KRAS inhibitors

Provided herein are compounds of the formula: wherein A, B, R1, R2, R3a, R3b, Z1, Z2, and Z3 are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and pharmaceutically acceptable salts thereof for treating patients with cancer.

1. 11. A compound of the formula: wherein: A is —C(H)— or —N—; B is —C(R4)— or —N—; R1 is a group of the formula R1b is H or C1-3 alkyl; R1d is C1-3 alkyl, C1-3 haloalkyl or C3-4 cycloalkyl; R1e is C1-3 alkylene; Ring A1 and Ring A2 are C3-4 cycloalkyl or a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S; X1 and X2 are —CH— or —N—; X3 is —CH2— or —O—; X4 and X5 are each independently C1-3 alkyl, halogen, or H; m, m′, s, t, u, v, and w are each 0 or 1; R2 is halogen or C1-3 alkyl; Z1 is —C(CN)— or —N—; Z2 is —C(R3c)— or —N—; Z3 is —O— or —S—; R3a, R3b, and R3c are each independently H, halogen, or C1-3 alkyl; R4 is H, C1-3 alkyl, C1-3 alkoxy optionally substituted with 1, 2, 3, or 4 substituents independently selected from hydroxyl and methyl, or R4 is a group of the formula wherein R4b is H or methyl; and R4c and R4d are each independently C1-3 alkyl, hydroxyl, or C1-3 haloalkyl; or R4c and R4d together with the nitrogen or carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle; or wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5d is C1-3 alkyl; R5e and R5f together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle; R5b and R5c are each independently H, C1-6 alkyl optionally substituted with one or more deuterium, C3-5 cycloalkyl optionally substituted with halogen or C1-3 haloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle or a 6-, 7-, or 8-membered spiro heterocycle, wherein each heterocycle or spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the heterocycle and the spiro heterocycle is each optionally substituted with one or more halogen, deuterium, C1-3 alkyl, or C1-3 haloalkyl; or R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-3 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl; and p and r are each 0, 1, or 2; wherein R6 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and C1-3 dialkylamino; and n is 0 or 1; and wherein R7 is a C1-3 alkyl; and R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S; or R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S; or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS
The present application claims the benefit of priority to European Patent Application Nos. EP 24383052.8, filed Oct. 1, 2024, EP 25382392.6, filed on Apr. 16, 2025, and, EP 25382911.3, filed on Aug. 28, 2025, the contents of which are incorporated herein by reference in their entireties.
FIELD
The present disclosure is directed to KRAS inhibitors useful in the treatment of diseases or disorders associated with KRAS modulation.
BACKGROUND
The MAPK/ERK signaling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses including cell proliferation, differentiation, and apoptosis. KRAS protein is an initiator of the MAPK/ERK signaling pathway and functions as a switch responsible for inducing cell division. In its inactive state, KRAS binds guanosine diphosphate (GDP), effectively sending a negative signal to suppress cell division. In response to an extracellular signal, KRAS is allosterically activated allowing for nucleotide exchange of GDP for guanosine triphosphate (GTP). In its GTP-bound active state, KRAS recruits and activates proteins necessary for the propagation of growth factor induced signaling, as well as other cell signaling receptors. Examples of the proteins recruited by KRAS-GTP are c-Raf and PI3-kinase. KRAS, as a GTP-ase, converts the bound GTP back to GDP, thereby returning itself to an inactive state, and again propagating signals to suppress cell division. KRAS gain of function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP into GDP. The result is an increased MAPK/ERK signal which promotes cancerous cell growth. Missense mutations of KRAS at codon 12 are the most common mutations and markedly diminish GTPase activity.
Oncogenic KRAS mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations, it has been a difficult therapeutic target. (Cox, A.D. Drugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, y et al. RAS Oncogenes: Weaving a Tumorigenic Web. Nat. Rev. Cancer 2011, 11, 761-774).
Thus far, work has focused on KRAS G12C mutant inhibitors (e.g., WO2019/099524, WO2020/081282, WO2020/101736, WO2020/146613, and WO2021/118877 disclose KRAS G12C inhibitors), whereas WO2021/041671 discloses small molecules inhibitors of KRAS G12D and WO2017/011920 discloses small molecule inhibitors of KRAS G12C, G12D, and G12V.
There remains a need to provide alternative, small molecule KRAS inhibitors. In particular, there is a need to provide orally deliverable KRAS inhibitors that are useful for treating cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRAS GTP activity. There is also a need to provide small molecule KRAS inhibitors that exhibit greater efficacy at the same or reduced KRAS inhibitory activity. Further, there is a desire to provide KRAS inhibitors that exhibit better pharmacokinetic/pharmacodynamic properties. Even further, there is a desire to provide KRAS inhibitors that exhibit good oral bioavailability and target coverage (KRAS G12V inhibition). Additionally, there is a need to provide KRAS inhibitors that exhibit selective inhibition preference for KRAS G12V mutant over KRAS wild-type and preferably also exhibit selective inhibition preference for KRAS G12V mutant over HRAS or NRAS. Also, there is a need to provide more potent KRAS inhibitors that exhibit increased efficacy with reduced or minimized untoward or undesired effects. The present invention addresses one or more of these needs by providing novel KRAS inhibitors.
SUMMARY
Compounds of Formula I are provided herein




    
    
        wherein:
        A is —C(H)— or —N—;
        B is —C(R4)— or —N—;
        R1 is a group of the formula
    
    






    
    
        
        
            R1b is H or C1-3 alkyl;
            R1d is C1-3 alkyl, C1-3 haloalkyl, or C3-4 cycloalkyl;
            R1e is C1-3 alkylene;
            Ring A1 and Ring A2 are C3-4 cycloalkyl or a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S;
            X1 and X2 are —CH— or —N—;
            X3 is —CH2— or —O—;
            X4 and X5 are each independently C1-3 alkyl, halogen, or H;
            m, m′, s, t, u, v, and w are each 0 or 1;
        
        
        R2 is halogen or C1-3 alkyl;
        Z1 is —C(CN)— or —N—;
        Z2 is —C(R3c)— or —N—;
        Z3 is —O— or —S—;
        R3a, R3b, and R3c are each independently H, halogen, or C1-3 alkyl;
        R4 is H, C1-3 alkyl, C1-3 alkoxy optionally substituted with 1, 2, 3, or 4 substituents independently selected from hydroxyl and methyl, or
        R4 is a group of the formula
    
    






    
    
        wherein
        
            R4b is H or methyl; and
            R4c and R4d are each independently C1-3 alkyl, hydroxyl, or C1-3 haloalkyl; or
            R4c and R4d together with the nitrogen or carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle;
            or
        
        
    
    






    
    
        wherein
        
            R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl;
            R5d is C1-3 alkyl;
            R5e and R5f together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle;
            R5b and R5c are each independently H, C1-6 alkyl optionally substituted with one or more deuterium, C3-5 cycloalkyl optionally substituted with halogen, hydroxyl, or C1-3 haloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or
            R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle or a 6-, 7-, or 8-membered spiro heterocycle optionally containing a further heteroatom selected from N, O, and S, and wherein the heterocycle and the spiro heterocycle is each optionally substituted with one or more halogen, deuterium, C1-3 alkyl, or C1-3 haloalkyl; or
            R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-3 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl; and
            p and r are each 0, 1, or 2;
        
        
    
    






wherein

    
    
        R6 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl,
        C1-3 alkoxy, and C1-3 dialkylamino; and
        n is 0 or 1; and
    
    






wherein

    
    
        R7 is a C1-3 alkyl; and
        R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S; or
        R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S;
        or a pharmaceutically acceptable salt thereof.
    
    


Also provided herein are methods of using the compounds of Formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, to treat cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. The methods include administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
Further provided herein, are compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in therapy. Additionally provided herein, are the compounds of Formula I, and pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. Also additionally provided herein is the use of compounds of Formula I, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancer, in particular for the treatment of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.


DETAILED DESCRIPTION
Novel inhibitors of the KRAS gain of function mutation G12V are described herein. These new compounds could address the needs noted above for inhibitors of KRAS GTP activity in gain of function mutants in the treatment of cancers such as lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer. Some of these new KRAS G12V mutant inhibitor compounds are selective to KRAS G12V mutants over wild-type KRAS, preferably they are also selective over hRAS and nRAS. Additionally, some of these new selective KRAS G12V mutant inhibitor compounds are also inhibitors of other mutant types such as KRAS G12C or G12D. Some of these new KRAS G12V mutant inhibitor compounds have good oral bioavailability and good target coverage (KRAS G12V mutant inhibition).
The present invention provides a compound of Formula I:




    
    
        wherein A, B, R1, R2, R3a, R3b, Z1, Z2, and Z3 are as defined above, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula I is represented by Formula I′:
    
    






The present invention provides a compound of Formula I′:




    
    
        wherein R1, R2, R3a, R3b, R4, Z1, Z2, and Z3 are as defined above, or a pharmaceutically acceptable salt thereof.
    
    


As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals of one to a specified number of carbon atoms, e.g., “C1-4 alkyl” or “C1-3 alkyl.” Examples of alkyls include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, and iso-butyl.
As used herein, the term “heterocyclyl” or “heterocycle” means mono, or polycyclic rings containing 3-24 atoms, preferably 3-10 atoms, which include carbon, and one, or more heteroatoms selected from N, O, S, P, and B, preferably 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and wherein the rings are not aromatic. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, R1b is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1d is methyl or ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1d is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1d is ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is methyl or ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is cyclopropyl, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, R1b is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1d is methyl, ethyl, or difluoromethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1d is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1d is ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is methyl or ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is ethyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1d is difluoromethyl, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, A is —N—.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, A is —C(H)—.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, B is —N—.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, B is —C(H)—.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, B is —C(R4)—.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, R1b is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1e is methylene, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and R1e is methylene, or a pharmaceutically acceptable salt thereof.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, R1b is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is H, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, t is 0 or 1. In an embodiment, t is 0. In an embodiment, t is 1. In an embodiment, Ring A1 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is oxetanyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is hydrogen, and Ring A1 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is hydrogen, and Ring A1 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is hydrogen, and Ring A1 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is oxetanyl, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, R1b is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A1 is oxetanyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A1 is oxetanyl, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, R1b is methyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A2 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A2 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A2 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A2 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In an embodiment, Ring A2 is oxetanyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A2 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A2 is cyclopropyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A2 is cyclobutyl, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A2 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof. In an embodiment, R1b is methyl, and Ring A2 is oxetanyl, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, X1 is —CH—, or a pharmaceutically acceptable salt thereof. In an embodiment, X1 is —N—, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, X1 is —CH—, or a pharmaceutically acceptable salt thereof. In an embodiment, X1 is —N—, or a pharmaceutically acceptable salt thereof. In an embodiment, X3 is —O—, or a pharmaceutically acceptable salt thereof. In an embodiment, X3 is —CH2—, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 and X5 are each halogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 and X5 are each fluoro, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is hydrogen, and X5 is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof. In an embodiment, X4 and X5 are each hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is C1-3 alkyl, and X5 is hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is C1-3 alkyl, and X5 is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof. In an embodiment, m and m′ are each 1. In an embodiment, m is 1 and m′ is 0.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, X1 is —CH—, or a pharmaceutically acceptable salt thereof. In an embodiment, X1 is —N—, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is halogen, and X5 is halogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is fluoro, and X5 is fluoro, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is hydrogen, and X5 is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is hydrogen, and X5 is hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is C1-3 alkyl, and X5 is hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is C1-3 alkyl, and X5 is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof. In an embodiment, m and m′ are each 1. In an embodiment, m is 1 and m′ is 0.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, X3 is —CH—, or a pharmaceutically acceptable salt thereof. In an embodiment, X3 is —O—, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 and X5 are hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is C1-2 alkyl, and X5 is hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, X4 is methyl, and X5 is hydrogen, or a pharmaceutically acceptable salt thereof. In an embodiment, m is 1.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of formula




In an embodiment, X2 is —CH—, or a pharmaceutically acceptable salt thereof. In an embodiment, X2 is —N—, or a pharmaceutically acceptable salt thereof. In an embodiment, X3 is —CH2—, or a pharmaceutically acceptable salt thereof. In an embodiment, X3 is —O—, or a pharmaceutically acceptable salt thereof. In an embodiment, X2 is —CH—, and X3 is —CH2—, or a pharmaceutically acceptable salt thereof. In an embodiment, X2 is —N—, and X3 is —CH2—, or a pharmaceutically acceptable salt thereof. In an embodiment, X2 is —CH—, and X3 is —O—, or a pharmaceutically acceptable salt thereof.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R1 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R2 is F, Cl, or methyl.
In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R2 is F or Cl.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R2 is F.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R2 is Cl.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R2 is methyl.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —C(CN)—, Z2 is —C(R3c)—, and Z3 is —S—. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R3a is H. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is halogen (preferably fluoro), and R3c is H. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is H, and R3c is halogen (preferably fluoro). In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is halogen (preferably fluoro), and R3c is halogen (preferably fluoro).
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —C(CN)—, Z2 is —N—, and Z3 is —S—. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R3a is H. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R3a is H, and R3b is halogen (preferably fluoro).
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —N—, Z2 is —C(R3c)—, and Z3 is —S—. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R3a is H. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is halogen (preferably fluoro), and R3c is H. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is H, and R3c is halogen (preferably fluoro). In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is halogen (preferably fluoro), and R3c is halogen (preferably fluoro). In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R3a is H, R3b is H, and R3c is H.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —N—, Z2 is —N—, and Z3 is —S—. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R3a is H. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R3a is H, and R3b is halogen (preferably fluoro).
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —C(CN)—, Z2 is —C(R3c)—, and Z3 is —O—. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R3a is H. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is halogen (preferably fluoro), and R3c is H. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is H, and R3c is halogen (preferably fluoro). In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is halogen (preferably fluoro), and R3c is halogen (preferably fluoro).
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —C(CN)—, Z2 is —N—, and Z3 is —O—. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R3a is H. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R3a is H, and R3b is halogen (preferably fluoro).
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —N—, Z2 is —C(R3c)—, and Z3 is —O—. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R3a is H. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is halogen (preferably fluoro), and R3c is H. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is H, and R3c is halogen (preferably fluoro). In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is halogen (preferably fluoro), and R3c is halogen (preferably fluoro). In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R3a is H, R3b is H, and R3c is H.
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, Z1 is —N—, Z2 is —N—, and Z3 is —O—. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R3a is H. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R3a is H, and R3b is halogen (preferably fluoro).
In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C1-3 alkyl, or C1-3 alkoxy optionally substituted with 1, 2, 3, or 4 substituents independently selected from hydroxyl and methyl. In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C1-3 alkyl, or C1-3 alkoxy optionally substituted with 1, 2, or 3 substituents independently selected from hydroxyl and methyl. In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C1-3 alkyl, or C1-3 alkoxy optionally substituted with 3 substituents independently selected from hydroxyl and methyl. In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is H, C1-3 alkyl, or C1-3 alkoxy optionally substituted with 2 substituents independently selected from hydroxyl and methyl. In an embodiment, R4 is H. In an embodiment, R4 is methyl. In an embodiment, R4 is methoxy. In an embodiment, R4 is




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R4b is H or methyl; and R4c and R4d are each independently C1-3 alkyl. In an embodiment, R4b is H. In an embodiment, R4b is methyl.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R4b is H or methyl; and R4c and R4d are each independently C1-3 alkyl. In an embodiment, R4b is H. In an embodiment, R4b is methyl. In an embodiment, R4b is H, and R4c and R4d together with the nitrogen atom to which they are attached form 4-, 5-, or 6-membered heterocycle. In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4b is H, and R4c and R4d together with the nitrogen atom to which they are attached form a 4-membered heterocycle (e.g., azetidinyl).

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R4c and R4d together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4c and R4d together with the carbon atom to which they are attached form a 4-membered heterocycle (e.g., oxetanyl). In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4c and R4d together with the carbon atom to which they are attached form a 5-membered heterocycle. In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4c and R4d together with the carbon atom to which they are attached form a 6-membered heterocycle (e.g., tetrahydro-2H-pyran-4-yl, 1,4-dioxanyl).

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5d is C1-3 alkyl, R5b and R5c are each independently H, C1-5 alkyl optionally substituted with one or more deuterium (preferably trideuteromethyl), C4-5 cycloalkyl optionally substituted with halogen (preferably F) or a C1-3 haloalkyl (preferably fluoromethyl), or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle or a 6- or 7-membered spiro heterocycle, wherein each heterocycle or spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the heterocycle and the spiro heterocycle is each optionally substituted with one or more halogen (preferably F), deuterium, C1-3 alkyl, or C1-3 haloalkyl; or R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5d and R5c are each independently methyl; and p and r are each 0 or 1. In one embodiment, R5b and R5c are each independently H, C1-5 alkyl optionally substituted with 1, 2, or 3 deuterium (e.g., trideuteromethyl), C4-5 cycloalkyl optionally substituted with halogen (preferably F) or a C1-3 haloalkyl (preferably fluoromethyl), or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; In one embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle or a 6- or 7-membered spiro heterocycle, wherein each heterocycle or spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the heterocycle and the spiro heterocycle is each optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents selected from halogen (preferably F), deuterium, C1-3 alkyl, or C1-3 haloalkyl.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5e and R5f together with the carbon atom to which they are attached form a 4- or 5-membered heterocycle.

In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c are each independently H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; or R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-3 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl; and p is 0 or 1.

In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c are each independently H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; and p is 0 or 1. In an embodiment, R5b is H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle, and R5c is H or C1-6 alkyl.

In an embodiment, R4 is group of the formula:




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; and p is 0 or 1. In an embodiment, R4 is group of the formula:





In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; and p is 0 or 1. In an embodiment, R4 is group of the formula:





In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S; R5c is C1-3 alkyl; and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl. In an embodiment, R5a and R5b together with the atoms to which they are attached form a 4-membered heterocyclic fused ring, and R5c is C1-3 alkyl. In an embodiment, R5a and R5b together with the atoms to which they are attached form a 5-membered heterocyclic fused ring, and R5c is C1-3 alkyl. In an embodiment, R5a and R5b together with the atoms to which they are attached form a 6-membered heterocyclic fused ring, and R5c is C1-3 alkyl. In an embodiment, R4 is group of the formula:





In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula







In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula







In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c are each independently H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; and p is 0, 1, or 2. In an embodiment, R5a is hydroxy or C1-3 alkyl. In an embodiment, p is 1. In an embodiment, p is 2. In an embodiment, R5b is H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle, and R5c is H or C1-6 alkyl. In an embodiment, R5b and R5c are each independently C1-3 alkyl. In an embodiment, R4 is a group of the formula:





In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl; R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; and p is 0, 1, or 2. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4- or 5-membered heterocycle optionally containing a further heteroatom selected from N, O, and S; and p is 1. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form a substituted 4- or 5-membered heterocycle; and p is 1. In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula





In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R6 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, C1-3 dialkylamino (preferably dimethylamino); and n is 0 or 1. In an embodiment, R6 is dimethylamino. In an embodiment, n is 1. In an embodiment, n is 0. In an embodiment, R4 is a group of the formula





In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




wherein R7 is a C1-3 alkyl; and

    
    
        R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S; or
        R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S.
    
    


In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




In an embodiment of a compound of Formula I, or a pharmaceutically acceptable salt thereof, R4 is a group of the formula




The present invention also provides a compound of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, or Formula If:




wherein R1b, R1d, R1e, R2, R3a, R3b, R4, Z1, Z2, Z3, X1, X2, X3, Ring A1, Ring A2, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, Formula If, Formula Ih, Formula II, Formula Ij, Formula Ik, or Formula Im:







    
    
        wherein R1b, R1d, R1e, R2, R3a, R3b, R4, Z1, Z2, Z3, X1, X2, X3, X4, X5, Ring A1, Ring A2, m, m′, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Rib is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and R3c is H. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and R3c is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In some embodiments, the compound is a compound of Formula Ia, Formula Ib, Formula Ic, Formula Id, Formula Ie, or Formula If. In some embodiments, the compound is a compound of Formula Ih, Formula Ii, Formula Ij, Formula Ik, or Formula Im.
    
    


The present invention also provides a compound of Formula Ia*, Formula Ib*, Formula Ic*, Formula Id*, Formula Ie*, or Formula If*




wherein R1b, R1d, R1e, R2, R3a, R3b, R4, Z1, Z2, Z3, X1, X2, X3, Ring A1, Ring A2, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ia*, Formula Ib*, Formula Ic*, Formula Id*, Formula Ie*, Formula If*, Formula Ih*, Formula II*, Formula Ij*, Formula Ik*, or Formula Im*:







wherein R1b, R1d, R1e, R2, R3a, R3b, R4, Z1, Z2, Z3, X1, X2, X3, X4, X5, Ring A1, Ring A2, m, m′, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ia-1, Formula Ib-1, Formula Ic-1, Formula Id-1, Formula Ie-1, or Formula If-1:




wherein R1b, R1d, R1e, R2, R3a, R3b, R4b, R4c, R4d, Z1, Z2, Z3, X1, X2, X3, Ring A1, Ring A2, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ia*-1, Formula Ib*-1, Formula Ic*-1, Formula Id*-1, Formula Ie*-1, or Formula If*-1:







wherein R1b, R1d, R1e, R2, R3a, R3b, R4b, R4c, R4d, Z1, Z2, Z3, X1, X2, X3, Ring A1, Ring A2, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ih-1:




wherein R2, R3a, R3b, R4c, R4d, Z1, Z2, Z3, X1, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 4-membered heterocycle. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 5-membered heterocycle. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 6-membered heterocycle. In an embodiment, R4c is hydroxy and R4d is C1-3 haloalkyl. In an embodiment, R4c is hydroxy, R4d is fluoromethyl, and v is 1.

The present invention also provides a compound of Formula Ih*-1:




wherein R2, R3a, R3b, R4c, R4d, Z1, Z2, Z3, X1, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 4-membered heterocycle. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 5-membered heterocycle. In an embodiment, R4c and R4d together with the carbon atom to which they are attached form a 6-membered heterocycle. In an embodiment, R4c is hydroxy and R4d is C1-3 haloalkyl. In an embodiment, R4c is hydroxy, R4d is fluoromethyl, and v is 1.

The present invention also provides a compound of Formula Ia-2, Formula Ib-2, Formula Ic-2, Formula Id-2, Formula Ie-2, or Formula If-2:







wherein R1b, R1d, R1e, R2, R3a, R3b, R5a, R5b, R5c, Z1, Z2, Z3, X1, X2, X3, Ring A1, Ring A2, p, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ia*-2, Formula Ib*-2, Formula Ic*-2, Formula Id*-2, Formula Ie*-2, or Formula If*-2:







wherein R1b, R1d, R1e, R2, R3a, R3b, R5a, R5b, R5c, Z1, Z2, Z3, X1, X2, X3, Ring A1, Ring A2, p, s, t, u, v, and w are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is hydrogen, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —S—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is Cl, and s, t, u, v, and w are 1. In an embodiment, R1b is methyl, Z1 is —N—, Z2 is —N—, Z3 is —O—, R2 is F, and s, t, u, v, and w are 1.

The present invention also provides a compound of Formula Ig-2:




wherein R2, R3a, R3b, R5a, R5b, R5c, R5d, Z1, Z2, Z3, X1, p, r, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, R2 is F, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, R2 is Cl, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, p′ is 0, and p and v are 1. In an embodiment, R5b and R5c are each independently C1-3 alkyl, C1-3 alkyl substituted with one or more deuterium, or a C3-5 cycloalkyl optionally substituted with halogen or a C1-3 haloalkyl. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle, wherein the heterocycle is optionally substituted with halogen, C1-3 alkyl, or C1-3 haloalkyl. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 6-, 7-, or 8-membered spiro heterocycle, wherein the spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the spiro heterocycle is optionally substituted with halogen, C1-3 alkyl, or C1-3 haloalkyl. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 6-membered spiro heterocycle, wherein the 6-membered spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the spiro heterocycle is optionally substituted with halogen. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 7-membered spiro heterocycle, wherein the 7-membered spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the spiro heterocycle is optionally substituted with halogen. In an embodiment, R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-2 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-2 alkyl.

The present invention also provides a compound of Formula Ig*-2:




wherein R2, R3a, R3b, R5a, R5b, R5c, R5d, Z1, Z2, Z3, X1, p, r, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, R2 is F, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is N—, Z3 is —S—, R2 is Cl, r is 0, and p and v are 1. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, r is 0, and p and v are 1. In an embodiment, R5b and R5c are each independently C1-3 alkyl, C1-3 alkyl substituted with 1, 2, or 3 deuterium, or a C3-5 cycloalkyl optionally substituted with halogen or C1-3 haloalkyl. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle, wherein the heterocycle is optionally substituted with one or more halogen, deuterium, C1-3 alkyl, or C1-3 haloalkyl. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 6-, 7-, or 8-membered spiro heterocycle, wherein the spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the spiro heterocycle is optionally substituted with halogen, C1-3 alkyl, or C1-3 haloalkyl. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 6-membered spiro heterocycle, wherein the 6-membered spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the spiro heterocycle is optionally substituted with halogen. In an embodiment, R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 7-membered spiro heterocycle, wherein the 7-membered spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the spiro heterocycle is optionally substituted with halogen. In an embodiment, R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-2 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-2 alkyl.

The present invention also provides a compound of Formula Ih-2:




wherein R2, R3a, R3b, R5e, R5f, Z1, Z2, Z3, X1, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and v is 1. In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 4-membered heterocycle (e.g., oxetanyl). In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 5-membered heterocycle. In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 6-membered heterocycle.

The present invention also provides a compound of Formula Ih*-2:




wherein R2, R3a, R3b, R5e, R5f, Z1, Z2, Z3, X1, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, and v is 1. In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle. In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 4-membered heterocycle (e.g., oxetanyl). In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 5-membered heterocycle. In an embodiment, R5e and R5f together with the carbon atom to which they are attached form a 6-membered heterocycle.

The present invention also provides a compound of Formula Ia-3:




wherein R2, R3a, R3b, R7, R7a, Z1, Z2, Z3, X1, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 4-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 5-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7 and R7a together with the atoms to which they are attached form a 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S.

The present invention also provides a compound of Formula Ja*-3:




wherein R2, R3a, R3b, R7, R7a, Z1, Z2, Z3, X1, and v are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 4-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 5-membered heterocycle optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7a is a 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S (e.g., 1,4-dioxanyl). In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is Cl, R7 is a C1-2 alkyl, and R7 and R7a together with the atoms to which they are attached form a 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S (e.g., morpholinyl).

The present invention also provides a compound of Formula Ig-1:




    
    
        wherein R2, R3a, R3b, R3c, R6, Z1, Z2, Z3, X1, v, and n are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is C1, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, v is 1, and n is 0. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, v is 1, and n is 0.
    
    


The present invention also provides a compound of Formula Ig*-1:




    
    
        wherein R2, R3a, R3b, R3c, R6, Z1, Z2, Z3, X1, v, and n are as defined above, or a pharmaceutically acceptable salt thereof. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —S—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is Cl. In an embodiment, Z1 is —N—, Z2 is —N—, Z3 is —O—, and R2 is F. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is C1, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, R2 is F, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is Cl, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, v is 1, and n is 0. In an embodiment, Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, R2 is F, v is 1, and n is 0. In an embodiment, Z1 is —N—, Z2 is —C(R3)—, Z3 is —S—, R2 is F, v is 1, and n is 0.
    
    


References to Formula I should be understood to refer to compounds of Formula I together with any and all sub-formulae disclosed herein, including Formulae I′, Ia, Ib, Ic, Id, Ie, If, Ih, Ii, Ij, Ik, Im, Ia*, Ib*, Ic*, Id*, Ie*, If*, Ih*, Ii*, Ij*, Ik*, Im*, Ia-1, Ib-1, Ic-1, Id-1, Ie-1, If-1, Ig-1, Ih-1, Ia*-1, Ib*-1, Ic*-1, Id*-1, Ie*-1, If*-1, Ig*-1, Ih*-1, Ia-2, Ib-2, Ic-2, Id-2, Ie-2, If-2, Ig-2, Ih-2, Ia*-2, Ib*-2, Ic*-2, Id*-2, Ie*-2, If*-2, Ig*-2, Ih*-2, Ia-3, or Ia*-3.
In the above embodiments of the compounds of Formula I, the chemical drawings are shown flat without chiral information. These compounds often have multiple chiral centers and are contemplated to exist in various forms with various combinations of chiral centers. Additionally, these compounds have various enantiomers, diastereomers, and atropisomers that can exist and are included herein.
In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound is an isotopic derivative of any one of the compounds described herein or a pharmaceutically acceptable salt thereof.
It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivatives can generally be prepared by carrying out the procedures disclosed in the schemes and/or in the examples described herein or a pharmaceutically acceptable salt thereof, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
In an embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound is a deuterium labeled compound of any one of the compounds described herein and pharmaceutically acceptable salts thereof. In a further embodiment of a compound of Formula I or a pharmaceutically acceptable salt thereof, the compound may be deuterated at one or more positions. Unless otherwise stated, when an atom is designated specifically as “H” or “hydrogen”, the atom is understood to have hydrogen at its natural abundance isotopic composition. Also, unless otherwise stated, when an atom is designated specifically as “D” or “deuterium”, the atom is understood to have deuterium at an abundance substantially greater than the natural abundance of deuterium, which is 0.015%.
The following are further numbered embodiments of the invention:
Embodiment 1. A compound of the formula:




    
    
        wherein:
        A is —C(H)— or —N—;
        B is —C(R4)— or —N—;
        R1 is a group of the formula
    
    






    
    
        
        
            R1b is H or C1-3 alkyl;
            R1d is C1-3 alkyl, C1-3 haloalkyl, or C3-4 cycloalkyl;
            R1e is C1-3 alkylene;
            Ring A1 and Ring A2 are C3-4 cycloalkyl or a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S;
            X1 and X2 are —CH— or —N—;
            X3 is —CH2— or —O—;
            X4 and X5 are each independently C1-3 alkyl, halogen, or H;
            m, m′, s, t, u, v, and w are each 0 or 1;
        
        
        R2 is halogen or C1-3 alkyl;
        Z1 is —C(CN)— or —N—;
        Z2 is —C(R3c)— or —N—;
        Z3 is —O— or —S—;
        R3a, R3b, and R3c are each independently H, halogen, or C1-3 alkyl;
        R4 is H, C1-3 alkyl, C1-3 alkoxy optionally substituted with 1, 2, 3, or 4 substituents independently selected from hydroxyl and methyl, or
        R4 is a group of the formula
    
    






wherein

    
    
        R4b is H or methyl; and
        R4c and R4d are each independently C1-3 alkyl, hydroxyl, or C1-3 haloalkyl; or
        R4c and R4d together with the nitrogen or carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle; or
    
    






wherein

    
    
        R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl;
        R5d is C1-3 alkyl;
        R5e and R5f together with the carbon atom to which they are attached form a 4-, 5-, or 6-membered heterocycle;
        R5b and R5c are each independently H, C1-6 alkyl optionally substituted with one or more deuterium, C3-5 cycloalkyl optionally substituted with halogen or C1-3 haloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or
        R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle or a 6-, 7-, or 8-membered spiro heterocycle, wherein each heterocycle or spiro heterocycle optionally contains a further heteroatom selected from N, O, and S, and wherein the heterocycle and the spiro heterocycle is each optionally substituted with one or more halogen, deuterium, C1-3 alkyl, or C1-3 haloalkyl; or R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-3 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl; and
        p and r are each 0, 1, or 2;
    
    






wherein

    
    
        R6 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl,
        C1-3 alkoxy, and C1-3 dialkylamino; and
        n is O or 1; and
    
    






wherein

    
    
        R7 is a C1-3 alkyl; and
        R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S; or
        R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S;

or a pharmaceutically acceptable salt thereof.

    
    


Embodiment 2. A compound of the formula:




    
    
        wherein:
        R1 is a group of the formula
    
    






    
    
        
        
            R1b is H or C1-3 alkyl;
            R1d is C1-3 alkyl;
            R1e is C1-3 alkylene;
            Ring A1 and Ring A2 are C3-4 cycloalkyl or a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S;
            X1 and X2 are —CH— or —N—;
            X3 is —CH2— or —O—;
            X4 and X5 are each independently C1-3 alkyl, halogen, or H;
            m, m′, s, t, u, v, and w are each 0 or 1;
        
        
        R2 is halogen;
        Z1 is —C(CN)— or —N—;
        Z2 is —C(R3c)— or —N—;
        Z3 is —O— or —S—;
        R3a, R3b, and R3c are each independently H or halogen;
        R4 is a group of the formula
    
    






wherein

    
    
        R4b is H or methyl; and
        R4c and R4d are each independently C1-3 alkyl; or
    
    






wherein

    
    
        R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl;
        R5b and R5c are each independently H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or
        R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; or
        R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-3 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl; and
        p is 0, 1, or 2;
    
    






wherein

    
    
        R6 is selected from halogen, hydroxy, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 alkoxy, and C1-3 dialkylamino; and
        n is 0 or 1;

or a pharmaceutically acceptable salt thereof.

    
    


Embodiment 3. A compound of the formula:




    
    
        wherein:
        R1 is a group of the formula
    
    






    
    
        
        
            R1b is C1-3 alkyl;
            R1d is C1-3 alkyl;
            R1e is C1-3 alkylene;
            Ring A1 and Ring A2 are C3-4 cycloalkyl or a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S;
            X1 and X2 are —CH— or —N—;
            X3 is —CH2— or —O—;
            s, t, u, v, and w are each 0 or 1;
        
        
        R2 is halogen;
        Z1 is —C(CN)— or —N—;
        Z2 is —C(R3c)— or —N—;
        Z3 is —O— or —S—;
        R3a, R3b, and R3c are each independently H or halogen;
        R4 is a group of the formula
    
    






wherein

    
    
        R4b is H or methyl; and
        R4c and R4d are each independently C1-3 alkyl; or
    
    






wherein

    
    
        R5a is halogen, hydroxy, C1-3 alkyl, C1-3 alkoxy, or C1-3 alkoxy-C1-3 alkyl;
        R5b and R5c are each independently H, C1-6 alkyl, C3-5 cycloalkyl, or 3-, 4-, or 5-membered heterocycle containing a heteroatom selected from N, O, and S; or
        R5b and R5c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S, wherein the heterocycle is optionally substituted with a C1-3 alkyl; or
        R5a and R5b together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic fused ring optionally containing a further heteroatom selected from N, O, and S, R5c is C1-3 alkyl, and the 4-, 5-, or 6-membered fused ring is optionally further substituted with a C1-3 alkyl; and
        p is0 or 1;

or a pharmaceutically acceptable salt thereof.

    
    


Embodiment 4. The compound according to any one of embodiments 1-3, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 5. The compound according to embodiment 4, wherein R1d is methyl or ethyl, or a pharmaceutically acceptable salt thereof.
Embodiment 6. The compound according to embodiment 1, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 7. The compound according to embodiment 1 or 6, wherein R1d is methyl, ethyl, or difluoromethyl, or a pharmaceutically acceptable salt thereof.
Embodiment 8. The compound according to any one of embodiments 1-3, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 9. The compound according to embodiment 8, wherein R1e is methylene, or a pharmaceutically acceptable salt thereof.
Embodiment 10. The compound according to any one of embodiments 1-3, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 11. The compound according to embodiment 10, wherein Ring A1 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof.
Embodiment 12. The compound according to embodiment 10, wherein Ring A1 is cyclopropyl, or a pharmaceutically acceptable salt thereof.
Embodiment 13. The compound according to embodiment 10, wherein Ring A1 is cyclobutyl, or a pharmaceutically acceptable salt thereof.
Embodiment 14. The compound according to embodiment 10, wherein Ring A1 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof.
Embodiment 15. The compound according to embodiment 10, wherein Ring A1 is oxetanyl, or a pharmaceutically acceptable salt thereof.
Embodiment 16. The compound according to any one of embodiments 1-3, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 17. The compound according to embodiment 16, wherein Ring A2 is C3-4 cycloalkyl, or a pharmaceutically acceptable salt thereof.
Embodiment 18. The compound according to embodiment 16, wherein Ring A2 is cyclopropyl, or a pharmaceutically acceptable salt thereof.
Embodiment 19. The compound according to embodiment 16, wherein Ring A2 is cyclobutyl, or a pharmaceutically acceptable salt thereof.
Embodiment 20. The compound according to embodiment 16, wherein Ring A2 is a 3- or 4-membered heterocycle containing a heteroatom selected from N, O, and S, or a pharmaceutically acceptable salt thereof.
Embodiment 21. The compound according to embodiment 16, wherein Ring A2 is oxetanyl, or a pharmaceutically acceptable salt thereof.
Embodiment 22. The compound according to any one of embodiments 1 or 4-21, wherein A is —C(H)—, or a pharmaceutically acceptable salt thereof.
Embodiment 23. The compound according to any one of embodiments 1 or 4-21, wherein A is —N—, or a pharmaceutically acceptable salt thereof.
Embodiment 24. The compound according to any one of embodiments 1 or 4-23, wherein B is —C(R4)—, or a pharmaceutically acceptable salt thereof.
Embodiment 25. The compound according to any one of embodiments 1 or 4-23, wherein B is —N—, or a pharmaceutically acceptable salt thereof.
Embodiment 26. The compound according to any one of embodiments 1-25, wherein R1b is C1-3 alkyl, or a pharmaceutically acceptable salt thereof.
Embodiment 27. The compound according to any one of embodiments 1-25, wherein R1b is methyl, or a pharmaceutically acceptable salt thereof.
Embodiment 28. The compound according to any one of embodiments 1-25, wherein R1b is hydrogen, or a pharmaceutically acceptable salt thereof.
Embodiment 29. The compound according to embodiment 1, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 30. The compound according to embodiment 29, wherein X4 and X5 are fluoro, or a pharmaceutically acceptable salt thereof.
Embodiment 31. The compound according to embodiment 29 or 30, wherein X3 is —O—, or a pharmaceutically acceptable salt thereof.
Embodiment 32. The compound according to embodiment 29 or 30, wherein X3 is —CH2—, or a pharmaceutically acceptable salt thereof.
Embodiment 33. The compound according to embodiment 1, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 34. The compound according to embodiment 33, wherein X4 is methyl and X5 is hydrogen, or a pharmaceutically acceptable salt thereof.
Embodiment 35. The compound according to embodiment 33 or 34, wherein X3 is —O—, or a pharmaceutically acceptable salt thereof.
Embodiment 36. The compound according to any one of embodiments 1-3, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 37. The compound according to embodiment 36, wherein X1 is —CH—, or a pharmaceutically acceptable salt thereof.
Embodiment 38. The compound according to embodiment 36, wherein X1 is —N—, or a pharmaceutically acceptable salt thereof.
Embodiment 39. The compound according to any one of embodiments 1-3, wherein R1 is a group of formula




or a pharmaceutically acceptable salt thereof.

Embodiment 40. The compound according to embodiment 39, wherein X2 is —CH—, or a pharmaceutically acceptable salt thereof.
Embodiment 41. The compound according to embodiment 39, wherein X2 is —N—, or a pharmaceutically acceptable salt thereof.
Embodiment 42. The compound according to any one of embodiments 39-41, wherein X3 is —CH2—, or a pharmaceutically acceptable salt thereof.
Embodiment 43. The compound according to any one of embodiments 39-41, wherein X3 is —O—, or a pharmaceutically acceptable salt thereof.
Embodiment 44. The compound according to any one of embodiments 1-3, wherein R1 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 45. The compound according to embodiment 44, wherein R1 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 46. The compound according to embodiment 1, wherein R1 is a group of the formula




pharmaceutically acceptable salt thereof.

Embodiment 47. The compound according to embodiment 1-2 or 46, wherein R1 is a group of the formula




pharmaceutically acceptable salt thereof.

Embodiment 48. The compound according to embodiment 46, wherein R1 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 49. The compound according to embodiment 46 or 47, wherein R1 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 50. The compound according to any one of embodiments 1-49, wherein R2 is F or Cl, or a pharmaceutically acceptable salt thereof.
Embodiment 51. The compound according to any one of embodiments 1-50, wherein R2 is F, or a pharmaceutically acceptable salt thereof.
Embodiment 52. The compound according to any one of embodiments 1-50, wherein R2 is Cl, or a pharmaceutically acceptable salt thereof.
Embodiment 53. The compound according to embodiment 1, wherein R2 is methyl, or a pharmaceutically acceptable salt thereof.
Embodiment 54. The compound according to any one of embodiments 1-53, wherein Z1 is —C(CN)—, Z2 is —C(R3c)—, Z3 is —S—, and R3a is H, or a pharmaceutically acceptable salt thereof.
Embodiment 55. The compound according to embodiment 54, wherein R3b is halogen (preferably fluoro), and R3c is H, or a pharmaceutically acceptable salt thereof.
Embodiment 56. The compound according to embodiment 54, wherein R3b is H, and R3c is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.
Embodiment 57. The compound according to embodiment 54, wherein R3b is halogen (preferably fluoro), and R3c is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.
Embodiment 58. The compound according to any one of embodiments 1-53, wherein Z1 is —C(CN)—, Z2 is —N—, Z3 is —S—, and R3a is H, or a pharmaceutically acceptable salt thereof.
Embodiment 59. The compound according to embodiment 58, wherein R3b is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.
Embodiment 60. The compound according to any one of embodiments 1-53, wherein Z1 is —N—, Z2 is —C(R3c)—, Z3 is —S—, and R3a is H, or a pharmaceutically acceptable salt thereof.
Embodiment 61. The compound according to embodiment 60, wherein R3b is halogen (preferably fluoro), and R3c is H, or a pharmaceutically acceptable salt thereof.
Embodiment 62. The compound according to embodiment 60, wherein R3b is H, and R3c is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.
Embodiment 63. The compound according to embodiment 60, wherein R3b is halogen (preferably fluoro), and R3c is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.
Embodiment 64. The compound according to embodiment 60, wherein R3b is H, and R3c is H, or a pharmaceutically acceptable salt thereof.
Embodiment 65. The compound according to any one of embodiments 1-53, wherein Z1 is —N—, Z2 is —N—, Z3 is —S—, and R3a is H, or a pharmaceutically acceptable salt thereof.
Embodiment 66. The compound according to embodiment 65, wherein R3b is halogen (preferably fluoro), or a pharmaceutically acceptable salt thereof.
Embodiment 67. The compound according to any one of embodiments 1-53, wherein Z1 is —N—, Z2 is —C(R3c)—, Z3 is —O—, and R3a is H, or a pharmaceutically acceptable salt thereof.
Embodiment 68. The compound according to embodiment 67, wherein R3b is hydrogen, or a pharmaceutically acceptable salt thereof.
Embodiment 69. The compound according to any one of embodiments 1-53, wherein R3b is fluoro or hydrogen, or a pharmaceutically acceptable salt thereof.
Embodiment 70. The compound according to any one of embodiments 1-53, wherein R3b is fluoro, or a pharmaceutically acceptable salt thereof.
Embodiment 71. The compound according to any one of embodiments 1 or 4-53, wherein R3a is methyl, or a pharmaceutically acceptable salt thereof.
Embodiment 72. The compound according to any one of embodiments 1-53, wherein R3b is hydrogen, or a pharmaceutically acceptable salt thereof.
Embodiment 73. The compound according to any one of embodiments 1 or 4-72, wherein R4 is H, C1-3 alkyl, or C1-3 alkoxy optionally substituted with 1, 2, 3, or 4 substituents independently selected from hydroxyl and methyl, or a pharmaceutically acceptable salt thereof.
Embodiment 74. The compound according to embodiment 73, wherein R4 is H, or a pharmaceutically acceptable salt thereof.
Embodiment 75. The compound according to any one of embodiments 1-72, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 76. The compound according to embodiment 75, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 77. The compound according to embodiment 76, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 78. The compound according to any one of embodiments 1 or 4-72, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 79. The compound according to embodiment 1 or 78, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 80. The compound according to any one of embodiments 1 or 4-72, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 81. The compound according to any one of embodiments 1 or 4-72, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 82. The compound according to embodiment 81, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 83. The compound according to any one of embodiments 1-72 or 81, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 84. The compound according to embodiment 83, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 85. The compound according to embodiment 1, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 86. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 87. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 88. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 89. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 90. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 91. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 92. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 93. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




Embodiment 94. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 95. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 96. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 97. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 98. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 99. The compound according to embodiment 84 or 85, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 100. The compound according to any one of embodiments 1-2 or 4-72, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 101. The compound according to embodiment 100, wherein n is 0, or a pharmaceutically acceptable salt thereof.
Embodiment 102. The compound according to embodiment 100, wherein R6 is selected from C1-3 alkyl, C1-3 haloalkyl, and C1-3 dialkylamino, or a pharmaceutically acceptable salt thereof.
Embodiment 103. The compound according to any one of embodiments 100-102, wherein R6 is dimethylamino, or a pharmaceutically acceptable salt thereof.
Embodiment 104. The compound according to any one of embodiments 102-103, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 105. The compound according to any one of embodiments 1 or 4-72, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 106. The compound according to embodiment 105, wherein

    
    
        R7 is a C1-3 alkyl; and
        R7a is a 4-, 5-, or 6-membered heterocycle optionally containing a further heteroatom selected from N, O, and S; or
        R7 and R7a together with the atoms to which they are attached form a 4-, 5-, or 6-membered heterocyclic ring optionally containing a further heteroatom selected from N, O, and S.
    
    


Embodiment 107. The compound according to embodiment 105 or 106, wherein R4 is a group of the formula




or a pharmaceutically acceptable salt thereof.

Embodiment 108. The compound according to any one of embodiments 1-3, wherein the compound is selected from
















    
    
        or a pharmaceutically acceptable salt thereof.
    
    


Embodiment 109. The compound according to any one of embodiments 1-3, or 108, wherein the compound is selected from













or a pharmaceutically acceptable salt thereof.

Embodiment 110. The compound according to embodiment 1 or 2, wherein the compound is selected from

























or a pharmaceutically acceptable salt thereof.

Embodiment 111. The compound according to any one of embodiments 1, 2, or 110, wherein the compound is selected from






















or a pharmaceutically acceptable salt thereof.

Embodiment 112. The compound according to embodiment 1, wherein the compound is selected from




























or a pharmaceutically acceptable salt thereof.

Embodiment 113. The compound according to embodiment 1 or 112, wherein the compound is selected from































or a pharmaceutically acceptable salt thereof.

Embodiment 114. A pharmaceutical composition comprising a compound according to any one of embodiments 1-113, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
Embodiment 115. A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to embodiment 114, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.
Embodiment 116. A method of treating a patient with cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to any one of embodiments 1-113, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.
Embodiment 117. The method according to embodiment 115 or embodiment 116, wherein the patient has a cancer that was determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
Embodiment 118. The method according to embodiment 115 or embodiment 116, wherein one or more cells express KRAS G12V mutant protein.
Embodiment 119. A method of treating a patient with a cancer that has a KRAS G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to any one of embodiments 1-113, or a pharmaceutically acceptable salt thereof.
Embodiment 120. The method according to embodiment 119, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.
Embodiment 121. The method according to any one of embodiments 115-120, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof.
Embodiment 122. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-113, for use in therapy.
Embodiment 123. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-113, for use in the treatment of cancer.
Embodiment 124. The compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 123, wherein the cancer has a KRAS G12V mutation.
Embodiment 125. The compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 123 or embodiment 124, wherein the cancer is selected from lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer.
Embodiment 126. The compound, or a pharmaceutically acceptable salt thereof, according to any one of embodiments 1-113 for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer.
Embodiment 127. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of a PD-1 inhibitor.
Embodiment 128. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of a PD-L1 inhibitor.
Embodiment 129. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of a CDK4/CDK6 inhibitor.
Embodiment 130. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of an EGFR inhibitor.
Embodiment 131. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of an ERK inhibitor.
Embodiment 132. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of an Aurora A inhibitor.
Embodiment 133. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of a SHP2 inhibitor.
Embodiment 134. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of a platinum agent.
Embodiment 135. The method according to embodiment 121, or compound, or a pharmaceutically acceptable salt thereof, for use according to embodiment 126, wherein the patient is also administered an effective amount of pemetrexed, or pharmaceutically acceptable salts thereof.
Embodiment 136. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is non-small cell lung cancer.
Embodiment 137. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is colorectal cancer.
Embodiment 138. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is pancreatic cancer.
Embodiment 139. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is cervical cancer.
Embodiment 140. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is esophageal cancer.
Embodiment 141. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is endometrial cancer.
Embodiment 142. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is ovarian cancer.
Embodiment 143. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is cholangiocarcinoma.
Embodiment 144. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is stomach adenocarcinoma.
Embodiment 145. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is invasive ductal carcinoma.
Embodiment 146. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is uterine carcinosarcoma.
Embodiment 147. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is a germ cell tumor.
Embodiment 148. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is bladder cancer.
Embodiment 149. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is small bowel adenocarcinoma.
Embodiment 150. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is appendix cancer.
Embodiment 151. The method according to any one of embodiments 115-121 or 127-135, or the compound, or a pharmaceutically acceptable salt thereof, for use according to any one of embodiments 123-135, wherein the cancer is peritoneum cancer.
The chemical drawings in the compounds above contain indications of chiral aspects of the specific compounds shown. However, the chemical drawings in the compounds above do not contain all the possible chiral features of these compounds and the chiral indications shown are not intended to exclude changes to the chiral aspects shown. Thus, alternate chiral versions of the compounds as well as different combinations of chiral attributes are contemplated and included herein.
Further provided herein are methods of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. In this method, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer. In this method, the cancer can more specifically be non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In an embodiment the cancer can be non-small cell lung cancer. In an embodiment the cancer can be pancreatic cancer. In an embodiment the cancer can be colorectal cancer. In an embodiment the cancer can be stomach adenocarcinoma. In an embodiment the cancer can be invasive ductal carcinoma. In an embodiment the cancer can be uterine carcinosarcoma. In an embodiment the cancer can be germ cell tumors. In an embodiment the cancer can be bladder cancer. In an embodiment the cancer can be small bowel adenocarcinoma. In an embodiment the cancer can be appendix cancer. In an embodiment the cancer can be peritoneum cancer.
Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. In this method, the cancer can be non-small cell lung cancer, pancreatic cancer, or colorectal cancer, in which the cancer has one or more cells that express a KRAS G12V mutant protein. In an embodiment, the cancer is non-small cell lung carcinoma in which the cancer has one or more cells that express a KRAS G12V mutant protein. In an embodiment, the cancer is mutant pancreatic cancer in which the cancer has one or more cells that express a KRAS G12V mutant protein. In an embodiment, the cancer is colorectal carcinoma in which the cancer has one or more cells that express a KRAS G12V mutant protein. This method also includes treating KRAS G12V mutant bearing cancers of other origins.
Further provided herein is a method of treating a patient with a cancer that has a KRAS G12V mutation comprising administering to a patient in need thereof an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt thereof. In this method, the cancer that has a KRAS G12V mutation can be KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant stomach adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumors, KRAS G12V mutant bladder cancer, KRAS G12V mutant small bowel adenocarcinoma, KRAS G12V mutant appendix cancer, and KRAS G12V mutant peritoneum cancer. In an embodiment the cancer that has a KRAS G12V mutation can be KRAS G12V mutant non-small cell lung cancer. In an embodiment the cancer that has a KRAS G12V mutation can be KRAS G12V mutant pancreatic cancer. In an embodiment the cancer that has a KRAS G12V mutation can be KRAS G12V mutant colorectal cancer.
Additionally provided herein is a method of modulating a mutant KRAS G12V enzyme in a patient in need thereof, by administering a compound according to Formula I, or a pharmaceutically acceptable salt thereof. In one embodiment this method comprises inhibiting a human mutant KRAS G12V enzyme.
Also provided herein is a method of treating cancer in a patient in need thereof, wherein the patient has a cancer that was determined to express the KRAS G12V mutant protein. The method comprises administering to a patient an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof. The G12V mutational status of one or more cancer cells can be determined by a number of assays known in the art. Typically, one or more biopsies containing one or more cancer cells are obtained, and subjected to sequencing and/or polymerase chain reaction (PCR). Circulating cell-free DNA can also be used, e.g. in advanced cancers. Non-limiting examples of sequencing and PCR techniques used to determine the mutational status (e.g., G12C, G12D, and/or G12V mutational status, in one or more cancer cells or in circulating cell-free DNA) include direct sequencing, next-generation sequencing, reverse transcription polymerase chain reaction (RT-PCR), multiplex PCR, and pyrosequencing and multi-analyte profiling.
Further provided herein is a compound or a pharmaceutically acceptable salt thereof according to Formula I for use in therapy. The compound or a pharmaceutically acceptable salt thereof, can be for use in treating cancer. For this use in treating cancer, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is cervical cancer. In an embodiment, the cancer is esophageal cancer. In an embodiment, the cancer is endometrial cancer. In an embodiment, the cancer is ovarian cancer. In an embodiment, the cancer is cholangiocarcinoma. In an embodiment, the cancer is colorectal cancer. In an embodiment, the cancer is stomach adenocarcinoma. In an embodiment, the cancer is invasive ductal carcinoma. In an embodiment, the cancer is uterine carcinosarcoma. In an embodiment, the cancer is germ cell tumors. In an embodiment, the cancer is bladder cancer. In an embodiment, the cancer is small bowel adenocarcinoma. In an embodiment, the cancer is appendix cancer. In an embodiment, the cancer is peritoneum cancer. The cancer can have one or more cancer cells that express the mutant KRAS G12V protein such as KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant stomach adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumors, KRAS G12V mutant bladder cancer, KRAS G12V mutant small bowel adenocarcinoma, KRAS G12V mutant appendix cancer, or KRAS G12V mutant peritoneum cancer. Additionally, the cancer can be non-small cell lung cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be colorectal cancer, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be pancreatic cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant cervical cancer, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant esophageal cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant endometrial cancer, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant ovarian cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant cholangiocarcinoma, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant stomach adenocarcinoma, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant invasive ductal carcinoma, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant uterine carcinosarcoma, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant germ cell tumors, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant bladder cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant small bowel adenocarcinoma, and one or more cells express KRAS G12V mutant protein. Additionally, the cancer can be KRAS G12V mutant appendix cancer, and one or more cells express KRAS G12V mutant protein. Further, the cancer can be KRAS G12V mutant peritoneum cancer, and one or more cells express KRAS G12V mutant protein. The patient can have a cancer that was determined to have one or more cells expressing the KRAS G12V mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof. The patient may have been treated with a different course of treatment prior to being treated as described herein.
The compounds provided herein according to Formula I, or a pharmaceutically acceptable salt thereof, may also be used in the manufacture of a medicament for treating cancer. When used in the manufacture of a medicament, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, and peritoneum cancer. In an embodiment, the cancer is non-small cell lung cancer. In an embodiment, the cancer is pancreatic cancer. In an embodiment, the cancer is cervical cancer. In an embodiment, the cancer is esophageal cancer. In an embodiment, the cancer is endometrial cancer. In an embodiment, the cancer is ovarian cancer. In an embodiment, the cancer is cholangiocarcinoma. In an embodiment, the cancer is colorectal cancer. In an embodiment, the cancer is stomach adenocarcinoma. In an embodiment, the cancer is invasive ductal carcinoma. In an embodiment, the cancer is uterine carcinosarcoma. In an embodiment, the cancer is germ cell tumors. In an embodiment, the cancer is bladder cancer. In an embodiment, the cancer is small bowel adenocarcinoma. In an embodiment, the cancer is appendix cancer. In an embodiment, the cancer is peritoneum cancer. The cancer can have one or more cancer cells that express the mutant KRAS G12V protein. When the cancer cells express KRAS G12V protein, the cancer can be selected from KRAS G12V mutant lung cancer, KRAS G12V mutant pancreatic cancer, KRAS G12V mutant cervical cancer, KRAS G12V mutant esophageal cancer, KRAS G12V mutant endometrial cancer, KRAS G12V mutant ovarian cancer, KRAS G12V mutant cholangiocarcinoma, KRAS G12V mutant colorectal cancer, KRAS G12V mutant stomach adenocarcinoma, KRAS G12V mutant invasive ductal carcinoma, KRAS G12V mutant uterine carcinosarcoma, KRAS G12V mutant germ cell tumors, KRAS G12V mutant bladder cancer, KRAS G12V mutant small bowel adenocarcinoma, KRAS G12V mutant appendix cancer, and KRAS G12V mutant peritoneum cancer.
Also provided herein is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided herein is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, in the treatment of cancer. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and one or more of a PD-1 or PD-L1 inhibitor, a CDK4/CDK6 inhibitor, an EGFR inhibitor, an ERK inhibitor, an Aurora A inhibitor, a SHP2 inhibitor, a platinum agent, and pemetrexed, or pharmaceutically acceptable salts thereof, for simultaneous, separate, or sequential use in the treatment of cancer.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a PD-1 or PD-L1 inhibitor, for use in the treatment of cancer. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the PD-1 or PD-L1 inhibitor can be pembrolizumab; the PD-1 or PD-L1 inhibitor can be nivolumab; the PD-1 or PD-L1 inhibitor can be cemiplimab; the PD-1 or PD-L1 inhibitor can be sintilimab; the PD-1 or PD-L1 inhibitor can be atezolizumab; the PD-1 or PD-L1 inhibitor can be avelumab; the PD-1 or PD-L1 inhibitor can be durvalumab; or the PD-1 or PD-L1 inhibitor can be lodapilimab.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. As used herein, the CDK4/CDK6 inhibitor can be abemaciclib; the CDK4/CDK6 inhibitor can be palbociclib; or the CDK4/CDK6 inhibitor can be ribociclib.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer. Additional provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the EGFR inhibitor can be erlotinib; the EGFR inhibitor can be afatinib; the EGFR inhibitor can be gefitinib; or the EGFR inhibitor can be cetuximab.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an ERK inhibitor, or a pharmaceutically acceptable salt thereof, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the ERK inhibitor can be LY3214996; the ERK inhibitor can be LTT462; or the ERK inhibitor can be KO-947.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with an Aurora A inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and an Aurora A inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the Aurora A inhibitor can be alisertib, tozasertib, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid, (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid: 2-methylpropan-2-amine (1:1) salt, and (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid:amine (1:1) salt, or a pharmaceutically acceptable salt thereof. In one embodiment, the Aurora A inhibitor is (2R,4R)-1-[(3-chloro-2-fluoro-phenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-pyridyl]methyl]-2-methyl-piperidine-4-carboxylic acid.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, can be a Type I SHP2 Inhibitor or a Type II SHP2 Inhibitor. Examples of Type I SHP2 inhibitors include, but are not limited to, PHPS1, GS-493, NSC-87877, NSC-117199, and Cefsulodin, and pharmaceutically acceptable salts thereof. Examples of Type II SHP2 inhibitors include, but are not limited to, JAB-3068, JAB-3312, RMC-4550, RMC-4630, SHP099, SHP244, SHP389, SHP394, TNO155, RG-6433, and RLY-1971, and pharmaceutically acceptable salts thereof. Additional examples of SHP2 inhibitors include, but are not limited to, BBP-398, IACS-15509, IACS-13909, X37, ERAS-601, SH3809, HBI-2376, ETS-001, and PCC0208023, and pharmaceutically acceptable salts thereof. This method also includes treating KRAS G12V mutant protein mutant bearing cancers of other origins.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with a platinum agent, or a pharmaceutically acceptable salt thereof, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and a platinum agent, for simultaneous, separate, or sequential use in the treatment of cancer. As used herein, the platinum agent can be cisplatin; the platinum agent can be carboplatin; or the platinum agent can be oxaliplatin.
Also provided is a method of treating cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Further provided is a compound according to Formula I, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate, or sequential combination with pemetrexed, for the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein. Additionally provided is a combination comprising a compound according to Formula I, or a pharmaceutically acceptable salt thereof, and pemetrexed, for simultaneous, separate, or sequential use in the treatment of cancer, in which the cancer has one or more cells that express a mutant KRAS G12V protein.
As described above, the cancer can be lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer, in which the cancer has one or more cells that express a KRAS G12V mutant protein, or the cancer can be mutant lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, colorectal cancer, stomach adenocarcinoma, invasive ductal carcinoma, uterine carcinosarcoma, germ cell tumors, bladder cancer, small bowel adenocarcinoma, appendix cancer, or peritoneum cancer, in which the cancer has one or more cells that express a KRAS G12V mutant protein. These methods also include treating KRAS G12V mutant bearing cancers of other origins.
The term “pharmaceutically acceptable salt” as used herein refers to a salt of a compound considered to be acceptable for clinical and/or veterinary use. Examples of pharmaceutically acceptable salts and common methodology for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and S. M. Berge, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19.
Pharmaceutical compositions containing the compounds of Formula I as described herein may be prepared using pharmaceutically acceptable additives. The term “pharmaceutically acceptable additive(s)” as used herein for the pharmaceutical compositions, refers to one or more carriers, diluents, and excipients that are compatible with the other additives of the composition or formulation and not deleterious to the patient. Examples of pharmaceutical compositions and processes for their preparation can be found in “Remington: The Science and Practice of Pharmacy”, Loyd, V., et al. Eds., 22nd Ed., Mack Publishing Co., 2012. Non-limiting examples of pharmaceutically acceptable carriers, diluents, and excipients include the following: saline, water, starch, sugars, mannitol, and silica derivatives; binding agents such as carboxymethyl cellulose, alginates, gelatin, and polyvinyl-pyrrolidone; kaolin and bentonite; and polyethyl glycols.
As used herein, the term “effective amount” refers to an amount that is a dosage, which is effective in achieving a desired therapeutic result such as treating a disorder or disease, like a cancerous lesion or progression of abnormal cell growth and/or cell division. Factors considered in the determination of an effective amount or dose of a compound include: whether the compound or its salt will be administered; the co-administration of other agents, if used; the species of patient to be treated; the patient's size, age, gender, and general health; the degree of involvement or stage and/or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of other concomitant medication.
A treating physician, veterinarian, or other medical person will be able to determine an effective amount of the compound for treatment of a patient in need. Pharmaceutical compositions can be formulated as a tablet or capsule for oral administration, a solution for oral administration, or an injectable solution. The tablet, capsule, or solution can include a compound of the present invention in an amount effective for treating a patient in need of treatment with cancer.
As used herein, the terms “treating”, “to treat”, or “treatment”, includes slowing, controlling, delaying, reducing, stopping, reversing, preventing, or ameliorating the progression or severity of an existing symptom, disorder, condition, which can include specifically slowing the growth of a cancerous lesion or progression of abnormal cell growth and/or cell division. Treating does not necessarily indicate a total elimination of all disorder or disease symptoms.
As used herein, the term “patient” refers to a mammal in need of treatment. Specifically, the patient can be a human that is in need of treatment with cancer, for example, KRAS G12V mutant protein mutant bearing cancers.
Certain abbreviations are defined as follows: “ACN” refers to acetonitrile; “AcOH” or “HOAc” refer to acetic acid; “aq.” refers to aqueous; “conc.” refers to concentrated; “DCM” refers to dichloromethane; “DIBAL-H” refers to diisobutylaluminum hydride; “DIEA” and “DIPEA” refer to N,N-diisopropyl ethylamine; “DMAP” refers to 4-dimethylaminopyridine; “DMEA” refers to N,N-dimethylethylamine; “DMF” refers to N,N-dimethylformamide; “DMSO” refers to dimethylsulfoxide; “ELISA” refers to enzyme-linked immunosorbent assay; “ERK” refers to extracellular signal-regulated kinases; “Et” refers to an ethyl group; “EtOAc” refers to ethyl acetate; “Et2O” refers to diethyl ether; “EtOH” refers to ethanol; “FA” refers to formic acid; “FBS” refers to fetal bovine serum; “GDP” refers to guanosine diphosphate; “GTP” refers to guanosine triphosphate; “h” refers to hour or hours; “Hex” or “hex” refers to hexane or hexanes; “HPLC” refers to high-performance liquid chromatography; “IPA” refers to isopropyl alcohol; “IPAm” refers to isopropyl amine; “KOAc” refers to potassium acetate; “LC-ES/MS” refers to liquid chromatograph-electrospray mass spectrometry; “LC-MS” refers to liquid chromatography mass spectrometry; “LiHMDS” refers to lithium bis(trimethylsilyl)amide; “MAPK” refers to mitogen-activated protein kinases; “mCPBA” refers to 3-chloro-peroxybenzoic acid; “Me” refers to a methyl group; “MeOH” refers to methanol; “min” refers to minute or minutes; “MTBE” refers to methyl tert-butyl ether; “NMP” refers to 1-methylpyrrolidin-2-one; “Pd(OAc)2 refers to palladium (II) acetate; “RT” refers to room temperature; “sat.” refers to saturated; “SCX” refers to strong cation exchange; “TBAF” refers to tetrabutylammonium fluoride; “tBu” refers to the tert-butyl group; “t-BuOH” refers to tert-butanol or tert-butyl alcohol; “TEA” refers to triethylamine; “TFA” refers to trifluoracetic acid; “THF” refers to tetrahydrofuran; “XantPhos” refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; “XPhos” refers to 2-(dicyclohexylphosphino)-2′,4′,6′-tri-isopropyl-1,1′-biphenyl.
Individual isomers, enantiomers, diastereomers, and atropisomers may be separated or resolved at any convenient point in the synthesis of compounds listed below, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen, “Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). The molecules described herein include compounds that are atropisomers and which can exist in different conformations or as different rotomers. Atropisomers are compounds that exist in different conformations arising from restricted rotation about a single bond. Atropisomers can be isolated as separate chemical species if the energy barrier to rotation about the single bond is sufficiently high that the rate of interconversion is slow enough to allow the individual rotomers to be separated from each other. This description is intended to include all of the isomers, enantiomers, diastereomers, and atropisomers possible for the compounds disclosed herein or that could be made using the compounds disclosed herein. In the molecules described herein, only molecules in which the absolute conformation of a chiral center (or atropisomer conformation) is known have used naming conventions or chemical formula that are drawn to indicate the chirality or atropisomerism. Those of skill in the art will readily understand when other chiral centers are present in the molecules described herein and be able to identify the same.
Compounds of any one of Formula I that are chemically capable of forming salts are readily converted to and may be isolated as a pharmaceutically acceptable salt. Salt formation can occur upon the addition of a pharmaceutically acceptable acid to form the acid addition salt. Salts can also form simultaneously upon deprotection of a nitrogen or oxygen, i.e., removing the protecting group. Examples, reactions and conditions for salt formation can be found in Gould, P. L., “Salt selection for basic drugs,” International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities,” Organic Process Research and Development, 4: 427-435 (2000); and Berge, S. M., et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 66: 1-19, (1977).
The compounds of the present invention, or salts thereof, may be prepared by a variety of procedures, some of which are illustrated in the Schemes, Preparations, and Examples below. The specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different routes, to prepare compounds or salts of the present invention. The products of each step in the Preparations below can be recovered by conventional methods, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization.
Preparation 1
tert-Butyl (4-bromo-5-fluorobenzo[id]thiazol-2-yl)carbamate




To a mixture of 4-bromo-5-fluorobenzo[d]thiazol-2-amine (10.6 g, 42.9 mmol) and di-tert-butyl dicarbonate (10.3 g, 47.2 mmol) in DCM (100 mL) was added 4-dimethylaminopyridine (0.262 g, 2.14 mmol). The mixture was stirred at room temperature overnight, then combined with diatomaceous earth. The crude material was purified on silica, eluting with 0-100% EtOAc in DCM to obtain the title compound (13.4 g, 90%) as an off-white solid. MS (ES) m/z=347 (M-1).
The following compounds in Table 1 were prepared in similar manner as described in Preparation 1. A base, such as triethylamine or diisopropylethylamine, may have been used. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 1








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







2
tert-Butyl (4-chloro-7- fluorothiazolo[4,5- c]pyridin-2-yl)carbamate




304









Preparation 3
(2-((tert-Butoxycarbonyl)amino)-5-fluorobenzo[d]thiazol-4-yl)boronic acid




Sodium hydride (60 wt % in mineral oil; 1.73 g, 43.2 mmol) was mixed with THF (100 mL) under argon and cooled to 0° C. A mixture of tert-butyl (4-bromo-5-fluorobenzo[d]thiazol-2-yl)carbamate (10.0 g, 28.8 mmol) in THF (35 mL) was added. The mixture was stirred at 0° C. for 30 min, cooled to −78° C., and n-butyllithium (2.5M in hexanes; 17.3 mL, 43.2 mmol) was slowly added. The mixture was stirred at −78° C. for 15 min, then triisopropyl borate (19.9 mL, 86.4 mmol) was slowly added. The mixture was stirred at −78° C. for 1 h, −40° C. for 1 h, −10° C. for 45 min, then slowly quenched with saturated aqueous ammonium chloride. The mixture was diluted with water (100 mL) and extracted with EtOAc (300 mL, 200 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was diluted with hexanes, stirred at 50° C. for 30 min, cooled to room temperature, and filtered. The solids were washed with hexanes and dried under vacuum to obtain the title compound (7.2 g, 80%) as a white solid. MS (ES) m/z=313 (M+1).
Preparation 1A
(2-((tert-Butoxycarbonyl)amino)benzo[d]oxazol-4-yl)boronic acid




tert-Butyl (4-bromobenzo[d]oxazol-2-yl)carbamate was used in a manner analogous to the method of Preparation 3 to afford the title compound (0.23 g, 69%) as a white solid. MS (ES) m/z=279 (M+1).
Preparation 4
Methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate




A solution of methyl thioglycolate (0.18 mL, 2.0 mmol, 1 eq.) in THF (5 mL) was flushed with N2 and charged with NaH (60 mass %) in mineral oil (0.101 g, 2.53 mmol, 1.24 eq.) at RT. Gas evolution was observed, and a precipitate formed in the flask. The reaction was stirred at RT for 20 min. A solution of 2-bromo-3,6-difluorobenzaldehyde (0.475 g, 2.04 mmol) in THF (5 mL) was added slowly via syringe over −2 min. The reaction was stirred at RT for 9 h. Additional methyl thioglycolate (0.1 mL, 1 mmol, 0.5 eq.) and sodium hydride (60 mass %) in mineral oil (0.050 g, 1.3 mmol, 0.6 eq.) were added and stirring was continued at RT for ˜18 h. The mixture was diluted with EtOAc and washed with sat. aq. NH4Cl and brine. The organics were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica, eluting with 2% MTBE/Hex to obtain the title compound (0.346 g, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.23-8.19 (dd, J=4.49, 8.9 Hz, 1H), 8.05 (s, 1H), 7.62 (t, J=9.0 Hz, 1H), 3.93 (s, 3H).
Preparation 5
4-Bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid




A solution of methyl 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylate (19.2 g, 66.4 mmol, 1 eq.) in MeOH (130 mL) and THF (130 mL) was charged with 5N NaOH (66 mL, 330 mmol, 5 eq.) and stirred at RT for 40 min. The mixture was concentrated and H2O (500 mL) was added. The pH was adjusted to ˜2 with 5N HCl. The mixture was extracted with EtOAc (2×500 mL) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The solids were dried under vacuum at 50° C. to afford the title compound (17.6 g, 96%) as a white solid. MS (ES) m/z=229 (M-1-CO2).
Preparation 6
tert-Butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate




A solution of 4-bromo-5-fluorobenzo[b]thiophene-2-carboxylic acid (1.5 g, 5.5 mmol) in t-butanol (30 mL) was charged with TEA (1.5 mL, 11 mmol, 2.0 eq.) and diphenylphosphoryl azide (1.5 mL, 6.9 mmol, 1.3 eq.) and heated at 95° C. for 1 h. The mixture was cooled and concentrated. The residue was purified on silica, eluting with MTBE/Hex (4% to 20%) to obtain the title compound (0.987 g, 52%) as a white solid. MS (ES) m/z=290 (M+1).
Preparation 7
tert-Butyl (4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate




A mixture of tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (3.08 g, 8.90 mmol) and bis(neopentyl glycolato)diboron (4.02 g, 17.8 mmol, 2 eq.) and KOAc (2.62 g, 26.7 mmol, 3 eq.) in 1,4-dioxane (70 mL, 819.9 mmol) was sparged with N2 for 20 min. To the mixture was added Pd(ddpf)Cl2 (0.69 g, 0.90 mmol, 0.1 eq.). The reaction was sonicated for 3 min, then put through a vacuum/N2 refill cycle (3×) and was heated at 100° C. for 3 h. The mixture was cooled to RT, filtered through diatomaceous earth and was rinsed with 1:4 EtOAc/Hex. The filtrate was concentrated and the residue was purified on silica (0-40% MTBE/Hex) to obtain the title compound (2.95 g, 87%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.81-10.79 (bs, 1H), 7.84-7.74 (dd, J=5.07, 8.59, 1H), 7.14 (s, 1H), 6.94-6.88 (m, 1H), 3.89 (bs, 4H), 1.49 (s, I0H), 1.03 (s, 6H).
Preparation 8
tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate




Ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A solution of 2-(4-chloro-5-fluoropyridin-3-yl)acetonitrile (11.8 g, 56.1 mmol) in DMF (112 mL) was cooled to 0° C. Potassium tert-butoxide (7.00 g, 61.1 mmol) was added. After 15 min, ethoxycarbonyl isothiocyanate (7.45 mL, 61.8 mmol) was added dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight. The reaction mixture was poured into a mixture of ice/water (1.5 L), stirred until all ice had melted, and filtered through diatomaceous earth. The solids were dried in a vacuum oven (60° C.) overnight and separated from the diatomaceous earth to give ethyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 79%) as a solid. MS (ES) m/z=266 (M+1).
2-Amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile. A suspension of ethyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (11.9 g, 44.4 mmol) in DMSO (90 mL) was cooled to 0° C. NaOH (5 M in water, 90 mL) was added dropwise over 15 min. The reaction mixture was heated to 105° C. for 1 h, then cooled to room temperature. The reaction mixture was poured into a mixture of ice/water (1.8 L), stirred until all ice had melted, and filtered through diatomaceous earth. The solids were dried in a vacuum oven (50° C.) overnight and separated from the diatomaceous earth to give crude 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile.
tert-Butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A mixture of crude 2-amino-7-fluorothieno[3,2-c]pyridine-3-carbonitrile (8.6 g, 44.4 mmol), DCM (90 mL), DMF (90 mL) and N,N-diisopropylethylamine (15.5 mL, 88.9 mmol) was cooled to 0° C. 4-dimethylaminopyridine (0.54 g, 4.42 mmol) and di-tert-butyl dicarbonate (14.6 g, 66.7 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the remaining material was diluted with DCM (400 mL) and 5% aq. citric acid (250 mL). The aqueous phase was washed twice with DCM. The combined organic phases were washed with sat. aq. NaHCO3, dried over MgSO4, filtered, and concentrated to give tert-butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (7.5 g, 58%) as a brown solid. MS (ES) m/z=294 (M+1).
2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide. 3-Chloroperoxybenzoic acid (9.00 g, 40.2 mmol) was added to a solution of tert-butyl (3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate (7.85 g, 26.8 mmol) in DCM (180 mL). The reaction mixture was stirred at room temperature overnight, then cooled to 0° C. for −15 min. Solids were collected by filtration and dried in a vacuum oven (60° C.). The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica, eluting with 0-6% MeOH in DCM. Fractions containing desired material were combined with the solids from the filtration and concentrated to give tert-butyl N-(3-cyano-7-fluoro-5-oxido-thieno[3,2-c]pyridin-5-ium-2-yl)carbamate (7.26 g, 88%) as an off-white solid. MS (ES) m/z=310 (M+1).
tert-Butyl (4-chloro-3-cyano-7-fluorothieno[3,2-c]pyridin-2-yl)carbamate. A suspension of 2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorothieno[3,2-c]pyridine 5-oxide (5.27 g, 17.0 mmol) in 1,2-dichloroethane (34 mL) was cooled to 0° C. A solution of phosphoryl chloride (32 mL, 344 mmol) in 1,2-dichloroethane (34 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 min, at 45° C. for 90 min, and cooled to room temperature. The reaction mixture was diluted with 1,2-dichloroethane (100 mL) and added to a mixture of sat. aq. NaHCO3 (500 mL), NaOH (5 M in water, 40 mL), and ice. Solid NaHCO3 was added to the stirred mixture to maintain pH ˜6-7. Once bubbling ceased, the phases were separated. The aqueous phase was extracted 3× with DCM. The combined organic phases were dried over MgSO4 and filtered. The filtrate was diluted with MeOH and silica gel, concentrated, and the residue was purified on silica, eluting with 50-100% DCM in hexanes. Fractions containing desired material were concentrated to give the title compound (3.87 g, 69%) as a white solid. MS (ES) m/z=328 (M+1).
Preparation 9
5-Fluoroisobenzofuran-1(3H)-one




To a stirred mixture of (2-bromo-5-fluorophenyl)methanol (500 g, 2.44 mol) and TEA (474.6 mL, 3.41 mol, 1.4 eq.) in ACN (2500 mL) was added Pd(OAc)2 (10.95 g, 48.77 mmol, 0.02 eq.) and XantPhos (42.33 g, 73.16 mmol, 0.03 equiv.) at RT, then stirred for 3 days at 120° C. under 10 atm of carbon monoxide. The reaction was cooled to RT and concentrated. The residue was diluted with H2O (1,000 mL), then extracted with EtOAc (2×2000 mL). The combined organic layers were washed with brine (2×1,000 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with 10:1 hexanes/EtOAc (1,100 mL) and then filtered. The filter cake was dried at 50° C. for ˜18 h to obtain the title compound as a yellow solid (300 g, 81%). MS (ES) m/Vz=153 (M+1).
Preparation 10
4-Bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one




To a stirred mixture of 5-fluoroisobenzofuran-1(3H)-one (300 g, 1.97 mol) in H2SO4 (1,500 mL) was added HNO3 (273.38 g, 4.348 mol, 2.2 eq.) dropwise at 65° C. The reaction was stirred for 1 h then cooled to RT. 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (2,255.43 g, 7.88 mol, 4 eq.) was added in portions over 20 min and was stirred at RT for ˜18 h. The mixture was poured onto ice/water (pre-treated with 3 kg Na2SO3) and filtered. The filter cake was dissolved in EtOAc (3,000 mL), washed with sat. aq. Na2CO3 (2×1,000 mL), brine (2×1,000 mL), dried over anhydrous Na2SO4 and concentrated. The residue was triturated with 10:1 hexanes/EtOAc (660 mL) and was filtered and dried at 50° C. for ˜18 h to obtain the title compound as a yellow solid (270 g, 49%) which was used in a subsequent step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 5.51 (s, 2H).
Preparation 11
4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran




To a stirred mixture of 4-bromo-5-fluoro-6-nitroisobenzofuran-1(3H)-one (270 g, 978 mmol) in DCM (2,500 mL) was added DIBAL-H (1M in THF, 1,467 mL, 1.467 mol, 1.5 eq.) dropwise at −78° C. under N2. The reaction was stirred for 5 h at −78° C., then was quenched with 5N NaOH (300 mL) at −78° C. The resulting mixture was allowed to warm to RT, then was concentrated. The residue was diluted with EtOAc (2,500 mL), washed with brine (2×1,000 mL) and dried over anhydrous Na2SO4 and concentrated. The residue was triturated with 10:1 hexanes/EtOAc (550 mL) and filtered. The solids were dried (190 g, 683.4 mmol) then dissolved in DCM (1,500 mL) and treated dropwise with Et3SiH (662 mL, 4.10 mol, 6 eq.) at 0° C. The reaction was stirred for 20 min at 0° C. TFA (152 mL, 2.05 mol, 3 eq.) was added dropwise at 0° C. The ice bath was removed, and the reaction was stirred at RT for ˜18 h. The reaction was concentrated to an oil, which was diluted with EtOAc (2,000 mL), washed with sat. aq. Na2CO3 (2×500 mL) and brine (2×500 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain the title compound (110 g, 42%) which was used in a subsequent step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (d, J=6.2 Hz, 1H), 5.18-5.15 (m, 2H), 5.11-5.06 (m, 2H).
Preparation 12
7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine




To a stirred mixture of 4-bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (110 g, 420 mmol) and NH4Cl (112.3 g, 2.10 mol, 5 eq.) in EtOH (1,000 mL) and H2O (200 mL) was added Fe (117.22 g, 2.09 mol, 5 eq.) in portions at RT, then stirred for ˜18 h at 80° C. The mixture was filtered and concentrated. The mixture was diluted with H2O (500 mL) and extracted with EtOAc (2×1,000 mL). The combined organic layers were washed with brine (2×500 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica (25% to 50% EtOAc/Hex) to afford the title compound (70 g, 72%) as a yellow solid. MS (ES) m/z=231 (M+1).
Preparation 13
(4-Chloro-1,2-phenylene)dimethanol




To a stirred mixture of LiAlH4 (1.9 L, 2.74 mol, 2 eq., 2.5 M in THF) in THF (1 L) was added 4-chlorophthalic anhydride (250 g, 1.34 mol, 1.00 eq.) in THF (500 mL) dropwise at −20° C. under N2. The resulting mixture was stirred for 30 min at 45° C. under N2. The reaction was quenched by the addition of H2O (1.5 L) and 15% NaOH (500 mL) at RT. The mixture was filtered, and the filter cake was washed with MTBE (3×250 mL). The filtrate was extracted with MTBE (3×1.5 L). The combined organic layers were washed with brine (2×2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (219.5 g, 93%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.45-7.36 (m, 2H), 7.28 (dd, J=8.2 Hz, 1H), 5.40-5.13 (m, 2H), 4.54 (s, 2H), 4.49 (s, 2H).
Preparation 14
5-Chloro-1,3-dihydroisobenzofuran




To a stirred mixture of (4-chloro-2-p enylene)dimethanol (219.5 g, 1.271 mol) and dimethyl carbonate (458.2 g, 5.082 mol, 4 eq.) in ACN (3 L) was added NaOMe (137.4 g, 2.544 mol, 2 eq.) in portions at RT. The resulting mixture was stirred for ˜18 h at 80° C. under N2. The mixture was concentrated under reduced pressure, diluted with H2O (2 L) and extracted with EtOAc (3×2 L). The combined organic layers were washed with brine (2×2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on silica (10:1 to 8:1 hex/EtOAc) to obtain the title compound (165 g, 82%) as a light-brown solid. 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.37 (m, 1H), 7.33 (d, J=1.4 Hz, 2H), 4.99 (s, 4H).
Preparation 15
5-Chloro-6-nitro-1,3-dihydroisobenzofuran




A solution of 5-chloro-1,3-dihydroisobenzofuran (110 g, 712 mmol) in H2SO4 (700 mL) at −10° C. was charged with a solution of KNO3 (64.74 g, 640 mmol, 0.9 eq.) in H2SO4 (200 mL) dropwise at −5° C.-0° C. The resulting mixture was stirred for additional 30 min at 0° C. and then was slowly added to stirred ice-cooled H2O. The precipitated solids were collected by filtration and washed with H2O (3×1 L). The filter cake was dried in vacuo to afford the title compound (110 g, 77%) as a light-brown solid which was used in a subsequent step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.75 (s, 1H), 5.07-5.02 (m, 4H).
Preparation 16
4-Bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran




To a stirred solution of 5-chloro-6-nitro-1,3-dihydroisobenzofuran (125 g, 626 mmol) in H2SO4 (700 mL) was added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (179.1 g, 626.3 mmol, 1 eq.) in portions at −10° C. The mixture was stirred for 1 h at −10° C. then slowly was added to stirred ice-cooled H2O. The precipitated solids were collected by filtration and washed with H2O (3×0.5 L). The filter cake was dried in vacuo and purified on silica (10:1 to 5:1 Hex/EtOAc) to obtain the title compound (83.5 g, 47.9%) as a white solid.
1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=1.1 Hz, 1H), 5.19 (dt, J=2.3, 1.1 Hz, 2H), 5.08 (t, 2H).
Preparation 17
7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine




To a stirred mixture of 4-bromo-5-chloro-6-nitro-1,3-dihydroisobenzofuran (37.0 g, 133 mmol) and NH4Cl (42.64 g, 797.2 mmol, 6 eq.) in EtOH (200 mL) and H2O (40 mL) was added Fe (44.52 g, 797.2 mmol, 6 equiv.) in portions at RT. The resulting mixture was stirred for ˜18 h at 80° C. The resulting mixture was filtered hot and the filter cake was washed with EtOAc (3×500 mL). The filtrate was concentrated under reduced pressure and was purified on silica (15:1 to 10:1 Hex/EtOAc) to obtain the title compound (25 g, 76%) as a light-yellow solid. MS (ES) m/z=248 (M+1).
Preparation 1B
4-Bromo-7,9-dichloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinoline




A mixture of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (5.00 g, 21.5 mmol), malonic acid (3.36 g, 32.3 mmol) and phosphoryl trichloride (19.9 mL, 215 mmol) was stirred for 15 h at 110° C., then cooled to room temperature. The mixture was diluted with cold water and extracted with DCM (3×200 mL). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% ethyl acetate in heptane, to give the title compound (3.4 g, 47%) as a solid. MS (ES) m/z=336 (M+1).
Preparation 2B
4-Bromo-5,7,9-trichloro-1,3-dihydrofuro[3,4-f]quinoline




7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner analogous to the method of Preparation 1B to afford the title compound (2.0 g, 28%) as a yellow solid. MS (ES) m/z=352 (M+1).
Preparation 3B
4-Bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-9-ol




5-(((7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione: A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (13 g, 89 mmol) and trimethoxymethane (180 mL, 1.64 mol) was stirred for 2 h at 100° C., then cooled to room temperature. 7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine (20 g, 80 mmol) was added and the mixture was stirred for 18 h at 100° C., then cooled to room temperature. The mixture was filtered. The solids were washed with methanol and dried to give 5-(((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (31.4 g, 97%) as an orange solid. MS (ES) m/z=402 (M+1).
4-Bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-9-ol: A mixture of 5-(((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 25 mmol) and oxydibenzene (100 mL, 629 mmol) was stirred for 30 min at 203° C., then cooled to room temperature. Heptane (300 mL) was added and the mixture was filtered. The solids were washed with heptane and dried to give the title compound (6.9 g, 92%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.03 (t, J=2.69 Hz, 2H) 5.55 (t, J=2.69 Hz, 2H) 6.12 (d, J=7.50 Hz, 1H) 7.81-7.86 (m, 1H) 11.37-11.50 (m, 1H).
Preparation 4B
4-Bromo-5,9-dichloro-1,3-dihydrofuro[3,4-f]cinnoline




7-Bromo-6-chloro-4-((trimethylsilyl)ethynyl)-1,3-dihydroisobenzofuran-5-amine: A solution of cuprous iodide (0.560 g, 2.94 mmol) and ethynyl-trimethyl-silane (1.88 g, 19.1 mmol) in triethylamine (45 mL) was sparged with argon. Bis-(triphenylphosphino)-palladous chloride (1.03 g, 1.47 mmol) was added and the mixture was allowed to stir at room temperature for 30 min. 7-Bromo-6-chloro-4-iodo-1,3-dihydroisobenzofuran-5-amine (prepared as in WO/2023183585; 5.50 g, 14.7 mmol) was added. The reaction vessel was sealed and the mixture was heated for 2 h at 90° C. The mixture was filtered through anhydrous sodium sulfate and the solids were washed with ethyl acetate. The combined filtrates were concentrated under reduced pressure. The residue was purified on silica, eluting with 0-60% ethyl acetate in DCM, to give 7-bromo-6-chloro-4-((trimethylsilyl)ethynyl)-1,3-dihydroisobenzofuran-5-amine (4.58 g, 90%) as a yellow solid. MS (ES) m/z=344 (M+1).
4-Bromo-5-chloro-1,3-dihydrofuro[3,4-f]cinnolin-9-ol: A suspension of 7-bromo-6-chloro-4-((trimethylsilyl)ethynyl)-1,3-dihydroisobenzofuran-5-amine (1.31 g, 3.80 mmol) in HCl (conc aqueous; 15 mL) was slowly treated with sodium nitrite (3.0 M in water; 1.58 mL, 4.75 mmol). The reaction vessel was sealed and the mixture was heated for 30 min at 80° C. The mixture was poured into a stirring mixture of ice and water. The resulting mixture was stirred for 20 min as the ice melted. The resulting suspension was filtered to give 4-bromo-5-chloro-1,3-dihydrofuro[3,4-f]cinnolin-9-ol (0.94 g, 73%) as a tan solid. MS (ES) m/z=301 (M+1).
4-Bromo-5,9-dichloro-1,3-dihydrofuro[3,4-f]cinnoline: A solution of 4-bromo-5-chloro-1,3-dihydrofuro[3,4-f]cinnolin-9-ol (0.94 g, 3.10 mmol) in DCM (10 mL) was treated with chloromethylene(dimethyl)ammonium chloride (0.834 g, 6.51 mmol). The mixture was allowed to stir at room temperature for 15 min. The mixture was concentrated under reduced pressure. The resulting solids were suspended in water (40 mL), sonicated (10 min), and filtered. The solids were washed with water (20 mL) and heptane:methyl tert-butyl ether (4:1; 30 mL), then dried to give the title compound (0.92 g, 93%) as a brown solid. MS (ES) m/z=319 (M+1).
Preparation 18
Ethyl N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate




A solution of 7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (20.4 g, 87.9 mmol) in DCM (550 mL) was charged with ethoxycarbonyl isothiocyanate (9.7 mL, 82 mmol, 0.93 eq.) slowly via addition funnel and subsequently stirred at RT for ˜4 h. The solids were filtered. The filtrate was concentrated, suspended in DCM (100 mL) and hexanes (350 mL) and stirred at RT. The resultant filtered solids and previous filtered solids were dried under vacuum at 50° C. for 2 h. The batches were combined to obtain the title compound (32.6 g, quantitative) as a white solid. MS (ES) m/z=363 (M+1).
Preparation 19
Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate




7-Bromo-6-chloro-1,3-dihydroisobenzofuran-5-amine was used in a manner analogous to the method of Preparation 18 to afford the title compound (14 g, 92%) as a white solid. MS (ES) m/z=379 (M+1).
Preparation 20
Ethyl (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate




A 2L 3-necked RBF, equipped with an overhead stirrer, dropping funnel and thermocouple was charged with a suspension of ethyl N-[(7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate (32.6 g, 89.8 mmol) and acetone (450 mL). To this was added solid K2CO3 (37.2 g, 269 mmol, 3.00 eq.) in several portions, followed by the dropwise addition of EtI (7.2 mL, 90 mmol, 1.0 eq.) over 20 min. The mixture was stirred at RT for ˜18 h. The solids were filtered and the filtrate was concentrated and partitioned between DCM (500 mL) and H2O (500 mL). The organics were further washed with brine and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica (0 to 30% EtOAc/Hex) to obtain the title compound (30.9 g, 85.6%) as a white solid. MS (ES) m/z=391 (M+1).
Preparation 21
Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate




Ethyl N-[(7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)carbamothioyl]carbamate was used in a manner analogous to the method of Preparation 20 to afford the title compound (15.4 g, crude) as a brown solid. MS (ES) m/z=407 (M+1).
Preparation 22
6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol




A 2 L 4-necked RBF was equipped with an overhead stirrer, dropping funnel, N2 inlet and thermocouple and was purged with N2. NMP (anhydrous, 300 mL) was added. The mixture was heated to 175° C. In a second flask, ethyl (((7-bromo-6-fluoro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate (22.63 g, 57.83 mmol) and NMP (anhydrous, 100 mL) were combined and stirred under N2 until a homogeneous solution was obtained. When the first flask had reached 175° C., the contents of the second flask were poured into the dropping funnel and were added dropwise but rapidly to the hot NMP. After 30 min, the heat was turned off and the reaction cooled to 45° C. H2O (500 mL) was slowly added and the mixture was stirred at RT for 1 h. The solids were filtered, rinsed with H2O (300 mL) and dried under vacuum at 50° C. for ˜18 h to afford the title compound (15.2 g, 73%) as an off-white solid. MS (ES) m/z=363 (M+1).
Preparation 23
6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol




Ethyl (((7-bromo-6-chloro-1,3-dihydroisobenzofuran-5-yl)amino)(ethylthio)methylene)carbamate was used in a manner analogous to the method of Preparation 22 to afford the title compound (11.4 g, 86%) as a white solid. MS (ES) m/z=361 (M+1).
Preparation 24
6-Bromo-3-(ethylthio)-5-fluoro-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydrofuro[3,4-f]quinazolin-1(2H)-one




A mixture of 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (30.1 g, 87.3 mmol) in DMF was heated to −70° C. to dissolve the solids, then cooled to 40° C. To the mixture was added diisopropylethylamine (30.4 mL, 175 mmol) and 2-(chloromethoxyethyl)trimethyl silane (23.2 mL, 131 mmol). The reaction mixture was stirred for 1 h at 40° C., then cooled to room temperature and diluted with water (1 L) and EtOAc (500 mL). The layers were separated and the organic layer was washed with brine (2×500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound (49.2 g, 85% purity) as a yellow oil. MS (ES) m/z=475 (M+1).
Preparation 25
6-Bromo-5-chloro-3-(ethylthio)-2-((2-(trimethylsilyl)ethoxy)methyl)-7,9-dihydrofuro[3,4-f]quinazolin-1(2H)-one




6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol was used in a manner analogous to the method of Preparation 24 to afford the title compound (10.5 g, 96%) as a pink solid. MS (ES) m/z=491 (M+1).
Preparation 26
6-Bromo-1-chloro-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazoline




A 5 L 3-necked RBF, equipped with a dropping funnel, thermocouple and an overhead stirrer was charged with a solution of DMF (50 mL, 646 mmol, 4 eq.) in DCM (1,000 mL) and was placed in an ice/water bath and cooled to −4° C. Oxalyl chloride (50.0 mL, 576 mmol, 4 eq.) was added dropwise via addition funnel over −40 min. When the addition was complete, the reaction was stirred at −4° C. for 15 min. Solid 6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (50.4 g, 140 mmol) was added in several portions to the reaction mixture and the resulting suspension was stirred at −4° C. for 30 min. The ice bath was removed and the reaction was allowed to warm to RT and stir for 1 h. Then H2O (1 L) was added and the mixture was stirred for 15 min. The mixture was partitioned and the organic layer was washed with brine (1 L) and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified on silica, eluting with DCM/Hex (60% to 90%) to obtain the title compound (45.1 g, 89%) as a white solid. MS (ES) m/z=363 (M+1).
Preparation 27
6-Bromo-1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazoline




6-Bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-ol was used in a manner analogous to the method of Preparation 26 to afford the title compound (0.81 g, 77%) as a yellow solid. MS (ES) m/z=382 (M+1).
Preparation 28
tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate




6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (0.80 g, 2.32 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (1.12 g, 2.78 mmol) and cesium carbonate (2.27 g, 6.95 mmol) were combined in DMF (12 mL) and the mixture was degassed by sparging with argon for 10 min. Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (Pd-117, 0.166 g, 0.232 mmol) was added and the mixture was heated to 100° C. After 24 h, the mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-10% MeOH in DCM to obtain the title compound (0.96 g, 74%) as a yellow solid. MS (ES) m/z=557 (M+1).
The following compounds in Table 2 were prepared in similar manner as described in Preparation 28. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 2








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







29
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




573


 


30 1
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 2




573


 


31
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




532


 


32 2
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 1




662


 


33
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




678


 


34 3
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 1




678


 


35
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




679


 


5B
tert-Butyl (4-(5-chloro-9- hydroxy-1,3- dihydrofuro[3,4- f]quinolin-4-yl)-3-cyano- 7- fluorobenzo[b]thiophen- 2-yl)carbamate




512


 


6B 4
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate, Atropisomer 1




703


 


7B
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




663


 


8B 5
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate




648





1 Prep-Chiral-HPLC; Phenomenex Lux Cellulose-5, 30 x 150 mm, 18-30% (1:1 methanol:ethanol) in heptane, 42.5 mL/min


2 Chiral SFC; Chiralpak IC, 50 x 250 mm, 25% (methanol w/ 0.2% dimethylethylamine) in CO2, 300 g/min


3 Chiral SFC; Chiralpak IC, 20 x 250 mm, 25% (isopropanol w/ 0.5% dimethylethylamine) in CO2, 80 mL/min


4 Chiral SFC; ColumnTek Enantiocel C4-5, 30 x 250 mm, 40% methanol in CO2, 75 mL/min


5 Prepared in similar manner as described in Preparation 73






Preparation 9B
tert-Butyl (4-(9-bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate




4-(2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-9-yl trifluoromethanesulfonate: 1,1,1-Trifluoro-N-phenyl-N—((trifluoromethyl)sulfonyl)methanesulfonamide (8.4 g, 23 mmol) was added to a suspension of tert-butyl (4-(5-chloro-9-hydroxy-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (10 g, 20 mmol) and triethylamine (8.2 mL, 59 mmol) in acetonitrile (60 mL). The mixture was stirred for 2 h at room temperature, then concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% ethyl acetate in heptane, to give 4-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-9-yl trifluoromethanesulfonate (10.1 g, 80%). MS (ES) m/z=644 (M+1).
tert-Butyl (4-(9-bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: A mixture of 4-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-9-yl trifluoromethanesulfonate (3.74 g, 5.81 mmol) and lithium bromide (10.1 g, 116 mmol) in acetonitrile (20 mL) was stirred for 75 min at 40° C. The mixture was concentrated under reduced pressure. The residue was diluted with DCM and saturated aqueous sodium chloride. The organic layer was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% ethyl acetate in heptane, to give the title compound (2.82 g, 85%) as a white solid. MS (ES) m/z=574 (M+1).
Preparation 10B
tert-Butyl (4-(5-chloro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate




A mixture of tert-butyl (4-(5-chloro-3-(ethylthio)-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate, Atropisomer 1 (0.500 g, 0.711 mmol) and palladium(II)chloride (6.30 mg, 0.036 mmol) in THF (5 mL) was sparged with argon. Triethylsilane (0.165 g, 0.227 mmol) was added and the reaction vessel was sealed and stirred for 5 h at room temperature. The mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude title compound (0.46 g). MS (ES) m/z=643 (M+1). Clean atropisomer, chiral purification from Preparation 6B.
Preparation 36
tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate




A mixture of tert-butyl (4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.750 g, 1.41 mmol) and acetonitrile (10 mL) was stirred at −40° C. Sulfurisocyanatidic chloride (0.184 mL, 2.12 mmol) was slowly added and the mixture was allowed to warm to 0° C. After consumption of the starting material (monitored by LCMS), the mixture was cooled to 0° C. DMF (4 mL) was slowly added. Upon reaction completion (monitored by LCMS), the mixture was diluted with DCM (20 mL) and saturated aq. ammonium chloride (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×30 mL). The combined organics were passed through a hydrophobic frit and concentrated under reduced pressure to obtain the crude title compound. MS (ES) m/z=557 (M+1).
The following compounds in Table 3 were prepared in similar manner as described in Preparation 36. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 3








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







37 1
tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-1- oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




687


 


38
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




703


 


39 2
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-oxo-2-((2- (trimethylsilyl)ethoxy) methyl)-1,2,7,9- tetrahydrofuro[3,4- f]quinazolin-6-yl)-3- fluorobenzo[b]thiophen- cyano-5- 2-yl)carbamate




703





1 Clean atropisomer, chiral purification from Preparation 32


2 Clean atropisomer, chiral purification from Preparation 34






Preparation 40
tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate




To a mixture of tert-butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2,7,9-tetrahydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (19.2 g, 26.3 mmol) in THF (192 mL) was added activated molecular sieves (4 angstrom, 38 g), followed by tetrabutylammonium fluoride (1M in THF, 105 mL, 105 mmol). The reaction mixture was heated for 9 h at a bath temperature of 80° C., then cooled to room temperature. Additional activated molecular sieves (4 angstrom, 17 g) were added, and the reaction mixture was heated overnight at a bath temperature of 80° C., then cooled to room temperature. The mixture was filtered and the filter cake was washed with EtOAc. The combined filtrates were concentrated under reduced pressure, diluted with 2-methyltetrahydrofuran (300 mL), and washed with water (3×300 mL). The combined aqueous layers were extracted with 2-methyltetrahydrofuran (300 mL). The combined organic layers were washed with 5% aqueous citric acid (300 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified on silica, eluting with 0-60% EtOAc in cyclohexane to obtain the title compound (9.42 g) as a yellow foam. MS (ES) nVz=557 (M+1). Clean atropisomer, chiral purification from Preparation 32.
The following compounds in Table 4 were prepared in similar manner as described in Preparation 40. Different deprotection conditions, such as cesium fluoride in DMF, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 4








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







41
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




573


 


42 1
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




573


 


43
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




549


 


11B 2
tert-Butyl (4-(5-chloro-1- hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




513


 


12B
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-hydroxy- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate




574


 


13B
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




533





1 Clean atropisomer, chiral purification from Preparation 34


2 Clean atropisomer, chiral purification from Preparation 6B






The following compounds in Table 5 were prepared in similar manner as described in Preparation 26. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 5








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







44 1
tert-Butyl (3-cyano-4- (1,5-dichloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophen- 2-yl)carbamate




591


 


45
tert-Butyl (4-(1-chloro-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




575


 


46
tert-Butyl (3-cyano-4- (1,5-dichloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




591


 


47 2
tert-Butyl (3-cyano-4- (1,5-dichloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




591


 


48
tert-Butyl (4-(1,5- dichloro-3-(ethylthio)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




567


 


14B
tert-Butyl (3-cyano-4- (1,5-dichloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno [3,2- c]pyridin-2-yl)carbamate




592





1 Clean atropisomer, chiral purification from Preparation 30


2 Clean atropisomer, chiral purification from Preparation 34






Preparation 49
6-Amino-4-methyl-4-azaspiro[2.5]octan-5-one




4-Methyl-4-azaspiro[2.5]octan-5-one. To a solution of 4-azaspiro[2.5]octan-5-one (5.00 g, 40.0 mmol) in THF (30 mL) was added sodium hydride (60 wt % in mineral oil; 1.92 g, 47.9 mmol). The mixture was stirred at room temperature for 30 min, then cooled to 0° C. A solution of iodomethane (3.73 mL, 59.9 mmol) in THF (5 mL) was added dropwise and the mixture was stirred at 0° C. for 5 min, then warmed to room temperature and stirred for 16 h. The mixture was diluted with water (5 mL) and extracted with EtOAc and DCM. The combined organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude 4-methyl-4-azaspiro [2.5]octan-5-one (3.03 g, 55%) as a light yellow oil. MS (ES) m/z=140 (M+1).
6-Chloro-4-methyl-4-azaspiro[2.5]octan-5-one. A solution of 4-methyl-4-azaspiro[2.5]octan-5-one (3.03 g, 21.8 mmol) in THF (50 mL) was cooled to −78° C. Lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 14.2 mL, 28.4 mmol) was added. The mixture was stirred at −78° C. for 20 min, then a solution of tosyl chloride (12.45 g, 65.3 mmol) in THF (5 mL) was slowly added. The mixture was stirred at −78° C. for 90 min. The mixture was diluted with water and extracted with DCM. The organics were dried over anhydrous Na2SO4, followed by reversed phase purification (C18 column), eluting with 0-100% acetonitrile in (0.1% formic acid in water), to obtain 6-chloro-4-methyl-4-azaspiro[2.5]octan-5-one (2.33 g, 62%) as a yellow oil. MS (ES) m/z=174 (M+1).
6-Amino-4-methyl-4-azaspiro[2.5]octan-5-one. A solution of 6-chloro-4-azaspiro[2.5]octan-5-one (7.02 g, 40.4 mmol) in acetonitrile (5 mL) and ammonium hydroxide (10 mL) was heated under microwave irradiation at 80° C. for 22 h. The mixture was concentrated under reduced pressure to give the title compound (5.8 g, crude) as a brown solid. MS (ES) m/z=155 (M+1).
The following compounds in Table 6 were prepared in similar manner as described in Preparation 49. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 6








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







50
7-Amino-5-methyl-5- azaspiro[3.5]nonan-6-one




169


 


51
7-Amino-5-methyl-5- azaspiro[2.5]octan-6-one




155


 


2A
6-Amino-4-methyl-4- azaspiro[2.4]heptan-5-one




141


 


15B
(6R)-3-Amino-6- (difluoromethyl)-1- methylpiperidin-2-one




179









Preparation 3A
7-Amino-5-azaspiro[3.5]nonan-6-one




tert-Butyl 6-oxo-5-azaspiro[3.5]nonane-5-carboxylate. To a solution of 5-azaspiro[3.5]nonanone (0.500 g, 3.59 mmol) in THF (10 mL) was added di-tert-butyl dicarbonate (1.02 g, 4.67 mmol) and 4-dimethylaminopyridine (0.088 g, 0.718 mmol). The mixture was stirred at 65° C. for 12 h, then concentrated under reduced pressure. The residue was purified by reversed phase purification (C18 column), eluting with 0-100% acetonitrile in (0.1% formic acid in water), to obtain tert-butyl 6-oxo-5-azaspiro[3.5]nonane-5-carboxylate (0.610 g, 71%) as a brown oil. MS (ES) m/z=184 (M+1-tBu).
tert-Butyl 7-chloro-6-oxo-5-azaspiro[3.5]nonane-5-carboxylate. tert-Butyl 6-oxo-5-azaspiro[3.5]nonane-5-carboxylate was used in a manner analogous to the method of Preparation 49 (Step 6-chloro-4-methyl-4-azaspiro[2.5]octan-5-one) to afford tert-butyl 7-chloro-6-oxo-5-azaspiro[3.5]nonane-5-carboxylate (0.28 g, 78%) as a yellow oil. MS (ES) m/z=218 (M+1-tBu).
7-Chloro-5-azaspiro[3.5]nonan-6-one. A mixture of tert-butyl 7-chloro-6-oxo-5-azaspiro[3.5]nonane-5-carboxylate in DCM (3 mL) was treated with HCl solution (3 mL) and stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give crude 7-chloro-5-azaspiro[3.5]nonan-6-one as a white solid. MS (ES) m/z=174 (M+1).
7-Amino-5-azaspiro[3.5]nonan-6-one. 7-Chloro-5-azaspiro[3.5]nonan-6-one was used in a manner analogous to the method of Preparation 49 (Step 6-amino-4-methyl-4-azaspiro[2.5]octan-5-one) to afford the title compound (0.24 g) as a yellow solid. MS (ES) m/z=155 (M+1).
Preparation 52
4-Amino-2-methyl-2-azabicyclo[3.1.1]heptan-3-one dihydrochloride




2-Methyl-2-azabicyclo[3.1.1]heptan-3-one. Sodium hydride (60 wt % in mineral oil 0.346 g, 8.64 mmol) was added to a solution of 2-azabicyclo[3.1.1]heptan-3-one (0.800 g, 7.20 mmol) in THF (15 mL). The mixture was stirred at 25° C. for 30 min, then cooled to 0° C. A solution of iodomethane (0.67 mL, 10.8 mmol) in THF (0.3 mL) was added dropwise. The mixture was stirred at 0° C. for 5 min, then at 25° C. for 16 h. Diluted with water (5 mL) and extracted with EtOAc, then DCM. The combined organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude 2-methyl-2-azabicyclo[3.1.1]heptan-3-one as a light yellow oil. MS (ES) m/z=126 (M+1).
Methyl 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate. To a −78° C. solution of 2-methyl-2-azabicyclo[3.1.1]heptan-3-one (1.09 g, 8.71 mmol) in THF (60 mL) was added lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 8.71 mL, 17.4 mmol). The mixture was stirred at −78° C. for 30 min. Methyl chloroformate (0.81 mL, 10.5 mmol) was added and the mixture was stirred at −78° C. for 2 h. The mixture was quenched with water, warmed to RT, and extracted with EtOAc, then DCM. The combined organics were concentrated under reduced pressure to give crude methyl 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate (1.37 g, 86%) as a light yellow oil. MS (ES) m/z=184 (M+1).
2-Methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxamide. To a mixture of methyl 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxylate (1.37 g, 7.47 mmol) in ammoniated methanol (7M; 53.4 mL, 374 mmol) was added sodium methoxide (0.404 g, 7.47 mmol). The mixture was stirred at 45° C. for 5 h, then cooled. The mixture was concentrated under reduced pressure. The residue was diluted with water, followed by reversed phase purification (C18 column), eluting with 0-100% acetonitrile in (0.1% formic acid in water), to obtain 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxamide (0.904 g, 72%) as a yellow solid. MS (ES) m/z=169 (M+1).
Methyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate. To a mixture of 2-methyl-3-oxo-2-azabicyclo[3.1.1]heptane-4-carboxamide (1.04 g, 6.20 mmol) and THF (15 mL) was added (diacetoxyiodo)benzene (2.20 g, 6.82 mmol). The mixture was stirred at 25° C. for 20 min, then concentrated under reduced pressure. MeOH (15 mL) was added and the mixture was stirred at 70° C. for 1 h. The mixture was concentrated under reduced pressure to give crude methyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate as a light yellow oil. MS (ES) m/z=199 (M+1).
tert-Butyl (methoxycarbonyl)(2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate. To a solution of methyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate (1.23 g, 6.21 mmol) in THF (12 mL) was added di-tert-butyl dicarbonate (2.71 g, 12.4 mmol) and dimethylaminopyridine (0.227 g, 1.86 mmol). The mixture was stirred at 65° C. for 4 h, then concentrated under reduced pressure. The residue was purified on silica, eluting with 60-100% EtOAc in heptane to obtain tert-butyl (methoxycarbonyl)(2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate (0.571 g, 31%) as a brown oil. MS (ES) m/z=199 (M+1, −Boc).
tert-Butyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate. To a 0° C. solution of tert-butyl (methoxycarbonyl)(2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate (0.571 g, 1.91 mmol) in MeOH (5 mL) was added sodium methoxide (0.031 g, 0.57 mmol). The mixture was stirred at 0° C. for 20 min, then 25° C. for 12 h. The mixture was quenched with ice and diluted with brine. The mixture was extracted with EtOAc, then DCM. The combined organics were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude tert-butyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate. MS (ES) m/z=185 (M+1, -tert-butyl).
4-Amino-2-methyl-2-azabicyclo[3.1.1]heptan-3-one dihydrochloride. HCl (4M in 1,4-dioxane; 3 mL) was added to a solution of tert-butyl (2-methyl-3-oxo-2-azabicyclo[3.1.1]heptan-4-yl)carbamate (0.460 g, 1.91 mmol) in DCM (3 mL). The mixture was stirred at RT for 6 h, then concentrated under reduced pressure to give the title compound (0.400 g, 98%). MS (ES) m/z=141 (M+1, free base).
Preparation 4A
4-Amino-2-methyl-2-azabicyclo[3.1.1]heptan-3-one hydrochloride




The title compound was made in a manner analogous to the method of Preparation 52. MS (ES) m/z=141 (M+1, free base).
Preparation 53
(8aR)-6-Aminohexahydroindolizin-5(1H)-one dihydrochloride




tert-Butyl (R)-2-(2-bromoethyl)pyrrolidine-1-carboxylate. To a mixture of tert-butyl (R)-2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (10 g, 46 mmol) in THF (200 mL) was added carbon tetrabromide (23 g, 70 mmol). The mixture was stirred at 0° C. for 10 min, then triphenylphosphine (18 g, 70 mmol) was added. The mixture was stirred at RT for 10 min, then quenched with saturated aqueous sodium bicarbonate (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified on silica, eluting with 5-75% EtOAc in heptane to obtain tert-butyl (R)-2-(2-bromoethyl)pyrrolidine-1-carboxylate (7.4 g, 57%) as a colorless oil.
Dimethyl (S)-2-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)malonate. To a mixture of dimethyl malonate (7.0 g, 53 mmol) in THF (100 mL) was added sodium hydride (60 wt % in mineral oil; 2.1 g, 53 mmol). The mixture was stirred at RT for 15 min. A solution of tert-butyl (R)-2-(2-bromoethyl)pyrrolidine-1-carboxylate (7.4 g, 27 mmol) in THF (100 mL) was added dropwise. The mixture was stirred at 75° C. for 20 h, then cooled and quenched with acetic acid (1.5 mL, 27 mmol). The mixture was diluted with chloroform (150 mL) and water (100 mL). The organic layer was passed through a hydrophobic frit and concentrated under reduced pressure. The residue was purified on silica, eluting with 5-100% EtOAc in heptane to obtain dimethyl (S)-2-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)malonate (7.0 g, 80%).
Dimethyl (S)-2-(2-(pyrrolidin-2-yl)ethyl)malonate hydrochloride. Acetyl chloride (30 mL, 430 mmol) was added dropwise to MeOH (20 mL) at 0° C. The mixture was stirred at 0° C. for 5 min, then a solution of dimethyl (S)-2-(2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)malonate (7.0 g, 21 mmol) in MeOH (5 mL) was added. The mixture was stirred at RT for 24 h. The mixture was concentrated under reduced pressure to give crude dimethyl (S)-2-(2-(pyrrolidin-2-yl)ethyl)malonate hydrochloride.
Methyl (8aS)-5-oxooctahydroindolizine-6-carboxylate. A mixture of dimethyl (S)-2-(2-(pyrrolidin-2-yl)ethyl)malonate hydrochloride (4.9 g, 18 mmol) and triethylamine (7.7 mL, 55 mmol) in DCM (100 mL) was stirred at RT for 24 h. The mixture was diluted with DCM (50 mL) and saturated aqueous sodium bicarbonate (75 mL). The organic layer was passed through a hydrophobic frit and concentrated under reduced pressure to give methyl (8aS)-5-oxooctahydroindolizine-6-carboxylate (1.8:1 mix of diastereomers; 2.6 g, 71%). MS (ES) m/z=198 (M+1).
(8aS)-5-Oxooctahydroindolizine-6-carboxamide. To a mixture of methyl (8aS)-5-oxooctahydroindolizine-6-carboxylate (2.7 g, 14 mmol) in ammoniated methanol (7M; 60 mL, 420 mmol) was added sodium methoxide (0.74 g, 14 mmol). The mixture was stirred at 45° C. for 5 h, then cooled. The mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 1-20% MeOH in DCM to obtain (8aS)-5-oxooctahydroindolizine-6-carboxamide (1.2 g, 48%) as a colorless oil.
tert-Butyl ((8aR)-5-oxooctahydroindolizin-6-yl)carbamate. To a mixture of (8aS)-5-oxooctahydroindolizine-6-carboxamide (5.7 g, 31 mmol), THF (75 mL) and tert-butanol (100 mL) was added (diacetoxyiodo)benzene (11 g, 34 mmol). The mixture was stirred at RT for 20 min, then 70° C. overnight. The mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-10% MeOH in DCM to obtain tert-butyl ((8aR)-5-oxooctahydroindolizin-6-yl)carbamate (7.0 g, 88%) as a colorless oil. MS (ES) m/z=255 (M+1).
(8aR)-6-Aminohexahydroindolizin-5(1H)-one dihydrochloride. HCl (4M in 1,4-dioxane; 3 mL) was added to a solution of tert-butyl ((8aR)-5-oxooctahydroindolizin-6-yl)carbamate (0.270 g, 1.06 mmol) in DCM (3 mL). The mixture was stirred at RT for 6 h, then concentrated under reduced pressure to give the title compound (0.241 g, 100%). MS (ES) n/Vz=155 (M+1, free base).
Preparation 5A
(8aR)-6-Aminohexahydroindolizin-5(1H)-one hydrochloride




The title compound was made in a manner analogous to the method of Preparation 53 (the (6R,8aR) diastereomer is predominant). MS (ES) m/z=155 (M+1, free base).
Preparation 6A
(9aS)-7-Aminohexahydropyrido[2,1-c][1,4]oxazin-6(1H)-one hydrochloride




tert-Butyl (S)-3-(2-hydroxyethyl)morpholine-4-carboxylate was used in a manner analogous to the method of Preparation 53 to afford the title compound (the (7R,9aS) diastereomer is predominant; 0.44 g). MS (ES) m/z=171 (M+1, free base).
Preparation 54
6-Aminotetrahydro-1H-pyrazolo[1,2-a]pyridazin-5(6H)-one trihydrochloride




tert-Butyl (4-hydroxy-1-oxo-1-(pyrazolidin-1-yl)butan-2-yl)carbamate. A solution of tert-butyl (R)-(2-oxotetrahydrofuran-3-yl)carbamate (5.00 g, 24.8 mmol) and pyrazolidine dihydrochloride (3.60 g, 24.8 mmol) in chloroform (34 mL) was treated with triethylamine (13.9 mL, 99.4 mmol). The mixture was stirred at 70° C. for 16 h, cooled to RT, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-10% MeOH in DCM to obtain tert-butyl (4-hydroxy-1-oxo-1-(pyrazolidin-1-yl)butan-2-yl)carbamate (enriched toward (R) enantiomer; 3.51 g, 52%) as a colorless oil. MS (ES) m/z=274 (M+1).
tert-Butyl (5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-yl)carbamate. A mixture of tert-butyl (4-hydroxy-1-oxo-1-(pyrazolidin-1-yl)butan-2-yl)carbamate (enriched toward (R) enantiomer; 2.51 g, 9.18 mmol) and 2-(tributylphosphoranylidene)acetonitrile (2.44 g, 10.1 mmol) in toluene (23 mL) was stirred at 100° C. for 15 h, cooled to RT, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-10% MeOH in DCM to obtain tert-butyl (5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-yl)carbamate (enriched toward (R) enantiomer; 1.96 g, 84%) as a light yellow solid. MS (ES) m/z=256 (M+1).
6-Aminotetrahydro-1H-pyrazolo[1,2-a]pyridazin-5(6H)-one trihydrochloride. HCl (4M in 1,4-dioxane; 18.9 mL) was added to a solution of tert-butyl (5-oxohexahydro-1H-pyrazolo[1,2-a]pyridazin-6-yl)carbamate (enriched toward (R) enantiomer; 1.93 g, 7.56 mmol) in DCM (19 mL). The mixture was stirred at RT for 31 h, then concentrated under reduced pressure. The solids were dried under vacuum to give the title compound (enriched toward (R) enantiomer; 2.00 g, 100%). MS (ES) m/Vz=156 (M+1, free base).
Preparation 7A
6-Aminotetrahydro-1H-pyrazolo[1,2-a]pyridazin-5(6H)-one dihydrochloride




The title compound was made in a manner analogous to the method of Preparation 54 (the (R) enantiomer is predominant). MS (ES) m/z=156 (M+1, free base).
Preparation 55
2-Aminohexahydropyridazino[1,2-a]pyridazin-1(2H)-one trihydrochloride




Hexahydropyridazine dihydrochloride was used in a manner analogous to the method of Preparation 54 to afford the title compound (enriched toward (R) enantiomer; 4.08 g). MS (ES) m/z=170 (M+1, free base).
Preparation 8A
2-Aminohexahydropyridazino[1,2-a]pyridazin-1(2H)-one dihydrochloride




The title compound was made in a manner analogous to the method of Preparation 54 (the (R) enantiomer is predominant). MS (ES) m/z=170 (M+1, free base).
Preparation 16B
(6R,8aR)-6-Aminohexahydroindolizin-5(1H)-one hydrochloride




tert-Butyl ((6R,8aR)-5-oxooctahydroindolizin-6-yl)carbamate: tert-Butyl ((8aR)-5-oxooctahydroindolizin-6-yl)carbamate (6.85 kg, 26.9 mol) was combined with dichloromethane:hexanes (1:50; 35 L). The mixture was filtered to give tert-butyl ((6R,8aR)-5-oxooctahydroindolizin-6-yl)carbamate (998 g, 14%) as an off-white solid. MS (ES) m/z=255 (M+1).
(6R,8aR)-6-Aminohexahydroindolizin-5(1H)-one hydrochloride: tert-Butyl ((6R,8aR)-5-oxooctahydroindolizin-6-yl)carbamate (27 g, 0.11 mol) was stirred in HCl (4 M in ethyl acetate; 270 mL, 1.1 mol) overnight. The mixture was concentrated under reduced pressure and the solids were dried to give the title compound (20 g, 99%) as a white solid. 1H NMR (400 MHz, MeOD) δ 3.91 (dd, J=12.1, 6.3 Hz, 1H), 3.69-3.43 (m, 3H), 2.39 (dddd, J=12.8, 6.5, 4.1, 2.7 Hz, 1H), 2.29 (dq, J=13.6, 3.6 Hz, 1H), 2.19-2.12 (m, 1H), 2.11-1.98 (m, 1H), 1.98-1.83 (m, 2H), 1.71-1.46 (m, 2H).
Preparation 17B
(6S)-3-Amino-1-azabicyclo[4.2.0]octan-2-one 2,2,2-trifluoroacetate




tert-Butyl (2S)-2-(3-(bis(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)azetidine-1-carboxylate: A solution of dipotassium phosphate (28.9 g, 166 mmol), (R)-2-(1-(tert-butoxycarbonyl)azetidin-2-yl)acetic acid (23.1 g, 108 mmol) 1.3 eq), methyl 2-[bis(tert-butoxycarbonyl)amino]prop-2-enoate (25 g, 83.0 mmol), and Ir[dF(CF3)ppy]2(dtbpy)(PF6) (2.33 g, 2.07 mmol) in DMF (1.25 L) was circulated through a photoreactor (light source 450 nm, 2400W) for 12 h. The mixture was diluted with ice water (1 L) and extracted with ethyl acetate (3×500 mL). The combined organic phases were washed with saturated aqueous sodium chloride (3×300 mL). The organic phase was dried over anhydrous sodium sulfate and the solvent was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-20% ethyl acetate in hexanes, to give tert-butyl (2S)-2-(3-(bis(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)azetidine-1-carboxylate (19.8 g, 45%) as a yellow gummy material.
Methyl 2-amino-4-((S)-azetidin-2-yl)butanoate bis-2,2,2-trifluoroacetate: To a solution of tert-butyl (2S)-2-(3-(bis(tert-butoxycarbonyl)amino)-4-methoxy-4-oxobutyl)azetidine-1-carboxylate (15.0 g, 31.7 mmol) in DCM (150 mL) was added trifluoroacetic acid (35.4 mL, 476 mmol) at 0° C. The mixture was stirred at 25° C. for 4 h, then concentrated under reduced pressure. The residue was diluted with DCM (80 mL) and concentrated under reduced pressure to give methyl 2-amino-4-((S)-azetidin-2-yl)butanoate bis-2,2,2-trifluoroacetate (12.71 g, 100%) as a yellow gummy material.
(6S)-3-Amino-1-azabicyclo[4.2.0]octan-2-one: To a solution of methyl 2-amino-4-((S)-azetidin-2-yl)butanoate bis-2,2,2-trifluoroacetate (12.71 g, 31.7 mmol) in water (120 mL) and methanol (120 mL) at 0° C. was added potassium carbonate (18.6 g, 135 mmol). The mixture was stirred at 0° C. for 15 min and 25° C. for 12 h. Potassium carbonate (4.39 g, 31.7 mmol) was added at 0° C. and the mixture was stirred at 25° C. for 24 h. The mixture was concentrated under reduced pressure to give crude (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one as a yellow oil.
tert-Butyl ((6S)-2-oxo-1-azabicyclo[4.2.0]octan-3-yl)carbamate, Isomers 1 and 2: To a solution of the crude (6S)-3-amino-1-azabicyclo[4.2.0]octan-2-one in THF (20 mL) was added di-tert-butyl dicarbonate (12.3 g, 56.5 mmol) at 0° C. over 5 min. The mixture was stirred at 0° C. for 5 min and 25° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-60% ethyl acetate in DCM, followed by chiral HPLC separation, to give tert-butyl ((6S)-2-oxo-1-azabicyclo[4.2.0]octan-3-yl)carbamate, Isomer 1 (5.0 g) and Isomer 2 (5.3 g). MS (ES) m/z=241 (M+1), for both. Isomer 1 elutes before Isomer 2 on Chiral SFC (ChiralPak AD-3, 4.6×100 mm, 5-40% (ethanol w/0.2% methylamine) in CO2, 2.8 mL/min). Isomer refers to a clean isomer at the 3-position of the azabicyclooctanone.
(6S)-3-Amino-1-azabicyclo[4.2.0]octan-2-one 2,2,2-trifluoroacetate: tert-Butyl ((6S)-2-oxo-1-azabicyclo[4.2.0]octan-3-yl)carbamate, Isomer 2 (0.500 g, 2.08 mmol) and trifluoroacetic acid (1.60 mL, 20.8 mmol) were stirred in DCM (10 mL) for 24 h. The mixture was concentrated under reduced pressure and the material dried to give the title compound (single diastereomer; 0.53 g, 100%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 4.81-4.64 (m, 1H), 4.25 (q, J=8.9 Hz, 1H), 4.20-4.09 (m, 1H), 4.00 (dd, J=11.5, 6.5 Hz, 1H), 2.50-2.38 (m, 3H), 2.22-2.13 (m, 1H), 2.07-1.92 (m, 1H), 1.88-1.74 (m, 1H).
Preparation 18B
(8aS)-6-Amino-2,2-difluorohexahydroindolizin-5(1H)-one hydrochloride




(S)-2-(1-(tert-Butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)acetic acid was used in a manner analogous to the method of Preparation 17B to afford tert-butyl ((8aS)-2,2-difluoro-5-oxooctahydroindolizin-6-yl)carbamate, Isomer 1 (5.5 g) and Isomer 2 (5.5 g). Isomer 1 elutes before Isomer 2 on Chiral SFC (ChiralPak AD-3, 4.6×100 mm, 5-40% (isopropanol w/0.2% methylamine) in CO2, 2.8 mL/min). Isomer refers to a clean isomer at the 6-position of the hexahydroindolizinone. Isomer 2 was used in a manner analogous to the method of Preparation 17B to give the title compound (single diastereomer; 1.5 g) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.11-3.92 (m, 3H), 3.73 (ddd, J=19.4, 14.0, 5.7 Hz, 1H), 2.68-2.52 (m, 1H), 2.49-2.16 (m, 2H), 2.04-1.89 (m, 1H), 1.80 (tdd, J=13.7, 10.8, 2.3 Hz, 1H).
Preparation 19B
4-Amino-1,2-dimethyltetrahydropyridazin-3(2H)-one




Benzyl (1-(1,2-dimethylhydrazineyl)-4-hydroxy-1-oxobutan-2-yl)carbamate: To a stirred solution of benzyl (R)-(2-oxotetrahydrofuran-3-yl)carbamate (6.00 g, 25.5 mmol) and 1,2-dimethylhydrazine hydrochloride (10.2 g, 76.5 mmol) in tetrahydrofuran (150 mL) was added triethylamine (33.6 g, 332 mmol) dropwise at room temperature under nitrogen. The mixture was stirred at 80° C. for 24 h, then filtered. The solids were washed with ethyl acetate (200 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified by reversed phase purification (C18 column), eluting with 25-35% acetonitrile in (10 mM ammonium bicarbonate in water), to give benzyl (1-(1,2-dimethylhydrazineyl)-4-hydroxy-1-oxobutan-2-yl)carbamate (6.05 g, 80%) as a colorless oil. MS (ES) m/z=296 (M+1).
Benzyl (1,2-dimethyl-3-oxohexahydropyridazin-4-yl)carbamate: A solution of benzyl (1-(1,2-dimethylhydrazineyl)-4-hydroxy-1-oxobutan-2-yl)carbamate (5.50 g, 18.6 mmol) and 2-(tributyl-lambda5-phosphanylidene)acetonitrile (45.0 g, 186 mmol) in toluene (150 mL) was stirred at 100° C. for 1.5 h under nitrogen. The mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 14-25% (7:3 ethyl acetate:methanol) in DCM, followed by reversed phase purification (C18 column), eluting with 25-35% acetonitrile in (0.1% formic acid in water), to give benzyl (1,2-dimethyl-3-oxohexahydropyridazin-4-yl)carbamate (1.5 g, 29%) as a yellow solid. MS (ES) m/z=278 (M+1).
4-Amino-1,2-dimethyltetrahydropyridazin-3(2H)-one: To a stirred solution of benzyl (1,2-dimethyl-3-oxohexahydropyridazin-4-yl)carbamate (1.5 g, 5.41 mmol) in methanol (50 mL) was added palladium hydroxide (Pd 20% on carbon powder, nominally 50% water; 1.2 g) in portions at room temperature under nitrogen. The mixture was stirred at room temperature for 2 h under hydrogen, then filtered. The solids were washed with methanol (200 mL). The combined filtrates were concentrated under reduced pressure to give the crude title compound (0.85 g) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 3.28 (t, 1H), 3.06 (dd, 2H), 2.91 (s, 3H), 2.59 (s, 3H), 2.11 (ddt, 1H), 1.81 (ddt,1H).
Preparation 20B
tert-Butyl (4-(5-chloro-9-(((6R,8aR)-5-oxooctahydroindolizin-6-yl)amino)-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate




A mixture of tert-butyl (4-(9-bromo-5-chloro-1,3-dihydrofuro[3,4-f]quinolin-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.152 g, 0.264 mmol), (6R,8aR)-6-aminohexahydroindolizin-5(1H)-one hydrochloride (0.151 g, 0.793 mmol), cesium carbonate (0.172 g, 0.529 mmol), 2,2′-bis(diphenylphosphaneyl)-1,1′-binaphthalene (0.020 g, 0.032 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.032 mmol) in toluene (2.40 mL) was stirred for 16 h at 100° C. The mixture was diluted with water and extracted with DCM (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-15% methanol in DCM, to give the title compound (0.16 g, 93%). MS (ES) m/z=648 (M+1).
Preparation 21B
tert-Butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-(((6R,8aR)-5-oxooctahydroindolizin-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate




BOP—Cl (CAS #68641-49-6; 0.274 g, 1.08 mmol) was added to a solution of tert-butyl (3-cyano-4-(3-(ethylthio)-5-fluoro-1-hydroxy-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (4.1 g, 7.2 mmol) and diisopropylethylamine (0.469 mL, 2.69 mmol). The mixture was stirred for 1 h at 60° C. (6R,8aR)-6-Aminohexahydroindolizin-5(1H)-one hydrochloride (0.257 g, 1.35 mmol) was added and the mixture was stirred for 2 h at 60° C. The mixture was concentrated under reduced pressure, diluted with DCM (150 mL), and washed with saturated aqueous sodium bicarbonate (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% ethyl acetate in DCM, to give the title compound (0.515 g, 83%) as a yellow solid. MS (ES) m/z=693 (M+1). Clean atropisomer, chiral purification from Preparation 32.
The following compounds in Table 7 were prepared in similar manner as described in Preparation 21B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 7








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







22B 2
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((6R,8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


23B 1
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((6R,8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


24B 
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


25B 4,5
tert-Butyl (3-cyano-4-(1- (((8aS)-2,2-difluoro-5- oxooctahydroindolizin-6- yl)amino)-3-(ethylthio)- 5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




729


 


26B 6,7
tert-Butyl (4-(5-chloro-1- (((6S)-2-oxo-1- azabicyclo[4.2.0]octan-3- f]quinazolin-6-yl)-3- dihydrofuro[3,4- yl)amino)-7,9- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




635





1 Clean atropisomer, chiral purification from Preparation 30


2 Clean atropisomer, chiral purification from Preparation 34


3 A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A


4 Clean atropisomer, chiral purification from Preparation 32


5 Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 18B


6 Clean atropisomer, chiral purification from Preparation 6B


7 Clean isomer at the 3-position of the azabicyclooctanone, chiral purification from Preparation 17B






Preparation 56
tert-Butyl (4-(5-chloro-3-(ethylthio)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate




To a mixture of tert-butyl (3-cyano-4-(1,5-dichloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.206 g, 0.348 mmol) and 6-amino-4-methyl-4-azaspiro[2.5]octan-5-one (0.161 g, 1.04 mmol) in acetonitrile (4 mL) was added diisopropylethylamine (0.30 mL, 1.74 mmol). The mixture was stirred at rt. After 16 h, the mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% EtOAc in heptane to obtain the title compound (0.107 g, 43%) as a white solid. MS (ES) nVz=709 (M+1).
The following compounds in Table 8 were prepared in similar manner as described in Preparation 56. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 8








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







571
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((5-methyl- 6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




723


 


581
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((4-methyl- 5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


591
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((5-methyl- 6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


60
tert-Butyl (3-cyano-4-(3- (ethylthio)-5-fluoro-1- ((4-methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




693


 


61
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((5-methyl- 6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


622
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((2-methyl- 3-oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




695


 


63
7-((6-Bromo-5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6-one




511


 


64
7-((6-Bromo-5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one




497


 


65
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((4-methyl- 5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




685


 


66
(8aR)-6-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




481


 


67
6-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one




483


 


68
7-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one




483


 


 9A2
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((5-methyl- 6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


10A1
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((4-methyl- 5-oxo-4- azaspiro[2.4]heptan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




695


 


11A1
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


12A
7-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6-one




495


 


13A3
(8aR)-6-((6-Bromo-5- chloro-3-(ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one, Isomer 1




497


 


14A3
(8aR)-6-((6-Bromo-5- chloro-3-(ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one, Isomer 2




497


 


15A
6-((6-Bromo-5-chloro-3- (ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one




497


 


16A4
(9aS)-7-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydropyrido [2,1-c][1,4]oxazin- 6(1H)-one




497


 


17A
7-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-azaspiro[3.5]nonan-6- one




481


 


18A2,4
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




709


 


19A4
(8aR)-6-((6-bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




481


 


27B
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-(((6R,8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate




710


 


28B
(6R,8aR)-6-((6-Bromo-5- chloro-3-(ethylthio)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




497


 


29B
(6R,8aR)-6-((4-Bromo-7- chloro-5-fluoro-1,3- dihydrofuro[3,4- f]quinolin-9- yl)amino) hexahydroindolizin- 5(1H)-one




454


 


30B
(6R)-3-((6-Bromo-3- (ethylthio)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 6-(difluoromethyl)-1- methylpiperidin-2-one




505


 


31B
(6R,8aR)-6-((4-Bromo- 5,7-dichloro-1,3- dihydrofuro[3,4- f]quinolin-9- yl)amino) hexahydroindolizin- 5(1H)-one




472





1Clean atropisomer, chiral purification from Preparation 30


2Clean atropisomer, chiral purification from Preparation 34


3Normal Phase; silica, 0-100% EtOAc in DCM, Isomer refers to a clean isomer at the 6-position of the hexahydroindolizinone


4A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A






The following compounds in Table 9 were prepared in similar manner as described in Preparation 28. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 9








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







69
tert-Butyl (4-(5-chloro-3- (ethylthio)-1-((5-methyl- 6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[d]thiazol-2- yl)carbamate




685


 


70
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- (((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




669


 


71
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- ((4-methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




669


 


72
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- ((5-methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




669


 


20A
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- ((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




683


 


21A1
tert-Butyl (4-(3- (ethylthio)-5-fluoro-1- (((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




669





1A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A






Preparation 73
tert-Butyl (4-(5-chloro-3-(ethylthio)-1-((5-methyl-6-oxo-5-azaspiro[3.5]nonan-7-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothiazolo[4,5-c]pyridin-2-yl)carbamate




7-((5-Chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one. To a solution of 7-((6-bromo-5-chloro-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one (0.292 g, 0.570 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (0.258 g, 1.14 mmol), and potassium acetate (0.168 g, 1.71 mmol) in 1,4-dioxane (5 mL) was added Pd-117 (CAS 205319-06-8; 0.012 g, 0.017 mmol). The mixture was stirred at 80° C. for 16 h, cooled, and filtered. The solids were washed with 1,4-dioxane (3×60 mL). The combined filtrates were concentrated under reduced pressure. The residue was purified on silica, eluting with 0-60% MeOH in DCM to obtain 7-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one (0.331 g) as a white solid. MS (ES) m/z=477 (M+1, boronic acid).
tert-Butyl (4-(5-chloro-3-(ethylthio)-1-((5-methyl-6-oxo-5-azaspiro[3.5]nonan-7-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorothiazolo[4,5-c]pyridin-2-yl)carbamate. To a mixture of tert-butyl (4-chloro-7-fluorothiazolo[4,5-c]pyridin-2-yl)carbamate (0.316 g, 1.04 mmol), 7-((5-chloro-6-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-(ethylthio)-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)-5-methyl-5-azaspiro[3.5]nonan-6-one (0.331 g, 0.570 mmol), 2-(dicyclohexylphosphanyl)-2′,4′,6′-tris(isopropyl)biphenyl (0.033 g, 0.069 mmol), and XPhos Pd(crotyl)C1 (CAS 1798782-02-1; 0.047 g, 0.069 mmol) in 1,4-dioxane (5 mL) was added a solution of dipotassium phosphate (0.362 g, 2.08 mmol) in water (1 mL). The mixture was degassed (direct nitrogen sparge) for 5 min, stirred at 80° C. for 16 h, and concentrated under reduced pressure. The residue was purified on silica, eluting with 0-100% ethyl acetate in heptane to obtain the title compound (0.276 g, 57%). MS (ES) m/z=700 (M+1).
The following compounds in Table 10 were prepared in similar manner as described in Preparation 73. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 10








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







22A
tert-Butyl (4-(5-chloro-3- (ethylthio)- 1-((5-methyl- 6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothiazolo[4,5- c]pyridin-2-yl) carbamate




686









Preparation 23A
(6R,8aR)-6-((6-Bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)hexahydroindolizin-5(1H)-one




To a solution of (8aR)-6-((6-bromo-3-(ethylthio)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)hexahydroindolizin-5(1H)-one (21.8 g, 45.2 mmol) in MeOH (400 mL) was added potassium carbonate (12.5 g, 90.5 mmol). The mixture was stirred at 40° C. for 16 h, then concentrated under reduced pressure. The residue was diluted with water (200 mL) and filtered to obtain the title compound (18.2 g, 84%) as a yellow solid. MS (ES) m/z=481 (M+1).
Preparation 74
tert-Butyl (4-(5-chloro-3-(ethylsulfonyl)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate




To a solution of tert-butyl (4-(5-chloro-3-(ethylthio)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.107 g, 0.150 mmol) in DCM (5 mL) was added mCPBA (70 wt %; 0.081 g, 0.330 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 30 min, then at room temperature for 2 h. The mixture was concentrated under reduced pressure. The crude material was purified on silica, eluting with 0-100% EtOAc in DCM to obtain the title compound (0.115 g, 100%) as a light yellow solid. MS (ES) nvz=741 (M+1).
The following compounds in Table 11 were prepared in similar manner as described in Preparation 74. Different oxidation conditions, such as hydrogen peroxide and hexaammonium heptamolybdate tetrahydrate in ethanol and DCM, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 11








MS


Prepar-


(ES) m/z


ation
Chemical Name
Structure
(M + 1)







751
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




755


 


761
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


771
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


78
tert-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




725


 


79
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


802
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((2- methyl-3-oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




727


 


81
6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1-ol




377


 


82
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothiazolo[4,5- c]pyridin-2-yl)carbamate




732


 


83
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[d]thiazol-2- yl)carbamate




717


 


84
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




717


 


853
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate, Enantiomer 1




701


 


863
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate, Enantiomer 2




701


 


87
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




701


 


88
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




701


 


24A2
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


25A2
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1- hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




605


 


26A1
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((4- methyl-5-oxo-4- azaspiro[2.4]heptan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




727


 


27A1
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1- hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




605


 


28A1,4
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate, Isomer 1




741


 


29A1,4
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate, Isomer 2




741


 


30A
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




715


 


31A5
(8aR)-6-((6-Bromo-5- chloro-3-(ethylsulfonyl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




529


 


32A6
(8aR)-6-((6-Bromo-5- chloro-3-(ethylsulfonyl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




529


 


33A
6-((6-Bromo-5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one




529


 


34A
7-((6-Bromo-5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one




529


 


35A
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothiazolo[4,5- c]pyridin-2-yl)carbamate




718


 


36A7
(9aS)-7-((6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydropyrido [2,1-c][1,4]oxazin- 6(1H)-one




529


 


37A
(6R,8aR)-6-((6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




513


 


38A
7-((6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-azaspiro[3.5]nonan-6- one




513


 


39A
7-((6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6-one




527


 


40A
6-Bromo-5-chloro-3- (ethylsulfonyl)-7,9- dihydrofuro[3,4- f]quinazolin-1-ol




392


 


41A2,7
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


42A7
(8aR)-6-((6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




513


 


43A7
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




701


 


32B2
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-5- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


33B1
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


34B1,7
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1-(((8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7- fluorobenzo[b]thiophen- 2-yl)carbamate




741


 


35B8
tert-Butyl (3-cyano-4-(3- (ethylsulfonyl)-5-fluoro- 1-(((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




725


 


36B8,9
tert-Butyl (3-cyano-4-(1- (((8aS)-2,2-difluoro-5- oxooctahydroindolizin-6- yl)amino)-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen- 2-yl)carbamate




761


 


37B
tert-Butyl (4-(5-chloro-3- (ethylsulfonyl)-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-3- cyano-7-fluorothieno[3,2- c]pyridin-2-yl)carbamate




742


 


38B
(6R,8aR)-6-((6-Bromo-5- chloro-3-(ethylsulfonyl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino) hexahydroindolizin- 5(1H)-one




529


 


39B
tert-Butyl (4-(3- (ethylsulfonyl)-5-fluoro- 1-hydroxy-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




563 (M − 1)


 


40B
(6R)-3-((6-Bromo-3- (ethylsulfonyl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 6-(difluoromethyl)-1- methylpiperidin-2-one




537





1Clean atropisomer, chiral purification from Preparation 30


2Clean atropisomer, chiral purification from Preparation 34


3Normal Phase; silica, 0-100% EtOAc in DCM


4Normal Phase; silica, 0-100% EtOAc in DCM, Isomer refers to a clean isomer at the 6-position of the hexahydroindolizinone


5Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 13A


6Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 14A


7A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A


8Clean atropisomer, chiral purification from Preparation 32


9Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 18B






Preparation 89
tert-Butyl 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate




tert-Butyl 3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (mix of cis isomers; 0.300 g, 1.51 mmol), formaldehyde (37 wt %; 0.737 g, 9.08 mmol), and sodium triacetoxyborohydride (1.92 g, 9.08 mmol) were dissolved in methanol (6 mL). The mixture was heated at 50° C. After 18 h, the mixture was cooled, concentrated under reduced pressure, and diluted with saturated aqueous sodium bicarbonate (20 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (mix of cis isomers; 0.365 g) as a colorless oil. MS (ES) m/z=213 (M+1).
The following compounds in Table 12 were prepared in similar manner as described in Preparation 89. Different reductive amination conditions, such as sodium cyanoborohydride with sodium dihydrogen phosphate, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 12








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







90
tert-Butyl (2S,3S)-3- (dimethylamino)-2- methylpyrrolidine-1- carboxylate




229


 


91
tert-Butyl (3aR,6aR)-1- methylhexahydropyrrolo [3,4-b]pyrrole-5(1H)- carboxylate




227


 


44A
tert-Butyl (3aS,6aS)-1- methylhexahydropyrrolo [3,4-b]pyrrole-5(1H)- carboxylate




227


 


45A
tert-Butyl (3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidine-1- carboxylate







 


46A
tert-Butyl (3S,4R)-3- hydroxy-4- (isopropylamino)pyrrolid ine-1-carboxylate







 


47A
tert-Butyl (3S,4R)-3- hydroxy-4- (isopropyl(methyl)amino) pyrrolidine-1-carboxylate




259


 


41B1,2
tert-Butyl (2S,3S)-2- methyl-3-((methyl- d3)amino)pyrrolidine-1- carboxylate







 


42B1
tert-Butyl (2S,3S)-3- (bis(methyl-d3)amino)-2- methylpyrrolidine-1- carboxylate




235


 


43B3
tert-Butyl (2S,3S)-3- (ethylamino)-2- methylpyrrolidine-1- carboxylate







 


44B
tert-Butyl (2S,3S)-3- (diethylamino)-2- methylpyrrolidine-1- carboxylate




257


 


45B
tert-Butyl (6S)-1,6- dimethylhexahydropyrrolo [3,4-b]pyrrole-5(1H)- carboxylate




241





1Reaction used deuterated formaldehyde, deuterated acetic acid, and sodium cyanoborodeuteride in methanol


2Not isolated; generated and consumed in the synthesis of Preparation 42B


3Not isolated; generated and consumed in the synthesis of Preparation 44B






Preparation 48A
tert-Butyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-methyl-3-oxopyrrolidine-1-carboxylate




To a solution of DMSO (2.03 mL, 28.6 mmol) in DCM (60 mL) was added oxalyl chloride (2M in DCM; 7.15 mL, 14.3 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 1 h, then tert-butyl (2S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (2.37 g, 7.15 mmol) in DCM (10 mL) was added. Triethylamine (5.98 mL, 42.9 mmol) was added. The mixture was stirred at −78° C. for 10 min, then at 25° C. for 45 min. The mixture was diluted with water and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound as an orange oil. MS (ES) m/z=274 (M+1-tBu).
Preparation 49A
tert-Butyl (2S,3S)-3-(ethyl(methyl)amino)-2-methylpyrrolidine-1-carboxylate




To a solution of tert-butyl (S)-2-methyl-3-oxopyrrolidine-1-carboxylate (1.00 g, 5.02 mmol), acetic acid (0.287 mL, 5.02 mmol), and N-methylethanamine (0.445 g, 7.53 mmol) in DCM (5 mL) was added sodium triacetoxyborohydride (1.70 g, 8.03 mmol) portionwise. The mixture was stirred at room temperature. After 22 h, the mixture was cooled to 0° C. and quenched with aqueous sodium bicarbonate. The two layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed phase purification (C18 column), eluting with 0-100% acetonitrile in (0.1% formic acid in water), to give the title compound (1.32 g) as a colorless oil. MS (ES) m/z=243 (M+1).
Preparation 50A
tert-Butyl (2S,3R,4S)-4-((tert-butyldimethylsilyl)oxy)-3-(dimethylamino)-2-methylpyrrolidine-1-carboxylate




tert-Butyl (2S,4S)-4-((tert-butyldimethylsilyl)oxy)-2-methyl-3-oxopyrrolidine-1-carboxylate and dimethylamine were used in a manner analogous to the method of Preparation 49A to afford the title compound (1.12 g) as a yellow oil. MS (ES) m/z=359 (M+1).
Preparation 51A
tert-Butyl (2S)-3-(azetidin-1-yl)-2-methylpyrrolidine-1-carboxylate




tert-Butyl (S)-2-methyl-3-oxopyrrolidine-1-carboxylate and azetidine were used in a manner analogous to the method ofPreparation 49A to afford the title compound (0.60 g, 99%) as a yellow oil. MS (ES) nVz=241 (M+1).
The following compounds in Table 13 were prepared in similar manner as described in Preparation 49A. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 13








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







46B
tert-Butyl (2S,3S)-3-(3- (fluoromethyl)azetidin-1- yl)-2-methylpyrrolidine-1- carboxylate




273


 


47B
tert-Butyl (2S)-2-methyl-3- (5-azaspiro[2.3]hexan-5- yl)pyrrolidine-1-carboxylate




267


 


48B
tert-Butyl (2S,3S)-3-(6- fluoro-2- azaspiro[3.3]heptan-2-yl)-2- methylpyrrolidine-1- carboxylate




299


 


49B
tert-Butyl (2S,3S)-2-methyl- 3-(5-azaspiro[2.3]hexan-5- yl)pyrrolidine-1-carboxylate




267


 


50B
tert-Butyl (2S,3S)-3-((3- fluorocyclobutyl)(methyl) amino)-2-methylpyrrolidine- 1-carboxylate




287









Preparation 52A
tert-Butyl (2'S,3'S)-2′-methyl-[1,3′-bipyrrolidine]-1′-carboxylate




tert-Butyl (2S,3S)-3-amino-2-methylpyrrolidine-1-carboxylate (2.5 g, 12 mmol), potassium iodide (1.0 g, 6.2 mmol), 1,4-dibromobutane (4.0 g, 19 mmol), and potassium carbonate (8.6 g, 62 mmol) were combined in acetonitrile (50 mL). The mixture was stirred at 70° C. overnight. The mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give the crude title compound (3.0 g, 94%). MS (ES) m/z=255 (M+1).
Preparation 92
6-Methyl-3,6-diazabicyclo[3.2.0]heptane dihydrochloride




To a mixture of tert-butyl 6-methyl-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate (mix of cis isomers; 0.370 g, 1.74 mmol) in DCM (3 mL) was added HCl (4M in 1,4-dioxane; 3 mL). The mixture was stirred at room temperature. After 6 h, the mixture was concentrated under reduced pressure to give the crude title compound (mix of cis isomers; 0.300 g) as a yellow solid. MS (ES) m/z=113 (M+1).
The following compounds in Table 14 were prepared in similar manner as described in Preparation 92. Different acidic conditions, such as trifluoroacetic acid, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 14








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







93
(2S,3S)-N,N,2- Trimethylpyrrolidin-3- amine dihydrochloride




129


 


94
(2S,3S)-N,N,2- Trimethylpyrrolidin-3- amine




129


 


95
(3aR,6aR)-1- Methyloctahydropyrrolo [3,4-b]pyrrole dihydrochloride




127


 


53A
(3aS,6aS)-1- Methyloctahydropyrrolo [3,4-b]pyrrole dihydrochloride




127


 


54A
(2S,3S)-N-Ethyl-N,2- dimethylpyrrolidin-3-amine dihydrochloride




143


 


55A
(2S,3S)-N-Ethyl-N,2- dimethylpyrrolidin-3-amine




143


 


56A
(3S,4R)-4- (Dimethylamino)pyrrolidin- 3-ol dihydrochloride




131


 


57A
(3S,4R)-4- (Isopropyl(methyl)amino) pyrrolidin-3-ol dihydrochloride




159


 


58A
(2S,3R,4S)-4-((tert- Butyldimethylsilyl)oxy)- N,N,2-trimethylpyrrolidin- 3-amine dihydrochloride




259


 


59A
(2S)-3-(Azetidin-1-yl)-2- methylpyrrolidine dihydrochloride




141


 


60A
(2′S,3′S)-2′-Methyl-1,3′- bipyrrolidine dihydrochloride




155


 


51B
(2S,3S)-3-(3- (Fluoromethyl)azetidin-1- yl)-2-methylpyrrolidine




173


 


52B
5-((2S)-2-Methylpyrrolidin- 3-yl)-5-azaspiro[2.3]hexane dihydrochloride




167


 


53B
(2S,3S)-2-Methyl-N,N- bis(methyl-d3)pyrrolidin-3- amine dihydrochloride




135


 


54B
(2S,3S)-N,N-Diethyl-2- methylpyrrolidin-3-amine




157


 


55B
6-Fluoro-2-((2S,3S)-2- methylpyrrolidin-3-yl)-2- azaspiro[3.3]heptane dihydrochloride




199


 


56B
5-((2S,3S)-2- Methylpyrrolidin-3-yl)-5- azaspiro[2.3]hexane dihydrochloride




167


 


57B
(2S,3S)-N-(3- Fluorocyclobutyl)-N,2- dimethylpyrrolidin-3-amine dihydrochloride




187


 


58B
(6S)-1,6- Dimethyloctahydropyrrolo [3,4-b]pyrrole  dihydrochloride




141









Preparation 59B
(6R,8aR)-6-((4-Bromo-7-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidin-1-yl)-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-9-yl)amino)hexahydroindolizin-5(1H)-one




To a mixture of (6R,8aR)-6-((4-bromo-7-chloro-5-fluoro-1,3-dihydrofuro[3,4-f]quinolin-9-yl)amino)hexahydroindolizin-5(1H)-one (0.083 g, 0.183 mmol), (2S,3S)—N,N,2-trimethylpyrrolidin-3-amine dihydrochloride (0.128 g, 0.639 mmol), and CsF (0.028 g, 0.183 mmol) in NMP (0.913 mL) was added diisopropylethylamine (0.32 mL, 1.83 mmol). The mixture was heated at 110° C. for 32 h, then cooled to room temperature and diluted with water. The mixture was purified by reversed phase purification (C18 column), eluting with 0-100% acetonitrile in (0.1% formic acid in water), to obtain the title compound (0.070 g, 70%). MS (ES) m/z=546 (M+1).
The following compounds in Table 15 were prepared in similar manner as described in Preparation 59B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 15








MS





(ES)





m/z


Prep
Chemical Name
Structure
(M + 1)







60B
(6R,8aR)-6-((4-Bromo-5- fluoro-7-((2′S,3′S)-2′-methyl- [1,3′-bipyrrolidin]-1′-yl)-1,3- dihydrofuro[3,4-f]quinolin-9- yl)amino)hexahydroindolizin- 5(1H)-one




572


 


61B
(6R,8aR)-6-((4-Bromo-5- chloro-7-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-1,3- dihydrofuro[3,4-f]quinolin-9- yl)amino)hexahydroindolizin- 5(1H)-one




562









Preparation 96
tert-Butyl (4-(3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidin-1-yl)-5-fluoro-1-((5-methyl-6-oxo-5-azaspiro[2.5]octan-7-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate




tert-Butyl (4-(3-(ethylsulfonyl)-5-fluoro-1-((5-methyl-6-oxo-5-azaspiro[2.5]octan-7-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-7-fluorobenzo[d]thiazol-2-yl)carbamate (0.080 g, 0.11 mmol) was mixed with diisopropylethylamine (0.30 mL, 1.7 mmol), (2S,3S)—N,N,2-trimethylpyrrolidin-3-amine dihydrochloride (0.11 g, 0.57 mmol), CsF (0.017 g, 0.11 mmol), and acetonitrile (3 mL). The mixture was heated at 70° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified on silica, eluting with 0-40% MeOH in DCM to obtain the title compound (0.072 g, 86%) as a yellow solid. MS (ES) n/z=735 (M+1).
The following compounds in Table 16 were prepared in similar manner as described in Preparation 96. Different bases may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 16








MS





(ES)





m/z


Prep
Chemical Name
Structure
(M + 1)







97
tert-Butyl (4-(5-chloro-3-((S)-3- (dimethylamino)pyrrolidin-1- yl)-1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




761


 


981
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




761


 


991
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




747


 


1001,4
diazabicyclo[3.2.0]heptan-3-yl)- tert-Butyl (4-(5-chloro-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 3-(6-methyl-3,6- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




759


 


1011
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




747


 


102
tert-Butyl (3-cyano-4-(3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5-fluoro- 1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate




759


 


103
tert-Butyl (3-cyano-4-(3-(3- (dimethylamino)azetidin-1-yl)- 5-fluoro-1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophen-2- yl)carbamate




731


 


104
tert-Butyl (4-(5-chloro-3-((S)-3- (dimethylamino)pyrrolidin-1- yl)-1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




761


 


1052
tert-Butyl (4-(5-chloro-1-((2- methyl-3-oxo-2- azabicyclo[3.1.1]heptan-4- yl)amino)-3-((3aR,6aR)-1- methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




759


 


1062
tert-Butyl (4-(5-chloro-3-((S)-3- (dimethylamino)pyrrolidin-1- yl)-1-((2-methyl-3-oxo-2- azabicyclo[3.1.1]heptan-4- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




747


 


107
6-Bromo-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-ol




411


 


108
tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-1-((5- methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothiazolo[4,5-c]pyridin-2- yl)carbamate




766


 


109
tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[d]thiazol-2- yl)carbamate




751


 


110
tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




751


 


111
tert-Butyl (4-(5-chloro-3-((S)-3- (dimethylamino)pyrrolidin-1- yl)-1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




737


 


1123
tert-Butyl (4-(3-((S)-3- (dimethylamino)pyrrolidin-1- yl)-5-fluoro-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




721


 


1133
tert-Butyl (4-(3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




735


 


114
tert-Butyl (4-(3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




735


 


61A2
tert-Butyl (4-(5-chloro-3- ((3R,4S)-3-(dimethylamino)-4- hydroxypyrrolidin-1-yl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




777


 


62A2
tert-Butyl (4-(5-chloro-1-((2- methyl-3-oxo-2- azabicyclo[3.1.1]heptan-4- yl)amino)-3-((3aS,6aS)-1- methylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




759


 


63A2
tert-Butyl (4-(5-chloro-3-((S)- 3-(dimethylamino)pyrrolidin- 1-yl)-1-hydroxy-7,9- dihydrofuro[3,4-f]quinazolin- 6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




625


 


64A1
tert-Butyl (4-(5-chloro-3-((S)- 3-(dimethylamino)pyrrolidin- 1-yl)-1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




761


 


65A1
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-((4-methyl-5-oxo-4- azaspiro[2.4]heptan-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




733


 


66A1
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-hydroxy-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




611


 


67A1,5
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1-yl)- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




747


 


68A1,6
tert-Butyl (4-(5-chloro-3-(3- (dimethylamino)azetidin-1- yl)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




747


 


69A
tert-Butyl (4-(3-((2S,3R,4S)-3- (dimethylamino)-4-hydroxy-2- methylpyrrolidin-1-yl)-5- fluoro-1-((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




765


 


70A7
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




563


 


71A8
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




563


 


72A8
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




577


 


73A
6-((6-Bromo-5-chloro-3- ((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)-4-methyl-4- azaspiro[2.5]octan-5-one




577


 


74A
7-((6-Bromo-5-chloro-3- ((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)-5-methyl-5- azaspiro[2.5]octan-6-one




577


 


75A
tert-Butyl (4-(5-chloro-3- ((2S,3S)-3-(dimethylamino)-2- methylpyrrolidin-1-yl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan-7-yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothiazolo[4,5-c]pyridin-2- yl)carbamate




752


 


76A3,9
tert-Butyl (4-(3-((2S)-3- (azetidin-1-yl)-2- methylpyrrolidin-1-yl)-5-fluoro- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate, Isomer 1




747


 


77A3,9
tert-Butyl (4-(3-((2S)-3- (azetidin-1-yl)-2- methylpyrrolidin-1-yl)-5-fluoro- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate, Isomer 2




747


 


78A
tert-Butyl (4-(3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7-yl) amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




749


 


79A10
(9aS)-7-((6-Bromo-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydropyrido [2,1-c][1,4]oxazin-6(1H)-one




563


 


80A
(6R,8aR)-6-((6-Bromo-5- fluoro-3-((2′S,3′S)-2′-methyl- [1,3′-bipyrrolidin]-1′-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




573


 


81A
7-((6-Bromo-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)-5- azaspiro [3.5]nonan-6-one




547


 


82A
7-((6-Bromo-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)-5- methyl-5-azaspiro[3.5]nonan-6- one




561


 


83A
(S)-6-Bromo-3-(3- (dimethylamino)pyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazolin-1- ol




397


 


84A
(S)-6-Bromo-5-chloro-3-(3- (dimethylamino)pyrrolidin-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-1-ol




413


 


85A
6-Bromo-5-chloro-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin- 1-ol




427


 


86A2,10
tert-Butyl (4-(5-chloro-3- ((3S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-5- fluorobenzo[b]thiophen-2- yl)carbamate




805


 


87A10
(8aR)-6-((6-Bromo-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




547


 


88A10,11
tert-Butyl (4-(3-((3- (dimethylamino)oxetan-3- yl)methoxy)-5-fluoro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




738


 


89A10
(8aR)-6-((6-Bromo-3-((S)-3- (dimethylamino)pyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




533


 


62B1
tert-Butyl (4-(3-([1,3′- biazetidin]-1′-yl)-5-chloro-1- ((5-methyl-6-oxo-5- azaspiro [3.5]nonan-7- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




773


 


63B1,10
tert-Butyl (4-(5-chloro-3-(2- hydroxy-2-methylpropoxy)- 1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-3-cyano-7- fluorobenzo[b]thiophen-2- yl)carbamate




737


 


64B
(6R,8aR)-6-((6-Bromo-5- fluoro-3-((2S,3S)-3-(3- (fluoromethyl)azetidin-1-yl)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




591


 


65B
(6R,8aR)-6-((6-Bromo-5- fluoro-3-((2S)-2-methyl-3-(5- azaspiro[2.3]hexan-5- yl)pyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




585


 


66B
(6R,8aR)-6-((6-Bromo-3-((6S)- 1,6- dimethylhexahydropyrrolo[3,4- b]pyrrol-5(1H)-yl)-5-fluoro-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




559


 


67B
tert-Butyl (4-(3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5-fluoro- 1-hydroxy-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[d]thiazol-2- yl)carbamate




599


 


68B
(6R)-3-((6-Bromo-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)-6- (difluoromethyl)-1- methylpiperidin-2-one




571


 


69B
(6R,8aR)-6-((3-((2S,3S)-3- (Bis(methyl-d3)amino)-2- methylpyrrolidin-1-yl)-6- bromo-5-fluoro-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




553


 


70B
7-((6-Bromo-5-chloro-3- ((2S,3S)-3-(diethylamino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)-5-methyl-5- azaspiro [2.5]octan-6-one




591


 


71B8
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-3-(6-fluoro-2- azaspiro[3.3]heptan-2-yl)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




633


 


72B8
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-2-methyl-3-(5- azaspiro[2.3]hexan-5- yl)pyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




601


 


73B8
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-3-((3- fluorocyclobutyl)(methyl) amino)-2-methylpyrrolidin- 1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




621


 


74B8
(8aR)-6-((6-Bromo-5-chloro-3- ((2S,3S)-3-(3- (fluoromethyl)azetidin-1-yl)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




607


 


75B
6-Bromo-5-chloro-3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quinazolin- 1-ol




441


 


76B8
(8aR)-6-((6-Bromo-5-chloro-3- ((2′S,3′S)-2′-methyl-[1,3′- bipyrrolidin]-1′-yl)-7,9- dihydrofuro[3,4-f]quinazolin-1- yl)amino)hexahydroindolizin- 5(1H)-one




589





1Clean atropisomer, chiral purification from Preparation 30


2Clean atropisomer, chiral purification from Preparation 34


3Clean enantiomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 86


4Mix of cis isomers


5Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 28A


6Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 29A


7Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 13A


8Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 14A


9Normal Phase; silica, 0-40% MeOH in DCM, Isomer refers to a clean isomer at the 3-position of the pyrrolidine


10A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A


11Lithium bis(trimethylsilyl)amide was used as base






The following compounds in Table 17 were prepared in similar manner as described in Preparation 26. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 17








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







90A1
tert-Butyl (3-cyano-4- (1,5-dichloro-3-(3- (dimethylamino)- azetidin-1-yl)-7,9- dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorobenzo[b]thio- phen-2-yl)carbamate




629





1Clean atropisomer, chiral purification from Preparation 30






The following compounds in Table 18 were prepared in similar manner as described in Preparation 56. Different bases may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 18








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







91A1
tert-Butyl (4-(5-chloro-3- (3-(dimethylamino)- azetidin-1-yl)-1-((1- oxooctahydropyridazino [1,2-a]pyridazin-2-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)-3- cyano-7-fluorobenzo[b] thiophen-2-yl)carbamate




762


 


77B
(6R,8aR)-6-((4-Bromo- 5-chloro-1,3-dihydro- furo[3,4-f]cinnolin-9- yl)amino)hexahydro- indolizin-5(1H)-one




437


 


78B2
4-((6-Bromo-5-chloro-3- ((2S,3S)-3-(dimethyl- amino)-2-methylpyrrol- idin-1-yl)-7,9-dihydro- furo[3,4-f]quinazolin-1- yl)amino)-1,2-dimethyl- tetrahydropyridazin- 3(2H)-one, Isomer 2




552


 


79B3
4-((6-Bromo-5-chloro-3- ((2S,3S)-3-(ethyl(methyl)- amino)-2-methylpyrrol- idin-1-yl)-7,9-dihydrofuro [3,4-f]quinazolin-1-yl)- amino)-1,2-dimethyltetra- hydropyridazin-3(2H)- one, Isomer 2




566





1Clean atropisomer, chiral purification from Preparation 30


2Chiral SFC; ChiralPak AD, 30 × 250 mm, 50% (isopropanol w/20 mM ammonia) in CO2, 100 mL/min, Isomer refers to a clean isomer at the 4-position of the pyridazinone.


3Chiral SFC; ChiralPak IK, 30 × 250 mm, 50% (3:1 isopropanol:dichlorometane w/20 mM ammonia) in CO2, 100 mL/min, Isomer refers to a clean isomer at the 4-position of the pyridazinone.






Preparation 115
2-((6-Bromo-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidin-1-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-yl)amino)hexahydropyridazino[1,2-a]pyridazin-1(2H)-one




To a mixture of 6-bromo-3-((2S,3S)-3-(dimethylamino)-2-methylpyrrolidin-1-yl)-5-fluoro-7,9-dihydrofuro[3,4-f]quinazolin-1-ol (0.129 g, 0.314 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (0.326 g, 0.627 mmol) in acetonitrile (2.6 mL) was added diisopropylethylamine (0.55 mL, 3.14 mmol). The mixture was stirred at RT for 1 h, then 2-aminohexahydropyridazino[1,2-a]pyridazin-1(2H)-one trihydrochloride (enriched toward (R) enantiomer; 0.306 g, 1.10 mmol) was added. The mixture was stirred at RT for 2.5 h, then concentrated under reduced pressure. The crude material was purified on silica, eluting with 10% MeOH in DCM to obtain the title compound (enriched toward (R) enantiomer; 0.176 g, 100%) as an off-white solid. MS (ES) m/z=564 (M+1).
The following compounds in Table 19 were prepared in similar manner as described in Preparation 115. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 19








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







1161
6-((6-Bromo-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-7,9-dihydro- furo[3,4-f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyrid- azin-5(6H)-one




550


 


92A2
tert-Butyl (4-(5-chloro-3- ((S)-3-(dimethylamino)- pyrrolidin-1-yl)-1-((5- oxohexahydro-1H-pyr- azolo[1,2-a]pyridazin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-3-cyano-5-fluoro- benzo[b]thiophen-2-yl)- carbamate




762


 


93A
(8aR)-6-((6-Bromo-3- ((2S,3S)-3-(dimethyl- amino)-2-methylpyr- rolidin-1-yl)-5-fluoro- 7,9-dihydrofuro[3,4-f] quinazolin-1-yl)amino)- hexahydroindolizin- 5(1H)-one




547


 


94A3
2-((6-Bromo-3-((S)-3- (dimethylamino)pyrrol- idin-1-yl)-5-fluoro-7,9- dihydrofuro[3,4-f]quin- azolin-1-yl)amino)hexa- hydropyridazino[1,2-a] pyridazin-1(2H)-one




548


 


95A3
6-((6-Bromo-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-7,9-dihydro- furo[3,4-f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyrid- azin-5(6H)-one




548


 


96A3
6-((6-Bromo-5-chloro-3- ((S)-3-(dimethylamino)- pyrrolidin-1-yl)-7,9- dihydrofuro[3,4-f]quin- azolin-1-yl)amino)tetra- hydro-1H-pyrazolo[1,2- a]pyridazin-5(6H)-one




550


 


97A3
6-((6-Bromo-5-chloro-3- ((2S,3S)-3-(dimethyl- amino)-2-methylpyrrol- idin-1-yl)-7,9-dihydro- furo[3,4-f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyrid- azin-5(6H)-one




564


 


80B
tert-Butyl (4-(1-((1,2- dimethyl-3-oxohexa- hydropyridazin-4-yl)- amino)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorobenzo[d] thiazol-2-yl)carbamate




724





1enriched toward (R) enantiomer


2Clean atropisomer, chiral purification from Preparation 34


3A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A






The following compounds in Table 20 were prepared in similar manner as described in Preparation 28. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 20








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







1171
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-((1-oxoocta- hydropyridazino[1,2-a] pyridazin-2-yl)amino)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)benzo [d]thiazol-2-yl)carbamate




732


 


1181
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-((5-oxohexa- hydro-1H-pyrazolo[1,2- a]pyridazin-6-yl)amino)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorobenzo[d]thiazol- 2-yl)carbamate




736


 


98A2
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-(((9aS)-6- oxooctahydropyrido [2,1-c][1,4]oxazin-7-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 7-fluorobenzo[d]thiazol- 2-yl)carbamate




751


 


99A
tert-Butyl (7-fluoro-4- (5-fluoro-3-((2′S,3′S)- 2′-methyl-[1,3′-bipyrrol- idin]-1′-yl)-1-(((6R,8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin-6- yl)benzo[d]thiazol-2- yl)carbamate




761


 


100A
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-((6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin-6- yl)-7-fluorobenzo[d] thiazol-2-yl)carbamate




735


 


101A2
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-((1-oxoocta- hydropyridazino[1,2-a] pyridazin-2-yl)amino)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorobenzo[d]thiazol- 2-yl)carbamate




750


 


102A2
tert-Butyl (4-(3-((S)-3- (dimethylamino)pyrrol- idin-1-yl)-5-fluoro-1- ((1-oxooctahydro- pyridazino[1,2-a]pyr- idazin-2-yl)amino)-7,9- dihydrofuro[3,4-f] quinazolin-6-yl)-5,7- difluorobenzo[d] thiazol-2-yl)carbamate




754


 


103A2
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-((5-oxohexa- hydro-1H-pyrazolo[1,2- a]pyridazin-6-yl)amino)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)-5,7- difluorobenzo[d]thiazol- 2-yl)carbamate




754


 


104A2
tert-Butyl (4-(5-chloro- 3-((S)-3-(dimethyl- amino)pyrrolidin-1-yl)- 1-((5-oxohexahydro- 1H-pyrazolo[1,2-a] pyridazin-6-yl)-amino)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)-5,7- difluorobenzo[d]thiazol- 2-yl)carbamate




756


 


105A2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(dimethyl- amino)-2-methylpyrrol- idin-1-yl)-1-((5-oxo- hexahydro-1H-pyrazolo [1,2-a]pyridazin-6-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 5,7-difluorobenzo[d] thiazol-2-yl)carbamate




770


 


106A2
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-(((8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin-6- yl)benzo[d]thiazol-2- yl)carbamate




717


 


107A2
tert-Butyl (4-(3-((S)-3- (dimethylamino)pyrrol- idin-1-yl)-5-fluoro-1- (((8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-5,7-difluoro- benzo[d]thiazol-2-yl)- carbamate




739


 


108A2
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-(((8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin-6- yl)-5,7-difluorobenzo [d]thiazol-2-yl)carbamate




753


 


81B
tert-Butyl (4-(5-chloro- 9-(((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-1,3-dihydro- furo[3,4-f]cinnolin-4- yl)-3-cyano-7-fluoro- benzo[b]thiophen-2-yl)- carbamate




649


 


82B
tert-Butyl (4-(5-fluoro- 3-((2′S,3′S)-2′-methyl- [1,3′-bipyrrolidin]-1′- yl)-1-(((6R,8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4-f] quinazolin-6-yl)benzo [d]thiazol-2-yl)- carbamate




743


 


83B
tert-Butyl (7-fluoro-4- (5-fluoro-3-((2S,3S)-3- (3-(fluoromethyl)azet- idin-1-yl)-2-methyl- pyrrolidin-1-yl)-1- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)benzo[d]thiazol-2- yl)carbamate




779


 


84B3
tert-Butyl (7-fluoro-4- (5-fluoro-3-((2S)-2- methyl-3-(5-azaspiro [2.3]hexan-5-yl)- pyrrolidin-1-yl)-1- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)benzo[d]thiazol-2- yl)carbamate, Isomer 1




773


 


85B3
tert-Butyl (7-fluoro-4- (5-fluoro-3-((2S)-2- methyl-3-(5-azaspiro [2.3]hexan-5-yl)- pyrrolidin-1-yl)-1- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin-6- yl)benzo[d]thiazol-2- yl)carbamate, Isomer 2




773


 


86B
tert-Butyl (4-(3-((6S)- 1,6-dimethylhexa- hydropyrrolo[3,4-b] pyrrol-5(1H)-yl)-5- fluoro-1-(((6R,8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorobenzo[d]thiazol- 2-yl)carbamate




747


 


87B
tert-Butyl (4-(7-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-9-(((6R,8aR)-5- oxooctahydroindolizin- 6-yl)amino)-1,3-dihydro- furo[3,4-f]quinolin-4-yl)- 7-fluorobenzo[d]thiazol- 2-yl)carbamate




734


 


88B
tert-Butyl (7-fluoro-4- (5-fluoro-7-((2′S,3′S)- 2′-methyl-[1,3′-bipyr- rolidin]-1′-yl)-9- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-1,3-dihydro- furo[3,4-f]quinolin-4- yl)benzo[d]thiazol-2- yl)carbamate




760


 


89B
tert-Butyl (4-(1-(((6R)- 6-(difluoromethyl)-1- methyl-2-oxopiperidin- 3-yl)amino)-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 7-fluorobenzo[d]thiazol- 2-yl)carbamate




759


 


90B
tert-Butyl (4-(3-((2S,3S)- 3-(bis(methyl-d3)amino)- 2-methylpyrrolidin-1-yl)- 5-fluoro-1-(((6R,8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin-6- yl)-7-fluorobenzo[d] thiazol-2-yl)carbamate




741





1enriched toward (R) enantiomer


2A predominant chiral center is present based on starting material from Preparation 53, 54, 55, 5A, 6A, 7A, or 8A


3Normal Phase; silica, 0-10% methanol in dichloromethane, Isomer refers to a clean diastereomer on the pyrrolidine






The following compounds in Table 21 were prepared in similar manner as described in Preparation 73. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 21








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







109A1
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(dimethyl- amino)-2-methylpyrrol- idin-1-yl)-1-(((8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorothiazolo [4,5-c]pyridin-2-yl) carbamate




752


 


110A2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(dimethyl- amino)-2-methylpyrrol- idin-1-y1)-1-(((8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4-f]quin- azolin-6-yl)-7-fluoro- thiazolo[4,5-c]pyridin- 2-yl)carbamate




752


 


111A2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(ethyl- (methyl)amino)-2- methylpyrrolidin-1- yl)-1-(((8aR)-5-oxo- octahydroindolizin-6- yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorothiazolo [4,5-c]pyridin-2-yl)- carbamate




766


 


112A3
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(ethyl- (methyl)amino)-2- methylpyrrolidin-1-yl)- 1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 7-fluorothiazolo[4,5-c] pyridin-2-yl)carbamate, Isomer 1




766


 


113A3
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(ethyl- (methyl)amino)-2- methylpyrrolidin-1-yl)- 1-((4-methyl-5-oxo-4- azaspiro[2.5]octan-6-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 7-fluorothiazolo[4,5-c] pyridin-2-yl)carbamate, Isomer 2




766


 


114A
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(ethyl- (methyl)amino)-2- methylpyrrolidin-1-yl)- 1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 7-fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




766


 


115A
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-((5-methyl-6- oxo-5-azaspiro[3.5] nonan-7-yl)amino)-7,9- dihydrofuro[3,4-f]quin- azolin-6-yl)-7-fluoro- thiazolo[4,5-c]pyridin- 2-yl)carbamate




750


 


116A
tert-Butyl (4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 5-fluoro-1-(((8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorothiazolo [4,5-c]pyridin-2-yl)- carbamate




736


 


91B
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(diethyl- amino)-2-methyl- pyrrolidin-1-yl)-1-((5- methyl-6-oxo-5-aza- spiro[2.5]octan-7-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorothiazolo [4,5-c]pyridin-2-yl)- carbamate




780


 


92B2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(6-fluoro- 2-azaspiro[3.3]heptan- 2-yl)-2-methylpyrrol- idin-1-yl)-1-(((8aR)-5- oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




822


 


93B2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-2-methyl-3- (5-azaspiro[2.3]hexan- 5-yl)pyrrolidin-1-yl)-1- (((8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorothiazolo [4,5-c]pyridin-2-yl)- carbamate




790


 


94B2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-((3-fluoro- cyclobutyl)(methyl)- amino)-2-methylpyr- rolidin-1-yl)-1-(((8aR)- 5-oxooctahydroindoli- zin-6-yl)amino)-7,9- dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




810


 


95B2
tert-Butyl (4-(5-chloro- 3-((2S,3S)-3-(3-(fluoro- methyl)azetidin-1-yl)- 2-methylpyrrolidin-1- yl)-1-(((8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 7-fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




796


 


96B4
tert-Butyl (4-(5-chloro- 1-((1,2-dimethyl-3-oxo- hexahydropyridazin-4- yl)amino)-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




741


 


97B5
tert-Butyl (4-(5-chloro- 1-((1,2-dimethyl-3-oxo- hexahydropyridazin-4- yl)amino)-3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4-f] quinazolin-6-yl)-7- fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




755


 


98B
tert-Butyl (4-(5-chloro- 7-((2S,3S)-3-(dimeth- ylamino)-2-methyl- pyrrolidin-1-yl)-9- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-1,3-dihydrofuro [3,4-f]quinolin-4-yl)-7- fluorothiazolo[4,5-c] pyridin-2-yl)carbamate




751


 


99B
tert-Butyl (7-fluoro-4- (5-fluoro-3-((2′S,3′S)- 2′-methyl-[1,3′- bipyrrolidin]-1′-yl)-1- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)thiazolo[4,5-c] pyridin-2-yl)carbamate




762





1Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 13A


2Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 14A


3Chiral SFC; Chiralcel OD, 20 × 250 mm, 20% (isopropanol w/0.5% dimethylethylamine) in CO2, 80 mL/min, Isomer refers to a clean isomer at the 6-position of the azaspirooctanone.


4Clean isomer at the 4-position of the pyridazinone, chiral purification from Preparation 78B


5Clean isomer at the 4-position of the pyridazinone, chiral purification from Preparation 79B






Preparation 100B
2-Amino-4-(5-chloro-3-(ethylsulfonyl)-1-(((6R,8aR)-5-oxooctahydroindolizin-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile




tert-Butyl (4-(5-chloro-3-(ethylsulfonyl)-1-(((6R,8aR)-5-oxooctahydroindolizin-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.200 g, 0.270 mmol) was diluted with acetonitrile (1.80 mL) and HCl (3M in cyclopentyl methyl ether; 0.45 mL, 1.35 mmol). The mixture was stirred for 16 h at room temperature. The mixture was concentrated under reduced pressure to obtain the title compound (0.17 g, 98%) as a yellow solid. MS (ES) m/z=641 (M+1). Clean atropisomer, chiral purification from Preparation 34.
The following compounds in Table 22 were prepared in similar manner as described in Preparation 100B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 22








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







101B1
2-Amino-4-(5-chloro- 3-(ethylsulfonyl)-1- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-7-fluorobenzo[b] thiophene-3-carbonitrile




641





1Clean atropisomer, chiral purification from Preparation 30






Preparation 102B
tert-Butyl (4-(5-chloro-1-(((6R,8aR)-5-oxooctahydroindolizin-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate




A mixture of tert-butyl (4-(5-chloro-3-(ethylsulfonyl)-1-(((6R,8aR)-5-oxooctahydroindolizin-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (0.050 g, 0.067 mmol) and sodium borohydride (0.0064 g, 0.17 mmol) in DCM (1 mL) and isopropanol (1 mL) was stirred for 40 minl at room temperature. The mixture was concentrated underreduced pressure. The residue was diluted with DCM and saturated aqueous sodium bicarbonate. The organic layer was concentrated under reduced pressure to obtain the crude title compound (0.044 g) as a white solid. MS (ES) m/z=651 (M+1). Clean atropisomer, chiral purification from Preparation 30.
The following compounds in Table 23 were prepared in similar manner as described in Preparation 102B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 23








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







103B1
tert-Butyl (4-(5-chloro- 1-((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-3-cyano-7-fluoro- benzo[b]thiophen-2-yl)- carbamate




663


 


104B2
tert-Butyl (3-cyano-5- fluoro-4-(5-fluoro-1- (((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)benzo[b]thio- phen-2-yl)carbamate




633


 


105B2,3
tert-Butyl (3-cyano-5- fluoro-4-(5-fluoro-3- methoxy-1-(((6R,8aR)- 5-oxooctahydroindoli- zin-6-yl)amino)-7,9- dihydrofuro[3,4-f]quin- azolin-6-yl)benzo[b] thiophen-2-yl)carbamate




663


 


106B2,4
tert-Butyl (3-cyano-4- (1-(((8aS)-2,2-difluoro- 5-oxooctahydroindoli- zin-6-yl)amino)-5- fluoro-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 5-fluorobenzo[b]thio- phen-2-yl)carbamate




669


 


107B
tert-Butyl (4-(5-chloro- 1-(((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydro- furo[3,4-f]quinazolin- 6-yl)-3-cyano-7-fluoro- thieno[3,2-c]pyridin- 2-yl)carbamate




650


 


108B
(6R,8aR)-6-((6-Bromo- 5-chloro-7,9-dihydro- furo[3,4-f]quinazolin- 1-yl)amino)hexahydro- indolizin-5(1H)-one




437





1Clean atropisomer, chiral purification from Preparation 30


2Clean atropisomer, chiral purification from Preparation 32


3Byproduct from Preparation 104B. Methanol was used in the reaction.


4Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 18B






The following compounds in Table 24 were prepared in similar manner as described in Preparation 28. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 24








MS





(ES) m/z


Preparation
Chemical Name
Structure
(M + 1)







109B
tert-Butyl (4-(5-chloro- 1-(((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 3-cyanobenzo[b]thio- phen-2-yl)carbamate




631


 


110B
tert-Butyl (4-(5-chloro- 1-(((6R,8aR)-5-oxoocta- hydroindolizin-6-yl)- amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)- 5-fluorobenzo[d]thiazol- 2-yl)carbamate




625









Examples 1-4
2-Amino-4-(5-chloro-3-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofuro[3,4-f]quinazolin-6-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile, Diastereomers 1-4




tert-Butyl (4-(5-chloro-3-((S)-3-(dimethylamino)pyrrolidin-1-yl)-1-((4-methyl-5-oxo-4-azaspiro[2.5]octan-6-yl)amino)-7,9-dihydrofuro [3,4-f]quinazolin-6-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.082 g, 0.11 mmol) was added to a mixture of DCM (1 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature. After 1 h, the mixture was concentrated under reduced pressure and diluted with aqueous ammonium hydroxide and DCM. The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by reversed phase purification (C18 column), eluting with 40-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol), to give the four title diastereomer compounds (0.017 g, 0.013 g, 0.014 g, 0.014 g; 81%). Diastereomer refers to both a clean atropisomer and a clean isomer on the piperidinone. MS (ES) m/z=661 (M+1), for all four compounds.
The following compounds in Table 25 were prepared in similar manner as described in Examples 1-4. Different acidic conditions, such as HCl in 1,4-dioxane, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art. Isomer separation methods may be found as footnotes.










TABLE 25








MS 





(ES) 





m/z 


Example 
Chemical Name 
Structure 
(M +1)







 51,4 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((5-methyl-6-oxo- 5-azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1  (Isomer 1) 




661 


 


 61,4 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((5-methyl-6-oxo- 5-azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 (Isomer 2) 




661 


 


 71,5 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((4-methyl-5-oxo- 4-azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1 (Isomer 1) 




647 


 


 81,5 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((4-methyl-5-oxo- 4-azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 (Isomer 2) 




647 


 


 91,6 
2-Amino-4-(5-chloro-1- ((4-methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-3-(6-methyl- 3,6- diazabicyclo[3.2.0]heptan- 3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1 (Isomer 1) 




659 


 


 101,6 
2-Amino-4-(5-chloro-1- ((4-methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-3-(6-methyl- 3,6- diazabicyclo[3.2.0]heptan- 3-yl)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 (Isomer 2) 




659 


 


 111,7 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((5-methyl-6-oxo- 5-azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1 (Isomer 1) 




647 


 


 121,7 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((5-methyl-6-oxo- 5-azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 (Isomer 2) 




647 


 


 138 
2-Amino-4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-((4-methyl-5- oxo-4-azaspiro[2.5]octan- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 




659 


 


 148 
2-Amino-4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-((4-methyl-5- oxo-4-azaspiro[2.5]octan- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 




659 


 


 158 
2-Amino-4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-((4-methyl-5- oxo-4-azaspiro[2.5]octan- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 3 




659 


 


 168 
2-Amino-4-(3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1-((4-methyl-5- oxo-4-azaspiro[2.5]octan- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 




659 


 


 179 
2-Amino-4-(3-(3- (dimethylamino)azetidin- 1-yl)-5-fluoro-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 




631 


 


 189 
2-Amino-4-(3-(3- (dimethylamino)azetidin- 1-yl)-5-fluoro-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 




631 


 


 199 
2-Amino-4-(3-(3- (dimethylamino)azetidin- 1-yl)-5-fluoro-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diasteromer 3 




631 


 


 209 
2-Amino-4-(3-(3- (dimethylamino)azetidin- 1-yl)-5-fluoro-1-((4- methyl-5-oxo-4- azaspiro[2.5]octan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 




631 


 


 2110 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino) pyrrolidin-1-yl)-1-((5- methyl-6-oxo-5- azaspiro[2.5]octan- 7-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 1 




661 


 


 2210 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((5-methyl-6- oxo-5-azaspiro[2.5]octan- 7-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 2 




661 


 


 2310 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((5-methyl-6- oxo-5-azaspiro[2.5]octan- 7-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 3 




661 


 


 2410 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((5-methyl-6- oxo-5-azaspiro[2.5]octan- 7-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Diastereomer 4 




661 


 


 252,11 
2-Amino-4-(5-chloro-1- ((2-methyl-3-oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-3- ((3aR,6aR)-1- methylhexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1 (Isomer 1) 




659 


 


 262,11 
2-Amino-4-(5-chloro-1- ((2-methyl-3-oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-3- ((3aR,6aR)-1- methylhexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 (Isomer 2) 




659 


 


 272,12 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((2-methyl-3- oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 1 (Isomer 1) 




647 


 


 282,12 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((2-methyl-3- oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Enantiomer 2 (Isomer 2) 




647 


 


 2913 
2-((6-(2- Aminobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- pyridazino[1,2-a] pyridazin-1(2H)-one, Enantiomer 1 (Isomer 1) 




632 


 


 3013 
2-((6-(2- Aminobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- pyridazino[1,2-a] pyridazin-1(2H)-one, Enantiomer 2 (Isomer 2) 




632 


 


 3114 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6- one, Enantiomer 1 (Isomer 1) 




666 


 


 3214 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6- one, Enantiomer 2 (Isomer 2) 




666 


 


 3315 
7-((6-(2-Amino-5- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Diastereomer 1 




651 


 


 3415 
7-((6-(2-Amino-5- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Diastereomer 2 




651 


 


 3515 
7-((6-(2-Amino-5- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Diastereomer 3 




651 


 


 3615 
7-((6-(2-Amino-5- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Diastereomer 4 




651 


 


 3716 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 1 




651 


 


 3816 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 2 




651 


 


 3916 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diasteromer 3 




651 


 


 4016 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 4 




651 


 


 4117 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 1 




637 


 


 4217 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 2 




637 


 


 4317 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 3 




637 


 


 4417 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Diastereomer 4 




637 


 


 453 
(8aR)-6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




621 


 


 463 
(8aR)-6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




635 


 


 4718 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one 




636 


 


 4819 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Enantiomer 1 (Isomer 1) 




636 


 


 4919 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Enantiomer 2 (Isomer 2) 




636 


 


 5020 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Enantiomer 1 (Isomer 1) 




635 


 


 5120 
6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one, Enantiomer 2 (Isomer 2) 




635 


 


 5221 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Enantiomer 1 (Isomer 1) 




635 


 


 5321 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Enantiomer 2 (Isomer 2) 




635 


 


 542,22 
2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin-1-yl)- 1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




677 


 


 552,22 
2-Amino-4-(5-chloro-3- ((3R,4S)-3- (dimethylamino)-4- hydroxypyrrolidin-1-yl)- 1-((5-methyl-6-oxo-5- azaspiro[2.5]octan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




677 


 


 562 
2-Amino-4-(5-chloro-3- ((3S,4R)-3-hydroxy-4- (isopropyl(methyl)amino) pyrrolidin-1-yl)-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 




705 


 


 572,23 
2-Amino-4-(5-chloro-1- ((2-methyl-3-oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-3- ((3aS,6aS)-1- methylhexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)- 7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




659 


 


 582,23 
2-Amino-4-(5-chloro-1- ((2-methyl-3-oxo-2- azabicyclo[3.1.1]heptan- 4-yl)amino)-3- ((3aS,6aS)-1- methylhexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)- 7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




659 


 


 592,24 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((5- oxohexahydro-1H- pyrazolo[1,2-a]pyridazin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




662 


 


 602,24 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((5- oxohexahydro-1H- pyrazolo[1,2-a]pyridazin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




662 


 


 611,25 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((4-methyl-5- oxo-4-azaspiro[2.5]octan- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




661 


 


 621,25 
2-Amino-4-(5-chloro-3- ((S)-3- (dimethylamino)pyrrolidin- 1-yl)-1-((4-methyl-5- oxo-4-azaspiro[2.5]octan- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




661 


 


 631,26 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((4-methyl-5-oxo- 4-azaspiro[2.4]heptan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




633 


 


 641,26 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((4-methyl-5-oxo- 4-azaspiro[2.4]heptan-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




633 


 


 651,27 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((1- oxooctahydropyridazino [1,2-a]pyridazin-2- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




662 


 


 661,27 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-((1- oxooctahydropyridazino [1,2-a]pyridazin-2- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




662 


 


 671,28 
2-Amino-4-(5-chloro-3- (3- (dimethylamino)azetidin- 1-yl)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 




647 


 


 681,29 
2-Amino-4-(5-chloro-3- (3-(dimethylamino)azetidin- 1-yl)-1-(((8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 




647 


 


 69 
(6R,8aR)-6-((6-(2- Aminobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




617 


 


 7030 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3R,4S)-3- (dimethylamino)-4- hydroxy-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6- one, Isomer 1 




665 


 


 7130 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3R,4S)-3- (dimethylamino)-4- hydroxy-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[3.5]nonan-6- one, Isomer 2 




665 


 


 7231 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




652 


 


 7332 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




652 


 


 7432 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




666 


 


 7533 
6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.4]octan-5-one 




666 


 


 7634 
6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 4-methyl-4- azaspiro[2.5]octan-5-one 




666 


 


 7735 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 1 




666 


 


 7835 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 2 




666 


 


 7936 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 1 




652 


 


 8036 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 2 




652 


 


 813,37 
(8aR)-6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S)-3-(azetidin-1- yl)-2-methylpyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl) amino)hexahydroindolizin- 5(1H)-one 




647 


 


 823,38 
(8aR)-6-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S)-3-(azetidin-1- yl)-2-methylpyrrolidin-1- yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




647 


 


 8339 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 1 




649 


 


 8439 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 2 




649 


 


 8540 
(9aS)-7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl)amino) hexahydropyrido[2,1-c] [1,4]oxazin-6(1H)-one 




651 


 


 86 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-5-fluoro-3-((2′S,3′S)- 2′-methyl-[1,3′- bipyrrolidin]-1′-yl)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




661 


 


 8741 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-azaspiro[3.5]nonan-6- one, Isomer 1 




635 


 


 8841 
7-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-azaspiro[3.5]nonan-6- one, Isomer 2 




635 


 


 8942 
2-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl) amino)hexahydro- pyridazino[1,2-a]pyridazin- 1(2H)-one, Isomer 1 




650 


 


 9042 
2-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- pyridazino[1,2-a]pyridazin- 1(2H)-one, Isomer 2 




650 


 


 91 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((3- (dimethylamino)oxetan- 3-yl)methoxy)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




638 


 


 9243 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)-5-methyl-5- azaspiro[3.5]nonan-6- one, Isomer 1 




650 


 


 9343 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)-5-methyl-5- azaspiro[3.5]nonan-6- one, Isomer 2 




650 


 


 9444 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one, Isomer 1 




636 


 


 9544 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one, Isomer 2 




636 


 


 9645 
(6R,8aR)-6-((6-(2- Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-5-fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl)amino) hexahydroindolizin- 5(1H)-one, Isomer 1 




639 


 


 9745 
(6R,8aR)-6-((6-(2- Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one, Isomer 2 




639 


 


 9846 
(2R)-2-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- pyridazino[1,2-a] pyridazin-1(2H)-one, Isomer 1 




654 


 


 9946 
(2R)-2-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-5-fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- pyridazino[1,2-a]pyridazin- 1(2H)-one, Isomer 2 




654 


 


10047 
(6R)-6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Isomer 1 




654 


 


10147 
(6R)-6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Isomer 2 




654 


 


10248 
(6R)-6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Isomer 2 




653 


 


10348 
(6R,8aR)-6-((6-(2- Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl)amino) hexahydroindolizin- 5(1H)-one, Isomer 1 




653 


 


10449 
(6R)-6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Isomer 1 




656 


 


10549 
(6R)-6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-5-chloro-3-((S)-3- (dimethylamino)pyrrolidin- 1-yl)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Isomer 2 




656 


 


10650 
6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Diastereomer 1 




670 


 


10750 
6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Diastereomer 2 




670 


 


10850 
6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Diastereomer 3 




670 


 


10950 
6-((6-(2-Amino-5,7- difluorobenzo[d]thiazol- 4-yl)-5-chloro-3- ((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)tetrahydro-1H- pyrazolo[1,2-a]pyridazin- 5(6H)-one, Diastereomer 4 




670 


 


 1B1,51 
4-(3-([1,3′-Biazetidin]-1′- yl)-5-chloro-1-((5- methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




673 


 


 2B1,51 
4-(3-([1,3′-Biazetidin]-1′- yl)-5-chloro-1-((5- methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




673 


 


 3B1 
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 




549 


 


 4B52 
2-Amino-4-(5-chloro-9- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-1,3- dihydrofuro[3,4- f]quinolin-4-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




548 


 


 5B52 
2-Amino-4-(5-chloro-9- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-1,3- dihydrofuro[3,4- f]quinolin-4-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




548 


 


 6B1,53 
2-Amino-4-(5-chloro-1- ((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




563 


 


 7B1,53 
2-Amino-4-(5-chloro-1- ((5-methyl-6-oxo-5- azaspiro[3.5]nonan-7- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




563 


 


 8B1,54 
2-Amino-4-(5-chloro-3- (2-hydroxy-2- methylpropoxy)-1- (((8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




637 


 


 9B1,54 
2-Amino-4-(5-chloro-3- (2-hydroxy-2- methylpropoxy)-1- (((8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




637 


 


10B55 
2-Amino-4-(5-chloro-9- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-1,3- dihydrofuro[3,4- f]cinnolin-4-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1 




549 


 


11B55 
2-Amino-4-(5-chloro-9- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-1,3- dihydrofuro[3,4- f]cinnolin-4-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2 




549 


 


12B56,57 
2-Amino-4-(5-chloro-1- (((6S)-2-oxo-1- azabicyclo[4.2.0]octan-3- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile 




535 


 


13B58 
2-Amino-5-fluoro-4-(5- fluoro-1-(((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile 




533 


 


14B58 
2-Amino-5-fluoro-4-(5- fluoro-3-methoxy-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene- 3-carbonitrile 




563 


 


15B58,59 
2-Amino-4-(1-(((8aS)- 2,2-difluoro-5- oxooctahydroindolizin-6- yl)amino)-5-fluoro- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile 




569 


 


16B60 
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 1 




550 


 


17B60 
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorothieno[3,2- c]pyridine-3-carbonitrile, Isomer 2 




550 


 


18B61 
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 1 




531 


 


19B61 
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)- 7,9-dihydrofuro[3,4- f]quinazolin-6- yl)benzo[b]thiophene-3- carbonitrile, Isomer 2 




531 


 


20B 
(6R,8aR)-6-((6-(2- Aminobenzo[d]thiazol-4- yl)-5-fluoro-3-((2′S,3′S)- 2′-methyl-[1,3′- bipyrrolidin]-1′-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




643 


 


21B62 
(6R,8aR)-6-((6-(2- Amino-5- fluorobenzo[d]thiazol-4- yl)-5-chloro-  7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one, Isomer 1 




525 


 


22B62 
(6R,8aR)-6-((6-(2- Amino-5- fluorobenzo[d]thiazol-4- yl)-5-chloro- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one, Isomer 2 




525 


 


23B 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-5-fluoro-3-((2S,3S)-3- (3- (fluoromethyl)azetidin-1- yl)-2-methylpyrrolidin-1- yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




679 


 


24B63 
(6R,8aS)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-5-fluoro-3-((2S)-2- methyl-3-(5- azaspiro[2.3]hexan-5- yl)pyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




673 


 


25B64 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-5-fluoro-3-((2S)-2- methyl-3-(5- azaspiro[2.3]hexan-5- yl)pyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




673 


 


26B65 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((6S)-1,6- dimethylhexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)- 5-fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino) hexahydroindolizin- 5(1H)-one, Isomer 1 




647 


 


27B65 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((6S)-1,6- dimethylhexahydropyrrolo [3,4-b]pyrrol-5(1H)-yl)- 5-fluoro-7,9-dihydrofuro [3,4-f]quinazolin-1-yl) amino)hexahydroindolizin- 5(1H)-one, Isomer 2 




647 


 


28B66 
4-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 1,2- dimethyltetrahydropyridazin- 3(2H)-one, Isomer 1 




624 


 


29B66 
4-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 1,2-dimethyltetrahydro- pyridazin-3(2H)-one, Isomer 2 




624 


 


30B 
(6R,8aR)-6-((4-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-7-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-1,3-dihydrofuro[3,4- f]quinolin-9-yl)amino) hexahydroindolizin- 5(1H)-one 




634 


 


31B 
(6R,8aR)-6-((4-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-5-fluoro-7-((2′S,3′S)- 2′-methyl-[1,3′- bipyrrolidin]-1′-yl)-1,3- dihydrofuro[3,4- f]quinolin-9-yl)amino) hexahydroindolizin-5(1H)- one 




660 


 


32B67 
(6R)-3-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl)amino)- 6-(difluoromethyl)-1- methylpiperidin-2-one, Isomer 1 




659 


 


33B67 
(6R)-3-((6-(2-Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9- dihydrofuro[3,4-f] quinazolin-1-yl)amino)- 6-(difluoromethyl)-1- methylpiperidin-2-one, Isomer 2 




659 


 


34B 
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]thiazol-4- yl)-3-((2S,3S)-3- (bis(methyl-d3)amino)-2- methylpyrrolidin-1-yl)-5- fluoro-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




642 


 


35B68 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (diethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 1 




680 


 


36B68 
7-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (diethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 5-methyl-5- azaspiro[2.5]octan-6-one, Isomer 2 




680 


 


37B32 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3-(6-fluoro-2- azaspiro[3.3]heptan-2- yl)-2-methylpyrrolidin-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




722 


 


38B32 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-2-methyl-3- (5-azaspiro[2.3]hexan-5- yl)pyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino) hexahydroindolizin- 5(1H)-one 




690 


 


39B32 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3-((3- fluorocyclobutyl) (methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




710 


 


40B32 
(8aR)-6-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3-(3- (fluoromethyl)azetidin-1- yl)-2-methylpyrrolidin-1- yl)-7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




696 


 


41B69 
4-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 1,2-dimethyltetrahydro- pyridazin-3(2H)-one 




641 


 


42B70 
4-((6-(2-Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 3-((2S,3S)-3- (ethyl(methyl)amino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1-yl)amino)- 1,2- dimethyltetrahydro- pyridazin-3(2H)-one 




655 


 


43B 
(6R,8aR)-6-((4-(2- Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-chloro- 7-((2S,3S)-3- (dimethylamino)-2- methylpyrrolidin-1-yl)- 1,3-dihydrofuro[3,4- f]quinolin-9- yl)amino)hexahydro- indolizin-5(1H)-one 




651 


 


44B 
(6R,8aR)-6-((6-(2- Amino-7- fluorothiazolo[4,5- c]pyridin-4-yl)-5-fluoro- 3-((2′S,3′S)-2′-methyl- [1,3′-bipyrrolidin]-1′-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one 




662





1Clean atropisomer, chiral purification from Preparation 30


2Clean atropisomer, chiral purification from Preparation 34


3Clean enantiomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 86


4Reverse Phase; C18, 51-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Enantiomer refers to a clean isomer at the 7-position of the azaspirononanone.


5Reverse Phase; C18, 56-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Enantiomer refers to a clean isomer at the 6-position of the azaspirooctane.


6Reverse Phase; C18, 51-100% (95:5 acetonitrile:water) in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Enantiomer refers to a clean isomer at the 6-position of the azaspirooctanone. Mixed cis isomers on the pyrrolidine.


7Reverse Phase; C18, 43-100% acetonitrile in (10 mM ammonium acetate 95:5 water:methanol). Enantiomer refers to a clean isomer at the 7-position of the azaspirooctanone.


8Reverse Phase; C18, 47-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomer refers to a clean atropisomer and a clean isomer at the 6-position of the azaspirooctanone.


9Reverse Phase; C18, 39-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol), to give a mix of Diastereomers 1 and 2 and a mix of Diastereomers 3 and 4. Diastereomers 1 and 2 were further separated with Prep-Chiral-HPLC; Phenomenex Lux Cellulose-2, 30 ×150 mm, 10-70% ethanol in heptane, 42.5 mL/min. Diastereomers 3 and 4 were further separated with Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 10-100% ethanol in heptane, 42.5 mL/min. Diastereomer refers to a clean atropisomer and a clean isomer at the 6-position of the azaspirooctanone.


10Reverse Phase; C18, 46-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbamate pH 10:methanol), to give a mix of Diastereomers 1 and 2 and a mix of Diastereomers 3 and 4. Diastereomers 1 and 2 were further separated with Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 25-100% (1:1 methanol:ethanol w/0.1% ispropylamine) in heptane, 45 mL/min. Diastereomers 3 and 4 were further separated with Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 20-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Diastereomer refers to a clean atropisomer and a clean isomer at the 7-position of the azaspirooctanone.


11Reverse Phase; C18, 10-70% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Enantiomer refers to a clean isomer at the 4-position of the azabicycloheptanone.


12Reverse Phase; C18, 35-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Enantiomer refers to a clean isomer at the 4-position of the azabicycloheptanone.


13Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 42.4 mL/min. Enantiomer refers to a clean isomer at the 2-position of the hexahydropyridozinopyridazinone.


14Reverse Phase; C18, 2-100% acetonitrile in (0.1% formic acid in water), followed by Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-80% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 42.5 mL/min. Enantiomer refers to a clean isomer at the 7-position of the azaspirononanone.


15Reverse Phase; C18, 53-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomer refers to a clean atropisomer and a clean isomer at the 7-position of the azaspirooctanone.


16Reverse Phase; C18, 55-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Diastereomer refers to a clean atropisomer and a clean isomer at the 6-position of the azaspirooctanone.


17Reverse Phase; C18, 46-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol), to give a mix of Diastereomers 1 and 2 and a mix of Diastereomers 3 and 4. Diastereomers 1 and 2 were further separated with Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-100% (ethanol w/0.1% isopropylamino) in heptane, 42.5 mL/min. Diastereomers 3 and 4 were further separated with Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 10-100% ethanol in heptane, 42.5 mL/min. Diastereomer refers to a clean atropisomer and a clean isomer at the 6-position of the azaspirooctanone.


18enriched toward (R) enantiomer


19Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 15-100% (ethanol w/0.1% isopropylamine) in heptane, 42.5 mL/min. Enantiomer refers to a clean isomer at the 6-position of the tetrahydropyrazolopyridazinone.


20Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-100% ethanol in heptane, 42.5 mL/min. Enantiomer refers to a clean isomer at the 6-position of the azaspirooctanone.


21Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 25-85% (1:1 methanol-ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Enantiomer refers to a clean isomer at the 7-position of the azaspirooctanone.


22Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 10-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 42.5 mL/min. Isomer refers to a clean isomer at the 7-position of the azaspirooctanone.


23Reverse Phase; C18, 10-70% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Isomer refers to a clean isomer at the 4-position of the azabicycloheptanone.


24Reverse Phase; C18, 35-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Isomer refers to a clean isomer at the 6-position of the tetrahydropyrazolopyridazinone.


25Reverse Phase; C18, 44-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Isomer refers to a clean isomer at the 6-position of the azaspirooctanone.


26Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 30-100% ethanol in heptane, 45 mL/min. Isomer refers to a clean isomer at the 6-position of the azaspiroheptanone.


27Prep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 ×150 mm, 15-60% (1:1 methanol:ethanol) in heptane, 45 mL/min. Isomer refers to a clean isomer at the 2 position of the hexahydropyridazinopyridazinone.


28Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 28A


29Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 29A


30Reverse Phase; C18, 38-100% acetonitrile in (95:5 10 mM aqueous ammonium acetate pH 10:methanol). Isomer refers to a clean isomer at the 7-position of the azaspirononanone.


31Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 13A


32Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 14A


33Clean isomer at the 6-position of the azaspirooctanone, chiral purification from Preparation 112A


34Clean isomer at the 6-position of the azaspriooctanone, chiral purification from Preparation 113A


35Chiral SFC; ChiralPak IJ, 30 ×250 mm, 20% (10 mM ammonium acetate in methanol) in CO2, 85 mL/min, Isomer refers to a clean isomer at the 7-position of the azaspirooctanone.


36Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Isomer refers to a clean isomer at the 7-position of the azaspirooctanone.


37Clean isomer at the 3-position of the pyrrolidine, chiral purification from Preparation 73A


38Clean isomer at the 3-position of the pyrrolidine, chiral purification from Preparation 72A


39Chiral SFC; ChiralPak IH, 20 ×250 mm, 35% (isopropanol w/0.5% dimethylethylamine) in CO2, 80 mL/min, Isomer refers to a clean isomer at the 7-position of the azaspirooctanone.


40Clean isomer at the 7-position of the hexahydropyridoxazinone


41Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 20-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Isomer refers to a clean isomer at the 7-position of the azaspirononanone.


42Prep-Chiral-HPLC; Phenomenex Lux Celluslose-1, 30 ×150 mm, 20-65% ethanol in heptane, 45 mL/min. Isomer refers to a clean isomer at the 2-position of the hexahydropyridazinopyridazinone.


43Prep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 ×150 mm, 25-100% ethanol in heptane, 45 mL/min. Isomer refers to a clean isomer at the 7-position of the azaspirononanone.


44Reverse Phase; C18, 31-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Isomer refers to a clean isomer at the 6-position of the hexahydroindolizinone.


45Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 35-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Isomer refers to a clean atropisomer.


46Reverse Phase; C18, 25-100% acetonitrile in (95:5 10 mM aqueous ammonium acetate pH 10:methanol). Isomer refers to a clean atropisomer.


47Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 15-100% ethanol in heptane, 42.5 mL/min. Isomer refers to a clean atropisomer.


48Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 35-100% (1:1 methanol-ethanol) in heptane, 45 mL/min. Isomer refers to a clean atropisomer.


49Reverse Phase; C18, 39-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Isomer refers to a clean atropisomer.


50Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-100% (ethanol w/0.1% isopropylamine) in heptane, 42.5 mL/min. Diastereomer refers to a clean atropisomer and a clean isomer at the 6-position of the tetrahydropyrazolopyridazinone.


51Reverse Phase; C18, 44-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Isomer refers to a clean isomer at the 7-position of the azaspirononanone.


52Reverse Phase; C18, 26-100% acetonitrile in (10 mM ammonium acetate in 95:5 water:methanol). Isomer refers to a clean atropisomer.


53Reverse Phase; C18, 35-100% acetonitrile in (95:5 10 mM aqueous ammonium bicarbonate pH 10:methanol). Isomer refers to a clean isomer at the 7-position of the azaspirononanone.


54Reverse Phase; C18, 10-100% acetonitrile in (0.1% formic acid in water). Isomer refers to a clean isomer at the 6-position of the hexahydroindolizinone.


55Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 25-100% (1:1 methanol:ethanol) in heptane, 45 mL/min. Isomer refers to a clean atropisomer.


56Clean atropisomer, chiral purification from Preparation 6B


57Clean isomer at the 3-position of the azabicyclooctanone, chiral purification from Preparation 17B


58Clean atropisomer, chiral purification from Preparation 32


59Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 18B


60Prep-Chiral-HPLC; Phenomenex Lux Cellulose-4, 30 ×150 mm, 20-100% (1:1 methanol:ethanol) in heptane, 45 mL/min. Isomer refers to a clean atropisomer.


61Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 ×150 mm, 30-100% (ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Isomer refers to a clean atropisomer.


62Prep-Chiral-HPLC; Phenomenex Lux i-Cellulose-5, 30 ×150 mm, 30-100% (1:1 methanol:ethanol w/0.1% isopropylamino) in heptane, 45 mL/min. Isomer refers to a clean atropisomer.


63Clean diastereomer on the pyrrolidine, chiral purification from Preparation 84B


64Clean diastereomer on the pyrrolidine, chiral purification from Preparation 85B


65Prep-Chiral-HPLC; Phenomenex Lux i-Amylose-3, 30 ×150 mm, 25-100% (ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Isomer refers to a clean cis stereocenter on the pyrrolopyrrol.


66Prep-Chiral-HPLC; Chiral Art Cellulose-SB, 30 ×250 mm, 50% ethanol in (hexanes w/0.5% 2M ammoniated methanol), 40 mL/min. Isomer refers to a clean isomer at the 4-position of the pyridazinone.


67Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 ×150 mm, 10-100% (ethanol w/0.1% isopropylamine) in heptane, 42.5 mL/min. Isomer refers to a clean isomer at the 3-position of the piperidinone.


68Chiral SFC; ChiralPak IC, 20 ×250 mm, 50% (ethanol w/0.5% dimethylethylamine) in CO2, 80 mL/min, Isomer refers to a clean isomer at the 7-position of the azaspirooctanone.


69Clean isomer at the 4-position of the pyridazinone, chiral purification from Preparation 78B


70Clean isomer at the 4-position of the pyridazinone, chiral purification from Preparation 79B






    
    
        isopropylamine) in heptane, 42.5 mL/min. Isomer refers to a clean isomer at the 3-position of the piperidinone.
        68 Chiral SFC; ChiralPak IC, 20×250 mm, 50% (ethanol w/0.5% dimethylethylamine) in CO2, 80 mL/min, Isomer refers to a clean isomer at the 7-position of the azaspirooctanone.
        69 Clean isomer at the 4-position of the pyridazinone, chiral purification from Preparation 78B
        70 Clean isomer at the 4-position of the pyridazinone, chiral purification from Preparation 79B
    
    


The following compounds in Table 26 were prepared in similar manner as described in Preparation 28. Different coupling conditions, such as base, ligands, or palladium sources, may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 26








MS





(ES) m/z


Example
Chemical Name
Structure
(M + 1)







110 1,3
(8aR)-6-((6-(2- Aminobenzo[d]oxazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one




617


 


111 2,3
(8aR)-6-((6-(2- Aminobenzo[d]oxazol-4- yl)-5-chloro-3-((2S,3S)- 3-(dimethylamino)-2- methylpyrrolidin-1-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one




617


 


 45B 2,3
(8aR)-6-((6-(2- Aminobenzo[d]oxazol-4- yl)-5-chloro-3-((2′S,3′S)- 2′-methyl-[1,3′- bipyrrolidin]-1′-yl)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one




643


 


 46B 3
(6R,8aR)-6-((6-(2- Amino-7- fluorobenzo[d]oxazol-4- yl)-5-fluoro-3-((2′S,3′S)- 2′-methyl-[1,3′- bipyrrolidin]-1′-yl)-7,9- dihydrofuro[3,4- f]quinazolin-1- yl)amino)hexahydro- indolizin-5(1H)-one




645





1 Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 13A


2 Clean isomer at the 6-position of the hexahydroindolizinone, chiral purification from Preparation 14A


3 BOC deprotection on the aminobenzoxazole occurred during the reaction






The following compounds in Table 27 were prepared in similar manner as described in Preparation 102B. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 27








MS





(ES) m/z


Example
Chemical Name
Structure
(M + 1)







47B 1
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-5- fluorobenzo[b]thiophene- 3-carbonitrile




549





1 Clean atropisomer, chiral purification from Preparation 34






The following compounds in Table 28 were prepared in similar manner as described in Preparation 96. Different bases may have been substituted. Various methods were used to purify the compounds, which would be apparent to one skilled in the art.










TABLE 28








MS





(ES) m/z


Example
Chemical Name
Structure
(M + 1)







48B 1,2
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-3-(1-oxa-6- azaspiro[3.4]octan-6-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 1




660


 


49B 1,2
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-3-(1-oxa-6- azaspiro[3.4]octan-6-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile, Isomer 2




660


 


50B 1
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-3-(2-oxa-6- azaspiro[3.3]heptan-6- yl)-7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile




646


 


51B 1
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-3-(7-oxa-2- azaspiro[3.5]nonan-2-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile




674


 


52B 1
2-Amino-4-(5-chloro-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-3-(5,8-dioxa-2- azaspiro[3.5]nonan-2-yl)- 7,9-dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile




676


 


53B 1
2-Amino-4-(5-chloro-3- morpholino-1- (((6R,8aR)-5- oxooctahydroindolizin-6- yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-7- fluorobenzo[b]thiophene- 3-carbonitrile




634


 


54B 1
4-(3-((((S)-1,4-Dioxan-2- yl)methyl)(methyl)amino)- 5-chloro-1-(((6R,8aR)- 5-oxooctahydroindolizin- 6-yl)amino)-7,9- dihydrofuro[3,4- f]quinazolin-6-yl)-2- amino-7- fluorobenzo[b]thiophene- 3-carbonitrile




678





1 Clean atropisomer, chiral purification from Preparation 30


2 Prep-Chiral-HPLC; (S,S)-Whelk-O1, 30 × 150 mm, 30-100% (1:1 methanol:ethanol w/0.1% isopropylamine) in heptane, 45 mL/min. Isomer refers to a clean isomer on the azaspirooctane.






Biological Assays

The following assays demonstrate that the exemplified compounds are inhibitors of KRAS G12V and inhibit growth of certain tumors in vitro and/or in vivo.
Cellular Phospho-ERK AlphaLISA® Assay for KRAS Inhibition
The purpose of these assays is to quantify the ability of test compounds to selectively inhibit KRAS signaling in cells with amplified KRAS and expressing activating KRAS G12 mutations (Table 1A). Cancer cell lines used in this study were selected based on the presence of homozygous activating KRAS G12 mutations, or amplification of the KRAS gene.







TABLE 1A







Cell Line Information











Cell Line 

Assay Seeding



Name
RAS Mutation/Features
Density (Cells/Well)







MKN45
WT KRAS Amplification/
20,000




Human Gastric Cancer




SW620
KRAS G12V/Human 
20,000




Colorectal Cancer










The compounds' activity is determined by measuring changes in the phosphorylation levels of the downstream effector Extracellular Signal-regulated Kinase-1 and 2 (ERK1/2) in the compound treated cells. Phosphorylation levels of ERK-1/2 are measured using the AlphaLISA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) Assay Kit (#ALSU-PERK-A50K, PerkinElmer® Waltham, MA). The AlphaLISA® assay is a quantitative sandwich immunoassay that can be used to detect phosphorylation of target proteins from cellular lysates using bead-based Alpha technology. The assay kit contains two antibodies, one that binds the phospho-Thr202/Tyr204 epitope on ERK-1/2, and another one that recognizes a separate site on the protein. One of these antibodies is biotinylated and associated with streptavidin-coated Alpha Donor beads, the other antibody is conjugated to AlphaLISA® Acceptor beads. When ERK-1/2 is phosphorylated in cellular lysate, the Donor and Acceptor beads are brought into proximity with each other. When the Donor bead is excited by 600 nm wavelength light, a photosensitizer inside the bead converts ambient oxygen to an excited singlet state. When the Acceptor bead is within 200 nm of this reaction, the singlet oxygen reacts with the Acceptor leading to a chemiluminescent emission. The amount of light measured is proportional to the amount of phosphorylated ERK-1/2 in the lysate. The AlphaLISA® SureFire® Ultra™ p-ERK 1/2 (Thr202/Tyr204) Assay Kit contains AlphaLISA® antibody-conjugated Donor and Acceptor Beads, Lysis buffer concentrate, and a set of proprietary buffers (Activation Buffer, Reaction Buffer 1, Reaction Buffer 2, and Dilution Buffer).
To perform the assays, test compounds and controls are acoustically dispensed (Labcyte ECHO®, San Jose, CA) into a white 384-well assay plate (Proxiplate-384, PerkinElmer #6008280) in a 10-point 3-fold dilution series in 30 nL DMSO. Cells are then added to the assay plate in 8 μL per well assay medium (HBSS, Sigma #55021C, 10% FBS, GIBCO #10082-147) at a cell line specific density (Table 1A). The final compound concentrations range from 0.5 to 10,000 nM and the final DMSO concentration is 0.375% in each well. Maximum signal control wells contain 0.375% DMSO only (negative control), and minimum signal control wells contain 10,000 nM control compound (positive control). Cells in suspension are incubated with the test and reference compounds for 2 h at 37° C./5% CO2. Following the 2 h incubation, cells are lysed by adding 2 μL of the AlphaLISA® Lysis buffer concentrate (5×) supplemented with protease/phosphatase inhibitor cocktail (Thermo Scientific #78442). The assay plate is covered with an opaque lid and shaken at 750 rpm on a multi-plate shaker (Heidolph, Schwabach, Germany) for 30 min at room temperature to induce cell lysis. During the lysis, the AlphaLISA® Acceptor beads are diluted 1:50 in a prepared buffer mixture (1:1 AlphaLISA® Reaction Buffers 1 and 2 with a 1:25 dilution of AlphaLISA® Activation Buffer). Following cell lysis, plates are centrifuged briefly, and 5 μL per well prepared Acceptor beads are added. The plate is then covered and incubated in the dark for 2 h at room temperature. During the Acceptor bead incubation, Donor beads are prepared by diluting the Alpha streptavidin Donor beads 1:50 in AlphaLISA® Dilution buffer. Following the Acceptor bead incubation, 5 μL per well of Donor bead mixture is added to the plates. Plates are then covered and allowed to incubate in the dark at room temperature for 2 h. After this incubation period, the AlphaLISA signal is read using a PHERAstar® FSX multimode plate reader (BMG Labtech, Ortenberg, Germany) equipped with an AlphaLISA® compatible optics cube.
Raw signal obtained from the AlphaLISA® assay is analyzed using Genedata Screener® 17.0.3. Within the program, data is normalized to 32 wells treated with inhibition control (max inhibition/positive control) and 32 wells treated with 0.375% DMSO only (minimum inhibition/negative control) to calculate the % Activity of the compound:



 
  
   
    
     
      %
      ⁢
         
      Activity
     
     =
     
      100
      ⁢
      
       x
       ⁡
       (
       
        1
        -
        
         
          (
          
           
            treated
            ⁢
               
            value
           
           -
           
            positive
            ⁢
               
            control
           
          
          )
         
         
          (
          
           
            negative
            ⁢
               
            control
           
           -
           
            positive
            ⁢
               
            control
           
          
          )
         
        
       
       )
      
     
    
   
   
    
     eq
     .
        
     1
    
   
  
 



% Activity values are fit to a four-parameter non-linear logistic equation using Genedata Screener® 17.0.3. to -determine IC50 values:




 
  
   
    
     y
     =
     
      Bottom
      +
      
       
        Top
        -
        Bottom
       
       
        1
        +
        
         
          (
          
           
            1
            ⁢
            
             0
             
              Log
              ⁡
              (
              
               IC
               
                5
                ⁢
                0
               
              
              )
             
            
           
           
            1
            ⁢
            
             0
             x
            
           
          
          )
         
         h
        
       
      
     
    
   
   
    
     eq
     .
        
     2
    
   
  
 



Where y=% Activity, Bottom=minimum asymptote, Top=maximum asymptote, x=compound concentration, IC50=the compound concentration where half maximal activity is achieved, and h=the Hill Coefficient.

Compounds of Examples 1, 5, 7, 9, 11, 14, 17, 22, 25, 27, 30, 32, 34, 38, 42, 45-47, 49, 51, 53, 55-57, 60, 61, 63, 64, 66, 68-70, 73-75, 78, 80, 81, 84-86, 88, 90, 91, 93, 94, 96, 98, 100, 102, 105, 109, 111, 1B, 3B, 4B, 6B, 8B, 11B-15B, 17B, 18B, 20B, 22B-27B, 29B-31B, 33B, 34B, 36B-48B and 50B-54B were tested in the SW620 Cellular Phospho-ERK AlphaLISA® Assay and exhibited an ability to reduce levels of phosphorylated ERK-1/2 in cells expressing KRAS indicating inhibition of constitutive RAS activity in cells expressing KRAS G12V with a relative IC50 of <50 nM. Compounds of Examples 1, 2, 5, 7, 9, 11, 13-15, 17, 22, 25, 27, 30, 32-35, 37-39, 42, 43, 45-47, 49, 51-53, 55-57, 60, 61, 64, 66, 68-70, 73-82, 84-86, 88, 90, 91, 93, 94, 96, 98, 100-103, 105, 109, 111, 1B, 6B, 14B, 20B, 22B-26B, 31B, 33B, 34B, 36B-40B, 43B-46B, 48B and 50B-54B were tested in both assays above (SW620, and MKN 45 Cellular Phospho-ERK AlphaLISA® Assays) and showed a greater than 5-fold selective inhibition preference for KRAS G12V mutant over KRAS wild-type. Further, the compounds of Examples 1, 2, 5, 7, 9, 11, 14, 15, 17, 22, 25, 27, 32, 34, 35, 37-39, 42, 45, 47, 51, 53, 55, 69, 70, 75, 77, 78, 80-82, 84, 93, 94, 96, 105, 6B, 20B, 40B, 50B and 54B showed a greater than 10-fold selective inhibition preference for KRAS G12V mutant over KRAS wild-type.
This data shows that compounds of Formula I as described herein are inhibitors of KRAS human cancer cells expressing KRAS demonstrating the ability to inhibit KRAS G12V mutants with a selective inhibition preference for the KRAS G12V mutant over KRAS WT.
CellTiter-Glo® Luminescent Cell Viability Assay for Anti-Proliferative Activity
The purpose of these assays is to quantify the ability of test compounds to selectively inhibit proliferative activity in cells harboring KRAS wild-type (WT) and activating KRAS G12 mutations (Table 1B) grown as tumor spheroids. Cancer cell lines used in this study were selected based on the presence of homozygous activating KRAS G12 mutations, or the KRAS WT gene.







TABLE 1B







Cell Line Information









Cell Line 

Assay Seeding


Name
RAS Mutation/Features
Density (Cells/Well)





MKN45
KRAS WT/Human 
1,000



Gastric Cancer



SW620
KRAS G12V/Human 
1,000



Colorectal Cancer









The compounds' anti-proliferative activity is determined by CellTiter-Glo 2.0 assay which quantifies changes in the cellular levels of ATP in compound treated cells. In the presence of Mg2+, ATP and molecular oxygen, Ultra-Glo™ Recombinant Luciferase catalyzes the mono-oxygenation of beetle luciferin and generates light. The luminescence readout is directly proportional to metabolically active cells in culture.
To perform the assays, 75 nL of test compounds, controls, and DMSO are acoustically dispensed using an ECHO 655 Acoustic Liquid Handler (Beckman Life Sciences) into clear round bottom ultra-low attachment spheroid 384-well assay plate (Spheroid Microplates, Corning®# CLS 3830) in a 10-point 3-fold dilution series. The spheroid microplates aid the formation of spheroids in the center of well by inhibiting cellular attachment. A Multidrop Combi Reagent Dispenser (Thermo Fisher Scientific) is used to dispense 40 μL/well of cell suspension in microplates containing compounds. Cells (Table 1B) were seeded at a density of 25,000 live cells/mL or 1,000 cells/well in growth medium (RPMI Gibco #11875-093, 10% FBS Gibco #10082-147). The final compound concentrations range from 0.5 to 10,000 nM and the final DMSO concentration is 0.2% in each well. Maximum signal control wells contain 0.2% DMSO only (negative control), and minimum signal control wells contain 10,000 nM control compound (positive control). Plates were sealed with Breathe-Easy® sealing membranes (Diversified Biotech), transferred to a 37° C. incubator with 5% CO2, and allowed to incubate for 4 days.
After 4-day incubation, CTG 2.0 reagent and assay plates were equilibrated at 25° C. for at least 30 minutes. A Multidrop Combi Reagent Dispenser (Thermo Fisher Scientific) was used to dispense 40 μL/well of CTG reagent in microplates. The assay plate was placed on a multi-plate shaker (Heidolph, Schwabach, Germany) at 750 RPM for 10 min at room temperature to induce cell lysis, followed by a 1-minute centrifugation at 1200 RPM. The luminescence was read using a PHERAstar FSX Multimode Plate reader (BMG LABTECH).
Raw luminescence data obtained by CTG assay were analyzed using Genedata Screener® 20.0.5. Within the program, data were normalized to the average signal from 14 wells treated with the positive control (10 mM LY3841814) and the average signal from 14 wells treated with the negative control (0.2% DMSO) to calculate the % Activity of the compound:



 
  
   
    
     
      %
      ⁢
         
      Activity
     
     =
     
      100
      ⁢
      
       x
       ⁡
       (
       
        1
        -
        
         
          (
          
           
            treated
            ⁢
               
            value
           
           -
           
            positive
            ⁢
               
            control
           
          
          )
         
         
          (
          
           
            negative
            ⁢
               
            control
           
           -
           
            positive
            ⁢
               
            control
           
          
          )
         
        
       
       )
      
     
    
   
   
    
     eq
     .
        
     1
    
   
  
 



% Activity values were fit to a four-parameter non-linear regression in Genedata Screener® 20.0.5. to determine IC50 values:




 
  
   
    
     y
     =
     
      Bottom
      +
      
       
        Top
        -
        Bottom
       
       
        1
        +
        
         
          (
          
           
            1
            ⁢
            
             0
             
              Log
              ⁡
              (
              
               IC
               
                5
                ⁢
                0
               
              
              )
             
            
           
           
            1
            ⁢
            
             0
             x
            
           
          
          )
         
         h
        
       
      
     
    
   
   
    
     eq
     .
        
     2
    
   
  
 



Where y=% Activity, Bottom=minimum asymptote, Top=maximum asymptote, x=compound concentration, IC50=the compound concentration where half maximal activity is achieved, and h=the Hill Coefficient.

Compounds of Examples 1, 5, 7, 9, 11, 14, 17, 22, 25, 27, 30, 32, 34, 35, 38, 42, 45-47, 49, 51, 53, 55-57, 60-62, 64, 66, 68-70, 73-75, 78, 81, 84-86, 88, 90, 91, 93, 94, 96, 98, 100, 102, 105, 109, 111, 1B, 3B, 4B, 6B, 8B, 11B-15B, 17B, 18B, 20B, 23B-27B, 29B-31B, 33B, 34B, 36B-38B and 40B-54B were tested in the SW620 4-day 3D proliferation assay and exhibited an ability to reduce ATP levels indicating inhibition of proliferative activity with a relative IC50 of <250 nM. Further, the compounds of Examples 1, 5, 7, 9, 11, 14, 17, 22, 25, 30, 32, 46, 47, 49, 57, 61, 66, 68, 73, 74, 81, 85, 86, 88, 90, 96, 98, 100, 102, 109, 1B, 3B, 4B, 8B, 11B, 13B-15B, 18B, 24B, 27B, 29B-31B, 33B, 34B, 41B-43B, 45B and 47B exhibited an ability to reduce ATP levels indicating inhibition of proliferative activity with a relative IC50 of <50 nM. Compounds of Examples 1, 5, 7, 9, 11, 14, 17, 22, 25, 27, 30, 32, 34, 35, 38, 42, 45, 46, 49, 51, 53, 55-57, 60-62, 68-70, 73-76, 78, 80, 81, 85, 86, 91, 93, 94, 96, 100, 102, 105, 109, 111, 1B, 3B, 4B, 6B, 8B, 9B, 11B, 13B-15B, 17B, 22B, 24B, 30B, 31B, 33B, 38B-51B, 53B and 54B were tested in both assays above (SW620 and MKN45 4-day 3D proliferation assays) and showed a greater than 5-fold selective inhibition preference for KRAS G12V mutant over KRAS wild-type.
These data show that compounds of Formula I as described herein are inhibitors of proliferative activity in KRAS tumor spheroids and inhibit KRAS G12V mutant with a selective inhibition preference over KRAS WT.







TABLE 1C





Abbreviations


















KRAS
Kirsten Rat Sarcoma Virus



ERK
Extracellular Signal-Regulated Kinase



AlphaLISA
Alpha-Linked Immunosorbent Assay



DMSO
Dimethyl Sulfoxide



HBSS
Hank's Balanced Salt Solution



FBS
Fetal Bovine Serum



CO2
Carbon Dioxide



ATP
Adenosine triphosphate



CTG
CellTiter-Glo



RPMI
Roswell Park Memorial Institute