenylene).
“Alkynylene” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. An alkynylene chain may be optionally substituted by one or more substituents such as those substituents described herein. In certain embodiments, an alkynylene comprises two to ten carbon atoms (i.e., C2-10 alkynylene). In certain embodiments, an alkynylene comprises two to eight carbon atoms (i.e., C2-8 alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5-8 alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-5 alkynylene).
The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6 alkyl” refers to saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term —Cx-y alkylene-refers to an alkylene chain with from x to y carbons in the alkylene chain. For example, —C1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which may be optionally substituted.
The terms “Cx-y alkenyl” and “Cx-y alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term —Cx-y alkenylene-refers to a alkenylene chain with from x to y carbons in the alkenylene chain. For example, —C2-6 alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which may be optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term —Cx-y alkynylene-refers to a alkynylene chain with from x to y carbons in the alkynylene chain. For example, —C2-6 alkynylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which may be optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.
The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. Carbocycle includes 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocycles may be fused, bridged or spiro-ring systems. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. Bicyclic carbocycles may be fused, bridged or spiro-ring systems. In some embodiments, the carbocycle is an aryl. In some embodiments, the carbocycle is a cycloalkyl. In some embodiments, the carbocycle is a cycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycle may be optionally substituted by one or more substituents such as those substituents described herein.
The term “carbocyclene” as used herein refers to a divalent saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A carbocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Carbocyclene includes divalent 3- to 10-membered monocyclic rings and divalent polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic carbocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. Polycyclic carbocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the carbocyclene to the rest of the molecule and the single bond connecting the carbocyclene to the radical group may be located on the same ring or different rings of a polycyclic carbocyclene. In some embodiments, the carbocycle is an arylene, for example, a phenylene. A “phenylene” as used herein refers to a divalent benzene group. The phenylene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. A phenylene may be optionally substituted by one or more substituents such as those substituents described herein.
“Cycloalkyl” refers to a stable fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused, bridged, or spiro-ring systems, and preferably having from three to twelve carbon atoms (i.e., C3-12 cycloalkyl). In certain embodiments, a cycloalkyl comprises three to ten carbon atoms (i.e., C3-10 cycloalkyl). In other embodiments, a cycloalkyl comprises five to seven carbon atoms (i.e., C5-7 cycloalkyl). The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Cycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
“Aryl” refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Aryl may be optionally substituted by one or more substituents such as those substituents described herein.
A “Cx-y carbocycle” is meant to include groups that contain from x to y carbons in a ring. For example, the term “C3-6 carbocycle” can be a saturated, unsaturated or aromatic ring system that contains from 3 to 6 carbon atoms—any one of which may be optionally substituted as provided herein.
The term “heterocycle” as used herein refers to a saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Polycyclic heterocycles may be fused, bridged or spiro-ring systems. Each ring of a polycyclic heterocycle may be selected from saturated, unsaturated, and aromatic rings. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycle comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocycle is a heteroaryl. In some embodiments, the heterocycle is a heterocycloalkyl. Exemplary heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein. Bicyclic heterocycles may be fused, bridged or spiro-ring systems. In an exemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Heterocycle may be optionally substituted by one or more substituents such as those substituents described herein.
The term “heterocyclene” as used herein refers to a divalent saturated, unsaturated, non-aromatic or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The single bond attaching the heterocyclene group to the rest of the molecule and the single bond attaching the heterocyclene group to the radical group may be each independently connected through any atom of the heterocyclene as valency permits, including a carbon atom in the heterocyclene ring or a heteroatom in the heterocyclene ring. A heterocyclene may be optionally substituted by one or more substituents such as those substituents described herein. Heterocyclenes include 3- to 10-membered monocyclic rings and polycyclic rings (e.g., 6- to 12-membered bicyclic rings). Each ring of a polycyclic heterocyclene may be selected from saturated, unsaturated, and aromatic rings. Polycyclic heterocyclenes may be fused, bridged or spiro-ring systems. The single bond connecting the heterocyclene to the rest of the molecule and the single bond connecting the heterocyclene to the radical group may be located on the same ring or different rings of a polycyclic heterocyclene and may be attached to the rest of the molecule or the radical group through any atom of the heterocyclene, valence permitting, such as a carbon or nitrogen atom of the heterocycle. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocyclene comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocyclene is a heteroarylene. In some embodiments, the heterocyclene is a heterocycloalkylene.
“Heterocycloalkyl” refers to a stable 3 to 12 membered non-aromatic ring radical that comprises two to twelve carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, Si, P, B, and S atoms. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heterocycloalkyl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. The heterocycloalkyl may be selected from monocyclic or bicyclic, and fused, bridged, or spiro-ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl is attached to the rest of the molecule through any atom of the heterocycloalkyl, valence permitting, such as any carbon or nitrogen atoms of the heterocycloalkyl. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxothiomorpholinyl. Heterocycloalkyl may be optionally substituted by one or more substituents such as those substituents described herein.
The term “heteroaryl” refers to a radical derived from a 5- to 12-membered aromatic ring radical whose ring structure comprise at least one heteroatom, preferably between one to four heteroatoms. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In some embodiments, the heteroaryl comprises at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Heteroaryl includes aromatic single ring structures, preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein. Heteroaryl also includes polycyclic ring systems having two or more rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other rings can be aromatic or non-aromatic carbocyclic, or heterocyclic. Heteroaryl may be optionally substituted by one or more substituents such as those substituents described herein.
An “X-membered heterocycle” refers to the number of endocyclic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.
“Alkoxy” refers to a radical bonded through an oxygen atom of the formula: —O-alkyl, where alkyl is an alkyl chain as defined above.
“Halo” or “halogen” refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.
As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, and I). When an alkyl group is substituted with more than one halogen radical, each halogen may be independently selected for example, 1-chloro,2-fluoroethane.
The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. Unless specified otherwise (e.g., by using the terms “substituted” or “optionally substituted,” or by the inclusion of an “—R” group), chemical groups described herein are unsubstituted. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.
In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO2), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH2), —Rb—ORa, —Rb—OC(O)Ra, —Rb—OC(O)ORa, —Rb—OC(O)N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)Ra (where t is 0, 1, or 2), —Rb—S(O), ORa (where t is 1 or 2), —Rb—S(O), N(Ra)2 (where t is 1 or 2), and —P(O)(Ra)2; and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any one of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO2), imino (═N—H), oximo (═N—OH), hydrazine (═N—NH2), —Rb—ORa, —Rb—OC(O)Ra, —Rb—OC(O)ORa, —Rb—OC(O)N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)tRa (where t is 1 or 2), —Rb—S(O)Ra (where t is 0, 1, or 2), —Rb—S(O)tORa (where t is 1 or 2), —Rb—S(O)tN(Ra)2 (where t is 1 or 2), and —P(O)(Ra)2; wherein each Ra is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO2), imino (═N—H), oximo (═N—OH), hydrazine (═N—NH2), —Rb—ORa, —Rb—OC(O)—Ra, —Rb—OC(O)—ORa, —Rb—OC(O)—N(Ra)2, —Rb—N(Ra)2, —Rb—C(O)Ra, —Rb—C(O)ORa, —Rb—C(O)N(Ra)2, —Rb—O—Rc—C(O)N(Ra)2, —Rb—N(Ra)C(O)ORa, —Rb—N(Ra)C(O)Ra, —Rb—N(Ra)S(O)Ra (where t is 1 or 2), —Rb—S(O)tRa (where t is 0, 1, or 2), —Rb—S(O), ORa (where t is 1 or 2), —Rb—S(O), N(Ra)2 (where t is 1 or 2), and —P(O)(Ra)2; and wherein each Rb is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Reis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.
The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
The terms “subject,” “individual,” and “patient” may be used interchangeably and refer to humans as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.
As used herein, the phrase “a subject in need thereof” refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.
The terms “administer,” “administered,” “administers,” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms “administer,” “administered,” “administers,” and “administering” a compound should be understood to mean providing a compound or salt of the invention or a prodrug of a compound or salt of the invention to the individual in need.
As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and/or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.
In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.
A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
Compounds
A compound represented by the structure of Formula (I):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 is selected from:
        
            hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN;
            C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; and
            C3-8 carbocycle and 4- to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR10, —SR10, —N(R10)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl;
        
        
        A1 and A2 are each independently selected from (i), (ii), and (iii):
        
            (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
            (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            
            
            (iii) 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN;
                C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
                
                    halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —CN; C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN;
                    C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN; and
                    C3-10 carbocycle and 4- to 10-membered heterocycle any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN;
                
                
            
            
        
        
        R3 is independently selected at each instance from:
        
            halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, ═O, ═S, ═N(R13), and —CN;
        
        
        R4 is independently selected at each instance from:
        
            halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN;
        
        
        L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from (a) and (b):
        
            (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
            (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN;
            wherein L1, L2, L3, and L4 are each optionally absent;
            wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent;
        
        
        Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; and
            3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
        
        
        Ring D is selected from:
    
    






    
    
        R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN;
        A3 is cysteine susceptible electrophile;
        R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from:
        
            hydrogen,
            C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
            C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl;
        
        
        m is selected from 0, 1, 2, and 3;
        n is selected from 0, 1, 2, and 3;
        q is selected from 1, 2, and 3; and
        p is selected from 0, 1, 2, 3, 4, and 5.
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from (i) and (ii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN; and
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from (i) and (ii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN; and
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from (i) and (ii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, and —CN; and
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from 3- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, 3- to 10-membered heterocycle and C3-10 carbocycle, the 3- to 10-membered heterocycle and C3-10 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, 3- to 6-membered heterocycle and C3-6carbocycle, the 3- to 6-membered heterocycle and C3-6 carbocycle are each optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, 3- to 6-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is




In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from (i) and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN; and
        (iii) 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN;
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN;
                C1-6 alkyl C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN; and
                C3-10 carbocycle and 4- to 10-membered heterocycle any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
            
            
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from (i) and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN; and
        (iii) 4- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —NO2, ═N(R11), and —CN;
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —NO2, ═N(R11), and —CN; and
            C3-10 carbocycle and 4- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —NO2, ═N(R11), —CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 haloalkenyl, C2-6 alkynyl, and C2-6 haloalkynyl.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from:

    
    
        hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, —CN; and
        4- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted by one or substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —NO2, ═N(R11), —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocycle and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I), A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, —CN, and 4- to 10-membered heterocycle and C3-10 carbocycle, the 4- to 10-membered heterocycle and C3-10 carbocycle are optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 4- to 10-membered heterocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, and 4- to 10-membered heterocycle and C3-10 carbocycle, the 4- to 10-membered heterocycle and C3-10 carbocycle are optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocycle and 4- to 10-membered heterocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, and 4- to 10-membered heterocycle and C3-10 carbocycle, the 4- to 10-membered heterocycle and C3-10 carbocycle are optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocycle and 4- to 6-membered heterocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —NO2, —CN, and 4- to 6-membered heterocycle and C3-6 carbocycle, the 4- to 6-membered heterocycle and C3-6 carbocycle are optionally substituted with one or more substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 carbocycle and 4- to 6-membered heterocycle. In some embodiments, A2 is selected from




In some embodiments, for the compound or salt of Formula (I), Ring D is selected from:




In some embodiments, Ring D is selected from:





and m is selected from 0, 1, and 2. In some embodiments, Ring D





and m is selected from 0, 1, and 2. In some embodiments, embodiments, Ring D is





and m is selected from 0, 1, and 2. In some embodiments, Ring D is





and m is selected from 0, 1, and 2.

In some embodiments, for the compound or salt of Formula (I), Ring D is selected from:




m is selected from 0, 1, and 2; and each R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN.

In some embodiments, for the compound or salt of Formula (I), Ring D is




and m is selected from 0 and 1. In some embodiments, Ring D is





m is selected from 0 and 1; and R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, Ring D is





In some embodiments, for the compound or salt of Formula (I), Ring D is




and m is selected from 0 and 1. In some embodiments, Ring D is





m is selected from 0 and 1; and R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, Ring D is





In some embodiments, for the compound or salt of Formula (I), Ring D is




and m is selected from 0 and 1. In some embodiments, Ring D is





m is selected from 0 and 1; and R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, Ring D is selected from





In some embodiments, Ring D is





In some embodiments, Ring D is selected from





In some embodiments, Ring D is





In some embodiments, Ring D is





In some embodiments, for the compound or salt of Formula (I), Ring D is




and m is selected from 1, 2, and 3. In some embodiments, Ring D is





m is selected from 1, 2, and 3; and each R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, Ring D is represented by





In some embodiments, for the compound or salt of Formula (I), Ring D is




m is selected from 0, 1, 2, and 3; and each R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, Ring D is represented by





In some embodiments, for the compound or salt of Formula (I), Ring D is




and each R2 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, Ring D is represented by





In some aspects, the structure Formula (I) is represented by the structure of Formula (II):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 is selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN;
        A1 and A2 are each independently selected from (i), (ii), and (iii):
        
            (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
            (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN;
                C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
                
                    halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
                    C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN;
                
                
            
            
        
        
        R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN;
        R3 is independently selected at each instance from:
        
            halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, ═O, ═S, ═N(R13), and —CN;
        
        
        R4 is independently selected at each instance from:
        
            halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN;
        
        
        L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from (a) and (b):
        
            (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
            (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN;
            wherein L2, L3, and L4 are each optionally absent;
            wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent;
        
        
        Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; and
            3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
        
        
        A3 is cysteine susceptible electrophile;
        R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from:
        
            hydrogen,
            C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
            C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl;
        
        
        m is selected from 0, 1, 2, and 3;
        n is selected from 0, 1, 2, and 3;
        q is selected from 1, 2, and 3; and
        p is selected from 0, 1, 2, 3, 4, and 5.
    
    


In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide. In some embodiments, the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, and a halo amidine. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, an alkene, an alkyne, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, and an alkyne. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne.
In some embodiments, for the compound or salt of Formula (I) or (II), the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl, an alpha-beta unsaturated sulfone, an alpha-beta unsaturated amide, and an alpha-beta unsaturated sulfonamide. In some embodiments, the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl and an alpha-beta unsaturated amide. In some embodiments, the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl.
In some embodiments, for the compound or salt of Formula (I) or (II), R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from

    
    
        hydrogen,
        C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
        C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, C1-6 alkyl, and C1-6 haloalkyl.
    
    


In some embodiments, for the compound or salt of Formula (I) or (II), R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from

    
    
        hydrogen,
        C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
        C3-6 carbocycle and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I) or (II), R15 is selected at each occurrence from

    
    
        hydrogen,
        C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
        C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, C1-6 alkyl, and C1-6 haloalkyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (I-A), (II), (II-A), (III), or (III-A), R15 is selected at each occurrence from:

    
    
        hydrogen,
        C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
        C3-6 carbocycle and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I) or (II), R15 is selected at each occurrence from hydrogen and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R15 is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R15 is C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —O—C1-6 alkyl, and 3- to 6-membered heterocycle. In some embodiments, R15 is C1-6 alkyl optionally substituted with one or more substituents independently selected from —O—C1-6 alkyl and 3- to 6-membered heterocycle. In some embodiments, R15 is C1-6 alkyl optionally substituted with one or more substituents independently selected from —O—C1-3 alkyl and 4- to 5-membered heterocycle. In some embodiments, R15 is C1-6 alkyl optionally substituted with —OCH3 or oxetanyl.
In some embodiments, for the compound or salt of Formula (I) or (II), L1 is —N(R15)—; and R15 is selected at each occurrence from C1-6 alkyl optionally substituted with one or more substituents independently selected from —O—C1-6 alkyl and 3- to 6-membered heterocycle. In some embodiments, L1 is —N(R15)—; and R15 is selected at each occurrence from C1-3 alkyl optionally substituted with one or more substituents independently selected from —O—C1-3 alkyl and 4- to 5-membered heterocycle. In some embodiments, L1 is —N(R15)—; and R15 is selected at each occurrence from C1-3 alkyl optionally substituted with one or more substituents independently selected from —OCH3 and oxetanyl.
In some embodiments, for the compound or salt of Formula (I) or (II), L is selected from




In some embodiments, L is





In some embodiments, L is





In some aspects, the structure Formula (I) or (II) is represented by the structure of Formula (II-A):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        the cysteine susceptible electrophile is R5;
        R5 is selected from:
        
            —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), and —CN;
            C1-6 alkyl substituted with one or more substituents independently selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, —S(O)2N(R17)(R19), and —CN;
            C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from —C(O)R19, —S(O)2R19, —N(R19)C(O)(R19), —C(O)N(R19)2, —N(R19)S(O)2R19, —S(O)2N(R19)(R19), and —CN; and
            C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), and —CN;
        
        
        R17 is independently selected at each occurrence from:
        
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
            C3-6 carbocyclenyl. 3- to 6-membered heterocyclenyl, and 3- to 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
        
        
        R18 and R19 are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I), (II) or (II-A), R5 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), and —CN. In some embodiments, R5 is selected from —C(O)R17—, N(R19)C(O)(R17), —C(O)N(R17)(R19), —S(O)2R17 and —CN. In some embodiments, R5 is selected from —C(O)R17—, N(R19)C(O)(R17), —C(O)N(R17)(R19), —S(O)2R17 and —CN, wherein each R19 is independently selected at each occurrence from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R5 is selected from —C(O)R17—, N(R19)C(O)(R17), —C(O)N(R17)(R19), —S(O)2R17 and —CN, wherein each R19 is independently selected at each occurrence from hydrogen and methyl. In some embodiments, R5 is selected from —CN,




In some embodiments, R5 is selected from





In some embodiments, R5 is selected from





In some embodiments, R5 is —CN.

In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R5 is C1-6 alkyl substituted with one or more substituents independently selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, —S(O)2N(R17)(R19), and —CN. In some embodiments, R5 is C1-6 alkyl substituted with one or more substituents independently selected from —N(R19)C(O)(R17) and —C(O)N(R17)(R19). In some embodiments, R5 is C1-6 alkyl substituted with one or more —N(R19)C(O)(R17). In some embodiments, R5 is C1-6 alkyl substituted with one or more —N(H)C(O)(R17). In some embodiments, R5 is




In some embodiments, R5 is selected from





In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R5 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from —C(O)R19, —S(O)2R19, —N(R19)C(O)(R19), —C(O)N(R19)2, —N(R19)S(O)2R19, —S(O)2N(R17)(R19), and —CN. In some embodiments, R5 is C2-6 alkenyl substituted with one or more substituents independently selected from —C(O)R19, —S(O)2R19, —N(R19)C(O)(R19), —C(O)N(R19)2, —N(R19)S(O)2R19, —S(O)2N(R17)(R19), and —CN. In some embodiments, R5 is C2-6 alkenyl substituted with one or more substituents independently selected from —N(R19)C(O)(R19) and —C(O)N(R19)2. In some embodiments, R5 is C2-3 alkenyl substituted with one or more —C(O)N(R19)2. In some embodiments R5 is




In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R5 is selected from C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), —S(O)2R17, and —CN. In some embodiments, R5 is 3- to 6-membered heterocycle substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), —S(O)2R17, and —CN. In some embodiments, R5 is 3- to 6-membered heterocycle substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, and —CN.
In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R5 is selected from azetidinyl and pyrrolidinyl each of which is substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), —S(O)2R17, and —CN. In some embodiments, R5 is selected from azetidinyl and pyrrolidinyl each of which is substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), —N(R19)S(O)2R17, —S(O)2N(R17)(R19), —S(O)2R17, and —CN. In some embodiments, R5 is selected from azetidinyl and pyrrolidinyl each of which is substituted with one or more substituents independently selected from ═O, C2-6 alkenyl, C2-6 alkynyl, —C(O)R17, and —CN. In some embodiments, R5 is selected from




In some embodiments, R5 is





In some embodiments, R5 is





In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R17 is independently selected at each occurrence from:

    
    
        C1-6 alkyl substituted with halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)Cd(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN;
        C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
        C3-6 carbocyclenyl. 3- to 6-membered heterocyclenyl, and 3- to 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R17 is C1-6 alkyl substituted with halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN. In some embodiments, R17 is C1-6 alkyl substituted with halogen, —OR18, —N(R18)2, —C(O)N(R18)2, —NO2, and —CN.
In some embodiments, for the compound or salt of Formula (II) or (II-A), R17 is independently selected at each occurrence from C3-6 carbocyclenyl. 3- to 6-membered heterocyclenyl, and 3- to 6-membered heterocyclyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN. In some embodiments, R17 is independently selected at each occurrence from C3-6 carbocyclenyl. 3- to 6-membered heterocyclenyl, and 3- to 6-membered heterocyclyl, each of which is optionally substituted with substituents independently selected from halogen, C1-6 alkyl, C1-6 haloalkyl, halogen, —OR18, —N(R18)2, —NO2, and —CN.
In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R5 is selected from —CN.




In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R5 is selected from —CN,




In some embodiments, for the compound or salt of Formula (I), (II), or (II-A),




is selected from:





In some embodiments, for the compound or salt of Formula (I), (II), or (II-A),




is selected from:





In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R18 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R18 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R18 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R18 is independently selected at each occurrence from: hydrogen and C1-3 alkyl. In some embodiments, R18 is independently selected at each occurrence from: hydrogen and methyl. In some embodiments, R18 is methyl.
In some embodiments, for the compound or salt of Formula (I), (II), or (II-A), R19 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R19 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R19 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R19 is independently selected at each occurrence from: hydrogen and C1-3 alkyl. In some embodiments, R19 is independently selected at each occurrence from: hydrogen and methyl.
In some aspects, the structure of Formula (I), (II), or (II-A), is represented by the structure of Formula (III):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        R1 is selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN;
        A1 and A2 are each independently selected from (i), (ii), and (iii):
        
            (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
            (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
                C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
                
                    halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
                    C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN;
                
                
            
            
        
        
        R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN;
        R3 is independently selected at each instance from:
        
            halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, ═O, ═S, —N(R13), and —CN;
        
        
        R4 is independently selected at each instance from:
        
            halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN;
        
        
        L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from (a) and (b):
        
            (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
            (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN;
            wherein L2, L3, and L4 are each optionally absent;
            wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent;
        
        
        Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR 16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; and
            3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
        
        
        A3 is cysteine susceptible electrophile;
        R10, R11, R12, R13, R14, R15, and R16 are each independently selected at each occurrence from:
        
            hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle;
        
        
        m is selected from 0, 1, 2, and 3;
        n is selected from 0, 1, 2, and 3;
        q is selected from 1, 2, and 3; and
        p is selected from 0, 1, 2, 3, 4, and 5.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), or (III), the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, acrylamide group, a vinyl group, a vinylsulfonamide group, and an ynamide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylamide group, a vinyl group, a vinylsulfonamide group, and an ynamide. In some embodiments, the cysteine susceptible electrophile is an acrylamide group.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), or (III), the cysteine susceptible electrophile of A3 is R5, wherein R5 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, and —S(O)2N(R17)(R19);

    
    
        R17 is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
        
        
        R18 and R19 are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), or (III), the cysteine susceptible electrophile is R5, wherein R5 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, and —S(O)2N(R17)(R19);

    
    
        R17 is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
        
        
        R18 and R19 are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), or (III), the cysteine susceptible electrophile is R5, wherein R5 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, and —S(O)2N(R17)(R19);

    
    
        R17 is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
        
        
        R18 and R19 are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), or (III), the cysteine susceptible electrophile is R5, wherein R5 is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group.
In some aspects, the structure of Formula (I), (II), (II-A), or (III), is represented by the structure of Formula (III-A):




    
    
        or a pharmaceutically acceptable salt thereof, wherein:
        the cysteine susceptible electrophile is R5;
        R5 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, and —S(O)2N(R17)(R19);
        R17 is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN; and
        
        
        R18 and R19 are each independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), q is selected from 1, 2, and 3. In some embodiments, q is selected from 1 and 2. In some embodiments, q is 1.
In some embodiments, for the compound or salt of Formula (I), (I), (II), (II-A), (III), or (III-A). m is selected from 0, 1, 2, and 3. In some embodiments, m is selected from 0, 1, and 2. In some embodiments, m is selected from 0 and 1. In some embodiments, m is 0.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), n is selected from 0, 1, 2, and 3. In some embodiments, n is selected from 0, 1, and 2. In some embodiments n is selected from 0 and 1. In some embodiments, n is 0.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), p is selected from 0, 1, 2, 3, 4, and 5. In some embodiments, p is selected from 0, 1, 2, 3, and 4. In some embodiments, p is selected from 0, 1, 2, and 3. In some embodiments, p is selected from 0, 1, and 2. In some embodiments, p is selected from 0 and 1. In some embodiments, p is 0.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R1 is selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R1 is selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN; and R10 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R1 is selected from hydrogen, halogen, —OR10, —N(R10)2, —NO2, —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR10, and —N(R10)2. In some embodiments, R1 is selected from hydrogen, —OR10, and —CN; and C1-6 alkyl optionally substituted with one or more —OR10.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R1 is selected from hydrogen, —OR10, and —CN; and C1-6 alkyl optionally substituted with one or more —OR10; and R10 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R1 is selected from hydrogen, —OR10, and —CN; and C1-6 alkyl optionally substituted with one or more —OR10; and R10 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R1 is selected from hydrogen, methoxy, —CN, methyl, ethyl, and (methoxy)methyl. In some embodiments, R1 is selected from hydrogen, methoxy, and methyl. In some embodiments, R1 is hydrogen.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN. In some embodiments, R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —N(R12)2, and —CN. In some embodiments, R2 is independently selected at each instance from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R2 is independently selected at each instance from halogen, C1-4 alkyl, and C1-4 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R12 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R12 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R12 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R12 is independently selected at each occurrence from: hydrogen and C1-3 alkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R3 is independently selected at each instance from:

    
    
        halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, and —CN; and
        C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR13, —SR13, —N(R13)2, —C(O)R13, —C(O)N(R13)2, —N(R13)C(O)R13, —C(O)OR13, —OC(O)R13, —NO2, ═O, ═S, ═N(R13), and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R3 is independently selected at each instance from halogen, —OR13, —N(R13)2, —CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3 is independently selected at each instance from halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R3 is independently selected at each instance from halogen, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R13 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R13 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R13 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R13 is independently selected at each occurrence from: hydrogen and C1-3 alkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R4 is independently selected at each instance from:

    
    
        halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN; and
        C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from halogen, —OR14, —SR14, —N(R14)2, —C(O)R14, —C(O)N(R14)2, —N(R14)C(O)R14, —C(O)OR14, —OC(O)R14, —NO2, ═O, ═S, ═N(R14), and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R4 is independently selected at each instance from halogen, —OR14, —N(R14)2, —NO2, ═O, —CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R4 is independently selected at each instance from halogen, —OR14, —N(R14)2, ═O, —CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R4 is independently selected at each instance from halogen, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, R4 is independently selected at each instance from halogen, C1-3 alkyl and C1-3 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R4 is selected from hydrogen, halogen, —OR14, —N(R14)2, —NO2, —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR14, and —N(R14)2. In some embodiments, R4 is selected from halogen, —OR14, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R4 is selected from fluoro, —OH, and —OCH3.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), R14 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R14 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R14 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R14 is independently selected at each occurrence from: hydrogen and C1-3 alkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 and A2 are each independently selected from (i), (ii), and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
                C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
            
            
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 and A2 are each independently selected from (i), (ii), and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, —O, and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 and A2 are each independently selected from (i), (ii), and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 and A2 are each independently selected from (i), (ii), and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, and —CN
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, halogen, —OR11, —N(R11)2, ═O, and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, ═O, and —CN; and
            C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, ═O, and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR11, —N(R11)2, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 and A2 are each independently selected:

    
    
        hydrogen, halogen, —OR11, —N(R11)2, ═O, C1-6 alkyl, and C1-6 haloalkyl; and
        5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle, wherein each of the C1-6 alkyl, C1-6 haloalkyl, C3-10 carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR11, —N(R11)2, and ═O.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 and A2 are each independently selected from hydrogen, halogen, —OR11, —N(R11)2. ═O, C1-6 alkyl, C1-6 haloalkyl, 5- to 10-membered heterocycle and C3-10 carbocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, —OR11, —N(R11)2, and —CN. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, A1 and A2 are each independently selected from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, 5- to 10-membered heterocycle and C3-10 carbocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, 5- to 10-membered heterocycle and C3-10 carbocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, 5- to 6-membered heterocycle and C3-6 carbocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, 5- to 6-membered heteroaryl and C3-6 saturated carbocycle. In some embodiments, A1 and A2 are each independently selected from hydrogen, 5-membered heteroaryl and C3-6 cycloalkyl. In some embodiments, A1 and A2 are each independently selected from hydrogen, pyrazole, triazole, and cyclopropyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 is selected from (i), (ii), and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
                C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
            
            
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 is selected from: hydrogen, halogen, —OR11, —N(R11)2, —CN, C1-6 alkyl, C1-6 haloalkyl, 5- to 6-membered heterocycle, and C3-6 carbocycle. In some embodiments, A1 is selected from: hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, —OR11, —N(R11)2, and —CN. In some embodiments, A1 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, —OR11, —N(R11)2, and —CN. In some embodiments, A1 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, A1 is selected from hydrogen, fluoro, and methyl. In some embodiments, A1 is hydrogen.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), or (III-A), A1 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, —OR11, —N(R11)2, —CN, 5- to 10-membered heterocycle and C3-10 carbocycle. In some embodiments, A1 is selected from hydrogen, halogen, and C1-3 alkyl, C1-3 haloalkyl, 3- to 6-membered heterocycle, and C3-6 carbocycle. In some embodiments, A1 is selected from hydrogen, fluoro, methyl,




In some aspects, the structure of Formula (I), (II), (II-A), (III), or (III-A), is represented by the structure of Formula (III-B):




or a pharmaceutically acceptable salt thereof.

In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from (i), (ii), and (iii).

    
    
        (i) hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, and —CN;
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, —N(R11), and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
                C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
            
            
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from (i), (ii), and (iii).

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN;
        (ii) C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
                C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN.
            
            
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from (i), (ii), and (iii).

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN;
        (ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
        
        
        C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
        
            C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
            
                halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
                C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN.
            
            
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from (i), (ii), and (iii).

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, and ═O;
        (ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, and ═O; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from (i), (ii), and (iii):

    
    
        (i) hydrogen, halogen, —OR11, —N(R11)2, and ═O;
        (ii) C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, and ═O; and
        (iii) 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, and ═O; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, and ═O.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from: hydrogen, halogen, —OR11, —N(R11)2, C1-6 alky, and C1-6 haloalkyl; and

    
    
        5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, C1-6 alkyl, and C1-6 haloalkyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from: hydrogen, halogen, C1-6 alky, and C1-6 haloalkyl; and 5- to 10-membered heterocycle and C3-10 carbocycle. In some embodiments, A2 is selected from hydrogen, halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, A2 is selected from 5- to 10-membered heterocycle and C3-10 carbocycle. In some embodiments, A2 is selected from 5- to 6-membered heterocycle and C3-6 carbocycle.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from hydrogen, halogen, —OR11, —N(R11)2, CN, and ═O; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, and ═O. In some embodiments, A2 is selected from hydrogen, halogen, —OR11, —N(R11)2, CN, and ═O; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen and —OR11. In some embodiments, A2 is selected from A2 is selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, —OR11, —N(R11)2, and —CN. In some embodiments, A2 is selected from hydrogen, halogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, A2 is C1-4 alkyl. In some embodiments, A2 is selected from hydrogen and methyl. In some embodiments, A2 is methyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
            C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN;
        C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN; and
            C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN;
        C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11. ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is selected from 5- to 10-membered heterocycle and C3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from 5- to 6-membered heteroaryl and C3-6 saturated carbocycle, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is selected from 5- to 6-membered heteroaryl and C3-6 saturated carbocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from pyrazolyl, triazolyl, and cyclopropyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is selected from pyrazolyl, triazolyl, and cyclopropyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2. In some embodiments, A2 is selected from pyrazolyl, triazolyl, and cyclopropyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2; and R11 is independently selected at each occurrence from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, A2 is selected from pyrazolyl, triazolyl, and cyclopropyl, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —CN, C1-6 alkyl, and C1-6 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
            C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN;
        C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, ═O, and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—O, and —CN; and
            C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN;
        C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, ═O, and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—O, and —CN; and
            C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN;
        C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11. ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2. In some embodiments, A2 is selected from 5- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, C1-6 alkyl, C1-6 haloalkyl. In some embodiments, A2 is selected from 5- to 10-membered heterocycle.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridinyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each of which is substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridinyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2. In some embodiments, A2 is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridinyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridinyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —CN, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridinyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, A2 is selected from pyrazolyl, triazolyl, oxazolyl, thiazolyl, morpholinyl, pyridinyl, pyrazinyl, and 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazinyl, each of which is optionally substituted with one or more substituents independently selected from fluoro, methyl, and —CHF2. In some embodiments, A2 is selected from




In some embodiments, A2 is





In some embodiments, A2 is selected from





In some embodiments, A2 is





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2. In some embodiments, A2 is selected from 5- to 6-membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, C1-6 alkyl, C1-6 haloalkyl. In some embodiments, A2 is selected from 5- to 6-membered heteroaryl. In some embodiments, A2 is 5-membered heteroaryl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from pyrazolyl and triazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2. In some embodiments, A2 is selected from pyrazolyl and triazolyl, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, C1-6 alkyl, C1-6 haloalkyl. In some embodiments, A2 is selected from pyrazolyl and triazolyl. In some embodiments, A2 is pyrazolyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is selected from




each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, and —N(R11)2. In some embodiments, A2 is selected from





each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, C1-6 alkyl, C1-6 haloalkyl. In some embodiments, A2 is selected from





In some embodiments, A2 is





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN. In some embodiments, A2 is 5- to 10-membered saturated heterocycle optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN. In some embodiments, A2 is 5- to 10-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 8-membered heterocycle optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN. In some embodiments, 5- to 8-membered saturated heterocycle optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, ═O, and —CN. In some embodiments, A2 is selected from




In some embodiments, A2 is selected from





In some embodiments, A2 is selected from





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, and —CN. In some embodiments, A2 is 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, and —CN. In some embodiments, A2 is 5- to 6-membered heteroaryl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, and —CN; and R11 is selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, A2 is selected from




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, ═O, and —CN. In some embodiments, A2 is 5- to 8-membered heterocycle optionally substituted with one or more C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, ═O, and —CN. In some embodiments, A2 is 5- to 8-membered saturated heterocycle optionally substituted with one or more C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —NO2, ═O, and —CN. In some embodiments, A2 is




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 6-membered heteroaryl optionally substituted with one or more C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —NO2, and —CN. In some embodiments, A2 is 5- to 6-membered heteroaryl optionally substituted with one or more C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —NO2, and —CN. In some embodiments, A2 is selected from




In some embodiments, A2 is 5-membered heteroaryl optionally substituted with one or more C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —NO2, and —CN. In some embodiments, A2 is selected from





In some embodiments, A2 is 6-membered heteroaryl optionally substituted with one or more C1-3 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —NO2, and —CN. In some embodiments, A2 is





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is 5- to 10-membered heterocycle optionally substituted with one or more C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, —CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, A2 is 5- to 10-membered heterocycle optionally substituted with one or more C3-6 saturated carbocycle and 3- to 6-membered saturated heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, —CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, A2 is 5- to 6-membered heterocycle optionally substituted with one or more C3-6 saturated carbocycle and 3- to 6-membered saturated heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, —CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, A2 is 5- to 6-membered heteroaryl optionally substituted with one or more C3-6 saturated carbocycle and 3- to 6-membered saturated heterocycle, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, —CN, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, A2 is selected from




In some embodiments, A2 is selected from





In some embodiments, A2 is





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-10 carbocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11—C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), —CN; and
            C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —SR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, —N(R11)S(O)2R11, —C(O)OR11, —OC(O)R11, —NO2, ═O, ═S, ═N(R11), and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-10 carbocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and
        C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and
        C3-10 carbocycle and 3- to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and
            C1-6 alkyl C2-6 alkenyl, and C3-6 alkynyl, any one of which is optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-10 carbocycle optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN;
        C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═0; and
        C3-10 carbocycle and 3- to 10-membered heterocycle; wherein the C3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11. ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-10 carbocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-6 saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is C3-6 saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is C3-6 saturated carbocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is C3-6 saturated carbocycle.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-6 cycloalkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is C3-6 cycloalkyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is C3-6 cycloalkyl optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is C3-6 cycloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is cyclopropyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is cyclopropyl optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is cyclopropyl optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is cyclopropyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is




optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is





optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is





substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, A2 is





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A2 is C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, ═O, and —CN; and C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —N(R11)2, —C(O)R11, —C(O)N(R11)2, —N(R11)C(O)R11, and ═O. In some embodiments, A2 is C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, —OR11, —N(R11)2, —CN, C1-6 alkyl. In some embodiments, A2 is selected from




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R11 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R11 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R11 is independently selected at each occurrence from: hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R11 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R11 is independently selected at each occurrence from: hydrogen and C1-3 alkyl. In some embodiments, R11 is independently selected at each occurrence from: hydrogen and methyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L is represented by -L1-L2-L3-L4-, wherein L1, L2, L3, and L4 are each independently selected from (a) and (b):

    
    
        (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
        (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN;
        wherein L2, L3, and L4 are each optionally absent;
        wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1, L2, L3, and L4 are each independently selected from (a) and (b):

    
    
        (a) —O—, —N(R15)—, —S—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—N(R15)N(R15)—, and (R15)NC(O)N(R15)—; and
        (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-6 carbocyclene, and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, ═O, and —CN;
        wherein L2, L3, and L4 are each optionally absent;
        wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1, L2, L3, and L4 are each independently selected from (a) and (b):

    
    
        (a) —O—, —N(R15)—, and —N(R15)C(O)—;
        (b) C1-6 alkylene;
        wherein L2, L3, and L4 are each optionally absent;
        wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent; and
        R15 is selected from hydrogen and C1-4 alkyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1, L2, L3, and L4 are each independently selected from (a) and (b):

    
    
        (a) —O—, —N(H)—, and —N(H)C(O)—;
        (b) C1-6 alkylene;
        wherein L2, L3, and L4 are each optionally absent;
        wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1, L2, L3, and L4 are each independently selected from (a) and (b):

    
    
        (a) —N(H)—, and —N(H)C(O)—;
        (b) methylene;
        wherein L2, L3, and L4 are each optionally absent;
        wherein no more than two of L1, L2, L3, and L4 are selected from (a) and the two selected are not adjacent.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L2, L3, and L4 are each optionally absent. In some embodiments, L3 and L4 are each optionally absent. In some embodiments, L4 is absent. In some embodiments, L3 is absent.
In some embodiments, for the compound or salt of Formula (II), (II-A), (III), (III-A), or (III-B), L2 is absent or selected from:

    
    
        (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
        (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L2 is absent or selected from:

    
    
        (a) —O—, —N(R15)—, —S—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—N(R15)N(R15)—, and (R15)NC(O)N(R15)—; and
        (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-6 carbocyclene, and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, ═O, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L2 is absent or selected from —O—, —N(R15)—, and —N(R15)C(O)—, and C1-6 alkylene.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L2 is absent or selected from —N(R15)— and —N(R15)C(O)—, and C1-3 alkyl; and R15 is selected at each occurrence from hydrogen and methyl. In some embodiments, L2 is absent or selected from —N(H)—, —N(H)C(O)—, and methylene. In some embodiments, L2 is absent or methylene. In some embodiments, L2 is absent.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 is selected from:

    
    
        (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, and —(R15)NC(O)N(R15)N(R15)—; and
        (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 is selected from:

    
    
        (a) —O—, —N(R15)—, —S—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—N(R15)N(R15)—, and (R15)NC(O)N(R15)—; and
        (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-6 carbocyclene, and 3- to 6-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, ═O, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 is selected from —O—, —N(R15)—, and —N(R15)C(O)—, and C1-6 alkylene. In some embodiments, L1 is selected from —O—, —N(R15)—, and —N(R15)C(O)—, and C1-6 alkylene, and R15 is selected at each occurrence from hydrogen and C1-4 alkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 is selected from —N(R15)— and —N(R15)C(O)—; and R15 is selected at each occurrence from hydrogen and methyl. In some embodiments, L1 is selected from —N(H)— and —N(H)C(O)—. In some embodiments, L1 is —N(H)C(O)—.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L is selected from —O—, —N(R15)—, —N(R15)—C1-3 alkyl-, and —N(R15)C(O)—; and R15 is selected from hydrogen and C1-4 alkyl. In some embodiments, L is selected from —O—, —N(R15)—, —N(R15)—C1-3 alkyl-, and —N(R15)C(O)—; and R15 is independently selected from hydrogen and methyl. In some embodiments, L is selected from —O—, —NH—,




In some embodiments, L is selected from —NH— and





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L is selected from —O—, —NH—, —N(CH3)—,




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), L1 is selected from —O—, —N(R15)—, —N(R15)C(O)—, C1-6 alkylene, and 3- to 6-membered heterocyclene. In some embodiments, L is selected from —O—, —NH—, —CH2—, —N(CH3)—,




In some embodiments, L is selected from —O—, —NH—, —CH2—, and —N(CH3)—. In some embodiments, L is selected from




In some embodiments, L is





In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R15 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R15 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R15 is independently selected at each occurrence from: hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R15 is independently selected at each occurrence from: hydrogen and C1-4 alkyl. In some embodiments, R15 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R15 is independently selected at each occurrence from: hydrogen and C1-3 alkyl. In some embodiments, R15 is independently selected at each occurrence from: hydrogen and methyl. In some embodiments, R15 hydrogen.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN;
        C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN; and
        3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        3- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-6 alkyl, C1-6 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        4- to 6-membered heterocycle and C3-6 carbocycle, each of which is optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from 3- to 10-membered heterocyclene and C3-10 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from 5- to 10-membered heterocyclene and C3-6 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from 5- to 10-membered heterocyclene and C3-6 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR16, and C1-3 alkyl. In some embodiments, Ring B is selected from 5- to 10-membered heterocyclene and C3-6 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR16, and C1-3 alkyl; and R16 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Ring B is selected from 5- to 10-membered heterocyclene and C3-6 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen and C1-3 alkyl. In some embodiments, Ring B is selected from 5- to 10-membered heterocyclene and C3-6 carbocyclene, any of which is optionally substituted with one or more substituents independently selected from fluoro and methyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from 5- to 10-membered saturated heterocyclene, 5- to 10-membered unsaturated heterocyclene, and C3-6 unsaturated carbocyclene, any of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from azetidinylene, pyrrolidinylene, piperidinylene, phenylene, pyridinylene, indolinylene, 3-azabicyclo[3.2.1]octanylene, cyclobutylene, cyclohexylene, pyrazolylene, 1,2,3,4-tetrahydroquinolinylene, azaspiro[3.5]nonanylene, azaspiro[3.3]heptanylene, azaspiro[3.4], octanylene, 1,4 oxazepanylene, 3-azabicyclo[3.1.1]heptanylene, 3-oxa-6-azabicyclo[3.2.2]nonanylene, piperazinylene, azepanylene, 2-azabicyclo[2.2.2]octanylene, 2-azabicyclo[2.2.1]heptanylene each of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, —O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from azetidinylene, pyrrolidinylene, piperidinylene, phenylene, pyridinylene, indolinylene, isoindolinylene, tetrahydroisoquinolinyl, 3-azabicyclo[3.2.1]octanylene, cyclobutylene, cyclohexylene, pyrazolylene, 1,2,3,4-tetrahydroquinolinylene, azaspiro[3.5]nonanylene, azaspiro[3.3]heptanylene, azaspiro[3.4], octanylene, 1,4 oxazepanylene, 3-azabicyclo[3.1.0]heptanylene, 3-azabicyclo[3.1.1]heptanylene, 3-oxa-6-azabicyclo[3.2.2]nonanylene, 3-oxa-7-azabicyclo[3.3.1]nonanylene, 3-azabicyclo[3.3.1]nonanylene, piperazinylene, azepanylene, 2-azabicyclo[2.2.2]octanylene, 2-azabicyclo[2.2.1]heptanylene, 2-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from azetidinylene, pyrrolidinylene, piperidinylene, phenylene, pyridinylene, indolinylene, and 3-azabicyclo[3.2.1]octanylene, each of which is optionally substituted one or more substituents independently selected from:

    
    
        halogen, —OR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —NO2, ═O, and —CN;
        C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —SR16, —N(R16)2, —NO2, and —CN; and
        C3-6 carbocycle optionally substituted with one or more substituents independently selected from: halogen, C1-4 alkyl, C1-4 haloalkyl, —OR16, —N(R16)2, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), Ring B is selected from azetidinylene, pyrrolidinylene, piperidinylene, phenylene, pyridinylene, indolinylene, and 3-azabicyclo[3.2.1]octanylene, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR16, —CN, and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted with halogen and —OR16; and R16 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, Ring B is selected from azetidinylene, pyrrolidinylene, piperidinylene, phenylene, pyridinylene, indolinylene, and 3-azabicyclo[3.2.1]octanylene, each of which is optionally substituted one or more substituents independently selected from: halogen, —OR16, and C1-3 alkyl; and R16 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R16 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle. In some embodiments, R16 is independently selected at each occurrence from: hydrogen, C1-6 alkyl, and C1-6 haloalkyl. In some embodiments, R16 is independently selected at each occurrence from: hydrogen, C1-4 alkyl, and C1-4 haloalkyl. In some embodiments, R16 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R16 is independently selected at each occurrence from: hydrogen, C1-3 alkyl, and C1-3 haloalkyl. In some embodiments, R16 is hydrogen.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, and —S(O)2N(R17)(R19); and
        R17 is independently selected at each occurrence from C2-6 alkenyl and C2-6 alkynyl each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is selected from —C(O)R17, —N(R19)C(O)(R17), and —N(R19)S(O)2R17; and
        R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is selected from —C(O)R17, —N(R19)C(O)(R17), and —N(R19)S(O)2R17; and
        R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is selected from —C(O)R17, —N(R19)C(O)(R17), and —N(R19)S(O)2R17; and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is selected from —C(O)R17, —N(R19)C(O)(R17), and —N(R19)S(O)2R17; and R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —NO2, and —CN.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is selected from —C(O)R17, —N(R19)C(O)(R17), and —N(R19)S(O)2R17; and R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —N(R18)2, —NO2, and —CN.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is —C(O)R17; and R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is —C(O)R17; and R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN. In some embodiments, R5 is —C(O)R17; and R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —N(R18)2, —NO2, and —CN. In some embodiments, R5 is —C(O)R17; R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: halogen, —OR18, —N(R18)2, —NO2, and —CN; and R18 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —C(O)R17; and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —N(R18)2, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —C(O)R17;
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —N(R18)2, —NO2, and —CN; and
        
        
        R18 is selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —C(O)R17; and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen and —N(R18)2.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —C(O)R17;
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen and —N(R18)2; and
        
        
        R18 is selected from hydrogen methyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —C(O)R17;
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            fluoro and —N(CH3)2.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17); and
        R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17); and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17); and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —N(R18)2, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17);
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —N(R18)2, —NO2, and —CN; and each of R18 and R19 are independently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17);
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more halogen.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17);
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more halogen; and
        R19 is independently selected from hydrogen and methyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)C(O)(R17);
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more fluoro; and
        R19 is independently selected from hydrogen and methyl.
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)S(O)2R17, and
        R17 is selected from C2-6 alkenyl and C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)S(O)2R17; and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —SR18, —N(R18)2, —C(O)N(R18)2, —C(O)OR18, —OC(O)R18, —N(R18)C(O)R18, —N(R18)S(O)2R18, —S(O)2N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)C(O)OR18, —OC(O)N(R18)2, —S(O)R18, —S(O)2R18, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)S(O)2R17, and
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —N(R18)2, —NO2, and —CN.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),

    
    
        R5 is —N(R19)S(O)2R17;
        R17 is selected from C2-4 alkenyl and C2-4 alkynyl, each of which is optionally substituted with one or more substituents independently selected from:
        
            halogen, —OR18, —N(R18)2, —NO2, and —CN; and each of R18 and R19 are independently selected from hydrogen, C1-3 alkyl, and C1-3 haloalkyl.
        
        
    
    


In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is —N(R19)S(O)2R17; and R17 is C2-4 alkenyl.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is —N(R19)S(O)2R17; R17 is C2-4 alkenyl; and R19 is hydrogen.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is selected from: wherein R5 is selected from:




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), R5 is selected from:




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), A3 is R5, wherein R5 is defined as in Formula (II-A). In some embodiments, A3 is selected from —C(O)R17, —S(O)2R17, —N(R19)C(O)(R17), —C(O)N(R17)(R19), and —N(R19)S(O)2R17, and —S(O)2N(R17)(R19), wherein R17 and R19 are defined as in Formula (II-A). In some embodiments, A3 is selected from:




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),




is selected from:




















In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),




is selected from:




















In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B),




is selected from:








In some aspects, for the compound or salt of Formula (I), q is 2; and the structure of Formula (I) is represented by




In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), the cysteine susceptible electrophile is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, an alkene, an alkyne, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, a vinylsulfone group, a vinylsulfonamide group, an alkene, and an alkyne. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group, an acrylamide group, an alkene, and an alkyne.
In some embodiments, for the compound or salt of Formula (I), (II), (II-A), (III), (III-A), or (III-B), the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl, an alpha-beta unsaturated sulfone, an alpha-beta unsaturated amide, and an alpha-beta unsaturated sulfonamide. In some embodiments, the cysteine susceptible electrophile is selected from an alpha-beta unsaturated carbonyl and an alpha-beta unsaturated amide. In some embodiments, the cysteine susceptible electrophile is an alpha-beta unsaturated carbonyl.
In certain aspects, the disclosure provides a compound or salt represented the structure of Formula (I) wherein:

    
    
        R1 is selected from hydrogen, halogen, —OR10, —SR10, —N(R10)2, —NO2, —CN, and C1-6 alkyl optionally substituted with one or more substituents independently selected from: halogen, —OR10, —SR10, —N(R10)2, —NO2, and —CN, for example R1 is hydrogen;
        A1 is selected from hydrogen, halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, —CN, C1-6 alkyl, and C1-6 haloalkyl, for example A1 is hydrogen;
        A2 is selected from:
        
            C1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), and —CN; and
            4- to 8-membered heterocycle and C3-8 carbocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OR11, —SR11, —N(R11)2, —C(O)N(R11)2, —N(R11)C(O)R11, —C(O)OR11, —OC(O)R11, —N(R11)C(O)OR11, —OC(O)N(R11)2, —N(R11)C(O)N(R11)2, —S(O)R11, —S(O)2R11, —N(R11)S(O)2R11, —S(O)2N(R11)2, —NO2, ═O, ═S, ═N(R11), —CN, C1-6 alkyl, and C1-6 haloalkyl, for example A2 is pyrazolyl;
        
        
        n is 0 or 1, for example n is 0;
        p is 0 or 1, for example p is 0;
        q is 1;
        L is represented by -L1-L2-, wherein L1 and L2 are each independently selected from (a) and (b):
        
            (a) —O—, —N(R15)—, —S—, —S(O)—, —S(O)2—, —S(O)(NR15)—, —N(R15)C(O)—, —N(R15)C(O)O—, —N(R15)S(O)2—, —N(R15)S(O)2N(R15)—, —S(O)(NR15)N(R15)—, —N(R15)N(R15)—, —(R15)NC(O)N(R15)—, —(R15)NC(O)N(R15)N(R15)—; and
            (b) C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, C3-8 carbocyclene, and 3- to 8-membered heterocyclene, any of which is optionally substituted with one or more substituents independently selected from halogen, —OR15, —SR15, ═O, ═S, and —CN;
            wherein L2 is optionally absent;
            wherein when both L1 and L2 are present, either: L1 is selected from (a) and L2 is selected from (b); or L1 is selected from (b) and L2 is selected from (a);
        
        
        Ring B is selected from 3- to 8-membered heterocyclene and C3-8 carbocyclene, each of which is optionally substituted halogen, —OR16, —SR16, —N(R16)2, —C(O)N(R16)2, —C(O)OR16, —OC(O)R16, —N(R16)C(O)R16, —N(R16)S(O)2R16, —S(O)2N(R16)2, —N(R16)C(O)N(R16)2, —N(R16)C(O)OR16, —OC(O)N(R16)2, —S(O)R16, —S(O)2R16, —NO2, ═O, ═S, ═N(R16), —CN, C1-6 alkyl, and C1-6 haloalkyl; for example Ring B is piperidinylene;
        Ring D is selected from:
    
    






    
    
        R2 is independently selected at each instance from halogen, C1-6 alkyl, C1-6 haloalkyl, —OR12, —SR12, —N(R12)2, —NO2, and —CN, for example R2 is —N(R12)2;
        A3 is selected from a haloacetamide, a haloalkyl ketone, a halo amidine, a halo benzylphosphonate, an acyloxyalkyl ketone, a sulfonyl oxirane, an epoxide, a diazoalkyl ketone, a halotriazine, an acrylamide, a cyano acrylamide, a vinyl sulfone, a vinyl sulfonamide, an acrylate, a fumarate, a carbonyl acrylate, a maleimide, a ketoamide, a nitrile, an alkene, an alkyne, a keto heterocycle, and an ynamide, for example A3 is an acrylate; and
        R10, R11, R12, R15, and R16 are each independently selected at each occurrence from: hydrogen,
        
            C1-6 alkyl, optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C3-6 carbocycle, and 3- to 6-membered heterocycle; and
            C3-6 carbocycle and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl.
        
        
    
    


In some embodiments, the compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B) is a compound of Table 1. * Denotes a stereocenter with an undetermined absolute stereochemistry of a single isomer.







TABLE 1







Chemical structures of selected compounds.








Comp.



No.
Structure





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While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E-form (or cis- or trans-form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), are intended to include all Z-, E- and tautomeric forms as well.
“Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(+)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.
The compounds or salts for Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization, or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and/or trituration.
In certain embodiments, compounds or salts for Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), may comprise two or more enantiomers or diastereomers of a compound wherein a single enantiomer or diastereomer accounts for at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 98% by weight, or at least about 99% by weight or more of the total weight of all stereoisomers. Methods of producing substantially pure enantiomers are well known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller (1975) J. Chromatogr., 113 (3): 283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.
A “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibrium include:




The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2H, 3H, 11C, 13C and/or 14C. In one particular embodiment, the compound may be deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Pat. Nos. 5,846,514 and 6,334,997. As described in U.S. Pat. Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.
In certain embodiments, the compounds disclosed herein have some or all of the 1H atoms replaced with 2H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.
Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45 (21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64 (1-2), 9-32.
Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.
Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13C- or 14C-enriched carbon are within the scope of the present disclosure.
The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with 2H, 11C, 13C, 14C, 15C, 12N, 13N, 15N, 16N, 16O, 17O, 14F, 15F, 16F, 17F, 18F, 33S, 34S, 35S, 36S, 35Cl, 37Cl, 79Br, 81Br, and 125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.
Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of the compounds of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). The compounds of the present disclosure may possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
The methods and compositions of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.
Compounds of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.
Included in the present disclosure are salts, particularly pharmaceutically acceptable salts, of compounds represented by Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). The compounds of the present invention that possess a sufficiently acidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganic bases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherently charged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g., a halide such as bromide, chloride, or fluoride, particularly bromide.
In certain embodiments, compounds or salts of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.
Pharmaceutical Formulations
In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and a pharmaceutically acceptable excipient.
Pharmaceutical compositions can be formulated using one or more physiologically-acceptable carriers comprising excipients and auxiliaries. Formulation can be modified depending upon the route of administration chosen. Pharmaceutical compositions comprising a compound, salt or conjugate can be manufactured, for example, by lyophilizing the compound, salt or conjugate, mixing, dissolving, emulsifying, encapsulating or entrapping the conjugate. The pharmaceutical compositions can also include the compounds, salts or conjugates in a free-base form or pharmaceutically-acceptable salt form.
A compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), may be formulated in any suitable pharmaceutical formulation. A pharmaceutical formulation of the present disclosure typically contains an active ingredient (e.g., compound or salt of any one of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), and one or more pharmaceutically acceptable excipients or carriers, including but not limited to: inert solid diluents and fillers, diluents, sterile aqueous solution and various organic solvents, permeation enhancers, antioxidents, solubilizers, and adjuvants.
Methods of Treatment
The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.
The compositions containing the compound(s) described herein can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.
In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.
In some aspects, the present disclosure provides a method for treatment, comprising administering to a subject in need thereof an effective amount of a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). In some aspects, the present disclosure provides a method for treating cancer in a patient in need thereof, comprising administering to the subject an effective amount of a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the cancer is selected from breast cancer, colorectal cancer, and meningioma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is meningioma. In some embodiments, the administration modulates the activity of wild-type AKT1. In some embodiments, the administration modulates the activity of a mutant AKT1. In some embodiments, the mutant AKT1 is AKT1 E17K.
In certain aspects, the present disclosure can be used as a method of inhibiting an AKT1 protein in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B), or a pharmaceutical composition of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the AKT protein is wild-type AKT1. In some embodiments, the AKT protein is a mutant AKT1 protein. In some embodiments, the mutant AKT1 protein comprises an E17K mutant. In some embodiments, the administrating modulates the activity of mutant AKT1. In some embodiments, the administrating modulates the activity of wild-type AKT1. In some aspects, the present disclosure provides a method of modulating activity of mutant AKT1. In some embodiments, the administering selectively modulates the activity of wild-type AKT1 over wild-type AKT2. In some embodiments, the administering selectively modulates the activity of mutant AKT1 over wild-type AKT2.
AKT1 Protein
In some aspects, the present disclosure provides an AKT1 protein covalently bound to a compound, wherein the compound is covalently bound to a cysteine residue of the AKT1 protein. In some embodiments, the compound is exogenous. In some embodiments, the exogenous compound is selected from an exogenous AKT1 inhibitor and an exogenous AKT1 activator. In some embodiments, the exogenous compound is an exogenous AKT1 modulator. In some embodiments, the exogenous compound is an exogenous AKT1 inhibitor.
In some embodiments, the AKT1 protein is selected from a wild-type AKT1 protein and a mutated AKT1 protein. In some embodiments, the AKT1 protein is a mutated AKT1 protein. In some embodiments, the mutated AKT1 protein comprises a mutation selected from a E17K mutation, a E40K mutation, and a E49K mutation. In some embodiments, the mutated AKT1 protein comprises a E17K mutation. In some embodiments, the mutated AKT1 protein comprises a E40K mutation. In some embodiments, the mutated AKT1 protein comprises a E49K mutation.
In some embodiments, the exogenous compound is in contact a cysteine residue of the AKT1 protein as described herein. In some embodiments, the contact is between the cysteine reside of the AKT1 protein and the exogenous compound is a covalent bond. In some embodiments, the cysteine reside is selected from C296 and C310. In some embodiments, the cysteine residue is C296. In some embodiments, the cysteine residue is C310.
In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible covalent bond. In some embodiments, the irreversible covalent bond is a single bond. In some embodiments, the irreversible covalent bond is a single bond between a carbon atom on the exogenous compound and the sulfur atom on the sidechain of the cysteine residue.
In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible covalent bond, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible single covalent bond, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible covalent bond, wherein the cysteine residue is C296. In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible covalent single bond, wherein the cysteine residue is C296. In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible covalent bond, wherein the cysteine residue is C310. In some embodiments, the covalent bond between the exogenous compound and the cysteine residue is an irreversible covalent single bond, wherein the cysteine residue is C310.
In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein comprises a carbon-sulfur interaction. In some embodiments, the carbon-sulfur interaction is a carbon-sulfur single bond.
In some embodiments, the AKT1 protein is covalently bound with the exogenous compound, wherein the exogenous compound is bound at only one residue of the AKT1 protein. In some embodiments, the AKT1 protein is covalently bond with the exogenous compound via one covalent bond. In some embodiments, the AKT1 protein is covalently bound with the exogenous compound, wherein the exogenous compound is bound at one cysteine residue. In some embodiments, the AKT1 protein has a single covalent bond between a cysteine residue and the exogenous compound. In some embodiments, the AKT1 protein has a single covalent bond between C296 and the exogenous compound. In some embodiments, the AKT1 protein has a single covalent bond between C310 and the exogenous compound.
In some embodiments, the exogenous compound has reduced engagement at other cysteine residues when covalently bound at a cysteine residue selected from C296 and C310. In some embodiments, the exogenous compound is in contact with one cysteine residue selected from C296 and C310, and has reduced engagement at the remaining cysteine residues. In some embodiments, the exogenous compound is in contact with C296, and has reduced engagement at C310. In some embodiments, the exogenous compound is in contact with C310, and has reduced engagement at C296.
In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the exogenous compound. In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the exogenous compound, wherein the single cysteine residue is selected from C296 and C310. In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the exogenous compound, wherein the single cysteine residue is C296. In some embodiments, the AKT1 protein has a single cysteine residue covalently bound with the exogenous compound, wherein the single cysteine residue is C310.
In some embodiments, the AKT1 protein is in vivo. In some embodiments, the AKT1 protein is in vitro. In some embodiments, the AKT1 protein is ex vivo. In some embodiments, the AKT1 protein is an in vivo engineered protein.
In some embodiments, the AKT1 protein is an in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the exogenous compound. In some embodiments, the AKT1 protein is a mammalian in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the exogenous compound. In some embodiments, the AKT1 protein is a human in vivo engineered AKT1 protein, wherein the in vivo engineered AKT1 protein is generated by contacting the AKT1 protein in vivo with the exogenous compound.
In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom and a sulfur atom. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of the cysteine residue. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of the cysteine residue selected from C296 and C310. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of the C296 cysteine residue. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is between a carbon atom of the exogenous compound and a sulfur atom of the C310 cysteine residue.
In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond. In some embodiments, the irreversible covalent bond in the in vivo AKT1 protein is a carbon-sulfur single bond between the exogenous compound and the cysteine residue. In some embodiments, the carbon-sulfur single bond is between the exogenous compound and the cysteine residue, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond is between the exogenous compound and the C296 cysteine residue. In some embodiments, the carbon-sulfur single bond is between the exogenous compound and the C310 cysteine residue.
In some embodiments, the exogenous compound comprises a cysteine susceptible electrophile. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group. In some embodiments, the exogenous compound comprises an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the exogenous compound comprises an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the exogenous compound comprises an acrylate group and an acrylamide group. In some embodiments, the exogenous compound comprises an acrylamide group.
In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the cysteine residue. In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the cysteine residue selected from C296 and C310. In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the C296 cysteine residue. In some embodiments, the irreversible covalent bond is between the cysteine susceptible electrophile and the C310 cysteine residue.
In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the exogenous compound and a cysteine residue. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the exogenous compound and a cysteine residue selected from C296 and C310. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the exogenous compound and the C296 cysteine residue. In some embodiments, the carbon-sulfur bond is an irreversible bond that results from an irreversible reaction between the exogenous compound and the C310 cysteine residue.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and a cysteine susceptible electrophile on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the cysteine susceptible electrophile on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and a cysteine susceptible electrophile on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and a cysteine susceptible electrophile on the exogenous compound.
In some embodiments, the cysteine susceptible electrophile of the exogenous compound is selected from: an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide, and an epoxide group. In some embodiments, the cysteine susceptible electrophile of the exogenous compound is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile of the exogenous compound is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile of the exogenous compound is an acrylamide group.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylate group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylate group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the acrylate group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the acrylate group on the exogenous compound.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylamide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the acrylamide group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the acrylamide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the acrylamide group on the exogenous compound.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinyl group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinyl group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the vinyl group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the vinyl group on the exogenous compound.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinylsulfone group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinylsulfone group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the vinylsulfone group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the vinylsulfone group on the exogenous compound.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinylsulfonamide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the vinylsulfonamide group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the vinylsulfonamide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the vinylsulfonamide group on the exogenous compound.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the ynamide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the ynamide group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the ynamide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the ynamide group on the exogenous compound.
In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the epoxide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of a cysteine residue and the epoxide group on the exogenous compound, wherein the cysteine residue is selected from C296 and C310. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C296 and the epoxide group on the exogenous compound. In some embodiments, the carbon-sulfur single bond results from an irreversible reaction between the thiol functional group of C310 and the epoxide group on the exogenous compound.
In some embodiments, the exogenous compound is a compound or salt as disclosed herein. In some embodiments, the exogenous compound is selected from a compound or salt of Formula (II), Formula (II-A), or Formula (III). In some embodiments, the exogenous compound is selected from a compound or salt in Table 1.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylate group and the cysteine residue of AKT1, wherein the acrylate group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylamide group and the cysteine residue of AKT1, wherein the acrylamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinyl group and the cysteine residue of AKT1, wherein the vinyl group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfone group and the cysteine residue of AKT1, wherein the vinylsulfone group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfone group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and the cysteine residue of AKT1, wherein the vinylsulfonamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous ynamide group and the cysteine residue of AKT1, wherein the ynamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous ynamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous epoxide group and the cysteine residue of AKT1, wherein the epoxide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous epoxide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylate group and the cysteine residue of AKT1, wherein the exogenous acrylate group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylamide group and the cysteine residue of AKT1, wherein the exogenous acrylamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinyl group and the cysteine residue of AKT1, wherein the exogenous vinyl group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfone group and the cysteine residue of AKT1, wherein the exogenous vinylsulfone group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfone group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and the cysteine residue of AKT1, wherein the exogenous vinylsulfonamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous ynamide group and the cysteine residue of AKT1, wherein the exogenous ynamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous ynamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous epoxide group and the cysteine residue of AKT1, wherein the exogenous epoxide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous epoxide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylate group and the cysteine residue of AKT1, wherein the exogenous acrylate group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylamide group and the cysteine residue of AKT1, wherein the exogenous acrylamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinyl group and the cysteine residue of AKT1, wherein the exogenous vinyl group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfone group and the cysteine residue of AKT1, wherein the exogenous vinylsulfone group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfone group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and the cysteine residue of AKT1, wherein the exogenous vinylsulfonamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous ynamide group and the cysteine residue of AKT1, wherein the exogenous ynamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous ynamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C296, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous epoxide group and the cysteine residue of AKT1, wherein the exogenous epoxide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous epoxide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylate group and the cysteine residue of AKT1, wherein the exogenous acrylate group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylate group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous acrylamide group and the cysteine residue of AKT1, wherein the exogenous acrylamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous acrylamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinyl group and the cysteine residue of AKT1, wherein the exogenous vinyl group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinyl group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfone group and the cysteine residue of AKT1, wherein the exogenous vinylsulfone group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfone group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous vinylsulfonamide group and the cysteine residue of AKT1, wherein the exogenous vinylsulfonamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous vinylsulfonamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous ynamide group and the cysteine residue of AKT1, wherein the exogenous ynamide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous ynamide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a non-naturally occurring irreversible covalent modification at a cysteine residue C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous epoxide group and the cysteine residue of AKT1, wherein the exogenous epoxide group undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous epoxide group and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprises a mutation selected from E17K, E40K, and E49K, a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue.
In certain aspects the present disclosure provides an in vivo engineered AKT1 protein comprising a E17K mutation, a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide group, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group.
In another aspect, the present disclosure provides an in vivo engineered AKT1 protein comprising a E17K mutation, a non-naturally occurring irreversible covalent modification at a cysteine residue selected from C296 and C310, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the in vivo engineered AKT1 protein is a human in vivo engineered AKT1 protein.
In certain aspects the present disclosure provides a human in vivo engineered AKT1 protein comprising a E17K mutation, a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide group, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group.
In another aspect, the present disclosure provides a human in vivo engineered AKT1 protein comprising a E17K mutation, a non-naturally occurring irreversible covalent modification at a cysteine residue, the irreversible covalent modification being generated from an in vivo nucleophilic reaction between an exogenous cysteine susceptible electrophile and the cysteine residue of AKT1, wherein the exogenous cysteine susceptible electrophile undergoes a nucleophilic addition with the thiol functional group on the cysteine residue and forming a carbon-sulfur single bond between the exogenous cysteine susceptible electrophile and the thiol functional group on the cysteine residue. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide group, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group.
Method of Modifying AKT1 Proteins
In some aspects the present disclosure provides a method of modifying an AKT1 protein as disclosed herein. In some embodiments, the method of covalently modifying an AKT1 protein, comprises contacting the AKT1 protein with an exogenous compound, wherein the exogenous compound comprises an irreversible electrophilic moiety thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contacting is in vitro or in vivo. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the AKT1 protein is wild type AKT1 or a mutated AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the wild type AKT1 protein is wild type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the exogenous compound is an AKT1 inhibitor. In some embodiments, the irreversible covalent moiety on the AKT1 inhibitor is a cysteine susceptible electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine reside of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C296 cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C310 cysteine residue of the AKT1 protein. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide group, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group.
In another aspect, the method of covalently modifying an AKT1 protein, comprises contacting the AKT1 protein with an exogenous AKT1 modulator, wherein the AKT1 modulator comprises an irreversible electrophilic moiety thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contacting is in vitro or in vivo. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the AKT1 protein is wild type AKT1 or a mutated AKT1. In some embodiments, the mutated AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the wild type AKT1 protein is wild type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the irreversible covalent moiety on the AKT1 modulator is a cysteine susceptible electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine reside of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C296 cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C310 cysteine residue of the AKT1 protein. In some embodiments, the exogenous AKT1 modulator is an AKT1 inhibitor. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinyl group, a vinylsulfone group, a vinylsulfonamide group, an ynamide group, and an epoxide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group, an acrylamide group, a vinylsulfone group, and a vinylsulfonamide group. In some embodiments, the cysteine susceptible electrophile is selected from: an acrylate group and an acrylamide group. In some embodiments, the cysteine susceptible electrophile is an acrylamide group.
In certain aspects the present disclosure provides a method of attenuating AKT1 activity. In some embodiments, the method of covalently modifying an AKT1 protein, comprises contacting the AKT1 protein with an exogenous AKT1 inhibitor, wherein the AKT1 modulator comprises an irreversible electrophilic moiety thereby forming an irreversible covalent AKT1 adduct. In some embodiments, the contacting is in vitro or in vivo. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the AKT1 protein is wild type AKT1 or a mutated AKT1. In some embodiments, the mutated AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the wild type AKT1 protein is wild type. In some embodiments, the AKT1 protein is E17K AKT1. In some embodiments, the irreversible covalent moiety on the AKT1 inhibitor is a cysteine susceptible electrophile. In some embodiments, the irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine reside of the AKT1 protein. In some embodiments, the irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the irreversible covalent moiety and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and a cysteine residue of the AKT1 protein selected from C296 and C310. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C296 cysteine residue of the AKT1 protein. In some embodiments, irreversible covalent AKT1 adduct is formed between the cysteine susceptible electrophile and the C310 cysteine residue of the AKT1 protein.
In some aspects, the method of attenuating AKT1 activity, comprises contacting AKT1 protein with an exogenous compound, wherein the exogenous compound comprises an irreversible electrophilic moiety. In some embodiments, the AKT1 protein is wild type AKT1 or a mutated AKT1. In some embodiments, the mutated AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the wild type AKT1 protein is wild type. In some embodiments, the contacting is in vitro or in vivo. In some embodiments, the contacting is in vitro.
In some embodiments, following the contacting, the AKT1 activity is attenuated by 50% to 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by 75% to 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by 50% or more relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by 70% or more relative to a control in the absence of the exogenous compound.
In some embodiments, following the contacting, the AKT1 activity is attenuated by about 50% to about 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 75% to about 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 50% or more relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 70% or more relative to a control in the absence of the exogenous compound.
In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 50% to at least 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 75% to at least 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 50% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 70% relative to a control in the absence of the exogenous compound.
In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 50% to at most 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 75% to at most 95% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 50% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 70% relative to a control in the absence of the exogenous compound. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, or at most 95% relative to a control in the absence of the exogenous compound.
In some embodiments, the exogenous compound is more selective toward mutated AKT1 than wild-type AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the exogenous compound is 2-fold to 100-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 2-fold to 10-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 2-fold to 5-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 2-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 3-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 4-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 5-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 10-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 50-fold, 75-fold, or 100-fold more selective for E17K AKT1 over wild-type AKT1.
In some embodiments, the exogenous compound is at least 2-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at least 3-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at least 4-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at least 5-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at least 10-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at least 2-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 50-fold, at least 75-fold, or at least 100-fold more selective for E17K AKT1 over wild-type AKT1.
In some embodiments, the exogenous compound is about 2-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is about 3-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is about 4-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is about 5-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is about 10-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 15-fold, about 20-fold, about 25-fold, about 50-fold, about 75-fold, or about 100-fold more selective for E17K AKT1 over wild-type AKT1.
In some embodiments, the exogenous compound is at most 2-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at most 3-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at most 4-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at most 5-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at most 10-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at most 2-fold more selective for E17K AKT1 over wild-type AKT1. In some embodiments, the exogenous compound is at most 2-fold, at most 3-fold, at most 4-fold, at most 5-fold, at most 6-fold, at most 7-fold, at most 8-fold at most 9-fold, at most 10-fold, at most 15-fold, at most 20-fold, at most 25-fold, at most 50-fold at most 75-fold, or at most 100-fold more selective for E17K AKT1 over wild-type AKT1.
In another aspect, the present disclosure provides a method of attenuating AKT1 activity, comprising contacting AKT1 protein with an AKT1 inhibitor, wherein the AKT1 inhibitor comprises an irreversible electrophilic moiety. In some embodiments, the AKT1 protein is wild type AKT1 or a mutated AKT1. In some embodiments, the mutated AKT1 is selected from E17K AKT1, E40K AKT1, and E49K AKT1. In some embodiments, the mutated AKT1 is E17K AKT1. In some embodiments, the wild type AKT1 protein is wild type. In some embodiments, the contacting is in vitro or in vivo. In some embodiments, the contacting is in vitro.
In some embodiments, following the contacting, the AKT1 activity is attenuated by 50% to 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by 75% to 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by 50% or more relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by 70% or more relative to a control in the absence of the exogenous AKT1 inhibitor.
In some embodiments, following the contacting, the AKT1 activity is attenuated by about 50% to about 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 75% to about 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or more relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 50% or more relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by about 70% or more relative to a control in the absence of the exogenous AKT1 inhibitor.
In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 50% to at least 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 75% to at least 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 50% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at least 70% relative to a control in the absence of the exogenous AKT1 inhibitor.
In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 50% to at most 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 75% to at most 95% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 50% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 70% relative to a control in the absence of the exogenous AKT1 inhibitor. In some embodiments, following the contacting, the AKT1 activity is attenuated by at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, or at most 95% relative to a control in the absence of the exogenous AKT1 inhibitor.
In some aspects, the exogenous compound is a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the exogenous AKT1 inhibitor is a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B). In some embodiments, the AKT1 inhibitor is a compound or salt of Formula (I), (I-A), (II), (II-A), (III), (III-A), or (III-B).
EXAMPLES
The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention in any way.
The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.
Example 1: (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide








Step 1: Synthesis of (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Example 1)
(S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) was dissolved in water and the pH was brought to 9-10 with saturated aqueous sodium bicarbonate. The mixture was extracted twice with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain the free base. To a cooled (0° C.) solution of free base (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (100 mg, 0.245 mmol, 1 equiv) and methyl 2-acrylamidobenzoate (Intermediate 1-3) (100 mg, 0.490 mmol, 2 equiv) in DCE (3 mL) was added trimethylaluminium (0.1 mL, 0.980 mmol, 1 M in toluene, 4 equiv). The resulting mixture was stirred overnight at 70° C. After cooling to room temperature, the reaction mixture was quenched by the addition of water and the resulting mixture was extracted 3 times with ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Example 1) (39.6 mg, 20%). MS (ESI) calcd. for C33H27O2N9: 581.23 m/z, found 582.30 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.32-8.38 (m, 2H), 8.27-8.32 (m, 1H), 7.98-8.02 (m, 1H), 7.91-7.96 (m, 1H), 7.83-7.75 (m, 2H), 7.49-7.56 (m, 1H), 7.40-7.45 (m, 1H), 7.36 (s, 1H), 7.23-7.30 (m, 2H), 7.16-7.23 (m, 1H), 6.51-6.56 (m, 1H), 6.42-6.49 (m, 1H), 6.34-6.41 (m, 1H), 6.21-6.28 (m, 1H), 5.78-5.84 (m, 1H), 5.57-5.64 (m, 1H), 2.98-3.07 (m, 1H), 2.84-2.94 (m 1H), 2.53-2.58 (m, 1H), 2.03-2.14 (m, 1H).
Intermediate 1-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide
To a mixture of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 1-2) (200 mg, 0.477 mmol, 1 equiv), pyrazole (39 mg, 0.57 mmol, 1.5 equiv), t-BuBrettPhos Pd G3 (41 mg, 0.048 mmol, 0.1 equiv), t-BuBrettPhos (23 mg, 0.048 mmol, 0.1 equiv) and K3PO4 (304 mg, 1.43 mmol, 3 equiv) was added 1,4-dioxane (5 mL) under N2 at room temperature. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. Brine was added and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using a gradient of methanol in ethyl acetate to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (84 mg, 39%) as a white solid. MS (ESI) calcd. for C25H22N8O: 450.19 m/z, found 451.15 [M+H]+.
Step 2: Synthesis of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1
To a stirred suspension of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (1.00 g, 2.22 mmol, 1 equiv) in methanol (5 mL) was added HCl (5 mL, concentrated) and the resulting solution was stirred at 90° C. overnight under nitrogen atmosphere. The solution was cooled to room temperature and diluted with dichloromethane. The solution was concentrated to dryness under reduced pressure. The crude solid was taken up into DMSO and pyrrolidine (395 mg, 5.55 mmol, 2.5 equiv) was added. The solution was stirred for 2 min followed by addition of TFA (959 mg, 6.66 mmol, 3 equiv). The solution was purified by preparative HPLC on a Phenomenex Gemini C18 Column using a gradient of acetonitrile in water (+0.05% TFA) to afford (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (TFA salt) (Intermediate 1-1) (869 mg, 75%) as a yellow solid. MS (ESI) calcd. for C23H20N8: 408.08 m/z, found 409.15 [M+H]+.
Intermediate 1-2: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide
To a mixture of (S)-5-bromo-2,3-dihydro-1H-inden-1-amine (74 g, 350 mmol, 1 equiv) and triethylamine (106 g, 1.05 mol, 3 equiv) in dichloromethane (1.5 L) was added acetic anhydride (55.2 g, 526 mmol, 1.5 equiv) at 0° C. and the mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by addition of water and extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was re-crystallized from petroleum ether to afford (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide (90 g, 83% yield) as a white solid. MS (ESI) calculated for C11H12BrNO: 253.01, found 254.00 [M+H]+, 256.00 [M+H+2]+.
Step 2: Synthesis of tert-butyl (S)-(1-acetamido-2,3-dihydro-1H-inden-5-yl)carbamate
To a mixture of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide (40 g, 157 mmol, 1 equiv), tert-butyl carbamate (27.66 g, 236 mmol, 1.5 equiv), XantPhos (9.11 g, 15.7 mmol, 10 mol %), palladium (III) acetate (3.54 g, 15.7 mmol, 10 mol %), and cesium carbonate (154 g, 472 mmol, 10 mol %) was added 1,4-dioxane (300 mL) under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100° C. The reaction mixture was quenched by addition of water and extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent of petroleum ether/dichloromethane/methanol (70:27:3) to afford tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 48%). MS (ESI) calculated for C16H22N2O3: 290.16 m/z, found 289.05 [M−H]−.
Step 3: Synthesis of (S)-N-(5-amino-2,3-dihydro-1H-inden-1-yl)acetamide
To a stirred solution of tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 148 mmol, 1 equiv) in dichloromethane (180 mL) was added 4N hydrochloric acid in 1,4-dioxane (185 mL, 742 mmol, 5 equiv). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and re-crystallized from ethyl acetate to afford N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (hydrochloride salt) (23 g, 81%) as a white solid. MS (ESI) calculated for C11H14N2O: 190.11 m/z, found 191.15 [M+H]+.
Step 4: Synthesis of N-[(1S)-5-[(6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (100 g, 526 mmol, 1 equiv) in ethanol (2 L) was added triethylamine (160 g, 1.58 mol, 3 equiv) and 2,6-dichloro-3-nitropyridine (122 g, 631 mmol, 1.2 equiv). The resulting mixture was stirred at 60° C. overnight. The mixture was then cooled to room temperature and quenched with water. The resulting precipitate was collected by filtration and rinsed with ethanol/water to afford N-[(1S)-5-[(6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (100 g, 49%) as a red solid. MS (ESI) calculated for C16H15ClN4O3: 346.08 m/z, found 345.00 [M−H]−.
Step 5: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-chloroimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 1-2
To a solution of N-[(1S)-5-[(6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (100 g, 288 mmol, 1 equiv) in dimethyl sulfoxide (1.8 L) and methanol (300 mL) was added 2-aminopyridine-3-carbaldehyde (38.74 g, 317.2 mmol, 1.1 equiv) and sodium dithionite (110 g, 634 mmol, 2.2 equiv). The resulting mixture was stirred at 100° C. overnight. Water was added and the precipitated solids were collected by filtration, rinsing with water. The solid collected was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-chloroimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 1-2) (43.2 g, 31%) as a yellow solid. MS (ESI) calculated for C22H19ClN6O: 418.13 m/z, found 419.10 [M+H]+.
Intermediate 1-3: methyl 2-acrylamidobenzoate




Synthetic Route:





Step 1: Synthesis of methyl 2-acrylamidobenzoate (Intermediate 1-3
To a cooled (0° C.) solution of methyl 2-aminobenzoate (500 mg, 3.31 mmol, 1 equiv) and triethylamine (1.004 g, 9.924 mmol, 3 equiv) in DCM (10 mL) was added acryloyl chloride (898 mg, 9.92 mmol, 3 equiv). The resulting mixture was stirred for 2 h at room temperature. The reaction was then quenched by the addition water and extracted with DCM 3 times. The organic phases were combined, dried over anhydrous Na2SO4 and concentrated in vacuum. The resulting residue was purified by flash column chromatography on silica gel using a gradient of ethyl acetate in petroleum ether to afford methyl 2-acrylamidobenzoate (Intermediate 1-3) (500 mg, 74%) as a colorless oil. MS (ESI) calcd. for C11H11O3N: 205.07 m/z, found 206.00 [M+H]+.
Example 2: (S)-3-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-3-(prop-2-enamido)benzamide (Example 2)
To a stirred mixture of (S)-3-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Intermediate 2-1) (180 mg, 0.341 mmol, 1 equiv) and triethylamine (69 mg, 0.68 mmol, 2 equiv) in DCM (15 mL) was added acryloyl chloride (124 mg, 1.36 mmol, 4 equiv) in portions at room temperature. The reaction mixture was stirred for 2 h. The resulting mixture was washed with water and the aqueous phase was extracted with dichloromethane 2 times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was then purified by preparative HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate) to afford (S)-3-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Example 2) (35 mg, 18%) as an off-white solid. MS (ESI) calcd. for C33H27N9O2: 581.23 m/z, found 582.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.36-8.38 (m, 2H), 8.19-8.21 (m, 1H), 8.14-8.15 (m, 1H), 8.02-8.04 (m, 1H), 7.94-7.96 (m, 1H), 7.80-7.88 (m, 1H), 7.62-7.64 (m, 1H), 7.42-7.45 (m, 3H), 7.31-7.38 (m, 2H), 6.54-6.56 (m, 1H), 6.46-6.48 (m, 2H), 6.26-6.30 (m, 1H), 5.77-5.80 (m, 1H), 5.62-5.64 (m, 1H), 3.00-3.02 (m, 1H), 2.94-3.00 (m, 1H), 2.51-2.52 (m, 1H), 2.10-2.30 (m, 1H).
Intermediate 2-1: (S)-3-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide




Synthetic Route:





Step 1: Synthesis of tert-butyl (S)-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamoyl)phenyl)carbamate
A solution of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (200 mg, 0.490 mmol), 3-((tert-butoxycarbonyl)amino)benzoic acid (128 mg, 0.539 mmol), PyBOP (255 mg, 0.490 mmol) and N,N-diisopropylethylamine (190 mg, 1.470 mmol) in DMF (3 mL) was stirred for 0.5 h at room temperature. The reaction mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford tert-butyl (S)-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamoyl)phenyl)carbamate (170 mg, 49%) as a yellow solid. MS (ESI) calcd. for C35H33N9O3: 627.27 m/z, found 628.20 [M+H]+.
Step 2: Synthesis of (S)-3-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Intermediate 2-1
A solution of tert-butyl (S)-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamoyl)phenyl)carbamate (160 mg, 0.255 mmol) in TFA (1.5 mL) and DCM (4.5 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (S)-3-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Intermediate 2-1) (130 mg, 97%) as a yellow solid. MS (ESI) calcd. for C30H25N9O: 527.22 m/z, found 528.20 [M+H]+.
Example 3: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1-(prop-2-enoyl)-2,3-dihydroindole-4-carboxamide




Synthetic Route:





Step 1: Synthesis of 2,3-dihydro-1H-indole-4-carboxylic acid
To a solution of methyl 2,3-dihydro-1H-indole-4-carboxylate (500 mg, 2.82 mmol) in THF (20 mL) was added potassium trimethylsilanolate (1.81 g, 14.1 mmol) and the obtained solution was stirred at room temperature for 2 h. The mixture was adjusted to pH-6 with 1M HCl and purified by reverse phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 2,3-dihydro-1H-indole-4-carboxylic acid (300 mg, 65%). MS (ESI) calcd. for C9H9NO2: 163.06 m/z, found 164.10 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2,3-dihydro-1H-indole-4-carboxamide
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (200 mg, 0.490 mmol) in DMF (5 mL) were added DIEA (190 mg, 1.47 mmol), PyBOP (306 mg, 0.588 mmol) and 2,3-dihydro-1H-indole-4-carboxylic acid (96 mg, 0.59 mmol). The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2,3-dihydro-1H-indole-4-carboxamide (150 mg, 55%) as a yellow solid. MS (ESI) calcd. for C32H27N9O: 553.23 m/z, found 554.30 [M+H]+.
Step 3: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1-(prop-2-enoyl)-2,3-dihydroindole-4-carboxamide (Example 3)
To a cooled (0° C.) solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2,3-dihydro-1H-indole-4-carboxamide (100 mg, 0.181 mmol) in DCM (5 mL) were added triethylamine (27.4 mg, 0.271 mmol) and acryloyl chloride (16.4 mg, 0.181 mmol). The mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.05% TFA) to N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1-(prop-2-enoyl)-2,3-dihydroindole-4-carboxamide (Example 3) (14.2 mg, 13%) as a yellow solid (TFA salt). MS (ESI) calcd. for C35H29N9O2: 607.24 m/z, found 608.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.41-8.43 (m, 2H), 8.37-8.38 (m, 1H), 8.05-8.07 (m, 1H), 7.99-8.01 (m, 1H), 7.82-7.83 (m, 1H), 7.69-7.70 (m, 1H), 7.29-7.45 (m, 5H), 6.74-6.77 (m, 2H), 6.56-6.57 (m, 1H), 6.33-6.34 (m, 1H), 5.83-5.86 (m, 1H), 5.59-5.60 (m, 1H), 4.23-4.24 (m, 2H), 3.42-3.44 (m, 2H), 3.09-3.10 (m, 1H), 2.91-2.93 (m, 1H), 2.50-2.51 (m, 1H), 2.05-2.15 (m, 1H).
Example 4: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(N-methylacrylamido)benzamide




Synthetic Route:





Step 1: Synthesis of methyl 2-(N-methylprop-2-enamido)benzoate
To a solution of methyl 2-(methylamino)benzoate (1.000 g, 6.054 mmol) in DCM (20 mL) was added NaHCO3 (1.02 g, 12.1 mmol) and acryloyl chloride (0.55 g, 6.1 mmol). The resulting mixture was stirred at room temperature for 2 h. The solvent was removed by distillation under vacuum. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate 3 times. The organic layers were combined, dried over Na2SO4, filtered, and concentrated to afford methyl 2-(N-methylprop-2-enamido)benzoate (1.4 g) as a yellow oil, which was used directly in the next step without further purification. MS (ESI) calcd. for C12H13NO3: 219.09 m/z, found 220.10 [M+H]+.
Step 2: Synthesis of 2-(N-methylprop-2-enamido)benzoic acid
To a solution of methyl 2-(N-methylprop-2-enamido)benzoate (220 mg, 1.00 mmol) in THF (10 mL) was added LiOH (4.01 mL, 8.02 mmol, 2M in H2O). The resulting mixture was stirred at room temperature for 3 h. The mixture was acidified to pH 6 with HCl (2M). The solvent was removed by distillation under vacuum to afford 2-(N-methylprop-2-enamido)benzoic acid (190 mg) (crude) as a light-yellow solid. MS (ESI) calcd. for C11H11NO3: 205.07 m/z, found 206.05 [M+H]+.
Step 3: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(N-methylprop-2-enamido)benzamide (Example 4
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (170 mg, 0.416 mmol) in DMF (3 mL) were added DIEA (161 mg, 1.25 mmol), PyBOP (217 mg, 0.416 mmol) and 2-(N-methylprop-2-enamido)benzoic acid (102 mg, 0.499 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3). The product was further purified by Prep-HPLC on a XSelect CSH F-Phenyl OBD column using a gradient of acetonitrile in water (+0.05% TFA) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(N-methylprop-2-enamido)benzamide (35 mg, 14%) as a yellow solid (TFA salt). MS (ESI) calcd. for C34H29N9O2: 595.24 m/z, found 596.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.37-8.42 (m, 2H), 7.99-8.02 (m, 2H), 7.79-7.81 (m, 2H), 7.47-7.58 (m, 3H), 7.24-7.41 (m, 4H), 6.81-6.84 (m, 1H), 6.12 (s, 1H), 5.85-6.12 (m, 2H), 5.37-5.52 (m, 2H), 3.14-3.22 (m, 3H), 2.81-2.97 (m, 2H), 2.42-2.51 (m, 1H), 1.88-2.02 (m, 1H).
Example 5: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(2-fluoroacrylamido)benzamide




Example 5 was prepared in a manner analogous to Example 4 (final step only) using Intermediate 5-1 in place of Intermediate 1-1 and 2-fluoroacrylic acid in place of 2-(N-methylprop-2-enamido)benzoic acid. MS (ESI) calcd. for C33H26FN9O2: 599.22 m/z, found 600.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.48-8.50 (m, 11H), 8.35-8.38 (m, 2H), 7.89-8.03 (m, 3H), 8.81-8.12 (m, 1H), 7.57-7.60 (m, 1H), 7.39-7.43 (m, 2H), 7.26-7.29 (m, 3H), 6.55-6.56 (m, 1H), 6.45-6.49 (m, 1H), 5.66-5.83 (m, 2H), 5.46-5.52 (m, 1H), 2.85-3.15 (m, 2H), 2.51-2.53 (m, 1H), 2.07-2.18 (m, 1H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −119.54. (formic acid salt)
Intermediate 5-1: (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide




Intermediate 5-1 was prepared in a manner analogous to Intermediate 2-1 using 2-((tert-butoxycarbonyl)amino)benzoic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid. MS (ESI) calcd. for C30H25N9O, 527.22 m/z, found 528.30 [M+H]+.
Example 6: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-fluoro-6-(prop-2-enamido)benzamide




Example 6 was prepared in a manner analogous to Example 1 (via Intermediate 1-3) starting from methyl 2-amino-6-fluorobenzoate instead of methyl 2-aminobenzoate. MS (ESI) calcd. for C33H26FN9O2: 599.22 m/z, found 600.20 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.39-8.45 (m, 1H), 8.30-8.39 (m, 1H), 8.00-8.10 (m, 2H), 7.80-7.89 (m, 1H), 7.75-7.80 (m, 1H), 7.58-7.75 (m, 1H), 7.45-7.58 (m, 3H), 7.30-7.40 (m, 1H), 7.10-7.20 (m, 1H), 6.85-6.90 (m, 1H), 6.55-6.65 (m, 1H), 6.40-6.55 (m, 1H), 6.10-6.30 (m, 1H), 5.75-5.95 (m, 1H), 5.45-5.75 (m, 1H), 2.85-3.10 (m, 2H), 2.40-2.50 (m, 1H), 1.85-2.05 (m, 1H). (TFA salt)
Example 7: (S)-1-acryloyl-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)indoline-6-carboxamide




Synthetic Route:





Step 1: Synthesis of methyl 1-acryloylindoline-6-carboxylate
Acryloyl chloride (1.02 g, 11.3 mmol) was added to a solution of methyl 2,3-dihydro-1H-indole-6-carboxylate (1.00 g, 5.64 mmol) and N,N-diisopropylethylamine (1.46 g, 11.3 mmol) in dichloromethane (10 mL) at 0° C. The reaction was stirred at 25° C. overnight. The reaction was quenched with saturated aqueous ammonium chloride and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford methyl 1-acryloylindoline-6-carboxylate (1.0 g, 70%) as a yellow solid. MS (ESI) calcd. for C13H3NO3: 231.09 m/z, found 232.15 [M−H]+.
Step 2: Synthesis of 1-acryloylindoline-6-carboxylic acid
To a cooled (0° C.) solution of methyl 1-acryloylindoline-6-carboxylate (200 mg, 0.865 mmol) in DCE (5 mL) was added trimethylstannanol (938 mg, 5.19 mmol). The resulting solution was then stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure to afford 1-acryloylindoline-6-carboxylic acid (130 mg, 69%) as a white solid which was used in the next step directly without further purification. MS (ESI) calcd. for C12H11NO3: 217.07 m/z, found 218.05 [M+H]+.
Step 3: Synthesis of (S)-1-acryloyl-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)indoline-6-carboxamide (Example 7
To a solution of 1-acryloylindoline-6-carboxylic acid (53.18 mg, 0.245 mmol) in DMF (3 mL) were added (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (100 mg, 0.245 mmol), N,N-diisopropylethylamine (127 mg, 0.980 mmol) and HATU (112 mg, 0.294 mmol) in sequence. The resulting solution was stirred at 25° C. for 1 h. The reaction was quenched with saturated aqueous ammonium chloride and extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.1% formic acid) to afford (S)-1-acryloyl-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)indoline-6-carboxamide (Example 7) (20.6 mg, 14%) as a white solid. MS (ESI) calcd. for C35H29N9O2: 607.24 m/z, found 608.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64-8.65 (m, 1H), 8.35-8.37 (m, 2H), 8.01-8.02 (m, 1H), 7.94-7.97 (m, 1H), 7.80-7.81 (m, 1H), 7.58-7.60 (m, 1H), 7.28-7.37 (m, 5H), 6.75-6.77 (m, 1H), 6.55-6.56 (m, 1H), 6.48-6.51 (m, 1H), 6.36-6.37 (m, 1H), 5.86-5.89 (m, 1H), 5.62-5.64 (m, 1H), 4.25-4.27 (m, 2H), 3.20-3.24 (m, 2H), 3.01-3.03 (m, 1H), 2.91-2.93 (m, 1H), 2.45-2.50 (m, 1H), 2.09-2.14 (m, 1H).
Example 8: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-(2-fluoroacrylamido)benzamide




Example 8 was prepared in a manner analogous to Example 4 (final step only) using Intermediate 2-1 in place of Intermediate 1-1 and 2-fluoroacrylic acid in place of 2-(N-methylprop-2-enamido)benzoic acid. MS (ESI) calcd. for C33H26FN9O2: 599.22 m/z, found 600.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30-8.45 (m, 2H), 8.15-8.30 (m, 1H), 8.00-8.05 (m, 1H), 7.90-8.00 (m, 1H), 7.80-7.90 (m, 1H), 7.70-7.80 (m, 1H), 7.60-7.70 (m, 1H), 7.40-7.50 (m, 1H), 7.30-7.40 (m, 2H), 7.20-7.30 (m, 2H), 6.50-6.60 (m, 1H), 6.35-6.50 (m, 1H), 5.60-5.90 (m, 2H), 5.30-5.50 (m, 1H), 2.85-3.15 (m, 2H), 2.50-2.60 (m, 1H), 2.00-2.20 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −116.82. (TFA salt)
Example 9: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(but-2-ynamido)benzamide




Example 9 was prepared in a manner analogous to Example 1 using Intermediate 9-1 in place of Intermediate 1-3 and a reaction time of 2 h instead of overnight. MS (ESI) calcd. for C34H27N9O2: 593.23 m/z, found 594.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.34 (m, 2H), 8.23-8.29 (m, 1H), 8.01-8.05 (m, 1H), 7.92-8.00 (m, 1H), 7.74-7.78 (m, 2H), 7.45-7.55 (m, 1H), 7.34-7.40 (m, 2H), 7.25-7.28 (m, 2H), 7.20-7.25 (m, 1H), 6.52-6.55 (m, 1H), 6.44-6.47 (m, 1H), 5.55-5.61 (m, 1H), 2.99-3.10 (m, 1H), 2.87-2.98 (m, 1H), 2.51-2.55 (m, 1H), 2.01-2.15 (m, 1H), 1.95-2.01 (m, 3H). (formic acid salt)
Intermediate 9-1: methyl 2-(but-2-ynamido)benzoate




Synthetic Route:





Step 1: Synthesis of methyl 2-(but-2-ynamido)benzoate (Intermediate 9-1
To a solution of 2-butynoic acid (1.67 g, 19.8 mmol) and DCC (2.05 g, 9.92 mmol) in DCM (30 mL) was added methyl anthranilate (1.00 g, 6.62 mmol). The mixture was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford methyl 2-(but-2-ynamido)benzoate (Intermediate 9-1) (1.4 g, 97%) as an off-white solid. MS (ESI) calcd. for C12H1NO3: 217.07 (m/z), found 218.05 [M+H]+.
Example 10: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]1-(prop-2-enoyl)-2,3-dihydroindole-7-carboxamide




Example 10 was prepared in a manner analogous to Example 3 using methyl 2,3-dihydro-1H-indole-7-carboxylate in place of methyl 2,3-dihydro-1H-indole-4-carboxylate. MS (ESI) calcd. for C35H29N9O2: 607.24 m/z, found 608.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42-8.44 (m, 1H), 8.35-8.36 (m, 1H), 8.06-8.08 (m, 1H), 7.99-8.02 (m, 1H), 7.82-7.83 (m, 1H), 7.72-7.73 (m, 1H), 7.62-7.70 (m, 1H), 7.29-7.40 (m, 4H), 7.11-7.15 (m, 1H), 6.79-6.80 (m, 1H), 6.56-6.57 (m, 2H), 6.27-6.28 (m, 1H), 5.78-5.81 (m, 1H), 5.41-5.50 (m, 1H), 4.17-4.19 (m, 2H), 3.08-3.10 (m, 2H), 2.91-3.00 (m, 1H), 2.85-2.90 (m, 1H), 2.45-2.50 (m, 1H), 2.05-2.15 (m, 1H). (TFA salt)
Example 11: (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)isonicotinamide




Example 11 was prepared in a manner analogous to Example 7 using methyl 2-aminoisonicotinate in place of methyl 2,3-dihydro-1H-indole-6-carboxylate and reaction times of 2 h for the first two steps. MS (ESI) calcd. for C32H26N10O2: 582.22 m/z, found 583.10 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ (ppm): 8.60-8.75 (m, 1H), 8.45-8.60 (m, 1H), 8.25-8.45 (m, 2H), 8.00-8.20 (m, 1H), 7.90-8.00 (m, 1H), 7.65-7.90 (m, 1H), 7.55-7.65 (m, 1H), 7.40-7.55 (m, 2H), 7.20-7.40 (m, 2H), 6.50-6.79 (m, 3H), 6.25-6.50 (m, 1H), 5.75-6.00 (m, 1H), 5.55-5.75 (m, 1H), 3.00-3.25 (m, 1H), 2.80-3.00 (m, 1H), 2.55-2.65 (m, 1H), 2.00-2.30 (m, 1H). (formic acid salt)
Example 12: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-3-(but-2-ynamido)benzamide




Example 12 was prepared in a manner analogous to Example 7 (starting from Step 2) using Intermediate 12-1 in place of the methyl ester staring material. MS (ESI) calcd. for C34H27N9O2: 593.23 m/z, found 594.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.38-8.40 (m, 2H), 8.06-8.07 (m, 1H), 7.97-8.02 (m, 2H), 7.82-7.83 (m, 1H), 7.67-7.69 (m, 1H), 7.58-7.63 (m, 2H), 7.46-7.48 (m, 1H), 7.37-7.44 (m, 2H), 7.30-7.32 (m, 1H), 6.69-6.71 (m, 1H), 6.58-6.60 (m, 1H), 5.58-5.62 (m, 1H), 3.04-3.06 (m, 1H), 2.92-2.94 (m, 1H), 2.45-2.50 (m, 1H), 2.11-2.14 (m, 1H), 2.02-2.04 (m, 3H). (formic acid salt)
Intermediate 12-1: methyl 3-(but-2-ynamido)benzoate




Intermediate 12-1 was prepared in a manner analogous to Intermediate 9-1 using 3-aminobenzoate in place of methyl anthranilate. MS (ESI) calcd. for C12H11NO3: 217.07 m/z, found 218.00 [M+H]+.
Example 13: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route





Step 1: Synthesis of 1-(4-{1[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 13)
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (200 mg, 0.490 mmol) in DCE (10 mL) was added 1-(prop-2-enoyl)piperidin-4-one (75 mg, 0.490 mmol). The resulting mixture was stirred at 40° C. overnight. NaBH3CN (123 mg, 1.960 mmol) was added and the mixture was stirred at 40° C. for 1 h. The reaction was quenched with H2O. The resulting mixture was extracted with dichloromethane 3 times. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting mixture was purified by reverse phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3). The material obtained was further purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.1% formic acid) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 13, formic acid salt) (41.6 mg, 15%) as an off-white solid. MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found 546.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.35 (m, 2H), 7.98-7.99 (m, 1H), 7.93-7.95 (m, 1H), 7.79-7.80 (m, 1H), 7.60-7.62 (m, 1H), 7.42-7.43 (m, 1H), 7.28-7.30 (m, 2H), 6.76-6.83 (m, 1H), 6.54-6.55 (m, 1H), 6.44-6.47 (m, 1H), 6.08-6.13 (m, 1H), 5.70-5.73 (m, 1H), 4.70-4.75 (m, 1H), 4.38-4.48 (m, 1H), 4.05-4.15 (m, 1H), 3.28-3.33 (m, 1H), 3.04-3.18 (m, 2H), 2.88-2.90 (m, 1H), 2.69-2.75 (m, 1H), 2.50-2.51 (m, 1H), 1.98-2.15 (m, 3H), 1.33-1.46 (m, 2H).
Example 14: 1-(8-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-azabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one




Example 14 was prepared in a manner analogous to Example 13 using Intermediate 14-1 in place of 1-(prop-2-enoyl)piperidin-4-one. MS (ESI) calcd. for C33H33N9O: 571.28 m/z, found 572.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.43-8.45 (m, 1H), 8.33-8.36 (m, 1H), 8.05-8.12 (m, 1H), 8.01-8.04 (m, 1H), 7.80-7.88 (m, 3H), 7.59-7.60 (m, 1H), 7.44-7.46 (m, 1H), 6.75-6.88 (m, 2H), 6.55-6.60 (m, 1H), 6.10-6.14 (m, 1H), 5.70-5.73 (m, 1H), 5.05-5.07 (m, 1H), 4.00-4.10 (m, 1H), 3.80-3.93 (m, 1H), 3.43-3.55 (m, 1H), 3.40-3.43 (m, 1H), 3.18-3.29 (m, 1H), 3.05-3.13 (m, 1H), 2.95-3.01 (m, 1H), 2.55-2.70 (m, 1H), 2.45-2.52 (m, 1H), 2.32-2.42 (m, 1H), 2.10-2.20 (m, 1H), 1.65-1.85 (m, 2H), 1.35-1.58 (m, 2H). (TFA salt)
Intermediate 14-1: 3-acryloyl-3-azabicyclo[3.2.1]octan-8-one




Synthetic Route:





Step 1: Synthesis of 3-azabicyclo[3.2.1]octan-8-one
To a solution of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (300 mg, 1.33 mmol) in DCM (10 mL) was added TFA (10 mL) and the resulting mixture was stirred at room temperature for 2 h. The solvent was removed by distillation under vacuum to afford 3-azabicyclo[3.2.1]octan-8-one (166 mg, crude quant) as a brown oil, which was used in the next step without purification. MS (ESI) calcd. for C7H11NO: 125.08 m/z, found 126.05 [M+H]+.
Step 2: Synthesis of 3-(prop-2-enoyl)-3-azabicyclo[3.2.1]octan-8-one
To a cooled (0° C.) solution of 3-azabicyclo[3.2.1]octan-8-one (166 mg, 1.33 mmol) and triethylamine (671 mg, 6.63 mmol) in DCM (10 mL) was added acryloyl chloride (180 mg, 1.99 mmol) and the residue mixture was stirred at room temperature for 2 h. The reaction was quenched with H2O and extracted with dichloromethane 3 times. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford 3-(prop-2-enoyl)-3-azabicyclo[3.2.1]octan-8-one (Intermediate 14-1) (150 mg, 63%) as a yellow oil. MS (ESI) calcd. for C10H13NO2: 179.09 m/z, found: 198.10 [M+H2O+H]+.
Example 15: (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-6-methylbenzamide




Example 15 was prepared in a manner analogous to Example 3 (starting from Step 2) using 2-amino-6-methylbenzoic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid and N,N-diisopropylethylamine/acetonitrile in place of triethylamine/dichloromethane. MS (ESI) calcd. for C34H29N9O2: 595.24 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.36 (m, 2H), 7.98-8.00 (m, 1H), 7.94-7.95 (m, 1H), 7.79-7.80 (m, 1H), 7.42-7.43 (m, 2H), 7.31-7.34 (m, 1H), 7.27-7.29 (m, 1H), 7.21-7.23 (m, 2H), 7.09-7.11 (m, 1H), 6.50-6.55 (m, 2H), 6.41-6.44 (m, 1H), 6.16-6.19 (m, 1H), 5.67-5.69 (m, 1H), 5.54-5.58 (m, 1H), 2.85-2.87 (m, 1H), 2.50-2.51 (m, 1H), 2.46-2.47 (m, 1H), 2.31 (s, 3H), 1.96-1.99 (m, 1H). (formic acid salt)
Example 16: (S,E)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(4-(dimethylamino)but-2-enamido)benzamide




Synthetic Route:





Step 1: Synthesis of (S,E)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(4-(dimethylamino)but-2-enamido)benzamide (Example 16)
To a solution of (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Intermediate 5-1) (150 mg, 0.284 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (55 mg, 0.43 mmol) in THE (5 mL) were added T3P (360 mg, 0.568 mmol, 50% in THF) and N,N-diisopropylethylamine (110 mg, 0.852 mmol). The resulting mixture was stirred overnight at 50° C. The reaction mixture was purified by reverse phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3). The material obtained was further purified by Prep-HPLC on a XSelect CSH Prep C18 OBD Column using a gradient of acetonitrile in water (+0.1% TFA) to afford (S,E)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(4-(dimethylamino)but-2-enamido)benzamide (Example 16, TFA salt) (29.6 mg, 13.6%) as an off-white solid. MS (ESI) calcd. for C36H34N10O2: 638.29 m/z, found 639.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.33-8.37 (m, 3H), 7.94-8.03 (m, 2H), 7.75-7.85 (m, 2H), 7.54-7.56 (m, 1H), 7.50-7.51 (m, 2H), 7.15-7.29 (m, 3H), 6.70-6.80 (m, 1H), 6.60-6.65 (m, 1H), 6.45-6.55 (m, 1H), 6.25-6.30 (m, 1H), 5.55-5.63 (m, 1H), 3.17-3.18 (m, 2H), 2.85-3.15 (m, 2H), 2.51-2.53 (m, 1H), 2.07-2.22 (m, 7H).
Example 17: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-methacrylamidobenzamide




Example 17 was prepared in a manner analogous to Example 4 (Step 3 only) using Intermediate 5-1 in place of Intermediate 1-1 and methacrylic acid in place of 2-(N-methylprop-2-enamido)benzoic acid. MS (ESI) calcd. for C34H29N9O2: 595.24 m/z, found 596.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.38-8.49 (m, 3H), 8.01-8.07 (m, 2H), 7.72-7.95 (m, 3H), 7.15-7.59 (m, 5H), 6.75-6.85 (m, 1H), 6.83-6.85 (m, 1H), 5.91 (s, 1H), 5.55-5.65 (m, 2H), 2.85-3.12 (m, 2H), 2.51-2.52 (m, 1H), 2.01-2.25 (m, 4H). (TFA salt) Example 18: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-(2-fluoroacryloyl)indoline-4-carboxamide




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)indoline-4-carboxamide
A solution of indoline-4-carboxylic acid (300 mg, 1.84 mmol), (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (826 mg, 2.02 mmol), PyBOP (1148 mg, 2.207 mmol) and N,N-diisopropylethylamine (594 mg, 4.60 mmol) in DMF (3 mL) was stirred for 1 h at room temperature. The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)indoline-4-carboxamide (130 mg, 13% yield) as a white solid. MS (ESI) calcd. for C32H27N9O: 553.23 m/z, found 554.30 [M+H]+.
Step 2: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-(2-fluoroacryloyl)indoline-4-carboxamide (Example 18)
A solution of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)indoline-4-carboxamide (130 mg, 0.235 mmol), 2-fluoroacrylic acid (25.4 mg, 0.282 mmol), PyBOP (122 mg, 0.235 mmol) and N,N-diisopropylethylamine (61 mg, 0.47 mmol) in DMF (2 mL) was stirred for 1 h at room temperature. The resulting mixture was purified by Prep-HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-(2-fluoroacryloyl)indoline-4-carboxamide (16.7 mg, 11% yield) as a white solid. MS (ESI) calcd. for C35H28FN9O2: 625.23 m/z, found 626.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.36-8.37 (m, 2H), 8.02-8.07 (m, 3H), 7.94-7.97 (m, 1H), 7.26-7.39 (m, 6H), 6.51-6.56 (m, 1H), 6.42-6.49 (m, 1H), 5.42-5.62 (m, 3H), 4.23-4.27 (m, 2H), 3.38-3.43 (m, 2H), 3.00-3.02 (m, 2H), 2.74-2.85 (m, 1H), 2.05-2.08 (m, 1H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −109.06.
Example 19: (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide




Example 19 was prepared in a manner analogous to Example 2 using Intermediate 19-2 in place of Intermediate 2-1. MS (ESI) calcd. for C32H26N10O2: 582.22 m/z, found 583.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 11.47-11.55 (m, 1H), 9.13-9.21 (m, 1H), 8.37-8.49 (m, 2H), 8.10-8.19 (m, 2H), 7.94-8.06 (m, 2H), 7.79-7.88 (m, 1H), 7.52-7.59 (m, 1H), 7.39-7.51 (m, 2H), 7.24-7.36 (m, 2H), 7.12-7.22 (m, 1H), 6.89-6.97 (m, 2H), 6.34-6.58 (m, 2H), 6.19-6.28 (m, 1H), 5.77-5.85 (m, 1H), 5.62-5.71 (m, 1H), 2.84-3.08 (m, 2H), 2.51-2.60 (m, 1H), 2.06-2.19 (m, 1H). (formic acid salt)
Intermediate 19-2: (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide




Intermediate 19-2 was prepared in a manner analogous to Intermediate 2-1 using 2-((tert-butoxycarbonyl)amino)benzoic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid, Intermediate 19-1 in place of Intermediate 1-1 and 4N HCl in dioxane in place of TFA. MS (ESI) calcd. for C29H24N10O: 528.21 m/z, found 529.25 [M+H]+.
Intermediate 19-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:








Step 1: Synthesis of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide
To a mixture of (S)-5-bromo-2,3-dihydro-1H-inden-1-amine (74 g, 350 mmol, 1 equiv) and triethylamine (106 g, 1.05 mol, 3 equiv) in dichloromethane (1.5 L) was added acetic anhydride (55.2 g, 526 mmol, 1.5 equiv) at 0° C. and the mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by addition of water and extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was re-crystallized from petroleum ether to afford (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide (90 g, 83% yield) as a white solid. MS (ESI) calculated for C11H12BrNO: 253.01, found 254.00 [M+H]+, 256.00 [M+H+2]+.
Step 2: Synthesis of tert-butyl (S)-(1-acetamido-2,3-dihydro-1H-inden-5-yl)carbamate
To a mixture of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide (40 g, 157 mmol, 1 equiv), tert-butyl carbamate (27.66 g, 236 mmol, 1.5 equiv), XantPhos (9.11 g, 15.7 mmol, 10 mol %), palladium (III) acetate (3.54 g, 15.7 mmol, 10 mol %), and cesium carbonate (154 g, 472 mmol, 10 mol %) was added 1,4-dioxane (300 mL) under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100° C. The reaction mixture was quenched by addition of water and extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent of petroleum ether/dichloromethane/methanol (70:27:3) to afford tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 48%). MS (ESI) calculated for C16H22N2O3: 290.16 m/z, found 289.05 [M−H]−.
Step 3: Synthesis of (S)-N-(5-amino-2,3-dihydro-1H-inden-1-yl)acetamide
To a stirred solution of tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 148 mmol, 1 equiv) in dichloromethane (180 mL) was added 4N hydrochloric acid in 1,4-dioxane (185 mL, 742 mmol, 5 equiv). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and re-crystallized from ethyl acetate to afford N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (hydrochloride salt) (23 g, 81%) as a white solid. MS (ESI) calculated for C11H14N2O: 190.11 m/z, found 191.15 [M+H]+.
Step 4: Synthesis of (S)-N-(5-((6-bromo-3-nitropyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide
A solution of (S)-N-(5-amino-2,3-dihydro-1H-inden-1-yl)acetamide (17 g, 89 mmol), 2,6-dibromo-3-nitropyridine (25.19 g, 89.36 mmol) and triethylamine (45.21 g, 446.8 mmol) in EtOH (200 mL) was stirred at room temperature for 2 h. The reaction was quenched with water and the precipitated solids were collected by filtration, washing with EtOH/H2O=1:1 to afford (S)-N-(5-((6-bromo-3-nitropyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (26 g, 74.37% yield) as an orange solid. MS (ESI) calcd. for C16H15BrN4O3: 390.03, found 413.00 [M+Na]+, 415.00 [M+Na+2]+.
Step 5: Synthesis of (S)-N-(5-((3-nitro-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide
To a solution of (S)-N-(5-((6-bromo-3-nitropyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (50.0 g, 128 mmol) in DMF (1.5 L) was added K2CO3 (52.99 g, 383.4 mmol) and 1H-1,2,3-triazole (17.65 g, 255.6 mmol). The resulting mixture was stirred at room temperature overnight. The product was precipitated by the addition of H2O. The precipitated solids were collected by filtration and washed with water. The crude product was re-crystallized from petroleum ether to afford (S)-N-(5-((3-nitro-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (45 g, 93%) as a yellow solid. MS (ESI) calculated for C18H17N7O3: 379.14 m/z, found 380.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.98 (s, 2H), 7.79 (d, J=2.1 Hz, 1H), 7.68 (dd, J=8.3, 2.1 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 7.13-7.04 (m, 2H), 5.18 (t, J=7.4 Hz, 1H), 2.93-2.85 (m, 1H), 2.80-2.70 (m, 1H), 2.43-2.31 (m, 1H), 1.87 (s, 3H), 1.82-1.71 (m, 1H).
Step 6: Synthesis of (S)-N-(5-((3-amino-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide
To a cooled (0° C.) solution of (S)-N-(5-((3-nitro-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (1.3 g, 3.4 mmol) and 4,4-bipyridine (27 mg, 0.17 mmol) in DMF (25 mL) was added B2(OH)4 (0.92 g, 10 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with H2O. The resulting mixture was extracted with ethyl acetate 3 times. The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford (S)-N-(5-((3-amino-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (800 mg, 67%) as a yellow solid. MS (ESI) calcd. for C18H19N7O: 349.17 m/z, found 350.15 [M+H]+.
Step 7: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide
To a solution of (S)-N-(5-((3-amino-6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (700 mg, 2.00 mmol) in AcOH (10 mL) and MeOH (2 mL) was added 2-aminonicotinaldehyde (269 mg, 2.20 mmol) and sodium perborate (328 mg, 4.00 mmol). The resulting mixture was stirred at 70° C. for 3 h. The solvent was removed by distillation under vacuum. The resulting mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (520 mg, 57%) as a reddish brown solid. MS (ESI) calcd. for C24H21N9O: 451.19 m/z, found 452.20 [M+H]+.
Step 8: Synthesis of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 19-1
A solution of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (520 mg, 1.152 mmol) in HCl (20 mL, concentrated) and MeOH (20 mL) was stirred at 90° C. overnight. The solvent was removed by distillation under vacuum to afford (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 19-1) (400 mg, 85%) crude as a yellow solid. MS (ESI) calcd. for C22H19N9: 409.18 m/z, found 410.20 [M+H]+.
Example 20: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-5-fluoro-2-(prop-2-enamido)benzamide




Example 20 was prepared in a manner analogous to Example 3 (steps 2 and 3 only) using 2-amino-5-fluorobenzoic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid. MS (ESI) calcd. for C33H26FN9O2: 599.22 m/z, found 600.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.36 (m, 2H), 8.27-8.31 (m, 1H), 8.01-8.02 (m, 1H), 7.94-7.97 (m, 1H), 7.81-7.82 (m, 1H), 7.63-7.66 (m, 1H), 7.46-7.48 (m, 1H), 7.38-7.41 (m, 2H), 7.26-7.31 (m, 2H), 6.55-6.57 (m, 1H), 6.45-6.47 (m, 2H), 6.23-6.28 (m, 1H), 5.80-5.83 (m, 1H), 5.61-5.82 (m, 1H), 2.98-3.05 (m, 1H), 2.91-2.93 (m, 1H), 2.51-2.55 (m, 1H), 2.05-2.10 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −118.14. (formic acid salt)
Example 21: (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-fluorobenzamide




Example 21 was prepared in a manner analogous to Example 3 (steps 2 and 3 only) using 2-amino-4-fluorobenzoic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid. MS (ESI) calcd. for C33H26FN9O2: 599.22 m/z, found 600.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.41-8.56 (m, 1H), 8.36-8.41 (m, 1H), 8.19-8.36 (m, 1H), 8.08-8.19 (m, 1H), 7.99-8.08 (m, 1H), 7.99-7.88 (m, 1H), 7.81-7.88 (m, 1H), 7.65-7.81 (m, 1H), 7.41-7.59 (m, 2H), 7.21-7.41 (m, 1H), 6.93-7.20 (m, 1H), 6.68-6.93 (m, 1H), 6.51-6.68 (m, 1H), 6.33-6.51 (m, 1H), 6.15-6.33 (m, 1H), 5.75-6.01 (m, 1H), 5.48-5.75 (m, 1H), 3.02-3.21 (m, 1H), 2.75-3.02 (m, 1H), 2.58-2.61 (m, 1H), 1.98-2.25 (m, 1H). (formic acid salt)
Example 22: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(prop-2-enamido)benzamide




Example 22 was prepared in a manner analogous to Example 1 using Intermediate 22-2 in place of Intermediate 1-1. MS (ESI) calcd. for C33H29N7O2: 555.24 m/z, found: 556.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.20-8.30 (m, 1H), 8.02-8.05 (m, 1H), 7.95-8.00 (m, 1H), 7.69-7.80 (m, 1H), 7.55-7.60 (m, 1H), 7.95-7.54 (m, 1H), 7.35-7.43 (m, 1H), 7.28-7.34 (m, 1H), 7.22-7.34 (m, 1H), 7.15-7.21 (m, 2H), 6.65-6.75 (m, 1H), 6.31-6.41 (m, 1H), 6.18-6.30 (m, 1H), 5.78-5.85 (m, 1H), 5.51-5.61 (m, 1H), 2.93-3.05 (m, 1H), 2.79-2.92 (m, 1H), 2.02-2.20 (m, 2H), 1.11-1.30 (m, 1H), 0.85-1.01 (m, 2H), 0.71-0.84 (m, 2H). (TFA salt)
Intermediate 22-2: 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
A mixture of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 22-1) (300 mg, 0.575 mmol), potassium cyclopropyltrifluoroboranuide (75 mg, 0.69 mmol), Pd(OAc)2 (12.9 mg, 0.057 mmol), Butyldi-1-adamantylphosphine (20.4 mg, 0.057 mmol) and Cs2CO3 (562 mg, 1.73 mmol) were suspended in dioxane (4 mL) and H2O (1 mL) at 25° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 120° C. under nitrogen atmosphere. After cooling to the room temperature, the reaction mixture was quenched by addition of water. The resulting mixture was extracted with ethyl acetate 3 times. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (210 mg, 76% yield) as a yellow solid. MS (ESI) calcd. for C28H30N6O2: 482.24 m/z, found: 483.25 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 22-2
A mixture of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (210 mg, 0.435 mmol) in HCl (10 mL, 4M in 1,4-dioxane) was stirred at room temperature for 1 h. The reaction mixture was concentrated to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 22-2) (110 mg, 66% yield) as a yellow solid. MS (ESI) calcd. for C23H22N6: 382.19 m/z, found: 383.20 [M+H]+.
Intermediate 22-1: tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of benzyl N-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (60.00 g, 192.18 mmol, 1 equiv), benzyl acetate (34.63 g, 230.6 mmol, 1.2 equiv) and XantPhos (22.24 g, 38.44 mmol, 0.2 equiv) in 1,4-dioxane (1200 mL) were added Cs2CO3 (125.23 g, 384.36 mmol, 2 equiv) and Pd(OAc)2 (4.31 g, 19.2 mmol, 0.1 equiv). The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The mixture was cooled to room temperature and the product was precipitated by the addition of H2O. The precipitated solids were collected by filtration and washed with water 3 times. The residue taken up into ethyl acetate the solids were removed by filtration, rinsing 3 times with ethyl acetate. The filtrate was concentrated under reduced pressure to afford benzyl N-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]carbamate (50 g, 46%) as a grey solid. MS (ESI) calcd. for C22H26N2O4: 382.19 m/z, found: 381.10 [M−H]−.
Step 2: Synthesis of tert-butyl N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of benzyl N-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]carbamate (50 g, 131 mmol, 1 equiv) in 500 mL CH3OH was added Pd(OH)2/C (5 g, 35.605 mmol, 0.27 equiv) (10%, 5 g) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen overnight. The resulting mixture was filtered through a Celite pad and concentrated under reduced pressure to afford tert-butyl N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]carbamate (40 g, 73%) as a brown solid. MS (ESI) calcd. for C14H20N2O2, 248.15 m/z, found: 249.15 [M+H]+.
Step 3: Synthesis of tert-butyl N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate
tert-Butyl N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]carbamate (40 g, 161 mmol, 1 equiv) was suspended in EtOH (800 mL) followed by addition of triethylamine (48.90 g, 483.2 mmol, 3 equiv). Once dissolved, 2,6-dibromo-3-nitropyridine (54.49 g, 193.3 mmol, 1.2 equiv) was added and the mixture was stirred at 30° C. overnight. The mixture was allowed to cool to rt. The precipitated solids were collected by filtration and washed with EtOH 3 times to afford tert-butyl N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate (30 g, 27%) as a red solid. MS (ESI) calcd. for C19H21BrN4O4: 448.07 m/z, found 447.00 [M−H]−.
Step 4: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 22-1
tert-Butyl N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate (30 g, 67 mmol, 1 equiv) was dissolved in DMSO (600 mL) and MeOH (100 mL), followed by addition of 2-aminopyridine-3-carbaldehyde (8.97 g, 73.4 mmol, 1.1 equiv) and Na2S2O4 (25.57 g, 146.9 mmol, 2.2 equiv). The resulting mixture was stirred at 100° C. overnight. The product was precipitated by the addition of H2O. The precipitated solids were collected by filtration and washed with H2O 3 times. The residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (10:1) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 22-1) (15 g, 36%) as a yellow solid. MS (ESI) calcd. for C25H25BrN6O2: 520.12 m/z, found: 521.20 [M+H]+.
Example 23: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(2H-1,2,3-triazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(2-fluoroacrylamido)benzamide




Example 23 was prepared in a manner analogous to Example 18 (last step only) using Intermediate 19-2 in place of the amine starting material. MS (ESI) calcd. for C32H25FN10O2: 600.21 m/z, found 601.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.43-8.52 (m, 2H), 8.11-8.14 (m, 3H), 8.03-8.05 (m, 1H), 7.80-7.89 (m, 2H), 7.55-7.65 (m, 1H), 7.39-7.45 (m, 2H), 7.32-7.38 (m, 1H), 7.22-7.28 (m, 1H), 6.75-6.85 (m, 1H), 5.60-5.80 (m, 2H), 5.42-5.55 (m, 1H), 3.05-3.12 (m, 1H), 2.85-3.00 (m, 1H), 2.51-2.52 (m, 1H), 2.05-2.20 (m, 1H). 19F NMR (300 MHz, DMSO-d6) δ (ppm): −119.76. (TFA salt)
Example 24: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(vinylsulfonamido)benzamide




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(vinylsulfonamido)benzamide (Example 24)
A solution of (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Intermediate 5-1) (60 mg, 0.11 mmol) and pyridine (18 mg, 0.23 mmol) in DCM (2 ml) was treated with vinylsulfonyl chloride (20 mg, 0.16 mmol) at 0° C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water and extracted with ethyl acetate 3 times. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(vinylsulfonamido)benzamide (14.3 mg, 20% yield) as an off-white solid. MS (ESI) calcd. for C32H27N9O3S: 617.20 m/z, found 618.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.46 (m, 2H), 8.02-8.10 (m, 1H), 7.96-8.01 (m, 1H), 7.84-7.92 (m, 1H), 7.79-7.83 (m, 1H), 7.51-7.58 (m, 1H), 7.39-7.50 (m, 3H), 7.26-7.34 (m, 2H), 7.15-7.24 (m, 1H), 6.79-6.90 (m, 1H), 6.56-6.62 (m, 1H), 6.48-6.54 (m, 1H), 6.18-6.30 (m, 1H), 6.07-6.16 (m, 1H), 5.57-5.66 (m, 1H), 3.01-3.13 (m, 1H), 2.89-2.99 (m, 1H), 2.58-2.62 (m, 1H), 2.09-2.21 (m, 1H).
Example 25: (2S)—N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1-(prop-2-enoyl)pyrrolidine-2-carboxamide




Example 25 was prepared in a manner analogous to Example 4 (final step only) using acryloyl-D-proline in place of 2-(N-methylprop-2-enamido)benzoic acid. MS (ESI) calcd. for C31H29N9O2: 559.24, m/z, found 560.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.38 (m, 2H), 7.96-8.02 (m, 1H), 7.91-7.94 (m, 1H), 7.78-7.82 (m, 1H), 7.25-7.37 (m, 4H), 6.34-6.66 (m, 3H), 6.15-6.22 (m, 1H), 5.64-5.77 (m, 1H), 5.33-5.42 (m, 1H), 4.38-4.55 (m, 1H), 3.43-3.73 (m, 2H), 2.85-2.96 (m, 2H), 2.41-2.47 (m, 1H), 2.13-2.35 (m, 1H), 1.87-2.01 (m, 4H).
Example 26: (S)-1-acryloyl-N—((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-2-carboxamide




Example 26 was prepared in a manner analogous to Example 4 (final step only) using acryloyl-L-proline in place of 2-(N-methylprop-2-enamido)benzoic acid. MS (ESI) calcd. for C31H29N9O2, 559.24: (m/z), found 560.30[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.40 (m, 2H), 7.99-8.04 (m, 1H), 7.91-7.96 (m, 1H), 7.78-7.82 (m, 1H), 7.25-7.34 (m, 4H), 6.34-6.61 (m, 3H), 6.15-6.22 (m, 1H), 5.74-5.77 (m, 1H), 5.33-5.42 (m, 1H), 4.39-4.55 (m, 1H), 3.43-3.73 (m, 2H), 2.85-2.96 (m, 2H), 2.41-2.47 (m, 1H), 2.13-2.35 (m, 1H), 1.87-2.00 (m, 4H).
Example 27: 1-(3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one




Example 27 was prepared in a manner analogous to Example 13 using Intermediate 27-1 in place of 1-(prop-2-enoyl)piperidin-4-one. MS (ESI) calcd. for C33H33N9O: 571.28 m/z, found: 572.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.40-8.45 (m, 1H), 8.36-8.39 (m, 1H), 8.07-8.12 (m, 1H), 7.99-8.04 (m, 1H), 7.80-7.85 (m, 1H), 7.64-7.75 (m, 2H), 7.55-7.59 (m, 1H), 7.40-7.48 (m, 1H), 6.65-6.81 (m, 2H), 6.57-6.60 (m, 1H), 6.13-6.21 (m, 1H), 5.68-5.78 (m, 1H), 4.85-4.92 (m, 1H), 4.52-4.65 (m, 2H), 3.09-3.20 (m, 1H), 2.89-3.02 (m, 2H), 2.52-2.68 (m, 2H), 2.41-2.45 (m, 1H), 1.85-2.19 (m, 3H), 1.53-1.84 (m, 4H).
Intermediate 27-1: 8-acryloyl-8-azabicyclo[3.2.1]octan-3-one




Intermediate 27-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C10H13NO2: 179.09 m/z, found: 180.10 [M+H]+.
Example 28: (S)-1-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)azetidin-1-yl)prop-2-en-1-one




Example 28 was prepared in a manner analogous to Example 13 using Intermediate 28-1 in place of 1-(prop-2-enoyl)piperidin-4-one. MS (ESI) calcd. for C29H27N9O: 517.23 m/z, found: 518.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.52 (m, 2H), 7.98-8.15 (m, 2H), 7.80-7.90 (m, 1H), 7.56-7.79 (m, 3H), 7.40-7.55 (m, 1H), 6.71-6.90 (m, 1H), 6.55-6.70 (m, 1H), 6.25-6.40 (m, 1H), 6.15-6.24 (m, 1H), 5.69-5.85 (m, 1H), 4.84-5.00 (m, 1H), 4.50-4.64 (m, 1H), 4.26-4.41 (m, 2H), 4.14-4.25 (m, 1H), 3.87-4.01 (m, 1H), 3.12-3.30 (m, 1H), 2.95-3.10 (m, 1H), 2.41-2.61 (m, 1H), 2.18-2.30 (m, 1H).
Intermediate 28-1: 1-acryloylazetidin-3-one




Intermediate 28-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl 3-oxoazetidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C6H7NO2: 125.05 m/z, found: 126.10 [M+H]+.
Example 29: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1-(prop-2-enoyl)piperidine-4-carboxamide




Example 29 was prepared in a manner analogous to Example 2 (via Intermediate 2-1) using 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid and 4N HCl in dioxane in place of TFA/DCM. MS (ESI) calcd. for C32H31N9O2: 573.26 m/z, found: 574.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.39 (m, 3H), 8.00-8.04 (m, 1H), 7.93-7.98 (m, 1H), 7.79-7.84 (m, 1H), 7.35-7.41 (m, 1H), 7.21-7.31 (m, 3H), 6.88-6.94 (m, 2H), 6.79-6.86 (m, 1H), 6.54-6.59 (m, 1H), 6.42-6.47 (m, 1H), 6.15-6.22 (m, 1H), 5.62-5.69 (m, 1H), 5.31-5.38 (m, 1H), 4.35-4.45 (m, 1H), 4.03-4.12 (m, 1H), 3.01-3.13 (m, 1H), 2.91-3.00 (m, 1H), 2.81-2.90 (m, 1H), 2.62-2.78 (m, 1H), 2.39-2.52 (m, 1H), 1.42-1.95 (m, 6H). (formic acid salt).
Example 30: 1-(2-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-7-azaspiro[3.5]nonan-7-yl)prop-2-en-1-one




Example 30 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C34H35N9O: 585.30 m/z, found: 586.25 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.40-8.48 (m, 1H), 8.35-8.39 (m, 1H), 8.01-8.05 (m, 2H), 7.81-7.90 (m, 1H), 7.72-7.80 (m, 2H), 7.57-7.62 (m, 1H), 7.41-7.48 (m, 1H), 6.75-6.90 (m, 2H), 6.55-6.62 (m, 1H), 6.08-6.15 (m, 1H), 5.68-5.76 (m, 1H), 4.72-4.81 (m, 1H), 3.35-3.59 (m, 4H), 3.12-3.25 (m, 1H), 2.95-3.05 (m, 1H), 2.48-2.60 (m, 2H), 2.13-2.35 (m, 3H), 1.91-2.05 (m, 2H), 1.49-1.70 (m, 4H). (TFA salt).
Example 31: 1-(6-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one




Example 31 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.38 (m, 2H), 8.27 (s, 1H), 7.95-8.00 (m, 2H), 7.81-7.82 (m, 1H), 7.57-7.60 (m, 1H), 7.41 (s, 1H), 7.26-7.31 (m, 2H), 6.54-6.55 (m, 1H), 6.42-6.45 (m, 1H), 6.25-6.32 (m, 1H), 6.08-6.13 (m, 1H), 5.68-5.70 (m, 1H), 4.42-4.43 (m, 1H), 4.25 (s, 1H), 4.15 (s, 1H), 3.98 (s, 1H), 3.87 (s, 1H), 3.47-3.71 (m, 1H), 3.02-3.04 (m, 1H), 2.85-2.87 (m, 1H), 2.37-2.53 (m, 2H), 2.10-2.18 (m, 2H), 1.96-2.00 (m, 1H). (formic acid salt).
Example 32: 1-(7-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azaspiro[3.5]nonan-2-yl)prop-2-en-1-one




Example 32 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C34H35N9O, 585.30 m/z, found 586.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.22-8.59 (m, 2H), 7.95-8.17 (m, 2H), 7.76-7.95 (m, 2H), 7.65-7.76 (m, 1H), 7.53-7.65 (m, 1H), 7.32-7.53 (m, 1H), 6.72-6.95 (m, 1H), 6.48-6.72 (m, 1H), 6.21-6.48 (m, 1H), 6.05-6.21 (m, 1H), 5.61-5.86 (m, 1H), 4.87-5.11 (m, 1H), 3.87-3.95 (m, 1H), 3.69-3.74 (m, 1H), 3.52-3.69 (m, 1H), 3.09-3.41 (m, 2H), 2.81-3.09 (m, 1H), 2.56-2.67 (m, 2H), 2.09-2.35 (m, 2H), 1.81-2.09 (m, 3H), 1.52-1.81 (m, 2H), 1.39-1.52 (m, 2H). (formic acid salt).
Example 33: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,2,3-triazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 33 was prepared in a manner analogous to Example 13 using Intermediate 19-1 in place of Intermediate 1-1. MS (ESI) calcd. for C30H30N10O, 546.26 m/z, found 547.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.39-8.56 (m, 1H), 8.21-8.39 (m, 1H), 8.07-8.21 (m, 2H), 8.01-8.07 (m, 1H), 7.88-8.01 (m, 1H), 7.51-7.72 (m, 1H), 7.36-7.51 (m, 1H), 7.18-7.36 (m, 2H), 6.64-6.95 (m, 1H), 6.38-6.61 (m, 1H), 5.95-6.28 (m, 1H), 5.56-5.86 (m, 1H), 4.52-4.78 (m, 1H), 4.28-4.52 (m, 1H), 3.91-4.22 (m, 1H), 2.95-3.38 (m, 3H), 2.72-2.95 (m, 2H), 2.03-2.23 (m, 1H), 1.82-2.03 (m, 2H), 1.56-1.21 (m, 2H). (formic acid salt).
Example 34: (2E)-1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one




Synthetic Route:





Step 1: Synthesis of tert-butyl 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidine-1-carboxylate
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (410 mg, 1.00 mmol) in DCE (10 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (200 mg, 1.00 mmol). The resulting mixture was stirred at 40° C. for 1 h. To the above mixture was added NaBH3CN (252 mg, 4.02 mmol). The resulting mixture was stirred overnight at 40° C. The mixture was filtered and the filter cake was washed with acetonitrile (3×5 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidine-1-carboxylate (260 mg, 44% yield) as a yellow solid. MS (ESI) calcd. for C33H37N9O2: 591.31 m/z, found: 592.40 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
A solution of tert-butyl 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidine-1-carboxylate (260 mg, 0.439 mmol) in 4N HCl in 1,4-dioxane (10 mL) was stirred at room temperature for 1 h. The solvent was removed by distillation under vacuum to afford 3-{3-[(1S)-1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine HCl (220 mg) as a yellow solid, which was used directly in the next step without further purification. MS (ESI) calcd. for C28H29N9: 491.25 m/z, found: 492.25 [M+H]+.
Step 3: Synthesis of (2E)-1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Example 34)
To a solution of 3-{3-[(1S)-1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (100 mg, 0.203 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (78.87 mg, 0.609 mmol), PyBOP (105.86 mg, 0.203 mmol), (2E)-4-(dimethylamino)but-2-enoic acid (39.4 mg, 0.304 mmol). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford (2E)-1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (80 mg) as a yellow solid. The product was then further purified by Prep-HPLC on a XSelect CSH Prep C18 OBD Column using a gradient of acetonitrile in water (+0.05% TFA) to afford (2E)-1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one (Example 34, TFA salt) (51.7 mg, 41.91% yield) as a light yellow solid. MS (ESI) calcd. for C34H38N10O: 602.32 m/z, found: 603.25 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) (ppm): 8.42-8.44 (m, 1H), 8.35-8.36 (m, 1H), 8.05-8.06 (m, 1H), 8.00-8.02 (m, 1H), 7.82-7.83 (m, 1H), 7.69-7.72 (m, 2H), 7.57-7.58 (m, 1H), 7.42-7.44 (m, 1H), 6.94-6.97 (m, 1H), 6.72-6.75 (m, 1H), 6.55-6.63 (m, 2H), 4.97-4.99 (m, 1H), 4.51-3.58 (m, 1H), 4.13-4.17 (m, 1H), 3.86-3.88 (m, 2H), 3.55-3.61 (m, 1H), 3.18-3.21 (m, 2H), 2.95-2.99 (m, 1H), 2.73-2.77 (m, 7H), 2.56-2.61 (m, 1H), 2.12-2.27 (m, 3H), 1.49-1.56 (m, 2H).
Example 35: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(2-fluoroacrylamido)-1-methyl-1H-pyrazole-5-carboxamide




Synthetic Route:





Step 1: Synthesis of 4-amino-1-methyl-1H-pyrazole-5-carboxylic acid
Methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate (300 mg, 1.93 mmol) was dissolved in THE (8 mL). A solution of LiOH (185.2 mg, 7.736 mmol) in H2O (2 mL) was added and the mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 4-amino-1-methyl-1H-pyrazole-5-carboxylic acid (300 mg, crude) as a white solid. MS (ESI) calcd. for C5H7N3O2, 141.05 m/z, found 142.05 [M+H]+.
Step 2: Synthesis of (S)-4-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-5-carboxamide
To a solution of 4-amino-1-methyl-1H-pyrazole-5-carboxylic acid (300 mg, 2.13 mmol) and (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (200 mg, 0.490 mmol) in DMF (5 mL) were added PyBOP (306 mg, 0.588 mmol) and N,N-diisopropylethylamine (190 mg, 1.47 mmol). The mixture was stirred at room temperature for 3 h. The reaction mixture was quenched with water (80 mL). The resulting mixture was extracted with ethyl acetate (3×80 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of dichloromethane in methanol to afford (S)-4-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (180 mg, 69% yield) as a yellow oil. MS (ESI) calcd. for C28H25N11O, 531.22 m/z, found 532.20. [M+H]+.
Step 3: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(2-fluoroacrylamido)-1-methyl-1H-pyrazole-5-carboxamide (Example 35)
To a solution of (S)-4-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1-methyl-1H-pyrazole-5-carboxamide (120 mg, 0.226 mmol) and 2-fluoroacrylic acid (40.7 mg, 0.452 mmol) in DCM (3 mL) was added 4-(dimethylamino)-1-trifluoromethanesulfonylpyridin-1-ium triflate (119 mg, 0.294 mmol) and DMAP (41.4 mg, 0.339 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (80 mL). The resulting mixture was extracted with ethyl acetate (3×80 mL). The organic phases were combined, dried by Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of methanol in dichloromethane to afford the crude product as a yellow solid. The crude product was purified by Prep-HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+0.5% TFA) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(2-fluoroacrylamido)-1-methyl-1H-pyrazole-5-carboxamide (Example 35, TFA salt) (17.0 mg, 10% yield) as a white solid. MS (ESI) calcd. for C31H26FN11O2, 603.23 m/z, found 604.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31-8.40 (m, 2H), 7.90-8.04 (m, 2H), 7.80 (s, 1H), 7.63 (s, 1H), 7.41-7.49 (m, 1H), 7.37 (s, 1H), 7.21-7.32 (m, 2H), 6.52-7.61 (m, 1H), 6.40-6.48 (m, 1H), 5.53-5.76 (m, 2H), 5.20-5.40 (m, 1H), 3.97 (s, 3H), 2.83-3.03 (m, 2H), 2.56-2.63 (m, 1H), 1.93-2.04 (m, 1H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −118.21.
Example 36: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(2-fluoroacrylamido)-1-methyl-1H-pyrazole-3-carboxamide




Example 36 was prepared in a manner analogous to Example 35 using methyl 4-amino-1-methyl-1H-pyrazole-3-carboxylate in place of 4-amino-1-methyl-1H-pyrazole-5-carboxylate, and for the final step: N,N-dimethylformamide in place of dichloromethane, PyBOP in place of Tf-DMAP and N,N-diisopropylethylamine in place of 4-dimethylaminopyridine. MS (ESI) calcd. for C31H26FN11O2, 603.23 m/z, found 604.10 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.46-8.36 (m, 2H), 8.29-8.31 (m, 1H), 8.02-8.06 (m, 1H), 7.99-8.01 (m, 1H), 7.81-7.83 (m, 1H), 7.71-7.73 (m, 1H), 7.44 (s, 1H), 7.28-7.39 (m, 2H), 6.71-6.84 (m, 1H), 6.51-6.56 (m, 1H), 5.71-5.79 (m, 1H), 5.57-5.70 (m, 1H), 5.31-5.51 (m, 1H), 3.92 (s, 3H), 3.00-3.11 (m, 1H), 2.81-2.99 (m, 1H), 2.39-2.42 (m, 1H), 2.19-2.23 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −121.08. (TFA salt).
Example 37: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(cyclopent-1-ene-1-carboxamido)benzamide




Synthetic Route:





Step 1: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(cyclopent-1-ene-1-carboxamido)benzamide (Example 37)
To a stirred solution of 2-amino-N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]benzamide (Intermediate 5-1) (100 mg, 0.190 mmol) in pyridine (1 mL) was added cyclopent-1-ene-1-carboxylic acid (31.9 mg, 0.284 mmol) and EDCI (43.6 mg, 0.227 mmol). The resulting mixture was stirred at 70° C. for 1 h. The crude reaction mixture was purified by Prep-HPLC on a XSelect CSH Prep C18 OBD Column using a gradient of acetonitrile in water (+0.05% TFA) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(cyclopent-1-ene-1-carboxamido)benzamide (TFA salt) (56.6 mg, 48% yield) as a yellow solid. MS (ESI) calcd. for C36H31N9O2, 621.26 m/z, found 622.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.44-8.52 (m, 1H), 8.38-8.40 (m, 1H), 8.37-8.38 (m, 1H), 8.07-8.08 (m, 1H), 8.01-8.03 (m, 1H), 7.85-7.87 (m, 2H), 7.83-7.84 (m, 1H), 7.75-7.77 (m, 1H), 7.51-7.56 (m, 2H), 7.34-7.47 (m, 1H), 7.14-7.18 (m, 1H), 6.81-6.82 (m, 1H), 6.79-6.80 (m, 1H), 6.68-6.78 (m, 1H), 5.56-5.57 (m, 1H), 3.52-3.53 (m, 2H), 2.92-3.10 (m, 2H), 2.60-2.64 (m, 3H), 2.13-2.16 (m, 1H), 1.97-1.98 (m, 2H).
Example 38: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(2-chloroacrylamido)benzamide




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(2-chloroacrylamido)benzamide (Example 38)
A solution of 2-chloroacrylic acid (300 mg, 2.82 mmol) in DCM (5 mL) was treated with (COCl)2 (286 mg, 2.25 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction mixture was added to a solution of (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide (Intermediate 5-1) (100 mg, 0.190 mmol) and pyridine (30.0 mg, 0.380 mmol) in DCM (1 ml). The mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of dichloromethane in methanol then by Prep-HPLC on a XBridge Prep Shield RP OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate) to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(2-chloroacrylamido)benzamide (Example 38) (27.2 mg, 23% yield) as a white solid. MS (ESI) calcd. for C33H26ClN9O2, 615.19 m/z, found 616.10 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.46-8.54 (m, 1H), 8.31-8.42 (m, 2H), 7.78-8.02 (m, 4H), 7.53-7.61 (m, 1H), 7.38-7.46 (m, 2H), 7.22-7.34 (m, 3H), 6.41-6.66 (m, 3H), 6.09-6.17 (m, 1H), 5.60-5.71 (m, 1H), 2.90-3.14 (m, 2H), 2.53-2.62 (m, 1H), 2.04-2.19 (m, 1H).
Example 39: N-[2-({[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}methyl)phenyl]prop-2-enamide




Example 39 was prepared in a manner analogous to Example 13 using Intermediate 39-1 in place of the ketone and a reaction temperature of room temperature instead of 40° C. MS (ESI) calcd. for C33H29N9O: 567.25 m/z, found: 568.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.40-8.43 (m, 1H), 8.36-8.39 (m, 1H), 8.01-8.09 (m, 2H), 7.82-7.86 (m, 1H), 7.71-7.78 (m, 1H), 7.60-7.66 (m, 2H), 7.55-7.59 (m, 1H), 7.44-7.49 (m, 1H), 7.36-7.42 (m, 3H), 6.69-6.74 (m, 1H), 6.53-6.57 (m, 1H), 6.41-6.50 (m, 1H), 6.25-6.31 (m, 1H), 5.77-5.82 (m, 1H), 4.88-4.93 (m, 1H), 4.10-4.20 (m, 2H), 3.12-3.22 (m, 1H), 2.92-3.01 (m, 1H), 2.51-2.65 (m, 1H), 2.30-2.39 (m, 1H). (TFA salt)
Intermediate 39-1: N-(2-formylphenyl)acrylamide




Intermediate 39-1 was prepared in a manner analogous to Intermediate 14-1 (step 2 only) using 2-aminobenzaldehyde in place of the ketone. MS (ESI) calcd. for C10H9NO2: 175.06 m/z, found: 176.00 [M+H]+.
Example 40: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1-(prop-2-enoyl)-3,4-dihydro-2H-quinoline-8-carboxamide




Example 40 was prepared in a manner analogous to Example 3 (steps 2 and 3 only) using 1,2,3,4-tetrahydroquinoline-8-carboxylic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid and sodium bicarbonate in place of triethylamine. MS (ESI) calcd. for C36H31N9O2: 621.26 m/z, found: 622.25 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.42 (m, 211), 7.98-8.03 (m, 2H), 7.78-7.80 (m, 2H), 7.41-7.78 (m, 3H), 7.27-7.40 (m, 2H), 6.78-6.82 (m, 1H), 6.54-6.55 (m, 1H), 6.08-6.17 (m, 2H), 5.28-5.75 (m 2H), 4.25-4.32 (m, 1H), 3.17-3.25 (m, 1H), 2.74-3.00 (m, 3H), 2.33-2.46 (m, 3H), 1.55-2.17 (m, 3H). (TFA salt).
Example 41: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-3-(prop-2-enamido)pyridine-4-carboxamide




Example 41 was prepared in a manner analogous to Example 3 (steps 2 and 3 only) using 3-aminoisonicotinic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid and acetonitrile in place of dichloromethane. The final product reaction mixture was purified directly by reverse phase column chromatography first on C18 silica gel then on an XSelect CSH Prep C18 OBD Column using a gradient of acetonitrile in water (+0.05% formic acid) to afford Example 41 as the formic acid salt. MS (ESI) calcd. for C32H26N10O2: 582.22 m/z, found 605.10 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.93-8.94 (m, 111), 8.58-8.60 (m, 111), 8.37-8.40 (m, 3H), 8.35-8.36 (m, 1H), 7.97-8.01 (m, 1H), 7.95-7.96 (m, 1H), 7.81-7.82 (m, 1H), 7.40-7.48 (m, 1H), 7.40-7.41 (m, 1H), 7.29-7.30 (m, 2H), 6.57-6.58 (m, 1H), 6.42-6.48 (m, 2H), 6.35-6.36 (m, 1H), 5.92-5.95 (m, 1H), 5.61-5.70 (m, 1H), 3.00-3.10 (m, 1H), 2.88-2.90 (m, 1H), 2.53-2.55 (m, 1H), 2.00-2.10 (m, 1H).
Example 42: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(3-methylene-2-oxopyrrolidin-1-yl)benzamide




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-bromobenzamide
To a suspension of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (203. mg, 0.497 mmol) in DMF (4 mL) was added 2-bromobenzoic acid (100 mg, 0.497 mmol), PyBOP (259 mg, 0.497 mmol) and N,N-diisopropylethylamine (193 mg, 1.49 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was purified directly by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-bromobenzamide (200 mg, 68% yield) as a light yellow solid. MS (ESI) calcd. for C30H23BrN8O, 590.12 m/z, found 591.15 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(3-methylidene-2-oxopyrrolidin-1-yl)benzamide (Example 42
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-bromobenzamide (200.98 mg, 0.340 mmol) in DMSO (4 mL) was added 3-methylidenepyrrolidin-2-one (66 mg, 0.68 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (4.83 mg, 0.034 mmol), CuI (12.9 mg, 0.068 mmol) and K2CO3 (117 mg, 0.850 mmol). The reaction mixture was stirred at 100° C. for 1 h under a nitrogen atmosphere. The mixture was purified directly by Prep-HPLC on YMC Triart C18 ExRs column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(3-methylidene-2-oxopyrrolidin-1-yl)benzamide (19.5 mg, 9% yield) as a light yellow solid. MS (ESI) calcd. for C35H29N9O2, 607.24, m/z, found 608.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.39-8.43 (m, 2H), 8.00-8.03 (m, 2H), 7.73-7.84 (m, 2H), 7.58-7.62 (m, 2H), 7.37-7.52 (m, 4H), 7.19-7.30 (m, 1H), 6.81-6.85 (m, 1H), 6.52-6.59 (m, 1H), 5.84-5.85 (m, 1H), 5.43-5.46 (m, 2H), 3.83-3.89 (m, 2H), 2.99-3.06 (m, 3H), 2.87-2.90 (m, 1H), 2.49-2.50 (m, 1H), 1.99-2.05 (m, 1H).
Example 43: (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)benzamide




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)-2-nitrobenzamide
A solution of 4-(difluoromethyl)-2-nitrobenzoic acid (150 mg, 0.691 mmol) in DCM (2 mL) was treated with (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (339 mg, 0.829 mmol), 4-(dimethylamino)-1-trifluoromethanesulfonylpyridin-1-ium triflate (334 mg, 0.829 mmol) and DMAP (101 mg, 0.829 mmol). The resulting mixture was stirred for 2 h at room temperature. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL) then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol in dichloromethane to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)-2-nitrobenzamide (200 mg, 48% yield) as an off-white solid. MS (ESI) calcd. for C31H23F2N9O3, 607.19 m/z, found 608.10 [M+H]+.
Step 2: Synthesis of (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)benzamide
A solution of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)-2-nitrobenzamide (120 mg, 0.198 mmol) in MeOH (50 mL) was treated with Pd/C (180 mg, 1.69 mmol) at room temperature. The resulting mixture was stirred for 24 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of dichloromethane in methanol to afford (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)benzamide (70 mg, 61% yield) as an off-white solid. MS (ESI) calcd. for C31H25F2N9O, 577.22 m/z, found 578.30 [M+H]+.
Step 3: Synthesis of (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)benzamide (Example 43)
A solution of (S)-2-amino-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)benzamide (20 mg, 0.035 mmol) and triethylamine (10.5 mg, 0.105 mmol) in DCM (1 ml) was treated with acryloyl chloride (3.1 mg, 0.035 mmol) and the mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL), extracted with ethyl acetate (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (0.1% TFA) to afford (S)-2-acrylamido-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-4-(difluoromethyl)benzamide (Example 43, TFA salt) (3.6 mg, 14% yield) as a yellow solid. MS (ESI) calcd. for C34H27F2N9O2, 631.23 m/z, found 632.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.51-8.60 (m, 1H), 8.37-8.48 (m, 2H), 7.99-8.14 (m, 2H), 7.91-7.98 (m, 1H), 7.82-7.90 (m, 1H), 7.77-7.81 (m, 1H), 7.38-7.54 (m, 2H), 7.19-7.27 (m, 1H), 7.01-7.12 (m, 1H), 6.89-6.98 (m, 1H), 6.76-6.85 (m, 1H), 6.56-6.62 (m, 1H), 6.37-6.48 (m, 1H), 6.26-6.33 (m, 1H), 5.85-5.93 (m, 1H), 5.66-5.75 (m, 1H), 2.87-3.15 (m, 2H), 2.47-2.52 (m, 1H), 2.02-2.23 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −111.15.
Example 44: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-3-fluoro-2-(prop-2-enamido)benzamide




Example 44 was prepared in a manner analogous to Example 3 (steps 2 and 3 only) using 2-amino-3-fluorobenzoic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid, potassium carbonate in place of triethylamine and acetonitrile in place of dichloromethane. MS (ESI) calcd. for C33H26FN9O2, 599.30, m/z, found 600.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.39-8.44 (m, 2H), 8.01-8.03 (m, 2H), 7.68-7.84 (m, 2H), 7.38-7.50 (m, 5H), 7.25-7.31 (m, 1H), 6.81-6.90 (m, 1H), 6.58-6.62 (m, 1H), 6.49-6.54 (m, 1H), 6.16-6.27 (m, 1H), 5.76-5.79 (m, 1H), 5.43-5.53 (m, 1H), 2.99-3.06 (m, 1H), 2.73-2.94 (m, 1H), 2.49-2.50 (m, 1H), 1.99-2.05 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −119.9. (TFA salt)
Example 45: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-[(1E)-2-carbamoyleth-1-en-1-yl]pyridine-3-carboxamide




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-bromopyridine-3-carboxamide
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (300 mg, 0.734 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (474.63 mg, 3.670 mmol), PyBOP (458.65 mg, 0.881 mmol) and 2-bromopyridine-3-carboxylic acid (178 mg, 0.881 mmol). The resulting mixture was stirred at room temperature for 1 h then purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-bromopyridine-3-carboxamide (500 mg, 90% yield) as a yellow solid. MS (ESI) calcd. for C29H22BrN9O: 591.11 m/z, found: 592.10 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-[(1E)-2-carbamoyleth-1-en-1-yl]pyridine-3-carboxamide (Example 45)
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-bromopyridine-3-carboxamide (200 mg, 0.338 mmol) and polyacrylamide (240 mg, 3.38 mmol) in 1,4-dioxane (10 mL) were added Pd2(dba)3 (61.8 mg, 0.068 mmol), RuPhos (31.5 mg, 0.068 mmol) and Na2CO3 (178.9 mg, 1.690 mmol). The resulting mixture was stirred at 100° C. for 6 h under N2 atmosphere. The resulting mixture was diluted with water (10 mL), extracted with ethyl acetate (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was then purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.05% TFA) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-[(1E)-2-carbamoyleth-1-en-1-yl]pyridine-3-carboxamide (Example 45) (14.5 mg, 7% yield) as a yellow solid. MS (ESI) calcd. for C32H26N10O2: 582.22 m/z, found: 583.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.68-8.70 (m, 111), 8.39-8.45 (m, 2H), 8.01-8.04 (m, 2H), 7.90-7.92 (m, 1H), 7.80-7.83 (m, 1H), 7.76-7.79 (m, 2H), 7.51-7.59 (m, 1H), 7.48-7.50 (m, 1H), 7.45 (s, 1H), 7.36-7.42 (m, 1H), 7.16-7.19 (m, 1H), 6.80-6.82 (m, 1H), 6.57-6.59 (m, 1H), 5.61-5.62 (m, 1H), 3.03-3.09 (m, 1H), 2.92-2.98 (m, 1H), 2.46-2.56 (m, 1H), 2.02-2.07 (m, 1H). (TFA salt)
Example 46: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-2-fluoroprop-2-en-1-one




Example 46 was prepared in a manner analogous to Example 13 using Intermediate 46-1 in place of 1-(prop-2-enoyl)piperidin-4-one. MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.41-8.43 (m, 1H), 8.35-8.36 (m, 1H), 7.99-8.04 (m, 2H), 7.81-7.82 (m, 1H), 7.69-7.73 (m, 2H), 7.55-7.56 (m, 1H), 7.41-7.43 (m, 1H), 6.73-6.77 (m, 1H), 6.57-6.58 (m, 1H), 5.11-5.34 (m, 2H), 4.96-4.99 (m, 1H), 4.35-4.39 (m, 1H), 3.97-4.05 (m, 1H), 3.58-3.60 (m, 1H), 3.14-3.27 (m, 2H), 2.82-2.98 (m, 2H), 2.56-2.59 (m, 1H), 2.13-2.28 (m, 3H), 2.52-2.59 (m, 2H). 19F NMR (400 MHz, DMSO-d6) δ (ppm): −105.08. (TFA salt).
Intermediate 46-1: 1-(2-fluoroacryloyl)piperidin-4-one




Synthetic Route:





Step 1: Synthesis of 1-(2-fluoroprop-2-enoyl)piperidin-4-one (Intermediate 46-1
To a solution of piperidin-4-one hydrochloride (200 mg, 2.02 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (782.3 mg, 6.051 mmol), PyBOP (1049.9 mg, 2.017 mmol) and 2-fluoroprop-2-enoic acid (181.7 mg, 2.017 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford 1-(2-fluoroprop-2-enoyl)piperidin-4-one (Intermediate 46-1) (200 mg, 57.91% yield) as a yellow oil. MS (ESI) calcd. for C8H10FNO2: 171.07 m/z, found 172.20 [M+H]+.
Example 47: N-((1*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)cyclohexyl)acrylamide and
Example 48: N-((1*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)cyclohexyl)acrylamide




Examples 47 and 48 were prepared in a manner analogous to Example 13 using Intermediate 47-1 in place of the ketone. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 47: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16-8.49 (m, 2H), 7.97-8.12 (m, 1H), 7.89-7.97 (m, 1H), 7.69-7.89 (m, 1H), 7.39-7.61 (m, 1H), 7.31-7.39 (m, 1H), 7.08-7.31 (m, 2H), 6.51-6.68 (m, 1H), 6.39-6.51 (m, 1H), 6.27-6.39 (m, 1H), 5.94-6.27 (m, 1H), 5.48-5.76 (m, 1H), 4.18-4.42 (m, 1H), 3.81-3.85 (m, 2H), 2.95-3.06 (m, 1H), 2.72-2.95 (m, 2H), 2.36-2.49 (m, 1H), 1.51-1.85 (m, 8H).
Example 48: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.41 (m, 2H), 7.97-8.09 (m, 1H), 7.91-7.97 (m, 1H), 7.69-7.89 (m, 1H), 7.41-7.63 (m, 1H), 7.28-7.41 (m, 1H), 7.11-7.28 (m, 2H), 6.51-6.68 (m, 1H), 6.32-6.51 (m, 1H), 6.14-6.32 (m, 1H), 5.94-6.14 (m, 1H), 5.48-5.69 (m, 1H), 4.18-4.42 (m, 1H), 3.39-3.68 (m, 1H), 2.85-3.12 (m, 1H), 2.68-2.85 (m, 1H), 2.55-2.66 (m, 1H), 2.39-2.50 (m, 1H), 1.99-2.15 (m, 1H), 1.88-1.99 (m, 1H), 1.74-1.88 (m, 3H), 1.32-1.05 (m, 4H).
Intermediate 47-1: N-(4-oxocyclohexyl)acrylamide




Intermediate 47-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl (4-oxocyclohexyl)carbamate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C9H13NO2, 167.20 m/z, found 168.15 [M+H]+.
Example 49: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 49 was prepared in a manner analogous to Example 13 using Intermediate 49-1 in place of Intermediate 1-1, 1,2-dichloroethane/methanol (1:1) in place of 1,2-dichloroethane and a reaction time and temperature of 2 h at 50° C. instead of 40° C. overnight. MS (ESI) calcd. for C31H30FN9O, 563.26 m/z, found 564.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.38-8.52 (m, 1H), 8.22-8.33 (m, 1H), 8.01-8.12 (m, 1H), 7.78-7.88 (m, 1H), 7.62-7.77 (m, 2H), 7.51-7.61 (m, 1H), 7.36-7.47 (m, 1H), 6.66-6.92 (m, 2H), 6.28-6.45 (m, 1H), 6.05-6.20 (m, 1H), 5.61-5.78 (m, 1H), 4.88-5.07 (m, 1H), 4.53 (s, 1H), 4.19 (s, 1H), 3.06-3.25 (m, 2H), 2.85-3.04 (m, 1H), 2.63-2.80 (m, 1H), 2.53-2.62 (m, 1H), 2.42-2.48 (m, 1H), 2.15-2.28 (m, 2H), 2.02-2.14 (m, 1H), 1.38-1.65 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −126.86. (TFA salt).
Intermediate 49-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 49-1 was prepared in a manner analogous to Intermediate 1-1 using 3-fluoro-1H-pyrazole in place of pyrazole. MS (ESI) calculated for C23H19FN8: 426.17 m/z, found 427.10 [M+H]+.
Example 50: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-methyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 50 was prepared in a manner analogous to Example 13 using Intermediate 50-1 in place of Intermediate 1-1, 1,2-dichloroethane/methanol (10:1) in place of 1,2-dichloroethane and a reaction time and temperature of 8 h at room temperature instead of 40° C. overnight. MS (ESI) calcd. for C29H31N7O: 493.26 m/z, found: 494.05 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29 (s, 1H), 8.03-8.09 (m, 1H), 7.95-7.98 (m, 1H), 7.52-7.58 (m, 1H), 7.22-7.33 (m, 1H), 7.15-7.21 (m, 3H), 6.75-6.85 (m, 1H), 6.48-6.53 (m, 1H), 6.05-6.15 (m, 1H), 5.65-5.73 (m, 1H), 4.31-4.59 (m, 2H), 4.00-4.10 (m, 1H), 3.08-3.17 (m, 2H), 2.95-3.02 (m, 1H), 2.73-2.86 (m, 2H), 2.45-2.51 (m, 4H), 1.85-2.11 (m, 3H), 1.23-1.40 (m, 2H). (formic acid salt).
Intermediate 50-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-methyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[(6-methyl-3-nitropyridin-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide (600 mg, 2.36 mmol, 1 equiv), 6-methyl-3-nitropyridin-2-amine (434 mg, 2.8 mmol, 1.2 equiv) and XantPhos (273 mg, 0.47 mmol, 0.2 equiv) in 1,4-dioxane (10 mL) were added cesium carbonate (2.3 g 7.1 mmol, 3 equiv) and Pd(OAc)2 (53 mg, 0.24 mmol, 0.1 equiv). The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting residue was purified by reverse-phase flash chromatography on C18 silica gel using a 10 to 50% gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford N-[(1S)-5-[(6-methyl-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (200 mg, 26%) as a brown solid. MS (ESI) calculated for C17H18N4O3: 326.14 m/z, found 327.05 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-methylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-[(6-methyl-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]formamide (190 mg, 0.61 mmol, 1 equiv) in DMSO (5 mL) and methanol (1 mL) were added 2-aminopyridine-3-carbaldehyde (78 mg, 0.64 mmol, 1.1 equiv) and sodium dithionite (223 mg, 1.3 mmol, 2.2 equiv). The resulting mixture was stirred overnight at 100° C. under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue purified by reverse-phase flash chromatography on C18 silica gel using a 10 to 50% gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-methylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (135 mg, 46%) as a yellow solid. MS (ESI) calculated for C23H22N6O: 398.19 m/z, found 399.25 [M+H]+.
Step 3: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-methylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 50-1
N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-methylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (135 mg, 0.34 mmol, 1 equiv) was dissolved methanol (10 mL). HCl (10 mL, concentrated) was added, and the resulting mixture was stirred at 90° C. overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-methylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 50-1) (100 mg, 75%) as a yellow solid. MS (ESI) calculated for C21H20N6: 356.17 m/z, found 357.15 [M+H]+.
Example 51: 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidine-1-carbonitrile




Example 51 was prepared in a manner analogous to Example 13 using 1,2-dichloroethane/methanol (5:1) in place of 1,2-dichloroethane. MS (ESI) calcd. for C29H28N10: 516.25 m/z, found: 517.25 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.39-8.48 (m, 1H), 8.32-8.39 (m, 1H), 7.99-8.15 (m, 2H), 7.78-7.85 (m, 2H), 7.68-7.76 (m, 1H), 7.55-7.61 (m, 1H), 7.40-7.48 (m, 1H), 6.76-6.85 (m, 1H), 6.53-6.60 (m, 1H), 4.94-5.05 (m, 1H), 3.40-3.59 (m, 3H), 3.10-3.22 (m, 3H), 2.91-3.05 (m, 1H), 2.55-2.62 (m, 1H), 2.16-2.28 (m, 2H), 2.05-2.15 (m, 1H), 1.68-1.85 (m, 2H). (TFA salt).
Example 52: (S)-N-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)-N-methylacrylamide




Synthetic Route:





Step 1: Synthesis of tert-butyl (S)-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)(methyl)carbamate
A solution of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (150 mg, 0.367 mmol), N-(tert-butoxycarbonyl)-N-methylglycine (83.4 mg, 0.440 mmol), TCFH (103 mg, 0.367 mmol) and NMI (120.6 mg, 1.468 mmol) in acetonitrile (3 mL) was stirred for 1 h at room temperature. The crude product was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford tert-butyl (S)-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)(methyl)carbamate (160 mg, 70% yield) as a yellow solid. MS (ESI) calcd. for C31H33N9O3, 579.27 m/z, found 580.25 [M+H]+.
Step 2: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(methylamino)acetamide
A solution of tert-butyl (S)-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)(methyl)carbamate (150 mg, 0.259 mmol) in TFA (1.5 mL) and DCM (7.5 mL) was stirred for 1 h at room temperature. The reaction mixture was concentrated to afford (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(methylamino)acetamide (120 mg, 85% yield) as a yellow solid. MS (ESI) calcd. for C26H25N9O, 479.22 m/z, found 480.25 [M+H]+.
Step 3: Synthesis of (S)-N-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)-N-methylacrylamide (Example 52
To a stirred solution of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(methylamino)acetamide (100 mg, 0.209 mmol) and triethylamine (42.2 mg, 0.418 mmol) in DCM (10 mL) was added acryloyl chloride (18.9 mg, 0.209 mmol) dropwise at 0° C. The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with H2O (100 mL). The resulting mixture was extracted with DCM (3×200 mL). The combined organic layers were washed with H2O (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was then purified by Prep-HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford (S)-N-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-oxoethyl)-N-methylacrylamide (Example 52) (35.14 mg, 31% yield) as a light yellow solid. MS (ESI) calcd. for C29H27N9O2, 533.23 m/z, found 534.25 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.26-8.42 (m, 2H), 7.99-8.08 (m, 1H), 7.88-7.98 (m, 1H), 7.81 (s, 1H), 7.18-7.42 (m, 4H), 6.60-6.89 (m, 1H), 6.49-6.59 (m, 1H), 6.38-6.48 (m, 1H), 6.03-6.25 (m, 1H), 5.55-5.78 (m, 1H), 5.28-5.43 (m, 1H), 3.98-4.23 (m, 2H), 3.13 (s, 2H), 2.78-3.03 (m, 3H), 2.35-2.48 (m, 1H), 1.88-2.01 (m, 1H).
Example 53: 1-((*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-1,4-oxazepan-4-yl)prop-2-en-1-one and Example 54: 1-((*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-1,4-oxazepan-4-yl)prop-2-en-1-one




Examples 53 and 54 were prepared in a manner analogous to Example 13 using Intermediate 53-1 in place of the ketone. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep HPLC on CHIRALPAKID-3 column using a mixture of ethanol and [3:1 Hexanes/dichloromethane+0.1% diethylamine].
Example 53: MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.38 (m, 2H), 8.01-8.02 (m, 1H), 7.94-8.00 (m, 1H), 7.81 (s, 1H), 7.48-7.50 (m, 1H), 7.33-7.35 (m, 1H), 7.21-7.21 (m, 2H), 6.96-6.97 (m, 2H), 6.77-6.88 (m, 1H), 6.54-6.56 (m, 1H), 6.40-6.43 (m, 1H), 6.14-6.19 (m, 1H), 5.69-5.71 (m, 1H), 4.30-4.32 (m, 1H), 4.12-4.16 (m, 1H), 3.85-3.95 (m, 2H), 3.53-3.74 (m, 6H), 3.05-3.12 (m, 1H), 2.95-3.00 (m, 1H), 2.78-2.82 (m, 1H), 2.45-2.50 (m, 1H), 1.78-1.82 (m, 1H).
Example 54: MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.36-8.38 (m, 2H), 7.94-8.01 (m, 2H), 7.81 (s, 1H), 7.45-7.48 (m, 1H), 7.34-7.36 (m, 1H), 7.22-7.28 (m, 2H), 6.79-6.97 (m, 3H), 6.54-6.56 (m, 1H), 6.42-6.45 (m, 1H), 6.15-6.20 (m, 1H), 5.69-5.72 (m, 1H), 4.37-4.40 (m, 1H), 3.88-3.98 (m, 1H), 3.65-3.77 (m, 6H), 3.53-3.56 (m, 2H), 3.06-3.07 (m, 1H), 2.95-3.00 (m, 1H), 2.75-2.81 (m, 1H), 2.45-2.50 (m, 1H), 1.76-1.79 (m, 1H).
Intermediate 53-1: 4-acryloyl-1,4-oxazepan-6-one




Intermediate 53-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and 4N HCl in dioxane in place of TFA/dichloromethane. MS (ESI) calcd. for C8H11NO3: 169.07 m/z, found: 170.15 [M+H]+.
Example 55: 1-((*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one and Example 56: 1-((*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,3-difluoropiperidin-1-yl)prop-2-en-1-one




Examples 55 and 56 were prepared in a manner analogous to Example 13 using Intermediate 55-1 in place of the ketone, 1,2-dichloroethane/AcOH (100:1) in place of 1,2-dichloroethane and a reaction time and temperature of room temperature and 8 h instead of 40° C. overnight. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep HPLC on CHIRALPAK IC column using mixture of MTBE in 1:1 ethanol/dichloromethane.
Example 55: MS (ESI) calcd. for C31H29F2N9O: 581.25 m/z, found: 582.05 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31-8.38 (m, 2H), 7.99-8.04 (m, 1H), 7.94-7.96 (m, 1H), 7.82-7.86 (m, 1H), 7.51-7.58 (m, 1H), 7.32-7.40 (m, 1H), 7.20-7.29 (m, 2H), 6.95 (s, 2H), 6.82-6.92 (m, 1H), 6.52-6.56 (m, 1H), 6.41-6.47 (m, 1H), 6.10-6.19 (m, 1H), 5.68-5.76 (m, 1H), 4.19-4.31 (m, 2H), 3.89-4.11 (m, 1H), 3.60-3.75 (m, 1H), 3.45-3.56 (m, 1H), 3.12-3.21 (m, 1H), 2.89-2.99 (m, 1H), 2.71-2.82 (m, 1H), 2.34-2.42 (m, 1H), 2.23-2.30 (m, 1H), 1.89-2.01 (m, 1H), 1.73-1.85 (m, 1H), 1.49-1.69 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −107.95, −117.76.
Example 56: MS (ESI) calcd. for C31H29F2N9O: 581.25 m/z, found: 582.05 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31-8.38 (m, 2H), 7.99-8.04 (m, 1H), 7.94-7.96 (m, 1H), 7.82-7.86 (m, 1H), 7.51-7.58 (m, 1H), 7.32-7.34 (m, 1H), 7.20-7.29 (m, 2H), 6.95 (s, 2H), 6.82-6.92 (m, 1H), 6.52-6.56 (m, 1H), 6.41-6.47 (m, 1H), 6.10-6.19 (m, 1H), 5.68-5.76 (m, 1H), 4.31-4.41 (m, 1H), 4.19-4.30 (m, 1H), 3.82-3.99 (m, 1H), 3.50-3.76 (m, 1H), 3.41-3.49 (m, 1H), 3.19-3.25 (m, 1H), 2.89-2.97 (m, 1H), 2.72-2.82 (m, 1H), 2.41-2.50 (m, 1H), 2.37-2.42 (m, 1H), 1.78-1.95 (m, 2H), 1.45-1.67 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −107.74, −117.03.
Intermediate 55-1: 1-acryloyl-3,3-difluoropiperidin-4-one




Intermediate 55-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and 4N HCl in dioxane in place of TFA/dichloromethane. MS (ESI) calcd. for C8H9F2NO2: 189.06 m/z, found: 190.10 [M+H]+.
Example 57: 1-((*)-3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one and Example 58: 1-((*)-3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one




Examples 57 and 58 were prepared in a manner analogous to Example 13 using 1-acryloylpyrrolidin-3-one in place of the ketone and 1,2-dichloroethane/methanol (10:1) in place of 1,2-dichloroethane. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep HPLC on a CHIRAL Cellulose SB column using a mix of tetrahydrofuran and [hexanes+0.1% diethylamine].
Example 57: MS (ESI) calcd. for C30H29N9O: 531.25 m/z, found: 532.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30-8.42 (m, 2H), 8.03-8.10 (m, 1H), 7.91-7.99 (m, 1H), 7.78-7.85 (m, 1H), 7.46-7.55 (m, 1H), 7.29-7.35 (m, 1H), 7.19-7.28 (m, 2H), 6.51-6.68 (m, 2H), 6.43-6.50 (m, 1H), 6.13-6.25 (m, 1H), 5.68-5.79 (m, 1H), 4.20-4.31 (m, 1H), 3.80-3.90 (m, 1H), 3.21-3.79 (m, 4H), 2.91-3.05 (m, 1H), 2.73-2.89 (m, 1H), 2.40-2.53 (m, 1H), 2.05-2.20 (m, 1H), 1.70-1.90 (m, 2H).
Example 58: MS (ESI) calcd. for C30H29N9O: 531.25 m/z, found: 532.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.37 (m, 2H), 7.98-8.02 (m, 1H), 7.88-7.97 (m, 1H), 7.75-7.82 (m, 1H), 7.43-7.50 (m, 1H), 7.26-7.32 (m, 1H), 7.18-7.25 (m, 2H), 6.48-6.63 (m, 2H), 6.38-6.47 (m, 1H), 6.08-6.16 (m, 1H), 5.61-5.71 (m, 1H), 4.20-4.29 (m, 1H), 3.48-3.62 (m, 2H), 3.40-3.47 (m, 1H), 3.25-3.39 (m, 1H), 3.13-3.22 (m, 1H), 2.90-3.00 (m, 1H), 2.70-2.81 (m, 1H), 2.35-2.48 (m, 1H), 1.99-2.18 (m, 1H), 1.70-1.91 (m, 2H).
Example 59: 1-((1R,5S,6*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-azabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one and
Example 60: 1-((1R,5S,6*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-azabicyclo[3.1.1]heptan-3-yl)prop-2-en-1-one




Examples 59 and 60 were prepared in a manner analogous to Example 13 using Intermediate 59-1 in place of the ketone and a reaction time and temperature of 1 h at room temperature instead of overnight at 40° C. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 59: MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.28-8.29 (m, 2H), 7.90-7.94 (m, 2H), 7.88-7.89 (m, 1H), 7.41-7.42 (m, 1H), 7.22-7.23 (m, 3H), 6.62-6.69 (m, 1H), 6.50-6.51 (m, 1H), 6.42-6.43 (m, 1H), 6.09-6.13 (m, 1H), 5.66-5.68 (m, 1H), 4.41-4.46 (m, 1H), 4.19-4.20 (m, 1H), 3.67-3.71 (m, 2H), 3.48-3.50 (m, 2H), 3.15-3.16 (m, 1H), 2.89-2.90 (m, 1H), 2.73-2.74 (m, 1H), 2.46-2.51 (m, 1H), 2.30-2.31 (m, 2H), 1.72-1.73 (m, 2H), 1.17-1.19 (m, 1H).
Example 60: MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.33 (m, 2H), 7.95-7.96 (m, 1H), 7.93-7.94 (m, 1H), 7.77-7.78 (m, 1H), 7.53-7.55 (m, 1H), 7.36-7.37 (m, 1H), 7.23-7.24 (m, 2H), 6.66-6.67 (m, 1H), 6.53-6.54 (m, 1H), 6.42-6.45 (m, 1H) 6.13-6.18 (m, 1H), 5.71-5.74 (m, 1H), 4.48-4.49 (m, 1H), 3.98-4.00 (m, 1H), 3.86-3.67 (m, 1H), 3.77-3.79 (m, 1H), 3.48-3.68 (m, 1H), 3.00-3.05 (m, 2H), 2.79-2.83 (m, 1H), 2.63-2.68 (m, 1H), 2.50-2.51 (m, 3H), 1.99-2.08 (m, 1H), 1.30-1.31 (m, 1H).
Intermediate 59-1: 3-acryloyl-3-azabicyclo[3.1.1]heptan-6-one




Intermediate 59-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl 6-oxo-3-azabicyclo[3.1.1]heptane-3-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C9H11NO2: 165.08 m/z, found 166.10 [M+H]+.
Example 61: 3-{3-[(1S)-1-{[1-(ethenesulfonyl)piperidin-4-yl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine




Example 61 was prepared in a manner analogous to Example 13 using Intermediate 61-1 in place of the ketone. MS (ESI) calcd. for C30H31N9O2S: 581.23 m/z, found: 582.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42-8.49 (m, 1H), 8.35-8.41 (m, 1H), 8.01-8.12 (m, 2H), 7.82-7.89 (m, 1H), 7.71-7.80 (m, 2H), 7.58-7.63 (m, 1H), 7.45-7.50 (m, 1H), 6.75-6.85 (m, 2H), 6.58-6.65 (m, 1H), 6.13-6.25 (m, 2H), 4.95-5.05 (m, 1H), 3.65-3.72 (m, 2H), 3.40-3.51 (m, 1H), 3.15-3.25 (m, 1H), 2.95-3.05 (m, 1H), 2.75-2.85 (m, 2H), 2.51-2.65 (m, 1H), 2.15-2.35 (m, 3H), 1.65-1.80 (m, 2H).
Intermediate 61-1: 1-(vinylsulfonyl)piperidin-4-one




Intermediate 61-1 was prepared in a manner analogous to Intermediate 14-1 (starting from step 2) using 4-piperidinone in place of the ketone and ethenesulfonyl chloride in place of acryloyl chloride. MS (ESI) calcd. for C7H11NO3S: 189.05 m/z, found: 190.10 [M+H]+.
Example 62: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 63: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 62 and 63 were prepared in a manner analogous to Example 13 using Intermediate 62-1 in place of the ketone. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 62: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.36 (m, 2H), 8.00-8.01 (m, 1H), 7.98-7.99 (m, 1H), 7.80-7.81 (m, 1H), 7.45-7.47 (m, 1H), 7.23-7.24 (m, 1H), 7.21-7.22 (m, 2H), 6.79-6.82 (m, 1H), 6.54-6.55 (m, 1H), 6.43-6.44 (m, 1H), 6.04-6.08 (m, 1H), 5.64-5.67 (m, 1H), 4.33-4.35 (m, 2H), 3.90-4.10 (m, 1H), 3.30-3.40 (m, 1H), 3.08-3.15 (m, 1H), 2.89-2.98 (m, 1H), 2.72-2.81 (m, 1H), 2.41-2.49 (m, 1H), 2.71-2.81 (m, 4H), 2.58-2.63 (m, 1H), 1.35-1.45 (m, 3H).
Example 63: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.36 (m, 2H), 8.00-8.01 (m, 1H), 7.98-7.99 (m, 1H), 7.80-7.81 (m, 1H), 7.45-7.47 (m, 1H), 7.23-7.24 (m, 1H), 7.21-7.22 (m, 2H), 6.79-6.82 (m, 1H), 6.54-6.55 (m, 1H), 6.43-6.44 (m, 1H), 6.04-6.08 (m, 1H), 5.64-5.67 (m, 1H), 3.90-4.90 (m, 3H), 2.70-3.12 (m, 4H), 2.50-2.51 (m, 1H), 2.04-2.07 (m, 1H), 1.80-1.82 (m, 2H), 1.32-1.42 (m, 1H), 1.10-1.21 (m, 4H).
Intermediate 62-1: (R)-1-acryloyl-2-methylpiperidin-4-one




Intermediate 62-1 was prepared in a manner analogous to Intermediate 14-1 using tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C9H13NO2, 167.09 m/z, found 168.15 [M+H]+.
Example 64: 1-(9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)prop-2-en-1-one (mix of diastereomers




Example 64 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 9-oxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C33H33N9O2: 587.28 m/z, found: 588.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.39 (m, 2H), 8.02-8.04 (m, 1H), 7.95-8.01 (m, 1H), 7.83-7.85 (m, 1H), 7.66-7.80 (m, 1H), 7.41-7.56 (s, 1H), 7.29-7.38 (m, 2H), 6.80-6.89 (m, 1H), 6.51-6.61 (m, 1H), 6.43-6.50 (m, 1H), 6.03-6.09 (m, 1H), 5.64-5.68 (m, 1H), 4.67-4.81 (m, 1H), 4.28-4.46 (m, 1H), 3.56-4.20 (m, 5H), 3.42-3.49 (m, 1H), 3.25-3.40 (m, 1H), 2.92-3.10 (m, 3H), 2.54-2.65 (m, 1H) 1.78-2.29 (m, 3H). (formic acid salt).
Example 65: 1-((2S,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 66: 1-((2S,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 65 and 66 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and using 1,2-dichloroethane/methanol (10:1) for 2 h at 50° C. instead of 1,2-dichloroethane overnight at 40° C. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 65: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.30[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.35 (m, 2H), 8.01-8.02 (m, 1H), 7.93-7.95 (m, 1H), 7.85-7.87 (m, 1H), 7.51-7.53 (m, 1H), 7.07-7.30 (m, 3H), 6.54-6.56 (m, 1H), 6.44-6.47 (m, 1H), 6.30-6.40 (m, 1H), 6.00-6.29 (m, 1H), 5.67-5.69 (m, 1H), 4.00-5.00 (m, 3H), 3.10-3.40 (m, 2H), 3.00-3.02 (m, 1H), 2.94-3.00 (m, 1H), 2.50-2.52 (m, 1H), 2.10-2.20 (m, 1H), 1.80-2.00 (m, 3H), 1.50-1.60 (m, 1H), 1.00-1.30 (m, 4H).
Example 66: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.35 (m, 2H), 7.90-8.10 (m, 2H), 7.85-7.87 (m, 1H), 7.40-7.50 (m, 1H), 7.10-7.30 (m, 3H), 6.70-6.90 (m, 1H), 6.44-6.47 (m, 1H), 6.30-6.40 (m, 1H), 6.00-6.29 (m, 1H), 5.67-5.69 (m, 1H), 4.20-4.50 (m, 2H), 3.80-4.10 (m, 1H), 3.30-3.40 (m, 1H), 3.08-3.20 (m, 1H), 2.90-3.00 (m, 1H), 2.70-2.80 (m, 1H), 2.50-2.52 (m, 1H), 1.80-1.90 (m, 1H), 1.60-1.78 (m, 4H), 1.40-1.50 (m, 3H).
Example 67: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one (Example 67)
To a cooled (0° C.) solution of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 13) (100 mg, 0.183 mmol) in MeOH (5.0 mL) was added HCHO (36.0 mg, 1.20 mmol) and NaBH3CN (34.6 mg, 0.549 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.1% formic acid) to afford (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)amino)piperidin-1-yl)prop-2-en-1-one (Example 67, formic acid salt) as an off-white solid (69.0 mg, 67% yield). MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found: 560.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.37 (m, 2H), 8.14-8.17 (m, 1H), 7.99-8.01 (m, 1H), 7.94-7.99 (m, 1H), 7.81-7.82 (m, 1H), 7.36-7.37 (m, 2H), 7.26-7.26 (m, 1H), 7.16-7.18 (m, 1H), 7.03 (s, 2H), 6.80-6.82 (m, 1H), 6.53-6.54 (m, 1H), 6.36-6.39 (m, 1H), 6.07-6.12 (m, 1H), 5.65-5.69 (m, 1H), 4.60-4.64 (m, 1H), 4.43-4.44 (m, 1H), 4.08-4.10 (m, 1H), 3.09-3.16 (m, 1H), 2.80-2.90 (m, 3H), 2.70-2.80 (m, 1H), 2.09-2.11 (m, 4H), 1.93-1.96 (m, 1H), 1.79-1.82 (m, 1H), 1.36-1.65 (m, 2H). (formic acid salt).
Example 68: 1-[4-({[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one




Example 68 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 4-formylpiperidine-1-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and using 4N HCl in dioxane instead of TFA in dichloromethane. MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.39-8.56 (m, 1H), 8.26-8.39 (m, 1H), 7.98-8.07 (m, 2H), 7.78-7.82 (m, 1H), 7.69-7.75 (m, 2H), 7.50-7.52 (m, 1H), 7.40-7.42 (m, 1H), 6.69-6.82 (m, 2H), 6.64-6.95 (m, 1H), 6.02-6.16 (m, 1H), 5.62-5.75 (m, 1H), 4.85-4.96 (m, 1H), 4.31-4.49 (m, 1H), 4.01-4.12 (m, 1H), 2.85-3.21 (m, 5H), 2.60-2.70 (m, 1H), 2.51-2.60 (m, 1H), 2.16-2.29 (m, 1H), 1.89-2.03 (m, 1H), 1.72-1.89 (m, 2H), 1.06-1.21 (m, 2H). (TFA salt).
Example 69: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)but-2-yn-1-one




Example 69 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from 4-piperidinone (at step 2 of Intermediate 14-1) in place of 3-azabicyclo[3.2.1]octan-8-one and using but-2-ynoyl chloride instead of acryloyl chloride. MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found 558.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42-8.44 (m, 1H), 8.36-8.37 (m, 1H), 8.07-8.09 (m, 1H), 8.00-8.01 (m, 1H), 7.72-7.74 (m, 1H), 7.63-7.65 (m, 1H), 7.59-7.61 (m, 2H), 7.43-7.45 (m, 1H), 6.68-6.69 (m, 1H), 6.58-6.59 (m, 1H), 5.00-5.05 (m, 1H), 4.35-4.44 (m, 2H), 3.22-3.26 (m, 2H), 2.93-3.01 (m, 1H), 2.74-2.80 (m, 1H), 2.60-2.67 (m, 1H), 2.50-2.55 (m, 1H), 2.22-2.29 (m, 3H), 2.00-2.10 (m, 3H), 1.30-1.60 (m, 2H). (TFA salt).
Example 70: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-4-hydroxy-2-(prop-2-enamido)benzamide




Example 70 was prepared in a manner analogous to Example 3 (starting from Step 2) using 2-amino-4-hydroxybenzoic acid in place of 2,3-dihydro-1H-indole-4-carboxylic acid. MS (ESI) calcd. for C33H27N9O3: 597.22 m/z, found: 598.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.41-8.43 (m, 1H), 8.36-8.37 (m, 1H), 8.05-8.07 (m, 2H), 8.01-8.04 (m, 1H), 7.72-7.82 (m, 3H), 7.42-7.44 (m, 1H), 7.39-7.41 (m, 1H), 7.31-7.34 (m, 1H), 6.76-6.79 (m, 1H), 6.53-6.57 (m, 2H), 6.22-6.27 (m, 2H), 5.82-5.85 (m, 1H), 5.59-5.63 (m, 1H), 3.03-3.08 (m, 1H), 2.86-2.92 (m, 1H), 2.50-2.52 (m, 1H), 2.05-2.13 (m, 1H).
Example 71: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(prop-2-enamidomethyl)benzamide




Example 71 was prepare in a manner analogous to Example 2 (via Intermediate 2-1) using 2-{[(tert-butoxycarbonyl) amino]methyl}benzoic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid, 4N HCl in dioxane in place of TFA in dichloromethane and acetonitrile instead of dichloromethane for the final step. MS (ESI) calcd. for C34H29N9O2: 595.24 m/z, found: 596.10 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.95-9.01 (m, 111), 8.57-8.61 (m, 1H), 8.30-8.39 (m, 2H), 7.92-8.07 (m, 2H), 7.80 (s, 1H), 7.41-7.55 (m, 2H), 7.30-7.40 (m, 2H), 7.23-7.29 (m, 2H), 6.54 (s, 1H), 6.40-6.48 (m, 1H), 6.27-6.38 (m, 1H), 6.08-6.18 (m, 1H), 5.52-5.65 (m, 2H), 4.42-4.59 (m, 2H), 3.91-4.07 (m, 2H), 2.83-3.07 (m, 2H), 2.57-2.63 (m, 1H), 1.98-2.11 (m, 1H). (formic acid salt).
Example 72: 1-((1R,5S,9*)-9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)prop-2-en-1-one and
Example 73: 1-((1R,5S,9*)-9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)prop-2-en-1-one




The diastereomers of Example 64 were separated by chiral Prep-HPLC on a CHIRALPAK-SB column using a mixture of [3:1 hexanes/dichloromethane (+0.5% 2M ammonia in methanol)] and ethanol to afford Examples 72 and 73. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 72: MS (ESI) calcd. for C33H33N9O2, 587.28 m/z, found 588.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.22-8.49 (m, 2H), 7.96-8.15 (m, 1H), 7.89-7.96 (m, 1H), 7.70-7.89 (m, 1H), 7.45-7.69 (m, 1H), 7.33-7.45 (m, 1H), 7.14-7.33 (m, 2H), 6.65-6.97 (m, 1H), 6.55-6.65 (m, 1H), 6.35-6.55 (m, 1H), 5.98-6.18 (m, 1H), 5.56-5.80 (m, 1H), 4.52-4.82 (m, 1H), 4.22-4.42 (m, 2H), 4.08-4.42 (m, 2H), 3.47-3.75 (m, 2H), 3.29-3.47 (m, 1H), 3.09-3.29 (m, 1H), 2.88-3.09 (m, 2H), 2.68-2.88 (m, 1H), 2.42-2.52 (m, 1H), 1.72-1.95 (m, 2H), 1.62-1.72 (m, 1H).
Example 73: MS (ESI) calcd. for C33H33N9O2, 587.28 m/z, found 588.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.22-8.49 (m, 2H), 7.96-8.15 (m, 1H), 7.89-7.96 (m, 1H), 7.70-7.89 (m, 1H), 7.41-7.65 (m, 1H), 7.31-7.41 (m, 1H), 7.12-7.31 (m, 2H), 6.65-6.97 (m, 1H), 6.51-6.65 (m, 1H), 6.35-6.51 (m, 1H), 5.98-6.18 (m, 1H), 5.56-5.80 (m, 1H), 4.18-4.42 (m, 2H), 3.96-4.08 (m, 1H), 3.75-4.02 (m, 3H), 3.41-3.71 (m, 2H), 3.24-3.41 (m, 1H), 3.09-3.24 (m, 1H), 2.88-3.09 (m, 1H), 2.68-2.88 (m, 1H), 2.38-2.52 (m, 1H), 1.93-2.06 (m, 1H), 1.62-1.93 (m, 2H).
Example 74: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](2-methoxyethyl)amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](2-methoxyethyl)amino}piperidin-1-yl)prop-2-en-1-one (Example 74)
A stirred solution of 1,1,2-trimethoxyethane (2.00 g, 16.6 mmol) in 1N aqueous HCl was heated to 55° C. for 4 hours. The reaction mixture was cooled to room temperature and saturated with NaCl. The reaction was extracted with DCM (5×30 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under vacuum at below 25° C. to afford crude methoxy-acetaldehyde as a light yellow oil. The aldehyde (135.76 mg, 1.835 mmol) was added to a cooled (0° C.) solution of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 13) (200 mg, 0.367 mmol) in MeOH (5 mL) followed by NaBH3CN (46.1 mg, 0.734 mmol). The resulting mixture was stirred overnight at room temperature then the reaction was quenched with 5 mL water. The mixture was concentrated in vacuo and the residue was purified directly by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](2-methoxyethyl)amino}piperidin-1-yl)prop-2-en-1-one (Example 74) (35.2 mg, 15.4 yield) as a white solid. MS (ESI) calcd. for C34H37N9O2: 603.31 m/z, found 604.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.23-8.35 (m, 2H), 7.91-8.02 (m, 2H), 7.79 (s, 1H), 7.80 (s, 1H), 7.13-7.38 (m, 4H), 6.75-6.80 (m, 1H), 6.51-6.52 (m, 1H), 6.38-6.42 (m, 1H), 6.10-6.17 (m, 1H), 5.71-5.77 (m, 1H), 4.42-4.55 (m, 1H), 4.04-4.15 (m, 2H), 4.24-4.26 (m, 1H), 3.13-3.15 (m, 1H), 3.10 (s, 3H), 3.01-3.05 (m, 1H), 2.76-2.88 (m, 3H), 2.60-2.62 (m, 1H), 2.41-2.45 (m, 1H), 2.07-2.13 (m, 1H), 1.88-1.97 (m, 2H), 1.67-1.73 (m, 1H), 1.40-1.55 (m, 1H), 1.21-1.33 (m, 1H).
Example 75: 1-(4-(((1R,2R)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and Example 76: 1-(4-(((1R,2S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 75 and 76 were prepared in a manner analogous to Example 13 using Intermediate 75-1 and 76-1 in place of Intermediate 1-1 (for Examples 75 and 76, respectively) and a reaction temperature and time of 2 h and 60° C. instead of overnight at 40° C. Absolute stereochemistry of Examples 75 and 76 was confirmed by X-ray crystallography.
Example 75: MS (ESI) calcd. for C31H30FN9O, 563.26 m/z, found 564.15 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.22-8.49 (m, 2H), 7.96-8.15 (m, 1H), 7.89-7.96 (m, 1H), 7.70-7.89 (m, 1H), 7.45-7.69 (m, 1H), 7.33-7.45 (m, 1H), 7.14-7.33 (m, 2H), 6.65-6.97 (m, 1H), 6.55-6.65 (m, 1H), 6.35-6.55 (m, 1H), 5.98-6.18 (m, 1H), 5.56-5.80 (m, 1H), 4.52-4.82 (m, 1H), 4.22-4.42 (m, 2H), 4.08-4.42 (m, 2H), 3.47-3.75 (m, 2H), 3.29-3.47 (m, 1H), 3.09-3.29 (m, 1H), 2.88-3.09 (m, 2H), 2.68-2.88 (m, 1H), 2.42-2.52 (m, 1H), 1.72-1.95 (m, 2H), 1.62-1.72 (m, 1H). (formic acid salt).
Example 76: MS (ESI) calcd. for C31H30FN9O, 563.26 m/z, found 564.15 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.49 (m, 2H), 7.96-8.15 (m, 1H), 7.89-7.96 (m, 1H), 7.69-7.89 (m, 1H), 7.48-7.69 (m, 1H), 7.35-7.48 (m, 1H), 7.15-7.35 (m, 2H), 6.68-6.95 (m, 1H), 6.55-6.68 (m, 1H), 6.37-6.55 (m, 1H), 5.98-6.25 (m, 1H), 5.66-5.88 (m, 1H), 5.18-5.62 (m, 1H), 4.41-4.65 (m, 1H), 4.21-4.41 (m, 1H), 4.08-4.11 (m, 1H), 3.15-3.36 (m, 2H), 3.02-3.15 (m, 2H), 2.75-3.02 (m, 1H), 2.04-2.25 (m, 1H), 1.76-2.04 (m, 1H), 1.19-1.53 (m, 2H). (formic acid salt).
Intermediate 75-1: 3-(3-((1R,2S*)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine and Intermediate 76-1: 3-(3-((1R,2R*)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:











Step 1: Synthesis of 5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one

To a solution of 5-bromo-1-indanone (5.00 g, 23.8 mmol) in methanol (50 mL) was added SelectFluor (10.0 g, 28.2 mmol) and the resulting mixture was stirred under reflux for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (50 mL), and 1 N hydrochloric acid (50 mL) was added followed by stirring at room temperature for 3 hours. To the reaction mixture, a 2 N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was diluted with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford 5-bromo-2-fluoro-2,3-dihydroinden-1-one (4.0 g, 74% yield) as a white solid. MS (ESI) calcd. for C9H6BrFO, 227.96 m/z, found: 229.00 [M+H]+.
Step 2: Synthesis of (S)-N-((Z)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide
To a solution of 5-bromo-2-fluoro-2,3-dihydroinden-1-one (3.0 g, 13 mmol) in toluene (5 mL) was added (S)-2-methylpropane-2-sulfinamide (1.90 g, 15.7 mmol) and Ti(OEt)4 (5.08 g, 22.2 mmol). The mixture was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction was quenched by the addition of 2M Rochelle's salt (30 mL). The resulting mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford (S)-N-(5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (3.0 g, 69% yield) as a yellow solid. MS (ESI) calcd. for C13H15BrFNOS: 331.00 m/z, found: 332.10 [M+H]+. Note that the (S)- applies to the sulfur stereocenter and not the C—F bond for this and all instances vide infra.
Step 3: Synthesis of (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide
To a cooled (−50° C.) solution of (S)-N-((Z)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (3.0 g, 9.0 mmol) was added LTBA (3.90 g, 15.4 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of 2M Rochelle's salt (30 mL). The mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.0 g, 66% yield) as a yellow solid. MS (ESI) calcd. for C13H17BrFNOS: 333.02 m/z, found: 334.10 [M+H]+.
Step 4: Synthesis of (S)-N-((1R)-2-fluoro-5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide
A mixture of (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.0 g, 6.0 mmol), 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine (1.35 g, 6.58 mmol), Pd(OAc)2 (0.13 g, 0.60 mmol), Cs2CO3 (5.86 g, 18.0 mmol) and XantPhos (0.35 g, 0.60 mmol) in dioxane (4.0 mL) was stirred at 100° C. for 2 h under nitrogen atmosphere. The reaction was quenched with water (100 mL) and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient of methanol in dichloromethane to afford (S)-N-((1R)-2-fluoro-5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.5 g, 91% yield) as a yellow solid. MS (ESI) calcd. for C21H23FN6O3S, 458.15 m/z, found: 459.10 [M+H]+.
Step 5: Synthesis of (S)-N-((1R)-5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide
To a solution of (S)-N-[(1R)-2-fluoro-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (2.5 g, 5.5 mmol) in DMF (30 mL) was added B2(OH)4 (1.47 g, 16.4 mmol) and 4-(pyridin-4-yl)pyridine (25.0 mg, 0.163 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of water (200 mL) and then the mixture was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (S)-N-((1R)-5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.0 g, 86% yield) as a yellow solid. MS (ESI) calcd. for C21H25FN6OS: 428.17 m/z. found: 429.15 [M+H]+.
Step 6: Synthesis of (S)-N-((1R)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide
To a solution of (S)-N-[(1R)-5-{[3-amino-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (2.0 g, 4.7 mmol) and 2-aminopyridine-3-carbaldehyde (0.68 g, 5.6 mmol) in AcOH (60 mL) was added Cu(OAc)2 (171 mg, 0.94 mmol). The mixture was stirred at 65° C. for 1.0 h. After cooling to room temperature, the mixture was concentrated and the residue obtained was purified by reverse phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05 mmol/L NH4HCO3) to afford (S)-N-((1R)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (1.47 g, 59% yield). MS (ESI) calcd. for C27H27FN8OS, 530.20 m/z, found: 531.25 [M+H]+. The two diastereomers were separated by chiral SFC on a (S,S)-Whelk-O 1 5 μm Kromasil column using a mix of CO2 and [acetonitrile/methanol 4:1]. The first eluting peak was carried through step 7 below to afford Intermediate 75-1 and the second eluting peak was converted to Intermediate 76-1.
Step 7: Synthesis of 3-(3-((1R)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediates 75-1 and 76-1
The two diastereomers of (S)-N-((1R)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (500 mg, 0.754 mmol) were dissolved separately in 4N HCl in dioxane (8 mL) and the resulting mixtures were stirred at room temperature for 1 h under nitrogen atmosphere. The solvent was removed under vacuum to afford 3-(3-((1R)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (400 mg, crude) as a light yellow solid. MS (ESI) calcd. For C23H19FN8: 426.17 m/z, found: 427.30 [M+H]+.
Example 77: 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazin-1-yl]prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of tert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazine-1-carboxylate
To a solution of 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydroinden-1-one (Intermediate 77-1) (300 mg, 0.736 mmol) in MeOH (10 mL) and AcOH (0.5 mL) was added tert-butyl 4-aminopiperazine-1-carboxylate (222.3 mg, 1.104 mmol). The resulting mixture was stirred for 12 h at 40° C. NaBH3CN (185.1 mg, 2.944 mmol) was added and the reaction mixture was stirred at 40° C. for another 1 hour. The resulting mixture was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford tert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazine-1-carboxylate (100 mg, 17% yield) as a yellow solid. MS (ESI) calcd. for C32H36N10O2: 592.30 m/z, found: 593.20 [M+H]+.
Step 2: Synthesis of N-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperazin-1-amine
A solution of tert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazine-1-carboxylate (100 mg, 0.169 mmol) in 4N HCl in 1,4-dioxane (4.2 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford N-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperazin-1-amine (120 mg, 85% yield) as a white solid. MS (ESI) calcd. for C27H28N10: 492.25 m/z, found: 493.30 [M+H]+.
Step 3: Synthesis of 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazin-1-yl]prop-2-en-1-one
To a cooled (0° C.) solution of N-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperazin-1-amine (100 mg, 0.203 mmol) in ACN (5 mL) were added triethylamine (102.7 mg, 1.015 mmol) and acryloyl chloride (3.67 mg, 0.041 mmol). The mixture was stirred at 0° C. for 10 min and then at ambient temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and the residue was purified by reverse-phase flash column chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3). The material obtained was further purified by Prep-HPLC on XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.05% TFA) to afford 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazin-1-yl]prop-2-en-1-one (8.9 mg, 8% yield) as a yellow solid. MS (ESI) calcd. for C30H30N10O: 546.26 m/z, found: 547.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.40-8.43 (m, 1H), 8.34-8.36 (m, 1H), 7.98-8.02 (m, 2H), 7.80-7.81 (m, 1H), 7.71-7.75 (m, 2H), 7.54-7.55 (m, 1H), 7.37-7.39 (m, 1H), 6.73-6.80 (m, 2H), 6.56-6.57 (m, 1H), 6.12-6.17 (m, 1H), 5.75-5.78 (m, 1H), 5.12-5.17 (m, 1H), 3.62-3.79 (m, 4H), 3.11-3.23 (m, 1H), 3.02-3.09 (m, 4H), 2.92-3.01 (m, 1H), 2.54-2.61 (m, 1H), 2.14-2.24 (m, 1H). (TFA salt).
Intermediate 77-1: 5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-one




Synthetic Route:





Step 1: Synthesis of 5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-one
To a solution of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine (15.0 g, 73.1 mmol, 1 equiv) and 5-bromo-2,3-dihydroinden-1-one (15.43 g, 73.11 mmol, 1 equiv) in 1,4-dioxane (400 mL) were added Pd(OAc)2 (1.64 g, 7.31 mmol, 0.1 equiv), XantPhos (4.23 g, 7.31 mmol, 0.1 equiv) and Cs2CO3 (71.46 g, 219.3 mmol, 3 equiv). The resulting mixture was maintained under nitrogen and stirred for 1 h at 100° C. The mixture was allowed to cool to room temperature. Water was added and the precipitated solids were collected by filtration to afford 5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-one (37 g, 91%) as a black solid. MS (ESI) calcd. for C17H13N5O3: 335.10 m/z, found: 336.00 [M+H]+.
Step 2: Synthesis of 5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-one
To a cooled (0° C.) solution of 5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-one (10.00 g, 29.82 mmol, 1 equiv) in DMF (100 mL) were added B2(OH)4 (8.02 g, 89.5 mmol, 3 equiv) and 4-(pyridin-4-yl)pyridine (232.9 mg, 1.491 mmol, 0.05 equiv). The resulting mixture was stirred for 1 h at room temperature. Water was added and the precipitated solids were collected by filtration to afford 5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-one (8.5 g, 50%) as a black solid. MS (ESI) calcd. for C17H15N5O: 305.13 m/z, found: 306.15 [M+H]+.
Step 3: Synthesis of 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydroinden-1-one (Intermediate 77-1
To a solution of 5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-one (8.5 g, 28 mmol, 1 equiv) in AcOH (400 mL) were added 2-aminopyridine-3-carbaldehyde (4.05 g, 33.2 mmol, 1.2 equiv) and Cu(OAc)2 (1.00 g, 5.53 mmol, 0.2 equiv). The resulting mixture was stirred for 12 h at 65° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH/DCM (0-10%) to afford 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydroinden-1-one (Intermediate 77-1) (2.5 g, 16%) as a black solid. MS (ESI) calcd. for C23H17N7O: 407.15 m/z, found: 408.15 [M+H]+.
Example 78: 1-((*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-azaspiro[3.5]nonan-2-yl)prop-2-en-1-one and
Example 79: 1-((*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-azaspiro[3.5]nonan-2-yl)prop-2-en-1-one




Examples 78 and 79 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 6-oxo-2-azaspiro[3.5]nonane-2-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and using a reaction time of 2 h instead of overnight for the final step. The two diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [MTBE+0.5% 2M NH3 in MeOH] and [1:1 ethanol/dichloromethane]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 78: MS (ESI) calcd. for C34H35N9O, 585.30 m/z, found 586.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.34 (m, 2H), 7.97-7.98 (m, 2H), 7.78-7.79 (m, 1H), 7.44-7.47 (m, 1H), 7.30-7.31 (m, 1H), 7.19-7.22 (m, 2H), 6.52-6.53 (m, 1H), 6.41-6.42 (m, 1H), 6.09-6.10 (m, 1H), 6.03-6.04 (m, 1H), 5.61-5.65 (m, 1H), 4.32-4.33 (m, 1H), 3.87-3.90 (m, 2H), 3.54-3.59 (m, 2H), 2.90-2.91 (m, 1H), 2.74-2.77 (m, 1H), 2.48-2.49 (m, 1H), 2.02-2.06 (m, 1H), 2.02-2.06 (m, 2H), 1.80-1.88 (m, 3H), 1.31-1.35 (m, 3H), 1.03-1.05 (m, 1H).
Example 79: MS (ESI) calcd. for C34H35N9O, 585.30 m/z, found 586.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31-8.34 (m, 2H), 7.97-7.98 (m, 2H), 7.78-7.79 (m, 1H), 7.44-7.47 (m, 1H), 7.30-7.31 (m, 1H), 7.19-7.21 (m, 2H), 6.53-6.54 (m, 1H), 6.40-6.41 (m, 2H), 6.09-6.10 (m, 1H), 5.61-5.65 (m, 1H), 4.35-4.36 (m, 1H), 3.88-3.90 (m, 2H), 3.58-3.59 (m, 2H), 2.60-3.01 (m, 3H), 2.48-2.49 (m, 1H), 2.19-2.20 (m, 1H), 1.63-1.75 (m, 4H), 1.32-1.52 (m, 3H), 1.01-1.09 (m, 1H).
Example 80: 1-(7-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-1-azaspiro[3.5]nonan-1-yl)prop-2-en-1-one




Example 80 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 7-oxo-1-azaspiro[3.5]nonane-1-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, using 4N HCl in dioxane instead of TFA in dichloromethane, and a reaction time of 2 h instead of overnight for the final step. The final product is a mix of diastereomers. MS (ESI) calcd. for C34H35N9O: 585.30 m/z, found: 586.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.42-8.44 (m, 1H), 8.36-8.37 (m, 1H), 8.00-8.06 (m, 2H), 7.83 (s, 1H), 7.63-7.71 (m, 2H), 7.56-7.58 (m, 1H), 7.33-7.43 (m, 1H), 6.71-6.76 (m, 1H), 6.50-6.59 (m, 2H), 6.10-6.15 (m, 1H), 5.66-5.69 (m, 1H), 4.91-4.93 (m, 1H), 4.06-4.10 (m, 1H), 3.64-3.68 (m, 1H), 3.45-3.60 (m, 2H), 3.12-3.20 (m, 2H), 2.85-2.98 (m, 2H), 2.15-2.26 (m, 2H), 2.01-2.04 (m, 1H), 1.78-1.85 (m, 3H), 1.68-1.71 (m, 1H), 1.50-1.60 (m, 1H), 1.35-1.42 (m, 1H). (TFA salt).
Example 81: 1-((*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)azepan-1-yl)prop-2-en-1-one and Example 82: 1-((*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)azepan-1-yl)prop-2-en-1-one




Examples 81 and 82 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 4-oxoazepane-1-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, 4N HCl in dioxane instead of TFA in dichloromethane, and a reaction time of 2 h instead of overnight for the final step. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IK column using a mixture of [MTBE+0.5% 2N NH3 in methanol] and tetrahydrofuran. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 81: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.26-8.61 (m, 2H), 7.95-8.21 (m, 2H), 7.76-7.95 (m, 2H), 7.62-7.76 (m, 1H), 7.52-7.62 (m, 1H), 7.31-7.52 (m, 1H), 6.68-6.96 (m, 2H), 6.48-6.68 (m, 1H), 6.05-6.36 (m, 1H), 5.64-5.92 (m, 1H), 4.85-5.14 (m, 1H), 3.78-3.92 (m, 1H), 3.43-3.78 (m, 3H), 3.25-3.43 (m, 2H), 3.11-3.25 (m, 1H), 2.86-3.11 (m, 1H), 2.28-2.38 (m, 1H), 2.14-2.28 (m, 2H), 1.90-2.11 (m, 1H), 1.48-1.84 (m, 3H).
Example 82: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.28-8.61 (m, 2H), 7.95-8.21 (m, 2H), 7.76-7.95 (m, 2H), 7.65-7.76 (m, 1H), 7.52-7.65 (m, 1H), 7.32-7.52 (m, 1H), 6.68-6.97 (m, 2H), 6.48-6.68 (m, 1H), 6.05-6.36 (m, 1H), 5.64-5.95 (m, 1H), 4.85-5.14 (m, 1H), 3.84-3.92 (m, 1H), 3.54-3.72 (m, 2H), 3.41-3.54 (m, 1H), 3.26-3.41 (m, 2H), 3.12-3.26 (m, 1H), 2.94-3.12 (m, 1H), 2.38-2.48 (m, 1H), 2.18-2.31 (m, 1H), 2.06-2.19 (m, 1H), 1.91-2.06 (m, 1H), 3.54-3.72 (m, 3H).
Example 83: (S)-1-(6-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-2-fluoroprop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of 2-azaspiro[3.3]heptan-6-one
To a stirred solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.37 mmol) in DCM (3 mL) was added TFA (1 mL) at 0° C. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum to afford 2-azaspiro[3.3]heptan-6-one (400 mg, crude) as a yellow oil. MS (ESI) calcd. for C6H9NO: 111.07 m/z, found 112.10 [M+H]+.
Step 2: Synthesis of 2-(2-fluoroacryloyl)-2-azaspiro[3.3]heptan-6-one
To a stirred solution of 2-azaspiro[3.3]heptan-6-one (300 mg, 2.70 mmol), 2-fluoroacrylic acid (291.7 mg, 3.239 mmol) and N,N-diisopropylethylamine (1.047 mg, 8.097 mmol) in DMF (4 mL) was added PyBOP (1.405 mg, 2.699 mmol). The reaction mixture was stirred for 2 h at room temperature. The mixture was quenched with water (80 mL). The resulting mixture was extracted with ethyl acetate (3×80 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography using a gradient of ethyl acetate in petroleum ether to afford 2-(2-fluoroacryloyl)-2-azaspiro[3.3]heptan-6-one (300 mg, 61% yield) as a yellow solid. MS (ESI) calcd. for C9H10NFO2: 183.07 m/z, found 184.15 [M+H]+.
Step 3: Synthesis of (S)-1-(6-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl) amino)-2-azaspiro[3.3]heptan-2-yl)-2-fluoroprop-2-en-1-one (Example 83)
A solution of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (200 mg, 0.490 mmol) and 2-(2-fluoroacryloyl)-2-azaspiro[3.3]heptan-6-one (89.7 mg, 0.490 mmol) in DCE (5 mL) and MeOH (0.5 mL) was stirred for additional 3 h at room temperature. To the mixture was added NaBH3CN (92.3 mg, 1.470 mmol) and the resulting mixture was stirred overnight at room temperature. The reaction was quenched with H2O (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.1% formic acid) to afford (S)-1-(6-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-2-fluoroprop-2-en-1-one (Example 83, formic acid salt) (20.4 mg, 7% yield) as a white solid. MS (ESI) calcd. for C32H30FN9O: 575.26 m/z, found 576.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.30 (m, 2H), 7.96-8.01 (m, 2H), 7.80 (s, 1H), 7.53-7.56 (m, 1H), 7.36 (s, 1H), 7.25-7.28 (m, 2H), 6.52 (s, 1H), 6.35-6.45 (m, 1H), 5.49-5.56 (m, 1H), 5.37-5.44 (m, 1H), 4.12-4.41 (m, 3H), 3.81-4.08 (m, 2H), 3.29-3.43 (m, 1H), 2.99-3.12 (m, 1H), 2.81-2.84 (m, 1H), 2.36-2.38 (m, 1H), 2.30-2.36 (m, 2H), 2.02-2.14 (m, 2H), 1.81-1.96 (m, 1H). 19F NMR (386 MHz, DMSO-d6) δ (ppm): −114.01.
Example 84: (S)-1-(2-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-7-azaspiro[3.5]nonan-7-yl)-2-fluoroprop-2-en-1-one




Example 84 was prepared in a manner analogous to Example 83 starting from tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate instead of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate. MS (ESI) calcd. for C34H34FN9O: 603.29 m/z, found: 604.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.45-8.47 (m, 111), 8.42-8.44 (m, 111), 7.98-8.13 (m, 2H), 7.63-7.89 (m, 3H), 7.55-7.62 (m, 1H), 7.41-7.49 (m, 1H), 6.68-6.75 (m, 1H), 6.54-6.59 (m, 1H), 5.02-5.32 (m, 2H), 4.72-4.85 (m, 1H), 3.89-4.02 (m, 1H), 3.43-3.45 (m, 1H), 3.31-3.42 (m, 2H), 3.11-3.24 (m, 1H), 2.90-3.03 (m, 1H), 2.43-2.48 (m, 2H), 2.10-2.31 (m, 3H), 1.94-2.09 (m, 2H), 1.45-1.75 (m, 4H). 19F-NMR (376 MHz, DMSO-d6) δ (ppm): −104.39. (TFA salt).
Example 85: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 85 was prepared in a manner analogous to Example 13 using Intermediate 85-2 in place of Intermediate 1-1, 1,2-dichloroethane/methanol (10:1) in place of 1,2-dichloroethane and a reaction temperature of 70° C. instead of 40° C. MS (ESI) calcd. for C31H33N7O, 519.27 m/z, found 520.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.02-8.03 (m, 111), 7.97-7.99 (m, 1H), 7.44-7.51 (m, 1H), 7.18-7.25 (m, 2H), 7.13-7.19 (m, 2H), 6.81-6.88 (m, 1H), 6.39-6.43 (m, 1H), 6.08-6.10 (m, 1H), 5.67-5.72 (m, 1H), 4.21-4.33 (m, 2H), 3.95-4.06 (m, 1H), 3.10-3.15 (m, 1H), 2.86-2.97 (m, 3H), 2.80-2.85 (m, 1H), 2.71-2.74 (m, 1H), 2.41-2.43 (m, 1H), 2.15-2.17 (m, 1H), 1.96-1.99 (m, 1H), 1.86-1.92 (m, 1H), 1.22-1.28 (m, 2H), 0.86-0.99 (m, 2H), 0.80-0.85 (m, 2H).
Intermediate 85-2: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl) carbamate
A mixture of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (1.00 g, 1.92 mmol), potassium cyclopropyltrifluoroborate (0.57 g, 3.8 mmol), Pd(OAc)2 (0.04 g, 0.192 mmol), Cs2CO3 (1.25 g, 3.85 mmol) and bis(adamantan-1-yl)(butyl)phosphane (0.07 g, 0.2 mmol) in water (4 mL) and dioxane (16 mL) was stirred for 2 h at 100° C. under N2 atmosphere. The reaction was quenched with water (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of methanol in dichloromethane to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (0.6 g, 65% yield) as a yellow oil. MS (ESI) calcd. for C28H30N6O2, 482.24 m/z, found 483.20 [M+H]+.
Step 2: Synthesis of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-2-yl) pyridin-2-amine (Intermediate 85-2
A solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (700 mg, 1.45 mmol) in TFA (3 mL) and DCM (15 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 85-2) (485 mg, 87% yield) as brown oil. MS (ESI) calcd. for C23H22N6, 382.19 m/z, found 383.25 [M+H]+.
Intermediate 85-1: tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of benzyl N-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (60.00 g, 192.2 mmol, 1 equiv), benzyl carbamate (34.63 g, 230.6 mmol, 1.2 equiv) and XantPhos (22.24 g, 38.44 mmol, 0.2 equiv) in 1,4-dioxane (1.2 L) were added Cs2CO3 (125.23 g, 384.36 mmol, 2 equiv) and Pd(OAc)2 (4.31 g, 19.2 mmol, 0.1 equiv). After stirring overnight at 100° C. under nitrogen atmosphere the mixture was cooled to room temperature and the product was precipitated by the addition of H2O. The precipitated solids were collected by filtration and washed with H2O (3×400 ml). The suspended in ethyl acetate and filtered, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to afford benzyl N-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]carbamate (50 g, 46%) as a grey solid. MS (ESI) calcd. for C22H26N2O4, 382.19 m/z, found: 381.10 [M−H]−.
Step 2: Synthesis of tert-butyl N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of benzyl N-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]carbamate (50.00 g, 130.7 mmol, 1 equiv) in 500 mL CH3OH was added 10% Pd(OH)2/C (5.00 g, 35.6 mmol, 0.27 equiv) in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi of hydrogen overnight then filtered through a Celite pad and concentrated under reduced pressure to afford tert-butyl N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]carbamate (40 g, 73%) as a brown solid. MS (ESI) calcd. for C14H20N2O2, 248.15 m/z, found: 249.15 [M+H]+.
Step 3: Synthesis of tert-butyl N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate
A mixture of tert-butyl N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]carbamate (40.0 g, 161 mmol, 1 equiv) and triethylamine (48.90 g, 483.2 mmol, 3 equiv) in EtOH (800 mL) was stirred at room temperature until dissolved. 2,6-dibromo-3-nitropyridine (54.49 g, 193.3 mmol, 1.2 equiv) was added and the mixture was stirred at 30° C. overnight. The mixture was allowed to cool to room temperature and the precipitated solids were collected by filtration and washed with EtOH (3×100 mL) to afford tert-butyl N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate (30 g, 27.30%) as a red solid. MS (ESI) calcd. for C19H21BrN4O4, 448.07 m/z, found: 447.00 [M−H]−.
Step 4: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1
To a solution of tert-butyl N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate (30.0 g, 66.8 mmol, 1 equiv) in DMSO (600 mL) and MeOH (100 mL) was added 2-aminopyridine-3-carbaldehyde (8.97 g, 73.4 mmol, 1.1 equiv) and the mixture was stirred until the solids were dissolved. Na2S2O4 (25.57 g, 146.9 mmol, 2.2 equiv) was added and the mixture was stirred at 100° C. overnight. The product was precipitated by the addition of H2O. The precipitated solids were collected by filtration and washed with H2O (3×500 ml). The residue was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (10:1) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (15 g, 36%) as a yellow solid. MS (ESI) calcd. for C25H25BrN6O2, 520.12 m/z, found: 521.20 [M+H]+.
Example 86: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 86 was prepared in a manner analogous to Example 13 using Intermediate 86-2 in place of Intermediate 1-1, 1,2-dichloroethane/methanol (10:1) in place of 1,2-dichloroethane and a reaction time and temperature of 5 h at 70° C. instead of overnight at 40° C. MS (ESI) calcd. for C32H36N8O2, 564.30 m/z, found 565.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.00-8.07 (m, 2H), 7.69-7.72 (m, 1H), 7.60-7.63 (m, 1H), 7.40-7.47 (m, 1H), 7.36-7.39 (m, 1H), 6.97-7.00 (m, 1H), 6.70-6.89 (m, 2H), 6.10-6.20 (m, 1H), 5.74-5.78 (m, 1H), 4.97-5.01 (m, 1H), 4.45-4.55 (m, 1H), 4.15-4.25 (m, 1H), 3.60-3.70 (m, 4H), 3.50-3.59 (m, 1H), 3.40-3.49 (m, 4H), 3.05-3.15 (m, 2H), 2.86-2.98 (m, 1H), 2.70-2.84 (m, 1H), 2.53-2.55 (m, 1H), 2.05-2.31 (m, 3H), 1.55-1.75 (m, 2H). (TFA salt).
Intermediate 86-2: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate
tert-Butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 86-1) (2.00 g, 4.19 mmol) was dissolved in DMSO (30 mL). Then morpholine (1.46 g, 16.8 mmol) was added and the mixture was stirred for 3 h at 140° C. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05 mmol/L ammonium bicarbonate) to afford tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1 g, 41% yield) as a brown solid. MS (ESI) calcd. for C29H33N7O3, 527.26 m/z, found 528.30 [M+H]+.
Step 2: Synthesis of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 86-2
tert-Butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (500 mg, 1.05 mmol) was dissolved in DCM (15 mL). TFA (3 mL) was added and the mixture was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-morpholino-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 86-2) (400 mg, 99% yield) as a brown oil. MS (ESI) calcd. for C24H25N7O, 427.21 m/z, found 428.25 [M+H]+.
Intermediate 86-1: tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
(S)-N-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 1-2) (200 mg, 0.478 mmol, 1 equiv) was dissolved in methanol (10 mL) and hydrochloric acid (10 mL, conc.) was added. The resulting mixture was stirred overnight at 90° C. The mixture was then cooled to room temperature and concentrated in vacuo to afford crude (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine as a yellow solid, which was used directly in the next step without further purification. MS (ESI) calculated for C20H17ClN6: 376.12 m/z, found 377.15 [M+H]+.
Step 2: Synthesis of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 86-1
Crude (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine was dissolved in dichloromethane (10 mL). di-tert-Butyl dicarbonate (148 mg, 0.678 mmol, 1.5 equiv) was added followed by triethylamine (137 mg, 1.36 mmol, 3 equiv) and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (10 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue obtained was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1) to afford tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 86-1) (180 mg, 80% over two steps) as a yellow solid. MS (ESI) calculated for C25H25ClN6O2: 476.17 m/z, found 477.20 [M+H]+.
Example 87: 1-((2S,4*,6R)-4-(((R)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2,6-dimethylpiperidin-1-yl)prop-2-en-1-one and
Example 88: 1-((2S,4*,6R)-4-(((R)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2,6-dimethylpiperidin-1-yl)prop-2-en-1-one




Examples 87 and 88 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl (2R,6S)-2,6-dimethyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, using 10:1 1,2-dichloroethane/methanol in place of 1,2-dichloroethane and a reaction time of 4 h for the final step. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IC3 column using a mixture of [MTBE (+0.1% diethylamine)] and [methanol/dichloromethane (1:1)]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 87: MS (ESI) calcd. for C33H35N9O: 573.30 m/z, found: 574.35 [M+H]+. H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.33 (m, 2H), 7.85-7.99 (m, 2H), 7.72-7.80 (m, 1H), 7.39-7.45 (m, 1H), 7.12-7.29 (m, 3H), 6.62-6.75 (m, 1H), 6.45-6.55 (m, 1H), 6.38-6.44 (m, 1H), 6.01-6.12 (m, 1H), 5.60-5.70 (m, 1H), 4.20-4.40 (m, 3H), 2.85-2.98 (m, 1H), 2.62-2.82 (m, 2H), 2.30-2.42 (m, 1H), 2.05-2.25 (m, 2H), 1.65-1.75 (m, 1H), 1.32-1.45 (m, 2H), 1.20-1.30 (m, 6H).
Example 88: MS (ESI) calcd. for C33H35N9O: 573.30 m/z, found: 574.25 [M+H]+. H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.38 (m, 2H), 7.96-8.05 (m, 1H), 7.89-7.95 (m, 1H), 7.75-7.82 (m, 1H), 7.42-7.51 (m, 1H), 7.28-7.35 (m, 1H), 7.18-7.27 (m, 2H), 6.70-6.82 (m, 1H), 6.49-6.58 (m, 1H), 6.40-6.48 (m, 1H), 6.02-6.15 (m, 1H), 5.62-5.72 (m, 1H), 4.60-4.75 (m, 1H), 4.28-4.42 (m, 2H), 3.95-4.09 (m, 1H), 3.15-3.25 (m, 1H), 2.92-3.05 (m, 1H), 2.70-2.85 (m, 1H), 2.38-2.45 (m, 1H), 1.78-1.90 (m, 2H), 1.30-1.50 (m, 2H), 1.10-1.29 (m, 6H).
Example 89: N-((1*,3*)-3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)cyclobutyl)acrylamide and
Example 90: N-((1*,3*)-3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)cyclobutyl)acrylamide




Examples 89 and 90 were prepared in a manner analogous to Example 14 (via Intermediate 14-1, starting from the second step) using 3-aminocyclobutan-1-one in place 3-azabicyclo[3.2.1]octan-8-one, using 10:1 1,2-dichloroethane/methanol in place of 1,2-dichloroethane and a reaction time and temperature of 7 h at room temperature. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IF column using a mixture of MTBE and [methanol/dichloromethane (1:1)]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 89: MS (ESI) calcd. for C30H29N9O: 531.25 m/z, found: 532.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.25-8.38 (m, 3H), 7.92-8.01 (m, 2H), 7.80-7.84 (m, 1H), 7.42-7.48 (m, 1H), 7.30-7.37 (m, 1H), 7.21-7.29 (m, 2H), 6.93-7.01 (m, 2H), 6.51-6.55 (m, 1H), 6.38-6.43 (m, 1H), 6.12-6.21 (m, 1H), 6.02-6.09 (m, 1H), 5.53-5.59 (m, 1H), 4.18-4.22 (m, 1H), 3.81-3.91 (m, 1H), 3.51-3.63 (m, 2H), 2.99-3.10 (m, 1H), 2.90-2.98 (m, 1H), 2.72-2.81 (m, 1H), 2.51-2.58 (m, 1H), 2.29-2.38 (m, 1H), 1.73-1.82 (m, 1H), 1.60-1.70 (m, 2H).
Example 90: MS (ESI) calcd. for C30H29N9O: 531.25 m/z, found: 532.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31-8.45 (m, 3H), 7.94-8.01 (m, 2H), 7.81-7.84 (m, 1H), 7.45-7.49 (m, 1H), 7.31-7.34 (m, 1H), 7.19-7.28 (m, 2H), 6.93-6.99 (m, 2H), 6.52-6.54 (m, 1H), 6.38-6.43 (m, 1H), 6.17-6.27 (m, 1H), 6.02-6.09 (m, 1H), 5.51-5.57 (m, 1H), 4.21-4.28 (m, 1H), 4.12-4.18 (m, 1H), 3.51-3.61 (m, 2H), 2.89-2.99 (m, 1H), 2.71-2.82 (m, 1H), 2.29-2.38 (m, 1H), 2.03-2.17 (m, 4H), 1.72-1.82 (m, 1H).
Example 91: 1-((*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-azaspiro[3.4]octan-2-yl)prop-2-en-1-one and
Example 92: 1-((*)-6-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-azaspiro[3.4]octan-2-yl)prop-2-en-1-one




Examples 91 and 92 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 6-oxo-2-azaspiro[3.4]octane-2-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK AD column using a mixture of [hexanes+0.5% 2M NH3-methanol] and [methanol/ethanol (1:1)]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 91: MS (ESI) calcd. for C33H33N9O, 571.28 m/z, found 572.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30-8.35 (m, 2H), 7.96-8.02 (m, 1H), 7.90-7.93 (m, 1H), 7.80 (s, 1H), 7.48-7.52 (m, 1H), 7.24-7.30 (m, 2H), 7.16-7.19 (m, 1H), 6.46-6.54 (m, 2H), 6.25-6.30 (m, 1H), 6.12-6.16 (m, 1H), 5.72-5.75 (m, 1H), 4.14-4.21 (m, 2H), 4.04-4.06 (m, 1H), 3.85-3.90 (m, 1H), 3.80-3.81 (m, 1H), 3.21-3.35 (m, 1H), 2.90-3.04 (m, 1H), 2.72-2.80 (m, 1H), 2.33-2.41 (m, 1H), 2.10-2.15 (m, 1H), 1.73-2.01 (m, 4H), 1.61-1.69 (m, 1H), 1.40-1.53 (m, 1H).
Example 92: MS (ESI) calcd. for C33H33N9O, 571.28 m/z, found 572.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.38 (m, 2H), 7.92-8.02 (m, 2H), 7.81 (s, 1H), 7.50-7.54 (m, 1H), 7.27-7.31 (m, 2H), 7.18-7.21 (m, 1H), 6.48-6.56 (m, 2H), 6.26-6.32 (m, 1H), 6.11-6.16 (m, 1H), 5.72-5.76 (m, 1H), 4.14-4.21 (m, 2H), 4.04-4.06 (m, 1H), 3.80-3.90 (m, 2H), 3.21-3.45 (m, 1H), 2.90-3.03 (m, 1H), 2.72-2.81 (m, 1H), 2.33-2.42 (m, 1H), 2.11-2.15 (m, 1H), 1.93-1.95 (m, 2H), 1.79-1.84 (m, 2H), 1.61-1.69 (m, 1H), 1.40-1.53 (m, 1H).
Example 93: 1-((*)-8-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-one and Example 94: 1-((*)-8-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-one




Examples 93 and 94 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 8-oxo-5-azaspiro[3.5]nonane-5-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and 1,2-dichloroethane/methanol (10:1) as the solvent for the final step. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK SC column using a mixture of [MTBE+0.5% 2M NH3-MeOH] and [methanol/ethanol (1:1)]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 93: MS (ESI) calcd. for C34H35N9O: 585.30 m/z, found: 586.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.39 (m, 2H), 7.98-8.02 (m, 1H), 7.91-7.97 (m, 1H), 7.76-7.85 (m, 1H), 7.42-7.50 (m, 1H), 7.28-7.35 (m, 1H), 7.17-7.27 (m, 2H), 6.51-6.70 (m, 2H), 6.36-6.45 (m, 1H), 5.98-6.01 (m, 1H), 5.58-5.65 (m, 1H), 4.28-4.38 (m, 1H), 2.65-3.05 (m, 4H), 2.35-2.54 (m, 3H), 2.01-2.22 (m, 3H), 1.81-2.00 (m, 2H), 1.55-1.80 (m, 3H), 1.38-1.50 (m, 1H), 1.85-1.00 (m, 1H).
Example 94: MS (ESI) calcd. for C34H35N9O: 585.30 m/z, found: 586.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.38 (m, 2H), 7.96-8.01 (m, 1H), 7.89-7.95 (m, 1H), 7.76-7.82 (m, 1H), 7.44-7.52 (m, 1H), 7.26-7.34 (m, 1H), 7.18-7.25 (m, 2H), 6.56-6.70 (m, 1H), 6.51-6.55 (m, 1H), 6.38-6.45 (m, 1H), 5.98-6.05 (m, 1H), 5.58-5.68 (m, 1H), 4.28-4.38 (m, 1H), 2.68-3.09 (m, 4H), 2.35-2.52 (m, 3H), 2.19-2.34 (m, 1H), 2.01-2.18 (m, 2H), 1.58-1.95 (m, 5H), 1.33-1.45 (m, 1H), 0.85-1.01 (m, 1H).
Example 95: (S,E)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)-4,4-dimethylpent-2-en-1-one




Example 95 was prepared in a manner analogous to Example 83 (starting at Step 2) using piperidin-4-one in place of 2-azaspiro[3.3]heptan-6-one, TCFH/NMI in place of PyBOP/DIPEA, (E)-4,4-dimethylpent-2-enoic acid in place of 2-fluoroacrylic acid, 1,2-dichloroethane/methanol (1:1) in place of 1,2-dichloroethane and a reaction time and temperature of 50° C. and 2 h for the final step. MS (ESI) calcd. for C35H39N9O3, 601.33 m/z, found: 602.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.43-8.45 (m, 1H), 8.36-8.37 (m, 1H), 8.08-8.09 (m, 1H), 8.01-8.03 (m, 1H), 7.84-7.85 (m, 1H), 7.72-7.74 (m, 2H), 7.68-7.70 (m, 1H), 7.44-7.46 (m, 1H), 6.71-6.75 (m, 2H), 6.58-6.71 (m, 1H), 6.31-6.35 (m, 1H), 4.99-5.03 (m, 1H), 4.44-4.64 (m, 1H), 4.12-4.32 (m, 1H), 3.51-3.56 (m, 1H), 3.17-3.21 (m, 2H), 2.98-3.02 (m, 1H), 2.68-2.70 (m, 1H), 2.60-2.61 (m, 1H), 2.54-2.58 (m, 2H), 2.00-2.10 (m, 1H), 1.50-1.60 (m, 2H), 1.07 (s, 9H). (TFA salt).
Example 96: (S,E)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)but-2-en-1-one




Example 96 was prepared in a manner analogous to Example 14 (via Intermediate 14-1, starting from Step 2) using piperidin-4-one in place of 3-azabicyclo[3.2.1]octan-8-one, 1,2-dichloroethane/methanol (10:1) instead of 1,2-dichloroethane and a reaction time and temperature of 3 h at room temperature for the final step. MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.37 (m, 2H), 7.97-7.99 (m, 1H), 7.92-7.94 (m, 1H), 7.76-7.79 (m, 1H), 7.45-7.78 (m, 1H), 7.30-7.32 (m, 1H), 7.22-7.24 (m, 2H), 6.59-6.72 (m, 1H), 6.46-6.54 (m, 2H), 6.43 (m, 1H), 4.32-4.52 (m, 2H), 3.99-4.12 (m, 1H), 3.08-3.17 (m, 1H), 2.73-3.01 (m, 4H), 2.72-2.75 (m, 1H), 1.65-2.15 (m, 6H), 1.01-1.35 (m, 2H).
Example 97: 1-((*)-3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)azepan-1-yl)prop-2-en-1-one and
Example 98: 1-((*)-3-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)azepan-1-yl)prop-2-en-1-one




Examples 97 and 98 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 3-oxoazepane-1-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK SB column using a mixture of [MTBE+0.5% 2M NH3-MeOH] and [dichloromethane/ethanol (1:1)]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 97: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.20-8.49 (m, 2H), 7.84-8.12 (m, 2H), 7.66-7.84 (m, 1H), 7.40-7.62 (m, 1H), 7.08-7.40 (m, 3H), 6.66-6.89 (m, 1H), 6.51-6.64 (m, 1H), 6.36-6.51 (m, 1H), 6.02-6.31 (m, 1H), 5.56-5.86 (m, 1H), 4.23-4.51 (m, 1H), 3.95-4.12 (m, 1H), 3.38-3.55 (m, 1H), 3.18-3.38 (m, 1H), 2.81-3.16 (m, 2H), 2.72-2.81 (m, 1H), 2.42-2.51 (m, 1H), 1.68-1.90 (m, 4H), 1.51-1.68 (m, 1H), 1.31-1.51 (m, 1H), 1.06-1.31 (m, 2H).
Example 98: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.20-8.49 (m, 2H), 7.97-8.12 (m, 1H), 7.84-7.97 (m, 1H), 7.66-7.84 (m, 1H), 7.38-7.66 (m, 1H), 7.29-7.39 (m, 1H) 7.08-7.29 (m, 2H), 6.64-6.94 (m, 1H), 6.51-6.64 (m, 1H), 6.32-6.51 (m, 1H), 6.02-6.32 (m, 1H), 5.56-5.86 (m, 1H), 4.21-4.47 (m, 1H), 3.95-4.21 (m, 1H), 3.58-3.80 (m, 1H), 3.09-3.21 (m, 1H), 2.85-3.01 (m, 2H), 2.67-2.85 (m, 1H), 2.34-2.49 (m, 1H), 1.68-1.97 (m, 4H), 1.38-1.68 (m, 2H), 1.10-1.38 (m, 2H).
Example 99: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one
Example 100: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one
Example 101: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one and
Example 102: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one




Examples 99, 100, 101, and 102 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using (R)-3-methyl-4-oxopiperidine-1-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. Note that the methyl stereocenter epimerized under the reaction conditions giving four stereoisomeric products. The diastereomers partially separated during reverse phase Prep-HPLC on a XBridge Prep OBD C18 column using a gradient of acetonitrile in water (+10 mM formic acid). Examples 99 and 101 required further separation by chiral Prep-HPLC on a CHIRALPAK IF column using a mixture of [MTBE+0.5% 2M NH3-MeOH] and [dichloromethane/methanol (1:1)]. Examples 100 and 102 required further separation by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [hexanes/dichloromethane (3:1)+0.5% 2M NH3-MeOH] and ethanol. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 99: MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.39 (m, 2H), 8.00-8.03 (m, 1H), 7.94-7.98 (m, 1H), 7.81 (s, 1H), 7.49-7.54 (m, 1H), 7.33 (s, 1H), 7.22-7.29 (m, 2H), 6.76-6.88 (m, 1H), 6.54-6.59 (m, 1H), 6.42-6.48 (m, 1H), 6.05-6.15 (m, 1H), 5.65-5.72 (m, 1H), 3.79-4.38 (m, 3H), 3.24-3.36 (m, 1H), 2.87-3.23 (m, 3H), 2.72-2.86 (m, 1H), 2.39-2.49 (m, 1H), 1.93-2.09 (m, 1H), 1.72-1.89 (m, 1H), 1.41-1.70 (m, 2H), 0.80-0.91 (m, 3H).
Example 100: MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.36 (m, 2H), 8.00-8.06 (m, 1H), 7.93-7.99 (m, 1H), 7.81 (s, 1H), 7.46-7.48 (m, 1H), 7.32 (s, 1H), 7.23-7.25 (m, 2H), 6.76-6.83 (m, 1H), 6.54-6.55 (m, 1H), 6.42-6.45 (m, 1H), 6.07-6.12 (m, 1H), 5.66-5.69 (m, 1H), 4.33-4.36 (m, 1H), 4.25-4.30 (m, 1H), 3.90-4.05 (m, 1H), 2.77-3.15 (m, 4H), 2.41-2.45 (m, 1H), 2.06-2.12 (m, 1H), 1.73-1.74 (m, 1H), 1.39-1.42 (m, 1H), 1.20-1.26 (m, 2H), 0.93-0.98 (m, 3H).
Example 101: MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.42 (m, 2H), 7.98-8.03 (m, 1H), 7.91-7.97 (m, 1H), 7.78-7.83 (m, 1H), 7.44-7.54 (m, 1H), 7.32 (s, 1H), 7.21-7.29 (m, 2H), 6.76-6.92 (m, 1H), 6.52-6.58 (m, 1H), 6.38-6.47 (m, 1H), 6.04-6.16 (m, 1H), 5.64-5.71 (m, 1H), 3.97-4.35 (m, 2H), 3.73-3.96 (m, 1H), 3.14-3.34 (m, 1H), 2.71-3.09 (m, 4H), 2.36-2.48 (m, 1H), 2.03-2.15 (m, 1H), 1.71-1.89 (m, 1H), 1.33-1.68 (m, 2H), 0.77-0.96 (m, 3H).
Example 102: MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.38 (m, 2H), 7.97-8.02 (m, 1H), 7.91-7.96 (m, 1H), 7.78-7.83 (m, 1H), 7.45-7.55 (m, 1H), 7.31 (s, 1H), 7.19-7.27 (m, 2H), 6.76-6.87 (m, 1H), 6.51-6.56 (m, 1H), 6.38-6.45 (m, 1H), 6.04-6.12 (m, 1H), 5.63-5.71 (m, 1H), 4.12-4.29 (m, 2H), 3.87-4.03 (m, 1H), 2.61-3.19 (m, 4H), 2.41-2.50 (m, 1H), 1.92-2.11 (m, 1H), 1.68-1.85 (m, 1H), 1.29-1.49 (m, 1H), 1.07-1.28 (m, 2H), 0.91-0.99 (m, 3H).
Example 103: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one
Example 104: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one
Example 105: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one and
Example 106: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one




Examples 103, 104, 105, and 106 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using (3S)-3-fluoro-4-oxopiperidine-1-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. Note that the fluoro stereocenter epimerized under the reaction conditions giving four stereoisomeric products. The diastereomers partially separated during reverse phase Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+10 mM formic acid). Examples 103 and 104 required further separation by chiral Prep-HPLC on a CHIRALPAK IC3 column using a mixture of [MTBE+0.1% diethylamine] and [dichloromethane/methanol (1:1)]. Examples 105 and 106 required further separation by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [hexanes/dichloromethane (3:1)+0.5% 2M NH3-MeOH] and ethanol. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 103: MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.36-8.38 (m, 2H), 8.00-8.01 (m, 1H), 7.94-7.97 (m, 1H), 7.81 (s, 1H), 7.48-7.50 (m, 1H), 7.35 (s, 1H), 7.22-7.28 (m, 2H), 6.96 (s, 2H), 6.77-6.86 (m, 1H), 6.55 (s, 1H), 6.42-6.45 (m, 1H), 6.08-6.13 (m, 1H), 5.67-5.70 (m, 1H), 4.86-5.02 (m, 1H), 4.05-4.72 (m, 3H), 3.16-3.25 (m, 1H), 2.95-3.05 (m, 2H), 2.74-2.83 (m, 1H), 2.43-2.48 (m, 1H), 2.18 (s, 1H), 1.77-1.83 (m, 2H), 1.48-1.62 (m, 1H), 1.38-1.40 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −203.65.
Example 104: MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.36-8.38 (m, 2H), 8.00-8.02 (m, 1H), 7.94-7.97 (m, 1H), 7.81-7.82 (m, 1H), 7.51-7.53 (m, 1H), 7.35 (s, 1H), 7.22-7.27 (m, 2H), 6.96 (s, 2H), 6.76-6.83 (m, 1H), 6.54-6.55 (m, 1H), 6.42-6.45 (m, 1H), 6.08-6.13 (m, 1H), 5.67-5.70 (m, 1H), 4.77-4.93 (m, 1H), 4.41-4.77 (m, 1H), 4.05-4.39 (m, 2H), 2.93-3.21 (m, 3H), 2.75-2.83 (m, 1H), 2.43-2.50 (m, 1H), 2.08-2.18 (m, 1H), 1.76-1.88 (m, 2H), 1.38-1.61 (m, 2H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −202.95.
Example 105: MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.38 (m, 2H), 8.00-8.02 (m, 1H), 7.94-7.97 (m, 1H), 7.81-7.82 (m, 1H), 7.49-7.52 (m, 1H), 7.35 (s, 1H), 7.23-7.29 (m, 2H), 6.96 (s, 2H), 6.83-6.90 (m, 1H), 6.55-6.56 (m, 1H), 6.42-6.46 (m, 1H), 6.10-6.14 (m, 1H), 5.68-5.71 (m, 1H), 4.38-4.48 (m, 2H), 3.89-4.01 (m, 1H), 3.43-3.83 (m, 3H), 3.10-3.15 (m, 1H), 2.94-2.96 (m, 1H), 2.77-2.81 (m, 1H), 2.32-2.34 (m, 2H), 1.88-2.02 (m, 1H), 1.75-1.80 (m, 1H), 1.52-1.58 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −185.50.
Example 106: MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.25 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.38 (m, 2H), 8.00-8.02 (m, 1H), 7.94-7.96 (m, 1H), 7.81-7.82 (m, 1H), 7.50-7.52 (m, 1H), 7.35 (s, 1H), 7.23-7.29 (m, 2H), 6.95 (s, 2H), 6.81-6.88 (m, 1H), 6.55-6.56 (m, 1H), 6.41-6.44 (m, 1H), 6.10-6.14 (m, 1H), 5.68-5.71 (m, 1H), 4.45-4.65 (m, 1H), 4.36-4.41 (m, 1H), 3.93-4.01 (m, 1H), 3.62-3.80 (m, 2H), 3.45-3.55 (m, 2H), 3.09-3.12 (m, 1H), 2.95-2.99 (m, 1H), 2.76-2.82 (m, 1H), 2.39-2.43 (m, 1H), 1.80-1.98 (m, 2H), 1.47-1.52 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −185.14.
Example 107: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[1-(difluoromethyl) pyrazol-3-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 107 was prepared in a manner analogous to Example 13 using 1-(prop-2-enoyl)piperidin-4-one in place of the ketone and Intermediate 107-1 in place of Intermediate 1-1. MS (ESI) calcd. For C32H31F2N9O, 595.26 m/z, found 596.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.15-8.31 (m, 2H), 7.95-8.12 (m, 2H), 7.66-7.95 (m, 1H), 7.46-7.66 (m, 1H), 7.32-7.46 (m, 1H) 7.08-7.32 (m, 2H), 6.89-7.04 (m, 1H), 6.65-6.89 (m, 1H), 6.31-6.59 (m, 1H), 5.95-6.28 (m, 1H), 5.56-5.86 (m, 1H), 4.46-4.52 (m, 1H), 4.28-4.46 (m, 1H), 3.97-4.28 (m, 1H), 2.95-3.31 (m, 3H), 2.75-2.95 (m, 2H), 2.41-2.55 (m, 1H), 1.96-2.22 (m, 1H), 1.71-1.96 (m, 2H), 1.09-1.52 (m, 2H). (formic acid salt).
Intermediate 107-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[1-(difluoromethyl)pyrazol-3-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-chloroimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 86-1) (2.00 g, 4.19 mmol) in 1,4-dioxane (24 mL) and H2O (6 mL) were added 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.23 g, 5.03 mmol), Pd(dppf)Cl2CH2Cl2 (0.34 g, 0.42 mmol) and Cs2CO3 (4.10 g, 12.6 mmol). The resulting mixture was stirred at 100° C. for 2 h under N2. The reaction was quenched by the addition of water (100 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[1-(difluoromethyl)pyrazol-3-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (1.5 g, 64%) as a yellow solid. MS (ESI) calcd. for C29H28F2N8O2: 558.23 m/z, found: 559.30 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-[1-(difluoromethyl)pyrazol-3-yl]imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 107-1
A solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[1-(difluoromethyl)pyrazol-3-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (1.5 g, 2.7 mmol) in HCl (15 mL, 4 M in 1,4-dioxane) was stirred for 1 h at room temperature. The residue was diluted with water (100 mL), then adjusted to pH 6-7 with sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-[1-(difluoromethyl)pyrazol-3-yl]imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 107-1) (1 g, 81%) as a yellow solid. MS (ESI) calcd. for C24H20F2N8, 458.18 m/z, found 459.15 [M+H]+.
Example 108: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-(2-methoxyacrylamido)benzamide




Example 108 was prepared in a manner analogous to Example 1 using Intermediate 5-1 in place of Intermediate 1-1, 2-methoxyacrylate in place of Intermediate 1-3 and 80° C. for 1 h in dichloromethane instead of 70° C. overnight in toluene. MS (ESI) calcd. for C34H29N9O3, 611.24 m/z, found 612.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.44-8.53 (m, 2H), 8.39-8.43 (m, 1H), 8.04-8.12 (m, 1H), 7.99-8.03 (m, 1H), 7.87-7.91 (m, 1H), 7.79-7.86 (m, 2H), 7.58-7.67 (m, 1H), 7.43-7.52 (m, 2H), 7.32-7.41 (m, 1H), 7.23-7.31 (m, 1H), 6.81-6.90 (m, 1H), 6.58-6.64 (m, 1H), 5.59-5.71 (m, 1H), 5.32-5.41 (m, 1H), 4.73-4.82 (m, 1H), 3.73 (s, 3H), 2.89-3.15 (m, 2H), 2.63-2.71 (m, 1H), 2.03-2.19 (m, 1H).
Example 109: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(oxazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 109 was prepared in a manner analogous to Example 13 using Intermediate 109-2 in place of Intermediate 1-1, and methanol+5 eq AcOH instead of 1,2-dichloroethane. MS (ESI) calcd. for C31H30N8O2, 546.25 m/z, found 547.20 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 8.39-8.46 (m, 1H), 8.18-8.30 (m, 2H), 8.04-8.15 (m, 1H), 7.70-7.84 (m, 2H), 7.53-7.61 (m, 1H), 7.40-7.52 (m, 2H), 6.70-6.90 (m, 2H), 6.10-6.20 (m, 1H), 5.69-5.80 (m, 1H), 4.96-5.10 (m, 1H), 4.48-4.60 (m, 1H), 4.12-4.28 (m, 1H), 3.50-3.61 (m, 1H), 3.08-3.25 (m, 2H), 2.90-3.05 (m, 1H), 2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 2.18-2.30 (m, 2H), 2.06-2.17 (m, 1H), 1.43-1.65 (m, 2H).
Intermediate 109-2: 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a stirred mixture of 2-(2-aminopyridin-3-yl)-3-[(1S)-1-[(tert-butoxycarbonyl)amino]-2,3-dihydro-1H-inden-5-yl]imidazo[4,5-b]pyridin-5-ylboronic acid (Intermediate 109-1) (300 mg, 0.617 mmol, 1 equiv) in dioxane (6 mL) was added 2-bromo-1,3-oxazole (109.5 mg, 0.740 mmol, 1.2 equiv), Pd(dtbpf)Cl2 (40 mg, 0.062 mmol, 0.1 equiv), K2CO3 (170.5 mg, 1.234 mmol, 2 equiv) and H2O (1.5 mL). The resulting mixture was stirred at 90° C. for 2 h under a nitrogen atmosphere. The mixture was purified by reverse phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (230 mg, 73%) as a yellow solid. MS (ESI) calcd. for C28H27N7O3: 509.22 m/z, found: 510.20 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 109-2
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (220 mg, 0.432 mmol, 1 equiv) in DCM (6 mL) was added TFA (2 mL) and the resulting mixture was stirred at r.t for 1 h. The mixture was basified to pH 8 with aq. NaOH (2 mol/L). The resulting mixture was extracted with ethyl acetate (2×20 ml). The combined organic layers were concentrated under reduced pressure to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 109-2) (200 mg, crude) as a yellow solid. MS (ESI) calcd. for C23H19N7O: 409.17 m/z, found: 410.20 [M+H]+.
Intermediate 109-1: (S)-(2-(2-aminopyridin-3-yl)-3-(1-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-5-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid




Synthetic Route:





Step 1: Synthesis of (S)-(2-(2-aminopyridin-3-yl)-3-(1-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-5-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Intermediate 109-1
To a solution of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 85-1) (3 g, 5.8 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.753 g, 6.905 mmol) in dioxane (30 mL) were added Pd(OAc)2 (77.5 mg, 0.345 mmol), PCy3 (193.6 mg, 0.690 mmol) and KOAc (1.412 g, 14.39 mmol) and the mixture was stirred for 2 h at 110° C. under a nitrogen atmosphere. After cooling to room temperature, the mixture was quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel flash column chromatography (0-15%, MeOH/DCM) to afford (S)-(2-(2-aminopyridin-3-yl)-3-(1-((tert-butoxycarbonyl)amino)-2,3-dihydro-1H-inden-5-yl)-3H-imidazo[4,5-b]pyridin-5-yl)boronic acid (Intermediate 109-1) (1.7 g, 61% yield) as a white solid. MS (ESI) calcd. for C25H27N6BO4: 486.21 m/z, found 487.25 [M+H]+.
Example 110: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 110 was prepared in a manner analogous to Example 109 (via Intermediate 109-2) using 3-bromopyridine in place of 2-bromo-1,3-oxazole. MS (ESI) calcd. for C33H32N8O, 556.27 m/z, found 557.25 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 9.25-9.35 (m, 1H), 8.65-8.75 (m, 1H), 8.60-8.64 (m, 1H), 8.40-8.50 (m, 1H), 8.05-8.22 (m, 2H), 7.66-7.85 (m, 3H), 7.56-7.65 (m, 1H), 7.45-7.55 (m, 1H), 6.75-6.90 (m, 2H), 6.08-6.20 (m, 1H), 5.68-5.78 (m, 1H), 4.88-5.08 (m, 1H), 4.40-4.60 (m, 1H), 4.12-4.25 (m, 1H), 3.50-3.60 (m, 1H), 3.06-3.25 (m, 2H), 2.90-3.05 (m, 1H), 2.67-2.80 (m, 1H), 2.54-2.65 (m, 1H), 2.18-2.30 (m, 2H), 2.05-2.17 (m, 1H), 1.42-1.62 (m, 2H).
Example 111: 1-((2*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-ethynylpiperidin-1-yl)prop-2-en-1-one and
Example 112: 1-((2*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-ethynylpiperidin-1-yl)prop-2-en-1-one




Examples and 112 were prepare in a manner analogous to Example 14 using Intermediate 111-1 in place of Intermediate 14-1. The diastereomers separated during Prep-HPLC on a Kinetex EVO C18 column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3). * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 111: MS (ESI) calcd. for C33H31N9O, 569.27 m/z, found 570.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 7.93-8.02 (m, 2H), 7.80 (s, 1H), 7.21-7.29 (m, 2H), 7.32-7.53 (m, 2H), 6.79-6.94 (m, 3H), 6.54-6.56 (m, 1H), 6.42-6.45 (m, 1H), 6.12-6.17 (m, 1H), 5.70-5.74 (m, 1H), 5.21-5.56 (m, 1H), 4.34-4.42 (m, 1H), 3.92-4.07 (m, 1H), 3.39-3.40 (m, 1H), 3.28-3.30 (m, 1H), 3.11-3.22 (m, 1H), 2.93-3.01 (m, 1H), 2.75-2.82 (m, 1H), 2.42-2.49 (m, 1H), 1.99-2.28 (m, 3H), 1.71-1.83 (m, 1H), 1.32-1.53 (m, 1H), 1.07-1.23 (m, 1H).
Example 112: MS (ESI) calcd. for C33H31N9O, 569.27 m/z, found 570.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 7.99-8.02 (m, 1H), 7.94-7.96 (m, 1H), 7.80 (s, 1H), 7.21-7.53 (m, 4H), 6.94 (s, 2H), 6.79-6.86 (m, 1H), 6.54-6.56 (m, 1H), 6.42-6.45 (m, 1H), 6.12-6.17 (m, 1H), 5.70-5.74 (m, 1H), 5.21-5.35 (m, 1H), 4.39-4.45 (m, 1H), 3.82-4.13 (m, 1H), 3.43-3.59 (m, 1H), 3.39-3.40 (m, 1H), 3.17-3.21 (m, 1H), 2.91-2.99 (m, 1H), 2.73-2.88 (m, 1H), 2.42-2.49 (m, 1H), 2.13-2.27 (m, 2H), 1.55-1.83 (m, 4H).
Intermediate 111-1: tert-butyl (*)-2-ethynyl-4-oxopiperidine-1-carboxylate and
Intermediate 111-2: tert-butyl (*)-2-ethynyl-4-oxopiperidine-1-carboxylate




Intermediates 111-1 and 111-2 were prepared in a manner analogous to Intermediate 14-1 using tert-butyl 2-ethynyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The enantiomers were separated by chiral HPLC on a CHIRALPAK IF column eluting using a mixture of [Hex (+0.5% 2M NH3-MeOH)] and ethanol to afford tert-butyl (S*)-2-ethynyl-4-oxopiperidine-1-carboxylate (Intermediate 111-1) as the second eluting peak and tert-butyl (R*)-2-ethynyl-4-oxopiperidine-1-carboxylate (Intermediate 111-2) as the first eluting peak. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer. MS (ESI) calcd. for C10H11NO2, 117.08 m/z, found 118.15 [M+H]+.
Example 113: 1-((2*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-ethynylpiperidin-1-yl)prop-2-en-1-one and
Example 114: 1-((2*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-ethynylpiperidin-1-yl)prop-2-en-1-one




Examples 113 and 114 were prepared in a manner analogous to Example 14 using Intermediate 111-2 in place of Intermediate 14-1. The diastereomers separated during Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.1% formic acid). * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 113: MS (ESI) calcd. for C33H31N9O, 569.27 m/z, found 570.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 7.96-8.08 (m, 2H), 7.80 (s, 1H), 7.41-7.46 (m, 1H), 7.17-7.36 (m, 3H), 6.94 (s, 2H), 6.79-6.85 (m, 1H), 6.53-6.55 (m, 1H), 6.42-6.45 (m, 1H), 6.12-6.17 (m, 1H), 5.69-5.74 (m, 1H), 5.21-5.56 (m, 1H), 4.31-4.42 (m, 1H), 3.92-4.07 (m, 1H), 3.43-3.60 (m, 1H), 3.39-3.41 (m, 1H), 3.08-3.12 (m, 1H), 2.88-3.01 (m, 1H), 2.75-2.82 (m, 1H), 2.35-2.49 (m, 1H), 2.04-2.28 (m, 2H), 1.98-2.01 (m, 1H), 1.63-1.83 (m, 1H), 1.11-1.42 (m, 2H). (formic acid salt).
Example 114: MS (ESI) calcd. for C33H31N9O, 569.27 m/z, found 570.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 7.99-8.02 (m, 1H), 7.94-7.96 (m, 1H), 7.80 (s, 1H), 7.41-7.46 (m, 1H), 7.29-7.32 (m, 1H), 7.18-7.26 (m, 2H), 6.94 (s, 2H), 6.79-6.85 (m, 1H), 6.53-6.55 (m, 1H), 6.42-6.45 (m, 1H), 6.12-6.17 (m, 1H), 5.69-5.74 (m, 1H), 5.17-5.26 (m, 1H), 4.23-4.39 (m, 1H), 3.89-4.01 (m, 1H), 3.49-3.62 (m, 1H), 3.09-3.11 (m, 1H), 2.88-3.02 (m, 1H), 2.72-2.81 (m, 1H), 2.39-2.41 (m, 1H), 2.07-2.29 (m, 2H), 1.97-2.03 (m, 2H), 1.88-1.91 (m, 1H), 1.78-1.85 (m, 1H), 1.53-1.70 (m, 1H). (formic acid salt).
Example 115: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxypiperidin-1-yl)prop-2-en-1-one
Example 116: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxypiperidin-1-yl)prop-2-en-1-one
Example 117: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxypiperidin-1-yl)prop-2-en-1-one and
Example 118: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methoxypiperidin-1-yl)prop-2-en-1-one




Examples 115, 116, 117 and 118 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 3-methoxy-4-oxopiperidine-1-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers separated partially during reverse phase Prep-HPLC on a XSelect CSH Fluoro column using a gradient of acetonitrile in water (+10 mM TFA). Examples 117 and 118 required further separation by chiral Prep-HPLC on a CHIRALPAK IG column eluting using a mixture of [3:1 Hexanes/dichloromethane (+0.5% 2M NH3-MeOH)] and ethanol * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 115: MS (ESI) calcd. for C32H33N9O2: 575.28 m/z, found: 576.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.30-8.42 (m, 2H), 7.92-8.05 (m, 2H), 7.78-7.88 (m, 1H), 7.40-7.51 (m, 1H), 7.20-7.38 (m, 3H), 6.73-6.85 (m, 1H), 6.52-6.60 (m, 1H), 6.42-6.51 (m, 1H), 6.05-6.19 (m, 1H), 5.68-5.75 (m, 1H), 4.15-4.60 (m, 3H), 3.91-4.00 (m, 1H), 3.54-3.68 (m, 1H), 3.28-3.41 (m, 3H), 3.12-3.25 (m, 1H), 2.95-3.05 (m, 2H), 2.75-2.85 (m, 1H), 2.35-2.45 (m, 1H), 1.80-1.91 (m, 1H), 1.41-1.71 (m, 2H).
Example 116: MS (ESI) calcd. for C32H33N9O2: 575.28 m/z, found: 576.25 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.30-8.40 (m, 2H), 7.92-8.05 (m, 2H), 7.79-7.85 (m, 1H), 7.21-7.52 (m, 4H), 6.75-6.85 (m, 1H), 6.42-6.58 (m, 2H), 6.08-6.18 (m, 1H), 5.68-5.78 (m, 1H), 4.18-4.40 (m, 2H), 3.89-4.17 (m, 1H), 3.41-3.50 (m, 1H), 3.29-3.35 (m, 3H), 3.21-3.28 (m, 1H), 2.90-3.18 (m, 3H), 2.72-2.88 (m, 1H), 2.40-2.51 (m, 1H), 1.48-1.82 (m, 3H).
Example 117: MS (ESI) calcd. for C32H33N9O2: 575.28 m/z, found: 576.15 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.32-8.40 (m, 2H), 7.93-8.05 (m, 2H), 7.78-7.84 (m, 1H), 7.48-7.55 (m, 1H), 7.22-7.35 (m, 3H), 6.72-6.89 (m, 1H), 6.52-6.59 (m, 1H), 6.42-6.50 (m, 1H), 6.08-6.18 (m, 1H), 5.68-5.75 (m, 1H), 4.32-4.39 (m, 1H), 3.89-4.20 (m, 1H), 3.62-3.71 (m, 1H), 3.40-3.50 (m, 1H), 3.20-3.39 (m, 4H), 3.05-3.19 (m, 1H), 2.85-3.00 (m, 2H), 2.70-2.84 (m, 1H), 2.42-2.51 (m, 1H), 1.78-2.01 (m, 2H), 1.31-1.45 (m, 1H). (TFA salt).
Example 118: MS (ESI) calcd. for C32H33N9O2: 575.28 m/z, found: 576.15 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.30-8.40 (m, 2H), 7.92-8.05 (m, 2H), 7.76-7.83 (m, 1H), 7.45-7.55 (m, 1H), 7.20-7.35 (m, 3H), 6.72-6.90 (m, 1H), 6.52-6.59 (m, 1H), 6.42-6.50 (m, 1H), 6.09-6.19 (m, 1H), 5.67-5.78 (m, 1H), 4.30-4.40 (m, 1H), 3.89-4.20 (m, 1H), 3.62-3.71 (m, 1H), 3.39-3.50 (m, 1H), 3.20-3.39 (m, 4H), 3.09-3.20 (m, 1H), 2.85-3.05 (m, 2H), 2.70-2.85 (m, 1H), 2.40-2.51 (m, 1H), 1.75-2.01 (m, 2H), 1.31-1.42 (m, 1H). (TFA salt).
Example 119: 1-(4-{[(1R)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,2-difluoro-1,3-dihydroinden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 119 was prepared in a manner analogous to Example 13 using Intermediate 119-2 in place of Intermediate 1-1 and a reaction time and temp of 2 h at 60° C. MS (ESI) calcd. for C31H29F2N9O, 581.25 m/z, found 582.15 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.22-8.49 (m, 2H), 7.89-8.15 (m, 2H), 7.69-7.89 (m, 1H), 7.42-7.64 (m, 1H), 7.31-7.42 (m, 2H), 7.13-7.31 (m, 1H), 6.65-6.96 (m, 1H), 6.52-6.65 (m, 1H), 6.36-6.52 (m, 1H), 5.98-6.25 (m, 1H), 5.61-5.85 (m, 1H), 4.49-4.76 (m, 1H), 4.11-4.39 (m, 1H), 3.32-3.61 (m, 2H), 3.02-3.32 (m, 2H), 2.77-3.02 (m, 1H), 2.51-2.56 (m, 1H), 1.98-2.19 (m, 1H), 1.78-1.98 (m, 1H), 1.15-1.49 (m, 2H). (formic acid salt).
Intermediate 119-2: (R)-3-(3-(1-amino-2,2-difluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 119-2 was prepared in a manner analogous to Intermediate 75-1 (starting from Step 2) using Intermediate 119-1 in place of 5-bromo-2-fluoro-2,3-dihydroinden-1-one and omitting the chiral separation by SFC. MS (ESI) calcd. for C23H18F2N8, 444.16 m/z, found: 445.15 [M+H]+.
Intermediate 119-1: 5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-one




Synthetic Route:





Step 1: Synthesis of 5-bromo-2-fluoro-2,3-dihydro-1-inden-1-one

To a solution of 5-bromo-1-indanone (5.00 g, 23.8 mmol) in methanol (50 mL) was added SelectFluor (10.0 g, 28.2 mmol) and the resulting mixture was stirred under reflux for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (50 mL), and 1 N hydrochloric acid (50 mL) was added followed by stirring at room temperature for 3 hours. To the reaction mixture, a 2 N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was diluted with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford 5-bromo-2-fluoro-2,3-dihydroinden-1-one (4.0 g, 74% yield) as a white solid. MS (ESI) calcd. for C9H6BrFO, 227.96 m/z, found: 229.00 [M+H]+.
Step 2: 5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-one (Intermediate 119-1
To a solution of 5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one (3.0 g, 13 mmol, 1 equiv) in DCM (30 mL) was added tert-butyldimethylsilyl trifluoromethanesulfonate (5.16 mL, 988 mmol, 70 equiv) and triethylamine (9.1 mL, 65.5 mmol, 5.0 equiv) and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (30 mL) and Selectfluor (5.57 g, 15.7 mmol, 1.2 equiv) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the resulting residue, hexane was added, and the precipitate was collected by filtration to afford 5-bromo-2,2-difluoro-2,3-dihydro-1H-inden-1-one (Intermediate 119-1) (2.3 g, 71%). MS (ESI) calcd. for C9H5BrF2O, 245.95 m/z, found: 247.00 [M+H]+.
Example 120: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyrazin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 120 was prepared in a manner analogous to Example 13 using Intermediate 120-1 in place of Intermediate 1-1. MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found 558.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.33 (s, 1H), 8.70-8.80 (m, 2H), 8.40-8.50 (m, 2H), 8.05-8.10 (m, 1H), 7.70-7.80 (m, 2H), 7.55-7.60 (m, 1H), 7.35-7.40 (m, 1H), 6.76-6.90 (m, 2H), 6.05-6.20 (m, 1H), 5.80-5.90 (m, 1H), 5.00 (s, 1H), 4.50-4.60 (m, 1H), 4.18-4.27 (m, 1H), 3.58-3.67 (m, 1H), 3.16-3.25 (m, 2H), 2.90-3.04 (m, 1H), 2.73-2.80 (m, 1H), 2.53-2.60 (m, 1H), 2.25-2.38 (m, 2H), 2.10-2.20 (m, 1H), 1.38-1.65 (m, 2H). (TFA salt).
Intermediate 120-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(pyrazin-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-7-amine




Intermediate 120-1 was prepared in a manner analogous to Intermediate 109-2 using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(III) in place of bis(di-tert-butylphosphino)ferrocene]dichloropalladium(III) and 2-bromopyrazine in place of 2-bromo-1,3-oxazole. MS (ESI) calcd. for C24H20N8: 420.18 m/z, found 421.15 [M+H]+.
Example 121: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 121 was prepared in a manner analogous to Example 120 (via Intermediate 120-1) using 2-bromo-6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine in place of 2-bromopyrazine. MS (ESI) calcd. for C34H35N9O2: 601.29 m/z, found 602.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.22-8.23 (m, 1H), 7.90-8.00 (m, 2H), 7.55-7.60 (m, 1H), 7.35-7.40 (m, 1H), 7.20-7.25 (m, 2H), 6.76-6.80 (m, 1H), 6.48-6.50 (m, 2H), 6.05-6.20 (m, 1H), 5.58-5.70 (m, 1H), 4.80 (s, 2H), 4.50-4.60 (m, 2H), 4.18-4.27 (m, 2H), 4.10-4.15 (m, 2H), 3.88-4.07 (m, 1H), 3.06-3.25 (m, 1H), 2.80-3.04 (m, 4H), 2.53-2.62 (m, 1H), 2.05-2.18 (m, 1H), 1.72-1.94 (m, 2H), 1.38-1.65 (m, 2H).
Example 122: 3-{3-[(1S)-1-({1-[(2R)-oxirane-2-carbonyl]piperidin-4-yl}amino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine




Example 122 was prepared in a manner analogous to Example 4 (last step only) using 3-{3-[(1S)-1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (precursor to Example 34) in place of Intermediate 1-1 and (2R)-oxirane-2-carboxylic acid in place of the carboxylic acid. MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.15 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.39 (m, 2H), 7.94-8.01 (m, 2H), 8.80-8.81 (m, 1H), 7.46-7.49 (m, 1H), 7.33-7.35 (m, 1H), 7.22-7.26 (m, 2H), 6.93-6.94 (m, 2H), 6.53-6.54 (m, 1H), 6.41-6.44 (m, 1H), 4.32-4.34 (m, 1H), 4.05-4.19 (m, 2H), 3.86-3.87 (m, 1H), 3.24-3.32 (m, 1H), 2.87-2.97 (m, 4H), 2.74-2.80 (m, 2H), 2.49-2.51 (m, 1H), 2.09-2.11 (m, 1H), 1.77-2.01 (m, 3H), 1.21-1.41 (m, 2H).
Example 123: 3-{3-[(1S)-1-({1-[(2S)-oxirane-2-carbonyl]piperidin-4-yl}amino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine




Example 123 was prepared in a manner analogous to Example 4 (last step only) using 3-{3-[(1S)-1-(piperidin-4-ylamino)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (precursor to Example 34) in place of Intermediate 1-1 and (2S)-oxirane-2-carboxylic acid in place of the carboxylic acid. MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.38 (m, 2H), 7.94-8.01 (m, 2H), 7.80-7.81 (m, 1H), 7.22-7.49 (m, 4H), 6.93-6.94 (m, 2H), 6.53-6.54 (m, 1H), 6.41-6.44 (m, 1H), 4.32-4.34 (m, 1H), 4.05-4.19 (m, 2H), 3.84-3.88 (m, 1H), 3.21-3.32 (m, 1H), 2.74-2.95 (m, 6H), 2.44-2.51 (m, 1H), 2.09-2.11 (m, 1H), 1.77-2.01 (m, 3H), 1.21-1.41 (m, 2H).
Example 124: 1-[(3*)-3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl]prop-2-en-1-one (assumed) and
Example 125: 1-[(3*)-3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl]prop-2-en-1-one (assumed




Examples 124 and 125 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 3-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, 4N HCl in dioxane in place of TFA in DCM, and 0° C. to room temperature for 2 h in methanol for the final step. The diastereomers were separated by chiral HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [hexanes/MTBE (1:1) (+0.5% 2M NH3-MeOH)] and tetrahydrofuran. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 124: MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found: 546.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 7.94-8.01 (m, 2H), 7.81 (s, 1H), 7.48-7.50 (m, 1H), 7.35-7.37 (m, 1H), 7.22-7.27 (m, 2H), 6.83-6.87 (m, 1H), 6.55 (s, 1H), 6.43-6.44 (m, 1H), 6.09-6.13 (m, 1H), 5.67-5.69 (m, 1H), 4.42-4.48 (m, 1H), 3.87-3.99 (m, 1H), 2.99-3.20 (m, 3H), 2.92-2.95 (m, 2H), 2.18-2.34 (m, 2H), 1.62-2.01 (m, 4H), 1.35-1.55 (m, 1H).
Example 125: MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found: 546.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.35 (m, 2H), 7.92-7.99 (m, 2H), 7.79 (s, 1H), 7.62-7.64 (m, 1H), 7.43-7.56 (m, 1H), 7.24-7.39 (m, 2H), 6.75-6.86 (m, 1H), 6.54 (s, 1H), 6.42-6.45 (m, 1H), 6.06-6.13 (m, 1H), 5.69-5.72 (m, 1H), 4.57-4.73 (m, 1H), 3.92-4.11 (m, 1H), 2.91-3.07 (m, 3H), 2.75-2.89 (m, 2H), 1.97-2.16 (m, 2H), 1.41-1.52 (m, 1H), 1.32-1.36 (m, 4H).
Example 126: 1-[(4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one and
Example 127: 1-[(4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of 1-[(4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one (Example 126) and 1-[(4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3,4-dihydro-2H-quinolin-1-yl]prop-2-en-1-one (Example 127)
To a solution of 1-(prop-2-enoyl)-2,3-dihydroquinolin-4-one (Intermediate 126-1) (100 mg, 0.497 mmol) in THF (5 mL) were added 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (203 mg, 0.497 mmol) and titanium tetraisopropoxide (28.3 mg, 0.497 mmol). The reaction mixture was stirred at 75° C. overnight. The mixture was cooled to room temperature and NaBH3CN (37.5 mg, 0.596 mmol) was added. Stirring was continue at room temperature for 1 h. The reaction was quenched with H2O (10 mL). The resulting mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+0.05% TFA). The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IG column using a mix of [hexanes/DCM (3:1) (+0.5% 2M NH3-MeOH)] and isopropanol to afford 1-((*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one (Example 126) (5.3 mg, 2%) as white solid and 1-((*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,4-dihydroquinolin-1(2H)-yl)prop-2-en-1-one (19.4 mg, 8%) as yellow solid. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 126: MS (ESI) calcd. for C35H31N9O: 593.27 m/z, found: 594.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.36 (m, 2H), 7.95-8.00 (m, 2H), 7.80-7.93 (m, 1H), 7.48-7.49 (m, 1H), 7.15-7.49 (m, 7H), 6.49-6.54 (m, 3H), 6.22-6.27 (m, 1H), 5.69-5.72 (m, 1H), 4.17-4.18 (m, 1H), 388-3.95 (m, 2H), 3.69-3.72 (m, 1H), 2.92-2.94 (m, 1H), 2.72-2.78 (m, 1H), 2.52-2.53 (m, 1H), 2.06-2.07 (m, 1H), 2.00-2.02 (m, 1H), 1.88-1.90 (m, 1H).
Example 127: MS (ESI) calcd. for C35H31N9O: 593.27 m/z, found: 594.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.34-8.35 (m, 2H), 7.94-8.00 (m, 2H), 7.80-7.82 (m, 1H), 7.50-7.52 (m, 2H), 7.17-7.32 (m, 6H), 6.52-6.56 (m, 2H), 6.42-6.45 (m, 1H), 6.22-6.27 (m, 1H), 5.72-5.75 (m, 1H), 4.40-4.42 (m, 1H), 4.00-4.02 (m, 1H), 3.97-3.99 (m, 2H), 2.94-2.95 (m, 1H), 2.77-2.79 (m, 1H), 2.40-2.52 (m, 1H), 2.08-2.09 (m, 1H), 2.00-2.03 (m, 1H), 1.78-1.79 (m, 1H).
Intermediate 126-1: 1-acryloyl-2,3-dihydroquinolin-4(1H)-one




Intermediate 126-1 was prepared in a manner analogous to Intermediate 14-1 using 2,3-dihydroquinolin-4(1H)-one in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. MS (ESI) calcd. for C12H11NO2, 201.08 m/z, found 202.10 [M+H]+.
Example 128: 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino-N}-(cyanomethyl)-N-methylpiperidine-1-carboxamide




Example 128 was prepared in a manner analogous to Example 13 using Intermediate 128-1 in place of the ketone. MS (ESI) calcd. for C32H33N11O: 587.29 m/z, found: 588.25 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.03-9.17 (m, 2H), 8.36-8.44 (m, 2H), 8.08-8.09 (m, 1H), 7.99-8.01 (m, 1H), 7.83-7.84 (m, 1H), 7.75-7.77 (m, 1H), 7.58-7.61 (m, 2H), 7.44-7.46 (m, 1H), 6.65-6.68 (m, 1H), 6.57-6.59 (m, 1H), 5.01-5.02 (m, 1H), 4.13 (s, 2H), 3.72-4.78 (m, 2H), 3.49-3.51 (m, 1H), 3.15-3.21 (m, 1H), 2.94-3.00 (m, 2H), 2.87-2.93 (m, 3H), 2.56-2.60 (m, 1H), 2.50-2.55 (m, 2H), 2.16-2.26 (m, 2H), 2.04-2.07 (m, 1H), 1.58-1.66 (m, 2H). (TFA salt).
Intermediate 128-1: N-(cyanomethyl)-N-methyl-4-oxopiperidine-1-carboxamide




Synthetic Route:





Step 1: Synthesis of N-(cyanomethyl)-N-methylcarbamoyl chloride
To a cooled (0° C.) solution of 2-(methylamino)acetonitrile (1 g, 14.3 mmol) in DCM (10 mL) was added pyridine (5.64 g, 71.3 mmol) and the resulting mixture was stirred at 0° C. for 20 min. Then a solution of triphosgene (4.23 g, 14.3 mmol) in DCM (10 mL) was added dropwise and the mixture was stirred at room temperature for 1 h. The reaction was quenched with H2O (50 mL). The resulting mixture was extracted with DCM (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford N-(cyanomethyl)-N-methylcarbamoyl chloride (1.27 g crude) as a brown oil. MS (ESI) calcd. for C4H5ClN2O: 132.01 m/z, found: 131.05 [M−H]−.
Step 2: Synthesis of N-(cyanomethyl)-N-methyl-4-oxopiperidine-1-carboxamide (Intermediate 128-1
To a solution of 4-piperidinone (299.2 mg, 3.018 mmol) in DCM (10 mL) was added triethylamine (916.1 mg, 9.054 mmol) and N-(cyanomethyl)-N-methylcarbamoyl chloride (400 mg, 3.02 mmol). The resulting mixture was stirred at room temperature for 1 h. The solvent was removed by distillation under vacuum to afford N-(cyanomethyl)-N-methyl-4-oxopiperidine-1-carboxamide (Intermediate 128-1) (500 mg crude) as a yellow oil. MS (ESI) calcd. for C9H13N3O2: 195.10 m/z, found: 196.15 [M+H]+.
Example 129: 1-[(2S,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-(methoxymethyl)piperidin-1-yl]prop-2-en-1-one and
Example 130: 1-[(2S,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-(methoxymethyl)piperidin-1-yl]prop-2-en-1-one




Examples 129 and 130 were prepared in a manner analogous to Example 13 (via Intermediate 14-1) using Intermediate 129-1 in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and TFA/acetonitrile at 80° C. overnight (under air) instead of TFA/DCM at room temperature for 2 h. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SC column using an mixture of [MTBE (+0.5% 2M NH3-MeOH)] and [methanol/DCM (1:1)].
Example 129: MS (ESI) calcd. for C33H35N9O2: 589.29 m/z, found: 590.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.41-8.28 (m, 2H), 7.98 (dd, J=23.3, 6.7 Hz, 2H), 7.81 (s, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.36 (s, 1H), 7.27 (dd, J=17.9, 7.8 Hz, 2H), 6.92 (s, 2H), 6.79 (dd, J=16.7, 10.4 Hz, 1H), 6.56 (s, 1H), 6.49-6.37 (m, 1H), 6.07 (d, J=16.8 Hz, 1H), 5.63 (d, J=10.5 Hz, 1H), 4.34 (s, 1H), 4.20-3.82 (m, 1H), 3.78-3.44 (m, 2H), 3.24 (s, 3H), 3.16-3.06 (m, 2H), 3.06-2.87 (m, 2H), 2.87-2.62 (m, 2H), 1.96 (d, J=14.3 Hz, 1H), 1.71 (d, J=29.8 Hz, 4H), 1.23 (s, 1H).
Example 130: MS (ESI) calcd. for C33H35N9O2: 589.29 m/z, found: 590.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.23 (s, 2H), 8.71-8.32 (m, 3H), 8.12-7.94 (m, 2H), 7.91-7.69 (m, 2H), 7.61-7.32 (m, 3H), 7.11 (d, J=51.0 Hz, 1H), 6.84 (td, J=17.1, 10.5 Hz, 1H), 6.62-6.54 (m, 1H), 6.12 (ddd, J=16.7, 5.8, 2.4 Hz, 1H), 5.82-5.63 (m, 1H), 4.99 (d, J=17.2 Hz, 1H), 4.52 (d, J=13.3 Hz, 1H), 3.27 (d, J=1.9 Hz, 3H), 3.15-2.77 (m, 3H), 2.43-2.14 (m, 3H), 1.90-1.39 (m, 3H), 1.17 (t, J=7.3 Hz, 4H).
Intermediate 129-1: tert-butyl (S)-7-(methoxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate




Synthetic Route:





Step 1: Synthesis of 8-(tert-butyl) 7-ethyl (S)-1,4-dioxa-8-azaspiro[4.5]decane-7,8-dicarboxylate
A solution of 1-tert-butyl 2-ethyl (2S)-4-oxopiperidine-1,2-dicarboxylate (2 g, 7.4 mmol, 1 equiv), ethylene glycol (2.29 g, 36.9 mmol, 5 equiv) and triethyl orthoformate (3.28 g, 22.1 mmol, 3 equiv) in toluene (20 mL) was treated with p-toluenesulfonic acid (0.06 g, 0.37 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred overnight at 90° C. The mixture was allowed to cool to room temperature. The reaction was quenched with water (50 mL) then extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 8-(tert-butyl) 7-ethyl (S)-1,4-dioxa-8-azaspiro[4.5]decane-7,8-dicarboxylate (2 g, 69%) was obtained as a light yellow oil. MS (ESI) calcd. for C15H25NO6: 315.17 m/z, found: 316.20 [M+H]+.
Step 2: Synthesis of tert-butyl (7S)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate
A cooled (0° C.) solution of 8-(tert-butyl) 7-ethyl (S)-1,4-dioxa-8-azaspiro[4.5]decane-7,8-dicarboxylate (2 g, 6.3 mmol, 1 equiv) in THE (20 mL) was treated with DIBAl—H (2.25 g, 15.9 mmol, 2.5 equiv) over 5 min under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 0° C. under nitrogen atmosphere. The reaction was quenched with water (50 mL) then extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with potassium sodium tartrate (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using (1:1) ethyl acetate in petroleum ether to afford tert-butyl (7S)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (1 g, 46%) as a yellow oil. MS (ESI) calcd. for C13H23NO5: 273.16 m/z, found: 274.15 [M+H]+.
Step 3: Synthesis of tert-butyl (7S)-7-(methoxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 129-1
A solution of tert-butyl (7S)-7-(hydroxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (804 mg, 2.94 mmol, 1 equiv) in THE (6 mL) was treated with NaH (141 mg, 5.88 mmol, 2 equiv) portion wise over 10 min at room temperature. The resulting mixture was stirred for 30 min at room temperature. To the above mixture was added methyl iodide (501 mg, 3.53 mmol, 1.2 equiv) dropwise over 2 min. The resulting mixture was stirred overnight at 50° C. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of water (50 mL) at 0° C. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl (7S)-7-(methoxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (Intermediate 129-1) (540 mg, 51%) as a brown/yellow oil. MS (ESI) calcd. for C14H25NO5: 287.17 m/z, found: 288.20 [M+H]+.
Example 131: 1-[(1R,4R,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one
Example 132: 1-[(1R,4R,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one
Example 133: 1-[(1S,4S,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one and
Example 134: 1-[(1S,4S,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one




Examples 131, 132, 133 and 134 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, using 4N HCl in dioxane in place of TFA in DCM, and methanol instead of 1,2-dichloroethane for the final step. Example 131 was separated from the other three diastereomers by chiral Prep HPLC on a CHIRALPAK IA3 column using a mixture of [MTBE (+0.1% diethylamine)] and [EtOH/DCM (1:1)]. Example 132 was separated from the remaining two diastereomers by chiral Prep HPLC on a CHIRALPAK OD column using a mix of [hexanes (+0.5% 2M NH3-MeOH)] and ethanol. Examples 133 and 134 were separated by chiral Prep-HPLC on a CHIRALPAK IA column using a mix of [MTBE (+0.5% 2M NH3-MeOH)] and [ethanol/DCM (1:1)]. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 131: MS (ESI) calcd. for C33H33N9O: 571.28 m/z, found: 572.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.37-8.40 (m, 2H), 8.00-8.05 (m, 2H), 7.78-7.83 (m, 2H), 7.51-7.58 (m, 1H), 7.41-7.49 (m, 1H), 7.38-7.40 (m, 1H), 6.58-6.70 (m, 3H), 6.12-6.24 (m, 1H), 5.68-5.69 (m, 1H), 4.96-4.97 (m, 1H), 4.20-4.49 (m, 1H), 3.80-3.88 (m, 1H), 3.73-3.79 (m, 2H), 3.38-3.42 (m, 1H), 3.18-3.19 (m, 1H), 3.00-3.01 (m, 1H), 2.52-2.53 (m, 1H), 2.43-2.44 (m, 1H), 2.23-2.28 (m, 2H), 1.67-1.79 (m, 4H).
Example 132: MS (ESI) calcd. for C33H33N9O: 571.28 m/z, found: 572.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.36 (m, 2H), 7.95-8.00 (m, 1H), 7.93-7.95 (m, 1H), 7.80-7.81 (m, 1H), 7.49-7.51 (m, 1H), 7.26-7.32 (m, 1H), 7.21-7.24 (m, 2H), 6.66-6.70 (m, 1H), 6.54-6.55 (m, 1H), 6.42-6.43 (m, 1H), 6.06-6.17 (m, 1H), 5.60-5.71 (m, 1H), 4.23-4.33 (m, 2H), 4.03-4.05 (m, 1H), 3.42-3.50 (m, 1H), 3.08-3.10 (m, 1H), 2.94-2.98 (m, 1H), 2.76-2.78 (m, 1H), 2.10-2.11 (m, 4H), 1.77-1.80 (m, 2H), 1.60-1.70 (m, 1H), 1.56-1.60 (m, 1H), 1.30-1.35 (m, 1H).
Example 133: MS (ESI) calcd. for C33H33N9O: 571.28 m/z, found: 572.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.34 (m, 2H), 7.97-7.99 (m, 1H), 7.92-7.94 (m, 1H), 7.78-7.79 (m, 1H), 7.43-7.45 (m, 1H), 7.23-7.29 (m, 1H), 7.20-7.21 (m, 2H), 6.65-6.68 (m, 1H), 6.52-6.53 (m, 1H), 6.40-6.43 (m, 1H), 6.09-6.16 (m, 1H), 5.60-5.70 (m, 1H), 4.19-4.34 (m, 2H), 3.99-4.00 (m, 1H), 3.36-3.39 (m, 1H), 3.00-3.10 (m, 1H), 2.90-2.93 (m, 1H), 2.70-2.80 (m, 1H), 2.30-2.45 (m, 1H), 2.04-2.06 (m, 1H), 1.80-1.85 (m, 1H), 1.71-1.79 (m, 1H), 1.50-2.51 (m, 4H), 1.35-1.40 (m, 1H).
Example 134: MS (ESI) calcd. for C33H33N9O: 571.28 m/z, found: 572.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.36 (m, 2H), 7.93-8.00 (m, 2H), 7.78-7.83 (m, 1H), 7.49-7.51 (m, 1H), 7.25-7.32 (m, 1H), 7.21-7.24 (m, 2H), 6.66-6.69 (m, 1H), 6.53-6.54 (m, 1H), 6.40-6.43 (m, 1H), 6.05-6.17 (m, 1H), 5.59-5.60 (m, 1H), 4.00-4.35 (m, 2H), 3.50-3.59 (m, 1H), 3.29-3.35 (m, 1H), 2.90-3.00 (m, 1H), 2.82-2.93 (m, 1H), 2.76-2.78 (m, 1H), 2.40-2.51 (m, 1H), 1.97-2.09 (m, 3H), 1.75-1.82 (m, 2H), 1.60-1.70 (m, 1H), 1.22-1.39 (m, 2H).
Example 135: 1-[(1S,4S,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one and
Example 136: 1-[(1S,4S,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one




Examples 135 and 136 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl (1S,4S)-5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and methanol (+5 eq AcOH) in place of 1,2-dichloroethane for the final step. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK OD column using a mix of [hexanes (+0.5% 2M NH3-MeOH)] and ethanol.
Example 135: MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.28-8.35 (m, 2H), 7.98-8.05 (m, 1H), 7.90-7.97 (m, 1H), 7.75-7.85 (m, 1H), 7.42-7.50 (m, 1H), 7.18-7.30 (m, 3H), 6.48-6.65 (m, 2H), 6.38-6.46 (m, 1H), 6.06-6.20 (m, 1H), 5.58-5.70 (m, 1H), 4.32-4.40 (m, 1H), 4.08-4.15 (m, 1H), 3.73-3.95 (m, 1H), 3.08-3.40 (m, 2H), 2.85-2.98 (m, 1H), 2.65-2.80 (m, 2H), 2.35-2.48 (m, 1H), 1.90-2.10 (m, 1H), 1.53-1.80 (m, 3H), 1.00-1.25 (m, 1H).
Example 136: MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.26-8.40 (m, 2H), 7.90-8.05 (m, 2H), 7.75-7.82 (m, 1H), 7.43-7.52 (m, 1H), 7.26-7.35 (m, 1H), 7.15-7.25 (m, 2H), 6.35-6.65 (m, 3H), 6.05-6.18 (m, 1H), 5.60-5.70 (m, 1H), 4.40-4.50 (m, 1H), 4.12-4.20 (m, 1H), 3.38-3.50 (m, 1H), 3.10-3.28 (m, 1H), 2.90-3.08 (m, 3H), 2.66-2.80 (m, 1H), 2.35-2.45 (m, 1H), 1.72-1.95 (m, 3H), 1.30-1.55 (m, 2H).
Example 137: 1-[(1R,4R,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one and
Example 138: 1-[(1R,4R,5*)-5-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-azabicyclo[2.2.1]heptan-2-yl]prop-2-en-1-one




Examples 137 and 138 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl (1R,4R)-5-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and methanol (+5 eq AcOH) in place of 1,2-dichloroethane for the final step. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK OD column using a mix of [hexanes (+0.5% 2M NH3-MeOH)] and ethanol.
Example 137: MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 8.30-8.40 (m, 2H), 7.96-8.05 (m, 1H), 7.90-7.95 (m, 1H), 7.75-7.82 (m, 1H), 7.45-7.52 (m, 1H), 7.28-7.35 (m, 1H), 7.19-7.25 (m, 2H), 6.45-6.65 (m, 2H), 6.38-6.44 (m, 1H), 6.05-6.18 (m, 1H), 5.60-5.70 (m, 1H), 4.32-4.40 (m, 1H), 4.10-4.20 (m, 1H), 3.82-3.90 (m, 1H), 3.05-3.40 (m, 2H), 2.88-3.00 (m, 1H), 2.65-2.80 (m, 1H), 2.53-2.60 (m, 1H), 2.30-2.42 (m, 1H), 1.95-2.12 (m, 1H), 1.73-1.85 (m, 1H), 1.55-1.70 (m, 2H), 1.01-1.12 (m, 1H).
Example 138: MS (ESI) calcd. for C32H31N9O: 557.27 m/z, found: 558.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.28-8.40 (m, 2H), 7.90-8.05 (m, 2H), 7.75-7.85 (m, 1H), 7.42-7.52 (m, 1H), 7.28-7.38 (m, 1H), 7.15-7.26 (m, 2H), 6.35-6.65 (m, 3H), 6.05-6.20 (m, 1H), 5.60-5.70 (m, 1H), 4.38-4.50 (m, 1H), 4.20-4.30 (m, 1H), 3.38-3.50 (m, 1H), 3.08-3.25 (m, 1H), 2.85-3.05 (m, 2H), 2.65-2.80 (m, 1H), 2.32-2.45 (m, 1H), 1.71-1.95 (m, 3H), 1.20-1.55 (m, 3H).
Example 139: 1-[(3*,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidin-1-yl]prop-2-en-1-one
Example 140: 1-[(3*,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidin-1-yl]prop-2-en-1-one
Example 141: 1-[(3*,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidin-1-yl]prop-2-en-1-one and
Example 142: 1-[(3*,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidin-1-yl]prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of tert-butyl 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidine-1-carboxylate
A solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (1 g, 2.4 mmol) and tert-butyl (3R)-3-hydroxy-4-oxopiperidine-1-carboxylate (0.74 g, 3.427 mmol) in MeOH (3 mL) and DCE (30 mL) was stirred at room temperature overnight. NaCNBH3 (0.19 g, 4.9 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (2 mL) and the mixture was concentrated and purified by Prep-HPLC on a XSelect CSH Fluoro Phenyl column using a gradient of acetonitrile in water (+0.1% NH3HCO3) to afford tert-butyl 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidine-1-carboxylate (900 mg, 60% yield) as a yellow solid. MS (ESI) calcd. for C33H37N9O3: 607.30 m/z, found: 608.30 [M+H]+.
Step 2: Synthesis of 4-{1[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-3-ol
A solution of tert-butyl 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-hydroxypiperidine-1-carboxylate (450 mg, 0.740 mmol) in 0.4N HCl in dioxane (10 mL) was stirred at room temperature for 1 h. The mixture was concentrated to afford 4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-3-ol (375 mg, crude quant) as an off-white solid. MS (ESI) calcd. for C28H29N9O: 507.25 m/z, found: 508.25 [M+H]+.
Step 3: Synthesis of 1-(4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-hydroxypiperidin-1-yl)prop-2-en-1-one (4 diastereomers, Examples 139-142
To a solution of (3R)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-3-ol (370 mg, 0.729 mmol) in DMF (4 mL) was added N,N-diisopropylethylamine (282.6 mg, 2.187 mmol), PyBOP (417.3 mg, 0.802 mmol) and acrylic acid (52.5 mg, 0.729 mmol). The resulting mixture was stirred at room temperature for 1 h. The mixture was purified by Prep-HPLC on a XSelect CSH Prep Fluoro-Phenyl Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to give a mixture of all 4 isomers. Examples 139 and 142 each separated from Examples 140 and 141 by chiral Prep HPLC on CHIRALPAK IG column using a mixture of [hexanes/DCM (3:1) (+0.5% 2M NH3-MeOH)] and isopropanol. Examples 140 and 141 required further separation by chiral Prep-HPLC on a CHIRALPAK SS column using an mixture of [hexanes/DCM (1:1) (+0.5% 2M NH3-methanol] and ethanol. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 139: MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31-8.38 (m, 2H), 7.93-8.02 (m, 2H), 7.79-7.83 (m, 1H), 7.40-7.48 (m, 1H), 7.32-7.38 (m, 1H), 7.19-7.30 (m, 2H), 6.79-6.99 (m, 3H), 6.52-6.56 (m, 1H), 6.38-6.43 (m, 1H), 6.08-6.13 (m, 1H), 5.61-5.71 (m, 1H), 4.97-5.07 (m, 1H), 4.32-4.45 (m, 1H), 4.01-4.09 (m, 1H), 3.88-3.95 (m, 1H), 3.38-3.50 (m, 2H), 3.18-3.28 (m, 1H), 2.90-3.06 (m, 2H), 2.73-2.86 (m, 2H), 2.55-2.59 (m, 1H), 1.84-1.95 (m, 1H), 1.65-1.78 (m, 1H), 1.22-1.40 (m, 1H).
Example 140: MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.19-8.38 (m, 3H), 7.94-8.03 (m, 2H), 7.82-7.85 (m, 1H), 7.55-7.65 (m, 1H), 7.36-7.45 (m, 1H), 7.21-7.32 (m, 2H), 6.90-6.98 (m, 2H), 6.73-6.88 (m, 1H), 6.50-6.58 (m, 1H), 6.38-6.46 (m, 1H), 6.09-6.18 (m, 1H), 5.65-5.70 (m, 1H), 4.15-4.30 (m, 1H), 3.90-4.09 (m, 2H), 3.52-3.56 (m, 1H), 2.99-3.19 (m, 2H), 2.90-2.97 (m, 2H), 2.82-2.89 (m, 2H), 2.61-2.65 (m, 1H), 2.05-2.19 (m, 1H), 1.90-2.01 (m, 1H), 1.31-1.41 (m, 1H).
Example 141: MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.19-8.39 (m, 3H), 8.01-8.06 (m, 1H), 7.92-8.01 (m, 1H), 7.89-7.95 (m, 1H), 7.59-7.75 (m, 1H), 7.39-7.43 (m, 1H), 7.28-7.34 (m, 1H), 7.21-7.27 (m, 1H), 6.91-6.98 (m, 2H), 6.70-6.89 (m, 1H), 6.51-6.57 (m, 1H), 6.38-6.42 (m, 1H), 6.02-6.15 (m, 1H), 5.65-5.72 (m, 1H), 4.02-4.18 (m, 1H), 3.75-3.99 (m, 2H), 3.50-3.53 (m, 1H), 3.25-3.31 (m, 2H), 2.99-3.13 (m, 2H), 2.80-2.98 (m, 2H), 2.75-2.80 (m, 1H), 1.70-1.99 (m, 2H), 1.58-1.69 (m, 1H).
Example 142: MS (ESI) calcd. for C31H31N9O2: 561.26 m/z, found: 562.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29-8.36 (m, 2H), 7.93-8.02 (m, 2H), 7.73-7.83 (m, 1H), 7.50-7.58 (m, 1H), 7.20-7.39 (m, 3H), 6.89-7.01 (m, 2H), 6.72-6.86 (m, 1H), 6.50-6.55 (m, 1H), 6.40-6.46 (m, 1H), 6.03-6.11 (m, 1H), 5.63-5.70 (m, 1H), 5.10-5.23 (m, 1H), 4.30-4.42 (m, 1H), 3.89-4.01 (m, 1H), 3.44-3.55 (m, 2H), 3.02-3.13 (m, 2H), 2.90-3.01 (m, 1H), 2.70-2.82 (m, 2H), 2.60-2.69 (m, 2H), 1.91-2.02 (m, 1H), 1.78-1.89 (m, 1H), 1.28-1.39 (m, 1H).
Example 143: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 144: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 143 and 144 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, using 4N HCl in dioxane instead of TFA in DCM, Intermediate 76-1 in place of Intermediate 1-1 and methanol at room temperature overnight for the final step instead of 1,2-dichloroethane at 40° C. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 143: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.33 (m, 2H), 7.98-8.00 (m, 1H), 7.91-7.93 (m, 1H), 7.77-7.78 (m, 1H), 7.48-7.50 (m, 1H), 7.31-7.34 (m, 2H), 7.22-7.24 (m, 1H), 6.71-6.78 (m, 1H), 6.51-6.52 (m, 1H), 6.40-6.43 (m, 1H), 6.05-6.10 (m, 1H), 5.54-5.64 (m, 1H), 5.40-5.41 (m, 1H), 4.41-4.49 (m, 2H), 3.90-4.00 (m, 1H), 3.35-3.40 (m, 1H), 3.08-3.22 (m, 3H), 1.88-1.92 (m, 1H), 1.71-1.74 (m, 3H), 1.37-1.43 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −197.958.
Example 144: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.31 (m, 2H), 7.91-7.97 (m, 2H), 7.76-7.89 (m, 1H), 7.47-7.49 (m, 1H), 7.22-7.30 (m, 3H), 6.70-6.77 (m, 1H), 6.53-6.54 (m, 1H), 6.41-6.45 (m, 1H), 6.00-6.08 (m, 1H), 5.65-5.68 (m, 1H), 5.40-5.55 (m, 1H), 4.80-4.81 (m, 1H), 4.35-4.38 (m, 2H), 3.17-3.20 (m, 2H), 3.06-3.12 (m, 1H), 2.77-2.80 (m, 1H), 2.10-2.13 (m, 1H), 1.75-1.78 (m, 1H), 1.39-1.47 (m, 1H), 1.11-1.20 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −197.128.
Example 145: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 146: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 145 and 146 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, using 4N HCl in dioxane instead of TFA in DCM, using Intermediate 75-1 in place of Intermediate 1-1 and methanol at room temperature overnight for the final step instead of 1,2-dichloroethane at 40° C. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 145: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.34 (m, 2H), 7.98-8.00 (m, 1H), 7.92-7.94 (m, 1H), 7.78-7.79 (m, 1H), 7.47-7.49 (m, 1H), 7.30-7.36 (m, 1H), 7.22-7.28 (m, 2H), 6.70-6.77 (m, 1H), 6.53-6.54 (m, 1H), 6.42-6.45 (m, 1H), 6.04-6.09 (m, 1H), 5.64-5.67 (m, 1H), 5.15-5.33 (m, 1H), 4.34-4.40 (m, 2H), 3.98-4.01 (m, 1H), 3.45-3.50 (m, 1H), 3.25-3.30 (m, 1H), 3.16-3.18 (m, 1H), 2.99-3.00 (m, 1H), 1.76-1.80 (m, 2H), 1.59-1.62 (m, 1H), 1.13-1.36 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −175.263.
Example 146: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.36 (m, 2H), 7.99-8.00 (m, 1H), 7.93-7.95 (m, 1H), 7.79-7.80 (m, 1H), 7.48-7.50 (m, 1H), 7.39-7.48 (m, 1H), 7.30-7.31 (m, 1H), 7.21-7.28 (m, 1H), 6.74-6.81 (m, 1H), 6.53-6.54 (m, 1H), 6.41-6.45 (m, 1H), 6.00-6.08 (m, 1H), 5.64-5.67 (m, 1H), 5.17-5.31 (m, 1H), 4.70-4.85 (m, 0.5H), 4.36-4.42 (m, 2H), 3.95-4.00 (m, 0.5H), 3.45-3.50 (m, 1H), 2.99-3.15 (m, 3H), 2.04-2.09 (m, 1H), 1.84-1.90 (m, 1H), 1.21-1.40 (m, 1H), 1.12-1.19 (m, 4H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −175.292 d.
Example 147: (*)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperazin-1-yl)prop-2-en-1-one and Example 148: (*)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperazin-1-yl)prop-2-en-1-one




The enantiomers of racemic Example 77 were separated by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [MTBE (+0.5% 2M NH3-MeOH)] and [EtOH/DCM 1:1] to afford Example 147 as the first eluting peak and Example 148 as the second eluting peak. * Denotes a stereocenter with undetermined absolute stereochemistry of a single enantiomer.
Example 147: MS (ESI) calcd. for C30H30N10O: 546.26 m/z, found: 547.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.38 (m, 2H), 7.99-8.01 (m, 1H), 7.93-7.97 (m, 1H), 7.73-7.79 (m, 1H), 7.61-7.64 (m, 1H), 7.40 (s, 1H), 7.25-7.31 (m, 2H), 6.75-6.82 (m, 1H), 6.53-6.54 (m, 1H), 6.44-6.49 (m, 1H), 6.10-6.15 (m, 1H), 5.70-5.73 (m, 1H), 4.72-4.73 (m, 1H), 3.63-3.70 (m, 4H), 3.01-3.07 (m, 1H), 2.81-2.90 (m, 5H), 2.34-2.38 (m, 1H), 2.03-2.09 (m, 1H).
Example 148: MS (ESI) calcd. for C30H30N10O: 546.26 m/z, found: 547.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.35 (m, 2H), 7.92-7.99 (m, 2H), 7.78-7.79 (m, 1H), 7.59-7.61 (m, 1H), 7.38 (s, 1H), 7.22-7.28 (m, 2H), 6.73-6.81 (m, 1H), 6.53-6.54 (m, 1H), 6.44-6.47 (m, 1H), 6.09-6.14 (m, 1H), 5.70-5.73 (m, 1H), 4.60-4.66 (m, 1H), 3.61-3.76 (m, 4H), 3.02-3.05 (m, 1H), 2.82-2.86 (m, 1H), 2.51-2.77 (m, 4H), 2.32-2.39 (m, 1H), 2.01-2.03 (m, 1H).
Example 149: 1-(4-{[(1R)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 149 was prepared in a manner analogous Example 13 using Intermediate 149-1 in place of Intermediate 1-1. MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found: 546.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.44-8.31 (m, 2H), 8.00 (dd, J=4.8, 1.9 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.84-7.78 (m, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.30-7.19 (m, 2H), 6.94 (s, 2H), 6.83 (dd, J=16.7, 10.4 Hz, 1H), 6.54 (dd, J=2.6, 1.7 Hz, 1H), 6.42 (dd, J=7.7, 4.8 Hz, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.4, 2.5 Hz, 1H), 4.34 (t, J=7.3 Hz, 1H), 4.24 (s, 1H), 4.00 (s, 1H), 3.19 (d, J=13.3 Hz, 1H), 2.90 (m, 3H), 2.70-2.87 (m, 1H), 2.43 (s, 1H), 2.03-1.70 (m, 3H), 1.25 (s, 2H).
Intermediate 149-1: (R)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate
To a stirred solution of (1R)-5-bromo-2,3-dihydro-1H-inden-1-amine (2 g, 9.4 mmol, 1 equiv) and triethylamine (2.86 g, 28.3 mmol, 3 equiv) in DCM (40 mL) was added Boc2O (2.47 g, 11.3 mmol, 1.2 equiv). The resulting mixture was stirred for 2 h at room temperature then concentrated under reduced pressure. The crude product was recrystallized from hexane (200 mL) to afford tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (2.7 g, 92%) as a white solid. MS (ESI) calcd. for C14H18BrNO2: 311.05 m/z, found: 255.90 [M-tBu]+.
Step 2: Synthesis of tert-butyl N-[(1R)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate
To a stirred solution of tert-butyl N-[(1R)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (2.7 g, 8.6 mmol, 1 equiv) and 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine (2.13 g, 10.4 mmol, 1.2 equiv) in dioxane (45 mL) were added Pd(OAc)2 (0.19 g, 0.87 mmol, 0.1 equiv), XantPhos (0.50 g, 0.865 mmol, 0.1 equiv) and Cs2CO3 (8.45 g, 25.9 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 5 h at 80° C. under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered; the filter cake was washed with 1,4-dioxane (3×10 mL). The filtrate was concentrated under reduced pressure. Water was added and the resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl N-[(1R)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (3.4 g, 90%) as a yellow solid. MS (ESI) calcd. for C22H24N6O4: 436.19 m/z, found: 437.15 [M+H]+.
Step 3: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a stirred solution of tert-butyl N-[(1S)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (3.4 g, 7.8 mmol, 1 equiv) and 2-aminopyridine-3-carbaldehyde (1.43 g, 11.7 mmol, 1.5 equiv) in DMSO (75 mL) and MeOH (13 mL) was added Na2S2O4 (2.98 g, 17.1 mmol, 2.2 equiv). The resulting mixture was stirred for 2 days at 100° C. under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate and the resulting mixture was extracted with EA (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (1.5 g, 38%) as a brown solid. MS (ESI) calcd. for C28H28N8O2: 508.23 m/z, found: 509.20 [M+H]+.
Step 4: Synthesis of 3-{3-[(1R)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 149-1
A solution of tert-butyl (R)-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.5 g, 3.8 mmol, 1 equiv) in HCl (4.0 M) in 1,4-dioxane (50 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL) and the mixture was basified to pH 10 with saturated NaHCO3 (aq.). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-{3-[(1R)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 149-1) (800 mg, crude) as a brown/yellow solid. MS (ESI) calcd. for C23H20N8: 408.18 m/z, found: 409.10 [M+H]+.
Example 150: 1-(4-(((1*,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 151: 1-(4-(((1*,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 150 and 151 were prepared in a manner analogous to Example 13 using Intermediate 150-1 and 151-1 in place of Intermediate 1-1 (for Examples 150 and 151, respectively), 1,2-dichloroethane/methanol (10:1) instead of 1,2-dichloroethane and room temperature instead of 40° C. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 150: MS (ESI) calcd. for C31H31N9O2, 561.28 m/z, found 562.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43-8.45 (m, 2H), 8.08-8.10 (m, 1H), 8.01-8.03 (m, 1H), 7.83-7.84 (m, 1H), 7.76-7.78 (m, 1H), 7.61-7.46 (m, 1H), 7.50-7.59 (m, 2H), 6.80-6.84 (m, 1H), 6.71-6.77 (m, 1H), 6.56-6.57 (m, 1H), 6.08-6.13 (m, 1H), 5.69-5.72 (m, 1H), 4.70-4.73 (m, 2H), 4.50-4.68 (m, 1H), 4.17-4.15 (m, 1H), 3.44-3.57 (m, 2H), 2.90-3.07 (m, 2H), 2.50-2.67 (m, 1H), 2.21-2.24 (m, 1H), 2.12-2.13 (m, 1H), 1.47-1.55 (m, 2H). (TFA salt).
Example 151: MS (ESI) calcd. for C31H31N9O2, 561.28 m/z, found 562.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43-8.45 (m, 2H), 8.08-8.10 (m, 1H), 8.01-8.03 (m, 1H), 7.83-7.84 (m, 1H), 7.77-7.78 (m, 1H), 7.60-7.61 (m, 1H), 7.53-7.58 (m, 2H), 6.80-6.85 (m, 1H), 6.70-6.78 (m, 1H), 6.57-6.58 (m, 1H), 6.08-6.13 (m, 1H), 5.69-5.72 (m, 1H), 4.74-4.75 (m, 2H), 4.50-4.51 (m, 1H), 4.10-4.20 (m, 1H), 3.45-3.55 (m, 2H), 2.90-3.02 (m, 2H), 2.61-2.67 (m, 1H), 2.23-2.28 (m, 1H), 2.11-2.15 (m, 1H), 1.40-1.55 (m, 2H). (TFA salt).
Intermediate 150-1: (1*,2*)-1-amino-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-2-ol and
Intermediate 151-1: (1*,2*)-1-amino-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-2-ol




Intermediate 150-1 and Intermediate 151-1 were prepared in a manner analogous to Intermediate 75-1 and Intermediate 76-1 (starting from Step 4) using Intermediate 150-2 in place of (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide. The diastereomers were separated prior to the final step by chiral SFC on a CHIRAL ART Amylose-SA column using a mix of CO2 and IPA. The precursor to Intermediate 150-1 eluted first. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Intermediate 150-2: trans-tert-butyl (-5-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of 4-bromo-1a,6a-dihydro-6H-indeno[1,2-b]oxirene
To a solution of 5-bromo-3H-indene (2.0 g, 10 mmol, 1 equiv) in DCM (50 mL) was added m-CPBA (3.54 g, 20.5 mmol, 2 equiv) and the resulting mixture was stirred at r.t. for 2 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether) to afford 4-bromo-1a,6a-dihydro-6H-indeno[1,2-b]oxirene (0.9 g, 42%) as a white solid. MS (ESI) calcd. for C9H7BrO, 209.96 m/z, found: 211.10 [M+H]+.
Step 2: Synthesis of trans-1-amino-5-bromo-2,3-dihydro-1H-inden-2-ol
To a solution of 4-bromo-1a,6a-dihydro-6H-indeno[1,2-b]oxirene (0.9 g, 4.3 mmol, 1 equiv) in THE (15 mL) was added NH4OH (15 mL, 385 mmol, 90 equiv) and the mixture was stirred at 80° C. for 2.0 h. After cooling to room temperature, the reaction was quenched with water (5 mL) and the mixture was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to yield crude trans-1-amino-5-bromo-2,3-dihydro-1H-inden-2-ol (1.0 g, crude) as a light yellow solid. MS (ESI) calcd. for C9H10BrNO, 226.99 m/z, found 228.10 [M+H]+.
Step 3: Synthesis of trans-tert-butyl (5-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 150-2
To a solution of trans-1-amino-5-bromo-2,3-dihydro-1H-inden-2-ol (1.0 g, 4.4 mmol, 1 equiv) in DCM (30 mL) was added (Boc)2O (1.15 g, 5.26 mmol, 1.2 equiv) and the mixture was stirred at r.t. for 18 h. The reaction was quenched with water (10 mL) and the mixture was extracted with DCM (3×25 mL). The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel column chromatography (0-10% ethyl acetate in petroleum ether to afford trans-tert-butyl N-(5-bromo-2-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 69%) as a yellow solid and as a mixture of diastereomers. MS (ESI) calcd. for C14H18BrNO3, 327.05 m/z, found: 328.10 [M+H]+. * Denotes a stereocenter with undetermined absolute stereochemistry.
Example 152: (S)-1-(4-((5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 152 was prepared in a manner analogous to Example 13 using Intermediate 152-1 in place of Intermediate 1-1. MS (ESI) calcd. for C32H31N7O: 529.26 m/z, found: 530.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.42-8.27 (m, 2H), 7.95 (d, J=8.6 Hz, 1H), 7.81 (dd, J=1.8, 0.7 Hz, 1H), 7.64-7.53 (m, 2H), 7.53-7.30 (m, 5H), 7.25 (dd, J=8.0, 2.0 Hz, 1H), 6.83 (dd, J=16.7, 10.4 Hz, 1H), 6.54 (dd, J=2.6, 1.7 Hz, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.5, 2.5 Hz, 1H), 4.36 (t, J=7.1 Hz, 1H), 4.25 (s, 1H), 3.99 (s, 1H), 3.15 (d, J=12.7 Hz, 1H), 3.02-2.88 (m, 2H), 2.87-2.66 (m, 1H), 2.48-2.36 (m, 1H), 2.04-1.71 (m, 4H), 1.24 (s, 3H).
Intermediate 152-1: (S)-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediate 152-1
Intermediate 152-1 was prepared in a manner analogous to Intermediate 149-1 using (1S)-5-bromo-2,3-dihydro-1H-inden-1-amine in place of (1R)-5-bromo-2,3-dihydro-1H-inden-1-amine, benzaldehyde in place of 2-aminopyridine-3-carbaldehyde and TFA+0.05 eq methanesulfonic acid in place of 4N HCl in dioxane. MS (ESI) calcd. for C24H20N6: 392.17 m/z, found: 393.20 [M+H]+.
Example 153: (S)-1-(4-((5-(5-(1H-pyrazol-1-yl)-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 153 was prepared in a manner analogous to Example 13 using Intermediate 153-1 in place of Intermediate 1-1. MS (ESI) calcd. for C31H30N8O: 530.25 m/z, found: 531.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=2.2 Hz, 1H), 8.63 (dd, J=4.9, 1.7 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.37 (d, J=2.5 Hz, 1H), 8.02-7.92 (m, 2H), 7.82 (d, J=1.6 Hz, 1H), 7.55-7.45 (m, 2H), 7.40 (d, J=1.9 Hz, 1H), 7.30 (dd, J=7.9, 2.0 Hz, 1H), 6.83 (dd, J=16.7, 10.5 Hz, 1H), 6.56 (t, J=2.1 Hz, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.4, 2.5 Hz, 1H), 4.37 (t, J=7.2 Hz, 1H), 4.25 (s, 1H), 4.00 (s, 1H), 3.19 (t, J=12.9 Hz, 1H), 3.09-2.88 (m, 3H), 2.88-2.74 (m, 2H), 2.49-2.40 (m, 3.5 Hz, 1H), 1.97 (s, 1H), 1.86 (d, J=12.7 Hz, 1H), 1.84-1.73 (m, 1H), 1.26 (s, 2H).
Intermediate 153-1: (S)-5-(5-(1H-pyrazol-1-yl)-2-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediate 153-1 was prepared in a manner analogous to Intermediate 149-1 using (1S)-5-bromo-2,3-dihydro-1H-inden-1-amine in place of (1R)-5-bromo-2,3-dihydro-1H-inden-1-amine, nicotinaldehyde in place of 2-aminopyridine-3-carbaldehyde and TFA+0.05 eq methanesulfonic acid in place of 4N HCl in dioxane. MS (ESI) calcd. for C23H19N7: 393.17 m/z, found: 394.05 [M+H]+.
Example 154: (S)-1-(4-((6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 154 was prepared in a manner analogous to Example 13 using Intermediate 154-1 in place of Intermediate 1-1 and 1,2-dichloroethane/methanol (1:1) in place of 1,2-dichloroethane. MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.45-8.30 (m, 2H), 8.05-7.89 (m, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.29-7.12 (m, 3H), 6.94 (s, 3H), 6.59-6.50 (m, 1H), 6.47-6.39 (m, 1H), 6.14-6.02 (m, 1H), 5.70-5.60 (m, 1H), 4.21 (d, J=13.5 Hz, 1H), 4.15-3.76 (m, 2H), 3.18 (s, 1H), 3.04-2.82 (m, 2H), 2.80-2.60 (m, 3H), 1.92 (d, J=7.9 Hz, 2H), 1.84-1.62 (m, 4H), 1.24 (s, 2H).
Intermediate 154-1: (S)-3-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 154-1 was prepared in a manner analogous to Intermediate 149-1 using (S)-6-bromo-1,2,3,4-tetrahydronaphthalen-1-amine in place of (1R)-5-bromo-2,3-dihydro-1H-inden-1-amine and TFA in place of 4N HCl in dioxane. MS (ESI) calcd. for C24H22N8: 422.20 m/z, found: 423.30 [M+H]+.
Example 155: (3*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidine-3-carbonitrile
Example 156: (3*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidine-3-carbonitrile and
Example 157: (3*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidine-3-carbonitrile




Examples 155, 156 and 157 were prepared in a manner analogous to Example 34 using tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate in place of tert-butyl 4-oxopiperidine-1-carboxylate and acrylic acid in place of (2E)-4-(dimethylamino)but-2-enoic acid. The diastereomers produced in step 1 were partially separated by chiral Prep HPLC on a CHIRALPAK IE column using a mix of [Hex/DCM 3:1 (+0.5% 2M NH3-MeOH)] and EtOH with the precursors to Examples 155 and 156 eluting together after the precursors to Example 157. Examples 155 and 156 were separated by chiral Prep HPLC on a CHIRALPAK IC3 column using a mix of [MTBE (+0.1% diethylamine)] and [methanol/DCM 1:1]. Example 157 is a mix of two diastereomers. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 155: MS (ESI) calcd. for C32H30N10O: 570.26 m/z, found: 571.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.38 (m, 2H), 7.93-8.01 (m, 2H), 7.79-8.02 (m, 1H), 7.47-7.51 (m, 1H), 7.34-7.38 (m, 1H), 7.20-7.29 (m, 2H), 6.79-6.97 (m, 3H), 6.53-6.58 (m, 1H), 6.38-6.42 (m, 1H), 6.09-6.16 (m, 1H), 5.68-5.72 (m, 1H), 4.46-4.68 (m, 1H), 4.08-4.38 (m, 2H), 3.32-3.38 (m, 1H), 3.08-3.17 (m, 2H), 2.89-2.99 (m, 2H), 2.65-2.78 (m, 2H), 2.39-2.43 (m, 2H), 1.91-1.99 (m, 1H), 1.76-1.86 (m, 1H).
Example 156: MS (ESI) calcd. for C32H30N10O: 570.26 m/z, found: 571.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.30-8.38 (m, 2H), 7.94-8.01 (m, 2H), 7.79-8.02 (m, 1H), 7.45-7.49 (m, 1H), 7.29-7.35 (m, 2H), 7.23-7.28 (m, 1H), 6.80-6.98 (m, 3H), 6.51-6.53 (m, 1H), 6.39-6.42 (m, 1H), 6.09-6.16 (m, 1H), 5.68-5.73 (m, 1H), 4.52-4.68 (m, 1H), 4.08-4.38 (m, 2H), 3.50-3.56 (m, 1H), 3.31-3.36 (m, 1H), 3.07-3.16 (m, 1H), 2.89-2.99 (m, 2H), 2.67-2.79 (m, 2H), 2.51-2.56 (m, 2H), 1.70-1.86 (m, 2H).
Example 157: MS (ESI) calcd. for C32H30N10O: 570.26 m/z, found: 571.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.42 (m, 2H), 8.01-8.09 (m, 1H), 7.95-8.00 (m, 1H), 7.81-7.85 (m, 1H), 7.38-7.72 (m, 5H), 7.10-7.25 (m, 1H), 6.81-6.99 (m, 1H), 6.51-6.62 (m, 2H), 6.10-6.21 (m, 1H), 5.71-5.80 (m, 1H), 4.86-5.01 (m, 1H), 4.33-4.48 (m, 1H), 4.03-4.20 (m, 2H), 3.60-3.65 (m, 1H), 3.29-3.40 (m, 1H), 3.00-3.19 (m, 3H), 2.88-2.92 (m, 1H), 2.52-2.59 (m, 1H), 2.11-2.22 (m, 1H), 2.08-2.10 (m, 1H), 1.59-1.69 (m, 1H). (TFA salt).
Example 158: (S)-1-(3-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)azetidin-1-yl)prop-2-en-1-one




Example 158 was prepared in a manner analogous to Example 14 (via Intermediate 14-1, starting from step 2) using 1-(azetidin-3-yl)piperidin-4-one in place of 3-azabicyclo[3.2.1]octan-8-one and 1,2-dichloroethane/methanol (1:1) in place of 1,2-dichloroethane. MS (ESI) calcd. for C34H36N10O, 600.31 m/z, found 601.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.44-8.47 (m, 1H), 8.37-8.38 (m, 1H), 8.09-8.11 (m, 2H), 7.77-7.85 (m, 3H), 7.45-7.47 (m, 2H), 6.78-6.80 (m, 1H), 6.57-6.59 (m, 1H), 6.30-6.32 (m, 1H), 6.13-6.18 (m, 1H), 5.78-5.79 (m, 1H), 5.04-5.05 (m, 1H), 4.49-4.52 (m, 2H), 4.19-4.21 (m, 2H), 4.00-4.02 (m, 1H), 3.61-3.62 (m, 2H), 3.55-3.56 (m, 1H), 3.15-3.16 (m, 1H), 3.00-3.03 (m, 3H), 2.70-2.72 (m, 1H), 2.65-2.66 (m, 1H), 2.25-2.30 (m, 2H), 1.92-1.95 (m, 2H). (TFA salt).
Example 159: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-thiazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 159 was prepared in a manner analogous to Example 13 using Intermediate 159-1 in place of Intermediate 1-1 and 1,2-dichloroethane/methanol (10:1) in place of 1,2-dichloroethane. MS (ESI) calcd. for C31H30N8OS: 562.22 m/z, found: 563.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.30-8.35 (m, 1H), 8.20-8.26 (m, 1H), 8.01-8.05 (m, 1H), 7.94-7.98 (m, 1H), 7.78-7.81 (m, 1H), 7.54-7.59 (m, 1H), 7.38-7.41 (m, 1H), 7.25-7.34 (m, 2H), 6.80-6.90 (m, 1H), 6.41-6.48 (m, 1H), 6.08-6.14 (m, 1H), 5.68-5.72 (m, 1H), 4.51-4.58 (m, 1H), 4.30-4.41 (m, 1H), 4.00-4.12 (m, 1H), 3.09-3.19 (m, 2H), 2.98-3.05 (m, 1H), 2.80-2.92 (m, 2H), 2.47-2.52 (m, 1H), 2.01-2.11 (m, 1H), 1.85-1.98 (m, 2H), 1.25-1.41 (m, 2H). (formic acid salt).
Intermediate 159-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(thiazol-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-thiazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-chloroimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 1-2) (300 mg, 0.716 mmol, 1 equiv) and 2-(tributylstannyl)-1,3-thiazole (1.34 g, 3.58 mmol, 5 equiv) in 1,4-dioxane (5 mL) were added tris(dibenzylideneacetone)dipalladium(0) (67 mg, 0.072 mmol, 0.1 equiv), tri-tert-butylphosphonium tetrafluoroborate (21 mg, 0.072 mmol, 0.1 equiv) and cesium fluoride (272 mg, 1.79 mmol, 2.5 equiv). The resulting mixture was stirred under nitrogen atmosphere for 12 h at 100° C. The resulting mixture was concentrated under reduced pressure and residue was purified by reverse-phase flash column chromatography on C18 silica gel using a 20-95% gradient of acetonitrile in water (+0.05% ammonium bicarbonate) with a 5-minute hold at 70% acetonitrile to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-thiazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (250 mg, 67%) as a brown solid. MS (ESI) calculated for C25H21N7OS: 467.15 m/z, found 468.15 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(1,3-thiazol-2-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 159-1
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,3-thiazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (250 mg, 0.535 mmol, 1 equiv) in methanol (20 mL) was added hydrochloric acid (20 mL, conc.). The resulting mixture was stirred at 90° C. overnight. The solvent was removed by distillation under vacuum to afford crude 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(1,3-thiazol-2-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 159-1) as a black solid, which was used in subsequent transformations without purification. MS (ESI) calculated for C23H19N7S: 425.14 m/z, found 426.10 [M+H]+.
Example 160: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(2-methyl-1,2,3-triazol-4-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 160 was prepared in a manner analogous to Example 13 using Intermediate 160-1 in place of Intermediate 1-1 and methanol in place of 1,2-dichloroethane. MS (ESI) calcd. for C31H32N10O, 560.28 m/z, found 561.15 [M+H]+ 0.1H NMR (400 MHz, DMSO-d6) δ ppm: 8.22-8.45 (m, 1H), 8.04-8.15 (m, 1H), 7.96-8.04 (m, 1H), 7.81-7.96 (m, 1H), 7.42-7.64 (m, 1H), 7.31-7.42 (m, 1H), 7.12-7.31 (m, 2H), 6.67-6.97 (m, 1H), 6.32-6.59 (m, 1H), 5.98-6.22 (m, 1H), 5.61-5.85 (m, 1H), 4.28-4.58 (m, 2H), 4.11-4.28 (m, 3H), 3.97-4.11 (m, 1H), 3.08-3.31 (m, 1H), 2.92-3.08 (m, 2H), 2.67-2.92 (m, 2H), 2.41-2.51 (m, 1H), 1.99-2.19 (m, 1H), 1.72-1.99 (m, 2H), 1.12-1.47 (m, 2H). (formic acid salt).
Intermediate 160-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(2-methyl-2H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 160-1 was prepared in a manner analogous to Intermediate 109-2 using 4-bromo-2-methyl-1,2,3-triazole in place of 2-bromo-1,3-oxazole. MS (ESI) calcd. for C23H21N9, 423.19 m/z, found 424.25 [M+H]+.
Example 161: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](oxetan-3-ylmethyl)amino}piperidin-1-yl)prop-2-en-1-one




Example 161 was prepared in a manner analogous to Example 67 using oxetane-3-carbaldehyde (2 equiv) in place of formaldehyde. The amine and aldehyde were stirred together for 1 h at room temperature prior to addition of the reducing agent. MS (ESI) calcd. for C35H37N9O2, 615.31 m/z, found 616.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.16-8.52 (m, 2H), 7.89-8.15 (m, 2H), 7.68-7.89 (m, 1H), 7.17-7.49 (m, 4H), 6.68-6.98 (m, 1H), 6.49-6.68 (m, 1H), 6.26-6.49 (m, 1H), 5.95-6.26 (m, 1H), 5.58-5.87 (m, 1H), 4.34-4.78 (m, 4H), 4.01-4.34 (m, 2H), 3.87-3.88 (m, 1H), 2.71-3.14 (m, 6H), 2.56-2.70 (m, 2H), 1.79-2.29 (m, 3H), 1.42-1.79 (m, 2H), 1.09-1.42 (m, 1H).
Example 162: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxy-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 163: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methoxy-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 162 and 163 were prepared in a manner analogous to Example 13 using Intermediate 162-1 and 163-1 in place of Intermediate 1-1 (for Examples 162 and 163, respectively) and methanol instead of 1,2-dichloroethane. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Example 162: MS (ESI) calcd. for C32H33N9O2, 575.28 m/z, found 576.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26-8.41 (m, 2H), 7.89-8.14 (m, 2H), 7.69-7.89 (m, 1H), 7.42-7.64 (m, 1H), 7.11-7.42 (m, 3H), 6.68-6.95 (m, 1H), 6.53-6.68 (m, 1H), 6.33-6.53 (m, 1H), 5.96-6.24 (m, 1H), 5.60-5.85 (m, 1H), 4.19-4.51 (m, 2H), 3.99-4.19 (m, 2H), 3.24-3.52 (m, 4H), 2.99-3.24 (m, 2H), 2.66-2.99 (m, 2H), 1.79-2.21 (m, 2H), 1.14-1.49 (m, 2H). (TFA salt).
Example 163: MS (ESI) calcd. for C32H33N9O2, 575.28 m/z, found 598.35 [M+Na]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.24-8.56 (m, 2H), 7.92-8.18 (m, 2H), 7.79-7.92 (m, 1H), 7.65-7.79 (m, 2H), 7.52-7.65 (m, 1H), 7.33-7.52 (m, 1H), 6.78-6.98 (m, 1H), 6.48-6.78 (m, 2H), 6.02-6.28 (m, 1H), 5.62-5.94 (m, 1H), 4.77-5.07 (m, 1H), 4.49-4.71 (m, 1H), 4.32-4.49 (m, 1H), 4.08-4.32 (m, 1H), 3.58-3.72 (m, 1H), 3.51-3.58 (m, 1H), 3.36-3.51 (m, 3H), 3.06-3.27 (m, 1H), 2.89-3.06 (m, 1H), 2.65-2.89 (m, 1H), 2.22-2.34 (m, 1H), 2.14-2.22 (m, 1H), 1.42-1.66 (m, 2H). (TFA salt).
Intermediate 162-1: 3-(3-((1R,2*)-1-amino-2-methoxy-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine and
Intermediate 163-1: 3-(3-((1R,2*)-1-amino-2-methoxy-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediates 162-1 and Intermediate 163-1 were prepared in a manner analogous to Intermediates 75-1 and Intermediate 76-1 (starting from Step 2) using Intermediate 162-2 in place of 5-bromo-2-fluoro-2,3-dihydroinden-1-one. The diastereomers were separated prior to the last step by SFC on a (S, S)-Whelk-O 1 5 μm Kromasil column using a mixture of CO2 and methanol. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer.
Intermediate 162-1: MS (ESI) calcd. for C24H22N8O: 438.19 m/z, found: 439.30 [M+H]+.
Intermediate 163-1: MS (ESI) calcd. for C24H22N8O: 438.19 m/z, found: 439.30 [M+H]+.
Intermediate 162-2: 5-bromo-2-methoxy-2,3-dihydro-1H-inden-1-one




Synthetic Route:





Step 1: Synthesis of 5-bromo-2-methoxy-2,3-dihydro-1H-inden-1-one
To a cooled (−20° C.) solution of H2SO4 (6.51 g, 66.3 mmol, 2.0 equiv) in MeOH (40.0 ml) was added 5-bromo-2,3-dihydroinden-1-one (7.0 g, 33 mmol, 1 equiv) and trimethyl orthoformate (8.80 g, 82.9 mmol, 2.5 equiv) followed by a solution of HTIB (14.31 g, 36.483 mmol, 1.1 equiv) in MeOH (40.0 ml). The mixture was stirred at room temperature for 18 h. The reaction was quenched by the addition of water (200 mL) and the mixture was filtered to afford 5-bromo-2-methoxy-2,3-dihydroinden-1-one (6.2 g, 78%) as an off-white solid. MS (ESI) calcd. for C10H9BrO2 m/z, 239.98 found: 241.105 [M+H]+.
Example 164: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-(methoxymethyl)piperidin-1-yl)prop-2-en-1-one and
Example 165: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-(methoxymethyl)piperidin-1-yl)prop-2-en-1-one




Examples 164 and 165 were prepared in a manner analogous to Example 13 (via Intermediate 14-1) using Intermediate 164-1 in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, TFA/methanesulfonic acid (5:1) at 80° C. overnight (under air) instead of TFA/DCM at room temperature for 2 h and 1,2-dichloroethane/methanol (1:1) instead of 1,2-dichloroethane. * Denotes a stereocenter with undetermined absolute stereochemistry of a single diastereomer. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IG column using a mix of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and EtOH.
Example 164: MS (ESI) calcd. for C33H35N9O2: 589.29 m/z, found: 590.20. 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.26 (m, 2H), 8.05-7.89 (m, 2H), 7.83-7.78 (m, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.30-7.17 (m, 2H), 6.94 (s, 2H), 6.88-6.72 (m, 1H), 6.57-6.49 (m, 1H), 6.48-6.33 (m, 1H), 6.06 (d, J=16.5 Hz, 1H), 5.64 (t, J=10.8 Hz, 1H), 4.41 (s, 1H), 4.31 (s, 1H), 3.62 (t, J=9.5 Hz, 1H), 3.46 (t, J=14.9 Hz, 1H), 3.26 (s, 3H), 3.17 (s, 1H), 3.08-2.86 (m, 2H), 2.86-2.64 (m, 2H), 2.42 (d, J=11.4 Hz, 1H), 2.06 (d, J=12.2 Hz, 2H), 2.00-1.87 (m, 1H), 1.87-1.66 (m, 1H), 1.40-0.94 (m, 2H).
Example 165: MS (ESI) calcd. for C33H35N9O2: 589.29 m/z, found: 590.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.35 (d, J=26.1 Hz, 2H), 8.05-7.90 (m, 2H), 7.84-7.78 (m, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.41-7.20 (m, 3H), 6.92 (s, 2H), 6.87-6.70 (m, 1H), 6.59-6.49 (m, 1H), 6.49-6.34 (m, 1H), 6.15-5.95 (m, 1H), 5.68-5.53 (m, 1H), 4.29 (s, 2H), 3.97 (s, 2H), 3.49 (d, J=10.8 Hz, 1H), 3.24 (s, 3H), 3.16 (s, 1H), 2.96 (t, J=11.7 Hz, 1H), 2.87-2.65 (m, 1H), 2.46-2.37 (m, 1H) 1.96 (s, 1H), 1.81 (d, J=18.9 Hz, 4H), 1.55-1.35 (m, 2H).
Intermediate 164-1: tert-butyl (7R)-7-(methoxymethyl)-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate




Intermediate 164-1 was prepared in a manner analogous to Intermediate 129-1 using 1-tert-butyl 2-ethyl (2R)-4-oxopiperidine-1,2-dicarboxylate instead of 1-tert-butyl 2-ethyl (2S)-4-oxopiperidine-1,2-dicarboxylate. MS (ESI) calcd. for C14H25NO5: 287.17 m/z, found: 188.05 [M-Boc]+.
Example 166: (S)-N-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)propyl)-N-methylacrylamide




Synthetic Route:





Step 1: Synthesis of 3-{3-[(1S)-1-{[(2,4-dimethoxyphenyl) methyl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
A stirred solution of (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 1-1) (500 mg, 1.22 mmol, 1 equiv) and 2,4-dimethoxybenzaldehyde (203.4 mg, 1.224 mmol, 1 equiv) in DICE (2 mL) and MeOH (8 mL) was stirred overnight at 50° C. To the mixture was added NaBH3CN (230.8 mg, 3.672 mmol, 3 equiv). The resulting mixture was stirred overnight at 50° C. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH/DCM (0-20%) to afford (S)-3-(3-(1-((2,4-dimethoxybenzyl)amino)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (300 mg, 44%) as a brown oil. MS (ESI) calcd. for C32H30N8O2, 558.25 m/z, found 559.30 [M+H]+.
Step 2: Synthesis of tert-butyl (S)-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl) (2,4-dimethoxybenzyl) amino) propyl)(methyl)carbamate
A solution of 3-{3-[(1S)-1-{[(2,4-dimethoxyphenyl) methyl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (300 mg, 0.537 mmol, 1 equiv) and tert-butyl N-methyl-N-(3-oxopropyl) carbamate (101 mg, 0.537 mmol, 1 equiv) in DCE (4 mL) and MeOH (2 mL) was stirred for 8 h at 50° C. To the mixture was added NaBH3CN (101 mg, 1.61 mmol, 3 equiv) and the resulting mixture was stirred for 2 h at 50° C. The reaction was quenched with H2O (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH/DCM (0-20%) to afford tert-butyl N-(3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl][(2,4-dimethoxyphenyl) methyl]amino}propyl)-N-methylcarbamate (200 mg, 51%) as a yellow solid. MS (ESI) calcd. for C41H47N9O4, 729.38 m/z, found 730.35 [M+H]+.
Step 3: Synthesis of (S)-N1-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-N1-(2,4-dimethoxybenzyl)-N3-methylpropane-1,3-diamine
A solution of tert-butyl N-(3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl][(2,4-dimethoxyphenyl) methyl]amino}propyl)-N-methylcarbamate (400 mg, 0.548 mmol, 1 equiv) in TFA (5 mL) and DCM (15 mL) was stirred for 3 h at r.t. The resulting mixture was concentrated under reduced pressure to afford 3-{3-[(1S)-1-{[(2,4-dimethoxyphenyl) methyl][3-(methylamino) propyl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (280 mg, 81%) as brown oil. MS (ESI) calcd. for C36H39N9O2, 629.32 m/z, found 630.30 [M+H]+.
Step 4: Synthesis of (S)-N-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl) (2,4-dimethoxybenzyl) amino) propyl)-N-methylacrylamide
To a stirred solution of 3-{3-[(1S)-1-{[(2,4-dimethoxyphenyl) methyl][3-(methylamino) propyl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (200 mg, 0.318 mmol, 1 equiv), acrylic acid (22.9 mg, 0.318 mmol, 1 equiv) and DIEA (123 mg, 0.954 mmol, 3 equiv) in dimethylformamide (5 mL) was added PyBOP (165 mg, 0.318 mmol, 1 equiv) and the resulting mixture was stirred for 5 h at r.t. The mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% TFA) to afford N-(3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl][(2,4-dimethoxyphenyl) methyl]amino}propyl)-N-methylprop-2-enamide (100 mg, 38%) as yellow solid. MS (ESI) calcd. for C39H41N9O3, 683.33 m/z, found 684.35 [M+H]+.
Step 5: Synthesis of (S)-N-(3-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl) amino) propyl)-N-methylacrylamide (Example 166
A solution of N-(3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl][(2,4-dimethoxyphenyl) methyl]amino}propyl)-N-methylprop-2-enamide (50 mg, 0.073 mmol, 1 equiv) in TFA (0.3 mL) and DCM (1 mL) was stirred overnight at 70° C. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC on a XBridge Prep Shield RP OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford N-(3-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}propyl)-N-methylprop-2-enamide (Example 166) (5.1 mg, 13%) as a yellow solid. MS (ESI) calcd. for C30H31N9O, 533.27 m/z, found 534.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29-8.37 (m, 2H), 7.92-8.02 (m, 1H), 7.81-7.89 (m, 1H), 7.76-7.78 (m, 1H), 7.46-7.54 (m, 1H), 7.31-7.36 (m, 1H), 7.15-7.26 (m, 2H), 6.71-6.89 (m, 1H), 6.52-6.55 (m, 1H), 6.41-6.52 (m, 1H), 6.08-6.19 (m, 1H), 5.63-5.76 (m, 1H), 4.18-4.28 (m, 1H), 3.42-3.56 (m, 2H), 2.97-3.04 (m, 4H), 2.71-2.89 (m, 1H), 2.51-2.65 (m, 2H), 2.31-2.42 (m, 1H), 1.79-1.92 (m, 1H), 1.61-1.78 (m, 2H).
Example 167: 1-((*)-3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)prop-2-en-1-one and
Example 168: 1-((*)-3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of tert-butyl 3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate
A solution of 3-{3-[(1S)-1-azido-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 167-1) (1 g, 2.3 mmol, 1 equiv), tert-butyl 3-ethynylpiperidine-1-carboxylate (9.63 g, 46.0 mmol, 20 equiv), CuSO4.5H2O (115 mg, 0.46 mmol, 0.2 equiv) and sodium L-ascorbate (0.18 g, 0.92 mmol, 0.4 equiv) in MeOH (50 mL) and H2O (50 mL) was stirred for 3 h at room temperature. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (960 mg, 65%) as a brown yellow solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C35H37N11O2: 643.31 m/z, found: 644.35 [M+H]+.
Step 2: Synthesis of 3-(3-((1S)-1-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
A solution of tert-butyl 3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidine-1-carboxylate (960 mg, 1.491 mmol, 1 equiv) in HCl (4M) in 1,4-dioxane (15 mL) was stirred for 3 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with DCM (20 mL). The precipitated solids were collected by filtration and washed with DCM (3×10 mL). The residue was suspended in saturated NaHCO3 (aq.) (30 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(3-((1S)-1-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (600 mg, 74%) as a brown solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C30H29N11: 543.26 m/z, found: 544.70 [M+H]+.
Step 3: Synthesis of 1-((*)-3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)prop-2-en-1-one (Example 167) and 1-((*)-3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)prop-2-en-1-one (Example 168)
To a stirred solution of 3-(3-((1S)-1-(4-(piperidin-3-yl)-1H-1,2,3-triazol-1-yl)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (600 mg, 1.104 mmol, 1 equiv) and EDCI (423.2 mg, 2.208 mmol, 2 equiv) in pyridine (5 mL) and DMF (15 mL) was added acrylic acid (119.3 mg, 1.656 mmol, 1.5 equiv) dropwise at room temperature. The resulting mixture was stirred for 3 h at 50° C. The mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate). The diastereomers (150 mg) were separated by Prep-HPLC on a CHIRALPAK IC column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [MeOH:DCM 1:1] to afford 1-((*)-3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)prop-2-en-1-one (Example 167) as the first eluting peak and 1-((*)-3-(1-((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1H-1,2,3-triazol-4-yl)piperidin-1-yl)prop-2-en-1-one (Example 168) as the second eluting peak. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 167: MS (ESI) calcd. for C33H31N11O: 597.27 m/z, found: 598.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.42-8.33 (m, 2H), 8.05-7.92 (m, 3H), 7.85-7.78 (m, 1H), 7.54 (s, 1H), 7.35-7.27 (m, 1H), 7.27-7.18 (m, 2H), 6.92 (s, 2H), 6.89-6.74 (m, 1H), 6.58-6.51 (m, 1H), 6.48-6.38 (m, 1H), 6.34-6.23 (m, 1H), 6.15-6.00 (m, 1H), 5.70-5.58 (m, 1H), 4.25-3.95 (m, 2H), 3.30-3.15 (m, 1H), 3.15-2.99 (m, 1H), 2.92-2.71 (m, 3H), 2.13-2.03 (m, 1H), 1.78-1.68 (m, 2H), 1.55-1.30 (m, 1H), 1.26-1.16 (m, 2H).
Example 168: MS (ESI) calcd. for C33H31N11O: 597.27 m/z, found: 598.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.43-8.34 (m, 2H), 8.04-7.92 (m, 3H), 7.84-7.79 (m, 1H), 7.54 (s, 1H), 7.34-7.26 (m, 1H), 7.26-7.20 (m, 2H), 6.93 (s, 2H), 6.88-6.77 (m, 1H), 6.57-6.52 (m, 1H), 6.48-6.40 (m, 1H), 6.32-6.24 (m, 1H), 6.15-6.02 (m, 1H), 5.70-5.60 (m, 1H), 4.51-3.95 (m, 2H), 3.32-3.20 (m, 2H), 3.13-2.99 (m, 2H), 2.95-2.68 (m, 3H), 2.13-2.05 (m, 1H), 1.77-1.70 (m, 2H), 1.60-1.40 (m, 1H).
Intermediate 167-1: (S)-3-(3-(1-azido-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: (S)-3-(3-(1-azido-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 167-1
A solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (300 mg, 0.734 mmol), imidazole-1-sulfonyl azide (153 mg, 0.881 mmol), potassium carbonate (409 mg, 2.94 mmol) and CuSO4.5H2O (9.2 mg, 0.037 mmol) in MeOH (5 mL) was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% TFA) to afford (S)-3-(3-(1-azido-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 167-1) (200 mg, 63% yield) as a yellow solid. MS (ESI) calcd. for C23H18N10, 434.17 m/z, found 435.15 [M+H]+.
Example 169: 1-(4-{1-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-1,2,3-triazol-4-yl}piperidin-1-yl)prop-2-en-1-one




Example 169 was prepared in a manner analogous to Example 167 using tert-butyl 4-ethynylpiperidine-1-carboxylate in place of tert-butyl 3-ethynylpiperidine-1-carboxylate and omitting the chiral separation. MS (ESI) calcd. for C33H31N11O: 597.27 m/z, found: 598.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.33 (m, 2H), 8.05-7.91 (m, 3H), 7.85-7.78 (m, 1H), 7.54 (s, 1H), 7.35-7.17 (m, 3H), 6.92 (s, 2H), 6.90-6.76 (m, 1H), 6.59-6.51 (m, 1H), 6.46-6.36 (m, 1H), 6.31-6.20 (m, 1H), 6.15-6.03 (m, 1H), 5.71-5.61 (m, 1H), 4.46-4.36 (m, 1H), 4.13-4.02 (m, 1H), 3.32-3.16 (m, 3H), 3.12-2.94 (m, 2H), 2.86-2.72 (m, 2H), 2.03-1.87 (m, 2H), 1.50 (s, 2H).
Example 170: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrrolidin-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 170 was prepared in a manner analogous to Example 13 using 1,2-dichloroethane/methanol (1:1) in place of 1,2-dichloroethane, Intermediate 170-1 in place of Intermediate 1-1 and a reaction time of 1 h instead of overnight. MS (ESI) calcd for C32H36N8O: 548.70, found: 549.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm) 8.21 (s, 1H), 7.93-7.87 (m, 2H), 7.43-7.45 (m, 1H), 7.19-7.12 (m, 2H), 6.99-7.02 (m, 1H), 6.77-6.87 (m, 1H), 6.47-6.50 (m, 1H), 6.31-6.36 (m, 1H), 6.05-6.11 (m, 1H), 5.64-5.68 (m, 1H), 4.33-4.38 (m, 1H), 4.27 (m, 1H), 4.01 (s, 1H), 3.35-3.38 (m, 2H), 3.15 (m, 1H), 2.74-2.93 (m, 5H), 2.44 (m, 1H), 1.89-1.93 (m, 8H), 1.25 (m, 2H).
Intermediate 170-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(pyrrolidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-(pyrrolidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (200 mg, 0.384 mmol, 1 equiv) in DMSO (5 mL) was added pyrrolidine (272.8 mg, 3.840 mmol, 10 equiv). The resulting mixture was stirred at 120° C. overnight. After cooling to room temperature, the mixture was poured into water. The precipitate was collected by filtration and dried, then purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrrolidin-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (103 mg, 52%) as a yellow solid. MS (ESI) calcd. for C29H33N7O2: 511.27. found: 512.35 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrrolidin-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 170-1
A solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrrolidin-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (103 mg, 0.201 mmol, 1 equiv) in HCl (5 mL, 4M in 1,4-dioxane) was stirred at room temperature for 3 h then concentrated under vacuum. The resulting mixture was purified by reverse-phase flash chromatography in C18 silica gel using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrrolidin-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (98 mg, crude) as a yellow solid. MS (ESI) calcd for C24H25N7: 411.22; found: 412.16 [M+H]+.
Example 171: 1-((1R,5S,9*)-9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)prop-2-en-1-one and
Example 172: 1-((1R,5S,9*)-9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-oxa-7-azabicyclo[3.3.1]nonan-7-yl)prop-2-en-1-one




Examples 171 and 172 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) starting from tert-butyl 9-oxo-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate instead of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and using Intermediate 85-2 in place of Intermediate 1-1. The diastereomers were separated after the final step by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [EtOH/DCM 1:1]. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 171: MS (ESI) calcd. for C33H35N7O2: 561.29 m/z, found: 562.35 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 7.95-8.10 (m, 2H), 7.55-7.80 (m, 1H), 7.30-7.45 (m, 1H), 7.15-7.29 (m, 3H), 6.75-6.90 (m, 1H), 6.37-6.45 (m, 1H), 6.00-6.13 (m, 1H), 5.61-5.72 (m, 1H), 4.62-4.75 (m, 1H), 4.22-4.35 (m, 1H), 3.99-4.19 (m, 2H), 3.52-3.60 (m, 2H), 3.32-3.50 (m, 2H), 2.80-3.22 (m, 3H), 2.55-2.65 (m, 1H), 1.75-2.36 (m, 4H), 1.12-1.30 (m, 1H), 0.88-1.00 (m, 2H), 0.70-0.87 (m, 2H).
Example 172: MS (ESI) calcd. for C33H35N7O2: 561.29 m/z, found: 562.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 7.95-8.10 (m, 2H), 7.55-7.80 (m, 1H), 7.30-7.45 (m, 1H), 7.15-7.29 (m, 3H), 6.75-6.90 (m, 1H), 6.37-6.45 (m, 1H), 6.00-6.13 (m, 1H), 5.61-5.72 (m, 1H), 4.62-4.75 (m, 1H), 4.22-4.35 (m, 1H), 3.99-4.19 (m, 2H), 3.52-3.60 (m, 2H), 3.32-3.50 (m, 2H), 2.80-3.22 (m, 3H), 2.55-2.65 (m, 1H), 1.75-2.36 (m, 4H), 1.12-1.30 (m, 1H), 0.88-1.00 (m, 2H), 0.70-0.87 (m, 2H).
Example 173: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-2-chloro-2-fluoroethanone




Example 173 was prepared in a manner analogous to Example 34 using chlorofluoroacetic acid in place of (2E)-4-(dimethylamino)but-2-enoic acid and HATU in place of PyBOP. MS (ESI) calcd. for C30H29ClFN9O, 585.22 m/z, found: 586.10 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.22-8.51 (m, 2H), 7.88-8.13 (m, 2H), 7.71-7.88 (m, 1H), 7.41-7.62 (m, 1H), 7.05-7.41 (m, 4H), 6.52-6.67 (m, 1H), 6.32-6.52 (m, 1H), 4.28-4.46 (m, 1H), 4.08-4.28 (m, 1H), 3.65-3.91 (m, 1H), 3.05-3.32 (m, 1H), 2.85-3.05 (m, 3H), 2.65-2.85 (m, 1H), 2.28-2.52 (m, 1H), 1.96-2.16 (m, 1H), 1.86-1.96 (m, 1H), 1.65-1.86 (m, 1H), 1.08-1.54 (m, 2H).
Example 174: 1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperazin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of methyl 5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-indene-1-carboxylate
A mixture of methyl 5-bromo-2,3-dihydro-1H-indene-1-carboxylate (6 g, 23.5 mmol, 1 equiv), 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine (5.79 g, 28.2 mmol, 1.2 equiv), Pd(OAc)2 (528 mg, 2.35 mmol, 0.1 equiv), XantPhos (1.36 g, 2.35 mmol, 0.1 equiv) and Cs2CO3 (22.99 g, 70.56 mmol, 3.00 equiv) in dioxane (120 mL) was stirred for 5 h at 100° C. under nitrogen atmosphere. The mixture was allowed to cool to room temperature then filtered rinsing with ethyl acetate (3×30 mL). The filtrate was concentrated under reduced pressure. The residue was suspended in water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with HCl (1M) (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-indene-1-carboxylate (6 g, crude) as a light brown solid. MS (ESI) calcd. for C19H17N5O4: 379.13 m/z, found: 380.10 [M+H]+. The crude product was used in the next step directly without further purification.
Step 2: Synthesis of methyl 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxylate
A mixture of methyl 5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-indene-1-carboxylate (6 g, 15.8 mmol, 1 equiv), 2-aminopyridine-3-carbaldehyde (2.90 g, 23.7 mmol, 1.5 equiv), and Na2S2O4 (6.06 g, 34.8 mmol, 2.2 equiv) in DMSO (120 mL) and MeOH (20 mL) was stirred overnight at 100° C. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford methyl 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxylate (1.5 g, 21%) as a light brown solid. MS (ESI) calcd. for C25H21N7O2: 451.18 m/z, found: 452.20 [M+H]+.
Step 3: Synthesis of 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxylic acid
A mixture of methyl 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxylate (1.4 g, 3.1 mmol, 1 equiv) and LiOH (223 mg, 9.30 mmol, 3.00 equiv) in THF (15 mL) and H2O (15 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water (30 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The aqueous layer was acidified to pH 2 with conc. HCl. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum to afford 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxylic acid (1.2 g, crude) as an off-white solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C24H19N7O2: 437.16 m/z, found: 438.20 [M+H]+.
Step 4: Synthesis of tert-butyl 4-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indene-1-carbonyl)piperazine-1-carboxylate
A solution of EDCI (310 mg, 1.62 mmol, 2 equiv) in pyridine (3 mL) and DMF (1 mL) was treated with 5-[2-(2-aminopyridin-3-yl)-5-(cyclopenta-2,4-dien-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-indene-1-carboxylic acid (352 mg, 0.808 mmol, 1 equiv) and tert-butyl piperazine-1-carboxylate (226 mg, 1.21 mmol, 1.5 equiv) for 5 min at room temperature. The resulting mixture was stirred overnight at 50° C. under air atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water (20 mL) and the resulting mixture was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford tert-butyl 4-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indene-1-carbonyl)piperazine-1-carboxylate (150 mg, 28%) as a brown yellow solid. MS (ESI) calcd. for C33H35N9O3: 605.29 m/z, found: 606.15 [M+H]+.
Step 5: Synthesis of tert-butyl 4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperazine-1-carboxylate
A solution of tert-butyl 4-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indene-1-carbonyl)piperazine-1-carboxylate (405 mg, 0.669 mmol, 1 equiv) and 4,4′-di-tert-butyl-2,2′-bipyridine; bis[2-(pyridin-2-yl)phenyl]iridiumylium; hexafluoro-lambda5-phosphanuide (40 mg, 0.044 mmol, 0.07 equiv) in THF (5 mL) was treated with nickel(II) chloride ethylene glycol dimethyl ether complex (44.1 mg, 0.201 mmol, 0.3 equiv) and phenylsilane (2.89 g, 26.8 mmol, 40 equiv) at room temperature under nitrogen atmosphere. The vial was sealed with a plastic screw cap and stirred overnight at room temperature whilst being irradiated with blue LED light. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford tert-butyl 4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperazine-1-carboxylate (140 mg, 33%) as a brown yellow solid. MS (ESI) calcd. for C33H37N9O2: 591.31 m/z, found: 592.20 [M+H]+.
Step 6: Synthesis of 3-{3-[1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
A solution of tert-butyl 4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}methyl)piperazine-1-carboxylate (140 mg, 0.237 mmol, 1 equiv) was treated with HCl (4 M) in 1,4-dioxane (5 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under air atmosphere. The reaction was quenched with water. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (3×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-{3-[1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (112 mg, crude) as a brown yellow solid. MS (ESI) calcd. for C28H29N9: 491.25 m/z, found: 492.25 [M+H]+. The crude product was used in the next step directly without further purification.
Step 7: Synthesis of 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}methyl)piperazin-1-yl]prop-2-en-1-one (Example 174)
A solution of EDCI (87 mg, 0.46 mmol, 2 equiv) in pyridine (3 mL) and DMF (1 mL) was treated with 3-{3-[1-(piperazin-1-ylmethyl)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (112 mg, 0.228 mmol, 1 equiv) and acrylic acid (33 mg, 0.46 mmol, 2 equiv). The resulting mixture was stirred for 4 h at 50° C. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3). The product was further purified by Prep-HPLC on a XSelect CSH Prep Fluoro-Phenyl Column using a gradient of acetonitrile in water (+10 mmoL/L ammonium bicarbonate) to afford 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}methyl)piperazin-1-yl]prop-2-en-1-one (Example 174) (1.3 mg, 1%) as an off-white solid. MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found: 546.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.43-8.26 (m, 2H), 8.06-7.88 (m, 2H), 7.81-7.60 (m, 1H), 7.58-7.44 (m, 1H), 7.35 (s, 1H), 7.27-7.13 (m, 2H), 6.94 (s, 2H), 6.89-6.74 (m, 1H), 6.59-6.50 (m, 1H), 6.47-6.35 (m, 1H), 6.18-6.05 (m, 1H), 5.71-5.63 (m, 1H), 3.71-3.43 (m, 4H), 3.03-2.73 (m, 2H), 2.73-2.58 (m, 1H), 2.49-2.38 (m, 5H), 2.37-2.16 (m, 1H), 1.92-1.72 (m, 1H), 1.44-1.09 (m, 1H).
Example 175: 1-(4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one
Example 176: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one and
Example 177: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoropiperidin-1-yl)prop-2-en-1-one




Examples 175, 176 and 177 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using (3S)-3-fluoro-4-oxopiperidine-1-carboxylate in place tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and Intermediate 85-2 in place of Intermediate 1-1. Note that the fluoro stereocenter epimerized under the reaction conditions giving four stereoisomeric products. The diastereomers partially separated during reverse phase Prep-HPLC on a XBridge Prep OBD C18 Column using a gradient of acetonitrile in water (+10 mM ammonium formate). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer. Note also that Example 175 is a mixture of two undetermined diastereomers.
Example 175: MS (ESI) calcd. for C31H32FN7O: 537.27 m/z, found: 538.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 7.99-8.05 (m, 1H), 7.91-7.98 (m, 1H), 7.41-7.49 (m, 1H), 7.07-7.25 (m, 4H), 6.68-6.85 (m, 1H), 6.35-6.45 (m, 1H), 6.04-6.15 (m, 1H), 5.63-5.75 (m, 1H), 4.70-4.91 (m, 1H), 4.39-4.48 (m, 1H), 4.01-4.38 (m, 2H), 3.09-3.50 (m, 1H), 2.65-3.05 (m, 4H), 2.31-2.45 (m, 1H), 2.10-2.20 (m, 1H), 1.71-1.90 (m, 2H), 1.38-1.60 (m, 1H), 0.85-1.00 (m, 2H), 0.70-0.84 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −203.15.
Example 176: MS (ESI) calcd. for C31H32FN7O: 537.27 m/z, found: 538.20 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 8.28-8.39 (m, 1H), 7.96-8.05 (m, 1H), 7.90-7.95 (m, 1H), 7.40-7.48 (m, 1H), 7.08-7.25 (m, 4H), 6.70-6.82 (m, 1H), 6.38-6.45 (m, 1H), 6.05-6.15 (m, 1H), 5.66-5.75 (m, 1H), 4.28-4.52 (m, 2H), 3.56-3.85 (m, 2H), 3.32-3.55 (m, 2H), 3.01-3.15 (m, 1H), 2.82-2.98 (m, 1H), 2.65-2.80 (m, 1H), 2.35-2.48 (m, 1H), 2.05-2.20 (m, 1H), 1.82-2.04 (m, 1H), 1.66-1.80 (m, 1H), 1.40-1.55 (m, 1H), 0.88-1.00 (m, 2H), 0.72-0.87 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −185.54.
Example 177: MS (ESI) calcd. for C31H32FN7O: 537.27 m/z, found: 538.25 [M+H]+. 1H-NMR (400 MHz, DMSO) δ (ppm): 7.98-8.05 (m, 1H), 7.92-7.97 (m, 1H), 7.41-7.50 (m, 1H), 7.15-7.25 (m, 2H), 7.10-7.14 (m, 2H), 6.71-6.83 (m, 1H), 6.35-6.45 (m, 1H), 6.05-6.15 (m, 1H), 5.65-5.75 (m, 1H), 4.40-4.62 (m, 1H), 4.30-4.39 (m, 1H), 3.89-4.06 (m, 1H), 3.48-3.60 (m, 2H), 3.35-3.45 (m, 1H), 3.02-3.12 (m, 1H), 2.85-2.95 (m, 1H), 2.65-2.80 (m, 1H), 2.40-2.50 (m, 1H), 2.10-2.20 (m, 1H), 1.70-2.00 (m, 2H), 1.40-1.50 (m, 1H), 0.89-1.00 (m, 2H), 0.70-0.85 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −185.85.
Example 178: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-ethynylphenyl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 178 was prepared in a manner analogous to Example 109 (via Intermediate 109-2) using Intermediate 85-1 and 3-ethynylphenylboronic acid with tribasic potassium phosphate instead of Intermediate 109-1, 2-bromo-1,3-oxazole and potassium carbonate for Step 1, HCl in dioxane instead of TFA/DCM and tetrahydrofuran as the solvent for the final step. MS (ESI) calcd. For C36H33N7O, 579.27 m/z, found 580.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=8.4 Hz, 1H), 8.16-7.94 (m, 4H), 7.56-7.43 (m, 3H), 7.36-7.25 (m, 2H), 7.22 (dd, J=7.7, 1.9 Hz, 1H), 7.00 (s, 2H), 6.83 (dd, J=16.7, 10.5 Hz, 1H), 6.42 (dd, J=7.6, 4.8 Hz, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.4, 2.5 Hz, 1H), 4.36 (t, J=7.3 Hz, 1H), 4.27 (s, 2H), 3.99 (s, 1H), 3.17 (s, 1H), 3.02-2.84 (m, 3H), 2.84-2.70 (m, 1H), 2.48-2.40 (m, 1H), 2.10-2.20 (m, 1H), 1.96 (s, 1H), 1.87 (s, 1H), 1.83-1.69 (m, 1H), 1.25 (s, 2H).
Example 179: 1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](methyl)amino}piperazin-1-yl)prop-2-en-1-one and
Example 180: 1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](methyl)amino}piperazin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of 1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](methyl)amino}piperazin-1-yl)prop-2-en-1-one (Example 179) and 1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](methyl)amino}piperazin-1-yl)prop-2-en-1-one (Example 180)
To a solution of 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)piperazin-1-yl]prop-2-en-1-one (Example 77) (500 mg, 0.915 mmol, 1 equiv) in MeOH (20 mL) was added paraformaldehyde (80.6 mg, 1.83 mmol, 2 equiv). The resulting mixture was stirred for 12 h at 40° C. NaBH3CN (172.4 mg, 2.745 mmol, 3 equiv) was added and the reaction mixture was stirred at 40° C. for another 1 hour. The mixture was purified directly by reverse-phase flash chromatography on a XBridge Prep Shield RP OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate). The racemic mixture was separated into enantiomers by chiral Prep-HPLC on a CHIRALPAK IF column using a mixture of [MTBE (0.5% 2M NH3-MeOH)] and [EtOH/DCM (1:1)] to afford {1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](methyl)amino}piperazin-1-yl)prop-2-en-1-one (Example 179) (12.3 mg, 2.39%) as a white solid and the first eluting isomer and {1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl](methyl)amino}piperazin-1-yl)prop-2-en-1-one (Example 180) (14.4 mg, 2.80%) as a white solid. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer.
Example 179: MS (ESI) calcd. for C31H32N10O: 560.28 m/z, found: 561.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.35 (m, 2H), 8.00-8.01 (m, 1H), 7.95-7.99 (m, 1H), 7.81-7.82 (m, 1H), 7.54-7.56 (m, 1H), 7.31-7.32 (m, 1H), 7.22-7.25 (m, 2H), 6.73-6.80 (m, 1H), 6.54-6.55 (m, 1H), 6.41-6.44 (m, 1H), 6.09-6.13 (m, 1H), 5.69-5.73 (m, 1H), 4.31-4.33 (m, 1H), 3.49-3.55 (m, 4H), 3.04-3.07 (m, 1H), 2.70-2.78 (m, 1H), 2.63-2.69 (m, 2H), 2.39-2.52 (m, 2H), 2.33 (s, 3H), 2.16-2.21 (m, 2H).
Example 180: MS (ESI) calcd. for C31H32N10O: 560.28 m/z, found: 561.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.35 (m, 2H), 8.00-8.01 (m, 1H), 7.95-7.99 (m, 1H), 7.81-7.82 (m, 1H), 7.54-7.56 (m, 1H), 7.32-7.33 (m, 1H), 7.22-7.25 (m, 2H), 6.73-6.80 (m, 1H), 6.54-6.55 (m, 1H), 6.41-6.44 (m, 1H), 6.08-6.13 (m, 1H), 5.69-5.72 (m, 1H), 4.31-4.33 (m, 1H), 3.52-3.72 (m, 4H), 3.02-3.07 (m, 1H), 2.72-2.84 (m, 1H), 2.62-2.63 (m, 2H), 2.49-2.54 (m, 2H), 2.33 (s, 3H), 2.18-2.22 (m, 2H).
Example 181: 1-(4-{[(1S,2*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2-methyl-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one and
Example 182: 1-(4-(((1S,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-methyl-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 181 and 182 were prepared in a manner analogous to Example 13 using Intermediate 181-1 and 182-1 respectively instead of Intermediate 1-1 and 10:1 methanol/AcOH for 1 h at 60° C. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 181: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.68 (m, 2H), 7.95-8.16 (m, 2H), 7.81-7.95 (m, 1H), 7.62-7.81 (m, 2H), 7.52-7.62 (m, 1H), 7.36-7.52 (m, 1H), 6.69-6.98 (m, 2H), 6.49-6.69 (m, 1H), 6.04-6.28 (m, 1H), 5.65-5.91 (m, 1H), 4.82-5.14 (m, 1H), 4.43-4.71 (m, 1H), 4.06-4.35 (m, 1H), 3.41-3.71 (m, 1H), 3.05-3.36 (m, 2H), 2.92-3.05 (m, 1H), 2.63-2.92 (m, 2H), 2.52-2.61 (m, 1H), 2.08-2.26 (m, 1H), 1.46-1.79 (m, 2H), 1.05-1.31 (m, 3H). (TFA salt)
Example 182: MS (ESI) calcd. for C32H33N9O, 559.28 m/z, found 560.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.14-8.50 (m, 3H), 7.89-8.14 (m, 2H), 7.69-7.89 (m, 1H), 7.45-7.69 (m, 1H), 7.09-7.45 (m, 3H), 6.68-6.95 (m, 1H), 6.53-6.68 (m, 1H), 6.32-6.53 (m, 1H), 5.98-6.28 (m, 1H), 5.61-5.88 (m, 1H), 4.48-4.66 (m, 1H), 4.28-4.48 (m, 1H), 4.06-4.28 (m, 1H), 3.08-3.35 (m, 2H), 2.92-3.08 (m, 1H), 2.76-2.91 (m, 2H), 2.63-2.76 (m, 1H), 1.95-2.26 (m, 2H), 1.28-1.54 (m, 2H), 0.79-1.12 (m, 3H). (TFA salt)
Intermediate 181-1: 3-(3-((1S,2*)-1-amino-2-methyl-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine and
Intermediate 182-1: 3-(3-((1S,2*)-1-amino-2-methyl-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediates 181-1 and 182-1 were prepared in a manner analogous to Intermediates 75-1 and 76-1 (starting from Step 2) using 5-bromo-2-methyl-2,3-dihydro-1H-inden-1-one in place of 5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one. The diastereomers were separated prior to the final step by chiral SFC on a Lux Sum Cellulose-3 column using a mixture of CO2 and methanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 183: 1-[4-({[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}methyl)-4-methoxypiperidin-1-yl]prop-2-en-1-one




Example 183 was prepared in a manner analogous to Example 34 using tert-butyl 4-formyl-4-methoxypiperidine-1-carboxylate in place of tert-butyl 4-oxopiperidine-1-carboxylate, MeOH instead of 1,2-dichloroethane and acrylic acid instead of (2E)-4-(dimethylamino)but-2-enoic acid. MS (ESI) calcd. for C33H35N9O2, 589.29 m/z, found 590.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.00-9.16 (m, 1H), 8.75-8.80 (m, 1H), 8.41-8.43 (m, 111), 8.35-8.36 (m, 1H), 8.05-8.07 (m, 1H), 7.99-8.01 (m, 1H), 7.82-7.83 (m, 2H), 7.57-7.60 (m, 2H), 7.39-7.41 (m, 1H), 7.00-7.30 (m, 1H), 6.79-6.86 (m, 1H), 6.57-6.59 (m, 2H), 6.08-6.13 (m, 1H), 5.67-5.70 (m, 1H), 4.98-5.00 (m, 1H), 4.09-4.15 (m, 2H), 3.15-3.30 (m, 3H), 2.95-3.02 (m, 5H), 2.78-2.81 (m, 1H), 2.55-2.60 (m, 1H), 2.20-2.33 (m, 1H), 1.80-1.83 (m, 2H), 1.42-1.50 (m, 2H). (TFA salt)
Example 184: (S)-1-(4-(((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one




Example 184 was prepared in a manner analogous to Example 34 using 1-acryloyl-4-fluoropiperidine-4-carbaldehyde in place of tert-butyl 4-oxopiperidine-1-carboxylate, MeOH instead of 1,2-dichloroethane and acrylic acid instead of (2E)-4-(dimethylamino)but-2-enoic acid. MS (ESI) calcd. for C32H32FN9O, 577.27 m/z, found 578.30 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ (ppm): 1H NMR (400 MHz, DMSO-d6) δ 9.24-9.26 (m, 2H), 8.37-8.44 (m, 2H), 7.98-8.08 (m, 2H), 7.81-7.84 (m, 2H), 7.57-7.60 (m, 2H), 7.42-7.44 (m, 1H), 7.00-7.25 (m, 1H), 6.82-6.89 (m, 1H), 6.57-6.58 (m, 2H), 6.11-6.16 (m, 1H), 5.70-5.73 (m, 1H), 4.97-5.00 (m, 1H), 4.29-4.30 (m, 1H), 4.01-4.04 (m, 1H), 3.32-3.33 (m, 2H), 3.28-3.29 (m, 2H), 2.92-2.99 (m, 2H), 2.50-2.58 (m, 1H), 2.20-2.30 (m, 1H), 1.98-2.07 (m, 2H), 1.60-1.90 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −73.98, −161.869. (TFA salt)
Example 185: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-3-methylbut-2-en-1-one




Example 185 was prepared in a manner analogous to Example 34 using 3-methylbut-2-enoic acid in place of (2E)-4-(dimethylamino)but-2-enoic acid. MS (ESI) calcd for C33H35N9O: 573.30, found: 574.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.12 (m, 1H), 8.96 (m, 1H), 8.43 (m, 1H), 8.35 (m, 1H), 8.07-8.00 (m, 1H), 7.98 (m, 1H), 7.83 (s, 1H), 7.76-7.74 (m, 1H), 7.64-7.58 (m, 2H), 7.54-7.42 (m, 1H), 6.63-6.57 (m, 2H), 5.96 (s, 1H), 5.01 (m, 1H), 4.51 (m, 1H), 4.03 (m, 1H), 3.55-3.55 (m, 1H), 3.22-3.00 (m, 2H), 2.98-2.92 (m, 1H), 2.69-2.50 (m, 2H), 2.50 (s, 1H), 2.23-2.20 (m, 2H), 2.10-2.07 (m, 1H), 2.07-1.84 (m, 6H), 1.82-1.23 (m, 2H). (formic acid salt)
Example 186: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(4,4-difluoropiperidin-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 186 was prepared in a manner analogous to Example 86 (via Intermediate 86-2) using 4,4-difluoropiperidine in place of morpholine. MS (ESI) calcd. for C33H36F2N8O: 598.30 m/z, found: 599.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.02-7.92 (m, 2H), 7.60-7.45 (m, 1H), 7.34-7.18 (m, 2H), 7.09-7.00 (m, 2H), 6.95 (s, 2H), 6.89-6.79 (m, 1H), 6.40-6.33 (m, 1H), 6.14-6.05 (m, 1H), 5.71-5.63 (m, 1H), 4.54-4.24 (m, 2H), 4.04 (s, 1H), 3.68-3.61 (m, 4H), 3.19-2.89 (m, 3H), 2.87-2.71 (m, 3H), 2.45-2.41 (m, 1H), 2.13-1.59 (m, 7H), 1.35-1.23 (m, 2H).
Example 187: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[1-(difluoromethyl) pyrazol-4-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 187 was prepared in a manner analogous to Example 109 (via Intermediate 109-2) using 4-bromo-1-(difluoromethyl) pyrazole in place of 2-bromo-1,3-oxazole. MS (ESI) calcd. for C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.52-8.79 (m, 1H), 8.23-8.46 (m, 1H), 8.16-8.23 (m, 1H), 7.96-8.16 (m, 1H), 7.55-7.96 (m, 2H), 7.44-7.55 (m, 1H), 7.29-7.44 (m, 1H), 7.08-7.29 (m, 2H), 6.67-6.95 (m, 1H), 6.36-6.59 (m, 1H), 5.96-6.26 (m, 1H), 5.58-5.85 (m, 1H), 4.21-4.56 (m, 2H), 3.97-4.21 (m, 1H), 2.91-3.32 (m, 3H), 2.67-2.91 (m, 2H), 2.41-2.52 (m, 1H), 1.98-2.21 (m, 1H), 1.68-1.98 (m, 2H), 1.07-1.47 (m, 2H). (formic acid salt)
Example 188: 1-((1R,5S,9*)-9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-azabicyclo[3.3.1]nonan-3-yl)prop-2-en-1-one and
Example 189: 1-((1R,5S,9*)-9-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-azabicyclo[3.3.1]nonan-3-yl)prop-2-en-1-one




Examples 188 and 189 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 9-oxo-3-azabicyclo[3.3.1]nonane-3-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and 4N HCl in dioxane in place of TFA in DCM. The diastereomers were separated by Prep-HPLC on a XBridge Prep Phenyl Hexy OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 188: MS (ESI) calcd. for C34H35N9O: 585.29 m/z, found: 586.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.30-8.37 (m, 2H), 7.93-8.03 (m, 2H), 7.79-7.82 (m, 1H), 7.49-7.55 (m, 1H), 7.33-7.37 (m, 1H), 7.21-7.31 (m, 2H), 6.81-6.98 (m, 3H), 6.50-6.56 (m, 1H), 6.40-6.44 (m, 1H), 6.01-6.10 (m, 1H), 5.61-5.68 (m, 1H), 4.50-4.60 (m, 1H), 4.09-4.29 (m, 2H), 3.38-3.40 (m, 1H), 2.81-3.00 (m, 3H), 2.70-2.80 (m, 1H), 2.48-2.52 (m, 1H), 2.00-2.19 (m, 3H), 1.90-1.99 (m, 1H), 1.76-1.87 (m, 2H), 1.28-1.60 (m, 4H).
Example 189: MS (ESI) calcd. for C34H35N9O: 585.29 m/z, found: 586.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.27-8.31 (m, 2H), 7.82-7.96 (m, 2H), 7.71-7.74 (m, 1H), 7.40-7.46 (m, 1H), 7.30-7.40 (m, 1H), 7.13-7.28 (m, 2H), 6.82-6.90 (m, 2H), 6.70-6.81 (m, 1H), 6.45-6.50 (m, 1H), 6.30-6.38 (m, 1H), 5.97-6.03 (m, 1H), 5.50-5.58 (m, 1H), 4.18-4.28 (m, 1H), 4.07-4.18 (m, 1H), 3.63-3.72 (m, 2H), 3.18-3.21 (m, 1H), 2.84-2.92 (m, 1H), 2.76-2.80 (m, 1H), 2.62-2.72 (m, 1H), 2.38-2.40 (m, 1H), 1.99-2.08 (m, 1H), 1.90-1.97 (m, 1H), 1.67-1.80 (m, 4H), 1.42-1.62 (m, 3H), 1.22-1.30 (m, 1H).
Example 190: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide
To a stirred solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-1) (500 mg, 1.079 mmol, 1 equiv) and pyridin-3-ylboronic acid (159 mg, 1.295 mmol, 1.2 equiv) in THF (4 mL) and H2O (4 mL) was added Pd(dtbpf)Cl2 (70 mg, 0.108 mmol, 0.1 equiv) and K3PO4 (687.2 mg, 3.237 mmol, 3 equiv) in portions at 50° C. under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 50° C. under nitrogen then allowed to cool to room temperature. The reaction was quenched with water. The resulting mixture was extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (240 mg, 44%) as a brown yellow solid. MS (ESI) calcd. for C27H23N7O: 461.20 m/z, found: 462.30 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-(pyridin-3-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
A solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (210 mg, 0.455 mmol, 1 equiv) in HCl (6 mL) and MeOH (6 mL) was stirred overnight at 90° C. under air atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-(pyridin-3-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (150 mg, 79%) as a brown yellow solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C25H21N7: 419.19 m/z, found: 420.20 [M+H]+.
Step 3: Synthesis of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 190)
A solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-(pyridin-3-yl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (120 mg, 0.286 mmol, 1 equiv) and 1-(prop-2-enoyl)piperidin-4-one (175.3 mg, 1.144 mmol, 4 equiv) in THF (5 mL) was stirred for 30 min at 50° C. To the above mixture was added NaBH3CN (71.9 mg, 1.144 mmol, 4 equiv) in portions at room temperature. The resulting mixture was stirred for 4 h at 50° C. The mixture was allowed to cool to room temperature. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyridin-3-yl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 190) (16.0 mg, 10%) as an off-white solid. MS (ESI) calcd. for C33H32N8O: 556.27 m/z, found: 557.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.05-8.98 (m, 1H), 8.71-8.59 (m, 2H), 8.59-8.54 (m, 1H), 8.26-8.16 (m, 1H), 8.06-7.98 (m, 1H), 7.60-7.49 (m, 2H), 7.42-7.36 (s, 1H), 7.34-7.26 (m, 1H), 7.26-7.17 (m, 1H), 7.12-6.96 (s, 2H), 6.91-6.76 (m, 1H), 6.48-6.38 (m, 1H), 6.15-6.03 (m, 1H), 5.72-5.61 (m, 1H), 4.47-4.41 (m, 1H), 4.33-4.27 (m, 1H), 4.04-3.98 (m, 1H), 3.26-3.08 (m, 2H), 3.02-2.96 (m, 2H), 2.89-2.73 (m, 2H), 2.44-2.31 (m, 1H), 1.99-1.93 (m, 2H), 1.92-1.86 (m, 1H), 1.33-1.27 (m, 2H).
Intermediate 190-1: (S)-N-(5-(2-(2-aminopyridin-3-yl)-6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-[(5-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide
A solution of 2,5-dibromo-3-nitropyridine (8 g, 28 mmol, 1.2 equiv) and N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-2) (4.50 g, 23.7 mmol, 1 equiv) in 1,4-dioxane (80 mL) was treated with DIEA (16.5 mL, 94.6 mmol, 4 equiv) over 10 min at room temperature. The resulting mixture was stirred for 5 h at 90° C. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water (3×100 mL). The residue was purified by trituration with Et2O (200 mL) to afford N-[(1S)-5-[(5-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (7 g, 58%) as a brown solid. MS (ESI) calcd. for C16H11BrN4O3: 390.03 m/z, found: 391.00 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-1
A solution of N-[(1S)-5-[(5-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (7 g, 18 mmol, 1 equiv) and 2-aminopyridine-3-carbaldehyde (2.6 g, 21 mmol, 1.2 equiv) in DMSO/MeOH=36 mL:6 mL was treated with Na2S2O4 (6.85 g, 39.4 mmol, 2.2 equiv) for 10 min at room temperature under air atmosphere. The resulting mixture was stirred for 2 days at 100° C. under air atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water. The mixture was basified to pH 10 with NaOH. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-1) (1.02 g, 11%) as a brown solid. MS (ESI) calcd. for C22H19BrN6O: 462.08 m/z, found: 463.10 [M+H]+.
Intermediate 190-2: (S)-N-(5-amino-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide
To a mixture of (S)-5-bromo-2,3-dihydro-1H-inden-1-amine (74 g, 350 mmol, 1 equiv) and triethylamine (106 g, 1.05 mol, 3 equiv) in dichloromethane (1.5 L) was added acetic anhydride (55.2 g, 526 mmol, 1.5 equiv) at 0° C. and the mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by addition of water (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was re-crystallized from petroleum ether to afford (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 13-1) (90 g, 83% yield) as a white solid. MS (ESI) calculated for C11H12BrNO: 253.01, found 254.00 [M+H]+, 256.00 [M+H+2]+.
Step 2: Synthesis of tert-butyl (S)-(1-acetamido-2,3-dihydro-1H-inden-5-yl)carbamate
To a mixture of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 13-1) (40 g, 157 mmol, 1 equiv), tert-butyl carbamate (27.66 g, 236 mmol, 1.5 equiv), XantPhos (CAS: 161265-03-8) (9.11 g, 15.7 mmol, 10 mol %), Pd(OAc)2 (3.54 g, 15.7 mmol, 10 mol %), and cesium carbonate (154 g, 472 mmol, 3 equiv) was added 1,4-dioxane (300 mL) under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100° C. The reaction mixture was quenched by addition of water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent of petroleum ether/dichloromethane/methanol (70:27:3) to afford tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 48% yield). MS (ESI) calculated for C16H22N2O3: 290.16, found 289.05 [M−H]−.
Step 3: Synthesis of (S)-N-(5-amino-2,3-dihydro-1H-inden-1-yl)acetamide
To a stirred solution of tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 148 mmol, 1 equiv) in dichloromethane (180 mL) was added 4N HCl in 1,4-dioxane (185 mL, 742 mmol, 5 equiv). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and re-crystallized from ethyl acetate to afford N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (hydrochloride salt) (23 g, 81% yield) as a white solid. MS (ESI) calculated for C11H14N2O: 190.11, found 191.15 [M+H]+.
Example 191: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-6-(pyridin-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 191 was prepared in a manner analogous to Example 190 using pyridin-4-ylboronic acid in place of pyridin-3-ylboronic acid. MS (ESI) calcd. for C33H32N8O: 556.27 m/z, found: 557.20[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.80-8.75 (m, 1H), 8.72-8.65 (m, 3H), 8.06-8.00 (m, 1H), 7.94-7.79 (m, 3H), 7.54-7.43 (m, 1H), 7.37-7.27 (m, 2H), 7.03-6.95 (s, 2H), 6.91-6.80 (m, 1H), 6.49-6.41 (m, 1H), 6.16-6.07 (m, 1H), 5.73-5.66 (m, 1H), 5.10-4.70 (m, 1H) 4.47-4.42 (m, 1H), 4.16-4.11 (m, 1H), 3.21-3.10 (m, 3H), 3.01-2.85 (m, 1H), 2.80-2.75 (m, 1H), 2.38-1.90 (m, 3H), 1.55-1.51 (m, 3H), 1.29-1.20 (m, 1H).
Example 192: N-{1-[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]piperidin-4-yl}prop-2-enamide and
Example 193: N-{1-[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]piperidin-4-yl}prop-2-enamide




Synthetic Route:





Step 1: Synthesis of tert-butyl N-(1-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperidin-4-yl)carbamate
To a solution of 5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydroinden-1-one (Intermediate 77-1) (500 mg, 1.227 mmol, 1 equiv) in THE (15 mL) were added tert-butyl N-(piperidin-4-yl)carbamate (369 mg, 1.841 mmol, 1.5 equiv) and Ti(OEt)4 (559.9 mg, 2.454 mmol, 2 equiv). The resulting mixture was stirred for 4 h at 80° C. A solution of NaBH3CN (308.5 mg, 4.908 mmol, 4 equiv) was added and the reaction mixture was stirred at 80° C. for another 1 hour. The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl N-(1-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperidin-4-yl)carbamate (200 mg, 27%) as a black solid. MS (ESI) calcd. for C33H37N9O2: 591.30 m/z, found: 592.20 [M+H]+.
Step 2: Synthesis of 3-{3-[1-(4-aminopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
To a solution of tert-butyl N-(1-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperidin-4-yl)carbamate (200 mg, 0.338 mmol, 1 equiv) in DCM (10 mL) was added HCl in 1,4-dioxane (10 mL). The resulting mixture was maintained under nitrogen and stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford 3-{3-[1-(4-aminopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (180 mg, crude quant) as a yellow solid. MS (ESI) calcd. for C28H29N9: 491.25 m/z, found: 492.15 [M+H]+.
Step 3: Synthesis of N-{1-[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]piperidin-4-yl}prop-2-enamide (Example 192) and N-{1-[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]piperidin-4-yl}prop-2-enamide (Example 193)
To a solution of 3-{3-[1-(4-aminopiperidin-1-yl)-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (170 mg, 0.346 mmol, 1 equiv) in ACN (5 mL) was added triethylamine (175 mg, 1.730 mmol, 5 equiv) and acryloyl chloride (31.3 mg, 0.346 mmol, 1 equiv) at 0° C. The resulting mixture was stirred for 1 h at room temperature. The mixture was purified directly by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.05% TFA). The enantiomers were separated by chiral Prep-HPLC on CHIRAL ART Cellulose-SB column using a mixture of [Hexanes (+0.5% 2M NH3-MeOH)] and isopropanol to afford N-{1-[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]piperidin-4-yl}prop-2-enamide (Example 192) (12.2 mg, 6.43%) as a white solid and was the first eluting peak and N-{1-[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]piperidin-4-yl}prop-2-enamide (Example 193) (10.4 mg, 5%) as a white solid and was the second eluting peak. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer.
Example 192: MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found: 546.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36-8.37 (m, 2H), 8.00-8.01 (m, 2H), 7.95-7.97 (m, 1H), 7.81 (s, 1H), 7.29-7.39 (m, 3H), 7.15-7.17 (m, 1H), 7.02 (s, 2H), 6.54-6.55 (m, 1H), 6.36-6.38 (m, 1H), 6.21-6.25 (m, 1H), 6.06-6.18 (m, 1H), 5.58-5.59 (m, 1H), 4.39-4.45 (m, 1H), 3.50-3.62 (m, 1H), 2.65-3.09 (m, 3H), 2.26-2.33 (m, 1H), 2.11-2.22 (m, 2H), 1.91-1.96 (m, 2H), 1.50-1.79 (m, 2H), 1.21-1.38 (m, 2H).
Example 193: MS (ESI) calcd. for C31H31N9O: 545.27 m/z, found: 546.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 8.00-8.07 (m, 2H), 7.95-7.99 (m, 1H), 7.81 (s, 1H), 7.29-7.39 (m, 2H), 7.14-7.16 (m, 1H), 7.09-7.12 (m, 1H), 7.03 (s, 2H), 6.52-6.54 (m, 1H), 6.35-6.38 (m, 1H), 6.19-6.26 (m, 1H), 6.06-6.10 (m, 1H), 5.56-5.59 (m, 1H), 4.44-4.54 (m, 1H), 3.60-3.67 (m, 1H), 2.94-3.03 (m, 2H), 2.86-2.87 (m, 1H), 2.30-2.36 (m, 1H), 2.15-2.19 (m, 2H), 1.76-1.91 (m, 2H), 1.40-1.45 (m, 2H), 1.20-1.23 (m, 2H).
Example 194: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[(3R)-3-fluoropyrrolidin-1-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 194 was prepared in a manner analogous to Example 86 (via Intermediate 86-2) using (2R)-2-fluoropyrrolidine in place of morpholine and HCl in dioxane instead of TFA in DCM. MS (ESI) calcd. for C32H35FN8O: 566.29 m/z, found: 567.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 7.98-7.89 (m, 2H), 7.45-7.40 (m, 1H), 7.33-7.11 (m, 2H), 7.08-6.94 (m, 3H), 6.89-6.76 (m, 1H), 6.58-6.50 (m, 1H), 6.36-6.31 (m, 1H), 6.13-6.04 (m, 1H), 5.69-5.63 (m, 1H), 5.53-5.29 (m, 1H), 4.39-4.16 (m, 2H), 4.05-3.91 (m, 1H), 3.77-3.54 (m, 3H), 3.53-3.41 (m, 1H), 3.33-3.11 (m, 1H), 3.00-2.82 (m, 3H), 2.80-2.67 (m, 2H), 2.34-2.14 (m, 2H), 2.14-2.02 (m, 1H), 2.00-1.90 (m, 1H), 1.90-1.70 (m, 2H), 1.34-1.13 (m, 2H).
Example 195: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclobutylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route:








Step 1: Synthesis of 1,3-dioxoisoindol-2-yl cyclobutanecarboxylate
To a solution of cyclobutanecarboxylic acid (1 g, 10 mmol, 1 equiv) in DCM (30 mL) was added phthalimide (1.47 g, 9.988 mmol, 1 equiv), EDCI (2.11 g, 11 mmol, 1.1 equiv) and DMAP (0.12 g, 0.999 mmol, 0.1 equiv). After stirring for 2 h at room temperature, the reaction was quenched by the addition of water (20 mL) at 0° C. The resulting mixture was extracted with DCM (30 mL×3). The combined organic layers were washed with water (10 mL×3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (0-30% ethyl acetate in petroleum ether) giving 1,3-dioxoisoindol-2-yl cyclobutanecarboxylate (2.2 g, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.86-7.89 (m, 2H), 7.78-7.81 (m, 2H), 3.49-3.53 (m, 1H), 2.51-2.57 (m, 2H), 2.40-2.49 (m, 2H), 2.04-2.14 (m, 2H).
Step 2: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclobutylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (1 g, 1.9 mmol, 1 equiv) in DMAc (10 mL) was added 1,3-dioxoisoindol-2-yl cyclobutanecarboxylate (0.52 g, 2.1 mmol, 1.1 equiv), 5-methoxypyridine-2-carboximidamide (0.06 g, 0.384 mmol, 0.2 equiv), Zn (1.25 g, 19.2 mmol, 10 equiv), TBAI (0.71 g, 1.9 mmol, 1 equiv), NiCl2-glyme (0.08 g, 0.38 mmol, 0.2 equiv) and TFA (0.11 g, 0.96 mmol, 0.5 equiv). After stirring for 2 h at room temperature under a nitrogen atmosphere, the resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclobutylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (400 mg, 42% yield) as a light yellow solid. MS (ESI) calcd. for C29H32N6O2, 496.26 m/z, found 497.25 [M+H]+.
Step 3: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclobutylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclobutylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (200 mg, 0.403 mmol, 1 equiv) in dioxane (5 mL) was added HCl (6 mL, 4 M in dioxane). After stirring for 2 h at room temperature under a nitrogen atmosphere, the resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclobutylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (150 mg, 94% yield) as a light yellow solid. MS (ESI) calcd. for C24H24N6, 396.21 m/z, found 397.25 [M+H]+.
Step 4: Synthesis of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclobutylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one
To a yellow solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-cyclobutylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (150 mg, 0.378 mmol, 1 equiv) in MeOH (3 mL) was added 1-(prop-2-enoyl)piperidin-4-one (86.93 mg, 0.567 mmol, 1.5 equiv) and NaBH3CN (47.55 mg, 0.756 mmol, 2 equiv) at 0° C. After being stirred overnight at rt, water (4 mL) was added to the solution and the mixture was concentrated directly. The residue was purified Prep-HPLC on a YMC Triart C18 ExRs column using a gradient of acetonitrile in water (+10 mmol/L ammonium bicarbonate) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclobutylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 195) (31.0 mg, 15% yield) as a white solid. MS (ESI) calcd. for C32H35N7O, 533.29 m/z, found 534.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.03-8.05 (m, 1H), 7.92-7.94 (m, 1H), 7.43-7.45 (m, 1H), 7.27-7.30 (m, 1H), 7.10-7.19 (m, 3H), 6.72-6.78 (m, 1H), 6.37-6.40 (m, 1H), 6.04-6.08 (m, 1H), 5.65-5.69 (m, 1H), 4.26-4.30 (m, 2H), 3.93-4.01 (m, 1H), 3.60-3.65 (m, 1H), 3.05-3.17 (m, 1H), 2.83-2.92 (m, 2H), 2.65-2.69 (m, 2H), 2.32-2.42 (m, 1H), 2.09-2.23 (m, 4H), 1.67-1.99 (m, 5H), 1.05-1.28 (m, 2H).
Example 196: 1-(4-{[(1R)-5-[2-(2-aminopyridin-3-yl)-5-(difluoromethyl)imidazo[4,5-b]pyridin-3-yl]-?3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 196 was prepared in a manner analogous to Example 195 using Step 1 detailed below instead of Steps 1 and 2. MS (ESI) calcd. for C29H29F2N7O: 529.24 m/z, found: 530.15 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 1H), 8.00-8.01 (m, 1H), 7.68-7.70 (m, 1H), 7.46-7.48 (m, 1H), 7.20-7.31 (m, 3H), 6.98-7.11 (m, 1H), 6.78-6.85 (m, 1H), 6.41-6.45 (m, 1H), 6.06-6.11 (m, 1H), 5.66-5.69 (m, 1H), 4.30-4.34 (m, 2H), 3.95-4.23 (m, 1H), 3.10-3.21 (m, 1H), 2.72-2.96 (m, 4H), 2.39-2.52 (m, 1H), 1.73-1.98 (m, 3H), 1.19-1.28 (m, 2H).
Synthetic Route:




Step 1: Synthesis of tert-butyl N-[(1R)-5-[2-(2-aminopyridin-3-yl)-5-(difluoromethyl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1R)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (150 mg, 0.288 mmol, 1 equiv), [1,3-Bis[2,6-bis(i-propyl)phenyl]-2-imidazolidinylidene]difluoromethyl silver(I) (238.0 mg, 0.432 mmol, 1.5 equiv), XPhos Pd G3 (24.35 mg, 0.029 mmol, 0.1 equiv) and XPhos (13.71 mg, 0.029 mmol, 0.1 equiv) in toluene (6 mL) was stirred for 4 h at 100° C. under nitrogen atmosphere in the dark. The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl N-[(1R)-5-[2-(2-aminopyridin-3-yl)-5-(difluoromethyl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (100 mg, 70.58%) as a yellow solid. MS (ESI) calcd. for C26H26F2N6O2: 492.21 m/z, found: 493.25[M+H]+.
Steps 2 and 3 were carried out in a manner analogous to Steps 3 and 4 from Example 195.
Example 197: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)-2-chloroethanone




Example 197 was prepared in a manner analogous to Example 34 using chloroacetic acid in place of (2E)-4-(dimethylamino)but-2-enoic acid. MS (ESI) calcd. for C30H30ClN9O, 567.23 m/z, found 568.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ(ppm) 8.35-8.33 (m, 2H), 8.29-8.23 (m, 1H), 8.00 (m, 1H), 7.92-7.99 (m, 1H), 7.79 (s, 1H), 7.59-7.61 (m, 1H), 7.40-7.30 (m, 1H), 7.28-7.24 (m, 2H), 6.54 (m, 1H), 6.42-6.46 (m, 1H), 4.66-4.63 (m, 1H), 4.40-4.30 (m, 2H) 3.86 (s, 1H), 3.71 (s, 2H), 3.21-2.81 (m, 3H), 2.77-2.46 (m, 2H), 2.07-1.99 (m, 3H), 1.50-1.36 (m, 2H). (formic acid salt)
Example 198: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-cyclopropoxyimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 198 was prepared in a manner analogous to Example 13 using Intermediate 198-1 in place of Intermediate 1-1. MS (ESI) calcd. for C31H33N7O2: 535.27 m/z, found: 536.20 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 8.18-8.25 (m, 1H), 8.00-8.06 (m, 1H), 7.62-7.72 (m, 2H), 7.50-7.55 (m, 1H), 7.30-7.40 (m, 1H), 7.01-7.10 (m, 1H), 6.68-6.90 (m, 2H), 6.10-6.18 (m, 1H), 5.68-5.76 (m, 1H), 4.94-5.02 (m, 1H), 4.45-4.60 (m, 1H), 4.11-4.25 (m, 1H), 4.05-4.10 (m, 1H), 3.49-3.60 (m, 1H), 3.08-3.20 (m, 2H), 2.89-3.00 (m, 1H), 2.64-2.80 (m, 1H), 2.54-2.63 (m, 1H), 2.04-2.27 (m, 3H), 1.40-1.60 (m, 2H), 0.62-0.80 (m, 4H). (TFA salt)
Intermediate 198-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-cyclopropoxy-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 198-1 was prepared in a manner analogous to Intermediate 50-1 using Intermediate 198-2 in place of 6-methyl-3-nitropyridin-2-amine. MS (ESI) calcd. for C23H22N6O: 398.19 m/z, found: 399.25 [M+H]+.
Intermediate 198-2: 6-cyclopropoxy-3-nitropyridin-2-amine




Synthetic Route:





Step 1: Synthesis of 6-cyclopropoxy-3-nitropyridin-2-amine (Intermediate 198-2
Cyclopropanol (1.34 g, 23 mmol, 2 equiv) was dissolved in tetrahydrofuran (10 mL) and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (60% dispersion in mineral oil) (0.92 g, 23 mmol, 2 equiv) was added and the resulting mixture was stirred at room temperature for 20 minutes. 6-chloro-3-nitropyridin-2-amine (2 g, 11 mmol, 1 equiv) was then added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and purified by flash column chromatography on silica gel column using a 0-50% gradient of ethyl acetate in petroleum ether to afford 6-cyclopropoxy-3-nitropyridin-2-amine (Intermediate 198-2) (1.5 g, 49%) as a yellow solid. MS (ESI) calculated for C8H9N3O3: 195.06 m/z, found 196.00 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.23-8.32 (m, 1H), 8.10-8.19 (m, 2H), 6.13-6.22 (m, 1H), 3.90 (s, 1H), 0.69-0.86 (m, 4H).
Example 199: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 199 was prepared in a manner analogous to Example 190 except that the conditions for Step 1 outlined below were used instead. MS (ESI) calcd. for C31H33N7O: 519.27 m/z, found: 520.25 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.24-8.14 (m, 1H), 8.04-7.92 (m, 1H), 7.85-7.72 (m, 1H), 7.47-7.35 (m, 1H), 7.35-7.24 (m, 1H), 7.24-7.16 (m, 1H), 7.16-7.07 (m, 1H), 7.05 (s, 2H), 6.90-6.70 (m, 1H), 6.45-6.32 (m, 1H), 6.09 (s, 1H), 5.74-5.55 (m, 1H), 4.46-4.11 (m, 2H), 4.10-3.78 (m, 1H), 3.26-3.05 (m, 1H), 3.03-2.84 (m, 3H), 2.84-2.61 (m, 1H), 2.47-2.32 (m, 1H), 2.22-2.01 (m, 2H), 2.01-1.81 (m, 2H), 1.81-1.63 (m, 1H), 1.24 (s, 2H), 1.08-0.91 (m, 2H), 0.91-0.70 (m, 2H).
Synthetic Route:




Step 1: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide
A mixture of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-1) (500 mg, 1.079 mmol, 1 equiv), potassium cyclopropyltrifluoroborate (192 mg, 1.295 mmol, 1.2 equiv), bis(adamantan-1-yl)(butyl)phosphane (77 mg, 0.216 mmol, 0.2 equiv) and Pd(OAc)2 (49 mg, 0.216 mmol, 0.2 equiv) in 1,4-dioxane/H2O=8 mL: 2 mL was treated with Cs2CO3 (1.05 g, 3.237 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120° C. under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with H2O (3×20 mL). The residue was dissolved in CH2Cl2 (20 mL). The resulting mixture was filtered, the filter cake was washed with CH2Cl2 (3×20 mL). The filtrate was concentrated under reduced pressure to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-cyclopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (393 mg, 71.64%) as a brown yellow solid. MS (ESI) calcd. for C25H24N6O: 424.20 m/z, found: 425.20 [M+H]+.
Steps 2 and 3 were carried out in a manner analogous to Example 190.
Example 200: 1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(3-fluoropyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperazin-1-yl)prop-2-en-1-one and
Example 201: 1-(4-{[(1*)-5-[2-(2-aminopyridin-3-yl)-5-(3-fluoropyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperazin-1-yl)prop-2-en-1-one




Examples 200 and 201 were prepared in a manner analogous to Example 77 using Intermediate 200-1 in place of Intermediate 77-1. The enantiomers were separated by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [EtOH/DCM (1:1)] with Example 200 eluting first. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer.
Example 200: MS (ESI) calcd. for C30H29FN10O: 564.25 m/z, found: 565.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.38 (m, 2H), 8.00-8.03 (m, 1H), 7.73-7.80 (m, 1H), 7.53-7.60 (m, 1H), 7.30-7.34 (m, 1H), 7.19-7.23 (m, 2H), 6.93-6.99 (m, 2H), 6.78-6.86 (m, 1H), 6.34-6.42 (m, 2H), 6.08-6.15 (m, 1H), 5.68-5.73 (m, 1H), 4.93-4.95 (m, 1H), 4.40-4.46 (m, 1H), 3.54-3.62 (m, 4H), 2.93-3.02 (m, 1H), 2.73-2.88 (m, 1H), 2.61-2.72 (m, 4H), 2.22-2.30 (m, 1H), 1.88-1.96 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −127.35.
Example 201: MS (ESI) calcd. for C30H29FN10O: 564.25 m/z, found: 565.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.38 (m, 2H), 8.00-8.03 (m, 1H), 7.73-7.80 (m, 1H), 7.53-7.60 (m, 1H), 7.30-7.34 (m, 1H), 7.19-7.23 (m, 2H), 6.93-6.99 (m, 2H), 6.78-6.86 (m, 1H), 6.40-6.43 (m, 1H), 6.34-6.39 (m, 1H), 6.08-6.15 (m, 1H), 5.68-5.73 (m, 1H), 4.93-4.95 (m, 1H), 4.40-4.46 (m, 1H), 3.54-3.65 (m, 4H), 2.93-3.02 (m, 1H), 2.73-2.88 (m, 1H), 2.61-2.72 (m, 4H), 2.22-2.30 (m, 1H), 1.88-1.96 (m, 1H). 19F-NMR (400 MHz, DMSO-d6) δ (ppm): −127.35.
Intermediate 200-1: 5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-one




Intermediate 200-1 was prepared in a manner analogous to Intermediate 1-1 using Intermediate 200-2 in place of Intermediate 1-2 and 3-fluoro-1H-pyrazole in place of pyrazole. MS (ESI) calcd. for C23H16FN7O: 425.14 m/z, found: 426.15 [M+H]+.
Intermediate 200-2: N-(3-(5-chloro-3-(2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-5-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl)pivalamide




Synthetic Route:





Step 1: Synthesis of 5-[(6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydroinden-1-one
To a solution of 5-amino-2,3-dihydroinden-1-one (50 g, 339.7 mmol, 1 equiv) and DIEA (131.73 g, 1.019 mmol, 3 equiv) in dioxane (1000 mL) was added 2,6-dichloro-3-nitropyridine (98.34 g, 509.590 mmol, 1.5 equiv) and the resulting mixture was stirred at 80° C. overnight. The mixture was allowed to cool to rt. The resulting mixture was filtered and the filter cake was washed with EtOH (3×200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with petroleum ether/ethyl acetate (10:1) (1000 mL). The residue was purified by trituration with water (1000 mL). The precipitated solids were collected by filtration and washed with water (3×200 mL). The resulting solid was dried under infrared light to afford 5-[(6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydroinden-1-one (75 g, 48%) as a brown solid. MS (ESI) calcd. for C14H10ClN3O3, 303.04 m/z, found: 303.95 [M+H]+.
Step 2: Synthesis of 6-chloro-N-{2′,3′-dihydrospiro[1,3-dithiolane-2,1′-inden]-5′-yl}-3-nitropyridin-2-amine
To a solution of 5-[(6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydroinden-1-one (68 g, 223.9 mmol, 1 equiv) and 1,2-ethanedithiol (63.27 g, 671.715 mmol, 3 equiv) in DCM (1400 mL) was added TMSOTf (9.95 g, 44.8 mmol, 0.2 equiv) and the resulting mixture was stirred at rt overnight. The reaction was quenched with water at room temperature and the mixture was extracted with CH2Cl2 (3×800 mL). The combined extracts were concentrated under reduced pressure and the residue was purified by trituration with petroleum ether/ethyl acetate (10:1) (1000 mL). The resulting solid was dried under infrared light to afford 6-chloro-N-{2′,3′-dihydrospiro[1,3-dithiolane-2,1′-inden]-5′-yl}-3-nitropyridin-2-amine (66 g, 43%) as a brown solid. MS (ESI) calcd. for C16H14ClN3O2S2, 379.02 m/z, found: 379.95 [M+H]+.
Step 3: Synthesis of N-[3-(5-chloro-3-{2′,3′-dihydrospiro[1,3-dithiolane-2,1′-inden]-5′-yl}imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl]-2,2-dimethylpropanamide (Intermediate 200-2
To a solution of 6-chloro-N-{2′,3′-dihydrospiro[1,3-dithiolane-2,1′-inden]-5′-yl}-3-nitropyridin-2-amine (50 g, 131.621 mmol, 1 equiv) and N-(3-formylpyridin-2-yl)-2,2-dimethylpropanamide (29.86 g, 144.783 mmol, 1.1 equiv) in DMSO (900 mL) and MeOH (150 mL) was added Na2S2O4 (50.41 g, 289.6 mmol, 2.2 equiv) and the resulting mixture was stirred at 100° C. overnight. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (3×500 mL). The filtrate was concentrated under reduced pressure. The mixture/residue was brought to pH 10 with saturated K2CO3 (aq.). The mixture was extracted with ethyl acetate (3×800 mL). The combined organic layers were washed with H2O (3×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from petroleum ether/ethyl acetate (5:1) (1000 mL) to afford N-[3-(5-chloro-3-{2′,3′-dihydrospiro[1,3-dithiolane-2,1′-inden]-5′-yl}imidazo[4,5-b]pyridin-2-yl)pyridin-2-yl]-2,2-dimethylpropanamide (Intermediate 200-2) (45 g, 45%) as a yellow solid. MS (ESI) calcd. for C27H26ClN5OS2, 535.13 m/z, found: 536.10 [M+H]+.
Example 202: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 203: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 202 and 203 were prepared in a manner analogous to Example 13 using Intermediates 202-1 and 203-1, respectively, in place of Intermediate 1-1. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 202: MS (ESI) calcd. for C31H32FN7O: 537.27 m/z, found: 538.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.05-8.12 (m, 2H), 7.72-7.76 (m, 2H), 7.51-7.52 (m, 2H), 7.33-7.49 (m, 1H), 7.33-7.35 (m, 1H), 6.75-6.78 (m, 1H), 6.14-6.18 (m, 1H), 5.92-5.93 (m, 1H), 5.74-5.79 (m, 1H), 5.22-5.28 (m, 1H), 4.51-4.62 (m, 1H), 4.15-4.26 (m, 1H), 3.29-3.74 (m, 4H), 2.63-2.82 (m, 1H), 2.33-2.42 (m, 1H), 2.17-2.22 (m, 2H), 1.53-1.64 (m, 2H), 0.97-1.00 (m, 2H), 0.81-0.84 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ −196.72. (TFA salt)
Example 203: MS (ESI) calcd. for C31H32FN7O: 537.27 m/z, found: 538.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.06-8.11 (m, 2H), 7.73-7.75 (m, 1H), 7.63-7.66 (m, 1H), 7.43-7.52 (m, 2H), 7.32-7.34 (m, 1H), 6.83-6.85 (m, 1H), 6.71-6.75 (m, 1H), 6.13-6.17 (m, 1H), 5.73-5.76 (m, 2H), 5.25-5.29 (m, 1H), 4.53-4.64 (m, 1H), 4.12-4.27 (m, 1H), 3.60-3.73 (m, 2H), 3.16-3.19 (m, 2H), 2.65-2.83 (m, 1H), 2.17-2.23 (m, 3H), 1.57-1.64 (m, 2H), 0.97-1.00 (m, 2H), 0.83-0.84 (m, 2H). 19F NMR (376 MHz, DMSO-d6) 5-177.97. (TFA salt)
Intermediate 202-1: 3-(3-((1R,2*)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine and
Intermediate 203-1: 3-(3-((1R,2*)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediates 202-1 and 203-1 were prepared in a manner analogous to Intermediates 75-1 and 76-1 starting from Step 4 using 6-cyclopropyl-3-nitropyridin-2-amine in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine. The diastereomers were separated prior to the final step by chiral Prep-HPLC in a CHIRALPAK IG column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and ethanol with Intermediate 202-1 eluting first. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 202-1: MS (ESI) calcd. for C23H21FN6: 400.18 m/z, found: 401.25 [M+H]+.
Intermediate 203-1: MS (ESI) calcd. for C23H21FN6: 400.18 m/z, found: 401.25 [M+H]+.
Example 204: 1-(4-{5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}piperazin-1-yl)prop-2-en-1-one




Example 204 was prepared in a manner analogous to Example 77 using tert-butyl piperazine-1-carboxylate in place of tert-butyl 4-aminopiperazine-1-carboxylate, DCE/MeOH instead of MeOH/AcOH and TFA in DCM instead of HCl in dioxane. MS (ESI) calcd. for C30H29N9O, 531.25 m/z, found 532.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.40-8.44 (m, 2H), 8.01-8.06 (m, 2H), 7.82-7.83 (m, 1H), 7.75-7.77 (m, 1H), 7.57-7.59 (m, 2H), 7.45-7.47 (m, 1H), 6.75-6.82 (m, 1H), 6.67-6.70 (m, 1H), 6.56-6.57 (m, 1H), 6.15-6.20 (m, 1H), 5.76-5.79 (m, 1H), 5.05-5.07 (m, 1H), 4.14-4.15 (m, 2H), 3.28-3.30 (m, 2H), 3.09-3.16 (m, 3H), 2.94-3.00 (m, 1H), 2.46-2.50 (m, 4H). (TFA salt)
Example 205: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,4-oxazepan-4-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 205 was prepared in a manner analogous to Example 170 (via Intermediate 170-1) using 1,4-oxazepane in place of pyrrolidine. MS (ESI) calcd. for C33H38N8O2: 578.31 m/z, found: 579.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 7.99-7.85 (m, 2H), 7.60 (s, 1H), 7.28 (s, 1H), 7.21-7.13 (m, 1H), 7.11-7.02 (m, 1H), 6.94 (s, 2H), 6.91-6.78 (m, 1H), 6.78-6.72 (m, 1H), 6.41-6.31 (m, 1H), 6.16-6.04 (m, 1H), 5.73-5.62 (m, 1H), 4.57 (s, 1H), 4.36 (s, 1H), 4.07 (s, 1H), 3.80-3.63 (m, 6H), 3.63-3.51 (m, 2H), 3.15 (s, 2H), 2.97 (s, 1H), 2.90-2.69 (m, 2H), 2.46 (s, 1H), 2.15-1.79 (m, 5H), 1.41 (s, 2H), 1.24 (s, 1H).
Example 206: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-methoxypyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 206 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 3-methoxy-1H-pyrazole in place of pyrazole, EPhos/EPhos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate, a reaction time of overnight for step 1, 4N HCl in dioxane at room temperature for 2 h for the deprotection and tetrahydrofuran instead of DCE for the final step. MS (ESI) calcd. For C32H33N9O2, 575.28 m/z, found 576.40 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.34-8.27 (m, 1H), 8.22-8.15 (m, 1H), 8.03-7.97 (m, 11H), 7.81-7.74 (m, 11H), 7.54-7.47 (m, 1H), 7.33 (s, 1H), 7.28-7.18 (m, 2H), 6.94 (s, 2H), 6.89-6.78 (m, 1H), 6.46-6.38 (m, 1H), 6.15-5.96 (m, 2H), 5.71-5.63 (m, 1H), 4.47-4.17 (m, 2H), 4.01 (s, 1H), 3.92 (s, 3H), 3.35 (s, 1H), 3.17 (s, 1H), 2.92-2.73 (m, 2H), 2.54-2.48 (m, 2H), 2.45 (s, 1H), 2.10-1.74 (m, 3H), 1.29 (s, 2H).
Example 207: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(pyridin-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 207 was prepared in a manner analogous to Example 159 (via Intermediate 159-1) using 2-(tributylstannyl)pyridine in place of 2-(tributylstannyl)-1,3-thiazole, Intermediate 85-1 in place of Intermediate 1-2 and 4N HCl in dioxane at room temperature for 2 h for the deprotection. MS (ESI) mass calcd. for C33H32N8O, 556.27 m/z, found 557.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.20-8.94 (m, 2H), 8.71 (dd, J=4.8, 1.7 Hz, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.40 (d, J=8.4 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.12 (dd, J=5.8, 1.7 Hz, 1H), 7.93 (td, J=7.7, 1.8 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.73 (dd, J=7.6, 1.7 Hz, 1H), 7.62 (d, J=1.9 Hz, 1H), 7.52 (dd, J=8.1, 2.0 Hz, 1H), 7.49-7.42 (m, 1H), 6.95-6.82 (m, 1H), 6.79-6.71 (m, 1H), 6.15 (dd, J=16.7, 2.4 Hz, 1H), 5.73 (dd, J=10.4, 2.4 Hz, 1H), 5.07-5.03 (m, 1H), 4.57-4.53 (m, 1H), 4.24-4.20 (m, 1H), 3.69-3.52 (m, 1H), 3.26-3.11 (m, 2H), 3.04-2.92 (m, 1H), 2.79-2.68 (m, 1H), 2.66-2.55 (m, 2H), 2.31-2.18 (m, 2H), 2.17-2.09 (m, 1H), 1.66-1.40 (m, 2H). (TFA salt)
Example 208: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 208 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 3-cyclopropyl-1H-pyrazole in place of pyrazole, EPhos/EPhos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate, a reaction time of overnight for step 1, 4N HCl in dioxane at room temperature for 2 h for the deprotection and MeOH instead of DCE for the final step. MS (ESI) calcd. For C34H35N9O, 585.30 m/z, found 586.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31 (d, J=8.4 MHz, 1H), 8.18-8.19 (m, 1H), 7.99-8.00 (m, 1H), 7.86 (d, J=8.8 MHz, 1H), 7.46 (d, J=8.0 MHz, 1H), 7.31-7.32 (m, 1H), 7.20-7.25 (m, 2H), 6.94 (s, 2H), 6.79-6.86 (m, 1H), 6.40-6.43 (m, 1H), 6.25-6.26 (m, 1H), 6.06-6.11 (m, 1H), 5.64-5.67 (m, 1H), 4.32-4.33 (m, 1H), 4.22-4.24 (m, 1H), 3.97-4.01 (m, 1H), 3.14-3.17 (m, 1H), 2.88-2.93 (m, 3H), 2.73-2.81 (m, 1H), 2.42-2.46 (m, 1H), 2.08-2.09 (m, 1H), 1.98-2.00 (m, 2H), 1.85-1.86 (m, 1H), 1.74-1.79 (m, 1H), 1.23-1.24 (m, 2H), 0.94-0.96 (m, 2H), 0.75-0.78 (m, 2H).
Example 209: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 209 was prepared in a manner analogous to Example 107 (via Intermediate 107-1) using phenylboronic acid instead of 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole and Intermediate 85-1 in place of Intermediate 86-1. MS (ESI) calcd. For C34H33N7O, 555.27 m/z, found 556.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.26 (d, J=8.4 Hz, 1H), 7.96-8.03 (m, 4H), 7.45-7.5 (m, 3H), 7.39-7.41 (m, 1H), 7.31-7.34 (m, 1H), 7.28-7.30 (m, 1H), 7.21-7.24 (m, 1H), 6.94 (s, 2H), 6.80-6.86 (m, 1H), 6.40-6.43 (m, 1H), 6.06-6.11 (m, 1H), 5.64-5.67 (m, 1H), 4.33-4.35 (m, 1H), 4.25-4.28 (m, 1H), 3.99-4.03 (m, 1H), 3.14-3.20 (m, 1H), 2.88-2.94 (m, 3H), 2.77-2.79 (m, 1H), 2.44-2.46 (m, 1H), 2.18-2.22 (m, 1H), 1.73-1.97 (m, 3H), 1.23-1.25 (m, 2H).
Example 210: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 211: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 210 and 211 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and Intermediate 85-2 in place of Intermediate 1-1. The diastereomers separated during purification by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate). Each were further purified separately by Prep HPLC on a XBridge Prep RP OBD C18 column using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 210: MS (ESI) calcd. for C32H35N7O, 533.29 m/z, found 534.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.03 (d, J=8.2 Hz, 1H), 7.95-7.98 (m, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.21-7.24 (m, 2H), 7.13-7.16 (m, 2H), 6.95 (s, 2H), 6.78-6.85 (m, 1H), 6.37-6.40 (m, 1H), 6.05-6.10 (m, 1H), 5.64-5.67 (m, 1H), 4.79-4.92 (m, 1H), 4.31-4.47 (m, 2H), 3.89-4.04 (m, 1H), 2.99-3.10 (m, 1H), 2.89-2.96 (m, 1H), 2.64-2.81 (m, 2H), 2.40-2.47 (m, 1H), 2.14-2.20 (m, 1H), 2.03-2.10 (m, 1H), 1.94-2.01 (m, 1H), 1.73-1.87 (m, 2H), 1.03-1.24 (m, 4H), 0.92-0.96 (m, 2H), 0.80-0.90 (m, 2H).
Example 211: MS (ESI) calcd. for C32H35N7O, 533.29 m/z, found 534.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.94-8.06 (m, 2H), 7.44 (d, J=7.9 Hz, 1H), 7.21-7.26 (m, 2H), 7.12-7.20 (m, 2H), 6.93 (s, 2H), 6.73-6.84 (m, 1H), 6.35-6.43 (m, 1H), 6.03-6.14 (m, 1H), 5.59-5.69 (m, 1H), 4.30-4.44 (m, 2H), 3.87-4.04 (m, 1H), 3.32-3.33 (m, 1H), 3.07-3.16 (m, 1H), 2.87-2.99 (m, 1H), 2.69-2.82 (m, 1H), 2.39-2.48 (m, 1H), 2.12-2.22 (m, 1H), 1.97-2.06 (m, 1H), 1.60-1.86 (m, 5H), 1.42 (d, J=6.8 Hz, 3H), 0.89-0.98 (m, 2H), 0.78-0.85 (m, 2H).
Example 212: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one
Example 213: 1-((2R,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one
Example 214: 1-((2S,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one and
Example 215: 1-((2S,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one







Examples 212, 213, 214 and 215 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 2-(difluoromethyl)-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. Examples 212 and 213 were separated from 214 and 215 by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate). Examples 212 and 213 were separated by chiral Prep-HPLC on a CHIRALPAK IE column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [MeOH/DCM (1:1)]. Examples 214 and 215 were separated by chiral Prep-HPLC on a CHIRALPAK IK column using a mixture of [hexanes (+0.5% 2M NH3-MeOH)] and ethanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 212: MS (ESI) calcd. for C32H31F2N9O: 595.26 m/z, found: 596.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43-8.45 (m, 1H), 8.36-8.36 (m, 1H), 8.07-8.09 (m, 1H), 8.01-8.03 (m, 1H), 7.79-8.83 (m, 1H), 7.77-7.78 (m, 1H), 7.70-7.71 (m, 1H), 7.60-7.69 (m, 1H), 7.44-7.46 (m, 1H), 6.80-6.85 (m, 2H), 6.57-6.58 (m, 1H), 6.15-6.20 (m, 1H), 5.75-5.81 (m, 1H), 5.01-5.04 (m, 2H), 4.20-4.60 (m, 1H), 2.96-3.27 (m, 3H), 2.57-2.61 (m, 2H), 2.23-2.36 (m, 4H), 1.80-1.95 (m, 1H), 1.51-1.65 (m, 1H). (TFA salt)
Example 213: MS (ESI) calcd. for C32H31F2N9O: 595.26 m/z, found: 596.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.34 (m, 2H), 7.97-7.99 (m, 1H), 7.92-7.94 (m, 1H), 7.79-7.80 (m, 1H), 7.46-7.48 (m, 1H), 7.29-7.30 (m, 1H), 7.21-7.24 (m, 2H), 6.79-6.83 (m, 1H), 6.52-6.53 (m, 1H), 6.41-6.44 (m, 1H), 6.09-6.14 (m, 1H), 5.70-5.75 (m, 1H), 4.50-5.05 (m, 1H), 4.00-4.50 (m, 2H), 3.22-3.52 (m, 1H), 2.90-3.05 (m, 2H), 2.74-2.80 (m, 2H), 2.37-2.39 (m, 1H), 2.20-2.22 (m, 1H), 1.95-1.98 (m, 1H), 1.75-1.80 (m, 1H), 1.33-1.38 (m, 1H), 1.16-1.20 (m, 1H).
Example 214: MS (ESI) calcd. for C32H31F2N9O: 595.26 m/z, found: 596.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.34 (m, 2H), 7.98-7.99 (m, 1H), 7.92-7.94 (m, 1H), 7.79-7.80 (m, 1H), 7.46-7.48 (m, 1H), 7.26-7.27 (m, 1H), 7.23-7.25 (m, 2H), 6.81-6.85 (m, 1H), 6.53-6.54 (m, 1H), 6.42-6.45 (m, 1H), 6.09-6.14 (m, 1H), 5.70-5.73 (m, 1H), 4.40-4.80 (m, 1H), 4.26-4.30 (m, 2H), 3.14-3.22 (m, 2H), 2.91-2.97 (m, 1H), 2.75-2.81 (m, 1H), 2.08-2.11 (m, 1H), 1.69-1.76 (m, 5H), 1.28-1.30 (m, 1H). (TFA salt)
Example 215: MS (ESI) calcd. for C32H31F2N9O: 595.26 m/z, found: 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30-8.33 (m, 2H), 7.97-7.98 (m, 1H), 7.96-7.97 (m, 1H), 7.77-7.78 (m, 1H), 7.46-7.48 (m, 1H), 7.28-7.30 (m, 1H), 7.20-7.25 (m, 2H), 6.75-6.81 (m, 1H), 6.52-6.53 (m, 1H), 6.42-6.45 (m, 1H), 6.09-6.13 (m, 1H), 5.70-5.73 (m, 1H), 4.40-4.75 (m, 1H), 4.22-4.26 (m, 2H), 3.45-3.70 (m, 1H), 2.89-3.17 (m, 3H), 2.71-2.76 (m, 1H), 2.39-2.41 (m, 1H), 1.75-1.86 (m, 4H), 1.50-4.65 (m, 1H).
Example 216: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(trifluoromethyl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-{[3-nitro-5-(trifluoromethyl) pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide
A solution of 2-chloro-3-nitro-5-(trifluoromethyl) pyridine (1 g, 4.4 mmol, 1 equiv) DIEA (1.71 g, 13.2 mmol, 3 equiv) and N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-2) (0.92 g, 4.8 mmol, 1.1 equiv) in EtOH (20 mL) was stirred overnight at 80° C. The mixture was allowed to cool to room temperature. The reaction was quenched with water. The precipitated solids were collected by filtration and washed with EtOH (20 mL) to afford N-[(1S)-5-{[3-nitro-5-(trifluoromethyl) pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (850 mg, 41%) as an orange solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C17H15F3N4O3: 380.11 m/z, found: 381.15 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(trifluoromethyl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide
A solution of N-[(1S)-5-{[3-nitro-5-(trifluoromethyl) pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (850 mg, 2.24 mmol, 1 equiv) 2-aminopyridine-3-carbaldehyde (286 mg, 2.347 mmol, 1.05 equiv) and Na2S2O4 (856 mg, 4.917 mmol, 2.2 equiv) in DMSO (24 mL) and MeOH (4 mL, 91.858 mmol) was stirred overnight at 105° C. under air atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water. The precipitated solids were collected by filtration and washed with water to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(trifluoromethyl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (800 mg, 67%) as a brown/yellow solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C23H19F3N6O: 452.16 m/z, found: 453.20 [M+H]+.
Step 3: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-(trifluoromethyl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
A solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(trifluoromethyl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (800 mg, 1.768 mmol, 1 equiv) in HCl (10 mL, conc) and MeOH (10 mL) was stirred overnight at 90° C. under air atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 8 with saturated NaHCO3 (aq.). The resulting mixture was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-(trifluoromethyl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (440 mg, 52%) as a brown yellow solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C21H17F3N6: 410.15 m/z, found: 411.25 [M+H]+.
Step 4: Synthesis of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(trifluoromethyl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 216)
A solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-(trifluoromethyl) imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (440 mg, 1.07 mmol, 1 equiv) and 1-(prop-2-enoyl)piperidin-4-one (657 mg, 4.288 mmol, 4 equiv) in THF (5 mL) was stirred for 30 min at 50° C. under air atmosphere. To the above mixture was added NaBH3CN (269.49 mg, 4.288 mmol, 4 equiv) in portions at room temperature. The resulting mixture was stirred for 4 h at 50° C. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(trifluoromethyl) imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (15.1 mg, 3%) as an off-white solid. MS (ESI) calcd. for C29H28F3N7O: 547.23 m/z, found: 548.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.73-8.61 (m, 2H), 8.06-7.98 (m, 1H), 7.49-7.40 (m, 1H), 7.39-7.27 (m, 2H), 7.24-7.16 (m, 1H), 6.94 (s, 2H), 6.90-6.75 (m, 1H), 6.49-6.39 (m, 1H), 6.14-6.02 (m, 1H), 5.70-5.60 (m, 1H), 4.35-4.29 (m, 1H), 4.25-4.19 (m, 1H), 4.05-3.91 (m, 1H), 3.20-3.14 (m, 1H), 2.93-2.87 (m, 4H), 2.47-2.36 (m, 1H), 2.11-1.99 (m, 1H), 1.97-1.73 (m, 3H), 1.27-1.21 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ −58.45.
Example 217: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 217 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 190-1 in place of Intermediate 1-2. MS (ESI) calcd. For C31H31N9O, 545.26 m/z, found 546.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.91-8.79 (m, 1H), 8.65-8.55 (m, 2H), 8.06-7.97 (m, 1H), 7.85-7.76 (m, 1H), 7.50-7.43 (m, 1H), 7.36 (s, 1H), 7.34-7.23 (m, 1H), 7.23-7.15 (m, 1H), 7.02 (s, 2H), 6.89-6.74 (m, 1H), 6.67-6.57 (m, 1H), 6.47-6.38 (m, 1H), 6.13-6.00 (m, 1H), 5.70-5.57 (m, 1H), 4.39-4.29 (m, 1H), 4.24 (s, 1H), 3.99 (s, 1H), 3.45-3.36 (m, 1H), 3.16 (s, 1H), 2.47-2.31 (m, 2H), 2.00-1.82 (m, 3H), 1.81-1.69 (m, 2H), 1.24 (s, 3H).
Example 218: 1-(4-(((1S,3*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 219: 1-(4-(((1S,3*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-hydroxy-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 218 and 219 were prepared in a manner analogous to Example 13 using Intermediate 218-1 and 219-1 in place of Intermediate 1-1. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 218: MS (ESI) calcd. for C31H31N9O2, 561.26 m/z, found 562.15 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.56 (m, 2H), 7.95-8.16 (m, 2H), 7.84-7.95 (m, 1H), 7.71-7.84 (m, 2H), 7.61-7.71 (m, 1H), 7.42-7.61 (m, 1H), 6.71-6.97 (m, 2H), 6.51-6.71 (m, 1H), 6.02-6.29 (m, 1H), 5.65-5.92 (m, 1H), 5.02-5.26 (m, 1H), 4.74-4.98 (m, 1H), 4.39-4.74 (m, 1H), 4.08-4.34 (m, 1H), 3.46-3.77 (m, 1H), 3.11-3.32 (m, 1H), 2.91-3.11 (m, 1H), 2.68-2.91 (m, 1H), 2.21-2.38 (m, 1H), 2.05-2.21 (m, 1H), 1.85-2.05 (m, 1H), 1.36-1.74 (m, 2H).
Example 219: MS (ESI) calcd. for C31H31N9O2, 561.26 m/z, found 562.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.61 (m, 2H), 7.95-8.21 (m, 2H), 7.84-7.95 (m, 1H), 7.72-7.84 (m, 2H), 7.62-7.72 (m, 1H), 7.42-7.62 (m, 1H), 6.71-6.97 (m, 2H), 6.51-6.71 (m, 1H), 6.02-6.29 (m, 1H), 5.65-5.92 (m, 1H), 5.28-5.53 (m, 1H), 4.96-5.21 (m, 1H), 4.41-4.72 (m, 1H), 4.11-4.41 (m, 1H), 3.46-3.77 (m, 1H), 3.04-3.38 (m, 1H), 2.71-2.86 (m, 1H), 2.58-2.71 (m, 1H), 2.31-2.46 (m, 1H), 2.05-2.31 (m, 2H), 1.41-1.72 (m, 2H).
Intermediate 218-1: (1*,3S)-3-amino-6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-ol and
Intermediate 219-1: (1*,3S)-3-amino-6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-ol




Synthetic Route:





Step 1: Synthesis of 3-amino-6-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-ol
To a solution of (S)-3-amino-6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-one (Intermediate 218-2) (230 mg, 0.544 mmol, 1 equiv) in methanol (5 mL) was added sodium borohydride (41 mg, 1.1 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the residue was purified by reverse-phase flash column chromatography on C18 silica gel using a 0-95% gradient of acetonitrile in water (+0.05% ammonium bicarbonate) with a 10 minute hold at 50% acetonitrile to afford (3S)-3-amino-6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-ol (144 mg, 62%) as a yellow solid. MS (ESI) calculated for C23H20N8O: 424.18 m/z, found 425.55 [M+H]+.
The resulting diastereomeric mixture was separated by chiral SFC on a CHIRALPAK IC-3 column eluting with a 70:30 mix of (hexanes/dichloromethane (3:1)+0.1% N,N-diisopropylethylamine):isopropanol with the first eluting peaked assigned as Intermediate 218-1 and the second eluting peak assigned as Intermediate 219-2. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 218-2: (S)-3-amino-6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-one




Intermediate 218-2 was prepared in a manner analogous to Intermediate 50-1 using 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine in place of 6-methyl-3-nitropyridin-2-amine and Intermediate 218-3 in place of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide. MS (ESI) calcd. for C23H18N8O, 422.16 m/z, found 423.25 [M+H]+.
Intermediate 218-3: (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





Step 1: Synthesis of N-[(1S)-5-bromo-3-oxo-1,2-dihydroinden-1-yl]acetamide (Intermediate 218-3
To a solution of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 218-4) (1.00 g, 3.94 mmol, 1 equiv) in dichloromethane (20 mL) was added chromium(VI) oxide (0.200 g, 1.97 mmol, 0.5 equiv) followed by tert-butyl hydroperoxide (5.05 g (70% aqueous), 39.4 mmol, 10 equiv). The resulting mixture was stirred at 50° C. overnight then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a 0-20% gradient of methanol in dichloromethane to afford N-[(1S)-5-bromo-3-oxo-1,2-dihydroinden-1-yl]acetamide (Intermediate 218-3) (250 mg, 23%) as a white solid. MS (ESI) calculated for C11H10BrNO2: 266.99 m/z, found 265.95 [M−H]−.
Intermediate 218-4: (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





To a mixture of (S)-5-bromo-2,3-dihydro-1H-inden-1-amine (74 g, 350 mmol, 1 equiv) and triethylamine (106 g, 1.05 mol, 3 equiv) in dichloromethane (1.5 L) was added acetic anhydride (55.2 g, 526 mmol, 1.5 equiv) at 0° C. and the mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched by addition of water (500 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was re-crystallized from petroleum ether to afford (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 218-4) (90 g, 83% yield) as a white solid. MS (ESI) calculated for C11H12BrNO: 253.01, found 254.00 [M+H]+, 256.00 [M+H+2]+.
Example 220: 1-((3*,4*,5*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,5-difluoropiperidin-1-yl)prop-2-en-1-one
Example 221: 1-((3*,4*,5*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,5-difluoropiperidin-1-yl)prop-2-en-1-one
Example 222: 1-((3*,5*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,5-difluoropiperidin-1-yl)prop-2-en-1-one and
Example 223: 1-((3*,5*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3,5-difluoropiperidin-1-yl)prop-2-en-1-one




Examples 220, 221, 222 and 223 were prepared in a manner analogous to Example 13 using Intermediate 220-1 in place of the ketone. Examples 220 and 221 separated from Examples 222 and 223 during purification by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.05% formic acid). Examples 220 and 221 were separated by chiral Prep-HPLC on a CHIRALPAK-IK column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [MeOH/DCM (1:1)]. Examples 222 and 223 were separated by chiral Prep-HPLC on a CHIRALPAK IE column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and MeOH. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 220: MS (ESI) calcd. for C31H29F2N9O: 581.25 m/z, found: 582.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29-8.41 (m, 2H), 7.88-8.05 (m, 2H), 7.75-7.88 (m, 1H), 7.40-7.51 (m, 1H), 7.35 (s, 1H), 7.14-7.31 (m, 2H), 6.96 (s, 2H), 6.48-6.58 (m, 1H), 6.35-6.46 (m, 1H), 5.02-5.15 (m, 1H), 4.43-4.77 (m, 1H), 4.06-4.31 (m, 2H), 3.59-4.05 (m, 2H), 3.04-3.23 (m, 1H), 2.89-3.04 (m, 1H), 2.66-2.89 (m, 3H), 2.52-2.60 (m, 1H), 2.23-2.42 (m, 1H), 1.70-1.91 (m, 1H), 1.37-1.72 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −201.82, −203.52.
Example 221: MS (ESI) calcd. for C31H29F2N9O: 581.25 m/z, found: 582.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29-8.40 (m, 2H), 7.88-8.05 (m, 2H), 7.75-7.88 (m, 1H), 7.13-7.51 (m, 4H), 6.96 (s, 2H), 6.48-6.57 (m, 1H), 6.33-6.47 (m, 1H), 5.02-5.14 (m, 1H), 4.43-4.47 (m, 1H), 4.05-4.32 (m, 2H), 3.59-4.05 (m, 2H), 3.05-3.24 (m, 1H), 2.89-3.04 (m, 1H), 2.78-2.89 (m, 2H), 2.69-2.78 (m, 1H), 2.58-2.60 (m, 1H), 2.30-2.45 (m, 1H), 1.72-1.90 (m, 1H), 1.45-1.70 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −201.82, −203.52.
Example 222: MS (ESI) calcd. for C31H29F2N9O: 581.25 m/z, found: 582.10 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.25-8.42 (m, 2H), 7.75-8.06 (m, 3H), 7.12-7.51 (m, 4H), 6.97 (s, 2H), 6.34-6.58 (m, 2H), 5.26-5.40 (m, 1H), 4.07-4.52 (m, 2H), 3.66-3.99 (m, 2H), 3.38-3.65 (m, 2H), 2.67-3.06 (m, 4H), 2.53-2.65 (m, 1H), 2.23-2.45 (m, 1H), 1.67-1.92 (m, 2H), 1.31-1.54 (m, 1H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −188.14, −188.65.
Example 223: MS (ESI) calcd. for C31H29F2N9O: 581.25 m/z, found: 582.10 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.26-8.42 (m, 2H), 7.87-8.05 (m, 2H), 7.76-7.84 (m, 1H), 7.15-7.50 (m, 4H), 6.97 (s, 2H), 6.35-6.58 (m, 2H), 5.26-5.40 (m, 1H), 4.07-4.50 (m, 2H), 3.65-4.00 (m, 2H), 3.39-3.65 (m, 2H), 2.89-3.04 (m, 1H), 2.67-2.89 (m, 3H), 2.53-2.65 (m, 1H), 2.20-2.45 (m, 1H), 1.64-1.98 (m, 2H), 1.29-1.53 (m, 1H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −188.14, −188.65.
Example 224: 1-(8-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one




Synthetic Route:








Step 1: Synthesis of 3-benzyl-6-oxa-3-azabicyclo[3.2.1]octan-8-one
To a solution of dihydrofuran-3-one (4.4 g, 51.1 mmol, 1 equiv) in ACN (380 mL) was added benzylbis(methoxymethyl)amine (18 g, 92 mmol, 1.8 equiv), methyltrichlorosilane (12.99 g, 86.89 mmol, 1.7 equiv) and MeOH (20 mL). After stirring overnight at rt, the reaction was quenched by the addition of water (200 mL) at 0° C. The mixture was basified to pH=9 with NaOH (1N in water). The resulting mixture was extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with water (500 mL×3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-80% ethyl acetate in petroleum ether) giving 3-benzyl-6-oxa-3-azabicyclo[3.2.1]octan-8-one (2 g, 18% yield) as a light yellow oil. MS (ESI) calcd. for C13H15NO2, 217.11 m/z, found 217.10.
Step 2: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-3-benzyl-6-oxa-3-azabicyclo[3.2.1]octan-8-amine
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (300 mg, 0.734 mmol, 1 equiv) in DCE (4 mL) and MeOH (0.4 mL) was added 3-benzyl-6-oxa-3-azabicyclo[3.2.1]octan-8-one (239.36 mg, 1.101 mmol, 1.5 equiv) and NaBH3CN (138.5 mg, 2.202 mmol, 3 equiv) at 0° C. After being stirred overnight at room temperature, water (4 mL) was added to the solution and the mixture was concentrated directly. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-3-benzyl-6-oxa-3-azabicyclo[3.2.1]octan-8-amine (300 mg, 67% yield) as a light yellow solid. MS (ESI) calcd. for C36H35N9O, 609.30 m/z, found 610.35 [M+H]+.
Step 3: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-6-oxa-3-azabicyclo[3.2.1]octan-8-amine
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-3-benzyl-6-oxa-3-azabicyclo[3.2.1]octan-8-amine (300 mg, 0.492 mmol, 1 equiv) in MeOH (30 mL) was added Pd/C (10%, 149.75 mg). The mixture was stirred at room temperature under hydrogen atmosphere for 18 h. The mixture was filtered through a Celite pad and concentrated under reduced pressure giving N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-6-oxa-3-azabicyclo[3.2.1]octan-8-amine (140 mg, 55% yield) as a light yellow solid. MS (ESI) calcd. for C29H29N9O, 519.25 m/z, found 520.30 [M+H]+.
Step 4: Synthesis of 1-(8-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-6-oxa-3-azabicyclo[3.2.1]octan-8-amine (50 mg, 0.096 mmol, 1 equiv) in DMF (3 mL) was added DIEA (24.87 mg, 0.192 mmol, 2 equiv) Pybop (50.08 mg, 0.096 mmol, 1 equiv) and acrylic acid (6.93 mg, 0.096 mmol, 1 equiv) The reaction mixture was stirred at room temperature for 2 h. The residue was purified directly by Prep-HPLC on a XSelect CSH F-phenyl OBD Column using a gradient of acetonitrile in water (+0.1% formic acid) to afford 1-(8-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-6-oxa-3-azabicyclo[3.2.1]octan-3-yl)prop-2-en-1-one (Example 224, formic acid salt) (3.5 mg, 6% yield) as a light yellow solid. MS (ESI) calcd. for C32H31N9O2, 573.26 m/z, found 574.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.33 (m, 2H), 7.91-7.98 (m, 2H), 7.77-7.78 (m, 1H), 7.47-7.51 (m, 1H), 7.30-7.31 (m, 1H), 7.22-7.24 (m, 2H), 6.69-6.76 (m, 1H), 6.50-6.54 (m, 1H), 6.40-6.44 (m, 1H), 6.06-6.10 (m, 1H), 5.65-5.69 (m, 1H), 4.21-4.29 (m, 1H), 3.71-4.15 (m, 4H), 3.54-3.67 (m, 3H), 3.27-3.34 (m, 2H), 2.74-3.12 (m, 2H), 2.31-2.33 (m, 1H), 1.79-1.84 (m, 1H).
Example 225: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[1-(trifluoromethyl)pyrazol-4-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 225 was prepared in a manner analogous to Example 190 using Intermediate 85-1 in place of Intermediate 190-1, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)pyrazole in place of pyridine-3-boronic acid and 4N HCl in dioxane at room temperature for 1 h for the deprotection. MS (ESI) calcd. for C32H30F3N9O, 613.25 m/z, found 614.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm) 8.98-8.99 (m, 1H), 8.33-8.34 (m, 1H), 8.31-8.32 (m, 1H), 8.06-8.08 (m, 1H), 7.92-7.94 (m, 1H), 7.70-7.82 (m, 2H), 7.57-7.60 (m, 1H), 7.42-7.44 (m, 1H), 6.74-6.87 (m, 2H), 6.10-6.15 (m, 1H), 5.71-5.72 (m, 1H), 4.99-5.00 (m, 1H), 4.53-4.54 (m, 1H), 4.18-4.20 (m, 1H), 3.12-3.18 (m, 2H), 2.93-3.00 (m, 1H), 2.70-2.76 (m, 1H), 2.55-2.67 (m, 2H), 2.33-2.35 (m, 2H), 2.10-2.13 (m, 1H), 1.51-1.52 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −59.34. (TFA salt)
Example 226: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[(3S)-3-fluoropyrrolidin-1-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 226 was prepared in a manner analogous to Example 86 (via Intermediate 86-2) using (3S)-3-fluoropyrrolidine hydrochloride (+2 eq triethylamine) in place of morpholine, Intermediate 85-1 in place of Intermediate 86-1 and 4N HCl in dioxane in place of TFA in DCM. MS (ESI) calcd. For C32H35FN8O, 566.69 m/z, found 567.15 [M+H]+. 1HNMR (300 MHz, DMSO-d6) δ (ppm): 7.96-7.87 (m, 2H), 7.47-7.38 (m, 1H), 7.22-7.09 (m, 2H), 7.06-6.97 (m, 3H), 6.89-6.74 (m, 1H), 6.58-6.49 (m, 1H), 6.38-6.28 (m, 1H), 6.13-6.01 (m, 1H), 5.70-5.59 (m, 1H), 5.52-5.25 (m, 1H), 4.40-4.15 (m, 2H), 4.08-3.86 (m, 2H), 3.79-3.52 (m, 4H), 3.04-3.26 (m, 1H), 3.00-2.79 (m, 2H), 2.80-2.62 (m, 1H), 2.46-2.35 (m, 1H), 2.31-2.13 (m, 2H), 2.03-1.60 (m, 3H), 1.38-0.99 (m, 3H).
Example 227: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3,3-difluorocyclobutyl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 227 was prepared in a manner analogous to Example 195 using 3,3-difluorocyclobutane-1-carboxylic acid in place of cyclobutenecarboxylic acid. MS (ESI) calcd. for C32H33F2N7O, 569.27 m/z, found 570.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.08-8.11 (m, 1H), 7.95-7.97 (m, 1H), 7.45-7.47 (m, 1H), 7.34-7.36 (m, 1H), 7.25-7.26 (m, 1H), 7.14-7.18 (m, 2H), 6.73-6.80 (m, 1H), 6.40-6.44 (m, 1H), 6.04-6.09 (m, 1H), 5.66-5.69 (m, 1H), 4.26-4.37 (m, 2H), 3.93-4.04 (m, 1H), 3.55-3.57 (m, 1H), 3.05-3.10 (m, 1H), 2.90-2.95 (m, 4H), 2.71-2.81 (m, 4H), 2.40-2.42 (m, 1H), 1.97-2.03 (m, 1H), 1.78-1.87 (m, 2H), 1.15-1.28 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −80.17, −95.74.
Example 228: 1-(4-{[(1R)-5-[2-(2-aminopyridin-3-yl)-5-[3-(difluoromethyl)pyrazol-1-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 228 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using 3-(difluoromethyl)-1H-pyrazole in place of pyrazole, Intermediate 85-1 in place of Intermediate 1-2, EPhos/EPhos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate, 4N HCl in dioxane at room temperature for 2 h for the deprotection and MeOH instead of DCE for the final step. MS (ESI) calcd. for C32H31F2N9O: 595.26 m/z, found: 596.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.40-8.43 (m, 1H), 8.37-8.39 (m, 1H), 7.99-8.01 (m, 1H), 7.92-7.95 (m, 1H), 7.47-7.49 (m, 1H), 7.30-7.32 (m, 1H), 6.99-7.31 (m, 3H), 6.76-6.83 (m, 2H), 6.41-6.45 (m, 1H), 6.05-6.10 (m, 1H), 5.65-5.68 (m, 1H), 4.30-4.33 (m, 2H), 3.95-4.15 (m, 1H), 3.11-3.18 (m, 1H), 2.70-2.98 (m, 4H), 2.39-2.46 (m, 1H), 1.71-2.01 (m, 3H), 1.18-2.27 (m, 2H).
Example 229: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one
Example 230: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one
Example 231: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one and
Example 232: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-methylpiperidin-1-yl)prop-2-en-1-one




Examples 229, 230, 231 and 232 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using (3S)-3-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, Intermediate 85-2 in place of Intermediate 1-1 and 4N HCl in dioxane in place of TFA in DCM. Example 229 was separated from Examples 230, 231 and 232 by chiral Prep-HPLC on a CHIRALPAK IK2 column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and isopropanol. Examples 230, 231 and 232 were separated by chiral Prep-HPLC on a CHIRALPAK IA column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [EtOH/DCM (1:1)]. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 229: MS (ESI) calcd. for C32H35N7O: 533.29 m/z, found: 534.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.95-8.02 (m, 2H), 7.42-7.44 (m, 1H), 7.19-7.22 (m, 2H), 7.12-7.14 (m, 2H), 6.77-6.84 (m, 1H), 6.37-7.39 (m, 1H), 6.01-6.11 (m, 1H), 5.65-5.68 (m, 1H), 3.81-4.25 (m, 3H), 3.21-3.28 (m, 1H), 2.67-3.06 (m, 4H), 2.39-2.48 (m, 1H), 2.03-2.16 (m, 2H), 1.73-1.79 (m, 1H), 1.41-1.56 (m, 2H), 0.88-0.94 (m, 2H), 0.78-0.86 (m, 5H).
Example 230: MS (ESI) calcd. for C32H35N7O: 533.29 m/z, found: 534.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.00-8.02 (m, 1H), 7.95-7.97 (m, 1H), 7.41-7.43 (m, 1H), 7.20-7.22 (m, 2H), 7.12-7.15 (m, 2H), 6.79-6.85 (m, 1H), 6.54-6.56 (m, 1H), 6.05-6.12 (m, 1H), 5.65-5.68 (m, 1H), 4.30-4.32 (m, 1H), 4.18-4.28 (m, 1H), 3.91-4.08 (m, 1H), 2.83-2.94 (m, 2H), 2.71-2.79 (m, 1H), 2.35-2.42 (m, 2H), 2.05-2.16 (m, 2H), 1.68-1.76 (m, 1H), 1.21-1.42 (m, 3H), 0.88-0.96 (m, 5H), 0.75-0.83 (m, 2H).
Example 231: MS (ESI) calcd. for C32H35N7O: 533.29 m/z, found: 534.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.00-8.02 (m, 1H), 7.95-7.97 (m, 1H), 7.44-7.46 (m, 1H), 7.18-7.22 (m, 2H), 7.11-7.15 (m, 2H), 6.78-6.85 (m, 1H), 6.35-6.38 (m, 1H), 6.06-6.10 (m, 1H), 5.64-5.68 (m, 1H), 4.20-4.24 (m, 2H), 3.88-3.99 (m, 1H), 2.85-2.94 (m, 2H), 2.66-2.76 (m, 1H), 2.38-2.47 (m, 2H), 2.13-2.18 (m, 1H), 1.95-2.07 (m, 1H), 1.71-1.78 (m, 1H), 1.15-1.42 (m, 3H), 0.89-0.96 (m, 5H), 0.76-0.81 (m, 2H).
Example 232: MS (ESI) calcd. for C32H35N7O: 533.29 m/z, found: 534.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.00-8.02 (m, 1H), 7.95-7.97 (m, 1H), 7.42-7.46 (m, 1H), 7.19-7.20 (m, 2H), 7.12-7.15 (m, 2H), 6.80-6.89 (m, 1H), 6.37-6.40 (m, 1H), 6.07-6.12 (m, 1H), 5.64-5.68 (m, 1H), 4.25-4.27 (m, 1H), 3.72-4.18 (m, 2H), 3.26-3.32 (m, 1H), 2.86-3.18 (m, 3H), 2.69-2.77 (m, 1H), 2.41-2.47 (m, 1H), 2.13-2.19 (m, 1H), 1.93-2.02 (m, 1H), 1.71-1.78 (m, 1H), 1.54-1.67 (m, 2H), 0.90-0.95 (m, 2H), 0.78-0.83 (m, 5H).
Example 233: 1-(4-(((1S,3*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 234: 1-(4-(((1S,3*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 233 and 234 were prepared in a manner analogous to Example 13 using Intermediates 233-1 and 234-1 in place of Intermediate 1-1 and TFA in place of DCE. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 233: MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.44-8.29 (m, 2H), 8.00-7.92 (m, 1H), 7.86-7.77 (m, 1H), 7.69-7.59 (m, 2H), 7.59-7.48 (m, 1H), 7.32-7.18 (m, 1H), 6.88 (s, 2H), 6.86-6.75 (m, 1H), 6.61-6.51 (m, 1H), 6.51-6.38 (m, 1H), 6.26-5.95 (m, 2H), 5.72-5.59 (m, 1H), 4.61 (s, 1H), 4.26 (s, 1H), 4.00 (s, 1H), 3.56-3.04 (m, 3H), 3.01-2.79 (m, 2H), 2.79-2.57 (m, 1H), 2.33-1.77 (m, 3H), 1.25 (s, 2H).
Example 234: MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.41-8.37 (m, 1H), 8.36-8.32 (m, 1H), 8.03-7.99 (m, 1H), 7.98-7.94 (m, 1H), 7.83-7.80 (m, 1H), 7.63-7.57 (m, 2H), 7.51-7.45 (m, 1H), 7.31-7.25 (m, 1H), 6.89-6.73 (m, 3H), 6.58-6.54 (m, 1H), 6.47-6.41 (m, 1H), 6.14-5.85 (m, 2H), 5.70-5.63 (m, 1H), 4.30-4.16 (m, 2H), 4.05-3.91 (m, 1H), 3.27-3.11 (m, 1H), 3.06-2.82 (m, 3H), 2.39-2.25 (m, 1H), 2.05-1.91 (m, 2H), 1.89-1.78 (m, 1H), 1.34-1.15 (m, 2H).
Intermediate 233-1: 3-(3-((1S,3*)-1-amino-3-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine and
Intermediate 234-1: 3-(3-((1S,3*)-1-amino-3-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl ((1S)-3-fluoro-5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)carbamate
To a solution of tert-butyl ((1S)-5-bromo-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 233-2) (4 g, 12 mmol, 1 equiv) and 3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-amine (2.73 g, 13.3 mmol, 1.1 equiv) in 1,4-dioxane (60 mL) were added Pd(OAc)2 (0.27 g, 1.2 mmol, 0.1 equiv), XantPhos (1.40 g, 2.42 mmol, 0.2 equiv) and Cs2CO3 (7.89 g, 24.2 mmol, 2 equiv). After stirring for 2 h at 100° C. under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl ((1S)-3-fluoro-5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)carbamate (4 g, 73% yield) as a brown solid. MS (ESI) calcd. for C22H23FN6O4, 454.18 m/z, found 455.15 [M+H]+.
Step 2: Synthesis of tert-butyl ((1S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate
To a stirred solution of tert-butyl ((1S)-3-fluoro-5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)carbamate (2 g, 4.4 mmol, 1 equiv) and 2-aminonicotinaldehyde (0.59 g, 4.8 mmol, 1.1 equiv) in DMSO (60 mL) and MeOH (10 mL) was added Na2S2O4 (1.69 g, 9.68 mmol, 2.2 equiv) at room temperature. The resulting mixture was stirred for 18 h at 100° C. The mixture was allowed to cool to room temperature. The mixture was basified to pH 7 with saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate). The diastereomers were separated by chiral Prep-HPLC on CHIRALPAK IG column using a mixture of [Hex (+0.5% 2M NH3-MeOH)] and [IPA/DCM (1:1)] to afford tert-butyl ((1S,3*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (250 mg, 11% yield) as a yellow solid and first eluting peak (MS (ESI) calcd. for C28H27FN8O2, 526.22 m/z, found 527.15 [M+H]+) and tert-butyl ((1S,3*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (230 mg, 9.9% yield) as a yellow solid (MS (ESI) calcd. for C28H27FN8O2, 526.22 m/z, found 527.15 [M+H]). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Step 3: Synthesis of 3-(3-((1S,3R*)-1-amino-3-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 233-1) and 3-(3-((1S,3S*)-1-amino-3-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 234-1)
The products of Step 2 vide supra were deprotected separately by dissolving the starting material (100 mg, 0.190 mmol, 1 equiv) in DCM (0.8 mL) and adding TFA (0.2 mL). The resulting mixture was stirred for 2 h at room temperature. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 3-(3-((1S,3*)-1-amino-3-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 233-1) (MS (ESI) calcd. for C23H19FN8, 426.17 m/z, found: 427.15 [M+H]+) and 3-(3-((1S,3*)-1-amino-3-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 234-1) (25.4 mg, 30.49% yield) as yellow solid (MS (ESI) calcd. for C23H19FN8, 426.17 m/z, found: 427.15 [M+H]+). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 233-2: tert-butyl ((1S)-5-bromo-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide
A solution of (1S)-5-bromo-2,3-dihydro-1H-inden-1-amine (50 g, 236 mmol, 1 equiv) and TEA (55.7 g, 550 mmol, 2 equiv) in DCM (750 mL) was added TFAA (63.25 g, 301.1 mmol, 1.3 equiv) at 0° C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with H2O (500 mL) at room temperature. The aqueous layer was extracted with DCM (2×500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude product (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (86 g) as a white solid. MS (ESI) calcd. for C11H9BrF3NO, 306.98 m/z, found: 306.10 [M−H]−.
Step 2: Synthesis of (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide
A solution of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (50 g, 162 mmol, 1.00 equiv) and CrO3 (48.8 g, 488 mmol, 3.00 equiv) in AcOH (600 mL) was stirred for 2 h at 50° C. under air atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0˜20%) to afford (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (11.5 g, 22%) as a white solid. MS (ESI) calcd. for C11H7BrF3NO2, 320.96 m/z, found: 319.90 [M−H]−.
Step 3: Synthesis of (S)-3-amino-6-bromo-2,3-dihydro-1H-inden-1-one
A solution of (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (10 g, 31 mmol, 1 equiv) in 6M aqueous HCl (200 mL) was refluxed 5 h. The resulting mixture was concentrated under reduced pressure and the residue was triturated with Et2O (200 mL). The residue was filtered and dried to afford (S)-3-amino-6-bromo-2,3-dihydro-1H-inden-1-one (7 g, crude quant.) as a white solid. MS (ESI) calcd. for C9H8BrNO, 224.98 m/z, found 224.05 [M−H]−.
Step 4: Synthesis of tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate
To a stirred solution of (S)-3-amino-6-bromo-2,3-dihydro-1H-inden-1-one (7 g, 31 mmol, 1 equiv) in THE (60 mL) and H2O (15 mL) were added NaHCO3 (5.20 g, 61.9 mmol, 2 equiv) and Boc2O (8.11 g, 37.2 mmol, 1.2 equiv) in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0˜50%) to afford tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (7 g, 69% yield) as an off-white solid. MS (ESI) calcd. for C14H16BrNO3, 325.03 m/z, found 324.10 [M−H]−.
Step 5: Synthesis of tert-butyl ((1S)-5-bromo-3-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate
To a stirred solution of tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (7 g, 21 mmol, 1 equiv) in MeOH (100 mL) was added NaBH4 (1.62 g, 42.9 mmol, 2 equiv) in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water (200 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0˜50%) to afford tert-butyl ((1S)-5-bromo-3-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (5 g, 71%) as a white solid. MS (ESI) calcd. for C14H18BrNO3, 327.05 m/z, found 326.10 [M−H]−.
Step 6: Synthesis of tert-butyl ((1S)-5-bromo-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 233-2
To a stirred solution of tert-butyl ((1S)-5-bromo-3-hydroxy-2,3-dihydro-1H-inden-1-yl)carbamate (5 g, 15 mmol, 1 equiv) in DCM (100 mL) was added DAST (4.91 g, 30.5 mmol, 2 equiv) in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (200 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0˜30%) to afford tert-butyl ((1S)-5-bromo-3-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 233-2) (4 g, 80% yield) as a white solid. MS (ESI) calcd. for C14H17BrFNO2, 329.04 m/z, found 310.15 [M-F]*.
Example 235: (S)-2-acryloyl-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide




Example 235 was prepared in a manner analogous to Example 2 (via Intermediate 2-1) using 2-(tert-butoxycarbonyl)-3,4-dihydro-1H-isoquinoline-8-carboxylic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid, 4N HCl in dioxane in place of TFA in DCM, sodium bicarbonate in place of triethylamine and tetrahydrofuran/water (4:1) in place of DCM. For the final step, the reagents were added at 0° C. followed by stirring at room temperature for 30 min. MS (ESI) calcd. for C36H31N9O2, 621.26 m/z, found 622.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.87-8.93 (m, 1H), 8.30-8.40 (m, 2H), 7.98-8.05 (m, 1H), 7.92-7.97 (m, 1H), 7.81 (s, 1H), 7.45-7.51 (m, 1H), 7.21-7.45 (m, 6H), 6.83-6.99 (m, 3H), 6.54 (s, 1H), 6.40-6.48 (m, 1H), 5.98-6.20 (m, 1H), 5.57-5.75 (m, 2H), 4.85-4.98 (m, 2H), 3.78-3.88 (m, 1H), 3.71-3.76 (m, 1H), 2.98-3.07 (m, 1H), 2.85-2.96 (m, 3H), 2.52-2.60 (m, 1H), 2.00-2.10 (m, 1H).
Example 236: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 237: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 236 and 237 were prepared in a manner analogous to Example 13 using Intermediate 236-1 and 237-1, respectively, in place of Intermediate 1-1. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 236: MS (ESI) calcd. for C31H29F2N9O: 581.24 m/z, found: 582.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.35-8.39 (m, 1H), 8.26-8.30 (m, 1H), 7.99-8.02 (m, 1H), 7.73-7.80 (m, 1H), 7.43-7.50 (m, 1H), 7.31-7.38 (m, 2H), 7.20-7.28 (m, 1H), 6.79-6.89 (m, 1H), 6.31-6.46 (m, 2H), 6.05-6.13 (m, 1H), 5.62-5.68 (m, 1H), 5.38-5.44 (m, 1H), 4.38-4.47 (m, 1H), 4.18-4.30 (m, 1H), 3.91-4.05 (m, 1H), 3.11-3.28 (m, 2H), 2.91-3.12 (m, 3H), 1.98-2.07 (m, 1H), 1.82-1.92 (m, 1H), 1.22-1.40 (m, 2H). 19F-NMR (400 MHz, DMSO) δ (ppm): −127.30, −196.72.
Example 237: MS (ESI) calcd. for C31H29F2N9O: 581.24 m/z, found: 582.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29-8.39 (m, 2H), 7.99-8.02 (m, 1H), 7.73-7.80 (m, 1H), 7.47-7.52 (m, 1H), 7.38-7.41 (m, 1H), 7.20-7.37 (m, 2H), 6.79-6.89 (m, 1H), 6.31-6.46 (m, 2H), 6.05-6.13 (m, 1H), 5.62-5.70 (m, 1H), 5.17-5.32 (m, 1H), 4.36-4.44 (m, 1H), 4.21-4.31 (m, 1H), 3.91-4.05 (m, 1H), 3.49-3.52 (m, 1H), 3.09-3.20 (m, 1H), 2.93-3.06 (m, 2H), 2.79-2.90 (m, 1H), 1.82-1.98 (m, 2H), 1.18-1.29 (m, 2H). 19F-NMR (400 MHz, DMSO) δ (ppm): −127.28, −175.93.
Intermediate 236-1: 3-(3-((1R,S*)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine and
Intermediate 237-1: 3-(3-((1R,2*)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediates 236-1 and 237-1 were prepared in a manner analogous to Intermediate 75-1 and 76-1 (last 3 steps only) using Intermediate 236-2 in place of (S)-N-((1R)-5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 236-1: MS (ESI) calcd. for C23H18F2N8, 444.16 m/z, found 445.15 [M+H]+.
Intermediate 237-1: MS (ESI) calcd. for C23H18F2N8, 444.16 m/z, found 445.15 [M+H]+.
Intermediate 236-2: (S)-N-[(1R)-5-{[3-amino-6-(3-fluoropyrazol-1-yl)pyridin-2-yl]amino}-2-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide




Intermediate 236-2 was prepared in a manner analogous to Intermediate 75-1 (using the first 5 steps only) and using Intermediate 236-3 in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine. MS (ESI) calcd. for C21H24F2N6OS, 446.17 m/z, found 447.25 [M+H]+.
Intermediate 236-3: 6-(3-fluoropyrazol-1-yl)-3-nitropyridin-2-amine




Step 1: Synthesis of 6-(3-fluoropyrazol-1-yl)-3-nitropyridin-2-amine
To a solution of 6-bromo-3-nitropyridin-2-amine (5 g, 22.935 mmol, 1 equiv) in DMF (80 mL) was added K2CO3 (9.51 g, 68.805 mmol, 3 equiv) and then 3-fluoro-1H-pyrazole (2.17 g, 25.229 mmol, 1.1 equiv) at 0° C. The resulting suspension was stirred overnight at 60° C. The mixture was poured into water (250 mL). The precipitated solids were collected by filtration and washed with water (3×150 mL) to afford 6-(3-fluoropyrazol-1-yl)-3-nitropyridin-2-amine (4.9 g, 95.74% yield) as a yellow solid. MS (ESI) calcd. for C8H6FN5O2, 223.05 m/z, found 224.15 [M+H]+.
Example 238: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(4-fluoropiperidin-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 238 was prepared in a manner analogous to Example 170 (via Intermediate 170-1) using 4-fluoropiperidine in place of pyrrolidine, NMP in place of DMSO and the first step was run in the microwave at 120° C. overnight. MS (ESI) calcd. for C33H37FN8O: 580.31 m/z, found: 581.40 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.27-9.23 (m, 1H), 9.20-9.16 (m, 1H), 8.06-7.97 (m, 2H), 7.80-7.73 (m, 1H), 7.47-7.41 (m, 2H), 7.41-7.34 (m, 1H), 7.05-6.98 (m, 1H), 6.94-6.78 (m, 1H), 6.67-6.60 (m, 1H), 6.18-6.09 (m, 1H), 5.75-5.67 (m, 1H), 5.06-4.77 (m, 2H), 4.56-4.51 (m, 1H), 4.23-4.18 (m, 1H), 3.83-3.64 (m, 3H), 3.59-3.54 (m, 1H), 3.50-3.41 (m, 2H), 3.17-3.09 (m, 2H), 2.97-2.85 (m, 1H), 2.77-2.66 (m, 1H), 2.60-2.52 (m, 1H), 2.26-2.19 (m, 2H), 2.15-2.08 (m, 1H), 1.96-1.84 (m, 2H), 1.71-1.67 (m, 2H), 1.58-1.53 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ −73.90, −176.58. (TFA salt)
Example 239: 1-(4-{[(1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route:








Step 1: Synthesis of tert-butyl N-[(1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-{[3-amino-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-1) (500 mg, 1.230 mmol, 1 equiv) in AcOH (8 mL) was added Cu(OAc)2 (44.68 mg, 0.246 mmol, 0.2 equiv) and thiophene-2-carbaldehyde (165.54 mg, 1.476 mmol, 1.2 equiv) and the resulting mixture was stirred at 70° C. for 1 h. The reaction was quenched with H2O (2 mL) and the resulting mixture was concentrated. The residue was purified by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford tert-butyl N-[(1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (300 mg, 48.91% yield) as a yellow solid. MS (ESI) calcd. for C27H26N6O2S: 498.18 m/z, found: 499.20 [M+H]+.
Step 2: Synthesis of (1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-amine
A solution of tert-butyl N-[(1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (200 mg, 0.401 mmol, 1 equiv) in 4N HCl in dioxane (6 mL) was stirred at r.t for 1 h. The resulting mixture was concentrated to afford (1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-amine (159 mg, crude) as a yellow solid. MS (ESI) calcd. for C22H18N6S: 398.13 m/z, found: 399.25 [M+H]+.
Step 3: Synthesis of 1-(4-{[(1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 239)
A solution of (1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-amine (160 mg, 0.402 mmol, 1 equiv) and 1-(prop-2-enoyl)piperidin-4-one (92.26 mg, 0.603 mmol, 1.5 equiv) in DCE (8 mL) and MeOH (0.8 mL) stirred at 50° C. for 1 h. NaBH3CN (126.16 mg, 2.010 mmol, 5 equiv) was added and the mixture was stirred at 50° C. for 1 h. The reaction was quenched with H2O (2 mL) and the mixture was concentrated. The residue was purified by Prep HPLC on XBridge Prep Phenyl Hexy OBD C18 Column using a gradient of acetonitrile in water (+10 mmol/L NH4HCO3) to afford 1-(4-{[(1S)-5-[5-(pyrazol-1-yl)-2-(thiophen-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 239) (81.7 mg, 36.43% yield) as an off-white solid. MS (ESI) calcd. for C30H29N7OS: 535.21 m/z, found: 536.15[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.23-8.29 (m, 2H), 7.88-7.92 (m, 1H), 7.72-7.82 (m, 2H), 7.59-7.65 (m, 1H), 7.39-7.48 (m, 2H), 7.00-7.08 (m, 1H), 6.79-6.89 (m, 2H), 6.47-6.52 (m, 1H), 6.07-6.13 (m, 1H), 5.63-5.70 (m, 1H), 4.38-4.45 (m, 1H), 4.23-4.33 (m, 1H), 3.96-4.08 (m, 1H), 3.11-3.22 (m, 1H), 2.79-3.04 (m, 4H), 2.48-2.52 (m, 1H), 1.92-2.01 (m, 1H), 1.79-1.97 (m, 2H), 1.19-1.37 (m, 2H).
Intermediate 239-1: tert-butyl (S)-(5-((3-amino-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)carbamate and
Intermediate 239-0: tert-butyl (S)-(5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-0
A mixture of tert-butyl N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate (500 mg, 1.602 mmol, 1 equiv), 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine (328.59 mg, 1.602 mmol, 1 equiv), Pd2(dba)3 (146.65 mg, 0.160 mmol, 0.1 equiv), xantphos (185.34 mg, 0.320 mmol, 0.2 equiv) and Cs2CO3 (1565.40 mg, 4.806 mmol, 3 equiv) in dioxane (10 mL) was stirred under N2 at 100° C. for 1 h. After concentration the crude material was washed with H2O (80 mL). After drying, the residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford tert-butyl N-[(1S)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-0) (500 mg, 71.53% yield) as a yellow solid. MS (ESI) calcd. for C22H24N6O4: 436.18 m/z, found: 437.20[M+H]+.
Step 2: Synthesis of tert-butyl N-[(1S)-5-{[3-amino-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-1
To a solution of tert-butyl N-[(1S)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-0) (500 mg, 1.146 mmol, 1 equiv) in DMF (4 mL) was added 4-(pyridin-4-yl)pyridine (8.95 mg, 0.057 mmol, 0.05 equiv) and B2(OH)4 (308.10 mg, 3.438 mmol, 3 equiv) at 0° C. The resulting mixture was stirred at r.t for 1 h. Water was added and the precipitate was collected by filtration to afford tert-butyl N-[(1S)-5-{[3-amino-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-1) (450 mg, 86.97% yield) as a black solid. MS (ESI) calcd. for C22H26N6O2: 406.21 m/z, found: 407.20 [M+H]+.
Example 240: 1-(4-{[(1S)-5-[2-(3-fluorophenyl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 240 was prepared in a manner analogous to Example 239 using 3-fluorobenzaldehyde in place of thiophene-2-carbaldehyde. MS (ESI) calcd. for C32H30FN7O: 547.25 m/z, found: 548.15[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.29-8.40 (m, 2H), 7.92-8.01 (m, 1H), 7.72-7.82 (m, 1H), 7.22-7.68 (m, 7H), 6.79-6.89 (m, 1H), 6.49-6.58 (m, 1H), 6.08-6.16 (m, 1H), 5.63-5.71 (m, 1H), 4.25-4.39 (m, 2H), 3.92-4.03 (m, 1H), 3.05-3.20 (m, 1H), 2.71-2.99 (m, 4H), 2.40-2.52 (m, 1H), 1.73-2.01 (m, 3H), 1.16-1.34 (m, 2H).
Example 241: 1-(4-{[(1S)-5-[2-(2-fluorophenyl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 241 was prepared in a manner analogous to Example 239 using 2-fluorobenzaldehyde in place of thiophene-2-carbaldehyde. MS (ESI) calcd for C32H30FN7O:547.25, found: 548.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm) 8.39-8.45 (m, 2H), 7.99-8.01 (m, 1H), 7.83-7.84 (m, 1H), 7.74-7.78 (m, 1H), 7.61-7.66 (m, 1H), 7.51-7.59 (m, 1H), 7.37-7.39 (m, 1H), 7.32-7.35 (m, 2H), 7.21-7.26 (m, 1H), 6.80-6.86 (m, 1H), 6.58-6.60 (m, 1H), 6.10-6.15 (m, 1H), 5.70-5.73 (m, 1H), 4.96-4.99 (m, 1H), 4.52-4.55 (m, 1H), 4.18-4.20 (m, 1H), 3.12-3.18 (m, 2H), 2.89-2.96 (m, 1H), 2.68-2.74 (m, 1H), 2.54-2.60 (m, 2H), 2.08-2.23 (m, 3H), 1.46-1.51 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −74.08, −112.64. (TFA salt)
Example 242: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-isopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route:








Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(prop-1-en-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (600 mg, 1.151 mmol, 1 equiv) in dioxane (6 mL) and H2O (1.5 mL) was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (290.05 mg, 1.727 mmol, 1.5 equiv), Pd(dtbpf)Cl2 (75.00 mg, 0.115 mmol, 0.1 equiv) and K3PO4 (732.76 mg, 3.453 mmol, 3 equiv). After stirring for 2 h at r.t under a nitrogen atmosphere, the reaction was quenched by the addition of saturated aqueous ammonium chloride at 0° C. The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with water (10 mL×3) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-5% MeOH/DCM) giving tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(prop-1-en-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (300 mg, 54.02% yield) as a light yellow solid. MS (ESI) calcd. for C28H30N6O2: 482.24 m/z, found: 483.20 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-isopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(prop-1-en-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (200 mg, 0.414 mmol, 1 equiv) in formic acid (6 mL) was added Zn (200 mg, 3.059 mmol, 7.38 equiv) and the resulting mixture was stirred at 50° C. for 3 h. The reaction was quenched with H2O (2 mL) and concentrated. The residue was purified by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.05% NH4HCO3) to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-isopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (90 mg, 56.48% yield) as a yellow solid. MS (ESI) calcd. for C23H34N6: 384.20 m/z, found: 385.25 [M+H]+.
Step 3: Synthesis of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-isopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 242)
A solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-isopropylimidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (80 mg, 0.208 mmol, 1 equiv) and 1-(prop-2-enoyl)piperidin-4-one (47.81 mg, 0.312 mmol, 1.5 equiv) in DCE (4 mL) and MeOH (0.4 mL) was stirred at 50° C. for 2 h. NaBH3CN (65.38 mg, 1.040 mmol, 5 equiv) was added and the mixture was stirred at 50° C. for 1 h. The reaction was quenched with H2O (2 mL) and concentrated. The residue was purified by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.1% FA) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-isopropylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 242) (16.0 mg, 14.52% yield) as an off-white solid. MS (ESI) calcd. for C31H35N7O: 521.29 m/z, found: 522.25[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.20-8.27 (m, 1H), 8.09-8.15 (m, 1H), 7.96-8.02 (m, 1H), 7.45-7.50 (m, 1H), 7.27-7.32 (m, 2H), 7.16-7.23 (m, 2H), 6.78-6.92 (m, 1H), 6.37-6.39 (m, 1H), 6.06-6.15 (m, 1H), 5.63-5.69 (m, 1H), 4.38-4.45 (m, 1H), 4.25-4.31 (m, 1H), 3.96-4.06 (m, 1H), 3.46-3.50 (m, 1H), 3.10-3.21 (m, 1H), 2.90-3.09 (m, 3H), 2.72-2.89 (m, 2H), 2.50-2.52 (m, 1H), 1.95-2.04 (m, 1H), 1.78-1.92 (m, 2H), 1.25-1.36 (m, 1H), 1.20-1.24 (m, 6H). (formic acid salt)
Example 243: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-methylpyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 243 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 3-methyl-1H-pyrazole in place of pyrazole, EPhos/EPhos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate, a reaction time of 4 h for step 1, 4N HCl in dioxane at room temperature overnight for the deprotection and tetrahydrofuran instead of DCE for the final step. MS (ESI) calcd. For C32H33N9O, 559.28 m/z, found 560.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.51-8.29 (m, 2H), 8.25-8.19 (m, 1H), 8.05-7.95 (m, 1H), 7.92-7.82 (m, 1H), 7.58-7.42 (m, 1H), 7.33 (s, 1H), 7.27-7.17 (m, 2H), 6.93 (s, 2H), 6.90-6.73 (m, 1H), 6.51-6.30 (m, 2H), 6.15-6.04 (m, 1H), 5.74-5.61 (m, 1H), 4.44-4.32 (m, 1H), 4.26 (s, 1H), 4.00 (s, 1H), 3.18 (s, 1H), 2.93 (s, 3H), 2.85-2.68 (m, 1H), 2.51 (s, 1H), 2.29 (s, 3H), 1.96 (s, 1H), 1.90-1.66 (m, 2H), 1.25 (s, 2H). (formic acid salt)
Example 244: 1-(4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-((*)-2,2-difluorocyclopropyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 245: 1-(4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-((*)-2,2-difluorocyclopropyl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 244 and 245 were prepared in a manner analogous to Example 190 using Intermediate 85-1 in place of Intermediate 190-1, potassium (2,2-difluorocyclopropyl)trifluoroborate in place of potassium cyclopropyltrifluoroborate, a reaction time of 2 h for the first step and 4N HCl in dioxane at room temperature for 1 h for the deprotection. The diastereomers were separated by chiral Prep-HPLC on a CelluloseSB column using a mixture of [MtBE/Hex (1:1) (+0.1% DEA)] and [IPA/tetrahydrofuran (1:1)]. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer.
Example 244: MS (ESI) calcd. For C31H31F2N7O: 555.26 m/z, found: 556.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.17-8.17 (m, 1H), 7.97-7.99 (m, 1H), 7.41-7.45 (m, 2H), 7.20-7.38 (m, 1H), 7.16-7.19 (m, 2H), 6.81-6.90 (s, 2H), 6.77 (s, 1H), 6.37-6.42 (m, 1H), 6.05-6.11 (m, 1H), 5.63-5.67 (m, 1H), 4.30-4.35 (m, 1H), 4.21-4.30 (m, 1H), 3.90-4.02 (m, 1H), 3.18-3.32 (m, 2H), 2.88-2.91 (m, 3H), 2.72-2.77 (m, 1H), 2.42-2.50 (m, 1H), 2.13-2.16 (m, 1H), 1.90-1.99 (m, 3H), 1.84-1.88 (m, 1H).
Example 244: MS (ESI) calcd. For C31H31F2N7O: 555.26 m/z, found: 556.30[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.14-8.17 (s, 1H), 7.97-8.00 (m, 1H), 7.20-7.48 (m, 2H), 7.18 (m, 3H), 6.89 (m, 3H), 6.38-6.42 (m, 1H), 6.05-6.06 (m, 1H), 5.63-5.68 (m, 1H), 4.39 (m, 1H), 4.26 (m, 1H), 4.00-4.02 (m, 1H), 3.12-3.33 (m, 2H), 2.50-2.98 (m, 4H), 2.42-2.49 (m, 1H), 2.11-2.17 (m, 1H), 1.23-1.99 (m, 4H).
Example 246: 1-(4-{[(1S)-5-{5-cyclopropyl-2-phenylimidazo[4,5-b]pyridin-3-yl}-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 246 was prepared in a manner analogous to Example 199 using Intermediate 246-1 in place of Intermediate 190-1 and tetrahydrofuran as the solvent for the final step. MS (ESI) calcd. For C32H33N5O: 503.27 m/z, found: 504.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.11-7.90 (m, 111), 7.57-7.44 (m, 3H), 7.44-7.27 (m, 3H), 7.27-7.07 (m, 3H), 6.90-6.66 (m, 1H), 6.18-5.92 (m, 1H), 5.72-5.55 (m, 1H), 4.50-4.36 (m, 1H), 4.28 (s, 1H), 4.15-3.89 (m, 1H), 3.25-3.06 (m, 1H), 3.06-2.56 (m, 5H), 2.47-2.29 (m, 1H), 2.23-2.05 (m, 1H), 2.05-1.68 (m, 3H), 1.40-1.08 (m, 2H), 1.08-0.52 (m, 4H). (formic acid salt)
Intermediate 246-1: N-[(1S)-5-{5-bromo-2-phenylimidazo[4,5-b]pyridin-3-yl}-2,3-dihydro-1H-inden-1-yl]acetamide




Synthetic Route:





Step 1: Synthesis N-[(1S)-5-{5-bromo-2-phenylimidazo[4,5-b]pyridin-3-yl}-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 246-1
A solution of N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 246-2) (3 g, 7.668 mmol, 1 equiv) and Na2S2O4 (2.94 g, 16.870 mmol, 2.2 equiv) in DMSO/MeOH (30 mL: 5 mL) was treated with benzaldehyde (0.85 g, 8.051 mmol, 1.05 equiv) at room temperature. The resulting mixture was stirred overnight at 105° C. under air atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with water (3×40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with Et2O (500 mL) to afford N-[(1S)-5-{5-bromo-2-phenylimidazo[4,5-b]pyridin-3-yl}-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 246-1) (1.26 g, 23.88%) as a brown yellow solid. The crude product was used in subsequent steps without further purification. MS (ESI) calcd. For C23H19BrN4O: 446.07 m/z, found: 447.10 [M+H]+.
Intermediate 246-2: (S)-N-(5-((6-bromo-3-nitropyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





Step 1: Synthesis of tert-butyl (S)-(1-acetamido-2,3-dihydro-1H-inden-5-yl)carbamate
To a mixture of N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 218-4) (40 g, 157 mmol, 1 equiv), tert-butyl carbamate (27.66 g, 236 mmol, 1.5 equiv), XantPhos (CAS: 161265-03-8) (9.11 g, 15.7 mmol, 10 mol %), Pd(Oac)2 (3.54 g, 15.7 mmol, 10 mol %), and cesium carbonate (154 g, 472 mmol, 10 mol %) was added 1,4-dioxane (300 mL) under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100° C. The reaction mixture was quenched by addition of water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using an eluent of petroleum ether/dichloromethane/methanol (70:27:3) to afford tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 48% yield). MS (ESI) calculated for C16H22N2O3: 290.16, found 289.05 [M−H]−.
Step 2: Synthesis of (S)-N-(5-amino-2,3-dihydro-1H-inden-1-yl)acetamide
To a stirred solution of tert-butyl N-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]carbamate (43.1 g, 148 mmol, 1 equiv) in dichloromethane (180 mL) was added 4N HCl in 1,4-dioxane (185 mL, 742 mmol, 5 equiv). The reaction mixture was stirred for 1 h at room temperature. The reaction mixture was concentrated in vacuo and re-crystallized from ethyl acetate to afford N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (hydrochloride salt) (23 g, 81% yield) as a white solid. MS (ESI) calculated for C11H14N2O: 190.11, found 191.15 [M+H]+.
Step 3: (S)-N-(5-((6-bromo-3-nitropyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 246-2
N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (17 g, 89 mmol) and 2,6-dibromo-3-nitropyridine (25.19 g, 89.36 mmol) were dissolved in triethylamine (45.21 g, 446.8 mmol, 5 equiv) and ethanol (200 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 400 mL water and the precipitate was rinsed with 1:1 ethanol/water (800 mL:800 mL) to afford N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 246-2) (26 g, 74% yield) as an orange solid. MS (ESI) calculated for C16H15BrN4O3: 390.03, found 413.00 [M+Na]+, 415.00 [M+Na+2]+.
Example 247: 1-(4-{[(1S)-5-[2-(4-fluorophenyl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 247 was prepared in a manner analogous to Example 239 using 4-fluorobenzaldehyde in place of thiophene-2-carbaldehyde. MS (ESI) calcd. For C32H30FN7O: 547.25 m/z, found: 548.30 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 8.32-8.40 (m, 2H), 7.95-8.00 (m, 1H), 7.78-7.85 (m, 1H), 7.66-7.75 (m, 1H), 7.56-7.65 (m, 2H), 7.52-7.55 (m, 1H), 7.72-7.40 (m, 1H), 7.20-7.31 (m, 2H), 6.75-6.90 (m, 1H), 6.54-6.60 (m, 1H), 6.09-6.20 (m, 1H), 5.70-5.79 (m, 1H), 4.96-5.05 (m, 1H), 4.48-4.60 (m, 1H), 4.12-4.25 (m, 1H), 3.51-3.63 (m, 1H), 3.10-3.22 (m, 2H), 2.91-3.05 (m, 1H), 2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 2.18-2.30 (m, 2H), 2.08-2.15 (m, 1H), 1.40-1.60 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −109.90, −73.89. (TFA salt)
Example 248: (S)-1-(4-((5-(2-cyclopropyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]-430-pyridine-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 248 was prepared in a manner analogous to Example 239 using cyclopropanecarbaldehyde in place of thiophene-2-carbaldehyde. MS (ESI) calcd. For C29H31N7O: 493.26 m/z, found: 494.15 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 8.25-8.33 (m, 1H), 8.11-8.20 (m, 1H), 7.81-7.90 (m, 2H), 7.75-7.80 (m, 1H), 7.65-7.74 (m, 1H), 7.60-7.64 (m, 1H), 6.75-6.90 (m, 1H), 6.50-6.55 (m, 1H), 6.10-6.20 (m, 1H), 5.70-5.79 (m, 1H), 4.99-5.10 (m, 1H), 4.48-4.60 (m, 1H), 4.13-4.25 (m, 1H), 3.55-3.65 (m, 1H), 3.12-3.30 (m, 2H), 3.00-3.11 (m, 1H), 2.68-2.81 (m, 1H), 2.55-2.67 (m, 1H), 2.20-2.30 (m, 2H), 2.10-2.19 (m, 1H), 1.88-1.99 (m, 1H), 1.44-1.62 (m, 2H), 1.18-1.25 (m, 2H), 1.05-1.17 (m, 2H). (TFA salt)
Example 249: 1-(4-(((1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 250: 1-(4-(((1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 249 and 250 were prepared in a manner analogous to Example 13 using Intermediates 249-1 and 250-1, respectively, in place of Intermediate 1-1 and MeOH/room temperature/2 h instead of DCE/40° C. overnight. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 249: MS (ESI) calcd. For C32H30FN7O: 547.25 m/z, found: 548.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.35-8.37 (m, 2H), 7.94-7.96 (m, 1H), 7.80-7.81 (m, 1H), 7.38-7.57 (m, 7H), 7.28-7.30 (m, 1H), 6.77-6.84 (m, 1H), 6.54-6.55 (m, 1H), 6.06-6.11 (m, 1H), 5.65-5.69 (m, 1H), 5.15-5.35 (m, 1H), 4.37-4.42 (m, 1H), 4.25-4.30 (m, 1H), 3.95-4.05 (m, 1H), 3.41-3.47 (m, 1H), 3.12-3.19 (m, 1H), 2.92-3.02 (m, 2H), 2.81-2.86 (m, 1H), 1.84-2.02 (m, 2H), 1.18-1.28 (m, 2H).
Example 250: MS (ESI) calcd. For C32H30FN7O: 547.25 m/z, found: 548.30 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.37 (m, 2H), 7.94-7.96 (m, 1H), 7.79-7.81 (m, 1H), 7.51-7.59 (m, 2H), 7.42-7.50 (m, 1H), 7.31-7.41 (m, 5H), 6.75-6.85 (m, 1H), 6.54-6.55 (m, 1H), 6.05-6.11 (m, 1H), 5.65-5.69 (m, 1H), 5.40-5.55 (m, 1H), 4.39-4.48 (m, 1H), 3.95-4.28 (m, 2H), 3.19-3.25 (m, 2H), 3.01-3.28 (m, 2H), 2.91-2.99 (m, 1H), 1.81-2.06 (m, 2H), 1.22-1.38 (m, 2H).
Intermediate 249-1: (1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine and
Intermediate 250-1: (1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediates 249-1 and 250-1 were prepared in a manner analogous to Intermediates 75-1 and 76-1 using benzaldehyde in place of 2-aminopyridine-3-carbaldehyde. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 249-1: MS (ESI) calcd. For C24H19FN6: 410.16 m/z, found: 411.15 [M+H]+.
Intermediate 250-1: MS (ESI) calcd. For C24H19FN6: 410.16 m/z, found: 411.15 [M+H]+.
Example 251: 1-(4-{[(1S)-5-[2-(2-fluoropyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 251 was prepared in a manner analogous to Example 239 using 2-fluoropyridine-3-carbaldehyde in place of thiophene-2-carbaldehyde. MS (ESI) calcd. For C31H29FN8O: 548.24 m/z, found: 549.30 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.37-8.45 (m, 4H), 8.03-8.05 (m, 1H), 7.85-7.86 (m, 1H), 7.68-7.70 (m, 1H), 7.55-7.61 (m, 2H), 7.38-7.40 (m, 1H), 6.80-6.87 (m, 1H), 6.59-6.61 (m, 1H), 6.14-6.18 (m, 1H), 5.76-5.79 (m, 1H), 4.99-5.04 (m, 1H), 4.55-4.56 (m, 1H), 4.19-4.20 (m, 1H), 3.62-3.93 (m, 1H), 3.15-3.21 (m, 2H), 2.96-3.00 (m, 1H), 2.73-2.79 (m, 1H), 2.58-2.63 (m, 1H), 2.20-2.27 (m, 2H), 2.11-2.14 (m, 1H), 1.51-1.56 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −66.94, −73.93. (TFA salt)
Example 252: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-chloropyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 252 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 3-chloro-1H-pyrazole in place of pyrazole, Ephos/Ephos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate, 4N HCl in dioxane at room temperature overnight for the deprotection and MeOH instead of DCE for the final step. MS (ESI) calcd. For C31H30ClN9O, 579.23 m/z, found 580.15 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.34-8.37 (m, 2H), 7.98-8.00 (m, 1H), 7.84 (d, J=8.7 MHz, 1H), 7.46-7.49 (m, 2H), 7.21-7.33 (m, 2H), 6.91 (s, 2H), 6.64-6.86 (m, 2H), 6.39-6.43 (m, 1H), 6.04-6.11 (m, 1H), 5.63-5.67 (m, 1H), 4.25-4.35 (m, 2H), 3.96-4.02 (m, 1H), 3.16-3.20 (m, 1H), 2.77-2.93 (m, 4H), 2.41-2.45 (m, 1H), 1.85-1.98 (m, 3H), 1.22-1.25 (m, 2H).
Example 253: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(4-methyl-1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 253 was prepared in a manner analogous to Example 109 (via Intermediate 109-2) using 2-bromo-4-methyl-1,3-oxazole in place of 2-bromo-1,3-oxazole, 4N HCl in dioxane in place of TFA in DCM and MeOH in place of DCE. MS (ESI) calcd. For C32H32N8O2, 560.20 m/z, found 561.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 7.99-8.00 (m, 1H), 7.92-7.93 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.32-7.33 (m, 1H), 7.23-7.28 (m, 2H), 6.99 (s, 2H), 6.80-6.87 (m, 1H), 6.39-6.43 (m, 1H), 6.07-6.11 (m, 1H), 5.64-5.67 (m, 1H), 4.34-4.36 (m, 1H), 4.22-4.26 (m, 1H), 3.97-4.02 (m, 1H), 3.16-3.20 (m, 1H), 2.89-2.95 (m, 3H), 2.75-2.79 (m, 1H), 2.44-2.46 (m, 1H), 2.12-2.17 (m, 4H), 1.88-1.97 (m, 2H), 1.78-1.81 (m, 1H), 1.23-1.27 (m, 2H).
Example 254: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(4-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 254 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 4-fluoro-1H-pyrazole in place of pyrazole, Ephos/Ephos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate, a reaction time of overnight for step 1, 4N HCl in dioxane at room temperature for 1 h for the deprotection and MeOH instead of DCE for the final step. MS (ESI) calcd. For C31H30FN9O, 563.26 m/z, found 564.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36-8.40 (m, 2H), 8.24 (s, 1H), 7.91-8.02 (m, 3H), 7.49 (d, J=8.0 MHz, 1H), 7.33-7.34 (m, 1H), 7.22-7.26 (m, 2H), 6.93 (s, 2H), 6.80-6.87 (m, 1H), 6.41-6.44 (m, 1H), 6.07-6.11 (m, 1H), 5.64-5.68 (m, 1H), 4.35-4.39 (m, 1H), 4.25-4.29 (m, 1H), 4.00-4.01 (m, 1H), 3.14-3.19 (m, 1H), 2.80-2.99 (m, 4H), 2.44-2.46 (m, 1H), 1.97-1.98 (m, 1H), 1.85-1.87 (m, 1H), 1.79-1.80 (m, 1H), 1.23-1.26 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −174.36. (formic acid salt)
Example 255: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(5-methyl-1,3-oxazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 255 was prepared in a manner analogous to Example 159 (via Intermediate 159-1) using 5-methyl-2-(tributylstannyl)-1,3-oxazole in place of 2-(tributylstannyl)-1,3-thiazole, Intermediate 85-1 in place of Intermediate 1-2 and 4N HCl in dioxane at room temperature for 2 h for the deprotection. MS (ESI) calcd. For C32H32N8O2, 560.66 m/z, found 561.15[M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.00 (dd, J=4.8, 1.8 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.34 (s, 1H), 7.27 (dd, J=7.9, 2.0 Hz, 1H), 7.23 (dd, J=7.7, 1.9 Hz, 1H), 7.04 (d, J=1.3 Hz, 1H), 6.97 (s, 2H), 6.86-6.81 (m, 1H), 6.42-6.40 (m, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.5, 2.5 Hz, 1H), 4.39-4.33 (m, 1H), 4.28-4.22 (m, 1H), 4.00-3.96 (m, 1H), 3.21-3.15 (m, 1H), 2.98-2.90 (m, 3H), 2.82-2.75 (m, 1H), 2.41-2.36 (m, 3H), 2.14-2.09 (m, 1H), 2.01-1.94 (m, 1H), 1.91-1.86 (m, 1H), 1.85-1.74 (m, 1H), 1.24 (s, 3H).
Example 256: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 256 was prepared in a manner analogous to Example 109 (via Intermediate 109-2) using 2-bromo-5-methyl-1,3,4-oxadiazole instead of 2-bromo-1,3-oxazole, Pd(dppf)Cl2 and tribasic potassium phosphate instead of Pd(dtbpf)Cl2 and potassium carbonate and HCl in dioxane instead of TFA/DCM. MS (ESI) mass calcd. For C31H31N9O2, 561.00 m/z, found 562.20[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J=8.3 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 8.02 (d, J=4.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.27 (t, J=8.1 Hz, 2H), 6.98 (s, 2H), 6.84 (dd, J=16.7, 10.4 Hz, 1H), 6.46-6.39 (m, 1H), 6.14-6.04 (m, 1H), 5.70-5.62 (m, 1H), 4.36 (t, J=7.3 Hz, 1H), 4.27-4.23 (m, 1H), 4.02-3.98 (m, 1H), 3.20-3.16 (m, 2H), 2.95-2.90 (m, 3H), 2.89-2.72 (m, 2H), 2.58 (s, 3H), 1.99-1.95 (m, 1H), 1.90-1.86 (m, 1H), 1.81-1.77 (m, 1H), 1.27-1.23 (m, 2H).
Example 257: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(5-methyl-1,3,4-thiadiazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 257 was prepared in a manner analogous to Example 109 (via Intermediate 109-2) using 2-bromo-5-methyl-1,3,4-thiadiazole, Pd(dppf)Cl2 and tribasic potassium phosphate instead of 2-bromo-1,3-oxazole, Pd(dtbpf)Cl2 and potassium carbonate, HCl in dioxane instead of TFA/DCM. MS (ESI) mass calcd. For C31H31N9OS, 577.24 m/z, found 578.35[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J=8.3 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.03 (dd, J=4.8, 1.8 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.33 (s, 1H), 7.31-7.23 (m, 2H), 6.94 (s, 2H), 6.84 (dd, J=16.7, 10.4 Hz, 1H), 6.44 (dd, J=7.7, 4.8 Hz, 1H), 6.10 (dd, J=16.7, 2.5 Hz, 1H), 5.67 (dd, J=10.4, 2.5 Hz, 1H), 4.37 (t, J=7.2 Hz, 1H), 4.29-4.25 (m, 1H), 4.03-3.99 (m, 1H), 3.20-3.16 (m, 1H), 2.99-2.78 (m, 5H), 2.74 (s, 3H), 2.50-2.43 (m, 1H), 2.01-1.97 (m, 1H), 1.90-1.72 (m, 2H), 1.29-1.22 (m, 2H).
Example 258: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 258 was prepared in a manner analogous to Example 75 (via Intermediate 75-1) omitting steps 1-3 and the chiral separation (of Intermediate 75-1) and using tert-butyl (S)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate in place of (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide and Intermediate 258-1 in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine. MS (ESI) calcd. For C34H38N8O2: 590.31 m/z, found: 591.20 [M+H]+. 1H-NMR (400 MHz, DMSO) S (ppm): 7.98-8.10 (m, 2H), 7.65-7.75 (m, 1H), 7.43-7.60 (m, 2H), 7.35-7.42 (m, 1H), 6.78-6.90 (m, 2H), 6.69-6.76 (m, 1H), 6.11-6.20 (m, 1H), 5.70-5.80 (m, 1H), 4.95-5.05 (m, 1H), 4.50-4.61 (m, 1H), 4.40-4.49 (m, 2H), 4.15-4.25 (m, 1H), 3.75-3.85 (m, 2H), 3.51-3.65 (m, 1H), 3.10-3.25 (m, 2H), 2.85-3.05 (m, 3H), 2.65-2.80 (m, 1H), 2.55-2.64 (m, 1H), 2.08-2.30 (m, 3H), 1.80-1.90 (m, 2H), 1.63-1.75 (m, 2H), 1.45-1.62 (m, 2H). (TFA salt).
Intermediate 258-1: 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-nitropyridin-2-amine




Synthetic Route:





Step 1: Synthesis of 6-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-nitropyridin-2-amine
A mixture of 6-bromo-3-nitropyridin-2-amine (1.2 g, 5.504 mmol, 1 equiv), 8-oxa-3-azabicyclo[3.2.1]octane (0.62 g, 5.504 mmol, 1 equiv) and K2CO3 (2.28 g, 16.512 mmol, 3 equiv) in DMF (15 mL) was stirred for 1 h at room temperature. The product was precipitated by the addition of H2O (50 mL). The precipitated solids were collected by filtration and washed with H2O (3×10 mL) to afford tert-butyl N-[(1S)-5-[(3-nitro-6-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl}pyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]carbamate (1.35 g, crude) as a yellow solid. MS (ESI) calcd. For C11H14N4O3: 250.11 m/z, found: 251.05 [M+H]−.
Example 259: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(4-methylpiperazin-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 259 was prepared in a manner analogous to Example 170 (via Intermediate 170-1) using 1-methylpiperazine in place of pyrrolidine and TFA in DCM in place of HCl in dioxane. MS (ESI) calcd. For C33H39N9O, 577.33 m/z, found 578.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.81-8.08 (m, 2H), 7.32-7.61 (m, 1H), 6.98-7.29 (m, 3H), 6.65-6.98 (m, 2H), 6.28-6.52 (m, 1H), 5.95-6.25 (m, 1H), 5.56-5.82 (m, 1H), 4.18-4.48 (m, 2H), 3.92-4.18 (m, 1H), 3.79-3.92 (m, 5H), 3.02-3.28 (m, 1H), 2.62-3.02 (m, 4H), 2.32-2.47 (m, 4H), 2.08-2.29 (m, 3H), 1.92-2.08 (m, 1H), 1.84-1.92 (m, 1H), 1.61-1.92 (m, 1H), 1.04-1.42 (m, 2H).
Example 260: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(morpholin-4-ylmethyl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 260 was prepared in a manner analogous to Example 199 using Intermediate 85-1 in place of Intermediate 190-1, potassium trifluoro(morpholin-4-ylmethyl)borate in place of potassium cyclopropyltrifluoroborate and 4N HCl in dioxane at room temperature for 1 h for the deprotection. MS (ESI) calcd. For C33H38N8O2: 578.31. found 579.40 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.32-8.35 (m, 1H), 8.00-8.01 (m, 1H), 7.60-7.65 (m, 3H), 7.52-7.58 (m, 1H), 7.31-7.34 (m, 1H), 6.70-6.79 (m, 2H), 6.09-6.14 (m, 1H), 5.73-5.76 (m, 1H), 4.92 (m, 1H), 4.48-4.50 (m, 3H), 3.53-3.93 (m, 4H), 3.10-3.49 (m, 6H), 2.90-2.95 (m, 1H), 2.69-2.72 (m, 1H), 2.61-2.68 (m, 1H), 2.01-2.29 (m, 4H), 1.42-1.59 (m, 3H). (formic acid salt)
Example 261: 1-[(2R,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,2,3-triazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-methylpiperidin-1-yl]prop-2-en-1-one and
Example 262: 1-[(2R,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,2,3-triazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-2-methylpiperidin-1-yl]prop-2-en-1-one




Example 261 and 262 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl (2R)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and 4N HCl in dioxane in place of TFA in DCM. The diastereomers were separated by Prep HPLC on a Xselect CSH OBD Column using a gradient of acetonitrile in water (+0.05% formic acid). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 261: MS (ESI) calcd. For C31H32N10O: 560.27 m/z, found: 561.20[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.35-8.45 (m, 1H), 7.96-8.32 (m, 4H), 7.49-7.56 (m, 1H), 7.22-7.48 (m, 3H), 6.89-7.01 (m, 2H), 6.78-6.89 (m, 1H), 6.39-6.46 (m, 1H), 6.02-6.12 (m, 1H), 5.61-5.70 (m, 1H), 4.78-4.89 (m, 1H), 4.33-4.52 (m, 2H), 3.09-3.24 (m, 2H), 2.90-3.03 (m, 1H), 2.72-2.86 (m, 2H), 2.40-2.45 (m, 1H), 2.02-2.10 (m, 1H), 1.72-1.96 (m, 2H), 1.31-1.49 (m, 1H), 1.06-1.26 (m, 4H). (formic acid salt)
Example 262: MS (ESI) calcd. For C31H32N10O: 560.27 m/z, found: 561.20[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.38-8.45 (m, 1H), 8.10-8.17 (m, 2H), 7.97-8.05 (m, 2H), 7.45-7.52 (m, 1H), 7.23-7.39 (m, 3H), 6.90-6.99 (m, 2H), 6.72-6.82 (m, 1H), 6.39-6.43 (m, 1H), 6.04-6.11 (m, 1H), 5.60-5.66 (m, 1H), 4.30-4.40 (m, 2H), 3.90-4.02 (m, 1H), 3.09-3.15 (m, 1H), 2.90-2.98 (m, 1H), 2.72-2.81 (m, 1H), 2.45-2.50 (m, 1H), 2.00-2.10 (m, 1H), 1.60-1.90 (m, 5H), 1.38-1.45 (m, 3H), 1.02-1.19 (m, 1H). (formic acid salt)
Example 263: (S)-N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(1,2,3-triazol-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(prop-2-enamidomethyl)benzamide




Example 263 was prepared in a manner analogous to Example 2 (via Intermediate 2-1) using 2-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid, Intermediate 19-1 in place of Intermediate 1-1, 4N HCl in dioxane in place of TFA in DCM, sodium bicarbonate in place of triethylamine and THF/water (4:1) in place of DCM. In the final step, the reagents were added 0° C. MS (ESI) calcd. For C33H28N10O2, 596.24 m/z, found 597.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (d, J=8.3 Hz, 1H), 8.52 (t, J=6.0 Hz, 1H), 8.43 (d, J=8.6 Hz, 1H), 8.13 (s, 2H), 7.99-8.04 (m, 2H), 7.47-7.50 (m, 2H), 7.39-7.45 (m, 2H), 7.29-7.36 (m, 3H), 7.26-7.28 (m, 1H), 6.95 (s, 2H), 6.41-6.44 (m, 1H), 6.29-6.36 (m, 1H), 6.09-6.14 (m, 1H), 5.58-5.65 (m, 2H), 4.49-4.60 (m, 2H), 2.97-3.03 (m, 1H), 2.85-2.94 (m, 1H), 2.53-2.58 (m, 1H), 2.01-2.10 (m, 1H).
Example 264: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-[(2-fluoroprop-2-enamido)methyl]benzamide




Synthetic Route:





Step 1: tert-butyl N-[(2-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamoyl}phenyl)methyl]carbamate
A mixture of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (500 mg, 1.224 mmol, 1.00 equiv), 2-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid (301 mg, 1.198 mmol, 0.98 equiv) and PyBOP (640 mg, 1.230 mmol, 1.00 equiv) in DMF (10 mL) was added DIEA (0.64 mL, 3.674 mmol, 3.00 equiv) in portions at room temperature. The resulting mixture was stirred for 30 min at room temperature then quenched with water (50 mL) at 0° C. The precipitated solids were collected by filtration, washed with water (3×10 mL) and purified by silica gel column chromatography, eluting with 7% MeOH in DCM to afford tert-butyl N-[(2-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamoyl}phenyl)methyl]carbamate (490 mg, 59.26% yield) as a yellow solid. MS (ESI) calcd. For C36H35N9O3: 641.29 m/z, found: 642.35 [M+H]+.
Step 2: 2-(aminomethyl)-N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]benzamide (HCl salt
To a stirred solution of tert-butyl N-[(2-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamoyl}phenyl)methyl]carbamate (450 mg, 0.701 mmol, 1.00 equiv) in 1,4-dioxane (5 mL) was added HCl (2.5 mL, 4M in 1,4-dioxane) dropwise at 0° C. under nitrogen atmosphere. After stirring for 2 h at room temperature, the resulting mixture was concentrated under reduced pressure to afford 2-(aminomethyl)-N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]benzamide (400 mg, 74.78% yield) (HCl salt) as a light yellow solid. MS (ESI) calcd. For C31H27N9O: 541.23 m/z, found: 542.30 [M+H]+.
Step 3: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-[(2-fluoroprop-2-enamido)methyl]benzamide (Example 264)
To a mixture of 2-(aminomethyl)-N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]benzamide (150 mg, 0.277 mmol, 1.00 equiv, HCl salt) and 2-fluoroprop-2-enoic acid (25 mg, 0.278 mmol, 1.00 equiv) DMF (4 mL) was added EDCI (80 mg, 0.417 mmol, 1.51 equiv) in in portions at room temperature. After stirring for 30 min at room temperature, the resulting mixture was quenched with water (20 mL). The precipitated solids were collected by filtration, washed with water (3×10 mL) and purified by silica gel column chromatography, eluting with 5% MeOH in DCM. The material was further purified Prep-HPLC on a Xbridge Prep Shield RP18 OBD C18 Column using a gradient of acetonitrile in water (+0.1% formic acid) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-[(2-fluoroprop-2-enamido)methyl]benzamide (Example 264) (42.0 mg, 24.34% yield) as an off-white solid. MS (ESI) calcd. For C34H28FN9O2: 613.23 m/z, found: 614.40 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.81-9.07 (m, 2H), 8.28-8.41 (m, 2H), 7.99-8.05 (m, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.42-7.56 (m, 3H), 7.40 (s, 1H), 7.29-7.38 (m, 3H), 7.25 (d, J=7.6 Hz, 1H), 6.94 (s, 2H), 6.54-6.56 (m, 1H), 6.40-6.47 (m, 1H), 5.47-5.68 (m, 2H), 5.30 (dd, J=16.0, 4.0 Hz, 1H), 4.54-4.66 (m, 2H), 3.00-3.06 (m, 1H), 2.87-2.95 (m, 1H), 2.53-2.61 (m, 1H), 2.00-2.14 (m, 1H). 19F-NMR (376 MHz, DMSO-d6) δ (ppm): −117.97.
Example 265: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)-2-((N-methylacrylamido)methyl)benzamide




Example 265 was prepared in a manner analogous to Example 2 using Intermediate 265-1 in place of Intermediate 2-1, sodium bicarbonate in place of triethylamine and THF/water (4:1) in place of DCM. In the final step, the reagents were added at 0° C. MS (ESI) calcd. For C35H31N9O2, 609.26 m/z, found 610.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.95 (d, J=8.2 Hz, 1H), 8.35-8.39 (m, 2H), 8.00-8.03 (m, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.81 (s, 1H), 7.29-7.56 (m, 6H), 7.26 (d, J=7.7 Hz, 1H), 7.17 (dd, J=19.8, 7.8 Hz, 1H), 6.90-6.98 (m, 2H), 6.67-6.89 (m, 1H), 6.53-6.57 (m, 1H), 6.44 (dd, J=7.6, 4.8 Hz, 1H), 6.14-6.23 (m, 1H), 5.55-5.77 (m, 2H), 4.81-4.94 (m, 1H), 4.78 (s, 1H), 2.84-3.09 (m, 5H), 2.53-2.60 (m, 1H), 1.98-2.11 (m, 1H).
Intermediate 265-1: 2-(aminomethyl)-N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]benzamide




Intermediate 265-1 was prepared in a manner analogous to Intermediate 2-2 using 2-{[(tert-butoxycarbonyl)(methyl)amino]methyl}benzoic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid, 4N HCl in dioxane in place of TFA in DCM. MS (ESI) calcd. For C31H27N9O: 541.23 m/z, found: 542.30 [M+H]+.
Example 266: (S)-2-acryloyl-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)isoindoline-4-carboxamide




Example 266 was prepared in a manner analogous to Example 2 (via Intermediate 2-1) using 2-(tert-butoxycarbonyl)-1,3-dihydroisoindole-4-carboxylic acid in place of 3-((tert-butoxycarbonyl)amino)benzoic acid, 4N HCl in dioxane in place of TFA in DCM, sodium bicarbonate in place of triethylamine and THF/water (4:1) in place of DCM. In the final step, the reagents were added at 0° C. MS (ESI) calcd. For C35H29N9O2: 607.24 m/z, found: 608.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.94 (t, J=7.6 Hz, 1H), 8.33-8.38 (m, 2H), 8.00-8.03 (m, 1H), 7.95 (d, J=4.0 Hz, 1H), 7.77-7.82 (m, 2H), 7.48-7.57 (m, 1H), 7.38-7.46 (m, 3H), 7.25-7.34 (m, 2H), 6.91 (s, 2H), 6.66-6.76 (m, 1H), 6.53-6.56 (m, 1H), 6.42-6.47 (m, 1H), 6.18-6.28 (m, 1H), 5.72-5.79 (m, 1H), 5.65 (q, J=8.4 Hz, 1H), 5.24 (s, 1H), 5.00 (d, J=9.6 Hz, 2H), 4.75 (s, 1H), 2.99-3.09 (m, 1H), 2.85-2.99 (m, 1H), 2.51-2.58 (m, 1H), 2.05-2.18 (m, 1H).
Example 267: N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]-2-(but-2-ynamidomethyl)benzamide




Intermediate 267 was prepared in a manner analogous to Example 4 (last step only) using Intermediate 265-1 in place of Intermediate 1-1 and 2-butynoic acid in place of 2-(N-methylprop-2-enamido)benzoic acid. MS (ESI) calcd. For C35H29N9O2: 607.24 m/z, found: 608.45 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.84-8.95 (m, 2H), 8.34-8.40 (m, 2H), 7.99-8.06 (m, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.81 (s, 1H), 7.42-7.53 (m, 3H), 7.39 (s, 1H), 7.28-7.37 (m, 3H), 7.22-7.28 (m, 1H), 6.95 (s, 2H), 6.52-6.58 (m, 1H), 6.40-6.48 (m, 1H), 5.60 (q, J=8.2 Hz, 1H), 4.41-4.57 (m, 2H), 2.97-3.08 (m, 1H), 2.84-2.96 (m, 1H), 2.53-2.60 (m, 1H), 2.01-2.14 (m, 1H), 1.96 (s, 3H).
Example 268: (S)-2-(2-acrylamidoethyl)-N-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)benzamide




Example 268 was prepared in a manner analogous to Example 4 (omitting step 2) using 2-(2-aminoethyl)benzoic acid hydrochloride in place of methyl 2-(methylamino)benzoate and THF/water (4:1) in place of DCM. MS (ESI) calcd. For C35H31N9O2, 609.26 m/z, found 610.45 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.87 (d, J=8.0 Hz, 1H), 8.34-8.40 (m, 2H), 8.32 (t, J=13.2 Hz, 1H), 7.99-8.03 (m, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.81 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.36-7.45 (m, 3H), 7.9-7.34 (m, 3H), 7.23-7.27 (m, 1H), 6.93 (s, 2H), 6.52-6.56 (m, 1H), 6.40-6.46 (m, 1H), 6.13-6.23 (m, 1H), 6.01-6.08 (m, 1H), 5.61 (q, J=8.2 Hz, 1H), 5.50-5.56 (m, 1H), 3.41 (q, J=5.6 Hz, 2H), 2.98-3.08 (m, 1H), 2.83-2.97 (m, 3H), 2.52-2.60 (m, 1H), 1.99-2.11 (m, 1H).
Example 269: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-(pyridin-2-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 269 was prepared in a manner analogous to Example 159 (via Intermediate 159-1) using 2-(tributylstannyl)pyridine in place of 2-(tributylstannyl)-1,3-thiazole and Intermediate 190-1 in place of Intermediate 1-2. MS (ESI) calcd. For C33H32N8O: 556.27 m/z, found: 557.00 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.10-911 (m, 1H), 8.88-8.89 (m, 1H), 8.75-8.76 (m, 1H), 8.16-8.19 (m, 1H), 8.05-8.09 (m, 2H), 7.91-7.93 (m, 1H), 7.72-7.75 (m, 1H), 7.60-7.61 (m, 1H), 7.52-7.55 (m, 1H), 7.43-7.45 (m, 1H), 6.81-6.88 (m, 2H), 6.14-6.18 (m, 1H), 5.76-5.79 (m, 1H), 5.00-5.02 (m, 1H), 4.56-4.58 (m, 1H), 4.20-4.22 (m, 1H), 3.59-3.60 (m, 1H), 3.16-3.22 (m, 2H), 3.00-3.02 (m, 1H), 2.76-2.79 (m, 1H), 2.59-2.62 (m, 1H), 2.24-2.27 (m, 2H), 2.14-2.17 (m, 1H), 1.51-1.57 (m, 2H). (TFA salt)
Example 270: 1-((2S,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 271: 1-((2S,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 270 and 271 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using Intermediate 236-1 in place of Intermediate 1-1 and tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IK column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [IPA/DCM (1:1)]. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 270: MS (ESI) calcd. For C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30-8.32 (m, 1H), 8.23-8.25 (m, 1H), 7.96-7.98 (m, 1H), 7.72-7.74 (m, 1H), 7.47-7.49 (m, 1H), 7.22-7.33 (m, 3H), 6.73-6.77 (m, 1H), 6.41-6.45 (m, 1H), 6.27-6.30 (m, 1H), 6.04-6.09 (m, 1H), 5.66-5.69 (m, 1H), 5.36-5.51 (m, 1H), 4.33-4.47 (m, 2H), 3.06-3.28 (m, 3H), 2.77-2.83 (m, 1H), 1.91-2.07 (m, 2H), 1.13-1.41 (m, 6H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −126.98, −196.72.
Example 271: MS (ESI) calcd. For C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.31 (m, 1H), 8.21-8.22 (m, 1H), 7.96-7.97 (m, 1H), 7.70-7.72 (m, 1H), 7.46-7.48 (m, 1H), 7.21-7.30 (m, 3H), 6.72-6.76 (m, 1H), 6.40-6.44 (m, 1H), 6.26-6.28 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.36-5.51 (m, 1H), 4.31-4.46 (m, 2H), 3.32-3.47 (m, 1H), 3.06-3.28 (m, 3H), 1.56-1.90 (m, 5H), 1.24-1.35 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −127.01, −197.59.
Example 272: 1-((2S,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 273: 1-((2S,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 272 and 273 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using Intermediate 237-1 in place of Intermediate 1-1 and tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and MeOH. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 272: MS (ESI) calcd. For C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.31 (m, 1H), 8.24-8.25 (m, 1H), 7.96-7.98 (m, 1H), 7.71-7.74 (m, 1H), 7.46-7.48 (m, 1H), 7.25-7.26 (m, 1H), 7.20-7.23 (m, 2H), 6.68-6.74 (m, 1H), 6.40-6.44 (m, 1H), 6.26-6.28 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.23-5.36 (m, 1H), 4.28-4.37 (m, 2H), 3.40-3.50 (m, 1H), 3.24-3.35 (m, 1H), 3.14-3.20 (m, 1H), 2.94-3.05 (m, 1H), 1.53-1.90 (m, 5H), 1.24-1.35 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −126.98, −175.13.
Example 273: MS (ESI) calcd. For C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.33 (m, 1H), 8.26-8.28 (m, 1H), 7.96-7.98 (m, 1H), 7.73-7.76 (m, 1H), 7.51-7.53 (m, 1H), 7.37-7.39 (m, 1H), 7.22-7.27 (m, 2H), 6.68-6.74 (m, 1H), 6.41-6.44 (m, 1H), 6.28-6.30 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.23-5.36 (m, 1H), 4.31-4.47 (m, 2H), 3.40-3.50 (m, 1H), 3.13-3.25 (m, 1H), 2.80-3.08 (m, 2H), 1.90-1.99 (m, 2H), 1.16-1.38 (m, 6H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −126.96, −176.06.
Example 274: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 275: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 274 and 275 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using Intermediate 236-1 in place of Intermediate 1-1 and tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers separated during Prep HPLC on a Xselect CSH F-Phenyl OBD column using a gradient of acetonitrile in water (+0.1% formic acid). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 274: MS (ESI) calcd. for C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.32 (m, 1H), 8.22-8.24 (m, 1H), 7.96-7.98 (m, 1H), 7.73-7.76 (m, 1H), 7.47-7.49 (m, 1H), 7.21-7.38 (m, 3H), 6.72-6.79 (m, 1H), 6.41-6.44 (m, 1H), 6.27-6.30 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.41-5.55 (m, 1H), 4.31-4.47 (m, 2H), 3.12-3.20 (m, 2H), 3.05-3.07 (m, 1H), 2.79-2.80 (m, 1H), 2.11-2.13 (m, 1H), 1.77-1.79 (m, 1H), 1.12-1.51 (m, 6H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −127.01, −197.01. (formic acid salt)
Example 275: MS (ESI) calcd. for C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.32 (m, 1H), 8.22-8.24 (m, 1H), 7.96-7.98 (m, 1H), 7.73-7.76 (m, 1H), 7.47-7.49 (m, 1H), 7.24-7.33 (m, 3H), 6.70-6.77 (m, 1H), 6.41-6.44 (m, 1H), 6.27-6.30 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.40-5.55 (m, 1H), 4.31-4.47 (m, 2H), 3.31-3.50 (m, 1H), 3.03-3.27 (m, 3H), 1.59-1.92 (m, 5H), 1.44-1.51 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −127.02, −198.02. (formic acid salt)
Example 276: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 277: 1-((2R,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-fluoro-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 276 and 277 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using Intermediate 237-1 in place of Intermediate 1-1 and tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK-IK, column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [MeOH/DCM (1:1)]. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 276: MS (ESI) calcd. for C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.29-8.32 (m, 1H), 8.22-8.24 (m, 1H), 7.96-7.98 (m, 1H), 7.72-7.75 (m, 1H), 7.45-7.48 (m, 1H), 7.31-7.33 (m, 1H), 7.21-7.26 (m, 2H), 6.70-6.75 (m, 1H), 6.42-6.45 (m, 1H), 6.27-6.30 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.18-5.32 (m, 1H), 4.23-4.38 (m, 2H), 3.39-3.47 (m, 1H), 3.21-3.27 (m, 1H), 3.11-3.15 (m, 1H), 2.97-3.04 (m, 1H), 1.56-1.82 (m, 5H), 1.29-1.38 (m, 3H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −127.00, −175.17.
Example 277: MS (ESI) calcd. for C32H31F2N9O, 595.26 m/z, found 596.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.30-8.33 (m, 1H), 8.24-8.26 (m, 1H), 7.96-7.99 (m, 1H), 7.72-7.75 (m, 1H), 7.45-7.49 (m, 1H), 7.33-7.36 (m, 1H), 7.21-7.26 (m, 2H), 6.71-6.77 (m, 1H), 6.42-6.45 (m, 1H), 6.27-6.30 (m, 1H), 6.04-6.09 (m, 1H), 5.65-5.68 (m, 1H), 5.18-5.33 (m, 1H), 4.32-4.43 (m, 2H), 3.38-3.50 (m, 1H), 2.77-3.16 (m, 3H), 2.04-2.07 (m, 1H), 1.80-1.87 (m, 1H), 1.14-1.21 (m, 6H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −126.99, −175.64.
Example 278: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-{3-oxa-8-azabicyclo[3.2.1]octan-8-yl}imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 278 was prepared in a manner analogous to Example 75 (via Intermediate 75-1) omitting steps 1-3 and the chiral separation (of Intermediate 75-1) and using tert-butyl (S)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate in place of (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide and Intermediate 278-1 in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine. MS (ESI) calcd. for C34H38N8O2: 590.31 m/z, found: 591.40 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.02-8.06 (m, 2H), 7.68-7.70 (m, 1H), 7.57-7.59 (m, 1H), 7.47 (s, 1H), 7.36-7.39 (m, 1H), 6.93-6.96 (m, 1H), 6.82-6.85 (m, 1H), 6.72-6.75 (m, 1H), 6.12-6.17 (m, 1H), 5.72-5.76 (m, 1H), 4.97-5.00 (m, 1H), 4.54-4.56 (m, 1H), 4.41-4.42 (m, 2H), 4.20-4.22 (m, 1H), 3.60-3.68 (m, 2H), 3.51-3.58 (m, 3H), 3.10-3.16 (m, 2H), 2.93-2.95 (m, 1H), 2.73-2.74 (m, 1H), 2.52-2.58 (m, 1H), 2.21-2.25 (m, 2H), 2.08-2.14 (m, 1H), 1.94-2.04 (m, 4H), 1.50-1.55 (m, 2H). (TFA salt)
Example 279: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-bromoimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 85-1) (100 mg, 0.192 mmol, 1 equiv) in DMF (5 mL) was added 4,4,5,5-tetramethyl-2-(oxetan-3-yl)-1,3,2-dioxaborolane (70.59 mg, 0.384 mmol, 2 equiv), morpholine (25.06 mg, 0.288 mmol, 1.5 equiv), dtbbpy (2.57 mg, 0.010 mmol, 0.05 equiv), iridium(1+) bis(2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine) 4,4′-di-tert-butyl-2,2′-bipyridine hexafluoro-lambda5-phosphanuide (2.16 mg, 0.002 mmol, 0.01 equiv) and NiCl2 (glyme) (2.11 mg, 0.010 mmol, 0.05 equiv). The resulting mixture was stirred at rt overnight under N2 atmosphere and blue LED. After cooling to room temperature, the mixture was poured into water. The resulting precipitate was isolated by filtration to afford crude tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (70 mg, crude) MS (ESI) calcd. for C28H30N6O3: 498.24 m/z, found: 499.20 [M+H]+.
Step 2: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(oxetan-3-yl)imidazo[4,5-b]pyridine-2-yl}pyridin-2-amine
A solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (60 mg, 0.120 mmol, 1 equiv) in HCl (10 mL, 4 M in 1,4-dioxane) was stirred at room temperature for 1 h. The solvent was removed by distillation under vacuum to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (60 mg, crude) as a light yellow solid. MS (ESI) calcd. for C23H22N6O: 398.19 m/z, found: 399.15 [M+H]+.
Step 3: Synthesis of 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 279)
A solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (50 mg, 0.125 mmol, 1 equiv) and 1-(prop-2-enoyl)piperidin-4-one (76.88 mg, 0.500 mmol, 4 equiv) in MeOH (4 mL) was stirred at 40° C. for 1 h. NaBH3CN (31.54 mg, 0.500 mmol, 4 equiv) was added and the mixture was stirred at 40° C. for 1 h. The solvent was removed under vacuum and the crude material was purified by Prep-HPLC on a XBridge Prep Shield RP OBD C18 Column using a gradient of acetonitrile in water (+0.1% formic acid) to afford 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(oxetan-3-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one (Example 279) (8.5 mg, 12.14%) as light yellow solid. MS (ESI) calcd. for C31H33N7O2, 535.27 m/z, found 536.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.09-8.52 (m, 2H), 7.82-8.09 (m, 1H), 7.51-7.75 (m, 1H), 7.32-7.51 (m, 2H), 7.08-7.32 (m, 2H), 6.65-6.95 (m, 1H), 6.32-6.65 (m, 1H), 5.95-6.26 (m, 1H), 5.56-5.86 (m, 1H), 4.84-4.96 (m, 2H), 4.67-4.84 (m, 3H), 4.34-4.53 (m, 2H), 4.08-4.19 (m, 1H), 3.98-4.02 (m, 1H), 3.25-3.51 (m, 1H), 2.95-3.25 (m, 2H), 2.82-2.95 (m, 1H), 2.65-2.82 (m, 1H) 1.85-2.28 (m, 3H), 1.22-1.61 (m, 2H). (formic acid salt)
Example 280: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[3-(methoxymethyl)pyrazol-1-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 280 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 3-(methoxymethyl)-1H-pyrazole in place of pyrazole, Ephos/EPhos Pd G4/cesium carbonate in place of tBuBrettPhos/tBuBrettPhos Pd G3/tribasic potassium phosphate and 4N HCl in dioxane at room temperature for 2 h for the deprotection. MS (ESI) calcd. for C33H35N9O2: 589.29 m/z, found: 590.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.43-8.44 (m, 1H), 8.33-8.34 (m, 111), 8.08-8.10 (m, 1H), 7.98-7.99 (m, 1H), 7.73-7.77 (m, 2H), 7.58-7.59 (m, 1H), 7.45-7.47 (m, 1H), 6.80-6.86 (m, 1H), 6.76-6.78 (m, 1H), 6.57-6.58 (m, 1H), 6.13-6.18 (m, 1H), 5.74-5.77 (m, 1H), 5.00-5.03 (m, 1H), 4.55-4.57 (m, 1H), 4.48 (s, 2H), 4.20-4.21 (m, 1H), 3.60-3.74 (m, 1H), 3.16-3.23 (m, 3H), 2.97-2.99 (m, 2H), 2.75-2.76 (m, 1H), 2.58-2.61 (m, 1H), 2.52-2.53 (m, 1H), 2.24-2.27 (m, 2H), 2.12-2.15 (m, 1H), 1.51-1.57 (m, 2H). (TFA salt)
Example 281: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-isopropylpyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 281 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using 3-isopropyl-1H-pyrazole in place of pyrazole. MS (ESI) calcd for C34H37N9O: 587.31, found 588.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.20-7.25 (m, 2H), 6.87-6.90 (m, 1H), 6.81-6.86 (m, 1H), 6.40-6.45 (m, 2H), 6.07 (d, J=16.8 Hz, 1H), 6.66 (d, J=10.5 Hz, 1H), 4.31-4.33 (m, 1H), 4.20-4.25 (m, 1H), 3.99-4.02 (m, 1H), 3.42-3.46 (m, 1H), 3.15-3.20 (m, 1H), 2.80-3.02 (m, 5H), 2.42-2.45 (m, 1H), 1.70-2.00 (m, 3H), 1.26 (d, J=6.9 Hz, 6H), 1.21-1.23 (m, 1H).
Example 282: 1-(4-{[(1S)-5-[5-(3-fluoropyrazol-1-yl)-2-phenylimidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 282 was prepared in a manner analogous to Example 13 using Intermediate 282-1 in place of Intermediate 1-1 and using 5 eq of TEA. MS (ESI) calcd. for C32H30FN7O: 547.25. found: 548.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.34 (d, J=8.7 Hz, 1H), 8.29 (s, 1H), 7.77 (m, 1H), 7.53-7.58 (m, 2H), 7.39-7.45 (m, 4H), 7.32 (s, 1H), 7.19-7.25 (m, 1H), 6.75-6.84 (m, 1H), 6.31-6.34 (m, 1H), 6.06 (d, J=2.4 Hz, 1H), 6.06 (d, J=3.0 Hz, 1H), 4.21-4.38 (m, 2H), 3.95-4.05 (m, 1H), 3.11-3.20 (m, 1H), 2.71-2.92 (m, 4H), 2.31-2.49 (m, 1H), 1.69-1.82 (m, 3H), 1.23 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −127.31.
Intermediate 282-1: (S)-5-(5-(3-fluoro-1H-pyrazol-1-yl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediate 282-1 was prepared in a manner analogous to Intermediate 50-1 using Intermediate 236-3 in place of 6-methyl-3-nitropyridin-2-amine, tert-butyl N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate in place of Intermediate 218-4, benzaldehyde in place of 2-aminopyridine-3-carbaldehyde and 4N HCl in dioxane/DCM (1:1) at room temperature for 2 h for the deprotection. MS (ESI) calcd. for C24H19FN6: 410.17. found: 411.20 [M+H]+.
Example 283: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-cyclobutylpyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 283 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using 3-cyclobutyl-1H-pyrazole in place of pyrazole and DCE/MeOH/AcOH (100:10:1) as the solvent. MS (ESI) calcd. for C35H37N9O: 599.31. found: 600.23[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.31 (d, J=8.4 Hz, 1H), 8.24 (s, 1H), 8.01 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.48 (d, J=7.84 Hz, 1H), 7.31 (s, 1H), 7.22-7.25 (m, 2H), 6.81-6.91 (m, 1H), 6.47 (s, 1H), 6.40-6.45 (m, 1H), 6.08 (d, J=16.5 Hz, 1H), 5.67 (d, J=10.5 Hz, 1H), 4.22-4.33 (m, 2H), 3.95-4.02 (m, 1H), 3.56-3.60 (m, 1H), 3.12-3.18 (m, 1H), 2.65-2.90 (m, 4H), 2.40-2.42 (m, 1H), 2.25-2.30 (m, 2H), 2.15-2.22 (m, 2H), 1.75-2.08 (m, 5H), 1.20-1.30 (m, 2H).
Example 284: 2-{3-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4-yl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}benzonitrile




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-cyanophenyl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a stirred solution of tert-butyl N-[(1S)-5-{[3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 239-0) (500 mg, 1.146 mmol, 1 equiv) and 2-formylbenzonitrile (180.26 mg, 1.375 mmol, 1.2 equiv) in DMSO (24 mL) and MeOH (4 mL) was added Na2S2O4 (498.60 mg, 2.865 mmol, 2.5 equiv) in portions at 25° C. The resulting mixture was stirred at 100° C. for 16 h. The mixture was allowed to cool to room temperature. The reaction was quenched with water at 0° C. The precipitated solids were collected by filtration and washed with water (3 mL×5). The residue was dissolved in MeOH (4 mL) and purified by silica gel column chromatography, eluting with 0-50%, ethyl acetate in petroleum ether to afford tert-butyl N-[(1S)-5-[2-(2-cyanophenyl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (170 mg, 25.80%) as a yellow oil. MS (ESI) calcd. for C30H27N7O2: 517.22 m/z, found: 518.20 [M+H]+.
Step 2: Synthesis of 2-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}benzonitrile
To a stirred solution of tert-butyl N-[(1S)-5-[2-(2-cyanophenyl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (170 mg, 0.328 mmol, 1 equiv) in DCM (3 mL) was added 4N HCl in 1,4-dioxane (10 mL) dropwise at 25° C. The resulting mixture was stirred at 25° C. for 2 h. The resulting mixture was concentrated under reduced pressure to afford 2-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}benzonitrile (80 mg, 58.34%) as a yellow oil. MS (ESI) calcd. for C25H19N7: 417.17 m/z, found: 418.10 [M+H]+.
Step 3: Synthesis of 2-{3-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4-yl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}benzonitrile (Example 284)
To a stirred solution of 2-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}benzonitrile (80 mg, 0.192 mmol, 1 equiv) in MeOH (2 mL) and DCE (20 mL) were added TEA (96.96 mg, 0.960 mmol, 5 equiv) dropwise at 25° C. The resulting mixture was stirred at 25° C. for 0.5 h. To the above mixture was added 1-(prop-2-enoyl)piperidin-4-one (58.71 mg, 0.384 mmol, 2 equiv) and AcOH (0.1 mL, 1.745 mmol, 9.11 equiv) in portions at 25° C. The resulting mixture was stirred at 50° C. for 1 h. To the above mixture was added NaBH3CN (36.13 mg, 0.576 mmol, 3 equiv) in portions at 0° C. The resulting mixture was stirred at 50° C. for 0.5 h. The residue was purified by silica gel column chromatography, eluting with 0-10% MeOH in DCM. The product was further purified by Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.05% TFA) to afford 2-{3-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4-yl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}benzonitrile (Example 284, TFA salt) (14.2 mg, 10.66%) as a white solid. MS (ESI) calcd. for C33H30N8O: 554.25 m/z, found: 555.25 [M+H]+. H NMR (400 MHz, DMSO-d6) δ ppm: 8.52-8.54 (m, 1H), 8.42 (s, 1H), 8.01-8.06 (m, 2H), 7.86 (s, 1H), 7.74-7.77 (m, 2H), 7.67-7.72 (m, 2H), 7.54 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.82-6.91 (m, 1H), 6.60-6.62 (m, 1H), 6.12-6.17 (m, 1H), 5.72-5.76 (m, 1H), 4.99-5.02 (m, 1H), 4.52-4.56 (m, 1H), 4.14-4.22 (m, 1H), 3.53-3.55 (m, 1H), 3.13-3.18 (m, 2H), 2.91-2.98 (m, 1H), 2.72-2.77 (m, 1H), 2.56-2.58 (m, 1H), 2.14-2.21 (m, 2H), 2.06-2.12 (m, 1H), 1.43-1.52 (m, 2H).
Example 285: (S)-1-(4-((5-(2-(2-(difluoromethyl)phenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 285 was prepared in a manner analogous to Example 284 using 2-(difluoromethyl)benzaldehyde in place of 2-formylbenzonitrile. MS (ESI) calcd. for C33H31F2N7O: 579.26. found: 580.20 [M+H]+, 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.38-8.42 (m, 2H), 8.00 (d, J=8.4 Hz, 1H), 7.80-7.83 (m, 2H), 6.65 (t, J=7.5 Hz, 1H), 7.50-7.53 (m, 1H), 7.13-7.48 (m, 5H), 6.75-6.85 (m, 1H), 6.57 (s, 1H), 6.09 (d, J=16.8 Hz, 1H), 5.69 (d, J=10.5 Hz, 1H), 4.26-4.31 (m, 2H), 3.98-4.02 (m, 1H), 3.11-3.20 (m, 1H), 2.70-3.00 (m, 4H), 2.41-2.45 (m, 1H), 1.85-2.00 (m, 2H), 1.70-1.75 (m, 1H), 1.12-1.30 (m, 2H).
Example 286: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 287: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 286 and 287 were prepared in a manner analogous to Example 13 using Intermediate 286-1 in place of Intermediate 1-1. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IK3 column using a mixture of [MtBE (+0.1% DEA)] and [EtOH/DCM (1:1)]. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 286: MS (ESI) calcd. for C32H32FN9O2, 593.26 m/z, found 594.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.6 Hz, 1H), 8.19 (d, J=2.7 Hz, 1H), 8.00 (dd, J=4.9, 1.8 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.21 (dd, J=7.6, 1.9 Hz, 1H), 6.91 (s, 2H), 6.86-6.72 (m, 1H), 6.42 (dd, J=7.6, 4.8 Hz, 1H), 6.12-6.04 (m, 2H), 5.66 (dd, J=10.4, 2.5 Hz, 1H), 5.34-5.08 (m, 1H), 4.48-4.12 (m, 1H), 4.24 (s, 1H), 4.00 (s, 1H), 3.92 (s, 3H), 3.57-3.39 (m, 1H), 3.17-3.02 (m, 1H), 3.08-2.99 (m, 2H), 2.87 (s, 1H), 2.32 (s, 2H), 2.00 (s, 1H), 1.89 (s, 1H). 19F NMR (377 MHz, DMSO-d6) δ −176.017.
Example 287: MS (ESI) calcd. for C32H32FN9O2, 593.26 m/z, found 594.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=8.6 Hz, 1H), 8.17 (d, J=2.7 Hz, 1H), 8.00 (dd, J=4.9, 1.9 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.38-7.29 (m, 2H), 7.22 (dd, J=7.7, 1.9 Hz, 1H), 6.92 (s, 2H), 6.90-6.78 (m, 1H), 6.41 (dd, J=7.7, 4.8 Hz, 1H), 6.15-6.01 (m, 2H), 5.66 (m, 1H), 5.60-5.35 (m, 1H), 4.54-4.44 (m, 1H), 4.23 (s, 1H), 4.01 (s, 1H), 3.91 (s, 3H), 2.5 (s, 1H), 3.27-2.88 (m, 5H), 2.23 (s, 1H), 2.00 (s, 1H), 1.88 (s, 1H). 19F NMR (377 MHz, DMSO-d6) δ −196.70.
Intermediate 286-1: 3-(3-((1R)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:





Step 1: Synthesis of tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate
A solution of tert-butyl ((1R)-5-((6-bromo-3-nitropyridin-2-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 286-2) (1 g, 2.140 mmol, 1 equiv) in DMSO (10 mL) and MeOH (1.5 mL) was treated with 2-aminonicotinaldehyde (287.48 mg, 2.354 mmol, 1.1 equiv) and Na2S2O4 (819.65 mg, 4.708 mmol, 2.2 equiv) for 24 h at 100° C. under nitrogen atmosphere. The reaction was quenched with H2O at r.t. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60˜80%) to afford tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (380 mg, 28%) as a yellow solid. MS (ESI) calcd. for C25H24BrFN6O2, 538.11 m/z, found 539.20 [M+H]+.
Step 2: Synthesis of tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate
A solution of tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (150 mg, 0.278 mmol, 1 equiv) in dioxane (5 mL) was treated with 3-methoxy-1H-pyrazole (54.56 mg, 0.556 mmol, 2 equiv), Cs2CO3 (181.21 mg, 0.556 mmol, 2 equiv), Ephos (29.74 mg, 0.056 mmol, 0.2 equiv) and EPhos Pd G4 (25.54 mg, 0.028 mmol, 0.1 equiv) at 100° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to r.t and was quenched with H2O. The resulting mixture was extracted with ethyl acetate (100 mL). The combined organic layers were washed with brine (30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60˜70%) to afford tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (120 mg, 62.02%) as a yellow oil. MS (ESI) calcd. for C29H29FN8O3, 556.23 m/z, found 557.30 [M+H]+.
Step 3: Synthesis of 3-(3-((1R)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 286-1
A solution of tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (110 mg, 0.198 mmol, 1 equiv) in DCM (5 mL) was treated with TFA (1 mL) at r.t for 1 h. The resulting mixture was concentrated under reduced pressure to afford 3-(3-((1R)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(3-methoxy-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 286-1) (90 mg, 99.76%) as a crude yellow solid which was used in subsequent transformations directly. MS (ESI) calcd. for C24H21FN8O, 456.18 m/z, found 457.20 [M+H]+.
Intermediate 286-2: tert-butyl ((1R)-5-((6-bromo-3-nitropyridin-2-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate




Intermediate 286-2 was prepared using procedure analogous to the first 3 steps in the route for Intermediate 85-1 using Intermediate 286-3 in place of tert-butyl N-[(1S)-5-bromo-2,3-dihydro-1H-inden-1-yl]carbamate. MS (ESI) calcd. for C19H20BrFN4O4, 466.07 m/z, found 467.10 [M+H]+.
Intermediate 286-3: tert-butyl ((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of 5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-one
To a solution of 5-bromo-1-indanone (5.00 g, 23.8 mmol) in methanol (50 mL) was added SelectFluor (10.0 g, 28.2 mmol) and the resulting mixture was stirred under reflux for 2 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (50 mL), and 1 N hydrochloric acid (50 mL) was added followed by stirring at room temperature for 3 hours. To the reaction mixture, a 2 N aqueous sodium hydroxide solution (50 mL) was added, and the mixture was diluted with a saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to afford 5-bromo-2-fluoro-2,3-dihydroinden-1-one (4.0 g, 74% yield) as a white solid. MS (ESI) calcd. for C9H6BrFO, 227.96 m/z, found: 229.00 [M+H]+.
Step 2: Synthesis of (S)-N-((Z)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide
To a solution of 5-bromo-2-fluoro-2,3-dihydroinden-1-one (3.0 g, 13 mmol) in toluene (5 mL) was added (S)-2-methylpropane-2-sulfinamide (1.90 g, 15.7 mmol) and Ti(OEt)4 (5.08 g, 22.2 mmol). The mixture was stirred at 90° C. for 2 h. After cooling to room temperature, the reaction was quenched by the addition of 2M Rochelle's salt (30 mL). The resulting mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford (S)-N-(5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (3.0 g, 69% yield) as a yellow solid. MS (ESI) calcd. for C13H15BrFNOS: 331.00 m/z, found: 332.10 [M+H]+. Note that the (S)- applies to the sulfur stereocenter and not the C—F bond for this and all instances vide infra.
Step 3: Synthesis of (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide
To a cooled (−50° C.) solution of (S)-N-((Z)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (3.0 g, 9.0 mmol) was added LTBA (3.90 g, 15.4 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of 2M Rochelle's salt (30 mL). The mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a gradient of ethyl acetate in petroleum ether to afford (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide (2.0 g, 66% yield) as a yellow solid. MS (ESI) calcd. for C13H17BrFNOS: 333.02 m/z, found: 334.10 [M+H]+.
Step 4: (S)-N-((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide
To a solution of N-[(1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl]-2-methylpropane-2-sulfinamide (20 g, 59.835 mmol, 1 equiv) in DCM (200 mL) was added 4N HCl in 1,4-dioxane (40 mL). The resulting mixture was maintained under nitrogen and stirred at 30° C. for 3 h. After cooling to rt, the mixture was concentrated under vacuum and purified by recrystallization with DCM (100 mL). The material was diluted with water, then adjusted to pH 9-10 with sodium bicarbonate. The resulting solution was extracted with DCM (3×500 mL). The organic layers were combined, washed with brine (500 mL), dried and concentrated under vacuum to afford (1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-amine (12 g, 81.06% yield) as a yellow solid. MS (ESI) calcd. for C9H9BrFN: 228.99 m/z, found: 230.00 [M+H]+.
Step 5: tert-butyl ((1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 286-3
To a solution of (1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-amine (12 g, 52.156 mmol, 1 equiv) in DCM (200 mL) was added DIEA (20.22 g, 156.468 mmol, 3.0 equiv) and Boc2O (12.52 g, 57.372 mmol, 1.1 equiv). The resulting mixture was maintained under nitrogen and stirred at 30° C. for 3 h. After cooling to rt, the reaction was quenched with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue obtained was purified by silica gel chromatography (0-20% ethyl acetate/petroleum ether) to afford tert-butyl N-[(1R)-5-bromo-2-fluoro-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 286-3) (14 g, 75.60% yield) as a yellow solid. MS (ESI) calcd. for C14H17BrFNO2: 329.04 m/z, found: 273.95 [M−56]+.
Example 288: 1-[(3*,4*)-4-{[(1R,2*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-3-methylpiperidin-1-yl]prop-2-en-1-one
Example 289: 1-[(3*,4*)-4-{[(1R,2*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-3-methylpiperidin-1-yl]prop-2-en-1-one
Example 290: 1-[(3*,4*)-4-{[(1R,2*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-3-methylpiperidin-1-yl]prop-2-en-1-one and
Example 291: 1-[(3*,4*)-4-{[(1R,2*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2-fluoro-2,3-dihydro-1H-inden-1-yl]amino}-3-methylpiperidin-1-yl]prop-2-en-1-one




Examples 288, 289, 290 and 291 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl (S)-3-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, MeOH in place of DCE for the final step, room temperature as the reaction temp for the final step and Intermediate 76-1 in place of Intermediate 1-1. Example 288 was separated from the other 3 isomers by chiral Prep HPLC on a CHIRALPAK Ik column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [EtOH/DCM (1:1)]. Example 289 was separated from Examples 290 and 291 by chiral Prep-HPLC on a CHIRALPAK IG column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and isopropanol. Examples 290 and 291 were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [EtOH/DCM (1:1)]. Note that the methyl group epimerized during the synthesis. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 288: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.39 (m, 2H), 7.98-8.02 (m, 1H), 7.92-7.97 (m, 1H), 7.78-7.82 (m, 1H), 7.48-7.53 (m, 1H), 7.39-7.42 (m, 1H), 7.30-7.35 (m, 1H), 7.21-7.28 (m, 1H), 6.78-6.85 (m, 1H), 6.54-6.56 (m, 1H), 6.42-6.46 (m, 1H), 6.05-6.13 (m, 1H), 5.63-5.69 (m, 1H), 5.12-5.25 (m, 1H), 4.35-4.43 (m, 1H), 4.21-4.31 (m, 1H), 3.91-4.17 (m, 1H), 2.81-3.22 (m, 2H), 2.81-2.89 (m, 1H), 2.12-2.24 (m, 1H), 1.22-1.42 (m, 3H), 0.92-0.99 (m, 3H). 19F-NMR (300 MHz, DMSO-d6) δ (ppm): −176.03.
Example 289: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.35 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.39 (m, 2H), 7.92-8.03 (m, 2H), 7.78-7.83 (m, 1H), 7.51-7.56 (m, 1H), 7.38-7.42 (m, 1H), 7.21-7.32 (m, 2H), 6.76-6.84 (m, 1H), 6.55-6.56 (m, 1H), 6.39-6.43 (m, 1H), 6.05-6.12 (m, 1H), 5.64-5.69 (m, 1H), 5.12-5.35 (m, 1H), 4.30-4.41 (m, 1H), 4.11-4.22 (m, 1H), 3.78-3.88 (m, 1H), 3.40-3.52 (m, 1H), 3.22-3.32 (m, 1H), 2.94-3.08 (m, 2H), 1.94-2.05 (m, 1H), 1.18-1.25 (m, 3H), 0.80-0.91 (m, 3H). 19F-NMR (300 MHz, DMSO-d6) δ (ppm): −176.0.
Example 290: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.40 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.33-8.38 (m, 2H), 8.01-8.04 (m, 1H), 7.96-7.99 (m, 1H), 7.81-7.82 (m, 1H), 7.51-7.53 (m, 1H), 7.41-7.43 (m, 1H), 7.32-7.37 (m, 1H), 7.21-7.27 (m, 1H), 6.78-6.84 (m, 1H), 6.57-6.58 (m, 1H), 6.41-6.45 (m, 1H), 6.04-6.15 (m, 1H), 5.64-5.69 (m, 1H), 5.22-5.45 (m, 1H), 4.30-4.38 (m, 1H), 4.20-4.29 (m, 1H), 3.81-3.95 (m, 1H), 3.41-3.46 (m, 1H), 3.21-3.28 (m, 1H), 3.01-3.13 (m, 2H), 2.06-2.14 (m, 1H), 1.20-1.62 (m, 3H), 0.82-0.88 (m, 3H). 19F-NMR (300 MHz, DMSO-d6) δ (ppm): −175.601.
Example 291: MS (ESI) calcd. for C32H32FN9O: 577.27 m/z, found: 578.40 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.32-8.38 (m, 2H), 7.98-8.02 (m, 1H), 7.92-7.98 (m, 1H), 7.79-7.81 (m, 1H), 7.52-7.57 (m, 1H), 7.39-7.42 (m, 1H), 7.31-7.35 (m, 1H), 7.22-7.25 (m, 1H), 6.76-6.84 (m, 1H), 6.55-6.56 (m, 1H), 6.38-6.43 (m, 1H), 6.06-6.11 (m, 1H), 5.65-5.69 (m, 1H), 5.13-5.27 (m, 1H), 4.31-4.39 (m, 1H), 4.18-4.26 (m, 1H), 3.82-4.15 (m, 1H), 3.39-3.48 (m, 1H), 2.85-3.21 (m, 3H), 2.02-2.15 (m, 1H), 1.20-1.42 (m, 3H), 0.89-0.93 (m, 3H). 19F-NMR (300 MHz, DMSO-d6) δ (ppm): −176.832.
Example 292: 1-((R)-4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-methylpiperazin-1-yl)prop-2-en-1-one and
Example 293: 1-((R)-4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)-2-methylpiperazin-1-yl)prop-2-en-1-one




Examples 292 and 293 were prepared in a manner analogous to Example 174 using tert-butyl (2R)-2-methylpiperazine-1-carboxylate in place of tert-butyl piperazine-1-carboxylate. The diastereomers were separated by chiral Prep-HPLC on a CHIRALPAK IG column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and EtOH. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 292: MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.40. [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.42-8.30 (m, 2H), 8.06-7.98 (m, 1H), 7.98-7.90 (m, 1H), 7.86-7.78 (m, 1H), 7.55-7.44 (m, 1H), 7.34 (s, 1H), 7.28-7.15 (m, 2H), 6.95 (s, 2H), 6.87-6.72 (m, 1H), 6.58-6.51 (m, 1H), 6.47-6.37 (m, 1H), 6.17-6.05 (m, 1H), 5.74-5.61 (m, 1H), 4.73-3.77 (m, 2H), 3.53-3.40 (m, 1H), 3.05-2.89 (m, 2H), 2.89-2.76 (m, 2H), 2.64-2.54 (m, 1H), 2.46-2.35 (m, 1H), 2.35-2.19 (m, 1H), 2.11 (s, 1H), 2.04-1.74 (m, 2H), 1.25 (s, 4H).
Example 293: MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.40-8.28 (m, 2H), 8.05-7.98 (m, 1H), 7.98-7.91 (m, 1H), 7.84-7.75 (m, 1H), 7.58-7.47 (m, 1H), 7.34 (s, 1H), 7.27-7.16 (m, 2H), 6.94 (s, 2H), 6.86-6.67 (m, 1H), 6.58-6.49 (m, 1H), 6.46-6.36 (m, 1H), 6.17-6.03 (m, 1H), 5.73-5.61 (m, 1H), 4.74-3.77 (m, 2H), 3.56-3.38 (m, 1H), 3.03-2.89 (m, 2H), 2.89-2.78 (m, 2H), 2.73-2.57 (m, 1H), 2.44-2.18 (m, 2H), 2.12 (s, 1H), 2.04-1.72 (m, 2H), 1.38-1.12 (m, 4H).
Example 294: 1-(2-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-6-azabicyclo[3.2.1]octan-6-yl)prop-2-en-1-one




Example 294 was prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 2-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, sodium bicarbonate in place of triethylamine, THF/water (4:1) in place of DCM (for step 2) and DCE/MeOH (10:1) for the final step. MS (ESI) calcd. for C33H33N9O, 571.28 m/z, found 572.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.38 (m, 2H), 7.99-8.03 (m, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.80-7.82 (m, 1H), 7.49-7.56 (m, 1H), 7.33-7.37 (m, 1H), 7.22-7.31 (m, 2H), 6.95 (s, 2H), 6.53-6.70 (m, 2H), 6.40-6.45 (m, 1H), 6.12-6.20 (m, 1H), 5.61-5.71 (m, 1H), 4.23-4.41 (m, 2H), 3.61-3.85 (m, 1H), 3.20-3.49 (m, 2H), 2.92-3.05 (m, 2H), 2.72-2.84 (m, 1H), 2.52-2.58 (m, 0.5H), 2.25-2.48 (m, 1.5H), 1.72-1.99 (m, 3H), 1.36-1.70 (m, 3H), 1.04-1.17 (m, 1H). (formic acid salt)
Example 295: 1-(4-{[(2R)-6-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-1,2,3,4-tetrahydronaphthalen-2-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 295 was prepared in a manner analogous to Example 13 using Intermediate 295-1 in place of Intermediate 1-1 and DCE/MeOH (10:1) as the solvent. MS (ESI) calcd. for C32H33N9O: 559.68. found: 560.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.28-8.32 (m, 2H), 7.95-7.97 (m, 1H), 7.84-7.90 (m, 1H), 7.76 (s, 1H), 7.30-7.35 (m, 1H), 7.23-7.25 (m, 2H), 7.12-7.19 (m, 1H), 6.68-6.75 (m, 1H), 6.48-6.53 (m, 2H), 6.05-6.09 (m, 1H), 5.70-5.72 (m, 1H), 4.40-4.43 (m, 1H), 4.05-4.08 (m, 1H), 3.21-3.34 (m, 2H), 3.10-3.19 (m, 2H), 2.83-2.94 (m, 1H), 2.65-2.70 (m, 2H), 2.11-2.13 (m, 1H), 2.00-2.03 (m, 2H), 1.59-1.62 (m, 1H), 1.33 (m, 2H).
Intermediate 295-1: (R)-3-(3-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 295-1 was prepared in a manner analogous to Intermediate 75-1 (starting from Step 2) using 6-bromo-3,4-dihydro-1H-naphthalen-2-one in place of 5-bromo-2-fluoro-2,3-dihydroinden-1-one and omitting the chiral separation. MS (ESI) calcd. for C24H22N8: 422.20. found: 423.25 [M+H]+.
Example 296: 1-(4-{[(2S)-6-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-1,2,3,4-tetrahydronaphthalen-2-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 296 was prepared in a manner analogous to Example 13 using Intermediate 296-1 in place of Intermediate 1-1 and DCE/MeOH (10:1) as the solvent. MS (ESI) calcd. for C32H33N9O: 559.28 m/z, found: 560.40[M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.35-8.39 (m, 2H), 7.93-8.05 (m, 2H), 7.79-7.82 (m, 1H), 7.18-7.28 (m, 4H), 6.90-6.98 (m, 2H), 6.79-6.88 (m, 1H), 6.42-6.56 (m, 2H), 6.07-6.13 (m, 1H), 5.65-5.71 (m, 1H), 4.33-4.42 (m, 1H), 4.02-4.12 (m, 1H), 3.30-3.35 (m, 1H), 3.08-3.21 (m, 2H), 2.65-2.96 (m, 4H), 1.56-2.21 (m, 5H), 1.20-1.39 (m, 3H).
Intermediate 296-1: (S)-3-(3-(6-amino-5,6,7,8-tetrahydronaphthalen-2-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 296-1 was prepared in a manner analogous to Intermediate 75-1 (starting from Step 2) using 6-bromo-3,4-dihydro-1H-naphthalen-2-one in place of 5-bromo-2-fluoro-2,3-dihydroinden-1-one, (R)-2-methylpropane-2-sulfinamide in place of (S)-2-methylpropane-2-sulfinamide and omitting the chiral separation. MS (ESI) calcd. for C24H22N8: 422.20. found: 423.10 [M+H]+.
Example 297: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 298: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 297 and 298 were prepared in a manner analogous to Examples 286 and 287 (via Intermediate 286-1) using 3-cyclopropyl-1H-pyrazole in place of 3-methoxy-1H-pyrazole. The diastereomers separated after the final step by Prep-HPlC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.1% FA). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 297: MS (ESI) calcd. for C34H34FN9O, 603.29 m/z, found 604.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 2H), 8.36 (d, J=8.6 Hz, 1H), 8.19 (d, J=2.5 Hz, 1H), 8.05 (dd, J=5.1, 1.7 Hz, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.59 (s, 1H), 7.54-7.38 (m, 2H), 7.16 (s, 1H), 6.88 (s, 1H), 6.54 (t, J=6.4 Hz, 1H), 6.29 (d, J=2.6 Hz, 1H), 6.19-6.09 (m, 1H), 5.96 (s, 1H), 5.78-5.68 (m, 1H), 5.33 (s, 1H), 4.65-4.46 (m, 1H), 4.24 (s, 1H), 3.41 (s, 1H), 3.30 (s, 1H), 3.28-3.12 (m, 1H), 2.78-2.69 (m, 1H), 2.41-2.29 (m, 1H), 2.16 (s, 1H), 2.02 (d, J=4.9 Hz, 1H), 1.71-1.45 (m, 2H), 1.56 (s, 1H), 0.98 (dq, J=8.5, 4.5, 2.5 Hz, 2H), 0.88-0.72 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ −195.54.
Example 298: MS (ESI) calcd. for C34H34FN9O, 603.29 m/z, found 604.25 [M+H]+. 1H HMR (300 MHz, DMSO-d6) δ 8.33 (d, J=8.6 Hz, 1H), 8.21 (d, J=2.5 Hz, 1H), 8.02 (dd, J=4.8, 1.8 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.50 (s, 2H), 7.38 (s, 1H), 6.98-6.75 (m, 2H), 6.44 (dd, J=7.6, 4.8 Hz, 1H), 6.27 (d, J=2.6 Hz, 1H), 6.18-6.03 (m, 1H), 5.76-5.67 (m, 1H), 4.11 (s, 2H), 3.79-3.47 (m, 2H), 3.15 (s, 3H), 2.82 (s, 1H), 2.12 (s, 1H), 2.05-1.96 (m, 2H), 1.76-1.23 (m, 4H), 1.24 (s, 1H), 1.02-0.90 (m, 3H), 0.89-0.71 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ −176.10.
Example 299: 1-(4-(((1R,2*)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 300: 1-(4-(((1R,2*)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 299 and 300 were prepared in a manner analogous to Example 13 using Intermediate 299-1 in place of Intermediate 1-1, and DCE/MeOH (1:1) instead of DCE. The diastereomers were separated by silica gel column chromatography using 0-30% MeOH in DCM. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 299: MS (ESI) calcd for C32H29F2N7O 565.24 m/z, found 566.15 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.45-8.39 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.75-7.72 (m, 1H), 7.60-7.56 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.30-7.22 (m, 2H), 6.87-6.81 (m, 1H), 6.57 (t, J=2.1 Hz, 1H), 6.10 (dd, J=16.7, 2.5 Hz, 1H), 5.67 (dd, J=10.2, 2.5 Hz, 1H), 5.44 (d, J=54.5 Hz, 1H), 4.42 (d, J=26.1 Hz, 1H), 4.24-4.20 (m, 1H), 4.04-3.97 (m, 1H), 3.27-3.15 (m, 2H), 3.13-2.91 (m, 3H), 2.21 (s, 1H), 2.02-1.95 (m, 1H), 1.92-1.84 (m, 1H), 1.39-1.24 (m, 2H).
Example 300: MS (ESI) calcd for C32H29F2N7O 565.24 m/z, found 566.15 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.46-8.38 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.74 (s, 1H), 7.61-7.57 (m, 1H), 7.46-7.34 (m, 3H), 7.26 (t, J=9.3 Hz, 2H), 6.86-6.81 (m, 1H), 6.58-6.57 (m, 1H), 6.10 (d, J=16.6 Hz, 1H), 5.67 (d, J=10.3 Hz, 1H), 5.23 (d, J=53.9 Hz, 1H), 4.43-4.33 (m, 2H), 4.01 (s, 1H), 3.20-3.12 (m, 1H), 2.99 (s, 2H), 1.99 (s, 2H), 1.69-1.03 (m, 4H), 0.97-0.78 (m, 1H).
Intermediate 299-1: (1R)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediate 299-1 was prepared in a manner analogous to Intermediate 75-1 using 2-fluorobenzaldehyde in place of 2-aminopyridine-3-carbaldehyde and omitting the chiral separation. MS (ESI) calcd for C24H18F2N6 428.16 m/z, found 429.50 [M+H]+.
Example 301: 1-((2*,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one
Example 302: 1-((2*,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one
Example 303: 1-((2*,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one and
Example 304: 1-((2*,4*)-4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one







Examples 301-304 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 2-(difluoromethyl)-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate, Intermediate 75-1 in place of Intermediate 1-1 and MeOH at 60° C. for the final step. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer. The four stereoisomers partially separated by Prep HPlC on a XSelect CSH OBD column using a gradient of acetonitrile in water (+0.05% TFA). The following groups were obtained:

    
    
        Group 1: Examples 302 and 303
        Group 2: Examples 301 and an undetermined mix of isomers
        Group 3: Examples 304 and an undetermined mix of isomers
    
    


Examples 302 and 303 were separated by chiral Prep-HPLC on a CHIRALPAK AD-H column using a mixture of [HEX (+0.5% 2M NH3-MeOH)] and isopropanol.
Examples 301 was separated from an undetermined mix of isomers by chiral Prep-HPLC on a CHIRALPAK IF column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [ethanol/DCM (1:1)].
Examples 304 was separated from an undetermined mix of isomers by chiral Prep-HPLC on a CHIRALPAK IG column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and ethanol.
Example 301: MS (ESI) calcd. for C32H30F3N9O, 613.25 m/z, found: 614.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.21-8.48 (m, 2H), 7.86-8.14 (m, 2H), 7.71-7.86 (m, 1H), 7.45-7.71 (m, 1H), 7.16-7.45 (m, 3H), 6.65-6.96 (m, 2H), 6.52-6.65 (m, 1H), 6.36-6.52 (m, 1H), 6.02-6.31 (m, 1H), 5.68-5.91 (m, 1H), 5.37-5.68 (m, 1H), 4.18-4.62 (m, 2H), 3.53-3.91 (m, 1H), 3.31-3.45 (m, 1H), 3.16-3.31 (m, 1H), 2.98-3.16 (m, 1H), 2.44-2.54 (m, 1H), 1.81-2.18 (m, 3H), 1.48-1.81 (m, 1H).
Example 302: MS (ESI) calcd. for C32H30F3N9O, 613.25 m/z, found: 614.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.18-8.52 (m, 2H), 7.89-8.18 (m, 2H), 7.64-7.89 (m, 1H), 7.45-7.64 (m, 1H), 7.12-7.45 (m, 3H), 6.71-7.04 (m, 1H), 6.01-6.71 (m, 4H), 5.68-5.96 (m, 1H), 5.24-5.68 (m, 1H), 4.32-4.78 (m, 2H), 2.82-3.35 (m, 4H), 2.05-2.41 (m, 2H), 1.32-1.71 (m, 2H), 1.24-1.31 (m, 1H).
Example 303: MS (ESI) calcd. for C32H30F3N9O, 613.25 m/z, found: 614.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.21-8.52 (m, 2H), 7.86-8.14 (m, 2H), 7.65-7.86 (m, 1H), 7.42-7.65 (m, 1H), 7.16-7.42 (m, 3H), 6.69-6.96 (m, 1H), 6.55-6.69 (m, 1H), 6.44-6.55 (m, 1H), 6.22-6.44 (m, 1H), 6.11-6.22 (m, 1H), 5.68-5.95 (m, 1H), 5.32-5.68 (m, 1H), 4.26-4.76 (m, 2H), 2.82-2.41 (m, 4H), 2.32-2.41 (m, 1H), 2.09-2.28 (m, 1H), 1.96-2.09 (m, 1H), 1.25-1.72 (m, 2H).
Example 304: MS (ESI) calcd. for C32H30F3N9O, 613.25 m/z, found: 614.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.18-8.48 (m, 2H), 7.96-8.18 (m, 1H), 7.86-7.96 (m, 1H), 7.76-7.86 (m, 1H), 7.42-7.62 (m, 1H), 7.24-7.42 (m, 3H), 6.66-7.24 (m, 2H), 6.38-6.66 (m, 2H), 6.01-6.33 (m, 1H), 5.72-5.95 (m, 1H), 5.37-5.72 (m, 1H), 4.21-4.68 (m, 2H), 3.61-4.08 (m, 1H), 3.36-3.61 (m, 1H), 2.92-3.34 (m, 4H), 2.14-2.34 (m, 1H), 1.56-1.92 (m, 3H).
Example 305: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 305 was prepared in a manner analogous to Example 13 using Intermediate 305-2 in place of Intermediate 1-1 and DCE/MeOH (10:1) as the solvent. MS (ESI) calcd. for C31H29F2N9O, 581.25 m/z, found 582.30 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.40 (m, 1H), 8.27-8.32 (m, 1H), 7.98-8.04 (m, 1H), 7.91-7.98 (m, 1H), 7.76-7.83 (m, 1H), 7.60-7.75 (m, 3H), 7.26-7.35 (m, 1H), 6.69-6.86 (m, 1H), 6.52-6.58 (m, 1H), 6.41-6.52 (m, 1H), 6.01-6.13 (m, 1H), 5.62-5.72 (m, 1H), 4.42-4.55 (m, 1H), 4.15-4.33 (m, 1H), 3.88-4.06 (m, 1H), 2.98-3.22 (m, 2H), 2.75-2.95 (m, 2H), 2.28-2.46 (m, 1H), 1.92-2.05 (m, 1H), 1.73-1.89 (m, 1H), 1.10-1.34 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −82.56, −85.53.
Intermediate 305-2: (S)-3-(3-(1-amino-3,3-difluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:








Step 1: Synthesis of tert-butyl (S)-(5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate
To a solution of tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 305-1) (1 g, 3.066 mmol, 1 equiv) and 3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-amine (0.69 g, 3.4 mmol, 1.1 equiv) in 1,4-dioxane (15 mL) were added Cs2CO3 (2.00 g, 6.13 mmol, 2 equiv), Pd(OAc)2 (0.07 g, 0.3 mmol, 0.1 equiv) and XantPhos (0.35 g, 0.61 mmol, 0.2 equiv) at room temperature under N2 atmosphere. After stirring for 2 h at 100° C. under a nitrogen atmosphere, the mixture was allowed to cool to room temperature. The resulting mixture was filtered, the filter cake was washed with ethyl acetate (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl (S)-(5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (1 g, 72%) as a brown solid. MS (ESI) calcd. for C22H22N6O5, 450.17 m/z, found 451.15 [M+H]+.
Step 2: Synthesis of tert-butyl (S)-(6-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-3-yl)carbamate
To a stirred solution of tert-butyl (S)-(5-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (1 g, 2.2 mmol, 1 equiv) and ethane-1,2-dithiol (0.42 g, 4.4 mmol, 2 equiv) in DCM (30 mL) was added TMSOTf (0.10 g, 0.44 mmol, 0.2 equiv) dropwise at 0° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0-50%) to afford tert-butyl (S)-(6-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-3-yl)carbamate (900 mg, 77% yield) as a brown solid. MS (ESI) calcd. for C24H26N6O4S2, 526.15 m/z, found 527.10 [M+H]+.
Step 3: Synthesis of tert-butyl (S)-(6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-3-yl)carbamate
To a stirred solution of tert-butyl (S)-(6-((3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-yl)amino)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-3-yl)carbamate (900 mg, 1.709 mmol, 1 equiv) and 2-aminonicotinaldehyde (229.58 mg, 1.880 mmol, 1.1 equiv) in DMSO (24 mL) and MeOH (4 mL) was added Na2S2O4 (654.57 mg, 3.760 mmol, 2.2 equiv) at room temperature. The resulting mixture was stirred for 18 h at 100° C. The mixture was allowed to cool to room temperature. The mixture was basified to pH 7 with sat. NaHCO3. The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl (S)-(6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-3-yl)carbamate (500 mg, 48.86% yield) as a yellow solid. MS (ESI) calcd. for C30H30N8O2S2, 598.19 m/z, found 599.20 [M+H]+.
Step 4: Synthesis of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)carbamate
To a solution of NIS (338.19 mg, 1.503 mmol, 3 equiv) in DCM (5 mL) was added dropwise pyridine hydrofluoride (993.15 mg, 10.020 mmol, 20 equiv) (70% in Pyridine) at −78° C. under N2 atmosphere. The reaction mixture was stirred at −78° C. for 30 mins. Then a solution of tert-butyl (S)-(6-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydrospiro[indene-1,2′-[1,3]dithiolan]-3-yl)carbamate (300 mg, 0.501 mmol, 1 equiv) in 2 mL DCM was added dropwise and the mixture was stirred for another 10 mins at −78° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with sat. NaHCO3 (50 mL), and the mixture was extracted with ethyl acetate (2*50 mL). The combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)carbamate (110 mg, 40.31% yield) as a yellow solid. MS (ESI) calcd. for C28H26F2N8O2, 544.21 m/z, found 545.20 [M+H]+.
Step 5: Synthesis of (S)-3-(3-(1-amino-3,3-difluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 305-1
A solution of tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-3,3-difluoro-2,3-dihydro-1H-inden-1-yl)carbamate (50 mg, 0.092 mmol, 1 equiv) in DCM (1.5 mL) was treated with TFA (0.5 mL) at room temperature. The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under vacuum and the residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford (S)-3-(3-(1-amino-3,3-difluoro-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (Intermediate 305-1) (9.5 mg, 22% yield) as a white solid. MS (ESI) calcd. for C23H18F2N8, 444.16 m/z, found 445.10 [M+H]+.
Intermediate 305-1: tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide
A solution of (1S)-5-bromo-2,3-dihydro-1H-inden-1-amine (50 g, 236 mmol, 1 equiv) and TEA (55.7 g, 550 mmol, 2 equiv) in DCM (750 mL) was added TFAA (63.25 g, 301.1 mmol, 1.3 equiv) at 0° C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with H2O (500 mL) at room temperature. The aqueous layer was extracted with DCM (2×500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford crude product (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (86 g) as a white solid. MS (ESI) calcd. for C11H9BrF3NO, 306.98 m/z, found: 306.10 [M−H]−.
Step 2: Synthesis of (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide
A solution of (S)-N-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (50 g, 162 mmol, 1.00 equiv) and CrO3 (48.8 g, 488 mmol, 3.00 equiv) in AcOH (600 mL) was stirred for 2 h at 50° C. under air atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0˜20%) to afford (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (11.5 g, 22%) as a white solid. MS (ESI) calcd. for C11H7BrF3NO2, 320.96 m/z, found: 319.90 [M−H]−.
Step 3: Synthesis of (S)-3-amino-6-bromo-2,3-dihydro-1H-inden-1-one
A solution of (S)-N-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)-2,2,2-trifluoroacetamide (10 g, 31 mmol, 1 equiv) in 6M aqueous HCl (200 mL) was refluxed 5 h. The resulting mixture was concentrated under reduced pressure and the residue was triturated with Et2O (200 mL). The residue was filtered and dried to afford (S)-3-amino-6-bromo-2,3-dihydro-1H-inden-1-one (7 g, crude quant.) as a white solid. MS (ESI) calcd. for C9H8BrNO, 224.98 m/z, found 224.05 [M−H]−.
Step 4: Synthesis of tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 305-1
To a stirred solution of (S)-3-amino-6-bromo-2,3-dihydro-1H-inden-1-one (7 g, 31 mmol, 1 equiv) in THE (60 mL) and H2O (15 mL) were added NaHCO3 (5.20 g, 61.9 mmol, 2 equiv) and Boc2O (8.11 g, 37.2 mmol, 1.2 equiv) in portions at 0° C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (0˜50%) to afford tert-butyl (S)-(5-bromo-3-oxo-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 305-1) (7 g, 69% yield) as an off-white solid. MS (ESI) calcd. for C14H16BrNO3, 325.03 m/z, found 324.10 [M−H]−.
Example 306: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-cyclopentylpyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 306 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using 3-cyclopentyl-1H-pyrazole in place of pyrazole and DCE/MeOH (10:1) as the solvent for the final step. MS (ESI) calcd. for C36H39N9O: 613.33. found: 614.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.31 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.89-7.90 (m, 1H), 7.41-7.45 (m, 1H), 7.30 (s, 1H), 7.26-7.29 (m, 2H), 6.88-6.91 (m, 1H), 6.81-6.89 (m, 1H), 6.50-6.55 (m, 2H), 6.11 (d, J=2.4 Hz, 1H), 5.66 (d, J=2.4 Hz, 1H), 4.21-4.32 (m, 2H), 3.91-4.05 (m, 1H), 3.11-3.20 (m, 2H), 2.81-2.92 (m, 4H), 2.35-2.41 (m, 1H), 1.91-1.99 (m, 3H), 1.72-7.75 (m, 1H), 1.51-1.69 (m, 7H), 1.11-1.21 (m, 2H).
Example 307: 1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidin-1-yl)prop-2-en-1-one
Example 308: 1-((3*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidin-1-yl)prop-2-en-1-one and
Example 309:1-((3*,4*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidin-1-yl)prop-2-en-1-one




Synthetic Route:







Step 1: Synthesis of tert-butyl 3-methyl-4-[(trimethylsilyl)oxy]-5,6-dihydro-2H-pyridine-1-carboxylate
To a solution of TMSOTf (6.25 g, 28.133 mmol, 1.2 equiv) in toluene (50 mL) was added tert-butyl 3-methyl-4-oxopiperidine-1-carboxylate (5 g, 23.444 mmol, 1 equiv) and Et3N (5.69 g, 56.266 mmol, 2.4 equiv) at 0° C. and the resulting mixture was stirred for 4 h at 0° C. The solution was quenched with water (40 ml) and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum to afford tert-butyl 3-methyl-4-[(trimethylsilyl)oxy]-5,6-dihydro-2H-pyridine-1-carboxylate (4 g, 59.77%) as yellow oil. MS (ESI) calcd. for C14H27NO3Si: 285.18. found: 286.45 [M+H]+.
Step 2: Synthesis of tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate
To a solution of tert-butyl 3-methyl-4-[(trimethylsilyl)oxy]-5,6-dihydro-2H-pyridine-1-carboxylate (4 g, 14.013 mmol, 1 equiv) in ACN (35 mL) was added SelectFluor (5.46 g, 15.414 mmol, 1.10 equiv) at 0° C. and the resulting mixture was stirred for 1 h. The solution was diluted with water (50 ml) and extracted with ethyl acetate. The organic layers washed with brine, dried over anhydrous sodium sulfate, filtered and concentrate in vacuum to afford tert-butyl 3-fluoro-3-methyl-4-oxopiperidine-1-carboxylate (2 g, 61.72%) as a light yellow oil. MS (ESI) calcd. for C11H18FNO3: 231.13. found: 232.26 [M+H]+.
Step 3: Synthesis of tert-butyl 4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidine-1-carboxylate
To a mixture of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 1-1) (3.55 g, 8.685 mmol, 1 equiv) in THF (20 mL) were added tert-butyl (3S)-3-fluoro-3-methyl-4-oxocyclohexane-1-carboxylate (2 g, 8.685 mmol, 1.00 equiv) and tetrakis(propan-2-yloxy)titanium (2.47 g, 8.685 mmol, 1 equiv). The reaction was stirred at 40° C. for 1 h, then NaBH3CN (2.18 g, 34.740 mmol, 4 equiv) was added and the mixture was stirred at 40° C. for 1 h. The reaction was quenched with H2O (15 mL) at 25° C. The resulting mixture was extracted with ethyl acetate (3×30 ml). The combined organic layers were washed with H2O (3×10 ml) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl 4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidine-1-carboxylate (700 mg, 10.32%) as a light yellow oil. MS (ESI) calcd. for C34H38FN9O2: 623.31. found: 624.35 [M+H]+.
Step 4: Synthesis of 3-(3-((1S)-1-((3-fluoro-3-methylpiperidin-4-yl)amino)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine
A solution of tert-butyl 4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidine-1-carboxylate (500 mg, 0.802 mmol, 1 equiv) in TFA (3 mL) and DCM (1 mL) was stirred at r.t. for 1 h. The solvent was removed by distillation under vacuum to afford 3-(3-((1S)-1-((3-fluoro-3-methylpiperidin-4-yl)amino)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine (620 mg, 62.04%) as a brown oil. MS (ESI) calcd. for C29H30FN9: 523.26. found: 524.45 [M+H]+.
Step 5: Synthesis of 1-(4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidin-1-yl)prop-2-en-1-one (Examples 307-308
To a solution of 3-{3-[(1S)-1-[(3-fluoro-3-methylpiperidin-4-yl)amino]-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (331 mg, 0.632 mmol, 1 equiv) in DCM (20 mL) was added TEA (191.90 mg, 1.896 mmol, 3 equiv). After cooled to 0° C., acryloyl chloride (28.61 mg, 0.316 mmol, 0.5 equiv) was added and the mixture was stirred at r.t for 30 min. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 1-(4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidin-1-yl)prop-2-en-1-one (Examples 307-309). The isomers were partially separated by chiral Prep-HPLC on a CHIRAL CelluloseSB column using a mixture of [Hex/DCM (3:1) (+0.1% diethylamine)] and ethanol to afford:
Example 307: 1-[(3*,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-fluoro-3-methylpiperidin-1-yl]prop-2-en-1-one (14.6 mg, 3.90%) as a light yellow solid. MS (ESI) calcd. for C32H32FN9O: 577.27. found: 578.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.28-8.31 (m, 2H), 7.87-7.95 (m, 2H), 7.76 (s, 1H), 7.49 (m, 1H), 7.18-7.32 (m, 3H), 6.65-6.91 (m, 1H), 6.39-6.50 (m, 2H), 6.01-6.11 (m, 1H), 5.59-5.81 (m, 1H), 3.07-3.34 (m, 1H), 2.79-2.96 (m, 5H), 2.33-2.40 (m, 2H), 2.03-2.13 (m, 1H), 1.78-1.91 (m, 2H), 1.31-1.46 (m, 4H), 0.95-0.96 (m, 1H).
Example 308: 1-((3*)-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-fluoro-3-methylpiperidin-1-yl)prop-2-en-1-one (9 mg, 2.45%) as a white solid. MS (ESI) calcd. for C32H32FN9O: 577.27. found: 578.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.28-8.31 (m, 3H), 7.87-7.95 (m, 2H), 7.76 (s, 1H), 7.49 (m, 1H), 7.18-7.29 (m, 3H), 6.70-6.75 (m, 1H), 6.43-6.52 (m, 2H), 6.05-6.11 (m, 1H), 5.69-5.72 (m, 1H), 3.77 (m, 1H), 3.03-3.46 (m, 2H), 2.69-3.01 (m, 4H), 178-1.94 (m, 3H), 1.22-1.54 (m, 5H), 0.95-0.96 (m, 1H). (mix of diastereomers)
Example 309: 1-[(3*,4*)-4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}-3-fluoro-3-methylpiperidin-1-yl]prop-2-en-1-one (6.1 mg, 1.66%) as a white solid. MS (ESI) calcd. for C32H32FN9O: 577.27. found: 578.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8.28-8.31 (m, 3H), 7.87-7.95 (m, 2H), 7.76 (s, 1H), 7.49 (m, 1H), 7.18-7.29 (m, 3H), 6.70-6.75 (m, 1H), 6.43-6.52 (m, 2H), 6.05-6.11 (m, 1H), 5.69-5.72 (m, 1H), 3.71-3.74 (m, 2H), 3.37-3.47 (m, 2H), 2.90-3.03 (m, 2H), 2.67-2.74 (m, 2H), 178-1.84 (m, 3H), 1.56-1.60 (m, 4H), 0.95-0.96 (m, 1H).
* Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 310: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1-(difluoromethyl)-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 310 was prepared in a manner analogous to Example 190 using Intermediate 310-1 in place of Intermediate 190-1, Pd(dppf)Cl2/sodium carbonate/dioxane/100° C./1 h instead of Pd(dtbpf)Cl2/K3PO4/THF/50° C./3 h, 1-(difluoromethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in place of the boronic acid, 4N HCl in dioxane at room temperature for 30 min for the deprotection and DCE/MeOH (10:1) at 40° C. for 2 h for the final step. MS (ESI) calcd. for C32H30F3N9O: 613.25 m/z, found: 614.15 [M+H]. 1H-NMR (400 MHz, DMSO) S (ppm): 8.25-8.40 (m, 2H), 7.98-8.15 (m, 2H), 7.65-7.90 (m, 2H), 7.50-7.68 (m, 2H), 6.80-6.95 (m, 2H), 6.70-6.79 (m, 1H), 6.10-6.20 (m, 1H), 5.78-6.00 (m, 1H), 5.70-5.77 (m, 1H), 5.18-5.32 (m, 1H), 4.50-4.62 (m, 1H), 4.15-4.30 (m, 1H), 3.60-3.65 (m, 2H), 3.29-3.45 (m, 2H), 3.11-3.28 (m, 1H), 2.65-2.82 (m, 1H), 2.30-2.40 (m, 1H), 2.11-2.25 (m, 1H), 1.48-1.65 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −195.60, −73.91, −94.25. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 310-0: tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate and
Intermediate 310-1: tert-butyl ((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:





Step 1: Synthesis of tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 310-0
A solution of tert-butyl ((1R)-5-((6-bromo-3-nitropyridin-2-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 286-2) (1 g, 2.140 mmol, 1 equiv) in DMSO (10 mL) and MeOH (1.5 mL) was treated with 2-aminonicotinaldehyde (287.48 mg, 2.354 mmol, 1.1 equiv) and Na2S2O4 (819.65 mg, 4.708 mmol, 2.2 equiv) for 24 h at 100° C. under nitrogen atmosphere. The reaction was quenched with H2O at r.t. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (60˜80%) to afford tert-butyl ((1R)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 310-0) (380 mg, 28%) as a yellow solid. MS (ESI) calcd. for C25H24BrFN6O2, 538.11 m/z, found 539.20 [M+H]+.
Step 2: Synthesis of tert-butyl ((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)carbamate (Intermediate 310-1
The stereoisomers of Intermediate 310-0 were separated by chiral SFC on a CHIRAL ART Amylose-SA column using a mix of CO2 and isopropanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 310-1: MS (ESI) calcd. for C25H24BrFN6O2: 538.11 m/z, found: 539.05 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.14-8.17 (m, 1H), 7.99-8.01 (m, 1H), 7.58-7.60 (m, 1H), 7.29-7.38 (m, 4H), 6.45-6.49 (m, 1H), 5.17-5.66 (m, 2H), 3.12-3.18 (m, 2H), 1.46 (s, 9H). 19F NMR (376 MHz, DMSO-d6) δ (ppm): −193.67.
Example 311: 1-(3-((1R,2*)-1-((1-acryloylpiperidin-4-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-5-yl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazole-3-carbonitrile and
Example 312: 1-(3-((1R,2*)-1-((1-acryloylpiperidin-4-yl)amino)-2-fluoro-2,3-dihydro-1H-inden-5-yl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazole-3-carbonitrile




Examples 311 and 312 were prepared in a manner analogous to Examples 286 and 287 (via Intermediate 286-1) using 1H-pyrazole-3-carbonitrile in place of 3-methoxy-1H-pyrazole and a reaction time of overnight for the pyrazole coupling. The diastereomers separated during Prep-HPLC on a XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.1% formic acid). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 311: MS (ESI) calcd. for C32H29FN10O, 588.25 m/z, found 589.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=2.7 Hz, 1H), 8.45 (d, J=8.5 Hz, 1H), 8.08-7.96 (m, 2H), 7.49 (m, 3H), 7.28 (m, 2H), 6.84 (m, 3H), 6.44 (m, 1H), 6.11 (m, 1H), 5.84-5.24 (m, 2H), 4.19 (m, 4H), 3.34 (m, 7H), 2.16 (m, 2H). 19F NMR (377 MHz, DMSO-d6) δ −196.66. (TFA salt)
Example 312: MS (ESI) calcd. for C32H29FN10O, 588.25 m/z, found 589.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=2.7 Hz, 1H), 8.44 (d, J=8.5 Hz, 1H), 8.02 (dd, J=4.8, 1.9 Hz, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.42 (s, 1H), 7.32 (dd, J=8.4, 1.9 Hz, 1H), 7.26 (q, J=3.3, 2.6 Hz, 2H), 6.90 (s, 2H), 6.83 (m, 1H), 6.44 (dd, J=7.7, 4.8 Hz, 1H), 6.09 (m, 1H), 5.66 (m, 1H), 5.24 (m, 1H), 4.40 (s, 1H), 4.26 (s, 1H), 4.00 (s, 1H), 3.56-3.40 (m, 2H), 3.23-3.06 (m, 2H), 3.04-2.93 (m, 2H), 2.87 (s, 1H), 2.00 (s, 1H), 1.89 (s, 1H). 19F NMR (377 MHz, DMSO-d6) δ −176.04. (TFA salt)
Example 313: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-6-fluoro-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 313 was prepared in a manner analogous to Example 13 using Intermediate 313-1 in place of Intermediate 1-1 and DCE/MeOH/AcOH (50:5:1) as the solvent. MS (ESI) calcd. for C31H30FN9O: 563.26. found: 564.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.46 (d, J=10.5 Hz, 1H), 8.19-8.21 (m, 1H), 7.99-8.05 (m, 1H), 7.80 (d, J=1.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.30-7.36 (m, 1H), 7.19-7.29 (m, 2H), 6.75-6.90 (m, 1H), 6.55-6.61 (m, 1H), 6.39-6.48 (m, 1H), 6.03-6.15 (m, 1H), 5.62-5.72 (m, 1H), 4.31 (t, J=6.9 Hz, 1H), 3.93-4.25 (m, 2H), 3.09-3.22 (m, 1H), 2.82-2.99 (m, 3H), 2.71-2.81 (m, 1H), 2.36-2.46 (m, 1H), 1.69-2.01 (m, 3H), 1.12-1.34 (m, 2H). 19F NMR (282 MHz, DMSO-d6) δ (ppm): −134.50.
Intermediate 313-1: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-6-fluoro-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Synthetic Route:








Step 1: Synthesis of 2,6-dichloro-3-fluoro-5-nitropyridine
To a stirred solution of 2,6-dichloro-3-fluoropyridine (10 g, 60.248 mmol, 1 equiv) in H2SO4 (23.69 g, 241.594 mmol, 4.01 equiv) were added HNO3 (29.19 g, 463.307 mmol, 7.69 equiv) in portions at 0° C. The resulting mixture was stirred at 0° C. for 1 h. Then the resulting mixture was stirred at 100° C. for 16 h. The mixture was allowed to cool to 25° C. To 200 ml ice water was added to the resulting mixture. The aqueous layer was extracted with DCM (3×200 mL). The resulting mixture was concentrated under reduced pressure to afford 2,6-dichloro-3-fluoro-5-nitropyridine (5 g, 33.90%) as a yellow oil. MS (ESI) calcd. for C5HCl2FN2O2: 209.94. found: 208.80 [M−H]+
Step 2: Synthesis of 2-chloro-5-fluoro-3-nitro-6-(pyrazol-1-yl)pyridine
To a stirred solution of 2,6-dichloro-3-fluoro-5-nitropyridine (4.8 g, 22.752 mmol, 1 equiv) and pyrazole (929.36 mg, 13.651 mmol, 0.6 equiv) in DMF (30 mL) was added K2CO3 (6.29 g, 45.504 mmol, 2 equiv) in portions at 25° C. The resulting mixture was stirred at 25° C. for 16 h. The reaction was quenched by the addition of water (50 mL) at 25° C. The aqueous layer was extracted with ethyl acetate (3×50 mL). The resulting mixture was washed with brine (3×50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/ethyl acetate (1:1) to afford 2-chloro-5-fluoro-3-nitro-6-(pyrazol-1-yl)pyridine (2.4 g, 41.16%) as a yellow solid. MS (ESI) calcd. for C8H4ClFN4O2: 242.00. found: 243.10 [M+H]+.
Step 3: Synthesis of N-[(1S)-5-{[5-fluoro-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide
To a stirred solution of 2-chloro-5-fluoro-3-nitro-6-(pyrazol-1-yl)pyridine (1.4 g, 5.771 mmol, 1 equiv) and N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-2) (1.44 g, 6.348 mmol, 1.1 equiv) in DMF (20 mL) were added K2CO3 (3.99 g, 28.855 mmol, 5 equiv) in portions at 25° C. The resulting mixture was stirred at 50° C. for 16 h. The reaction was quenched by the addition of water (50 mL) at 25° C. The aqueous layer was extracted with ethyl acetate (3×50 mL). The resulting mixture was washed with brine (3×50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH (10:1) to afford N-[(1S)-5-{[5-fluoro-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (800 mg, 34.97%) as a yellow solid. MS (ESI) calcd. for C19H17FN6O3: 396.13. found: 397.10 [M+H]+.
Step 4: Synthesis of N-[(1S)-5-{[3-amino-5-fluoro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide
To a stirred solution of N-[(1S)-5-{[5-fluoro-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (750 mg, 1.892 mmol, 1 equiv) and 4-(pyridin-4-yl)pyridine (29.55 mg, 0.189 mmol, 0.1 equiv) in DMF (15 mL) was added B2(OH)4 (508.88 mg, 5.676 mmol, 3 equiv) in portions at 0° C. The resulting mixture was stirred at 0° C. for 2 h. The reaction was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford N-[(1S)-5-{[3-amino-5-fluoro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (400 mg, 57.70%) as a yellow solid. MS (ESI) calcd. for C19H19FN6O: 366.16. found: 367.10 [M+H]+.
Step 5: Synthesis of N-(3-{3-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]-6-fluoro-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-yl)-2,2-dimethylpropanamide
To a stirred solution of N-[(1S)-5-{[3-amino-5-fluoro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (370 mg, 1.010 mmol, 1 equiv) and N-(3-formylpyridin-2-yl)-2,2-dimethylpropanamide (249.93 mg, 1.212 mmol, 1.2 equiv) in AcOH (15 mL) was added Cu(OAc)2 (36.68 mg, 0.202 mmol, 0.2 equiv) in portions at 25° C. The resulting mixture was stirred at 60° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (10 mL). The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% TFA) to afford N-(3-{3-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]-6-fluoro-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-yl)-2,2-dimethylpropanamide (400 mg, 71.68%) as a yellow solid. MS (ESI) calcd. for C30H29FN8O2: 552.24. found: 553.35 [M+H]+.
Step 6: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-fluoro-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 313-1
N-(3-{3-[(1S)-1-acetamido-2,3-dihydro-1H-inden-5-yl]-6-fluoro-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-yl)-2,2-dimethylpropanamide (370 mg, 0.670 mmol, 1 equiv) was dissolved in MeOH (10 mL) and HCl (10 mL) at 25° C. The resulting mixture was stirred at 90° C. for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (10 mL). The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-6-fluoro-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (Intermediate 313-1) (180 mg, 63.04%) as a yellow solid. MS (ESI) calcd. for C23H19FN8: 426.17. found: 427.05 [M+H]+.
Example 314: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-(3-cyclopropoxypyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 314 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using DCE/MeOH (10:1)+0.1 eq AcOH as the solvent for the final step and 3-cyclopropoxy-1H-pyrazole in place of pyrazole. MS (ESI) calcd. for C34H35N9O2: 601.29. found: 602.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.29 (d, J=8.4 Hz, 1H), 8.12 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.76 (d, J=8.7 Hz, 1H), 7.41-7.45 (m, 1H), 7.25 (s, 1H), 7.12-7.21 (m, 2H), 6.91-6.95 (m, 2H), 6.78-6.88 (m, 1H), 6.32-6.42 (m, 1H), 6.17-6.19 (m, 1H), 6.08-6.11 (m, 1H), 5.65 (d, J=8.1 Hz, 1H), 4.27-4.31 (m, 1H), 4.21-4.23 (m, 1H), 4.02-4.07 (m, 1H), 3.92-3.98 (m, 1H), 3.27 (s, 1H), 3.01-3.11 (m, 3H), 2.79-2.85 (m, 1H), 2.49 (s, 1H), 2.19-2.20 (m, 1H), 2.01-2.05 (m, 1H), 1.91-1.97 (m, 1H), 1.79-1.85 (m, 1H), 1.11-1.25 (m, 2H), 0.72-0.77 (m, 4H).
Example 315: 2-(2-aminopyridin-3-yl)-3-[(1S)-1-{[1-(prop-2-enoyl)piperidin-4-yl]amino}-2,3-dihydro-1H-inden-5-yl]-5-(pyrazol-1-yl)imidazo[4,5-b]pyridine-7-carbonitrile




Example 315 was prepared in a manner analogous to Example 13 using Intermediate 315-2 in place of Intermediate 1-1 and MeOH/room temperature instead of DCE/40° C. MS (ESI) calcd. for C32H30N10O, 570.26 m/z, found 571.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.28-8.29 (m, 1H), 8.18-8.19 (m, 1H), 7.95-8.00 (m, 1H), 7.80-7.81 (m, 1H), 7.46-7.48 (m, 1H), 7.26-7.28 (m, 2H), 7.19-7.22 (m, 1H), 6.72-6.79 (m, 1H), 6.54-6.56 (m, 1H), 6.43-6.47 (m, 1H), 6.04-6.08 (m, 1H), 5.66-5.69 (m, 1H), 4.27-4.31 (m, 2H), 3.99-4.10 (m, 1H), 3.05-3.11 (m, 1H), 2.84-2.91 (m, 2H), 2.71-2.78 (m, 2H), 2.39-2.41 (m, 1H), 1.84-1.96 (m, 1H), 1.72-1.80 (m, 2H), 1.12-1.27 (m, 2H).
Intermediate 315-2: (S)-3-(1-amino-2,3-dihydro-1H-inden-5-yl)-2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridine-7-carbonitrile




Synthetic Route:





Step 1: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-cyano-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate
To a solution of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 315-1) (100 mg, 0.170 mmol, 1 equiv) in DMF (2 mL) was added Zn(CN)2 (29.98 mg, 0.255 mmol, 1.5 equiv) and Pd(PPh3)4 (9.84 mg, 0.009 mmol, 0.05 equiv). The mixture was stirred for 2 h at 120° C. under nitrogen atmosphere. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-cyano-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (80 mg, 88.08% yield) as a yellow green solid. MS (ESI) calcd. for C29H27N9O2, 533.22 m/z, found 534.25 [M+H]+.
Step 2: Synthesis of 3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridine-7-carbonitrile (Intermediate 315-2
To a suspension of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-cyano-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (70 mg, 0.131 mmol, 1 equiv) in dioxane (3 mL) was added HCl (3 mL, 4 M in dioxane). The mixture was stirred for 2 h at rt. The residue was concentrated and purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridine-7-carbonitrile (Intermediate 315-2) (50 mg, 87.93% yield) as a yellow green solid. MS (ESI) calcd. for C24H19N9, 433.17 m/z, found 434.20 [M+H]+.
Intermediate 315-1: tert-butyl (S)-(5-(2-(2-aminopyridin-3-yl)-7-bromo-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate




Synthetic Route:








Step 1: Synthesis of N-[(1S)-5-[(4-amino-6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of 2,6-dichloro-3-nitropyridin-4-amine (15 g, 72.115 mmol, 1 equiv) and N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (Intermediate 190-2) (13.72 g, 72.115 mmol, 1 equiv) in dioxane (150 mL) was added DIEA (27.96 g, 216.345 mmol, 3 equiv). The mixture was stirred for 4 h at 80° C. After being cooled to rt, the resulting mixture was poured into water (1000 mL). The precipitated solids were collected by filtration and washed with water (2×500 mL). The resulting solid was triturated in ethyl acetate/petroleum ether (200 mL/600 mL) for 1 h. The solids were collected by filtration to afford N-[(1S)-5-[(4-amino-6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (18 g, 68.99% yield) as a red solid. MS (ESI) calcd. for C16H16ClN5O3, 361.09 m/z, found 362.15 [M+H]+.
Step 2: Synthesis of N-[(1S)-5-{[4-amino-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-[(4-amino-6-chloro-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (18 g, 49.753 mmol, 1 equiv) and pyrazole (5.08 g, 74.630 mmol, 1.5 equiv) in dioxane (270 mL) were added EPhos (5.32 g, 9.951 mmol, 0.2 equiv) EPhos Pd G4 (9.14 g, 9.951 mmol, 0.2 equiv) and Cs2CO3 (32.42 g, 99.506 mmol, 2 equiv). The mixture was stirred for 4 h at 100° C. under nitrogen atmosphere. After being cooled to rt, the resulting mixture was poured into water (1500 mL). The precipitated solids were collected by filtration and washed with water (3×500 mL). The resulting solid was triturated with ethyl acetate/petroleum ether (500 mL/500 mL) for 1 h. The solids were collected by filtration to afford N-[(1S)-5-{[4-amino-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (17 g, 86.85% yield) as a light brown solid. MS (ESI) calcd. for C19H19N7O3, 393.15 m/z, found 394.25 [M+H]+.
Step 3: Synthesis of N-[(1S)-5-{[4-bromo-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-{[4-amino-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (9 g, 22.877 mmol, 1 equiv), CuBr (9.85 g, 68.631 mmol, 3 equiv) in ACN (150 mL) was added tBuONO (10.72 g, 91.508 mmol, 4 equiv) at room temperature and the mixture was stirred for 3 h at 70° C. under N2 atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched by the addition of saturated aqueous ammonium chloride (500 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3×800 mL). The combined organic layers were washed with NaCl/H2O (3×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with ethyl acetate/petroleum ether (1:5, 200 mL) to afford N-[(1S)-5-{[4-bromo-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (9 g, 86.03% yield) as a red solid. Ms (ESI) calcd. for C19H17BrN6O3, 456.05 m/z, found 457.10 [M+H]+.
Step 4: Synthesis of N-[(1S)-5-{[3-amino-4-bromo-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-{[4-bromo-3-nitro-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (8 g, 17.494 mmol, 1 equiv) in DMF (80 mL) was added bipyridine (0.14 g, 0.875 mmol, 0.05 equiv) and B2(OH)4 (4.71 g, 52.482 mmol, 3 equiv) at 0° C. and the mixture was stirred 0.5 h at 0° C. The resulting mixture was poured into ice water (300 mL). The precipitated solids were collected by filtration and washed with water (3×100 mL) to afford N-[(1S)-5-{[3-amino-4-bromo-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (7 g, 93.64% yield) as a black solid. Ms (ESI) calcd. for C19H19BrN6O, 426.08 m/z, found 427.10 [M+H]+.
Step 5: Synthesis of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide
To a solution of N-[(1S)-5-{[3-amino-4-bromo-6-(pyrazol-1-yl)pyridin-2-yl]amino}-2,3-dihydro-1H-inden-1-yl]acetamide (3.4 g, 7.957 mmol, 1 equiv) and 2-aminopyridine-3-carbaldehyde (1.17 g, 9.548 mmol, 1.2 equiv) in AcOH (34 mL) was stirred for 2 h at 70° C. The mixture was allowed to cool to room temperature. The mixture was concentrated directly and the residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (400 mg, 9.50% yield) as a brown solid. Ms (ESI) calcd. for C25H21BrN8O, 528.10 m/z, found 529.15 [M+H]+.
Step 6: Synthesis of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine
To a solution of N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]acetamide (390 mg, 0.737 mmol, 1 equiv) in MeOH (15 mL) was added HCl (15 mL, conc.) dropwise. The obtained solution was stirred overnight at 100° C. The mixture was allowed to cool to room temperature. The mixture was concentrated directly. The residue was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate) to afford 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (350 mg, 97.48%) as a brown solid. Ms (ESI) calcd. for C23H19BrN8, 486.09 m/z, found 487.15 [M+H]+.
Step 7: Synthesis of tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 315-1
To a solution of 3-{3-[(1S)-1-amino-2,3-dihydro-1H-inden-5-yl]-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine (160 mg, 0.328 mmol, 1 equiv) in DCM (6 mL) was added TEA (99.66 mg, 0.984 mmol, 3 equiv) and Boc2O (107.48 mg, 0.492 mmol, 1.5 equiv) dropwise. The obtained solution was stirred for 1 h at rt. The reaction was quenched by the addition of water (15 mL) at rt. The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with water (3×20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with MeOH/DCM (7:100) to afford tert-butyl N-[(1S)-5-[2-(2-aminopyridin-3-yl)-7-bromo-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]carbamate (Intermediate 315-1) (100 mg, 51.85%) as a light yellow solid. Ms (ESI) calcd. for C28H27BrN8O2, 586.14 m/z, found 587.15 [M+H]+.
Example 316: 1-((2R,4*)-4-(((1R,2*)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one
Example 317: 1-((2R,4*)-4-(((1R,2*)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one
Example 318: 1-((2R,4*)-4-(((1R,2*)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one and
Example 319: 1-((2R,4*)-4-(((1R,2*)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one




Examples 316, 317, 318 and 319 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using Intermediates 316-1 in place of Intermediate 1-1, DCE/MeOH (1:1) instead of DCE and tert-butyl (R)-2-methyl-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate. Examples 316 and 317 were separated from Example 318 and 319 by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate). Examples 316 and 317 were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [MtBE (+0.5% 2M NH3-MeOH)] and [ethanol/DCM (1:1)]. Example 318 and 319 were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [Hex (+0.5% 2M NH3-MeOH)] and ethanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 316: MS (ESI) calcd for C33H31F2N7O 579.26 m/z, found 580.40[M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.45-8.39 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.83-7.82 (m, 1H), 7.75-7.72 (m, 1H), 7.62-7.54 (m, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.27-7.23 (m, 2H), 6.84-6.79 (m, 1H), 6.57 (dd, J=2.6, 1.7 Hz, 1H), 6.08 (dd, J=16.6, 2.4 Hz, 1H), 5.65 (dd, J=10.5, 2.5 Hz, 1H), 5.54-5.36 (m, 1H), 4.42 (d, J=24.9 Hz, 2H), 3.21-3.14 (m, 2H), 3.13-3.01 (m, 2H), 2.80 (s, 1H), 2.13-2.10 (m, 2H), 1.98-1.78 (m, 1H), 1.49-1.41 (m, 1H), 1.24-1.14 (m, 4H).
Example 317: MS (ESI) calcd for C33H31F2N7O 579.26 m/z, found 580.40[M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.45-8.39 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.75-7.72 (m, 1H), 7.60-7.56 (m, 1H), 7.46-7.32 (m, 3H), 7.29-7.21 (m, 2H), 6.83-6.78 (m, 1H), 6.58-6.57 (m, 1H), 6.07 (d, J=16.8 Hz, 1H), 5.65 (dd, J=10.4, 2.5 Hz, 1H), 5.28-5.15 (m, 1H), 4.41-4.36 (m, 2H), 3.52-3.39 (m, 1H), 3.24-2.70 (m, 3H), 2.13-2.02 (m, 1H), 1.88-1.76 (m, 1H), 1.67-0.78 (m, 6H).
Example 318: MS (ESI) calcd for C33H31F2N7O 579.26 m/z, found 580.35[M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.45-8.39 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.84-7.83 (m, 1H), 7.76-7.72 (m, 1H), 7.60-7.56 (m, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.38-7.34 (m, 2H), 7.31 (d, J=2.0 Hz, 1H), 7.30-7.23 (m, 1H), 6.82-6.77 (m, 1H), 6.60-6.55 (m, 1H), 6.09 (dd, J=16.6, 2.6 Hz, 1H), 5.65 (dd, J=10.5, 2.5 Hz, 1H), 5.54-5.41 (m, 1H), 4.49 (d, J=26.5 Hz, 2H), 3.25-3.08 (m, 3H), 2.21 (s, 1H), 1.96-1.93 (m, 1H), 1.76-1.62 (m, 3H), 1.45 (d, J=6.9 Hz, 3H), 1.24 (s, 1H), 0.95-0.80 (m, 1H).
Example 319: MS (ESI) calcd for C33H31F2N7O 579.26 m/z, found 580.40 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.44-8.42 (m, 2H), 8.00 (d, J=8.6 Hz, 1H), 7.84 (d, J=1.6 Hz, 1H), 7.76-7.72 (m, 1H), 7.61-7.56 (m, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.40-7.33 (m, 2H), 7.30-7.23 (m, 2H), 6.80-6.75 (m, 1H), 6.58-6.53 (m, 1H), 6.08 (dd, J=16.6, 2.6 Hz, 1H), 5.64 (dd, J=10.4, 2.6 Hz, 1H), 5.35-5.19 (m, 1H), 4.40 (d, J=19.3 Hz, 2H), 3.53-3.39 (m, 1H), 3.23-3.21 (m, 1H), 3.04-2.95 (m, 1H), 2.27 (s, 1H), 2.03-1.48 (m, 3H), 1.40 (d, J=6.9 Hz, 3H), 1.24 (s, 1H), 1.03-0.78 (m, 1H).
Intermediate 316-1: (1R)-2-fluoro-5-(2-(2-fluorophenyl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediate 316-1 was prepared in a manner analogous to Intermediate 75-1 using 2-fluorobenzaldehyde in place of 2-aminopyridine-3-carbaldehyde and omitting the chiral separation. MS (ESI) calcd for C24H18F2N6428.16 m/z, found 429.50 [M+H]+.
Example 320: (S)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 320 was prepared in a manner analogous to Example 13 using Intermediate 320-2 in place of Intermediate 1-1 and DCE/MeOH (10:1) as the solvent. MS (ESI) calcd. for C33H33N9OS, 603.25 m/z, found 604.35[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.3 Hz, 1H), 8.02 (dd, J=4.8, 1.9 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.36-7.18 (m, 3H), 6.97-6.78 (m, 3H), 6.43 (dd, J=7.7, 4.8 Hz, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.4, 2.5 Hz, 1H), 4.39-4.22 (m, 2H), 4.09-3.94 (m, 1H), 3.24-3.11 (m, 1H), 3.00-2.87 (m, 3H), 2.87-2.71 (m, 1H), 2.65-2.52 (m, 2H), 2.21-2.05 (m, 1H), 2.03-1.92 (m, 1H), 1.92-1.82 (m, 1H), 1.82-1.72 (m, 1H), 1.36-1.14 (m, 4H), 1.14-1.03 (m, 2H).
Intermediate 320-2: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-5-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 320-2 was prepared in a manner analogous to Intermediate 109-2 using 2-bromo-5-cyclopropyl-1,3,4-thiadiazole instead of 2-bromo-1,3-oxazole, Pd(dppf)Cl2/tribasic potassium phosphate/THF instead of Pd(dtbpf)Cl2/potassium carbonate/dioxane, Intermediate 320-1 in place of Intermediate 109-1 and conc HCl/MeOH (1:1) at 100° C. overnight for the deprotection. MS (ESI) calcd. for C25H22N8S, 466.16 m/z, found 467.30 [M+H]+.
Intermediate 320-1: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide




Intermediate 320-1 was prepared in a manner analogous to Intermediate 109-1 using Intermediate 320-0 in place of Intermediate 85-1, Pd(dppf)Cl2 in place of Pd(OAc)2/PCy3 and a reaction time of overnight. MS (ESI) calcd. for C28H31BN6O3, 510.26 m/z, found 429.20[M+H]+.
Intermediate 320-0: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide




Synthetic Route:





Step 1: (S)-N-(5-((6-bromo-3-nitropyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide
N-[(1S)-5-amino-2,3-dihydro-1H-inden-1-yl]acetamide (17 g, 89 mmol), 2,6-dibromo-3-nitropyridine (Intermediate 190-2) (25.19 g, 89.36 mmol) was dissolved in triethylamine (45.21 g, 446.8 mmol, 5 equiv) and ethanol (200 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with 400 mL water and the precipitate was rinsed with 1:1 ethanol/water (800 mL:800 mL) to afford N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (26 g, 74% yield) as an orange solid. MS (ESI) calculated for C16H15BrN4O3: 390.03, found 413.00 [M+Na]+, 415.00 [M+Na+2]+.
Step 2: Synthesis of (S)-N-(5-((3-amino-6-bromopyridin-2-yl)amino)-2,3-dihydro-1H-inden-1-yl)acetamide
To a cooled (0° C.) solution of N-[(1S)-5-[(6-bromo-3-nitropyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (25 g, 64 mmol, 1 equiv) in N,N-dimethylformamide (250 mL) was added 4,4′-bipyridine (0.5 g, 2 mmol, 3 mol %), followed by hypodiboric acid (17.3 g, 0.192 mol, 3 equiv). The resulting mixture was stirred at 0° C. for 0.5 h. The reaction mixture was quenched by addition of 500 mL saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate (3×250 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography, eluting with petroleum ether/dichloromethane/methanol (70:27:3) to afford N-[(1S)-5-[(3-amino-6-bromopyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (16 g, 69%). MS (ESI) calculated for C16H17BrN4O: 360.06, found 361.00 [M+H]+, 363.00 [M+2+H]+.
Step 3: Synthesis of (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 320-0
A solution of N-[(1S)-5-[(3-amino-6-bromopyridin-2-yl)amino]-2,3-dihydro-1H-inden-1-yl]acetamide (15.5 g, 42.9 mmol, 1 equiv) in methanol (72 mL) and acetic acid (14 mL) was treated with 2-aminopyridine-3-carbaldehyde (6.29 g, 51.5 mmol, 1.2 equiv) followed by the addition of sodium perborate tetrahydrate (26.41 g, 172 mmol, 4 equiv) portion wise. The resulting mixture was stirred at 55° C. for 2 h. The reaction mixture was concentrated under reduced pressure and then brought to pH 8-9 with saturated aqueous sodium bicarbonate. The resulting precipitate was filtered. The filter cake was then washed with ethyl acetate (3×100 mL). The resulting filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using a 0 to 20% gradient of ethyl acetate in petroleum ether followed by a 0 to 10% gradient of dichloromethane in methanol to provide (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide (Intermediate 320-0) (4 g, 18% yield). MS (ESI) calculated for C22H19BrN6O: 462.08, found 463.00 [M+H]+, 465.00 [M+H+2]+.
Example 321: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[3-(oxan-4-yl)pyrazol-1-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 321 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using DCE/MeOH (10:1) in place of DCE and 3-(oxan-4-yl)-1H-pyrazole in place of pyrazole. MS (ESI) calcd. for C36H39N9O2: 629.32 m/z, found: 630.40 [M+H]+/1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.23-8.30 (m, 1H), 7.87-8.00 (m, 2H), 7.47 (d, J=7.8, 1H), 7.19-7.31 (m, 3H), 6.78-6.93 (m, 3H), 6.41-6.43 (m, 2H), 6.05-6.11 (m, 1H), 5.65 (dd, J=2.4, 2.4 Hz, 1H), 4.11-4.39 (m, 2H), 3.90-3.94 (m, 3H), 3.42-3.49 (m, 2H), 3.05-3.32 (m, 1H), 2.65-2.95 (m, 5H), 2.33-2.45 (m, 1H), 1.90-2.02 (m, 2H), 1.76-1.88 (m, 3H), 1.67-1.75 (m, 3H), 1.11-1.40 (m, 2H).
Example 322: (S)-1-(1-(3-(1-((1-acryloylpiperidin-4-yl)amino)-2,3-dihydro-1H-inden-5-yl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b]pyridin-5-yl)-1H-pyrazol-3-yl)cyclopropane-1-carbonitrile




Example 322 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 85-1 in place of Intermediate 1-2, 1-(1H-pyrazol-3-yl)cyclopropane-1-carbonitrile in place of pyrazole, DCM/4N HCl in dioxane (5:2) at room temperature for 30 min for the deprotection and DCE+3 equiv triethylamine for the final step (imine formation) and DCE/AcOH (25:1) for the reduction. MS (ESI) calcd. for C35H34N10O: 610.29 m/z, found: 611.20[M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.36 (d, J=8.5 Hz, 1H), 8.30 (d, J=2.6 Hz, 1H), 8.00 (dd, J=4.8, 1.9 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.32 (s, 1H), 7.28-7.19 (m, 2H), 6.93 (s, 2H), 6.83 (dd, J=16.7, 10.5 Hz, 1H), 6.50 (d, J=2.6 Hz, 1H), 6.42 (dd, J=7.6, 4.8 Hz, 1H), 6.09 (dd, J=16.7, 2.5 Hz, 1H), 5.66 (dd, J=10.4, 2.5 Hz, 1H), 4.33 (t, J=7.2 Hz, 1H), 4.27-4.23 (m, 1H), 4.01-3.97 (m, 1H), 3.19-3.15 (m, 1H), 3.00-2.83 (m, 3H), 2.83-2.71 (m, 1H), 2.48-2.38 (m, 2H), 1.98-1.94 (m, 1H), 1.91-1.70 (m, 4H), 1.59 (q, J=4.8 Hz, 2H), 1.26-1.22 (m, 2H).
Example 323: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-5-[3-(1-fluorocyclopropyl)pyrazol-1-yl]imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 323 was prepared in a manner analogous to Example 13 (via Intermediate 1-1) using Intermediate 320-1 in place of Intermediate 1-2, 3-(1-fluorocyclopropyl)-1H-pyrazole in place of pyrazole, and DCE/MeOH (10:1)+0.5 equiv AcOH instead of DCE. MS (ESI) calcd. for C34H34FN9O: 603.29 m/z, found: 604.40 [M+H]+/1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.32-8.35 (m, 2H), 7.99-8.01 (m, 1H), 7.87 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.20-7.32 (m, 3H), 6.77-7.21 (m, 3H), 6.61 (d, J=2.7 Hz, 1H), 6.39-6.43 (m, 1H), 6.05-6.11 (m, 1H), 5.65 (d, J=10.5, 1H), 4.33-4.40 (m, 1H), 4.20-4.22 (m, 1H), 3.90-4.10 (m, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.75-2.93 (m, 4H), 2.35-2.49 (m, 1H), 2.02-2.21 (m, 1H), 1.95-2.00 (m, 1H), 1.71-1.90 (m, 2H), 2.45-2.52 (m, 2H), 1.15-1.25 (m, 4H).
Example 324: 1-(4-{[(1R,2*)-5-{2,5-diphenylimidazo[4,5-b]pyridin-3-yl}-2-fluoro-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one and
Example 325: 1-(4-{[(1R,2*)-5-{2,5-diphenylimidazo[4,5-b]pyridin-3-yl}-2-fluoro-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Examples 324 and 325 were prepared in a manner analogous to Example 13 using Intermediates 324-1 and 325-1, respectively, in place of Intermediate 1-1 and MeOH in place of DCE. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 324: MS (ESI) calcd. for C35H32FN5O: 557.25 m/z, found: 558.40 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.24-8.26 (m, 1H), 7.95-8.01 (m, 3H), 7.57-7.62 (m, 3H), 7.34-7.56 (m, 8H), 6.77-6.84 (m, 1H), 6.05-6.12 (m, 1H), 5.65-5.69 (m, 1H), 5.37-5.55 (m, 1H), 4.39-4.48 (m, 1H), 4.18-4.28 (m, 1H), 3.95-4.15 (m, 1H), 2.89-3.26 (m, 5H), 1.83-2.07 (m, 2H), 1.25-1.34 (m, 2H). 19F-NMR (300 MHz, DMSO-d6) δ (ppm): −196.86.
Example 325: MS (ESI) calcd. for C35H32FN5O: 557.25 m/z, found: 558.20 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.24-8.26 (m, 1H), 7.95-8.03 (m, 3H), 7.39-7.62 (m, 10H), 7.31-7.35 (m, 1H), 6.78-6.84 (m, 1H), 6.05-6.12 (m, 1H), 5.65-5.69 (m, 1H), 5.17-5.35 (m, 1H), 4.39-4.45 (m, 1H), 3.95-4.28 (m, 2H), 3.38-3.50 (m, 1H), 3.12-3.19 (m, 1H), 2.93-3.02 (m, 2H), 2.81-2.89 (m, 1H), 1.86-2.03 (m, 2H), 1.18-1.29 (m, 2H). 19F-NMR (300 MHz, DMSO-d6) δ (ppm): −175.79.
Intermediate 324-1: (1R,2*)-5-(2,5-diphenyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-amine and
Intermediate 325-1: (1R,2*)-5-(2,5-diphenyl-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-amine




Intermediates 324-1 and 325-1 were prepared in a manner analogous to Intermediates 75-1 and 76-1 using 3-nitro-6-phenylpyridin-2-amine in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine and benzaldehyde in place of 2-aminopyridine-3-carbaldehyde. The diastereomers were separated prior to the final step by chiral prep-HPLC on a CHIRALPAK SS column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and EtOH. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 324-1: MS (ESI) calcd. for C27H21FN4: 420.17 m/z, found: 421.15 [M+H]+.
Intermediate 325-1: MS (ESI) calcd. for C27H21FN4: 420.17 m/z, found: 421.15 [M+H]+.
Example 326: 2-((2*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-2-yl)acetonitrile and
Example 327: 2-((2*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-2-yl)acetonitrile




Examples 326 and 327 were prepared in a manner analogous to Example 13 using Intermediate 326-1 in place of the ketone and DCE/MeOH (1:1) as the solvent. The diastereomers were separated by Prep-HPLC on a XBridge Prep Shield RP OBD C18 column using a gradient of acetonitrile in water (+10 mM ammonium bicarbonate). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 326: MS (ESI) calcd. for C33H32N10O, 584.28 m/z, found, 585.20 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.41-8.35 (m, 1H), 8.31-8.23 (m, 1H), 8.08-7.88 (m, 2H), 7.75 (dd, J=3.3, 1.6 Hz, 1H), 7.61-7.54 (m, 1H), 7.43-7.20 (m, 3H), 6.84 (dd, J=17.0, 11.0 Hz, 1H), 6.48 (ddq, J=10.2, 5.0, 2.2 Hz, 2H), 6.25 (dd, J=16.7, 1.9 Hz, 1H), 5.80 (dd, J=10.8, 1.9 Hz, 1H), 4.77 (s, 1H), 4.46-4.40 (m, 1H), 4.03 (s, 1H), 3.59 (s, 1H), 3.46-3.33 (m, 2H), 3.15 (dd, J=16.4, 6.3 Hz, 1H), 3.06 (d, J=5.7 Hz, 1H), 2.93-2.86 (m, 1H), 2.58 (s, 1H), 2.06-2.02 (m, 1H), 1.92 (s, 4H).
Example 327: MS (ESI) calcd. for C33H32N10O, 584.28 m/z, found, 585.20 [M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.38 (d, J=2.6 Hz, 1H), 8.28 (dd, J=8.6, 1.3 Hz, 1H), 8.03 (dd, J=8.6, 1.0 Hz, 1H), 7.99 (dd, J=5.0, 1.8 Hz, 1H), 7.76 (d, J=1.7 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 6.94-6.77 (m, 1H), 6.52-6.45 (m, 2H), 6.24 (dd, J=16.9, 8.2 Hz, 1H), 5.81 (t, J=9.2 Hz, 1H), 5.26 (d, J=7.4 Hz, 1H), 4.72-4.06 (m, 2H), 3.50-3.34 (m, 1H), 3.30-3.22 (m, 1H), 3.16-3.10 (m, 1H), 2.97-2.88 (m, 3H), 2.59-2.52 (m, 1H), 2.32 (d, J=15.8 Hz, 1H), 2.10 (d, J=13.0 Hz, 1H), 2.03-1.92 (m, 1H), 1.61-1.51 (m, 1H), 1.41 (s, 1H).
Intermediate 326-1: (*)-2-(1-acryloyl-4-oxopiperidin-2-yl)acetonitrile and
Intermediate 327-2: (*)-2-(1-acryloyl-4-oxopiperidin-2-yl)acetonitrile




Synthetic Procedure:








Step 1: Synthesis of methyl-4-oxopiperidine-2-carboxylate
1-tert-butyl 2-methyl 4-oxopiperidine-1,2-dicarboxylate (25 g, 97.17 mmol) was dissolved in 4M HCl in dioxane (100 mL) and the resulting mixture was stirred overnight then concentrated under vacuum to afford methyl 4-oxopiperidine-2-carboxylate hydrochloride (50 g, crude) as a light yellow solid, which was used in the next step without further purification. MS (ESI) calcd. for C7H11NO3: 157.07 m/z, found: 158.10 [M+H]+.
Step 2: Synthesis of methyl 1-benzyl-4-oxopiperidine-2-carboxylate
A mixture of methyl 4-oxopiperidine-2-carboxylate hydrochloride (50 g, 258.22 mmol) and THF (500 mL) was treated with DIEA (134 g, 1036.78 mmol) and BnBr (53 g, 309.87 mmol) at rt. The resulting mixture was stirred at 50° C. for 2 h. The reaction was diluted with water and extracted with DCM (3×800 mL). The organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum pressure. The obtained residue was purified by silica gel column (0-80% petroleum ether/ethyl acetate) to afford methyl 1-benzyl-4-oxopiperidine-2-carboxylate (25 g, 39.15% yield) as a white solid. MS (ESI) calcd. for C14H17NO3: 247.12 m/z, found: 248.15 [M+H]+.
Step 3: Synthesis of methyl 1-benzyl-4,4-diethoxypiperidine-2-carboxylate
To a solution of methyl-1-benzyl-4-oxopiperidine-2-carboxylate (20 g, 80.875 mmol, 1 equiv) in EtOH (190 ml) were added CH(OEt)3 (113 g, 762.473 mmol, 9.43 equiv) dropwise, and TsOH (22 g, 127.758 mmol, 1.58 equiv) in batches at r.t. The resulting mixture was stirred overnight at r.t., then washed with a solution of NaHCO3 (200 mL×3). The combined NaHCO3 aqueous washes were washed with DCM (500 mL×3). Then the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (0-29% petroleum ether/ethyl acetate) to afford methyl-1-benzyl-4,4-diethoxypiperidine-2-carboxylate (25 g, 96.17%) as colorless oil. MS (ESI) calcd. for C18H27NO4, 321.19 m/z, found, 322.10 [M+H]+.
Step 4: Synthesis of (1-benzyl-4,4-diethoxypiperidin-2-yl)methanol
To a solution of methyl-1-benzyl-4,4-diethoxypiperidine-2-carboxylate (24 g, 74.669 mmol, 1 equiv) in Et2O (240 mL) was added LiAlH4 (95 mL, 95.000 mmol, 1.27 equiv, 1M/L) dropwise at r.t. under N2. The resulting mixture was stirred for 2 h at 40° C. then quenched with water (7 mL), filtered, and washed with DCM (3×200 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (0-78% ethyl acetate in petroleum ether) to afford (1-benzyl-4,4-diethoxypiperidin-2-yl)methanol (19.3 g, 88.09%) as a colorless oil. MS (ESI) calcd. for C17H27NO3, 293.20 m/z, found, 294.15 [M+H]+.
Step 5: Synthesis of (1-benzyl-4,4-diethoxypiperidin-2-yl)methyl methanesulfonate
A solution of (1-benzyl-4,4-diethoxypiperidin-2-yl)methanol (5 g, 17.041 mmol, 1 equiv) and Et3N (2.6 g, 25.693 mmol, 1.51 equiv) in DCM (50 mL) was treated with MsCl (3.1 g, 27.065 mmol, 1.59 equiv) dropwise at 0° C. The resulting mixture was stirred for 1 h at 0° C. then diluted with water and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (1-benzyl-4,4-diethoxypiperidin-2-yl)methyl methanesulfonate (6.33 g, 99.99%). MS (ESI) calcd. for C18H29NO5S, 371.18 m/z, found, 372.10 [M+H]+.
Step 6: Synthesis of 2-(1-benzyl-4,4-diethoxypiperidin-2-yl)acetonitrile
A solution of (1-benzyl-4,4-diethoxypiperidin-2-yl)methyl methanesulfonate (6.33 g, 17.039 mmol, 1 equiv) in DCM (60 mL) was treated with TMSCN (2.7 g, 27.216 mmol, 1.60 equiv) and TBAF (22 mL, 22.000 mmol, 1.29 equiv, 1M/L) dropwise at r.t. The resulting mixture was stirred overnight at 50° C. then diluted with water and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (0-27% ethyl acetate in petroleum ether) to afford 2-(1-benzyl-4,4-diethoxypiperidin-2-yl)acetonitrile (4.18 g, 81.12%) as white solid. MS (ESI) calcd. for C18H26N2O2, 302.20 m/z, found, 303.15 [M+H]+. The two enantiomeric products were separated by chiral Prep HPLC on a CHIRALPAK IG column using a mixture of CO2 and MeOH (+0.1% 2M NH3-MeOH). The second eluting peak was carried through steps 7-9 vide infra to provide Intermediate 326-1. The first eluting peak was carried through the same procedure to provide Intermediate 327-2. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer.
Step 7: Synthesis of (*)-2-(4,4-diethoxypiperidin-2-yl)acetonitrile
A solution of (*)-2-(1-benzyl-4,4-diethoxypiperidin-2-yl)acetonitrile (400 mg, 1.323 mmol, 1 equiv) in EtOH (8 mL) was treated with Pd/C (40 mg, 0.376 mmol, 0.28 equiv) in batches and HCl (0.66 mL, 1.980 mmol, 1.50 equiv, 3M/L) dropwise at r.t. The resulting mixture was stirred for 2 h at r.t., under H2 then filtered and concentrated under vacuum to afford (S*)-2-(4,4-diethoxypiperidin-2-yl)acetonitrile (383 mg, crude) as an off-white solid. MS (ESI) calcd. for C11H20N2O2, 212.15 m/z, found, 167.15 [M-C2H5O]1.
Step 8: Synthesis of (*)-2-(1-acryloyl-4,4-diethoxypiperidin-2-yl)acetonitrile
A solution of (*)-2-(4,4-diethoxypiperidin-2-yl)acetonitrile (281 mg, 1.324 mmol, 1 equiv) and triethylamine (437 mg, 4.318 mmol, 3.26 equiv) in DCM (5 mL) was treated with acryloyl chloride (146 mg, 1.613 mmol, 1.22 equiv) dropwise at 0° C. The resulting mixture was stirred for 1.5 h at r.t. then diluted with water and extracted with DCM (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford (*)-2-(1-acryloyl-4,4-diethoxypiperidin-2-yl)acetonitrile (396 mg, crude) as colorless oil. MS (ESI) calcd. for C14H22N2O3, 266.16 m/z, found, 221.10 [M-C2H5O]1.
Step 9: Synthesis of (*)-2-(1-acryloyl-4-oxopiperidin-2-yl)acetonitrile (Intermediate 326-1
A mixture of (*)-2-(1-acryloyl-4,4-diethoxypiperidin-2-yl)acetonitrile (396 mg, 1.487 mmol, 1 equiv) in HCl (4 mL, 2M/L) aq was stirred overnight at r.t. then diluted with water and extracted with DCM (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with (0-7% MeOH in DCM) to afford (*)-2-(1-acryloyl-4-oxopiperidin-2-yl)acetonitrile (Intermediate 326-1) (104 mg, three-step yield: 40.94%) as colorless oil. MS (ESI) calcd. for C10H12N2O2, 192.09 m/z, found, 193.10 [M+H]+. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer.
Example 328: 1-((2*,4*)-2-(difluoromethyl)-4-(((1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one
Example 329: 1-((2*,4*)-2-(difluoromethyl)-4-(((1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one
Example 330: 1-((2*,4*)-2-(difluoromethyl)-4-(((1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 331: 1-((2*,4*)-2-(difluoromethyl)-4-(((1R,2*)-2-fluoro-5-(2-phenyl-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 328, 329, 330 and 331 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 2-(difluoromethyl)-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and Intermediate 324-1 in place of Intermediate 1-1. Examples 328 and 329 were separated from 330 and 331 by Prep HPLC on XBridge Prep Shield RP OBD C18 column using a gradient of acetonitrile in water (+0.05% ammonium bicarbonate). Examples 328 and 329 were separated by chiral Prep-HPLC on a CHIRALPAK IG column using a mixture of [Hex/DCM (3:1) (+0.5% 2M NH3-MeOH)] and ethanol. Examples 330 and 331 were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [hexanes (+0.5% 2M NH3-MeOH)] and ethanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 328: MS (ESI) calcd. for C33H30F3N7O: 597.25 m/z, found: 598.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.41-8.29 (m, 2H), 7.98-7.90 (m, 1H), 7.82-7.77 (m, 1H), 7.60-7.53 (m, 2H), 7.53-7.29 (m, 6H), 6.94-6.78 (m, 1H), 6.62-6.20 (m, 2H), 6.20-6.08 (m, 1H), 5.78-5.64 (m, 1H), 5.55-5.26 (m, 1H), 4.73-4.34 (m, 2H), 3.26-3.02 (m, 4H), 2.23-2.06 (m, 2H), 1.45 (s, 2H), 1.22 (s, 2H). 19F NMR (282 MHz, DMSO-d6) δ −119.45-126.62 (m), −196.47.
Example 329: MS (ESI) calcd. for C33H30F3N7O: 597.25 m/z, found: 598.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.43-8.28 (m, 2H), 7.99-7.89 (m, 1H), 7.80 (s, 1H), 7.61-7.52 (m, 2H), 7.52-7.23 (m, 6H), 6.94-6.76 (m, 1H), 6.64-6.20 (m, 2H), 6.19-6.07 (m, 1H), 5.71 (s, 1H), 5.53-5.25 (m, 1H), 5.12-3.96 (m, 2H), 3.26-2.65 (m, 5H), 2.37-2.11 (m, 2H), 2.10-1.90 (m, 1H), 1.67-1.36 (m, 1H), 1.35-1.07 (m, 1H). 19F NMR (282 MHz, DMSO-d6) δ −119.22-125.65 (m), −196.20.
Example 330: MS (ESI) calcd. for C33H30F3N7O: 597.25 m/z, found: 598.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.43-8.27 (m, 2H), 8.03-7.89 (m, 1H), 7.87-7.74 (m, 1H), 7.66-7.52 (m, 3H), 7.52-7.31 (m, 5H), 7.31-6.97 (m, 1H), 6.97-6.79 (m, 1H), 6.59-6.47 (m, 1H), 6.22-6.08 (m, 1H), 5.79-5.38 (m, 2H), 5.04-3.42 (m, 3H), 3.32-2.96 (m, 4H), 2.45 (s, 1H), 2.32-2.08 (m, 1H), 1.78 (s, 3H). 19F NMR (282 MHz, DMSO-d6) δ −117.89 (dd, J=279.2, 194.5 Hz), −127.34 (dd, J=278.4, 84.4 Hz), −198.29 (d, J=44.8 Hz).
Example 331: MS (ESI) calcd. for C33H30F3N7O: 597.25 m/z, found: 598.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 8.40-8.31 (m, 2H), 8.01-7.89 (m, 1H), 7.83-7.77 (m, 1H), 7.67-7.55 (m, 3H), 7.52-7.31 (m, 5H), 7.07-6.76 (m, 2H), 6.69-6.49 (m, 1H), 6.21-6.09 (m, 1H), 5.77-5.33 (m, 2H), 4.95-4.15 (m, 3H), 3.51 (s, 1H), 3.25-2.99 (m, 3H), 2.21-1.79 (m, 4H), 1.65 (s, 1H). 19F NMR (282 MHz, DMSO-d6) δ −119.19 (t, J=260.3 Hz), −126.55 (d, J=280.4 Hz), −197.88.
Example 332: 1-(4-(((1R,2*)-2-fluoro-5-(5-(3-fluoro-1H-pyrazol-1-yl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Example 332 was prepared in a manner analogous to Example 13 using Intermediate 332-1 in place of Intermediate 1-1. The diastereomers were separated by chiral Prep HPLC on a CHIRALPAK IA column using a mixture of [Hex (+0.5% 2M NH3-MeOH)] and IPA. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer. MS (ESI) calcd. for C32H29F2N7O: 565.24 m/z, found: 566.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.34-8.41 (m, 1H), 8.26-8.31 (m, 1H), 7.73-7.81 (m, 1H), 7.55-7.61 (m, 2H), 7.44-7.54 (m, 2H), 7.30-7.43 (m, 4H), 6.76-6.89 (m, 1H), 6.32-6.39 (m, 1H), 6.05-6.16 (m, 1H), 5.64-5.73 (m, 1H), 5.38-5.58 (m, 1H), 4.36-4.51 (m, 1H), 4.17-4.34 (m, 1H), 3.92-4.11 (m, 1H), 3.18-3.31 (m, 2H), 3.14-3.17 (m, 1H), 3.01-3.13 (m, 1H), 2.87-3.00 (m, 1H), 1.97-2.11 (m, 1H), 1.82-1.96 (m, 1H), 1.19-1.46 (m, 2H). 19F-NMR (376 MHz, DMSO-d6) δ (ppm): −127.25, −196.93.
Intermediate 332-1: (1R)-2-fluoro-5-(5-(3-fluoro-1H-pyrazol-1-yl)-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-amine




Intermediate 332-1 was prepared in a manner analogous to Intermediate 75-1 (starting from Step 4) using Intermediate 286-3 in place of the bromide, Intermediate 236-3 in place of the aniline, a reaction time of overnight for the Buchwald coupling, benzaldehyde in place of 2-aminopyridine-3-carbaldehyde, AcOH/MeOH under air at 60° C. for 3 h instead of AcOH/Cu(OAc)2, DCM/TFA (3:1) at room temperature overnight for the deprotection and omitting the chiral separation. MS (ESI) calcd. for C24H18F2N6: 428.16 m/z, found: 429.15 [M+H]+.
Example 333: 1-((2*,4*)-4-(((1*,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one
Example 334: 1-((2*,4*)-4-(((1*,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one
Example 335: 1-((2*,4*)-4-(((1*,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one and
Example 336: 1-((2*,4*)-4-(((1*,2*)-5-(2-(2-aminopyridin-3-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2-fluoro-2,3-dihydro-1H-inden-1-yl)amino)-2-(difluoromethyl)piperidin-1-yl)prop-2-en-1-one




Examples 333, 334, 335 and 336 were prepared in a manner analogous to Example 14 (via Intermediate 14-1) using tert-butyl 2-(difluoromethyl)-4-oxopiperidine-1-carboxylate in place of tert-butyl 8-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate and Intermediate 333-1 in place of Intermediate 1-1. Examples 333 and 334 were separated from 335 and 336 by Prep HPLC on XSelect CSH OBD Column using a gradient of acetonitrile in water (+0.05% formic acid). Examples 333 and 334 were separated by chiral Prep-HPLC on a CHIRAL ART Cellulose-SB column using a mixture of [MtBE (+2 mM NH3-MEOH)] and EtOH. Examples 335 and 336 were separated by Prep-HPLC on a XSelect CSH OBD column using a gradient of acetonitrile in water (+0.1% formic acid). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 333: MS (ESI) calcd. for C35H34F3N9O, 653.28 m/z, found: 654.20 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.42 (m, 1H), 8.08-8.25 (m, 1H), 7.95-8.08 (m, 1H), 7.79-7.95 (m, 1H), 7.39-7.65 (m, 1H), 7.18-7.39 (m, 3H), 6.68-6.93 (m, 1H), 6.43-6.59 (m, 1H), 6.06-6.42 (m, 3H), 5.71-5.92 (m, 1H), 5.28-5.62 (m, 1H), 4.92-5.11 (m, 1H), 4.31-4.72 (m, 2H), 2.82-3.34 (m, 4H), 2.26-2.42 (m, 1H), 1.92-2.14 (m, 2H), 1.43-1.69 (m, 1H), 1.22-1.41 (m, 1H), 0.91-1.10 (m, 2H), 0.61-0.87 (m, 2H).
Example 334: MS (ESI) calcd. for C35H34F3N9O, 653.28 m/z, found: 654.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.42 (m, 1H), 8.11-8.25 (m, 1H), 7.95-8.11 (m, 1H), 7.73-7.95 (m, 1H), 7.42-7.64 (m, 1H), 7.15-7.42 (m, 3H), 6.68-6.96 (m, 1H), 6.42-6.59 (m, 1H), 6.06-6.42 (m, 3H), 5.68-5.92 (m, 1H), 5.28-5.62 (m, 1H), 4.84-5.14 (m, 1H), 4.51-4.75 (m, 1H), 4.34-4.51 (m, 1H), 2.82-3.36 (m, 4H), 2.08-2.38 (m, 2H), 1.98-2.07 (m, 1H), 1.47-1.68 (m, 1H), 1.21-1.39 (m, 1H), 0.93-1.06 (m, 2H), 0.69-0.87 (m, 2H).
Example 335: MS (ESI) calcd. for C35H34F3N9O, 653.28 m/z, found: 654.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.42 (m, 1H), 8.06-8.25 (m, 1H), 7.95-8.09 (m, 1H), 7.72-7.95 (m, 1H), 7.42-7.62 (m, 1H), 7.21-7.42 (m, 3H), 6.59-7.01 (m, 2H), 6.39-6.59 (m, 1H), 6.06-6.32 (m, 2H), 5.71-5.86 (m, 1H), 5.28-5.65 (m, 1H), 4.08-4.98 (m, 3H), 4.02-4.04 (m, 1H), 3.52-3.93 (m, 1H), 3.14-3.24 (m, 1H), 3.05-3.14 (m, 1H), 1.79-2.11 (m, 4H), 1.55-1.79 (m, 1H), 0.89-1.06 (m, 2H), 0.65-0.81 (m, 2H).
Example 336: MS (ESI) calcd. for C35H34F3N9O, 653.28 m/z, found: 654.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.25-8.38 (m, 1H), 8.10-8.25 (m, 1H), 7.95-8.09 (m, 1H), 7.75-7.94 (m, 1H), 7.42-7.62 (m, 1H), 7.25-7.41 (m, 3H), 6.88-7.25 (m, 1H), 6.66-6.88 (m, 1H), 6.31-6.56 (m, 1H), 6.03-6.31 (m, 2H), 5.68-5.96 (m, 1H), 5.34-5.68 (m, 1H), 4.01-5.09 (m, 3H), 3.60-3.91 (m, 1H), 3.18-3.34 (m, 2H), 3.05-3.18 (m, 1H), 2.13-2.32 (m, 1H), 1.97-2.09 (m, 1H), 1.64-1.81 (m, 3H), 0.89-1.08 (m, 2H), 0.68-0.85 (m, 2H).
Intermediate 333-1: 3-(3-((1R,2S)-1-amino-2-fluoro-2,3-dihydro-1H-inden-5-yl)-5-(3-cyclopropyl-1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 333-1 was prepared in a manner analogous to Intermediate 75-1 using Intermediate 333-0 in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine. MS (ESI) calcd. for C26H23FN8: 466.20 m/z, found: 467.15 [M+H]+. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Intermediate 333-0: 6-(3-cyclopropyl-1H-pyrazol-1-yl)-3-nitropyridin-2-amine




Synthetic Route:





Step 10: Synthesis of 6-(3-cyclopropylpyrazol-1-yl)-3-nitropyridin-2-amine
To a stirred solution of 3-cyclopropyl-1H-pyrazole (1.37 g, 12.675 mmol, 1.1 equiv) in DMF (50 mL) was added NaH (0.83 g, 34.569 mmol, 3 equiv) and 6-chloro-3-nitropyridin-2-amine (2 g, 11.523 mmol, 1 equiv) at rt. The resulting mixture was stirred for 2 h at 80° C. After cooling to room temperature, the mixture was dropped into water. The mixture was filtered and dried to afford 6-(3-cyclopropylpyrazol-1-yl)-3-nitropyridin-2-amine (Intermediate 333-0) (2.2 g, crude) MS (ESI) calcd. for C11H11N5O2: 245.09 m/z, found: 246.15 [M+H]+.
Example 337: 1-(4-{[(1S)-5-[2-(2-aminopyridin-3-yl)-7-methoxy-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]amino}piperidin-1-yl)prop-2-en-1-one




Example 337 was prepared in a manner analogous to Example 13 using MeOH as the solvent and Intermediate 337-2 in place of Intermediate 1-1. MS (ESI) calcd. For C32H33N9O2, 575.28 m/z, found 576.40 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.30-8.31 (m, 1H), 7.96-7.98 (m, 1H), 7.78-7.79 (m, 1H), 7.44-7.49 (m, 2H), 7.28-7.29 (m, 1H), 7.15-7.22 (m, 2H), 6.94 (s, 2H), 6.77-6.86 (m, 1H), 6.51-6.52 (m, 1H), 6.37-6.41 (m, 1H), 6.04-6.10 (m, 1H), 5.62-5.66 (m, 1H), 4.23-4.35 (m, 2H), 4.19 (s, 3H), 3.94-4.00 (m, 1H), 3.11-3.20 (m, 1H), 2.87-2.92 (m, 3H), 2.71-2.79 (m, 1H), 2.42-2.44 (m, 1H), 2.14-2.20 (m, 1H), 1.93-1.97 (m, 1H), 1.70-1.83 (m, 2H), 1.22-1.27 (m, 2H).
Intermediate 337-2: (S)-3-(3-(1-amino-2,3-dihydro-1H-inden-5-yl)-7-methoxy-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine




Intermediate 337-2 was prepared in a manner analogous to Intermediate 1-1 using EPhos/EPhos Pd G4/Cs2CO3 for step 1 and Intermediate 337-1 in place of Intermediate 1-2. MS (ESI) calcd. For C24H22N8O, 438.19 m/z, found 439.25 [M+H]+.
Intermediate 337-1: (S)-N-(5-(2-(2-aminopyridin-3-yl)-5-chloro-7-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)acetamide




Intermediate 337-1 was prepared in a manner analogous to Intermediate 77-1 using 2,6-dichloro-4-methoxy-3-nitropyridine in place of 5-bromo-2,3-dihydroinden-1-one, Intermediate 218-4 in place of 3-nitro-6-(pyrazol-1-yl)pyridin-2-amine and Pd2(dba)3/RuPhos/sodium carbonate/overnight instead of Pd(OAc)2/XantPhos/Cs2CO3/2 h. MS (ESI) calcd. For C23H21ClN6O2, 448.14 m/z, found 449.20 [M+H]+.
Example 338: 2-((2*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-2-yl)acetonitrile and
Example 339: 2-((2*,4*)-1-acryloyl-4-(((S)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)piperidin-2-yl)acetonitrile




Examples 338 and 339 were prepared in a manner analogous to Example 13 using Intermediate 326-2 in place of the ketone and DCE/MeOH (1:1) as the solvent. The diastereomers were separated by SFC on a DAICEL DCpak P4VP column using a mixture of CO2 and MeOH (+20 mM NH3). * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 338: MS (ESI) calcd for C33H32N10O 584.68 m/z, found 585.25[M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.40 (dd, J=2.6, 0.7 Hz, 1H), 8.28 (d, J=8.6 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.99 (dd, J=5.0, 1.8 Hz, 1H), 7.76 (dd, J=1.7, 0.7 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.37 (dd, J=7.6, 1.8 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.0, 2.0 Hz, 1H), 6.84 (dd, J=16.8, 10.7 Hz, 1H), 6.53-6.45 (m, 2H), 6.24 (dd, J=16.8, 2.0 Hz, 1H), 5.79 (dd, J=10.7, 2.0 Hz, 1H), 4.78 (s, 1H), 4.52-4.49 (m, 1H), 4.04 (s, 1H), 3.57 (s, 1H), 3.35-3.31 (m, 3H), 3.10-3.05 (m, 1H), 2.94-2.88 (m, 1H), 2.66-2.56 (m, 1H), 2.17-2.08 (m, 1H), 2.00-1.82 (m, 3H), 1.77 (d, J=13.9 Hz, 1H).
Example 339: MS (ESI) calcd for C33H32N10O 584.68 m/z, found 585.20[M+H]+. 1H NMR (500 MHz, Methanol-d4) δ 8.39 (d, J=2.6 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.99 (dd, J=5.0, 1.8 Hz, 1H), 7.76 (dd, J=1.7, 0.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.40-7.34 (m, 2H), 7.29 (dd, J=8.1, 2.0 Hz, 1H), 6.92-6.79 (m, 1H), 6.52-6.45 (m, 2H), 6.27-6.22 (m, 1H), 5.81-5.79 (m, 1H), 5.25 (s, 1H), 4.54-4.51 (m, 1H), 4.15 (d, J=14.5 Hz, 1H), 3.30-3.18 (m, 1H), 3.14-3.11 (m, 1H), 3.01-2.88 (m, 3H), 2.57-2.54 (m, 1H), 2.26-2.21 (m, 1H), 2.17-2.10 (m, 1H), 2.02-1.93 (m, 1H), 1.63-1.61 (m, 1H), 1.50-1.31 (m, 3H).
Example 340: 1-[4-({5-[2-(2-aminopyridin-3-yl)-5-(3-fluoropyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}methyl)piperazin-1-yl]prop-2-en-1-one




Example 340 was prepared in a manner analogous to Example 174 using Intermediate 236-3 as the starting material. MS (ESI) calcd. for C31H30FN9O: 563.26 m/z, found: 564.20 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 8.40-8.26 (m, 2H), 8.15 (s, 1H), 8.04-7.93 (m, 1H), 7.81-7.71 (m, 1H), 7.59-7.43 (m, 1H), 7.34 (s, 1H), 7.26-7.13 (m, 2H), 6.98-6.87 (m, 2H), 6.86-6.74 (m, 1H), 6.49-6.27 (m, 2H), 6.18-6.04 (m, 1H), 5.81-5.59 (m, 1H), 3.62-3.57 (m, 6H), 3.11-2.73 (m, 4H), 2.71-2.57 (m, 2H), 2.43-2.32 (m, 1H), 2.29-2.18 (m, 1H), 1.91-1.71 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ −73.429, −127.376. (TFA salt)
Example 341: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one and
Example 342: 1-(4-(((1R,2*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,7-difluoro-2,3-dihydro-1H-inden-1-yl)amino)piperidin-1-yl)prop-2-en-1-one




Examples 341 and 342 were prepared in a manner analogous to Examples 75 and 76 using 5-bromo-7-fluoro-2,3-dihydro-1H-inden-1-one as the starting material. The chiral separation was performed after the final step on a CHIRALPAKIF-3 column using a mixture of [Hex/DCM (3:1) (+0.1% DEA)] and ethanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 341: MS (ESI) calcd. for C31H29F2N9O, 581.24 m/z, found 582.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (dd, J=5.6, 3.1 Hz, 2H), 8.07-8.01 (m, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.33 (s, 3H), 6.81 (s, 3H), 6.57 (s, 1H), 6.49 (dd, J=7.6, 4.9 Hz, 1H), 6.10 (m, 1H), 5.67 (m, 1H), 5.46 (s, 1H), 4.71-4.01 (s, 2H), 3.00 (s, 4H), 2.90 (m, 2H), 2.21 (m, 1H), 1.93 (s, 2H), 1.23 (s, 2H).
Example 342: MS (ESI) calcd. for C31H29F2N9O, 581.24 m/z, found 582.25 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.40-8.34 (m, 2H), 8.03 (dd, J=4.8, 1.9 Hz, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.82 (d, J=1.6 Hz, 1H), 7.35-7.20 (m, 2H), 6.87 (s, 1H), 6.83 (s, 3H), 6.56 (t, J=2.1 Hz, 1H), 6.48 (dd, J=7.6, 4.8 Hz, 1H), 6.09 (m, 1H), 5.66 (m, 1H), 5.46 (s, 1H), 4.78 (s, 1H), 4.32 (s, 2H), 3.27 (s, 2H), 3.21 (s, 1H), 3.14 (s, 2H), 2.27 (s, 1H), 1.91 (s, 2H), 1.32 (s, 2H).
Example 343: (*)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one and
Example 344: (*)-1-(4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one




Synthetic Route:








Step 1: Synthesis of 5-bromo-2,3-dihydro-1H-inden-1-ol
To a stirred solution of 5-bromo-2,3-dihydroinden-1-one (5 g, 23.690 mmol, 1 equivalents) in MeOH (100 mL) was added NaBH4 (1.79 g, 47.380 mmol, 2 equivalents) at 25° C. The reaction mixture was stirred at 25° C. for 2 h. To this mixture, Et2O (100 mL) and water (50 mL) were added. After separation of phases, the aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated to afford 5-bromo-2,3-dihydro-1H-inden-1-ol (5 g, 99.05% yield) as a white solid. MS (ESI) calculated for C9H9BrO, 211.98 m/z, found 194.98 [M+H-OH]+.
Step 2: Synthesis of bromo(5-bromo-2,3-dihydro-1H-inden-1-yl)triphenyl-15-phosphane
To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-ol (2.5 g, 11.733 mmol, 1 equivalents) in toluene (20 mL) was added triphenylphosphine hydrobromide (4.43 g, 12.906 mmol, 1.1 equiv). The reaction mixture was stirred at 100° C. for 5 h under N2. The precipitate was filtered off and dried. The solid was suspended in dry diethyl ether and stirred for 10 min. The phosphonium salt was filtered and washed with diethyl ether to afford bromo(5-bromo-2,3-dihydro-1H-inden-1-yl)triphenyl-15-phosphane (5 g, 79.17% yield) as a yellow solid. MS (ESI) calcd. for C27H23Br2P, 537.99 m/z, found 457.07 [M+H-Br]+.
Step 3: Synthesis of tert-butyl 4-((5-bromo-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate
To a stirred solution of bromo(5-bromo-2,3-dihydro-1H-inden-1-yl)triphenyl-15-phosphane (3.3 g, 6.131 mmol, 1 equiv), tert-butyl 4-formylpiperidine-1-carboxylate (2.62 g, 12.262 mmol, 2 equiv) and 18-crown-6 (243.07 mg, 0.920 mmol, 0.15 equiv) in DCM (27 mL) was added K2CO3 (8.64 g, 62.536 mmol, 10.2 equiv). The reaction mixture was stirred at 40° C. for 5 h under N2. To this mixture, DCM (50 mL) and water (50 mL) were added. After separation of phases, the aqueous phase was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether) to afford tert-butyl 4-((5-bromo-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate (1.2 g, 49.89% yield) as a white solid. MS (ESI) calcd. for C20H26BrNO2, 391.11 m/z, found 336.15 [M+H-tBu]+.
Step 4: Synthesis of tert-butyl 4-((5-(3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate
To a stirred solution of tert-butyl 4-((5-bromo-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate (1 g, 2.549 mmol, 1 equiv), 3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-amine (575.26 mg, 2.804 mmol, 1.1 equiv), XantPhos (294.97 mg, 0.510 mmol, 0.2 equiv) and Pd(OAc)2 (114.45 mg, 0.510 mmol, 0.2 equiv) in dioxane (15 mL) was added Cs2CO3 (2.49 g, 7.647 mmol, 3 equiv). The reaction mixture was stirred at 100° C. for 2 h under N2. To this mixture, ethyl acetate (50 mL) and water (50 mL) were added. After separation of phases, the aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether) to afford tert-butyl 4-((5-(3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate (980 mg, 74.43% yield) as a yellow solid. MS (ESI) calcd. for C28H34N6O4, 516.26 m/z, found 417.15 [M+H-Boc]+.
Step 5: Synthesis of tert-butyl 4-((5-(3-amino-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate
To a stirred solution of tert-butyl 4-((5-(3-nitro-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate (1.1 g, 2.129 mmol, 1 equiv) in THF (15 mL) was added Raney Nickel (500 mg, 8.519 mmol, 4.00 equiv). The reaction mixture was stirred at room temperature for 2 h under H2. The reaction mixture was filtered and concentrated to afford tert-butyl 4-((5-(3-amino-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate (930 mg, 89.75% yield) as a yellow solid. MS (ESI) calcd. for C28H34N6O2, 486.27 m/z, found 487.10 [M+H]+.
Step 6: Synthesis of tert-butyl 4-((5-(3-amino-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methyl)piperidine-1-carboxylate
To a stirred solution of tert-butyl 4-((5-(3-amino-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methylene)piperidine-1-carboxylate (930 mg, 1.911 mmol, 1 equiv) in ethyl acetate (13 mL) was added Pd/C (500 mg, 4.698 mmol, 2.46 equiv). The reaction mixture was stirred at room temperature for 2 h under H2. The reaction mixture was filtered and concentrated to afford tert-butyl 4-((5-(3-amino-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methyl)piperidine-1-carboxylate (930 mg, 99.59% yield) as a yellow solid. MS (ESI) calcd. for C28H36N6O2, 488.29 m/z, found 489.20 [M+H]+.
Step 7: Synthesis of tert-butyl 4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidine-1-carboxylate
To a stirred solution of tert-butyl 4-((5-(3-amino-6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-2,3-dihydro-1H-inden-1-yl)methyl)piperidine-1-carboxylate (930 mg, 1.903 mmol, 1 equiv) and 2-aminonicotinaldehyde (278.93 mg, 2.284 mmol, 1.2 equiv) in DMSO (16 mL) was added AcOH (4 mL). The reaction mixture was stirred at 70° C. overnight. To this mixture, ethyl acetate (100 mL) and sat. NH4HCO3 (100 mL) were added. After separation of phases, the aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over anhydrous Na2SO4, filtered and concentrated. The residue was then purified by silica gel chromatography (0-100% ethyl acetate/petroleum ether) to afford tert-butyl 4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidine-1-carboxylate (900 mg, 80.05% yield) as a yellow solid. MS (ESI) calcd. for C34H38N8O2, 590.31 m/z, found 591.12 [M+H]+.
Step 8: Synthesis of 3-(3-(1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride
To a stirred solution of tert-butyl 4-((5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidine-1-carboxylate (900 mg, 1.524 mmol, 1 equiv) in DCM (15 mL) was added HCl (15.00 mL, 60.015 mmol, 39.38 equiv, 4M in dioxane) at room temperature. The mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated to afford 3-(3-(1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride (1.2 g, crude) as a green solid. MS (ESI) calcd. for C29H30N8, 490.26 m/z, found 491.25 [M+H]+.
Step 9: Synthesis of 1-(4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one (Example 343) and 1-(4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one (Example 344)
To a solution of 3-(3-(1-(piperidin-4-ylmethyl)-2,3-dihydro-1H-inden-5-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride (750 mg, 1.423 mmol, 1 equiv) and TEA (719.97 mg, 7.115 mmol, 5 equiv) in DCM (10 mL) was added acryloyl chloride (64.40 mg, 0.712 mmol, 0.5 equiv) in DCM (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched by the addition of H2O (50 mL) at room temperature. The resulting mixture was extracted with DCM (3×50 mL) and the organic layers were combined, then it was concentrated under vacuum. The resulting mixture was purified by reverse-phase flash chromatography on C18 silica gel using a gradient of acetonitrile in water (+0.1% formic acid). The enantiomers were separated by chiral SFC on a CHIRALPAK IH column using a mixture of CO2 and [IPA/DCM (1:1) (+0.1% 7M NH3-MeOH)] to afford 1-(4-{[(*)-5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl]methyl}piperidin-1-yl)prop-2-en-1-one (Example 343) (99.1 mg, 12.56% yield) as a pink solid. MS (ESI) calcd. for C32H32N8O: 544.27 m/z, found: 545.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.23-8.49 (m, 2H), 7.88-8.10 (m, 2H), 7.81 (s, 1H), 7.09-7.49 (m, 4H), 6.73-6.87 (m, 1H), 6.47-6.59 (m, 1H), 6.36-6.48 (m, 1H), 6.02-6.16 (m, 1H), 5.60-5.71 (m, 1H), 4.37-4.50 (m, 1H), 4.00-4.11 (m, 1H), 3.19-3.32 (m, 1H), 3.01-3.16 (m, 1H), 2.78-2.82 (m, 2H), 2.60-2.71 (m, 1H), 2.29-2.38 (m, 1H), 1.77-1.89 (m, 5H), 1.31-1.46 (m, 1H), 1.02-1.14 (m, 2H); and 1-(4-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)methyl)piperidin-1-yl)prop-2-en-1-one (Example 343) (103.4 mg, 13.10% purity) as a pink solid. * Denotes a stereocenter with undetermined absolute stereocenter of a single enantiomer. MS (ESI) calcd. for C32H32N8O: 544.27 m/z, found: 545.35 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.22-8.49 (m, 2H), 7.87-8.13 (m, 2H), 7.75-7.87 (m, 1H), 7.15-7.44 (m, 4H), 6.74-6.88 (m, 1H), 6.38-6.61 (m, 2H), 6.01-6.17 (m, 1H), 5.60-6.79 (m, 1H), 4.37-4.50 (m, 1H), 4.00-4.11 (m, 1H), 3.20-3.31 (m, 1H), 3.02-3.14 (m, 1H), 2.79-2.91 (m, 2H), 2.61-2.72 (m, 1H), 2.30-2.42 (m, 1H), 1.84-2.02 (m, 1H), 1.64-1.77 (m, 4H), 1.32-1.45 (m, 1H), 0.94-1.18 (m, 2H).
Example 345: 1-[(1R,5S,6R)-6-({5-[2-(2-aminopyridin-3-yl)-5-(pyrazol-1-yl)imidazo[4,5-b]pyridin-3-yl]-2,3-dihydro-1H-inden-1-yl}amino)-3-azabicyclo[3.1.0]hexan-3-yl]prop-2-en-1-one




Example 345 was prepared in a manner analogous to Example 34 using Intermediate 77-1 and tert-butyl (1R,5S,6R)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate in MeOH for the reductive amination and prop-2-enoic acid for the final step. MS (ESI) calcd. for C31H29N9O, 543.25 m/z, found 544.20 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.33-8.35 (m, 2H), 8.17-8.18 (m, 1H), 7.95-7.98 (m, 1H), 7.93-7.94 (m, 1H), 7.79-7.80 (m, 1H), 7.45-7.47 (m, 1H), 7.33-7.34 (m, 1H), 7.20-7.22 (m, 2H), 6.53-6.54 (m, 1H), 6.45-6.50 (m, 1H), 6.36-6.39 (m, 1H), 6.07-6.11 (m, 1H), 5.63-5.65 (m, 1H), 4.25-4.28 (m, 1H), 3.69-3.72 (m, 1H), 3.35-3.38 (m, 1H), 2.94-2.96 (m, 1H), 2.75-2.79 (m, 1H), 2.33-2.39 (m, 2H), 1.90-1.95 (m, 1H), 1.85-1.90 (m, 1H), 1.54-1.56 (m, 3H).
Example 346: 1-((1R,5S,6s)-6-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one and
Example 347: 1-((1R,5S,6s)-6-(((*)-5-(2-(2-aminopyridin-3-yl)-5-(1H-pyrazol-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)-3-azabicyclo[3.1.0]hexan-3-yl)prop-2-en-1-one




Examples 346 and 347 were prepared in a manner analogous to Example 34 using Intermediate 77-1 and tert-butyl (1R,5S,6S)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate for step 1 and acrylic acid for step 3. The diastereomers were separated by chiral Prep HPLC on a CHIRALPAK AD column using a mixture of [Hexanes (+0.5% 2M NH3-MeOH)] and ethanol. * Denotes a stereocenter with undetermined absolute stereocenter of a single diastereomer.
Example 346: MS (ESI) calcd. for C31H29N9O, 543.25 m/z, found 544.40 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.35 (m, 2H), 7.92-8.00 (m, 2H), 7.79 (s, 1H), 7.17-7.35 (m, 4H), 6.39-6.54 (m, 3H), 6.05-6.10 (m, 1H), 5.57-5.62 (m, 1H), 4.14-4.19 (m, 1H), 3.73-3.76 (m, 1H), 3.55-3.58 (m, 1H), 3.28-3.48 (m, 2H), 2.88-2.92 (m, 1H), 2.74-2.79 (m, 1H), 2.33-2.42 (m, 2H), 1.66-1.84 (m, 3H).
Example 347: MS (ESI) calcd. for C31H29N9O, 543.25 m/z, found 544.35 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.31-8.35 (m, 2H), 7.98-8.00 (m, 1H), 7.92-7.95 (m, 1H), 7.79 (s, 1H), 7.16-7.35 (m, 4H), 6.53-6.54 (m, 1H), 6.42-6.49 (m, 2H), 6.04-6.10 (m, 1H), 5.55-5.62 (m, 1H), 4.13-4.21 (m, 1H), 3.74-3.78 (m, 1H), 3.55-3.58 (m, 1H), 3.28-3.49 (m, 2H), 2.88-2.93 (m, 1H), 2.73-2.78 (m, 1H), 2.33-2.43 (m, 2H), 1.65-1.84 (m, 3H).
Example 348: AKT1 Inhibition Data
Antiproliferative Effects in LAPC4 Cells.
LAPC4 prostate cancer cells (Klein, K. A. et al. Nat Med 1997, 3, 402-408), which express the AKT1 E17K allele, were grown in IMDM media (Hyclone) supplemented with 12% FBS+1% P/S. To assess compound effects on growth, 1,000 cells/well were seeded in 384 well assay plates, incubated with compound dilutions dissolved in DMSO. After 72 h, intracellular ATP content was assessed with CellTiter Glo reagent (Promega) according to the manufacturer's instructions. IC50 values were calculated by fitting luminescence values to a log(inhibitor) vs. response Hill equation.
Determining Live Cell AKT1 E17K, AKT1 WT, and AKT2 Target Engagement by NanoBRET Competitive Probe Displacement.
Live cell target engagement assays were performed as described (Vasta, J. D. et al. Cell Chem Biol 2018, 25(11), 206-214). Briefly, HEK293 cells were transfected with plasmids encoding kinase-NanoLuciferase fusion proteins overnight. Cells were then treated with serial dilutions of compound and an ˜EC50 concentration of fluorescently-tagged ATP-competitive tracer (Promega). After incubation for 2 h at 37° C., luciferase substrate and extracellular luciferase inhibitor were added to all wells, and luminescent intensity at 460 nm and 600 nm were measured on a multimode plate-reader. The ratio of E600/E460 was calculated to give the tracer engagement signal (BRET). IC50 values were calculated by fitting BRET values to a log(inhibitor) vs. response Hill equation.
The results of these assay studies are provided in Table 2.







TABLE 2







IC50 values for selected compounds of the present disclosure.













AKT2

LAPC4


Compound
AKT1 E17K
IC50
AKT1 WT
proliferation


No.
IC50 (nM)
(nM)
IC50 (nM)
IC50 (nM)














1
12.2
35
11.7
25.4


2
22.7
117
18.7
189


3
32.8
70
15.1
833


4
823
3750
212
4210


5
46.2
271
19.4
310


6
20.1
22
11.9
144


7
42.8
69.4
20.7
2060


8
112
71.5
7.07
1120


9
96.9
440
21.9
528


10
>1.00E+03
1470
121
1860


11
7.03
25.9
4.29
650


12
12.9
129
11.2
343


13
56.1
224
17
144


14
436
1420
85.3
1160


15
78.7
377
34.3
366


16
52.7
67.8
11.3
183


17
146
1020
43
2330


18
243
208
61.5
1570


19
27
326
15.8
88


20
9.64
20.2
7.5
18.3


21
32.8
74.8
22.6
88.5


23
135
2250
50.1
426


24
14.1
37.9
12
238


25
>1.00E+03
>10.0E+03
>1.00E+03
>10.0E+03


26
>1.00E+03
>10.0E+03
>1.00E+03
2050


27
107
192
39.4
425


28
81.6
250
50.1
216


29
81.6
250
50.1
216


30
>1.00E+03
4830
296
2600


31
12.6
57.9
12.9
30.8


32
10.1
41.6
13.1
14.1


33
20.7
152
21.2
52


34
194
1200
55.1
398


35
>1.00E+03
2940
243
5660


36
179
982
64.5
533


37
246
738
93
581


38
881
2090
204
>10.0E+03


39
94.9
94.8
64.2
1600


40
94
265
48.1
948


41
>1.00E+03
5060
305
9840


42
897
252
289
3650


43
>1.00E+03
>10.0E+03
317
>10.0E+03


44
49
103
34.5
122


45
68.4
717
43
296


46

>10.0E+03
726


47
548
2570
200
4270


48
799
1280
111
1400


49
146
980
50.9
406


50
95.1
348
17.6
161


51
727
5560
115
1460


52
949
3480
174
911


53
>1.00E+03
3940
407
2850


54
58.5
292
27.1
107


55
215
1120
93.7
617


56
23.9
104
6.71
144


57
21.9
84.6
10.4
104


58
189
1030
50.2
438


59
242
648
44.8
377


60
406
1680
>1.00E+03
1380


61
28.6
52.4
19
72.4


62
8.39
31.7
9.35
17.1


63
47.5
248
24.1
124


64
53.3
158
20
145


65
58.3
397
29.6
203


66
29.6
51.5
12.1
68


67
87.9
107
21.8
287


68
21.9
74.2
9.84
75.6


69
57.7
226
25.3
358


70
288
1340
83.7
1040


71
9.43
31.8
11.5
29.8


72
75.2
289
15.8
493


73
19
86.3
16
74.4


74
>1.00E+03
2940
179
1630


75
35.9
511
20
287


76
60.1
232
23.3
369


77
86.3
346
17.9
247


78
63
136
22
212


79
14.2
27.1
11.9
16.8


80
41.7
166
15.7
120


81
>1.00E+03
1200
93.2
7600


82
247
640
78.1
568


83
192
583
56.2
506


84
264
278
34.1
327


85
546
865
46
1390


86
153
584
13.7
180


87
165
577
25.5
364


88
48.7
180
21.5
87.7


89
22.9
75.2
8.15
74.9


90
156
109
41.2
351


91
116
558
36.6
351


92
18.9
58.8
6.94
30.7


93
6.16
11.4
5.63
5.02


94
652
2640
147
1170


95
312
1190
110
677


96
>1.00E+03
3910
58
3650


97
419
1300
39.6
2600


98
549
862
39.3
1650


99
89.4
560
33.4
716


100
53.6
135
9.09
187


101
82.3
290
18.3
270


102
35.4
101
8.09
147


103
80.1
547
19.3
317


104
20.6
92.7
4.52
120


105
14.8
50.1
4.51
53


106
20.3
120
3.85
93


107
18.1
192
6.19
164


108
42.4
165
10.2
94.3


109
124
454
24.9
3160


110
141
628
21.8
298


111
127
143
21.6
343


112
8.06
17.6
9.52
11.8


113
8.87
50.9
7.33
25.3


114
8.34
21.9
8.56
12.5


115
9.26
40.4
8.19
40.7


116
339
942
32.1
422


117
482
780
41.6
557


118
42
320
21.3
167


119
582
3590
85.6
595


120
185
885
23.6
814


121
174
358
43.3
248


122
112
305
41.3
116


123
42.4
393
30.9
736


124
99.2
1120
54.1
4860


125
914
3280
292
2110


126
671
8570
>1.00E+03
5050


127
8.17
36.9
9.06
37.1


128
8.62
43
10.6
44.8


129
>1.00E+03
2720
115
>10.0E+03


130
76.4
672
26.5
174


131
>1.00E+03
9530
>1.00E+03
1840


132
326
2250
97.5
1510


133
13.4
47
9.71
16.3


134
232
2710
72.4
1150


135
152
478
22.2
302


136
211
1950
95.8
520


137
71.6
244
14.2
161


138
744
1810
289
963


139
29.7
114
13.5
41.9


140
>1.00E+03
3580
370
1490


141
554
872
148
1700


142
>1.00E+03
>10.0E+03
>1.00E+03
3460


143
353
1260
60.2
499


144
74.1
1180
26
293


145
187
1030
29.7
436


146
78.4
1580
22.9
448


147
151
903
32
398


148
38
61
12.5
93.3


149
60.8
189
23.5
109


150
213
781
31.1
478


151
>1.00E+03
>10.0E+03
>1.00E+03
>10.0E+03


152
>1.00E+03
>10.0E+03
>1.00E+03
>10.0E+03


153
168
1080
26.9
362


154
>1.00E+03
>10.0E+03
301
>10.0E+03


155
>1.00E+03
1230
83.6
490


156
11.3
64.7
9.8
30.2


157
54.5
216
17.2
110


158
358
1870
72.6
1090


159
56.2
146
20
71.2


160
26.9
29.6
9.31
27.4


161
110
198
18.3
100


162
645
5880
102
1600


163
642
1910
71.7
879


164
475
4100
58
489


165
143
163
39.3
187


166
74
257
21.9
116


167
37.1
151
823
479


168
32.6
369
571
858


169
53.7
115
593
565


170
12.5
61
114
160


171
>1.00E+03
>1.00E+03
>10.0E+03
6610


172
50.9
211
5000
510


173
56.5
324
1340
748


174
8.46
12.7
65.5
89


175
17.9
123
820
271


176
37.8
484
967
433


177
36.9
114
1520
416


178
18.1
26.7
33.2
71


179
203
>1.00E+03
2890
3520


180
18.6
160
244
625


181
58.7
513
1140
941


182
152
>1.00E+03
>10.0E+03
3160


183
99.4
633
1260
1600


184
17.8
27.2
104
184


185
53.2
912
2170
4130


186
30.6
954
877
801


187
7.3
28.7
46.4
64.4


188
5.65
8.14
35
56.3


189
60.9
740
1470
1370


190
99.4
>1.00E+03
735
1320


191
221
>1.00E+03
1250
3370


192
>1.00E+03
>1.00E+03
>10.0E+03
>10.0E+03


193
10.2
12.9
71.5
58.4


194
13.8
142
446
310


195
7.45
80.8
415
319


196
96.6
>1.00E+03
1990
1210


197
18.9
28.6
121
469


198
16
27
835
461


199
67.4
802
603
2380


200
15.9
80.1
281
317


201
10.2
41
96.8
127


202
111
>1.00E+03
5950
3090


203
32.2
874
6630
1760


204
287
>1.00E+03
5790
3820


205
112
835
1740
1190


206
7.65
24.8
80.5
62.7


207
7.07
35.2
48.8
114


208
5.74
26.1
77.8
69.8


209
2.29
7.12
3.78
17


210
16.8
272
919
380


211
23.7
79.8
1100
319


212
6.9
12.7
36.1
36.6


213
4.87
11.8
13.8
9.69


214
4.72
7.48
36.5
26.7


215
4.56
11.4
17
42.3


216
140
352
2350
3960


217
321
>1.00E+03
1870
3470


218
52.3
140
365
226


219
45.8
95.7
279
77.1


220
380
>1.00E+03
>10.0E+03
>10.0E+03


221
567
>1.00E+03
>10.0E+03
>10.0E+03


222
>1.00E+03
>1.00E+03
>10.0E+03
>10.0E+03


223
>1.00E+03
>1.00E+03
>10.0E+03
>10.0E+03


224
70.6
256
1240
719


225
31.8
239
308
394


226
22.5
68.9
105
276


227
39
283
703
540


228
16.7
69.9
215
161


229
21.9
97.7
756
334


230
41.9
346
890
600


231
74.8
174
1220
398


232
20.8
168
1080
651


233
14.6
28
59.7
70


234
12.1
70.4
317
330


235
12.6
14.3
51.5
65.8


236
12.4
87.2
778
300


237
17.7
89.5
542
362


238
37.2
666
679
667


239
43.2
334
1450
1030


240
42.6
309
2540
1040


241
5.56
18.8
205
77.3


242
30.4
>1.00E+03
1430
756


243
17.3
98.5
217
150


244
20.1
199
984
371


245
37.6
354
715
526


246
65.6
711
2510
1600


247
113
469
3120
1680


248
>1.00E+03
>1.00E+03
>10.0E+03
>10.0E+03


249
12.6
143
3890
614


250
14.7
134
5850
559


251
113
280
2160
2230


252
10.4
38.5
127
90


253
14.5
58.8
318
127


254
10.9
36.8
89.7
93.3


255
33.2
177
547
214


256
186
394
1690
809


257
13.8
73
432
103


258
94.7
915
1320
526


259
150
968
3290
1520


260
>1.00E+03
>1.00E+03
>10.0E+03
>10.0E+03


261
43.3
136
555
227


262
29.6
45.9
650
83.7


263
39.8
153
2940
680


264
27.8
171
937
1330


265
10.2
24.6
89.6
101


266
3.34
4.07
5.31
4.4


267
5.9
53.6
86.4
335


268
14.8
55.9
297
358


269
247
>1.00E+03
2120
5390


270
7.21
21
162
76.3


271
21.7
248
928
674


272
23.6
92.1
1240
351


273
11.5
27.9
157
134


274
18.8
94.4
696
323


275
84
81.9
2620
326


276
30.7
106
1350
378


277
23.3
54.6
821
138


278
164
>1.00E+03
>10.0E+03
1850


279
168
>1.00E+03
5280
1570


280
20.3
82.1
127
104


281
15.4
80.8
254
253


282
15.2
86
1590
464


283
9.03
42
133
835


284
273
>1.00E+03
6430
7210


285
604
>1.00E+03
>10.0E+03
1550


286
10.7
36.3
273
124


287
7.68
41.8
227
110


288
38
212
2090
1530


289
19.6
145
799
682


290
19.4
122
666
455


291
68.3
358
1580
1110


292
6.85
9.7
44.9
134


293
29.1
86.4
282
440


294
28.6
56.7
301
217


295
9.37
10.9
23.5
17.9


296
33.2
36.6
93.4
59.1


297
23.8
108
588
509


298
14.2
57.3
294
314


299
9.32
61
1180
603


300
9.07
34.9
2330
389


301
8.86
15.1
105
172


302
16.9
33.3
82.1
129


303
10.9
14.5
22.1
15.1


304
11.6
36.2
264
641


305
63.4
>1.00E+03
>10.0E+03
2740


306
15.7
72.3
186
203


307
12.3
106
294
345


308
11.8
62.3
307
300


309
8.12
22.4
146
110


310
34.5
277
1480
553


311
34.9
246
1190
496


312
11.6
102
652
440


313
21.8
113
518
347


314
7.44
23.8
95.1
54.9


315
14.3
70.3
183
120


316
19.2
112
8920
540


317
20.3
68.4
2590
464


318
29.7
111
6880
626


319
49.6
301
7040
1600


320
11.8
45.5
290
78.2


321
7.19
24.2
158
80.7


322
5.51
41.4
247
137


323
6.22
45.3
263


324
16.3
88.1
396


325
7.92
101
298


326
7.25
29.3
98.8


327
25.2
99.4
204


328
17.7
90.3
4720


329
5.37
17.9
156


330
31
69.3
1480


331
18.1
128
807


332
27.9
481
8080


333
4.33
9.57
28.5


334
6.75
23.5
137


335
9.48
28.3
288


336
16.4
25.4
523


337
6.33
29.4
30.3
99.5


338
12.3
13.7
108


339
32.7
78.8
331


340


341
80.3
>1.00E+03
>10.0E+03


342
23.9
194
3800


343
6.65
15.9
86.1


344
21.4
549
418


345
34
63.5
268


346
444
>1.00E+03
2770


347
234
>1.00E+03
2210


349
32
432
1640
1160


350
72.7
416
2510
1090


348
32
362
2670
872









Example 349: Crystallography Studies Showing Covalent Complex Formation
Protein Expression and Purification







Akt1(DrLink)-WT Sequence No. 1:


(SEQ ID NO: 1)


MSHHHHHHHHGSENLYFQSDVAIVKEGWLHKRGEYIKTWRPRYFLLKND


 


GTFIGYKERPQDVDQREAPLNNFSVAQCQLMKTERPRPNTFIIRCLQWT


 


TVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDASAEHTDMEVS


 


LAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVI


 


VAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGEL


 


FFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDK


 


DGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWW


 


GLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSG


 


LLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTS


 


ETDTRYFDEEFTAQM


 


Akt1(DrLink)-E17K Sequence No. 2:


(SEQ ID NO: 2)


MSHHHHHHHHGSENLYFQSDVAIVKEGWLHKRGKYIKTWRPRYFLLKND


 


GTFIGYKERPQDVDQREAPLNNFSVAQCQLMKTERPRPNTFIIRCLQWT


 


TVIERTFHVETPEEREEWTTAIQTVADGLKKQEEEEMDASAEHTDMEVS


 


LAKPKHRVTMNEFEYLKLLGKGTFGKVILVKEKATGRYYAMKILKKEVI


 


VAKDEVAHTLTENRVLQNSRHPFLTALKYSFQTHDRLCFVMEYANGGEL


 


FFHLSRERVFSEDRARFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDK


 


DGHIKITDFGLCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWW


 


GLGVVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLLSG


 


LLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSPPFKPQVTS


 


ETDTRYFDEEFTAQM 






Akt1(DrLink)-WT/E17K Baculovirus Preparation

Akt1(DrLink)-WT/E17K were gene synthesized and cloned by Gibson assembly into the pFastBac vector. The plasmid was transformed into DH10Bac cells and the recombinant bacmid was isolated and used to generate baculovirus in Sf9 cells.
Expression and Purification of Akt1(DrLink)-WT/E17K
Expression of Akt1(DrLink)-WT/E17K was induced in Sf9 cells by infection of 3.0 L of cultured cells (1.5 M/mL) with 30 mL of baculovirus solution and incubated for 72 h. The cells were harvested (4000 rpm, 10 min) and the pellets were frozen down into 1.5 L cell pellets. One 1.5 L cell pellet was thawed and resuspended in 100 mL lysis buffer (25 mM Hepes, pH 8.0, 150 mM NaCl, 1.0 mM DTT) supplemented with protease inhibitor cocktail (Roche). The cells were lysed by sonication and the cell debris pelleted by centrifugation (12000 rpm, 30 min). The clarified lysate was incubated with Ni-NTA (2.0 mL) for at least one hour at 4° C. and the resin was washed with 5 mL wash buffer (10 mM imidazole, 25 mM Hepes, pH 8.0, 150 mM NaCl, 1.0 mM DTT). Akt1 was eluted in 6 mL of elution buffer (300 mM imidazole, 25 mM Hepes, pH 8.0, 150 mM NaCl, 1.0 mM DTT). The eluted protein was diluted 50 mL in lysis buffer (25 mM Hepes, pH 8.0, 150 mM NaCl, 1.0 mM DTT) and 1.29 mg TEV protease was added and then rotated overnight at 4° C. After overnight, LCMS showed complete TEV cleavage. The resulting protein was purified further by gel filtration on a Superdex 200 (10/300 GL) column (gel filtration buffer: 25 mM HEPES pH 8.0, 150 mM NaCl, 1 mM DTT) through two injections. The protein was then concentrated to 7.67 mg/mL, flash-frozen in liquid nitrogen and stored at −80° C. The final yield was ˜1.3 mg Akt1(DrLink)-WT.







NB41 Sequence No. 3:


(SEQ ID NO: 3)


QVQLQESGGGLVQAGGSLRLSCAASGIDVRIKTMAWYRQAPGKQRELLA


 


SVLVSGSTNYADPVKGRFTISRDNAKNTVYLQMNKLIPDDTAVYYCNTY


 


GRLRRDVWGPGTQVTVSSHHHHHHEPEA 






NB41 Construct

NB41 was gene synthesized and cloned by Gibson assembly into a PET26b vector containing an N-terminal PelB signal sequence.
NB41 Expression and Purification
Rosetta 2(DE3)pLysS cells were transformed with the NB41 PET26b plasmid. The transformed bacteria were grown in 3 L LB+kanamycin+chloramphenicol at 37° C. until it reached OD600=0.6-0.8. The culture was cooled to 18° C., induced with 0.25 mM IPTG and expressed overnight at 18° C. The bacteria were harvested (5000 rpm, 10 min) and the resulting pellets were frozen into 3 tubes (1 L pellet each).
The 1 L pellet was warmed to 4° C. and lysed in 15 mL TS buffer (TS buffer=200 mM Tris pH 8.0, 500 mM sucrose) supplemented with protease inhibitor cocktail (Roche) with rotation. After 1 h, 30 mL of TS/4 buffer was added (TS/4 buffer=50 mM Tris, 125 mM Sucrose). After a further 45 min rotation at 4° C., the sample was centrifuged for 30 min at 7500 g at 4° C. The supernatant was collected and incubated with 2 mL Ni-NTA resin. The resin was washed with 5 mL wash buffer (10 mM imidazole, 50 mM Tris, pH 8.0, 500 mM NaCl). NB41 was eluted in 5 mL of elution buffer (400 mM imidazole, 50 mM Tris, pH 8.0, 500 mM NaCl). Final concentration of 10 mM EDTA was added to the eluted protein. The resulting protein was purified further by gel filtration on a Superdex 75 (10/300) column (gel filtration buffer: 20 mM Tris pH 8.0, 100 mM NaCl). The protein was then concentrated to 4.8 mg/mL and flash-frozen in liquid nitrogen and stored at −80° C.
Akt1(DrLink)-NB41 Complex Formation
NB41 was added to AKT(DrLink)-WT/E17K using a 1.2:1 molar ratio and incubated for 10 minutes at 4° C. Final concentration of 10 mM EDTA was then added to this complex. The complex was purified by gel filtration on Superdex 200 (10/300 GL) column (gel filtration buffer: 20 mM HEPES pH 8.0, 20 mM NaCl, 5 mM DTT). The resulting complex was then concentrated to −6 mg/mL and flash-frozen in liquid nitrogen and stored at −80° C. This complex was then used for crystal formation.
Crystallization, Data Collection and Structure Determination
6 mg/mL AKT1 WT or E17K DrLink-NB41 complex is incubated with 1 mM TMB Compound 13 on ice for 2 hours prior to crystallization trials. Crystals were obtained by the vapor diffusion technique at 20′C after mixing an equal volume of the complex with the well solution containing 17-23% PEG3350, 200 mM Li2SO4, 100 mM Bis Tris Propane pH 6.5-9.0, 10% ethylene glycol. Crystals grew within 3 days. Crystals were cryo protected in mother liquor supplemented with 150 ethylene glycol and flash cooled in liquid nitrogen for storage and data collection. All diffraction datasets were collected and processed by Helix Biostructures at ESRF beamline TD30B on Sep. 1, 2023. These datasets were further processed with xia2 (CCP4). The initial structures were determined through molecular replacement with Phaser in CCP4 suite with the structure ofPDB TiD 7APJ as a search model. A chemical restraint dictionary was generated using ACEDRG and CCP4i2. The models were manually adjusted using Coot, refined with REFMAC5 to a final resolution of 2.57 Å and 2.49 Å for the AKT1-WT/Compound 13 and AKT1-E17K/Compound 13 complex.







TABLE 3







Data collection and refinement statistics










AKT1(DrLink)-
AKT1(DrLink)-



WT-NB41-
E17K-NB41-



Compound 13
Compound 13













Wavelength
0.8731
0.8731











Resolution range
57.69-2.57
(2.662-2.57)
43.88-2.49
(2.579-2.49)









Space group
C 2 2 2 1
C 2 2 2 1


Unit cell
76.74 87.48
77.06 87.75



202.34 90 90 90
200.8 90 90 90











Total reflections
162076
(16955)
181713
(18987)


Unique
22090
(2166)
24277
(2400)


reflections


Multiplicity
7.3
(7.8)
7.5
(7.9)


Completeness (%)
99.83
(99.49)
99.91
(99.79)


Mean I/sigma(II)
11.81
(0.74)
13.57
(0.78)









Wilson B-factor
80.04
79.84











R-merge
0.116
(3.31)
0.07873
(2.502)


R-meas
0.1248
(3.542)
0.08466
(2.678)


R-pim
0.04546
(1.253)
0.03078
(0.9467)


CC½
0.998
(0.316)
0.999
(0.349)


CC*
1
(0.693)
1
(0.719)


Reflections used
22072
(2157)
24266
(2398)


in refinement


Reflections used
1103
(95)
1182
(117)


for R-free


R-work
0.2228
(0.4333)
0.2347
(0.4299)


R-free
0.2263
(0.4422)
0.2406
(0.4402)


CC(work)
0.952
(0.598)
0.951
(0.579)


CC(free)
0.931
(0.616)
0.934
(0.634)









Number of non-
4292
4293


hydrogen atoms


macromolecules
4243
4243


ligands
46
46


solvent
3
4


Protein residues
523
523


RMS(bonds)
0.008
0.007


RMS(angles)
1.43
1.41


Ramachandran
92.04
89.90


favored (%)


Ramachandran
7.18
8.35


allowed (%)


Ramachandran
0.78
1.75


outliers (%)


Rotamer
4.39
3.07


outliers (%)


Clashscore
9.31
7.30


Average B-factor
95.43
94.27


macromolecules
95.61
94.44


ligands
80.89
81.52


solvent
68.54
63.64





Statistics for the highest-resolution shell are shown in parentheses.






FIGS. 1A to 1C provide crystal structure representations for the co-crystallization of Compound 13 and to AKT1 WT. In FIG. 1A, the AKT1 WT/Compound 13 co-crystallization complex is shown. For the 2Fo-Fc maps contoured at 1.0a, the AKT1 WT complex is shown in cartoon rending and Compound 13 with the side chain of C296 of AKT1 WT are represented by a stick model. The electron density indicates covalent bond formation with C296 and AKT1 WT. FIG. 1B provides a close-up from the crystal structure of the co-crystallization of Compound 13 and AKT1 WT. In FIG. 1B, Compound 13 and the side chain of residue C296 are represented by a thicker stick model and the adjacent residues of AKT1 WT, including the side chain of E17, are represented by a thinner stick model. Hydrogen bonds are depicted by dashed lines. FIG. 1B shows the covalent bond formed between the sulfur of C296 and the acrylamide of Compound 13. FIG. 1C provides a 2-D diagram detailing the interactions between Compound 13 and residues of the AKT1 WT protein. In FIG. 1C, the covalent bond is depicted by the line between C296 and the methylene of Compound 13. Additionally, hydrogen bonds are depicted as arrows between Compound 13 and the residues of the AKT1 WT protein (contains SEQ ID NO: 4).
FIGS. 2A to 2C provide crystal structure representations for the co-crystallization of Compound 13 and to AKT1 E17K. In FIG. 2A, the AKT1 E17K/Compound 13 co-crystallization complex is shown. For the 2Fo-Fc maps contoured at 1.0N, the AKT1 E17K complex is shown in cartoon rending and Compound 13 with the side chain of C296 of AKT1 E17K are represented by a stick model. The electron density indicates covalent bond formation with C296 and AKT1 E17K. FIG. 2B provides a close-up from the crystal structure of the co-crystallization of Compound 13 and AKT1 E17K. In FIG. 2B, Compound 13 and the side chain of residue C296 are represented by a thicker stick model and the adjacent residues of AKT1 E17K, including the side chain of E17, are represented by a thinner stick model. Hydrogen bonds are depicted by dashed lines. FIG. 2B shows the covalent bond formed between the sulfur of C296 and the acrylamide of Compound 13. FIG. 2C provides a 2-D diagram detailing the interactions between Compound 13 and residues of the AKT1 E17K protein. In FIG. 2C, the covalent bond is depicted by the line between C296 and the methylene of Compound 13. Additionally, hydrogen bonds are depicted as arrows between Compound 13 and the residues of the AKT1 E17K protein (contains SEQ ID NO: 4).
Sequences







TABLE 4







Protein Amino Acid Sequences









Sequence




No.
Protein Amino Acid Sequence(s)
Annotation(s)












1
MSHHHHHHHHGSENLYFQSDVAIVKEGWLHKRGEYIKTWRPR
Akt1(DrLink)-



YFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQCQLMKTERP
WT Sequence



RPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQ




EEEEMDASAEHTDMEVSLAKPKHRVTMNEFEYLKLLGKGTFGK




VILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSR




HPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRA




RFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFG




LCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLG




VVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLL




SGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSP




PFKPQVTSETDTRYFDEEFTAQM (SEQ ID NO: 1)



 


2
MSHHHHHHHHGSENLYFQSDVAIVKEGWLHKRGKYIKTWRPR
Akt1(DrLink)-



YFLLKNDGTFIGYKERPQDVDQREAPLNNFSVAQCQLMKTERP
E17K Sequence



RPNTFIIRCLQWTTVIERTFHVETPEEREEWTTAIQTVADGLKKQ




EEEEMDASAEHTDMEVSLAKPKHRVTMNEFEYLKLLGKGTFGK




VILVKEKATGRYYAMKILKKEVIVAKDEVAHTLTENRVLQNSR




HPFLTALKYSFQTHDRLCFVMEYANGGELFFHLSRERVFSEDRA




RFYGAEIVSALDYLHSEKNVVYRDLKLENLMLDKDGHIKITDFG




LCKEGIKDGATMKTFCGTPEYLAPEVLEDNDYGRAVDWWGLG




VVMYEMMCGRLPFYNQDHEKLFELILMEEIRFPRTLGPEAKSLL




SGLLKKDPKQRLGGGSEDAKEIMQHRFFAGIVWQHVYEKKLSP




PFKPQVTSETDTRYFDEEFTAQM (SEQ ID NO: 2)



 


3
QVQLQESGGGLVQAGGSLRLSCAASGIDVRIKTMAWYRQAPGK
NB41 Sequence



QRELLASVLVSGSTNYADPVKGRFTISRDNAKNTVYLQMNKLIP




DDTAVYYCNTYGRLRRDVWGPGTQVTVSSHHHHHHEPEA




(SEQ ID NO: 3)



 


4
VVYRD (SEQ ID NO: 4)
Fragment of




SEQ ID NO: 1




and SEQ ID




NO:2