Glutamine analogs

The invention relates to novel glutamine analogs, a composition containing the glutamine analogs and the use thereof.

1. 11. A compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof, wherein the compound is selected from: 1 isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 2 methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid 4 ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 5 isopropyl (S)-6-diazo-2-(2-methoxyacetamido)-5-oxohexanoate 6 isopropyl (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate 7 isopropyl (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate 8 isopropyl (S)-6-diazo-2-((S)-2-hydroxy-4-methylpentanamido)-5- oxohexanoate 9 isopropyl (S)-6-diazo-2-((S)-2-ethoxypropanamido)-5-oxohexanoate 10 isopropyl (S)-6-diazo-2-((S)-2-isopropoxypropanamido)-5- oxohexanoate 11 isopropyl (S)-6-diazo-2-(2-hydroxyacetamido)-5-oxohexanoate 12 isopropyl (S)-6-diazo-2-((S)-2-hydroxybutanamido)-5-oxohexanoate 13 isopropyl (S)-6-diazo-2-((S)-2-methoxybutanamido)-5-oxohexanoate 14 isopropyl (S)-6-diazo-2-((S)-2-ethoxybutanamido)-5-oxohexanoate 15 isopropyl (S)-6-diazo-2-((S)-2-isopropoxybutanamido)-5-oxohexanoate 16 isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate 17 isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-methylbutanamido)-5- oxohexanoate 18 isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-methylbutanamido)-5- oxohexanoate 19 isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3-methylbutanamido)-5- oxohexanoate 20 isopropyl (S)-6-diazo-2-((2S,3R)-2-hydroxy-3-methylpentanamido)-5- oxohexanoate 21 isopropyl (S)-6-diazo-2-((2S,3R)-2-methoxy-3-methylpentanamido)-5- oxohexanoate 22 isopropyl (S)-6-diazo-2-((2S,3R)-2-ethoxy-3-methylpentanamido)-5- oxohexanoate 23 isopropyl (S)-6-diazo-2-((2S,3R)-2-isopropoxy-3-methylpentanamido)- 5-oxohexanoate 24 isopropyl (S)-6-diazo-2-((S)-2-hydroxypentanamido)-5-oxohexanoate 25 isopropyl (S)-6-diazo-2-((S)-2-methoxypentanamido)-5-oxohexanoate 26 isopropyl (S)-6-diazo-2-((S)-2-ethoxypentanamido)-5-oxohexanoate 27 isopropyl (S)-6-diazo-2-((S)-2-isopropoxypentanamido)-5- oxohexanoate 28 isopropyl (S)-6-diazo-2-((S)-2-methoxy-4-methylpentanamido)-5- oxohexanoate 29 isopropyl (S)-6-diazo-2-((S)-2-ethoxy-4-methylpentanamido)-5- oxohexanoate 30 isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-4-methylpentanamido)-5- oxohexanoate 31 isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3,3-dimethylbutanamido)-5- oxohexanoate 32 isopropyl (S)-6-diazo-2-((S)-2-methoxy-3,3-dimethylbutanamido)-5- oxohexanoate 33 isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3,3-dimethylbutanamido)-5- oxohexanoate 34 isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3,3-dimethylbutanamido)-5- oxohexanoate 35 isopropyl (S)-6-diazo-2-((S)-2-hydroxyhexanamido)-5-oxohexanoate 36 isopropyl (S)-6-diazo-2-((S)-2-methoxyhexanamido)-5-oxohexanoate 37 isopropyl (S)-6-diazo-2-((S)-2-ethoxyhexanamido)-5-oxohexanoate 38 isopropyl (S)-6-diazo-2-((S)-2-isopropoxyhexanamido)-5-oxohexanoate 39 isopropyl (S)-6-diazo-2-(3-methoxy-2-oxopropanamido)-5- oxohexanoate 40 isopropyl (S)-6-diazo-2-(3-hydroxy-2-oxopropanamido)-5- oxohexanoate 41 isopropyl (S)-6-diazo-2-(3-hydroxypropanamido)-5-oxohexanoate 42 isopropyl (S)-6-diazo-2-((S)-3-hydroxybutanamido)-5-oxohexanoate 43 isopropyl (S)-6-diazo-2-(3-methoxypropanamido)-5-oxohexanoate 44 isopropyl (S)-6-diazo-2-((S)-3-methoxybutanamido)-5-oxohexanoate 45 isopropyl (S)-6-diazo-2-((S)-3-hydroxy-2-methylpropanamido)-5- oxohexanoate 46 isopropyl (S)-6-diazo-2-((S)-3-methoxy-2-methylpropanamido)-5- oxohexanoate 47 isopropyl (S)-6-diazo-2-((2S,3R)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 48 isopropyl (S)-6-diazo-2-((2S,3R)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 49 isopropyl (S)-6-diazo-2-((2R,3R)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 50 isopropyl (S)-6-diazo-2-((2R,3R)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 51 isopropyl (S)-6-diazo-2-((2R,3S)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 52 isopropyl (S)-6-diazo-2-((2R,3S)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 53 isopropyl (S)-6-diazo-2-((R)-3-hydroxybutanamido)-5-oxohexanoate 54 isopropyl (S)-6-diazo-2-((2S,3S)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 55 isopropyl (S)-6-diazo-2-((2S,3S)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 56 isopropyl (S)-6-diazo-2-((R)-3-methoxybutanamido)-5-oxohexanoate 57 isopropyl (S)-6-diazo-2-((R)-3-hydroxy-2-methylpropanamido)-5- oxohexanoate 58 isopropyl (S)-6-diazo-2-((R)-3-methoxy-2-methylpropanamido)-5- oxohexanoate 59 tert-butyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 60 tert-butyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate 61 isopropyl (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoate 62 isopropyl (S)-6-diazo-2-(2-hydroxy-2-methylpropanamido)-5- oxohexanoate 63 methyl (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoate 64 methyl (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate 65 methyl (S)-6-diazo-2-(2-isopropoxyacetamido)-5-oxohexanoate 66 (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoic acid 67 isopropyl (S)-6-diazo-2-(2-isopropoxyacetamido)-5-oxohexanoate 68 methyl (S)-6-diazo-2-(2-methoxyacetamido)-5-oxohexanoate 69 S-isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanethioate 70 (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoic acid 71 isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 72 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoic acid 73 methyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 74 ethyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate 75 S-isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanethioate 76 isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio) butanamido)-5-oxohexanoate 77 methyl-d3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 78 ethyl-2,2,2-d3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanoate 79 isopropyl (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5- oxohexanoate 80 isopropyl (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5-oxohexanoate 81 ethyl-d5 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 82 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanoate 83 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5- oxohexanoate 84 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate 85 propan-2-yl-d7 (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate 86 S-(propan-2-yl-d7) (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanethioate 87 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio) butanamido)-5-oxohexanoate 88 methyl-d3 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 89 ethyl-2,2,2-d3 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 90 ethyl-d5 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 91 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 92 propan-2-yl-d7 (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5- oxohexanoate 93 S-(propan-2-yl-d7) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanethioate 94 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-(methoxy-d3)-4- (methylthio)butanamido)-5-oxohexanoate 95 propan-2-yl-d7 (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5- oxohexanoate 96 methyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d 97 ethyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d 98 isopropyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d 99 isopropyl 6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate-2-d 100 S-isopropyl 6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanethioate-2-d 101 isopropyl 6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoate-2-d 102 isopropyl 6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate-2-d 103 isopropyl 6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate-2-d 104 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-(methoxy- d3)propanamido)-5-oxohexanoate 105 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3) acetamido)-5-oxohexanoate 106 S-(propan-2-y1-1,1,1,3,3,3-d6) (S)-6-diazo-2-((S)-2-(methoxy- d3)propanamido)-5-oxohexanethioate 107 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-(methoxy-d3)-4- (methylthio)butanamido)-5-oxohexanoate 108 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5- oxohexanoate 109 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-hydroxypropanamido)- 5-oxohexanoate 110 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-hydroxy-3- methylbutanamido)-5-oxohexanoate 111 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-(methoxy-d3) propanamido)-5-oxohexanoate 112 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5- oxohexanoate 113 S-(propan-2-y1-1,1,1-d3) (2S)-6-diazo-2-((S)-2-(methoxy- d3 )propanamido)-5-oxohexanethioate 114 propan-2-yl-1, 1,1-d3 (2S)-6-diazo-2-((S)-2-(methoxy-d3)-4- (methylthio)butanamido)-5-oxohexanoate 115 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5- oxohexanoate 116 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-hydroxypropanamido)-5- oxohexanoate 117 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-hydroxy-3- methylbutanamido)-5-oxohexanoate 118 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-methoxypropanamido)- 5-oxohexanoate 119 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-ethoxyacetamido)-5- oxohexanoate 120 S-(propan-2-y1-1,1,1,3,3,3-d6) (S)-6-diazo-2-((S)-2- methoxypropanamido)-5-oxohexanethioate 121 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-methoxy-4- (methylthio)butanamido)-5-oxohexanoate 122 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanoate 123 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-ethoxyacetamido)-5- oxohexanoate 124 S-(propan-2-y1-1,1,1-d3) (2S)-6-diazo-2-((S)-2-methoxypropanamido)- 5-oxohexanethioate 125 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-methoxy-4- (methylthio)butanamido)-5-oxohexanoate.

CROSS-REFERENCE TO RELATED APPLICATIONS
The application is a U.S. Nat'l Phase of Int'l Appl. No. PCT/CN2021/123674, filed Oct. 14, 2021, which claims the benefit of PCT application Ser. No. PCT/CN2020/121114 filed on Oct. 15, 2020; PCT application Ser. No. PCT/CN2021/072111 filed on Jan. 15, 2021; and PCT application Ser. No. PCT/CN2021/076491 filed on Feb. 10, 2021. The entire contents of these applications are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The invention relates to a novel glutamine analogs, a composition containing the glutamine analogs and the use thereof.
BACKGROUND ART
Glutamine analogs, such as 6-diazo-5-oxo-L-norleucine (DON) have been shown to exhibit anti-cancer activities. However, the occurrence of severe toxicity (e.g., dose limiting GI toxicities, such as oral mucositis, gastric bleeding, nausea and vomiting, and abdominal pain) has hampered their clinical development when administering such glutamine antagonists at therapeutic dose levels.
Prior attempts to mitigate the severe toxicity associated with glutamine antagonists such as DON, have been unsuccessful. Therefore, it's needed to develop novel glutamine antagonists to meet the clinical needs.
SUMMARY OF INVENTION
In one aspect, provided here is a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:




    
    
        Wherein,
        Z is OR1 or SR1; R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, C1-6alkoxy, —C3-8cycloalkyl, —C0-6alkylene-C3-8heterocyclyl, —C0-6alkylene-NH—C0-6alkylene C6-10aryl, —C0-6alkylene-NH—C0-6alkylene-5-12 membered heteroaryl, —C0-6alkylene-C6-10aryl and —C0-6alkylene-5-12 membered heteroaryl; and each of which can be optional substituted with one or more substituents independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8cycloalkyl, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —NH—C3-8cycloalkyl, carboxyl, —CO—C1-6alkyl; each of the heteroaryl and heterocyclyl contains 1, 2 or 3 heteroatoms selected from N, O or S;
        X is selected from the group consisting of hydrogen, deuterium, C1-6alkyl, —C(═O)-G, —C(═O)—W—(CRX1RX2)m—O—RX3, —C(═O)—W—(CRX1RX2)m—S—RX3, C(═O)—W—(CRX1RX2)m—SO—RX3, C(═O)—W—(CRX1RX2)m—SO2—RX3, —C(═O)—W—(CRX1RX2)m-G, —C(═O)—W—(CRX1RX2)m—NR5R5′, —P(═O)(OR6)p(NHR7)q, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)—R8, —C(═O)—W—(CRX1RX2)m-G-O—R8, —C(═O)—O—(CRX1RX2)m—O—C(═O)—R9, —C(═O)—O—R7, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)-G, and —C(═O)—W—(CRX1RX2)m-G-NR5R5′;
        
            W is oxygen, CO or a bond;
            m is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
            p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, NH2, C1-6 alkyl, C1-6alkoxy, C4-10 cycloalkyl, —C(═O)—C1-6alkyl, C5-12aryl, —C1-6 alkylene-C5-12aryl, -5-12 membered heteroaryl, and —C1-6 alkylene-5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C1-6alkoxy, said C4-10 cycloalkyl, said C5-12aryl, said-C1-6 alkylene-C5-12aryl, said -5-12 membered heteroaryl, and said-C1-6 alkylene-5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, —S—C1-6alkyl, carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
            or RX1 and RX2 together with the carbon atom to which they are attached form C3-10carbocyclic ring, C3-10 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —NH2, —CN, —OH, —NO2, carbonyl, ═O, oxo, carboxyl, C1-6alkoxy, C1-6alkyl;
            RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, —C(═O)—C1-6 alkyl, and —C1-6alkylenen-C5-12 aryl, wherein said C1-6 alkyl, said C1-6 alkoxy, said C3-8 cycloalkyl, said —C(═O)—C1-6 alkyl, and said —C1-6alkylenen-C5-12 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl, 4-8 membered heterocyclyl,
        
        
    
    






    
    
        
        
             —C6-12aryl, —C(═O)—C1-6alkyl, —NH—C(═O)—C1-6alkyl, —C(═O)—NH2, —C(═O)—NH—C1-6alkyl, and —C(═O)—N(C1-6 alkyl)2;
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-12 membered heterocyclyl, wherein said 5-12 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
            R5 and R5′ are each independently selected from the group consisting of hydrogen, deuterium, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, C5-12 aryl, 5-12 membered heteroaryl, 5-12 membered heterocyclyl, and wherein said —C1-6 alkyl, said —C1-6 alkoxy, said —C3-8 cycloalkyl, said C5-12 aryl, said 5-12 membered heteroaryl, said 5-12 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            each of R6 is independently selected from the group consisting of hydrogen, deuterium, —C1-6 alkyl, —C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, —C1-6 alkenyl, and —C3-8 cycloalkenyl, and wherein said —C1-6 alkyl, said —C3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said —C1-6 alkenyl, and said —C3-8 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
            each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, C3-8 cycloalkyl, 5-12 membered heterocyclyl ring, C1-6 alkenyl, C3-8 cycloalkenyl, C5-12 aryl, and 5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C3-8 cycloalkyl, said 5-12 membered heterocyclyl ring, said C1-6 alkenyl, said C3-8 cycloalkenyl, said C5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            R8 and R9 are each independently selected from the group consisting of C1-6 alkyl, C3-8 cycloalkyl, monosaccharide, acylated monosaccharide, C5-12 aryl, and 5-12 membered heteroaryl, and wherein said C1-6 alkyl, said C3-8 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-12 aryl, and said 5-12 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            G is C5-12 aryl, or 5-12 membered heteroaryl, wherein C5-12 aryl, and 5-12 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
        
        
        R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
        R3 and R3′ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
        Y is a bond, oxygen, or —(CRY1RY2)n—;
        
            n is selected from 1, 2, 3, 4, 5, 6, 7 or 8;
            RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
        
        
        R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6alkyl, —C1-6alkoxy, —C3-8cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
        R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-6 alkyl, and C1-6 alkoxy, and wherein said C1-6 alkyl, and said C1-6 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6alkyl, —C1-6alkoxy, —C3-8cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl.
    
    


In some embodiments of the compound of Formula I, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein the compound is of formula I-A:




In some embodiments of the compound of Formula I, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein the compound is of formula I-B:




In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, —C3-8cycloalkyl, —C0-3alkylene-C3-8heterocyclyl, —C0-3alkylene-NH—C0-3alkylene C6-10aryl, —C0-3alkylene-NH—C0-3alkylene-5-12membered heteroaryl, —C0-3alkylene-C6-10aryl and —C0-3alkylene-5-12 membered heteroaryl; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —NH—C3-8 cycloalkyl, —N(C1-6alkyl)2, carboxyl, —CO—C1-6 alkyl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N, O or S.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, —C3-8cycloalkyl, —C0-3alkylene-C3-8heterocyclyl, —C0-3alkylene-NH—C0-3alkylene C6-10aryl, —C0-3alkylene-NH—C0-3alkylene-5-12 membered heteroaryl, —C0-3alkylene-C6-10aryl and —C0-3alkylene-5-12 membered heteroaryl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N or O; and wherein each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-6 alkyl), —NH—C3-6 cycloalkyl, —N(C1-3alkyl)2, carboxyl, —CO—C1-3alkyl; each of the heteroaryl and heterocyclyl contains 1 or 2 heteroatoms selected from N or O.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,







and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-6 alkyl), —NH—C3-6 cycloalkyl, —N(C1-3alkyl)2, carboxyl, —CO—C1-3alkyl.

In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy,







and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, —NH-cyclopropyl, —NH-cyclobutyl, —NH-cyclopentyl, —NH-cyclohexyl, carboxyl and —CO-tert-butyl.

In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, —CF3, —CH2CF3, —CH(CH3)CF3, —CH(CH3)CH2CF3, —(CH2)2CF3, —(CH2)2—CH(CH3)2, —C(CH3)2CF3, —C(CH3)2CH2CF3, —CN, —CH2CN, —CH(CH3)CN, —CH2CH2CN, —CH(CH3)CH2CN, —C(CH3)2CN, —C(CH3)2CH2CN, —CH2OH, —CH2—O—CH3, —CH2—O—CH2CH3, —CH2—O—CH(CH3)2,







In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is selected from the group consisting of hydrogen, deuterium, C1-6 alkyl, —C(═O)-G, —C(═O)—W—(CRX1RX2)m—O—RX3, —C(═O)—W—(CRX1RX2)m—S—RX3, C(═O)—W—(CRX1RX2)m—SO—RX3, C(═O)—W—(CRX1RX2)m—SO2—RX3, —C(═O)—W—(CRX1RX2)m-G, —C(═O)—W—(CRX1RX2)m—NR5R5′, —P(═O)(OR6)p(NHR7)q, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)—R8, —C(═O)—W—(CRX1RX2)m-G-O—R8, —C(═O)—O—(CRX1RX2)m—O—C(═O)—R9, —C(═O)—O—R7, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)-G, and —C(═O)—W—(CRX1RX2)m-G-NR5R5′;
        
            W is oxygen, CO or a bond;
            m is selected from 1, 2 or 3;
            p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, C1-4alkyl, C1-3alkoxy, C4-8 cycloalkyl, —C(═O)—C1-3alkyl, C5-10aryl, —C1-3 alkylene-C5-10aryl, 5-10 membered heteroaryl, and —C1-3 alkylene-5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C1-3alkoxy, said C4-8 cycloalkyl, said C5-10aryl, said —C1-3 alkylene-C5-10aryl, said 5-10 membered heteroaryl, and said —C1-3 alkylene-5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, —S—C1-6alkyl or carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
            or RX1 and RX2 together with the carbon atom to which they are attached form C4-8carbocyclic ring, C4-8 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —NH2, —CN, —OH, —NO2, carbonyl, ═O, oxo, carboxyl, C1-6alkoxy, C1-6alkyl;
            RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, —C(═O)—C1-3 alkyl, and —C1-3alkylenen-C5-10 aryl, wherein said C1-3 alkyl, said C1-3 alkoxy, said C3-6 cycloalkyl, said —C(═O)—C1-3 alkyl, and said —C1-3alkylenen-C5-10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl, 4-8 membered heterocyclyl,
        
        
    
    






    
    
        
        
             —C6-12aryl, —C(═O)—C1-6alkyl, —NH—C(═O)—C1-6alkyl, —C(═O)—NH2, —C(═O)—NH—C1-6alkyl, and —C(═O)—N(C1-6 alkyl)2;
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-10 membered heterocyclyl, wherein said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
            R5 and R5′ are each independently selected from the group consisting of hydrogen, deuterium, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, C5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, and wherein said —C1-3 alkyl, —C1-3 alkoxy, said —C3-6cycloalkyl, said C5-10 aryl, said 5-10 membered heteroaryl, said 5-10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            each of R6 is independently selected from the group consisting of hydrogen, deuterium, —C1-3 alkyl, —C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, —C1-3alkenyl, and —C3-6 cycloalkenyl, and wherein said —C1-3 alkyl, said —C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said —C1-3alkenyl, and said —C3-6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
            each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C1-3 alkenyl, C3-6 cycloalkenyl, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said C1-3 alkenyl, said C3-6 cycloalkenyl, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl;
            R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl; or
            G is C5-10 aryl, or 5-10 membered heteroaryl, wherein C5-10 aryl, and 5-10 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, carboxyl.
        
        
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, —C(═O)-G, —C(═O)—W—(CRX1RX2)m—O—RX3, —C(═O)—W—(CRX1RX2)m—S—RX3, C(═O)—W—(CRX1RX2)m—SO—RX3, C(═O)—W—(CRX1RX2)m—SO2—RX3, —C(═O)—W—(CRX1RX2)m-G, —C(═O)—W—(CRX1RX2)m—NR5R5′, —P(═O)(OR6)p(NHR7)q, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)—R8, —C(═O)—W—(CRX1RX2)m-G-O—R8, —C(═O)—O—(CRX1RX2)m—O—C(═O)—R9, —C(═O)—O—R7, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)-G, and —C(═O)—W—(CRX1RX2)m-G-NR5R5′;
        
            W is oxygen or a bond;
            m is selected from 1, 2 or 3;
            p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, C1-4 alkyl, C1-3alkoxy, C4-8 cycloalkyl, —C(═O)—C1-3alkyl, C5-10aryl, —C1-3 alkylene-C5-10aryl, 5-10 membered heteroaryl, and —C1-3 alkylene-5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C1-3alkoxy, said C4-8cycloalkyl, said C5-10aryl, said-C1-3 alkylene-C5-10aryl, said 5-10 membered heteroaryl, and said —C1-3 alkylene-5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-3alkyl)2, —S—C1-3alkyl carboxyl; and each of the heteroaryl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
            or RX1 and RX2 together with the carbon atom to which they are attached form C4-6carbocyclic ring, C4-6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —NH2, —CN, —OH, —NO2, oxo, carboxyl, C1-3alkoxy, C1-3alkyl;
            RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, C3-6 cycloalkyl, —C(═O)—C1-3 alkyl, and —C1-3alkylenen-C5-10aryl, wherein said C1-3 alkyl, said C1-3 alkoxy, said C3-6 cycloalkyl, said —C(═O)—C1-3 alkyl, and said —C1-3alkylenen-C5-10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, —S—C1-3alkyl carboxyl, 4-6 membered heterocyclyl,
        
        
    
    






    
    
        
        
             —C6-10aryl, —C(═O)—C1-3alkyl, —NH—C(═O)—C1-3alkyl, —C(═O)—NH2, —C(═O)—NH—C1-3alkyl, —C(═O)—N(C1-3alkyl)2;
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form a 5-10 membered heterocyclyl, wherein said 5-10 membered heterocyclyl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl; and each of the heterocyclyl independently optionally contains 1, 2 or 3 heteroatoms selected from N, O or S;
            R5 and R5′ are each independently selected from the group consisting of hydrogen, deuterium, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, C5-10 aryl, 5-10 membered heteroaryl, 5-10 membered heterocyclyl, and wherein said —C1-3 alkyl, —C1-3 alkoxy, said —C3-6cycloalkyl, said C5-10 aryl, said 5-10 membered heteroaryl, said 5-10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl;
            each of R6 is independently selected from the group consisting of hydrogen, deuterium, —C1-3 alkyl, —C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, —C1-3alkenyl, and —C3-6 cycloalkenyl, and wherein said —C1-3 alkyl, said —C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said —C1-3alkenyl, and said —C3-6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl;
            or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
            each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, C3-6 cycloalkyl, 5-10 membered heterocyclyl ring, C1-3 alkenyl, C3-6 cycloalkenyl, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said 5-10 membered heterocyclyl ring, said C1-3 alkenyl, said C3-6 cycloalkenyl, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl;
            R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl; or
            G is C5-10 aryl, or 5-10 membered heteroaryl, wherein C5-10 aryl, and 5-10 membered heteroaryl can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl.
        
        
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, —C(═O)-G, —C(═O)—W—(CRX1RX2)m—O—RX3, —C(═O)—W—(CRX1RX2)m—S—RX3, C(═O)—W—(CRX1RX2)m—SO—RX3, C(═O)—W—(CRX1RX2)m—SO2—RX3, —C(═O)—W—(CRX1RX2)m-G, —C(═O)—W—(CRX1RX2)m—NR5R5′, —P(═O)(OR6)p(NHR7)q, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)—R8, —C(═O)—W—(CRX1RX2)m-G-O—R8, —C(═O)—O—(CRX1RX2)m—O—C(═O)—R9, —C(═O)—O—R7, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)-G, and —C(═O)—W—(CRX1RX2)m-G-NR5R5′;
        
            W is oxygen or a bond;
            m is selected from 1, 2 or 3;
            p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—CH2CH2CH3, —C(═O)—CH(CH3)2, C5 aryl, C6aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, —CH2—C5 aryl, —CH2—C6aryl, —CH2—C7 aryl, —CH2—C8 aryl, —CH2—C9 aryl, —CH2—C10 aryl, —(CH2)2—C5 aryl, —(CH2)2-C6aryl, —(CH2)2—C7 aryl, —(CH2)2—C5 aryl, —(CH2)2—C9 aryl, —(CH2)2—C10 aryl, —(CH2)3—C5 aryl, —(CH2)3-C6aryl, —(CH2)3—C7 aryl, —(CH2)3—C5 aryl, —(CH2)3—C9 aryl, —(CH2)3—C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, —CH2-5 membered heteroaryl, —CH2-6 membered heteroaryl, —CH2-7 membered heteroaryl, —CH2-8 membered heteroaryl, —CH2-9 membered heteroaryl, —CH2-10 membered heteroaryl, —(CH2)2-5 membered heteroaryl, —(CH2)2-6 membered heteroaryl, —(CH2)2-7 membered heteroaryl, —(CH2)2-8 membered heteroaryl, —(CH2)2-9 membered heteroaryl, —(CH2)2-10 membered heteroaryl, —(CH2)3-5 membered heteroaryl, —(CH2)3-6 membered heteroaryl, —(CH2)3-7 membered heteroaryl, —(CH2)3-8 membered heteroaryl, —(CH2)3-9 membered heteroaryl, and —(CH2)3-10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C5 aryl, said C6aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said —CH2—C5 aryl, said —CH2—C6aryl, said —CH2—C7 aryl, said —CH2—C8 aryl, said —CH2—C9 aryl, said —CH2—C10 aryl, said —(CH2)2—C8 aryl, said —(CH2)2-C6aryl, said —(CH2)2—C7 aryl, said —(CH2)2—C5 aryl, said —(CH2)2—C9 aryl, said —(CH2)2—C10 aryl, said —(CH2)3—C5 aryl, said —(CH2)3-C6aryl, said —(CH2)3—C7 aryl, said —(CH2)3—C5 aryl, said —(CH2)3—C9 aryl, said —(CH2)3—C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said —CH2-5 membered heteroaryl, said —CH2-6 membered heteroaryl, said —CH2-7 membered heteroaryl, said —CH2-8 membered heteroaryl, said —CH2-9 membered heteroaryl, said —CH2-10 membered heteroaryl, said —(CH2)2-5 membered heteroaryl, said —(CH2)2-6 membered heteroaryl, said —(CH2)2-7 membered heteroaryl, said —(CH2)2-8 membered heteroaryl, said —(CH2)2-9 membered heteroaryl, said —(CH2)2-10 membered heteroaryl, said —(CH2)3-5 membered heteroaryl, said —(CH2)3-6 membered heteroaryl, said —(CH2)3-7 membered heteroaryl, said —(CH2)3-8 membered heteroaryl, said —(CH2)3-9 membered heteroaryl, and said —(CH2)3-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-3alkyl)2, —S—C1-3alkyl, carboxyl; and each of the heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
            or RX1 and RX2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, or 6-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O;
            each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, —F, —Cl, —Br, —I, —NH2, —CN, —OH, —NO2, oxo, carboxyl, C1-3alkoxy, C1-3alkyl;
            RX3 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—CH2CH2CH3, —C(═O)—CH(CH3)2, —CH2—C5 aryl, —(CH2)2—C5 aryl, —(CH2)3—C5 aryl, —CH2—C6 aryl, —(CH2)2—C6 aryl, —(CH2)3—C6 aryl, —CH2—C7 aryl, —(CH2)2—C7 aryl, —(CH2)3—C7 aryl, —CH2—C8 aryl, —(CH2)2—C8 aryl, —(CH2)3—C8 aryl, —CH2—C9 aryl, —(CH2)2—C9 aryl, —(CH2)3—C9 aryl, —CH2—C10 aryl, —(CH2)2—C10 aryl, —(CH2)3—C10 aryl, wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said —C(═O)—CH3, said —C(═O)—CH2CH3, said —C(═O)—CH2CH2CH3, said —C(═O)—CH(CH3)2, said —CH2—C5 aryl, said —(CH2)2—C5 aryl, said —(CH2)3-C5 aryl, said —CH2-C6 aryl, said —(CH2)2-C6 aryl, said —(CH2)3-C6 aryl, said —CH2-C7 aryl, said —(CH2)2-C7 aryl, said —(CH2)3-C7 aryl, said —CH2-C8 aryl, said —(CH2)2-C8 aryl, said —(CH2)3-C8 aryl, said —CH2-C9 aryl, said —(CH2)2-C9 aryl, said —(CH2)3-C9 aryl, said —CH2-C10 aryl, said —(CH2)2-C10 aryl, and said —(CH2)3-C10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl, 4-6 membered heterocyclyl,
        
        
    
    






    
    
        
        
             C6-10aryl, —C(═O)—C1-3alkyl, —NH—C(═O)—C1-3alkyl, —C(═O)—NH2, —C(═O)—NH—C1-3alkyl, and —C(═O)—N(C1-3alkyl)2;
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl; and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
            R5 and R5′ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said —C3 cycloalkyl, said —C4 cycloalkyl, said —C5 cycloalkyl, said —C6 cycloalkyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl;
            each of R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, —C3 cycloalkenyl, —C4 cycloalkenyl, —C5 cycloalkenyl, —C6 cycloalkenyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said —C3 cycloalkyl, said —C4 cycloalkyl, said —C5 cycloalkyl, said —C6 cycloalkyl, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said —C3 cycloalkenyl, said —C4 cycloalkenyl, said —C5 cycloalkenyl, said —C6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl;
            or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
            each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said 5-10 membered heterocyclyl ring, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said C3 cycloalkenyl, said C4 cycloalkenyl, said C5 cycloalkenyl, said C6 cycloalkenyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxyl;
            R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3alkyl, —C1-3alkoxy, —C3-6cycloalkyl, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, or carboxyl; or
            G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, wherein said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, or said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3alkyl, —C1-3alkoxy, —C3-6cycloalkyl, —NH2, —NH(C1-3alkyl), —N(C1-3alkyl)2, carboxyl.
        
        
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, —C(═O)-G, —C(═O)—W—(CRX1RX2)m—O—RX3, —C(═O)—W—(CRX1RX2)m—S—RX3, C(═O)—W—(CRX1RX2)m—SO—RX3, C(═O)—W—(CRX1RX2)m—SO2—RX3, —C(═O)—W—(CRX1RX2)m-G, —C(═O)—W—(CRX1RX2)m—NR5R5′, —P(═O)(OR6)p(NHR7)q, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)—R8, —C(═O)—W—(CRX1RX2)m-G-O—R8, —C(═O)—O—(CRX1RX2)m—O—C(═O)—R9, —C(═O)—O—R7, —C(═O)—W—(CRX1RX2)m-G-O—C(═O)-G, and —C(═O)—W—(CRX1RX2)m-G-NR5R5′;
        
            W is oxygen or a bond;
            m is selected from 1, 2 or 3;
            p and q are each independently selected from 0, 1 or 2 provided that the sum of p and q is 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—CH2CH2CH3, —C(═O)—CH(CH3)2, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, —CH2—C5 aryl, —CH2—C6aryl, —CH2—C7 aryl, —CH2—C5 aryl, —CH2—C9 aryl, —CH2—C10 aryl, —(CH2)2—C5 aryl, —(CH2)2-C6aryl, —(CH2)2—C7 aryl, —(CH2)2—C5 aryl, —(CH2)2—C9 aryl, —(CH2)2—C10 aryl, —(CH2)3—C5 aryl, —(CH2)3-C6aryl, —(CH2)3—C7 aryl, —(CH2)3—C8 aryl, —(CH2)3—C9 aryl, —(CH2)3—C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, —CH2-5 membered heteroaryl, —CH2-6 membered heteroaryl, —CH2-7 membered heteroaryl, —CH2-8 membered heteroaryl, —CH2-9 membered heteroaryl, —CH2-10 membered heteroaryl, —(CH2)2-5 membered heteroaryl, —(CH2)2-6 membered heteroaryl, —(CH2)2-7 membered heteroaryl, —(CH2)2-8 membered heteroaryl, —(CH2)2-9 membered heteroaryl, —(CH2)2-10 membered heteroaryl, —(CH2)3-5 membered heteroaryl, —(CH2)3-6 membered heteroaryl, —(CH2)3-7 membered heteroaryl, —(CH2)3-8 membered heteroaryl, —(CH2)3-9 membered heteroaryl, and —(CH2)3-10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C5 aryl, said C6aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said —CH2—C5 aryl, said —CH2—C6aryl, said —CH2—C7 aryl, said —CH2—C8 aryl, said —CH2—C9 aryl, said —CH2—C10 aryl, said —(CH2)2—C5 aryl, said —(CH2)2-C6aryl, said —(CH2)2—C7 aryl, said —(CH2)2—C8 aryl, said —(CH2)2—C9 aryl, said —(CH2)2—C10 aryl, said —(CH2)3—C5 aryl, said —(CH2)3-C6aryl, said —(CH2)3—C7 aryl, said —(CH2)3—C8 aryl, said —(CH2)3—C9 aryl, said —(CH2)3—C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said —CH2-5 membered heteroaryl, said —CH2-6 membered heteroaryl, said —CH2-7 membered heteroaryl, said —CH2-8 membered heteroaryl, said —CH2-9 membered heteroaryl, said —CH2-10 membered heteroaryl, said —(CH2)2-5 membered heteroaryl, said —(CH2)2-6 membered heteroaryl, said —(CH2)2-7 membered heteroaryl, said —(CH2)2-8 membered heteroaryl, said —(CH2)2-9 membered heteroaryl, said —(CH2)2-10 membered heteroaryl, said —(CH2)3-5 membered heteroaryl, said —(CH2)3-6 membered heteroaryl, said —(CH2)3-7 membered heteroaryl, said —(CH2)3-8 membered heteroaryl, said —(CH2)3-9 membered heteroaryl, and said —(CH2)3-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, —NH— cyclopropyl, —NH-cyclobutyl, —NH-cyclopentyl, —NH-cyclohexyl, —S-methyl and carboxyl; and each of the heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
            or RX1 and RX2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, —F, —Cl, —Br, —I, —NH2, —CN, —OH, —NO2, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;
            RX3 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—CH2CH2CH3, —C(═O)—CH(CH3)2, —CH2-C5 aryl, —(CH2)2-C6 aryl, —(CH2)3-C5 aryl, —CH2-C6 aryl, —(CH2)2-C6 aryl, —(CH2)3—C6 aryl, —CH2-C7 aryl, —(CH2)2-C7 aryl, —(CH2)3-C7 aryl, —CH2-C5 aryl, —(CH2)2-C6 aryl, —(CH2)3—C8 aryl, —CH2-C9 aryl, —(CH2)2-C9 aryl, —(CH2)3-C9 aryl, —CH2-C10 aryl, —(CH2)2-C10 aryl, —(CH2)3—C10 aryl, wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said —C(═O)—CH3, said —C(═O)—CH2CH3, said —C(═O)—CH2CH2CH3, said —C(═O)—CH(CH3)2, said —CH2-C5 aryl, said —(CH2)2-C5 aryl, said —(CH2)3-C5 aryl, said —CH2-C6 aryl, said —(CH2)2-C6 aryl, said —(CH2)3-C6 aryl, said —CH2-C7 aryl, said —(CH2)2-C7 aryl, said —(CH2)3-C7 aryl, said —CH2-C5 aryl, said —(CH2)2-C5 aryl, said —(CH2)3-C8 aryl, said —CH2-C9 aryl, said —(CH2)2-C9 aryl, said —(CH2)3-C9 aryl, said —CH2-C10 aryl, said —(CH2)2-C10 aryl, and said —(CH2)3-C10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl,
        
        
    
    






    
    
        
        
             —C6aryl, —C(═O)—CH3, —NH—C(═O)—CH3, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—N(CH3)2, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl;
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl; and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
            R5 and R5′ are each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said —C3 cycloalkyl, said —C4 cycloalkyl, said —C5 cycloalkyl, said —C6 cycloalkyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl;
            each of R6 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, —C3 cycloalkenyl, —C4 cycloalkenyl, —C5 cycloalkenyl, —C6 cycloalkenyl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said —C3 cycloalkyl, said —C4 cycloalkyl, said —C5 cycloalkyl, said —C6 cycloalkyl, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said —C3 cycloalkenyl, said —C4 cycloalkenyl, said —C5 cycloalkenyl, said —C6 cycloalkenyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl;
            or R6 together with the oxygen atom to which it is attached forms a purine or pyrimidine nucleoside;
            each of R7 is independent selected from the group consisting of hydrogen, deuterium, halogen, methyl, ethyl, propyl, isopropyl, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, 5-10 membered heterocyclyl ring, 5 membered heterocyclyl ring, 6 membered heterocyclyl ring, 7 membered heterocyclyl ring, 8 membered heterocyclyl ring, 9 membered heterocyclyl ring, 10 membered heterocyclyl ring, vinyl, allyl, C3 cycloalkenyl, C4 cycloalkenyl, C5 cycloalkenyl, C6 cycloalkenyl, C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said 5-10 membered heterocyclyl ring, said 5 membered heterocyclyl ring, said 6 membered heterocyclyl ring, said 7 membered heterocyclyl ring, said 8 membered heterocyclyl ring, said 9 membered heterocyclyl ring, said 10 membered heterocyclyl ring, said vinyl, said allyl, said C3 cycloalkenyl, said C4 cycloalkenyl, said C5 cycloalkenyl, said C6 cycloalkenyl, said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl;
            R8 and R9 are each independently selected from the group consisting of C1-3 alkyl, C3-6 cycloalkyl, monosaccharide, acylated monosaccharide, C5-10 aryl, and 5-10 membered heteroaryl, and wherein said C1-3 alkyl, said C3-6 cycloalkyl, said monosaccharide, said acylated monosaccharide, said C5-10 aryl, and said 5-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl; or
            G is C5 aryl, C6 aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, or 10 membered heteroaryl, wherein said C5 aryl, said C6 aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, or said 10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl.
        
        
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is —C(═O)—W—(CRX1RX2)m—O—RX3;
        
            W is a bond;
            m is 1 or 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—CH2CH2CH3, —C(═O)—CH(CH3)2, C5 aryl, C6aryl, C7 aryl, C8 aryl, C9 aryl, C10 aryl, —CH2—C5 aryl, —CH2—C6aryl, —CH2—C7 aryl, —CH2—C8 aryl, —CH2—C9 aryl, —CH2—C10 aryl, —(CH2)2—C5 aryl, —(CH2)2-C6aryl, —(CH2)2—C7 aryl, —(CH2)2—C8 aryl, —(CH2)2—C9 aryl, —(CH2)2—C10 aryl, —(CH2)3—C5 aryl, —(CH2)3-C6aryl, —(CH2)3—C7 aryl, —(CH2)3—C8 aryl, —(CH2)3—C9 aryl, —(CH2)3—C10 aryl, 5 membered heteroaryl, 6 membered heteroaryl, 7 membered heteroaryl, 8 membered heteroaryl, 9 membered heteroaryl, 10 membered heteroaryl, —CH2-5 membered heteroaryl, —CH2-6 membered heteroaryl, —CH2-7 membered heteroaryl, —CH2-8 membered heteroaryl, —CH2-9 membered heteroaryl, —CH2-10 membered heteroaryl, —(CH2)2-5 membered heteroaryl, —(CH2)2-6 membered heteroaryl, —(CH2)2-7 membered heteroaryl, —(CH2)2-8 membered heteroaryl, —(CH2)2-9 membered heteroaryl, —(CH2)2-10 membered heteroaryl, —(CH2)3-5 membered heteroaryl, —(CH2)3-6 membered heteroaryl, —(CH2)3-7 membered heteroaryl, —(CH2)3-8 membered heteroaryl, —(CH2)3-9 membered heteroaryl, and —(CH2)3-10 membered heteroaryl, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C5 aryl, said C6aryl, said C7 aryl, said C8 aryl, said C9 aryl, said C10 aryl, said —CH2—C5 aryl, said —CH2—C6aryl, said —CH2—C7 aryl, said —CH2—C8 aryl, said —CH2—C9 aryl, said —CH2—C10 aryl, said —(CH2)2—C5 aryl, said —(CH2)2-C6aryl, said —(CH2)2—C7 aryl, said —(CH2)2—C8 aryl, said —(CH2)2—C9 aryl, said —(CH2)2—C10 aryl, said —(CH2)3—C5 aryl, said —(CH2)3-C6aryl, said —(CH2)3—C7 aryl, said —(CH2)3—C8 aryl, said —(CH2)3—C9 aryl, said —(CH2)3—C10 aryl, said 5 membered heteroaryl, said 6 membered heteroaryl, said 7 membered heteroaryl, said 8 membered heteroaryl, said 9 membered heteroaryl, said 10 membered heteroaryl, said —CH2-5 membered heteroaryl, said —CH2-6 membered heteroaryl, said —CH2-7 membered heteroaryl, said —CH2-8 membered heteroaryl, said —CH2-9 membered heteroaryl, said —CH2-10 membered heteroaryl, said —(CH2)2-5 membered heteroaryl, said —(CH2)2-6 membered heteroaryl, said —(CH2)2-7 membered heteroaryl, said —(CH2)2-8 membered heteroaryl, said —(CH2)2-9 membered heteroaryl, said —(CH2)2-10 membered heteroaryl, said —(CH2)3-5 membered heteroaryl, said —(CH2)3-6 membered heteroaryl, said —(CH2)3-7 membered heteroaryl, said —(CH2)3-8 membered heteroaryl, said —(CH2)3-9 membered heteroaryl, and said —(CH2)3-10 membered heteroaryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, —NH— cyclopropyl, —NH-cyclobutyl, —NH-cyclopentyl, —NH-cyclohexyl, —S-methyl and carboxyl; and each of the heteroaryl independently optionally contains 1 or 2 heteroatoms selected from N, O or S;
            or RX1 and RX2 together with the carbon atom to which they are attached form 3-membered carbocyclic ring, 4-membered carbocyclic ring, 5-membered carbocyclic ring, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N or O; each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
            RX3 is independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—CH2CH2CH3, —C(═O)—CH(CH3)2, —CH2-C5 aryl, —(CH2)2-C5 aryl, —(CH2)3-C5 aryl, —CH2-C6 aryl, —(CH2)2-C6 aryl, —(CH2)3—C6 aryl, —CH2-C7 aryl, —(CH2)2-C7 aryl, —(CH2)3-C7 aryl, —CH2-C8 aryl, —(CH2)2-C8 aryl, —(CH2)3—C8 aryl, —CH2-C9 aryl, —(CH2)2-C9 aryl, —(CH2)3-C9 aryl, —CH2-C10 aryl, —(CH2)2-C10 aryl, —(CH2)3—C10 aryl, wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, said isopropoxy, said C3 cycloalkyl, said C4 cycloalkyl, said C5 cycloalkyl, said C6 cycloalkyl, said —C(═O)—CH3, said —C(═O)—CH2CH3, said —C(═O)—CH2CH2CH3, said —C(═O)—CH(CH3)2, said —CH2-C5 aryl, said —(CH2)2-C5 aryl, said —(CH2)3-C5 aryl, said —CH2-C6 aryl, said —(CH2)2-C6 aryl, said —(CH2)3-C6 aryl, said —CH2-C7 aryl, said —(CH2)2-C7 aryl, said —(CH2)3-C7 aryl, said —CH2-C8 aryl, said —(CH2)2-C8 aryl, said —(CH2)3-C8 aryl, said —CH2-C9 aryl, said —(CH2)2-C9 aryl, said —(CH2)3-C9 aryl, said —CH2-C10 aryl, said —(CH2)2-C10 aryl, and said —(CH2)3-C10 aryl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl,
        
        
    
    






    
    
        
        
             —C6aryl, —C(═O)—CH3, —NH—C(═O)—CH3, —C(═O)—NH2, —C(═O)—NH—CH3, —C(═O)—N(CH3)2, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl;
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, 7 membered heterocyclyl, 8 membered heterocyclyl, 9 membered heterocyclyl, 10 membered heterocyclyl, wherein said 4 membered heterocyclyl, said 5 membered heterocyclyl, said 6 membered heterocyclyl, said 7 membered heterocyclyl, said 8 membered heterocyclyl, said 9 membered heterocyclyl, said 10 membered heterocyclyl, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl; and each of the heterocyclyl independently optionally contains 1 or 2 heteroatoms selected from N, O or S.
        
        
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is —C(═O)—W—(CRX1RX2)m—O—RX3;
        
            W is a bond;
            m is 1 or 2;
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, —C(O)—CH3,
        
        
    
    






    
    
        
        
             and each of which is independently optionally substituted with deuterium, —F, —Cl, —Br, —I, —NH2, —CN, —OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —NHmethyl, —NHethyl, —NHpropyl, —NHcyclopropyl, —NHisopropyl, —N(CH3)2, —NH-cyclobutyl, —NH— cyclopentyl, —NH-cyclohexyl, or —S-methyl;
            or RX1 and RX2 together with the carbon atom to which they are attached form
        
        
    
    






    
    
        
        
            RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, —CD3, —C(═O)—CH2—CN, —C(═O)—C(CH3)3, —C(═O)—CH3, —C(═O)—CH2CH3, —C(═O)—NH—CH3, —C(═O)—CH2—N(CH3)2, —CH2—C(═O)—CH3, —CH2—C(═O)—NHCH3, —CH2—C(═O)—N(CH3)2, —CH2—NH2, —CH2—NH—CH3, —CH2CH2—OH, —CH2CH2—CN, —CH2—CN, —CH2CH2—C(═O)—NH2, —CH2CH2—C(═O)—NH—CH3, —CH2CH2—NH—C(═O)—CH3,
        
        
    
    






    
    
        
        
            or RX1 and RX3 together with the carbon atom and the oxygen atom to which they are attached respectively form
        
        
    
    






In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        X is —C(═O)—CRX1RX2—O—RX3;
        
            RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, —C(═O)—CH3, —CH2— cyclopropyl, —CH2— cyclobutyl, —CH2-cyclopentyl, —CH2-cyclohexyl,
        
        
    
    









    
    
        
        
            RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, —CD3, —C(═O)—CH2—CN, —C(═O)—C(CH3)3, —C(═O)—CH3, —C(═O)—CH2CH3,
        
        
    
    






In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R2 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl. Preferably, R2 is selected from hydrogen or deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3′ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3′ are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3′ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R3 and R3′ are each independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH(CH3)2)2, and carboxyl. Preferably, R3 and R3′ are each independently selected from hydrogen or deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        Y is a bond, or —(CRY1RY2)n—;
        n is selected from 1, 2, or 3;
        RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, and carboxyl.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        Y is a bond, or —(CRY1RY2)n—;
        n is selected from 1, 2, or 3;
        RY1 and RY2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        Y is a bond, or —(CRY1RY2)n—;
        n is selected from 1, 2, or 3;
        RY1 and RY2 are each independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein

    
    
        Y is a bond, or —(CRY1RY2)n—;
        n is selected from 1, 2, or 3;
        RY1 and RY2 are each independently selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, and —N(CH(CH3)2)2, and carboxyl.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein Y is —CH2—.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R4 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, and —N(CH(CH3)2)2, and carboxyl. Preferably, R4 is selected from hydrogen or deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, halogen, —OH, oxo, —CN, —C1-6 alkyl, —C1-6 alkoxy, —C3-8 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-6alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, halogen, C1-3 alkyl, and C1-3 alkoxy, and wherein said C1-3 alkyl, and said C1-3 alkoxy can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, and carboxyl.
In some embodiments of the compound of Formula I, I-A, I-B, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R10 is selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, and isopropoxy, and wherein said methyl, said ethyl, said propyl, said isopropyl, said methoxy, said ethoxy, said propoxy, and said isopropoxy, can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —C3 cycloalkyl, —C4 cycloalkyl, —C5 cycloalkyl, —C6 cycloalkyl, —NH2, —NHCH3, —NHCH2CH3, —NHCH2CH2CH3, —NHCH(CH3)2, —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, and —N(CH(CH3)2)2, and carboxyl. Preferably, R10 is hydrogen or deuterium.
A compound of Formula I-C, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:




    
    
        wherein Q is O, S, SO, or SO2; Z, RX1, RX2, RX3, and m are the same as defined herein.
    
    


A compound of Formula II, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof:




    
    
        wherein Z, RX1, RX2, RX3, and m are the same as defined herein.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, I-C, or II, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, the compound is of Formula III:




    
    
        wherein R1, RX1, RX2, RX3, and m are the same as defined herein.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, or III, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, the compound is of Formula IV:




In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, or IV, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, the compound is of Formula V:




In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, or IV, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, the compound is of Formula VI:




In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, or IV, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, the compound is of Formula VII:




In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, or IV, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, the compound is of Formula VIII and a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic substitution thereof:




    
    
        wherein R1, RX1, RX2, RX3, and m are the same as defined herein
    
    


In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein one or more hydrogen is optionally substituted with deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein one or more hydrogen in R1 or RX3 is substituted with deuterium, preferably, all hydrogens on one or more methyl groups, methylene groups, or methane groups are substituted with deuterium.
In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy;

    
    
        RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, OH, C1-4alkyl, C1-3alkoxy, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-6 alkyl), —N(C1-3alkyl)2, —S—C1-3alkyl; or
        RX3 is independently selected from the group consisting of hydrogen, deuterium, C1-3 alkyl, C1-3 alkoxy, each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, —C1-3 alkyl, —C1-3 alkoxy, —C3-6 cycloalkyl, —NH2, —NH(C1-3 alkyl), —N(C1-3alkyl)2, carboxy, —S—C1-3alkyl.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; and each of which can be optional substituted with one or more substituents, which are independently selected from the group consisting of deuterium, F, Cl, Br, I, —OH, oxo, —CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy;

    
    
        RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, CN, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl, and each of which is independently optionally substituted with deuterium, —F, —Cl, —Br, —I, —NH2, —CN, —OH, oxo, carboxyl, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy; or
        RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, each of which can be substituted with deuterium.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from hydrogen, deuterium, isopropyl, methyl, ethyl, -tert-butyl, isopentyl, —CD3, —CH2CD3, —CD2CD3, —CD(CD3)2, —CH(CD3)2,




    
    
        RX1 and RX2 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CN, OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, butyl, sec-butyl, iso-butyl, tert-butyl,
    
    






    
    
         or
        RX3 is independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, —CD3, —CH2CD3, —CD2CD3.
    
    


In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein R1 is selected from —CD3, —CH2CD3, —CD2CD3, —CD(CD3)2, —CH(CD3)2,




the deuterated RX3 is selected from —CD3, —CH2CD3, —CD2CD3 

In some embodiments of the compound of Formula I, I-A, I-B, I-C, II, III, IV, V, VI, VII, or VIII, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention, wherein the compound is selected from:













1
isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


2
isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


3
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(7-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


4
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


5
isopropyl (S)-6-diazo-2-(2-methoxyacetamido)-5-oxohexanoate


6
isopropyl (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate


7
isopropyl (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate


8
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-phenylpropanamido)-5-oxohexanoate


9
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-phenylpropanamido)-5-oxohexanoate


10
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-4-methylpentanamido)-5-oxohexanoate


11
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-phenylacetamido)-5-oxohexanoate


12
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-phenylacetamido)-5-oxohexanoate


13
isopropyl (S)-2-((S)-2-(2-cyanoacetoxy)-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


14
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-(pivaloyloxy)propanamido)-6-diazo-5-oxohexanoate


15
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(1H-indol-1-yl)propanamido)-5-oxohexanoate


16
isopropyl (S)-6-diazo-2-((S)-2-(4-fluorophenyl)-2-hydroxyacetamido)-5-oxohexanoate


17
isopropyl (S)-6-diazo-2-(2-((4-fluorobenzyl)oxy)acetamido)-5-oxohexanoate


18
isopropyl (S)-2-((S)-3-(7-cyano-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


19
isopropyl (S)-2-((S)-3-(6-cyano-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


20
isopropyl (S)-2-((S)-3-(5-cyano-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


21
isopropyl (S)-2-((S)-3-(4-cyano-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


22
isopropyl (S)-2-((S)-3-(7-cyano-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


23
isopropyl (S)-2-((S)-3-(6-cyano-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


24
isopropyl (S)-2-((S)-3-(5-cyano-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


25
isopropyl (S)-2-((S)-3-(4-cyano-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


26
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(6-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


27
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(5-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


28
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(4-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


29
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(6-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


30
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(5-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


31
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(4-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


32
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(7-methoxy-1H-indol-3-yl)propanamido)-5-oxohexanoate


33
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(1-methyl-1H-imidazol-4-yl)propanamido)-5-oxohexanoate


34
isopropyl (2S)-6-diazo-2-(2-hydroxy-3-(1H-indol-3-yl)-2-methylpropanamido)-5-oxohexanoate


35
isopropyl (S)-6-diazo-2-((S)-3-(6-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


36
isopropyl (S)-6-diazo-2-((S)-3-(5-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


37
isopropyl (S)-6-diazo-2-((S)-3-(4-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


38
isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


39
isopropyl (S)-6-diazo-2-((S)-3-(6-fluoro-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


40
isopropyl (S)-6-diazo-2-((S)-3-(5-fluoro-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


41
isopropyl (S)-6-diazo-2-((S)-3-(4-fluoro-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


42
isopropyl (S)-2-((S)-3-(7-chloro-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


43
isopropyl (S)-2-((S)-3-(6-chloro-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


44
isopropyl (S)-2-((S)-3-(5-chloro-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


45
isopropyl (S)-2-((S)-3-(4-chloro-1H-indol-3-yl)-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


46
isopropyl (S)-2-((S)-3-(7-chloro-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


47
isopropyl (S)-2-((S)-3-(6-chloro-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


48
isopropyl (S)-2-((S)-3-(5-chloro-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


49
isopropyl (S)-2-((S)-3-(4-chloro-1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


50
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(7-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


51
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(6-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


52
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(5-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


53
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(4-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


54
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(7-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


55
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(6-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


56
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(5-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


57
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(4-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


58
isopropyl (S)-6-diazo-2-((S)-3-(7-(dimethylamino)-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


59
isopropyl (S)-6-diazo-2-((S)-3-(6-(dimethylamino)-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


60
isopropyl (S)-6-diazo-2-((S)-3-(5-(dimethylamino)-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


61
isopropyl (S)-6-diazo-2-((S)-3-(4-(dimethylamino)-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate


62
isopropyl (S)-6-diazo-2-((S)-3-(7-(dimethylamino)-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


63
isopropyl (S)-6-diazo-2-((S)-3-(6-(dimethylamino)-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


64
isopropyl (S)-6-diazo-2-((S)-3-(5-(dimethylamino)-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


65
isopropyl (S)-6-diazo-2-((S)-3-(4-(dimethylamino)-1H-indol-3-yl)-2-methoxypropanamido)-5-oxohexanoate


66
S-isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(1H-indol-3-yl)propanamido)-5-oxohexanethioate


67
isopropyl (S)-6-diazo-2-((S)-2-ethoxypropanamido)-5-oxohexanoate


68
isopropyl (S)-6-diazo-2-((S)-2-isopropoxypropanamido)-5-oxohexanoate


69
isopropyl (S)-2-((S)-2-cyclopropoxypropanamido)-6-diazo-5-oxohexanoate


70
isopropyl (S)-6-diazo-2-(2-hydroxyacetamido)-5-oxohexanoate


71
isopropyl (S)-2-(2-cyclopropoxyacetamido)-6-diazo-5-oxohexanoate


72
isopropyl (S)-6-diazo-2-((S)-2-hydroxybutanamido)-5-oxohexanoate


73
isopropyl (S)-6-diazo-2-((S)-2-methoxybutanamido)-5-oxohexanoate


74
isopropyl (S)-6-diazo-2-((S)-2-ethoxybutanamido)-5-oxohexanoate


75
isopropyl (S)-6-diazo-2-((S)-2-isopropoxybutanamido)-5-oxohexanoate


76
isopropyl (S)-2-((S)-2-cyclopropoxybutanamido)-6-diazo-5-oxohexanoate


77
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5-oxohexanoate


78
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-methylbutanamido)-5-oxohexanoate


79
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-methylbutanamido)-5-oxohexanoate


80
isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3-methylbutanamido)-5-oxohexanoate


81
isopropyl (S)-2-((S)-2-cyclopropoxy-3-methylbutanamido)-6-diazo-5-oxohexanoate


82
isopropyl (S)-6-diazo-2-((2S,3R)-2-hydroxy-3-methylpentanamido)-5-oxohexanoate


83
isopropyl (S)-6-diazo-2-((2S,3R)-2-methoxy-3-methylpentanamido)-5-oxohexanoate


84
isopropyl (S)-6-diazo-2-((2S,3R)-2-ethoxy-3-methylpentanamido)-5-oxohexanoate


85
isopropyl (S)-6-diazo-2-((2S,3R)-2-isopropoxy-3-methylpentanamido)-5-oxohexanoate


86
isopropyl (S)-2-((2S,3R)-2-cyclopropoxy-3-methylpentanamido)-6-diazo-5-oxohexanoate


87
isopropyl (S)-6-diazo-2-((S)-2-hydroxypentanamido)-5-oxohexanoate


88
isopropyl (S)-6-diazo-2-((S)-2-methoxypentanamido)-5-oxohexanoate


89
isopropyl (S)-6-diazo-2-((S)-2-ethoxypentanamido)-5-oxohexanoate


90
isopropyl (S)-6-diazo-2-((S)-2-isopropoxypentanamido)-5-oxohexanoate


91
isopropyl (S)-2-((S)-2-cyclopropoxypentanamido)-6-diazo-5-oxohexanoate


92
isopropyl (S)-6-diazo-2-((S)-2-methoxy-4-methylpentanamido)-5-oxohexanoate


93
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-4-methylpentanamido)-5-oxohexanoate


94
isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-4-methylpentanamido)-5-oxohexanoate


95
isopropyl (S)-2-((S)-2-cyclopropoxy-4-methylpentanamido)-6-diazo-5-oxohexanoate


96
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3,3-dimethylbutanamido)-5-oxohexanoate


97
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3,3-dimethylbutanamido)-5-oxohexanoate


98
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3,3-dimethylbutanamido)-5-oxohexanoate


99
isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3,3-dimethylbutanamido)-5-oxohexanoate


100
isopropyl (S)-2-((S)-2-cyclopropoxy-3,3-dimethylbutanamido)-6-diazo-5-oxohexanoate


101
isopropyl (S)-6-diazo-2-((S)-2-hydroxyhexanamido)-5-oxohexanoate


102
isopropyl (S)-6-diazo-2-((S)-2-methoxyhexanamido)-5-oxohexanoate


103
isopropyl (S)-6-diazo-2-((S)-2-ethoxyhexanamido)-5-oxohexanoate


104
isopropyl (S)-6-diazo-2-((S)-2-isopropoxyhexanamido)-5-oxohexanoate


105
isopropyl (S)-2-((S)-2-cyclopropoxyhexanamido)-6-diazo-5-oxohexanoate


106
isopropyl (S)-2-((S)-2-cyclopentyl-2-hydroxyacetamido)-6-diazo-5-oxohexanoate


107
isopropyl (S)-2-((S)-2-cyclopentyl-2-methoxyacetamido)-6-diazo-5-oxohexanoate


108
isopropyl (S)-2-((S)-2-cyclopentyl-2-ethoxyacetamido)-6-diazo-5-oxohexanoate


109
isopropyl (S)-2-((S)-2-cyclopentyl-2-isopropoxyacetamido)-6-diazo-5-oxohexanoate


110
isopropyl (S)-2-((S)-2-cyclopentyl-2-cyclopropoxyacetamido)-6-diazo-5-oxohexanoate


111
isopropyl (S)-2-((S)-3-cyclopentyl-2-hydroxypropanamido)-6-diazo-5-oxohexanoate


112
isopropyl (S)-2-((S)-3-cyclopentyl-2-methoxypropanamido)-6-diazo-5-oxohexanoate


113
isopropyl (S)-2-((S)-3-cyclopentyl-2-ethoxypropanamido)-6-diazo-5-oxohexanoate


114
isopropyl (S)-2-((S)-3-cyclopentyl-2-isopropoxypropanamido)-6-diazo-5-oxohexanoate


115
isopropyl (S)-2-((S)-3-cyclopentyl-2-cyclopropoxypropanamido)-6-diazo-5-oxohexanoate


116
isopropyl (S)-2-((S)-2-cyclohexyl-2-hydroxyacetamido)-6-diazo-5-oxohexanoate


117
isopropyl (S)-2-((S)-2-cyclohexyl-2-methoxyacetamido)-6-diazo-5-oxohexanoate


118
isopropyl (S)-2-((S)-2-cyclohexyl-2-ethoxyacetamido)-6-diazo-5-oxohexanoate


119
isopropyl (S)-2-((S)-2-cyclohexyl-2-isopropoxyacetamido)-6-diazo-5-oxohexanoate


120
isopropyl (S)-2-((S)-2-cyclohexyl-2-cyclopropoxyacetamido)-6-diazo-5-oxohexanoate


121
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-2-phenylacetamido)-5-oxohexanoate


122
isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-2-phenylacetamido)-5-oxohexanoate


123
isopropyl (S)-2-((S)-2-cyclopropoxy-2-phenylacetamido)-6-diazo-5-oxohexanoate


124
isopropyl (S)-6-diazo-2-((S)-2-(4-fluorophenyl)-2-methoxyacetamido)-5-oxohexanoate


125
isopropyl (S)-2-((S)-2-(4-chlorophenyl)-2-methoxyacetamido)-6-diazo-5-oxohexanoate


126
isopropyl (S)-2-((S)-2-(4-chlorophenyl)-2-hydroxyacetamido)-6-diazo-5-oxohexanoate


127
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(4-methoxyphenyl)acetamido)-5-oxohexanoate


128
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(4-methoxyphenyl)acetamido)-5-oxohexanoate


129
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(4-hydroxyphenyl)acetamido)-5-oxohexanoate


130
isopropyl (S)-6-diazo-2-((S)-2-(4-hydroxyphenyl)-2-methoxyacetamido)-5-oxohexanoate


131
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(p-tolyl)acetamido)-5-oxohexanoate


132
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(p-tolyl)acetamido)-5-oxohexanoate


133
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-phenylpropanamido)-5-oxohexanoate


134
isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3-phenylpropanamido)-5-oxohexanoate


135
isopropyl (S)-2-((S)-2-cyclopropoxy-3-phenylpropanamido)-6-diazo-5-oxohexanoate


136
isopropyl (S)-6-diazo-2-((S)-3-(4-fluorophenyl)-2-hydroxypropanamido)-5-oxohexanoate


137
isopropyl (S)-6-diazo-2-((S)-3-(4-fluorophenyl)-2-methoxypropanamido)-5-oxohexanoate


138
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-(4-fluorophenyl)propanamido)-5-oxohexanoate


139
isopropyl (S)-6-diazo-2-((S)-3-(4-fluorophenyl)-2-isopropoxypropanamido)-5-oxohexanoate


140
isopropyl (S)-2-((S)-2-cyclopropoxy-3-(4-fluorophenyl)propanamido)-6-diazo-5-oxohexanoate


141
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(4-hydroxyphenyl)propanamido)-5-oxohexanoate


142
isopropyl (S)-6-diazo-2-((S)-3-(4-hydroxyphenyl)-2-methoxypropanamido)-5-oxohexanoate


143
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-(4-hydroxyphenyl)propanamido)-5-oxohexanoate


144
isopropyl (S)-6-diazo-2-((S)-3-(4-hydroxyphenyl)-2-isopropoxypropanamido)-5-oxohexanoate


145
isopropyl (S)-2-((S)-2-cyclopropoxy-3-(4-hydroxyphenyl)propanamido)-6-diazo-5-oxohexanoate


146
isopropyl (S)-6-diazo-2-(1-hydroxycyclobutane-1-carboxamido)-5-oxohexanoate


147
isopropyl (S)-6-diazo-2-(1-methoxycyclobutane-1-carboxamido)-5-oxohexanoate


148
isopropyl (S)-6-diazo-2-(3-hydroxyoxetane-3-carboxamido)-5-oxohexanoate


149
isopropyl (S)-6-diazo-2-(3-methoxyoxetane-3-carboxamido)-5-oxohexanoate


150
isopropyl (S)-6-diazo-2-(1-hydroxycyclopentane-1-carboxamido)-5-oxohexanoate


151
isopropyl (S)-6-diazo-2-(1-methoxycyclopentane-1-carboxamido)-5-oxohexanoate


152
isopropyl (2S)-6-diazo-2-(3-hydroxytetrahydrofuran-3-carboxamido)-5-oxohexanoate


153
isopropyl (2S)-6-diazo-2-(3-methoxytetrahydrofuran-3-carboxamido)-5-oxohexanoate


154
isopropyl (S)-6-diazo-2-(1-hydroxycyclohexane-1-carboxamido)-5-oxohexanoate


155
isopropyl (S)-6-diazo-2-(1-methoxycyclohexane-1-carboxamido)-5-oxohexanoate


156
isopropyl (S)-6-diazo-2-(4-hydroxy-1-methylpiperidine-4-carboxamido)-5-oxohexanoate


157
isopropyl (S)-6-diazo-2-(4-methoxy-1-methylpiperidine-4-carboxamido)-5-oxohexanoate


158
isopropyl (2S)-6-diazo-5-oxo-2-(tetrahydrofuran-2-carboxamido)hexanoate


159
isopropyl (2S)-6-diazo-5-oxo-2-(tetrahydro-2H-pyran-2-carboxamido)hexanoate or


160
isopropyl (2S)-6-diazo-2-(hexahydro-1H-cyclopenta[c]furan-1-carboxamido)-5-oxohexanoate.


161
isopropyl (S)-2-(2-(cyclopropylmethoxy)acetamido)-6-diazo-5-oxohexanoate


162
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-phenylpropanamido)-5-oxohexanoate


163
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-phenylpropanamido)-5-oxohexanoate


164
isopropyl (S)-2-((S)-2-(2-cyanoacetoxy)-3-(7-fluoro-1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


165
isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


166
isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-(isobutyryloxy)propanamido)-5-oxohexanoate


167
(S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid


168
methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


169
1-methylpiperidin-4-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


170
isopropyl (S)-6-diazo-5-oxo-2-((S)-tetrahydrofuran-2-carboxamido)hexanoate


171
isopropyl (S)-6-diazo-5-oxo-2-((S)-tetrahydro-2H-pyran-2-carboxamido)hexanoate


172
isopropyl (S)-6-diazo-5-oxo-2-((S)-tetrahydrofuran-3-carboxamido)hexanoate


173
isopropyl (S)-6-diazo-5-oxo-2-((S)-tetrahydro-2H-pyran-3-carboxamido)hexanoate


174
isopropyl (S)-6-diazo-2-(3-methoxy-2-oxopropanamido)-5-oxohexanoate


175
isopropyl (S)-6-diazo-2-(3-hydroxy-2-oxopropanamido)-5-oxohexanoate


176
ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


177
cyclopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


178
cyclobutyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


179
cyclopentyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


180
2-(pyrrolidin-1-yl)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


181
(pivaloyloxy)methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


182
isopentyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


183
isopropyl (S)-6-diazo-2-(3-hydroxypropanamido)-5-oxohexanoate


184
isopropyl (S)-6-diazo-2-((S)-3-hydroxybutanamido)-5-oxohexanoate


185
isopropyl (S)-6-diazo-2-(3-methoxypropanamido)-5-oxohexanoate


186
isopropyl (S)-6-diazo-2-((S)-3-methoxybutanamido)-5-oxohexanoate


187
isopropyl (S)-6-diazo-2-((S)-3-hydroxy-2-methylpropanamido)-5-oxohexanoate


188
isopropyl (S)-6-diazo-2-((S)-3-methoxy-2-methylpropanamido)-5-oxohexanoate


189
isopropyl (S)-6-diazo-2-((S)-oxetane-2-carboxamido)-5-oxohexanoate


190
isopropyl (S)-6-diazo-2-((2S,3R)-3-hydroxy-2-methylbutanamido)-5-oxohexanoate


191
isopropyl (S)-6-diazo-2-((2S,3R)-3-methoxy-2-methylbutanamido)-5-oxohexanoate


192
isopropyl (S)-6-diazo-2-((2R,3R)-3-hydroxy-2-methylbutanamido)-5-oxohexanoate


193
isopropyl (S)-6-diazo-2-((2R,3R)-3-methoxy-2-methylbutanamido)-5-oxohexanoate


194
isopropyl (S)-6-diazo-2-((2R,3S)-3-hydroxy-2-methylbutanamido)-5-oxohexanoate


195
isopropyl (S)-6-diazo-2-((2R,3S)-3-methoxy-2-methylbutanamido)-5-oxohexanoate


196
isopropyl (S)-6-diazo-2-((R)-3-hydroxybutanamido)-5-oxohexanoate


197
isopropyl (S)-6-diazo-2-((2S,3S)-3-hydroxy-2-methylbutanamido)-5-oxohexanoate


198
isopropyl (S)-6-diazo-2-((2S,3S)-3-methoxy-2-methylbutanamido)-5-oxohexanoate


199
isopropyl (S)-6-diazo-5-oxo-2-((R)-tetrahydrofuran-2-carboxamido)hexanoate


200
isopropyl (S)-6-diazo-5-oxo-2-((R)-tetrahydro-2H-pyran-2-carboxamido)hexanoate


201
isopropyl (S)-6-diazo-5-oxo-2-((R)-tetrahydrofuran-3-carboxamido)hexanoate


202
isopropyl (S)-6-diazo-5-oxo-2-((R)-tetrahydro-2H-pyran-3-carboxamido)hexanoate


203
isopropyl (S)-6-diazo-2-((R)-3-methoxybutanamido)-5-oxohexanoate


204
isopropyl (S)-6-diazo-5-oxo-2-((R)-3,3,3-trifluoro-2-methoxypropanamido)hexanoate


205
isopropyl (S)-6-diazo-5-oxo-2-((R)-3,3,3-trifluoro-2-hydroxypropanamido)hexanoate


206
isopropyl (S)-6-diazo-5-oxo-2-((S)-3,3,3-trifluoro-2-methoxypropanamido)hexanoate


207
isopropyl (S)-6-diazo-5-oxo-2-((S)-3,3,3-trifluoro-2-hydroxypropanamido)hexanoate


208
isopropyl (S)-6-diazo-2-((R)-oxetane-2-carboxamido)-5-oxohexanoate


209
isopropyl (S)-6-diazo-2-(oxetane-3-carboxamido)-5-oxohexanoate


210
isopropyl (S)-6-diazo-2-((R)-3-hydroxy-2-methylpropanamido)-5-oxohexanoate


211
isopropyl (S)-6-diazo-5-oxo-2-(tetrahydro-2H-pyran-4-carboxamido)hexanoate


212
isopropyl (2S)-6-diazo-5-oxo-2-((1S)-tetrahydro-1H,3H-furo[3,4-c]furan-1-carboxamido)hexanoate


213
isopropyl (2S)-6-diazo-5-oxo-2-((1R)-tetrahydro-1H,3H-furo[3,4-c]furan-1-carboxamido)hexanoate


214
isopropyl (S)-2-((S)-2-cyano-2-hydroxyacetamido)-6-diazo-5-oxohexanoate


215
isopropyl (S)-2-((S)-2-cyano-2-methoxyacetamido)-6-diazo-5-oxohexanoate


216
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-oxobutanamido)-5-oxohexanoate


217
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-oxobutanamido)-5-oxohexanoate


218
isopropyl (S)-6-diazo-2-((R)-3-methoxy-2-methylpropanamido)-5-oxohexanoate


219
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(thiazol-4-yl)acetamido)-5-oxohexanoate


220
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(thiazol-4-yl)acetamido)-5-oxohexanoate


221
isopropyl (S)-2-((R)-2-cyano-2-hydroxyacetamido)-6-diazo-5-oxohexanoate


222
isopropyl (S)-2-((R)-2-cyano-2-methoxyacetamido)-6-diazo-5-oxohexanoate


223
isopropyl (S)-6-diazo-2-((R)-2-methoxy-3-oxobutanamido)-5-oxohexanoate


224
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-3-oxobutanamido)-5-oxohexanoate


225
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(thiazol-4-yl)acetamido)-5-oxohexanoate


226
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(thiazol-4-yl)acetamido)-5-oxohexanoate


227
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(1H-pyrrol-2-yl)acetamido)-5-oxohexanoate


228
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(1H-pyrrol-3-yl)acetamido)-5-oxohexanoate


229
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(1H-pyrrol-2-yl)acetamido)-5-oxohexanoate


230
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(1H-pyrrol-3-yl)acetamido)-5-oxohexanoate


231
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(oxazol-4-yl)acetamido)-5-oxohexanoate


232
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(oxazol-4-yl)acetamido)-5-oxohexanoate


233
isopropyl (S)-6-diazo-2-((S)-2-(furan-2-yl)-2-methoxyacetamido)-5-oxohexanoate


234
isopropyl (S)-6-diazo-2-((S)-2-(furan-3-yl)-2-methoxyacetamido)-5-oxohexanoate


235
isopropyl (S)-6-diazo-2-((S)-2-(furan-2-yl)-2-hydroxyacetamido)-5-oxohexanoate


236
isopropyl (S)-6-diazo-2-((S)-2-(furan-3-yl)-2-hydroxyacetamido)-5-oxohexanoate


237
isopropyl (S)-2-((S)-2-(1H-imidazol-4-yl)-2-methoxyacetamido)-6-diazo-5-oxohexanoate


238
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(1H-imidazol-4-yl)acetamido)-5-oxohexanoate


239
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(1H-pyrrol-2-yl)acetamido)-5-oxohexanoate


240
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(1H-pyrrol-3-yl)acetamido)-5-oxohexanoate


241
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1H-pyrrol-2-yl)acetamido)-5-oxohexanoate


242
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1H-pyrrol-3-yl)acetamido)-5-oxohexanoate


243
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(oxazol-4-yl)acetamido)-5-oxohexanoate


244
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(oxazol-4-yl)acetamido)-5-oxohexanoate


245
isopropyl (S)-6-diazo-2-((R)-2-(furan-2-yl)-2-methoxyacetamido)-5-oxohexanoate


246
isopropyl (S)-6-diazo-2-((R)-2-(furan-3-yl)-2-methoxyacetamido)-5-oxohexanoate


247
isopropyl (S)-6-diazo-2-((R)-2-(furan-2-yl)-2-hydroxyacetamido)-5-oxohexanoate


248
isopropyl (S)-6-diazo-2-((R)-2-(furan-3-yl)-2-hydroxyacetamido)-5-oxohexanoate


249
isopropyl (S)-2-((R)-2-(1H-imidazol-4-yl)-2-methoxyacetamido)-6-diazo-5-oxohexanoate


250
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1H-imidazol-4-yl)acetamido)-5-oxohexanoate


251
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(thiophen-2-yl)acetamido)-5-oxohexanoate


252
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(thiophen-3-yl)acetamido)-5-oxohexanoate


253
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(thiophen-2-yl)acetamido)-5-oxohexanoate


254
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(thiophen-3-yl)acetamido)-5-oxohexanoate


255
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(thiazol-2-yl)acetamido)-5-oxohexanoate


256
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(thiazol-2-yl)acetamido)-5-oxohexanoate


257
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(1-methyl-1H-imidazol-2-yl)acetamido)-5-oxohexanoate


258
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)acetamido)-5-oxohexanoate


259
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(1-methyl-1H-imidazol-4-yl)acetamido)-5-oxohexanoate


260
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(1-methyl-1H-imidazol-4-yl)acetamido)-5-oxohexanoate


261
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(oxazol-2-yl)acetamido)-5-oxohexanoate


262
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(oxazol-2-yl)acetamido)-5-oxohexanoate


263
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(1-methyl-1H-imidazol-4-yl)acetamido)-5-oxohexanoate


264
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1-methyl-1H-imidazol-4-yl)acetamido)-5-oxohexanoate


265
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(oxazol-2-yl)acetamido)-5-oxohexanoate


266
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(oxazol-2-yl)acetamido)-5-oxohexanoate


267
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(thiophen-2-yl)acetamido)-5-oxohexanoate


268
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(thiophen-3-yl)acetamido)-5-oxohexanoate


269
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(thiophen-2-yl)acetamido)-5-oxohexanoate


270
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(thiophen-3-yl)acetamido)-5-oxohexanoate


271
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(thiazol-2-yl)acetamido)-5-oxohexanoate


272
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(thiazol-2-yl)acetamido)-5-oxohexanoate


273
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(1-methyl-1H-imidazol-2-yl)acetamido)-5-oxohexanoate


274
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1-methyl-1H-imidazol-2-yl)acetamido)-5-oxohexanoate


275
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(thiazol-5-yl)acetamido)-5-oxohexanoate


276
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(thiazol-5-yl)acetamido)-5-oxohexanoate


277
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(1-methyl-1H-imidazol-5-yl)acetamido)-5-oxohexanoate


278
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1-methyl-1H-imidazol-5-yl)acetamido)-5-oxohexanoate


279
isopropyl (S)-2-((R)-2-(1H-imidazol-2-yl)-2-methoxyacetamido)-6-diazo-5-oxohexanoate


280
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1H-imidazol-2-yl)acetamido)-5-oxohexanoate


281
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(oxazol-5-yl)acetamido)-5-oxohexanoate


282
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(oxazol-5-yl)acetamido)-5-oxohexanoate


283
isopropyl (S)-2-((S)-2-(1H-imidazol-5-yl)-2-methoxyacetamido)-6-diazo-5-oxohexanoate


284
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(1H-imidazol-5-yl)acetamido)-5-oxohexanoate


285
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(pyridin-2-yl)acetamido)-5-oxohexanoate


286
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(pyridin-2-yl)acetamido)-5-oxohexanoate


287
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(pyrimidin-4-yl)acetamido)-5-oxohexanoate


288
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(pyrimidin-4-yl)acetamido)-5-oxohexanoate


289
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(pyrimidin-2-yl)acetamido)-5-oxohexanoate


290
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(pyrimidin-2-yl)acetamido)-5-oxohexanoate


291
isopropyl (S)-6-diazo-2-((S)-2-(3-fluoropyridin-4-yl)-2-methoxyacetamido)-5-oxohexanoate


292
isopropyl (S)-6-diazo-2-((S)-2-(3-fluoropyridin-4-yl)-2-hydroxyacetamido)-5-oxohexanoate


293
isopropyl (S)-6-diazo-2-((S)-2-(5-fluoropyridin-2-yl)-2-methoxyacetamido)-5-oxohexanoate


294
isopropyl (S)-6-diazo-2-((S)-2-(5-fluoropyridin-2-yl)-2-hydroxyacetamido)-5-oxohexanoate


295
isopropyl (S)-6-diazo-2-((S)-2-(5-fluoropyridin-3-yl)-2-methoxyacetamido)-5-oxohexanoate


296
isopropyl (S)-6-diazo-2-((S)-2-(5-fluoropyridin-3-yl)-2-hydroxyacetamido)-5-oxohexanoate


297
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(3-methoxypyridin-4-yl)acetamido)-5-oxohexanoate


298
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(3-methoxypyridin-4-yl)acetamido)-5-oxohexanoate


299
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(5-methoxypyridin-2-yl)acetamido)-5-oxohexanoate


300
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(5-methoxypyridin-2-yl)acetamido)-5-oxohexanoate


301
isopropyl (S)-6-diazo-2-((S)-2-methoxy-2-(5-methoxypyridin-3-yl)acetamido)-5-oxohexanoate


302
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-2-(5-methoxypyridin-3-yl)acetamido)-5-oxohexanoate


303
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(5-methoxypyridin-2-yl)acetamido)-5-oxohexanoate


304
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(5-methoxypyridin-2-yl)acetamido)-5-oxohexanoate


305
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(5-methoxypyridin-3-yl)acetamido)-5-oxohexanoate


306
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(5-methoxypyridin-3-yl)acetamido)-5-oxohexanoate


307
isopropyl (S)-2-((R)-2-(1H-imidazol-5-yl)-2-methoxyacetamido)-6-diazo-5-oxohexanoate


308
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(1H-imidazol-5-yl)acetamido)-5-oxohexanoate


309
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(pyridin-2-yl)acetamido)-5-oxohexanoate


310
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(pyridin-2-yl)acetamido)-5-oxohexanoate


311
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(pyrimidin-4-yl)acetamido)-5-oxohexanoate


312
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(pyrimidin-4-yl)acetamido)-5-oxohexanoate


313
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(pyrimidin-2-yl)acetamido)-5-oxohexanoate


314
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(pyrimidin-2-yl)acetamido)-5-oxohexanoate


315
isopropyl (S)-6-diazo-2-((R)-2-(3-fluoropyridin-4-yl)-2-methoxyacetamido)-5-oxohexanoate


316
isopropyl (S)-6-diazo-2-((R)-2-(3-fluoropyridin-4-yl)-2-hydroxyacetamido)-5-oxohexanoate


317
isopropyl (S)-6-diazo-2-((R)-2-(5-fluoropyridin-2-yl)-2-methoxyacetamido)-5-oxohexanoate


318
isopropyl (S)-6-diazo-2-((R)-2-(5-fluoropyridin-2-yl)-2-hydroxyacetamido)-5-oxohexanoate


319
isopropyl (S)-6-diazo-2-((R)-2-(5-fluoropyridin-3-yl)-2-methoxyacetamido)-5-oxohexanoate


320
isopropyl (S)-6-diazo-2-((R)-2-(5-fluoropyridin-3-yl)-2-hydroxyacetamido)-5-oxohexanoate


321
isopropyl (S)-6-diazo-2-((R)-2-methoxy-2-(3-methoxypyridin-4-yl)acetamido)-5-oxohexanoate


322
isopropyl (S)-6-diazo-2-((R)-2-hydroxy-2-(3-methoxypyridin-4-yl)acetamido)-5-oxohexanoate


323
tert-butyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


324
phenyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


325
benzyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


326
cyclohexyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


327
cycloheptyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


328
cyclooctyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


329
cyclooctyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


330
tert-butyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


331
phenyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


332
benzyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


333
cyclohexyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


334
cycloheptyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


335
1-methylpiperidin-4-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


336
pyridin-4-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


337
pyridin-4-ylmethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


338
tetrahydro-2H-pyran-4-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


339
piperidin-4-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


340
(R)-oxepan-4-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


341
(S)-oxepan-4-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


342
oxocan-5-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


343
pyridin-4-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


344
pyridin-4-ylmethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


345
tetrahydro-2H-pyran-4-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


346
piperidin-4-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


347
(R)-oxepan-4-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


348
(S)-oxepan-4-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


349
oxocan-5-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


350
trifluoromethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


351
2,2,2-trifluoroethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


352
(S)-1,1,1-trifluoropropan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


353
3,3,3-trifluoropropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


354
(S)-4,4,4-trifluorobutan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


355
1,1,1-trifluoro-2-methylpropan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


356
4,4,4-trifluoro-2-methylbutan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


357
cyanic (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic anhydride


358
cyanomethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


359
(S)-1-cyanoethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


360
2-cyanoethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


361
1-cyanopropan-2-yl (2S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


362
2-cyanopropan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


363
1-cyano-2-methylpropan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


364
hydroxymethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


365
methoxymethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


366
ethoxymethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


367
isopropoxymethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


368
cyclopropoxymethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


369
cyclobutoxymethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


370
trifluoromethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


371
2,2,2-trifluoroethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


372
(S)-1,1,1-trifluoropropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


373
(R)-1,1,1-trifluoropropan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


374
(R)-4,4,4-trifluorobutan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


375
(R)-1-cyanoethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


376
(R)-1-cyanopropan-2-yl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


377
(R)-1,1,1-trifluoropropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


378
3,3,3-trifluoropropyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


379
(S)-4,4,4-trifluorobutan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


380
(R)-4,4,4-trifluorobutan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


381
1,1,1-trifluoro-2-methylpropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


382
4,4,4-trifluoro-2-methylbutan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


383
cyanic (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoic anhydride


384
cyanomethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


385
(S)-1-cyanoethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


386
(R)-1-cyanoethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


387
2-cyanoethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


388
(S)-1-cyanopropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


389
(R)-1-cyanopropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


390
2-cyanopropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


391
1-cyano-2-methylpropan-2-yl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


392
hydroxymethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


393
methoxymethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


394
ethoxymethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


395
isopropoxymethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


396
cyclopropoxymethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


397
cyclobutoxymethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


398
2-(pyrrolidin-1-yl)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


399
2-methoxyethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


400
2-ethoxyethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


401
2-isopropoxyethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


402
2-aminoethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


403
2-(methylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


404
2-(dimethylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


405
2-(ethylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


406
2-(isopropylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


407
2-(cyclopropylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


408
2-(cyclobutylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


409
2-(cyclopentylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


410
2-(cyclohexylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


411
2-(azetidin-1-yl)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


412
2-(piperidin-1-yl)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


413
2-(azepan-1-yl)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


414
2-(azocan-1-yl)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


415
2-morpholinoethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


416
2-(phenylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


417
2-(pyridin-4-ylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


418
2-(benzylamino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


419
2-((pyridin-4-ylmethyl)amino)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


420
2-(4-methylpiperazin-1-yl)ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


421
2-methoxyethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


422
2-ethoxyethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


423
2-isopropoxyethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


424
2-aminoethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


425
2-(methylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


426
2-(dimethylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


427
2-(ethylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


428
2-(isopropylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


429
2-(cyclopropylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


430
2-(cyclobutylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


431
2-(cyclopentylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


432
2-(cyclohexylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


433
2-(azetidin-1-yl)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


434
2-(piperidin-1-yl)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


435
2-(azepan-1-yl)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


436
2-(azocan-1-yl)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


437
2-morpholinoethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


438
2-(phenylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


439
2-(pyridin-4-ylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


440
2-(benzylamino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


441
2-((pyridin-4-ylmethyl)amino)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


442
2-(4-methylpiperazin-1-yl)ethyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate


443
isopropyl (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoate


444
isopropyl (S)-6-diazo-2-(2-hydroxy-2-methylpropanamido)-5-oxohexanoate


445
methyl (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoate


446
methyl (S)-6-diazo-2-((S)-2-hydroxy-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


447
methyl (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5-oxohexanoate


448
methyl (S)-6-diazo-2-(2-isopropoxyacetamido)-5-oxohexanoate


449
(S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoic acid


450
isopropyl (S)-2-((S)-2-acetoxy-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


451
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-methoxypropanamido)-6-diazo-5-oxohexanoate


452
isopropyl (S)-6-diazo-2-(2-isopropoxyacetamido)-5-oxohexanoate


453
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(1-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


454
isopropyl (S)-6-diazo-2-((R)-2-methoxy-3-(1-methyl-1H-indol-3-yl)propanamido)-5-oxohexanoate


455
isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


456
methyl (S)-6-diazo-2-((S)-2-hydroxy-2-phenylacetamido)-5-oxohexanoate


457
methyl (S)-6-diazo-2-((S)-2-methoxy-2-phenylacetamido)-5-oxohexanoate


458
methyl (S)-6-diazo-2-(2-methoxyacetamido)-5-oxohexanoate


459
S-isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanethioate


460
(S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoic acid


461
isopropyl (2S)-2-(2-acetoxy-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


462
isopropyl (2S)-2-(2-(2-cyanoacetoxy)-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


463
isopropyl (2S)-6-diazo-2-(2-((dimethylglycyl)oxy)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


464
isopropyl (2S)-2-(3-(1H-indol-3-yl)-2-(2-(2-oxopyrrolidin-1-yl)acetoxy)propanamido)-6-diazo-5-oxohexanoate


465
isopropyl (2S)-6-diazo-2-(2-hydroxy-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


466
isopropyl (S)-6-diazo-2-((S)-2-(2-hydroxyethoxy)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


467
isopropyl (S)-2-((S)-2-(2-acetamidoethoxy)-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


468
isopropyl (S)-2-((S)-2-(2-cyanoethoxy)-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


469
isopropyl (S)-2-((S)-2-(cyanomethoxy)-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


470
isopropyl (S)-6-diazo-2-((S)-2-(2-(dimethylamino)-2-oxoethoxy)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


471
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-(2-(methylamino)-2-oxoethoxy)propanamido)-6-diazo-5-oxohexanoate


472
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-(2-oxopropoxy)propanamido)-6-diazo-5-oxohexanoate


473
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)propanamido)-6-diazo-5-oxohexanoate


474
isopropyl (S)-2-((S)-2-(3-amino-3-oxopropoxy)-3-(1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate


475
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-(3-(methylamino)-3-oxopropoxy)propanamido)-6-diazo-5-oxohexanoate


476
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


477
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(1H-pyrrolo[3,2-b]pyridin-3-yl)propanamido)-5-oxohexanoate


478
isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanamido)-5-oxohexanoate


479
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)propanamido)-5-oxohexanoate


480
isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propanamido)-5-oxohexanoate


481
isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-(7-fluoro-1H-indol-3-yl)propanamido)-5-oxohexanoate


482
isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-isopropoxypropanamido)-5-oxohexanoate


483
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-phenoxypropanamido)-6-diazo-5-oxohexanoate


484
isopropyl (2S)-2-(3-(1H-indol-3-yl)-2-((methylglycyl)oxy)propanamido)-6-diazo-5-oxohexanoate


485
isopropyl (2S)-6-diazo-2-(2-(glycyloxy)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


486
isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


487
(S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoic acid


488
methyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


489
ethyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


490
S-isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanethioate


491
isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamido)-5-oxohexanoate


492
methyl-d3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


493
ethyl-2,2,2-d3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


494
isopropyl (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5-oxohexanoate


495
isopropyl (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5-oxohexanoate


496
ethyl-d5 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


497
propan-2-yl-d7 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


498
propan-2-yl-d7 (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate


499
propan-2-yl-d7 (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5-oxohexanoate


500
propan-2-yl-d7 (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate


501
S-(propan-2-yl-d7) (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanethioate


502
propan-2-yl-d7 (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoate


503
methyl-d3 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


504
ethyl-2,2,2-d3 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


505
ethyl-d5 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


506
propan-2-yl-d7 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


507
propan-2-yl-d7 (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5-oxohexanoate


508
S-(propan-2-yl-d7) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanethioate


509
propan-2-yl-d7 (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamido)-5-oxohexanoate


510
propan-2-yl-d7 (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5-oxohexanoate


511
methyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d


512
ethyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d


513
isopropyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d


514
isopropyl 6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate-2-d


515
S-isopropyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanethioate-2-d


516
isopropyl 6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoate-2-d


517
isopropyl 6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate-2-d


518
isopropyl 6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5-oxohexanoate-2-d


519
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


520
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5-oxohexanoate


521
S-(propan-2-yl-1,1,1,3,3,3-d6) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanethioate


522
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamido)-5-oxohexanoate


523
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5-oxohexanoate


524
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate


525
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5-oxohexanoate


526
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate


527
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5-oxohexanoate


528
S-(propan-2-yl-1,1,1-d3) (2S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanethioate


529
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio)butanamido)-5-oxohexanoate


530
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5-oxohexanoate


531
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate


532
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5-oxohexanoate


533
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


534
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate


535
S-(propan-2-yl-1,1,1,3,3,3-d6) (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanethioate


536
propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoate


537
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate


538
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate


539
S-(propan-2-yl-1,1,1-d3) (2S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanethioate


540
propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5-oxohexanoate


541
methyl (S)-6-diazo-2-((S)-2-(methylthio)propanamido)-5-oxohexanoate


542
ethyl (S)-6-diazo-2-((S)-2-(methylthio)propanamido)-5-oxohexanoate


543
isopropyl (S)-6-diazo-2-((S)-2-(methylthio)propanamido)-5-oxohexanoate


544
isopropyl (S)-6-diazo-2-((S)-2-mercaptopropanamido)-5-oxohexanoate


545
isopropyl (S)-6-diazo-2-((S)-2-mercapto-3-methylbutanamido)-5-oxohexanoate


546
isopropyl (S)-6-diazo-2-(2-(ethylthio)acetamido)-5-oxohexanoate


547
S-isopropyl (S)-6-diazo-2-((S)-2-(methylthio)propanamido)-5-oxohexanethioate


548
isopropyl (S)-2-((S)-2,4-bis(methylthio)butanamido)-6-diazo-5-oxohexanoate


549
isopropyl (S)-6-diazo-2-((S)-2-(ethylthio)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


550
isopropyl (S)-2-((S)-2-(acetylthio)-4-(methylthio)butanamido)-6-diazo-5-oxohexanoate


551
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-(methylthio)propanamido)-6-diazo-5-oxohexanoate


552
isopropyl (S)-6-diazo-2-(2-(isopropylthio)acetamido)-5-oxohexanoate


553
isopropyl (S)-6-diazo-2-((S)-2-(methylthio)-3-phenylpropanamido)-5-oxohexanoate


554
isopropyl (S)-6-diazo-2-((S)-2-(methylthio)-2-phenylacetamido)-5-oxohexanoate


555
isopropyl (S)-6-diazo-2-((S)-2-(methylthio)butanamido)-5-oxohexanoate


556
isopropyl (S)-6-diazo-2-((S)-3-methyl-2-(methylthio)butanamido)-5-oxohexanoate


557
cyclopentyl (S)-6-diazo-2-((S)-2-(methylthio)propanamido)-5-oxohexanoate


558
isopropyl (S)-6-diazo-5-oxo-2-((S)-thietane-2-carboxamido)hexanoate


559
methyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)propanamido)-5-oxohexanoate


560
ethyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)propanamido)-5-oxohexanoate


561
isopropyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)propanamido)-5-oxohexanoate


562
isopropyl (2S)-6-diazo-2-(2-(ethylsulfinyl)acetamido)-5-oxohexanoate


563
S-isopropyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)propanamido)-5-oxohexanethioate


564
isopropyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)-4-(methylthio)butanamido)-5-oxohexanoate


565
isopropyl (2S)-6-diazo-2-((2S)-2-(ethylsulfinyl)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


566
isopropyl (2S)-2-((2S)-3-(1H-indol-3-yl)-2-(methylsulfinyl)propanamido)-6-diazo-5-oxohexanoate


567
isopropyl (2S)-6-diazo-2-(2-(isopropylsulfinyl)acetamido)-5-oxohexanoate


568
isopropyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)-3-phenylpropanamido)-5-oxohexanoate


569
isopropyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)-2-phenylacetamido)-5-oxohexanoate


570
isopropyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)butanamido)-5-oxohexanoate


571
isopropyl (2S)-6-diazo-2-((2S)-3-methyl-2-(methylsulfinyl)butanamido)-5-oxohexanoate


572
cyclopentyl (2S)-6-diazo-2-((2S)-2-(methylsulfinyl)propanamido)-5-oxohexanoate


573
methyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)propanamido)-5-oxohexanoate


574
ethyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)propanamido)-5-oxohexanoate


575
isopropyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)propanamido)-5-oxohexanoate


576
isopropyl (S)-6-diazo-2-(2-(ethylsulfonyl)acetamido)-5-oxohexanoate


577
S-isopropyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)propanamido)-5-oxohexanethioate


578
isopropyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)-4-(methylthio)butanamido)-5-oxohexanoate


579
isopropyl (S)-6-diazo-2-((S)-2-(ethylsulfonyl)-3-(1H-indol-3-yl)propanamido)-5-oxohexanoate


580
isopropyl (S)-2-((S)-3-(1H-indol-3-yl)-2-(methylsulfonyl)propanamido)-6-diazo-5-oxohexanoate


581
isopropyl (S)-6-diazo-2-(2-(isopropylsulfonyl)acetamido)-5-oxohexanoate


582
isopropyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)-3-phenylpropanamido)-5-oxohexanoate


583
isopropyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)-2-phenylacetamido)-5-oxohexanoate


584
isopropyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)butanamido)-5-oxohexanoate


585
isopropyl (S)-6-diazo-2-((S)-3-methyl-2-(methylsulfonyl)butanamido)-5-oxohexanoate


586
cyclopentyl (S)-6-diazo-2-((S)-2-(methylsulfonyl)propanamido)-5-oxohexanoate









Methods of Preparation

The compounds of the present invention can be prepared in a number ways well known to one skilled in the art of organic synthesis using the methods described below or variations thereon as appreciated by those skilled in the art. The references cited herein are hereby incorporated by reference in their entirety.
The methods of synthesis described herein after are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Compounds of any of the formulae described herein may be synthesized by reference to methods illustrated in the following schemes. As shown herein, the end compound is a product having the same structural formula depicted as any of formulas. It will be understood that any compound of the formulas may be prepared by the suitable selection of reagents with appropriate substitution. Solvents, temperature, pressures, and other reaction conditions may be readily selected by one of ordinary skill in the art.
For illustrative purposes, Scheme 1 and Scheme 2 show general synthetic methods for preparing the compounds described herein. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known those skilled in the art.








General routes to compounds illustrated in the invention is described in Scheme 1 and Scheme 2, where the Z, RX1, RX2, RX3, and m etc. substituents are defined previously in the text or a functional group that can be converted to the desired final substituent.
As depicted in Scheme 1 and Scheme 2, condensation reaction of the acid i with the amine ii gives iii using organic base and condensation reagents. Hydrolysis reaction of iii can provide iv using LiOH, NaOH, etc. Under organic base and condensation reagents, condensation reaction between iv and alcohols or mercaptans gives iii as a different ester or thioester.
Wherein the organic base is preferably DIPEA, NMM, 1-Methylimidazole, 2,4,6-Collidine and so on. The condensation reagents is preferably HATU, TCFH, XtalFluor-E, N,N′-Diisopropylcarbodiimide and so on.
It will be appreciated that other synthetic routes may be available for practice of the present invention.
In another aspect, provided here is a pharmaceutical composition comprising the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; and a pharmaceutically acceptable carrier, diluent or excipient.
In another aspect, provided here is a method for treating a disease or a condition, the method comprising administering to a subject in need of treatment of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof; or a pharmaceutical composition thereof, in an amount effective for treating the disease or condition. In still other aspects, the presently disclosed subject matter provides the use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof, for treating a disease or condition. In some embodiments, the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
As used herein, a “cancer” in a patient refers to the presence of cells possessing characteristics typical of cancer-causing cells, for example, uncontrolled proliferation, loss of specialized functions, immortality, significant metastatic potential, significant increase in anti-apoptotic activity, rapid growth and proliferation rate, and certain characteristic morphology and cellular markers. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells. A “tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. A “solid tumor,” as used herein, is an abnormal mass of tissue that generally does not contain cysts or liquid areas. A solid tumor may be in the brain, colon, breasts, prostate, liver, kidneys, lungs, esophagus, head and neck, ovaries, cervix, stomach, colon, rectum, bladder, uterus, testes, and pancreas, as non-limiting examples. In some embodiments, the solid tumor regresses or its growth is slowed or arrested after the solid tumor is treated with the presently disclosed methods. In other embodiments, the solid tumor is malignant. In some embodiments, the cancer comprises Stage 0 cancer. In some embodiments, the cancer comprises Stage I cancer. In some embodiments, the cancer comprises Stage II cancer. In some embodiments, the cancer comprises Stage III cancer. In some embodiments, the cancer comprises Stage IV cancer. In some embodiments, the cancer is refractory and/or metastatic. For example, the cancer may be refractory to treatment with radiotherapy, chemotherapy or monotreatment with immunotherapy. Cancer as used herein includes newly diagnosed or recurrent cancers, including without limitation, acute lymphoblastic leukemia, acute myelogenous leukemia, advanced soft tissue sarcoma, brain cancer, metastatic or aggressive breast cancer, breast carcinoma, bronchogenic carcinoma, choriocarcinoma, chronic myelocytic leukemia, colon carcinoma, colorectal carcinoma, Ewing's sarcoma, gastrointestinal tract carcinoma, glioma, glioblastoma multiforme, head and neck squamous cell carcinoma, hepatocellular carcinoma, Hodgkin's disease, intracranial ependymoblastoma, large bowel cancer, leukemia, liver cancer, lung carcinoma, Lewis lung carcinoma, lymphoma, malignant fibrous histiocytoma, a mammary tumor, melanoma, mesothelioma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, a pontine tumor, premenopausal breast cancer, prostate cancer, rhabdomyosarcoma, reticulum cell sarcoma, sarcoma, small cell lung cancer, a solid tumor, stomach cancer, testicular cancer, and uterine carcinoma.
In yet another aspect, provided here is a method of treating a subject having a cancer, said method comprising administering to the subject a therapeutically effective amount of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention.
In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
In another aspect, provided here is use of the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for the manufacture of a medicament for the treatment of a cancer.
In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
In some embodiments, the medicament is used as a glutamine antagonist.
As used herein, the term “glutamine antagonist” refers to a glutamine analog that interferes with a glutamine metabolic pathway, e.g., the inhibition or blocking of a metabolic pathway downstream of glutamine in which glutamine acts as a precursor of one or more non-glutamine compounds. Examples of such metabolic pathways are well known (see, e.g., Hensley et al, “Glutamine and cancer: cell biology, physiology, and clinical opportunities” J Clin Invest. 2013; 123(9):3678-3684; DeBerardinis et al, “Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer” Oncogene. 2009; 29(3):313-324; and Medina et al, “Relevance of glutamine metabolism to tumor cell growth” Mol Cell Biochem. 1992; 113(1): 1-15). In some contexts, the term glutamine antagonist also includes glutamine analogs that inhibit glutamine uptake by cells, thereby reducing its biological activity. Diseases or conditions wherein excess and/or aberrant glutamine.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for use in therapy.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for use as a medicament.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention, for use in treating the disease or condition. In some embodiments, the disease or condition is selected from the group consisting of an infection, cancer, an autoimmune disease, an inflammatory disease, and a neurodegenerative or neurological disease.
In yet another aspect, provided here is the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof of the present invention; or the pharmaceutical composition of the present invention for use in the treatment of a cancer.
In some embodiments, the cancer is selected from lung cancer, pancreatic cancer, liver cancer, breast cancer, colon cancer, leukemia, glioblastoma or head and neck cancer.
The compounds provided herein used as active ingredient, are characterized by improved solubility, improved stability, improved safety, improved pKa properties, and high pharmacokinetics.



BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the plasma stability of compounds after incubation for 4 hours in the presence of dog, monkey, swine and human plasma.
FIG. 2 shows the body weight changes following administration of Reference compound A and Compound 2 in C57BL/6 mice bearing MC38 tumors.
FIG. 3 shows the anti-tumor efficacy of Reference compound A and Compound 2 in C57BL/6 mice bearing MC38 tumors.
FIG. 4 shows the body weight changes following administration of Reference compound A and Compound 2 in CES1−/− mice bearing MC38 tumors.
FIG. 5 shows the anti-tumor efficacy of Reference compound A and Compound 2 in CES1−/− mice bearing MC38 tumors.
FIG. 6 shows the body weight changes following administration of Compound 2, compound 3, compound 81, compound 443 and compound 459 in C57BL/6 mice bearing MC38 tumors.
FIG. 7 shows the anti-tumor efficacy of Compound 2, compound 3, compound 81, compound 443 and compound 459 in C57BL/6 mice bearing MC38 tumors.



DEFINITION
The term “halogen”, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include F, Cl and Br. The terms “haloC1-6alkyl”, “haloC2-6alkenyl”, “haloC2-6alkynyl” and “haloC1-6alkoxy” mean a C1-6alkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embodiment, preferred are fluoroC1-6alkyl, fluoroC2-6alkenyl, fluoroC2-6alkynyl and fluoroC1-6alkoxy groups, in particular fluoroC1-3alkyl, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3 and fluoroC1-3alkoxy groups, for example, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, cyclobutyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C1-6, as in C1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
The term “alkylene” means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., —CH2—), ethylene (i.e., —CH2—CH2— or —CH(CH3)—) and propylene (i.e., —CH2—CH2—CH2—, —CH(—CH2—CH3)— or —CH2—CH(CH3)—).
The term “alkenyl” means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, “C2-6alkenyl” contains from 2 to 6 carbon atoms. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
The term “alkynyl” contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, “C2-6alkynyl” contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
The term “alkoxy” radicals are oxygen ethers formed from the previously described alkyl groups.
The term “aryl”, as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
The term “heterocyclyl”, as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising monocyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or spiro heterocyclic ring. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition. Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.
The term “heteroaryl”, as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon(s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms). Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.
The term “cycloalkyl” refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, spiro ring non-aromatic ring system one containing carbon atoms. Exemplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
wherein the term “substituted” refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, T, C1-6alkyl, C1-6alkoxy, C3-20 cycloalkyl, —OR13, SR13, ═O, ═S, —C(O)R13, —C(S)R13, ═NR13, —C(O)OR13, —C(S)OR13, —NR13R14, —C(O)NR13R14, cyano, nitro, —S(O)2R13, —OS(O2)OR13, —OS(O)2R13, or —OP(O)(OR13)(OR14); wherein each T is independently a halogen (F, Cl, Br or I), and R13 and R14 is independently selected from —H, C1-6 alkyl and C1-6 haloalkyl. In some embodiments, the substituent(s) is independently selected from the group consisting of —F, —Cl, —Br, —I, —OH, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, CHF2, methoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, —SCH3, —SC2H5, formaldehyde group, —C(OCH3), cyano, nitro, CF3, —OCF3, amino, dimethylamino, methyl thio, sulfonyl and acetyl. Particularly preferred substituent(s) is —F, —Cl or —Br.
The term “composition”, as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
The compounds of the present invention may also be present in the form of pharmaceutically acceptable salt(s). For use in medicine, the salts of the compounds of this invention refer to non-toxic “pharmaceutically acceptable salt(s)”. The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.
The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.
The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
The term “stereoisomer” as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as 1H(hydrogen), 2H(deuterium) and 3H(tritium). They are also commonly denoted as D for deuterium and T for tritium. In the application, CD3 denotes a methyl group wherein all of the hydrogen atoms are deuterium. Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
When a tautomer of the compound exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.
When the compound and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.
The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).
The pharmaceutical compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
In practice, the compounds or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.
A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.01 mg to about 2 g of the active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.
Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.
Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.
Generally, dosage levels on the order of from about 0.001 mg/kg to about 150 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), may be effectively treated by the administration of from about 0.001 to 50 mg of the compound per kilogram of body weight per day or alternatively about 0.05 mg to about 3.5 g per patient per day.
It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
These and other aspects will become apparent from the following written description of the invention.
EXAMPLES
The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:













DMF
N,N-Dimethylformamide


EA
Ethyl acetate


MeONa
Sodium methanolate


MeOH
Methanol


DCM
Dichloromethane


DCE
1,2-Dichloroethane


EtOH
Ethanol


THF
Tetrahydrofuran


MeCN
Acetonitrile


NMM
4-Methylmorpholine


DIPEA
N,N-Diisopropylethylamine


TEA
Triethylamine


Ts
4-methyl benzenesulfonyl


HATU
2-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-



tetramethyluronium



hexafluorophosphate


XtalFluor-E
N,N-Diethyl-S,S-difluorosulfiliminium



tetrafluoroborate


TCFH
N-(chloro(dimethylamino)methylene)-N-



methylmethanaminium



hexafluorophosphate(V)


BOP
1H-Benzotriazol-1-yloxytris(dimethylamino)phosphonium



Hexafluorophosphate


RT
Room temperature


min
minute(s)


h
hour(s)


aq
aqueous


sat
saturated


FLASH
Medium pressure chromatograph


Prep - TLC
Preparative thin layer chromatography


Pre-HPLC
High pressure chromatograph









Intermediate A1




Intermediate A1 was prepared referring to the compound 3 in WO2017023774 in Scheme 1 at page 82.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.




Intermediate B1




Step a: To a solution of 7-Fluoroindole (308 mg, 2.279 mmol) and Ytterbium(III) triflate hydrate (219 mg, 343.119 μmol) in Chloroform (3 mL) was added (2S)-Methylglycidate (121 mg, 1.185 mmol) under N2. The mixture was heated to 85° C. and stirred for 3 h. The reaction mixture was cooled to RT. The reaction mixture was quenched with Na2CO3 (aq) (10 mL), and adjusted the pH to 5-6 with 2M HCl. The aqueous layer was separated and extracted with DCM (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with EtOAc/Hexane(1:2) to afford methyl (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoate (136 mg, 573.292 μmol). MS: m/z 238(M+H)+.
Step b: To a solution of methyl (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoate (136 mg, 573.292 μmol) in water (1 mL) was added LiOH (2M solution in water, 1 mL). The mixture was stirred for overnight at RT-60° C., Citric acid(solid) was added, diluted with water (5 mL) and extracted with EA (2×10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoic acid (165 mg, 739.247 mol) which was used in next step without any further purification. MS: m/z (224)+.
Intermediate B2




Step a: To a solution of Indole (302 mg, 2.578 mmol) in DMF (3 mL) was added NaH (217 mg, 9.043 mmol) at ice-water bath for 1 h. (2S)-Methylglycidate (685 mg, 6.710 mmol) was added and the mixture was stirred over night at RT. The reaction mixture was quenched with H2O, and adjusted the pH to 3-4 with citric acid. The aqueous layers were extracted with EA. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by FLASH with H2O/MeCN (5%-˜95%) to afford (S)-2-hydroxy-3-(1H-indol-1-yl)propanoic acid (222 mg, 1.082 mmol). MS: m/z 206(M+H)+.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.










Intermediate C1




Step a: To a solution of Methyl (S)-(−)-lactate (1099 mg, 10.5567 mmol), Iodoethane (3726 mg, 23.8900 mmol) in Diethyl ether (10 mL) was added Ag2O (4772 mg, 20.5925 mmol) under N2. The reaction mixture was stirred over night at RT by light-avoiding. The reaction mixture was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by THF (3 mL), MeOH (3 mL), H2O (3 mL) and then the reaction mixture was added LiOH (246 mg, 10.2721 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was monitored by TLC and adjusted the pH to 2 with 1N HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layers were extracted with EA (3×10 mL). The combined organic layers were washed with saturated solution of NaCl (3×10 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (S)-2-ethoxypropanoic acid (772 mg, 6.5351 mmol). MS: m/z 119(M+H)+.
Intermediate C2




Step a: To a solution of 2-hydroxy-4-(methylthio)butanoic acid (0.68 g, 4.5274 mmol), CH3I (3.35 g, 23.6019 mmol) in Diethyl ether (10 mL) was added Ag2O (4.41 g, 19.0303 mmol). The reaction mixture was stirred over night at RT. The reaction mixture was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by MeOH (6 mL), H2O (2 mL) and then the reaction mixture was added NaOH (318 mg, 7.9506 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was monitored by TLC and adjusted the pH to 3 with 1M HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layers were extracted with EA (3×10 mL). The combined organic layers were washed with saturated solution of NaCl (3×10 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2-methoxy-4-(methylthio)butanoic acid (128 mg, 779.4318 μmol). MS: m/z 165(M+H)+.
Intermediate C3




Step a: To a solution of 2-hydroxy-3-(1H-indol-3-yl)propanoic acid (152 mg, 740.706 mol) in THF (10 mL) was added NaH (55 mg, 2.292 mmol). The reaction mixture was stirred for 20 min at RT and then CH3I (370 mg, 2.607 mmol) was added. The reaction mixture was monitored by LC-MS. CH3I (358 mg, 2.522 mmol) was added again. The reaction mixture was monitored by LC-MS. The reaction mixture was stirred for 3 h at 40° C. The reaction mixture was added H2O (5 mL) and extracted with EA (10 mL). The aqueous layers were combined and purified by FLASH with H2O/MeCN (0%-100%, 40 min, C18). The product layers were concentrated under reduced pressure to afford 2-methoxy-3-(1-methyl-1H-indol-3-yl)propanoic acid (119 mg, 510.155 μmol). MS: m/z 234 (M+H)+.
The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.































Intermediate D1




Step a: To a solution of methyl (S)-2-hydroxy-3-(1H-indol-3-yl)propanoate(2 g, 9.123 mmol) in DCM (20 mL) was added Imidazole(2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol). The mixture was stirred for overnight at RT. The reaction mixture was quenched with Water (10 mL) and extracted with DCM (10 mL). The reaction mixture was separated and organic extracts were collected. The aqueous solution was extracted with DCM (2×10 mL). The residue was purified by wet column chromatography with EA/Hex (0-20%). The product's solution was concentrated under reduced pressure. The methyl (S)-2-((tert-butyldimethylsilyl)oxy)-3-(1H-indol-3-yl)propanoate (3099 mg) was obtained. MS: m/z 334(M+H)+.
Step b: To a −78° C. solution of methyl (S)-2-((tert-butyldimethylsilyl)oxy)-3-(1H-indol-3-yl)propanoate (3.099 g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol). The mixture was stirred for 30 min at −78° C. Then Carbobenzyloxy chloride (4623 mg, 27.100 mmol) was dropped into the mixture at −78° C. The reaction mixture was stirred for 1 h at this temperature. Quenched the reaction with sat. NH4Cl, and the aqueous solution was extracted with EA (2×10 mL). The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure. The benzyl (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (4345 mg) was obtained. MS: m/z 468(M+H)+.
Step c: To a solution of benzyl(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (4.345 g, 9.292 mmol) in THF (30 mL) was added Tetrabutylammonium fluoride (5 mL). The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH with EA/Hex(0-60%). The product's solution was concentrated under reduced pressure. The benzyl 3-[(2S)-2-hydroxy-3-methoxy-3-oxo-propyl]indole-1-carboxylate (2.21 g) was obtained. MS: m/z 354(M+H)+.
Step d: To a solution of benzyl 3-[(2S)-2-hydroxy-3-methoxy-3-oxo-propyl]indole-1-carboxylate(103 mg, 291.481 μmol), and 4 Å molecular sieve in CH3I (1 mL) was added Silver oxide(216 mg, 932.098 μmol). The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5 mL) and filtered, the filtrate was concentrated to afford benzyl (S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate (107.088 mg, 100.000% yield). MS: m/z 368(M+H)+.
Step e: To a solution of benzyl(S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate (0.107 g, 291.240 μmol) in THF (5 mL) and MeOH(5 mL) was added NaOH(3 mL, 3M/L). The mixture was stirred for 1 h at RT. The reaction mixture was adjusted the pH to 3 with 1M HCl. The aqueous solution was extracted with EA (2×10 mL). The combined organic extracts were washed with brine (3×10 mL), dried over anhydrous Na2SO4. The organic phase was concentrated under reduced pressure and (S)-3-(1H-indol-3-yl)-2-methoxypropanoic acid (71 mg) was obtained. MS: m/z 220(M+H)+.
The following compounds were synthesized using intermediate D1 and the above procedure or modification procedure with the corresponding starting materials.













Example 1
Isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate (Compound 1)




To a solution of (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoic acid (0.165 g, 739.247 μmol) and isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoate(123 mg, 576.834 μmol) in DCM (2 mL) was added N,N′-Diisopropylcarbodiimide (95 mg, 752.779 μmol), 2,4,6-Collidine (115 mg, 949.008 μmol) and
Ethyl cyanoglyoxylate-2-oxime (83 mg, 584.044 μmol) at 0° C. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC, and concentrated under reduced pressure to afford isopropyl (2S)-6-diazo-2-[[(2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoyl]amino]-5-oxo-hexanoate (41.6 mg, 99.422 μmol) by lyophilization. MS: m/z 419(M+H)+, 1H NMR (400 MHz, CDCl3) δ 8.47-8.39 (m, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.21-7.19 (m, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.05 (td, J=7.9, 4.8 Hz, 1H), 6.93 (dd, J=10.8, 7.8 Hz, 1H), 5.09 (s, 1H), 5.03 (dt, J=12.5, 6.3 Hz, 1H), 4.53-4.45 (m, 1H), 4.43 (s, 1H), 3.29 (ddd, J=21.3, 14.8, 5.4 Hz, 2H), 2.73-2.60 (m, 1H), 2.43-2.25 (m, 1H), 2.18-1.98 (m, 2H), 1.97-1.80 (m, 1H), 1.30-1.22 (m, 6H).
Example 2
Isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (Compound 2)




To a solution of (S)-2-methoxypropanoic acid (267 mg, 2.565 mmol) and isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoate(0.152 g, 712.835 μmol) in DMF (5 mL) was added N,N′-Diisopropylcarbodiimide (327 mg, 2.591 mmol), 2,4,6-Collidine (412 mg, 3.400 mmol) and Ethyl cyanoglyoxylate-2-oxime (375 mg, 2.639 mmol) at 0° C. The mixture was stirred at RT for 15 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (50 mL×3) and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=5-100%, 40 min) and concentrated under reduced pressure to afford isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (60.2 mg, 201.1211 μmol, easily dissolved in water). MS: m/z 300(M+H)+, 1H NMR (400 MHz, CDCl3) δ 7.22-7.08 (m, 1H), 5.12-5.01 (m, 1H), 4.57 (td, J=8.7, 4.8 Hz, 1H), 3.77 (dt, J=6.7, 5.7 Hz, 1H), 3.45 (s, 3H), 2.82-2.58 (m, 1H), 2.50-2.22 (m, 2H), 2.09-1.85 (m, 1H), 1.44-1.35 (m, 3H), 1.31-1.26 (m, 6H).
Example 3
Methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (Compound 3)




To a solution of (S)-2-methoxypropanoic acid (2.06 g, 19.7879 mmol) and methyl (S)-2-amino-6-diazo-5-oxohexanoate (2308 mg, 12.4635 μmol) in DMF (5 mL) was added NMM (3.73 g, 36.8770 mmol) and HATU (6.26 g, 16.4637 mmol) at 0° C. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=0-100%, min) and concentrated under reduced pressure to afford methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (2.87 g, 10.5799 mmol, easily dissolved in water). MS: m/z 272(M+H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 4.46 (dd, J=8.9, 4.8 Hz, 1H), 3.79-3.74 (m, 1H), 3.72 (s, 3H), 3.40 (s, 3H), 2.43 (s, 2H), 2.33-2.15 (m, 1H), 2.08-1.90 (m, 1H), 1.33 (d, J=6.7 Hz, 3H).
Example 4
(S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid (Compound 4)




To a solution of methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (0.96 g, 3.5389 mmol) in THF (10 mL) was added a solution of NaOH (176 mg, 4.4003 mmol) in water (5 mL) at 0° C. The mixture was stirred at RT for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=0-80%, 30 min) and concentrated under reduced pressure to afford (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid (866 mg, 3.3665 mmol, easily dissolved in water). MS: m/z 258(M+H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 4.27 (t, J=5.8 Hz, 1H), 3.72 (q, J=6.6 Hz, 1H), 3.40 (s, 3H), 2.46-2.27 (m, 2H), 2.28-2.13 (m, 1H), 2.06-1.91 (m, 1H), 1.33 (d, J=6.7 Hz, 3H).
Example 5
Isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate (Compound 5)




To a solution of isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate (0.166 g, 396.7325 mol) in DMF (3.5 mL) was added pyridine (189 mg, 2.3894 mmol) and acetic anhydride (104 mg, 1.0187 mmol) at RT. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=2-80%) and concentrated under reduced pressure to afford isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate (75.2 mg, 163.3196 μmol). MS: m/z 461(M+H)+, 1H NMR (400 MHz, CD3OD) δ 7.39 (d, J=7.9 Hz, 1H), 7.17 (s, 1H), 6.96 (dd, J=13.4, 6.4 Hz, 1H), 6.88-6.76 (m, 1H), 5.24 (t, J=5.4 Hz, 1H), 4.96 (dt, J=12.4, 6.3 Hz, 1H), 4.27 (d, J=8.7 Hz, 1H), 3.28 (d, J=5.6 Hz, 2H), 2.26-2.13 (m, 1H), 2.10 (s, 3H), 2.05 (d, J=10.2 Hz, 2H), 1.88-1.75 (m, 1H), 1.22 (t, J=6.8 Hz, 6H).
Example 6
Ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (Compound 6)




To a solution of (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid (104 mg, 404.2870 mol) and EtOH (96 mg, 2.0839 mmol) in DMF (5 mL) was added NMM (117 mg, 1.1567 mmol) and HATU (237 mg, 623.3081 μmol) at 0° C. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=0-100%, min) and concentrated under reduced pressure to afford ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (0.0332 g, 116.3705 mol, easily dissolved in water). MS: m/z 286(M+H)+, 1H NMR (400 MHz, CD3OD) δ 4.49-4.35 (m, 1H), 4.23-4.13 (m, 2H), 3.83-3.71 (m, 1H), 3.44-3.35 (m, 3H), 2.43 (s, 2H), 2.30-2.15 (m, 1H), 2.08-1.93 (m, 1H), 1.36-1.31 (m, 3H), 1.29-1.24 (m, 3H).
The following compounds were synthesized using the above procedure or modification procedure of the above schemes with the corresponding starting materials.













Com-





pound
Structure
IUPAC Name
1HNMR & MS: (M + H)+


















7




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(7- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
MS: m/z 431 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.08- 4.95 (m, 2H), 4.47 (td, J = 8.1, 4.3 Hz, 1H), 4.40 (dd, J = 10.6, 4.9 Hz, 1H), 3.94 (s, 3H), 3.26 (ddd, J = 21.3, 14.7, 5.5 Hz, 2H), 2.66 (d, J = 4.9 Hz, 1H), 2.15-2.01 (m, 2H), 2.01-1.80 (m, 2H), 1.24 (dd, J = 7.6, 6.4 Hz, 6H).


 


8




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate
MS: m/z 401 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J = 20.1 Hz, 1H), 7.70 (t, J = 8.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.19-6.98 (m, 3H), 5.03 (dd, J = 13.1, 7.0 Hz, 2H), 4.54 (s, 1H), 4.44 (s, 1H), 3.33 (dd, J = 37.0, 16.6 Hz, 2H), 2.62- 2.51 (m, 1H), 2.39-2.24 (m, 1H), 2.15-2.05 (m, 1H), 2.01-1.85 (m, 1H), 1.27 (t, J = 5.9 Hz, 6H).


 


9




isopropyl (S)-6- diazo-2-(2- methoxyacetamido)- 5-oxohexanoate
286


 


10




isopropyl (S)-6- diazo-2-(2- ethoxyacetamido)- 5-oxohexanoate
MS: m/z 300 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.08-4.95 (m, 1H), 4.46- 4.37 (m, 1H), 4.02-3.89 (m, 2H), 3.67-3.47 (m, 2H), 2.44 (s, 2H), 2.29-2.11 (m, 1H), 2.10-1.92 (m, 1H), 1.26 (s, 9H).


 


11




isopropyl (S)-6- diazo-2-((S)-2- hydroxypropanamido)- 5- oxohexanoate
MS: m/z 286 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.09-4.95 (m, 1H), 4.42- 4.32 (m, 1H), 4.18-4.08 (m, 1H), 2.42 (s, 2H), 2.30-2.13 (m, 1H), 2.08-1.88 (m, 1H), 1.40-1.31 (m, 3H), 1.26 (s, 6H).


 


12




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3- phenylpropanamido)- 5-oxohexanoate
MS: m/z 362 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.34-7.12 (m, 5H), 5.05- 4.92 (m, 1H), 4.38-4.22 (m, 2H), 3.09 (d, 1H), 2.94-2.76 (m, 1H), 2.27-1.97 (m, 3H), 1.94-1.77 (m, 1H), 1.25 (d, J = 3.7 Hz, 6H).


 


13




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3- phenylpropanamido)- 5-oxohexanoate
MS: m/z 376 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 7.35-7.17 (m, 9H), 7.02 (d, J = 8.5 Hz, 1H), 5.15 (s, 1H), 5.02 (dt, J = 12.3, 6.3 Hz, 1H), 4.55-4.44 (m, 1H), 3.95-3.87 (m, 1H), 3.46- 3.38 (m, 3H), 3.21-3.09 (m, 1H), 3.01-2.89 (m, 1H), 2.19-1.91 (m, 3H), 1.89- 1.76 (m, 1H), 1.24 (t, J = 6.2 Hz, 6H).


 


14




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-4- methylpentanamido)- 5-oxohexanoate
MS: m/z 328 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 7.08 (d, J = 7.9 Hz, 1H), 5.23 (s, 1H), 5.04-4.91 (m, 1H), 4.46 (td, J = 8.4, 4.7 Hz, 1H), 4.13-4.03 (m, 1H), 2.73- 2.55 (m, 1H), 2.41-2.28 (m, 1H), 2.20-2.09 (m, 1H), 2.02-1.90 (m, 1H), 1.87- 1.74 (m, 1H), 1.57-1.39 (m, 2H), 1.22-1.16 (m, 6H), 0.90 (dd, J = 6.6, 3.1 Hz, 6H).


 


15




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- phenylacetamido)- 5-oxohexanoate
MS: m/z 348 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.48 (d, J = 6.8 Hz, 2H), 7.42- 7.20 (m, 3H), 5.18-4.91 (m, 2H), 4.46-4.18 (m, 1H), 2.34 (s, 2H), 2.28-2.08 (m, 1H), 2.11-1.90 (m, 1H), 1.21 (s, 6H).


 


16




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- phenylacetamido)- 5-oxohexanoate
MS: m/z 362 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 34.5 Hz, 5H), 4.99 (s, 1H), 4.67 (s, 1H), 4.35 (s, 1H), 3.43 (s, 3H), 2.33 (s, 2H), 2.18 (s, 1H), 1.99 (s, 1H), 1.24 (s, 6H).


 


17




isopropyl (S)-2- ((S)-2-(2- cyanoacetoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
MS: m/z 468 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.67-7.53 (m, 1H), 7.39-7.26 (m, 1H), 7.22- 7.14 (m, 1H), 7.14-6.88 (m, 2H), 5.40-5.27 (m, 1H), 5.03-4.90 (m, 1H), 4.31- 4.11 (m, 1H), 3.32 (s, 1H), 3.24-3.08 (m, 1H), 2.22-1.58 (m, 4H), 1.22 (s, 6H).


 


18




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(pivaloyloxy) propanamido)- 6-diazo-5- oxohexanoate
MS: m/z 485 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.62 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.15- 7.08 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 5.59 (s, 1H), 5.21 (t, J = 6.0 Hz, 1H), 4.99 (dt, J = 12.4, 6.1 Hz, 1H), 4.35-4.26 (m, 1H), 3.31-3.26 (m, 2H), 2.31-2.17 (m, 1H), 2.17- 1.98 (m, 2H), 1.92-1.78 (m, 1H), 1.25 (t, J = 6.3 Hz, 6H), 1.18 (s, 9H).


 


19




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1H- indol-1- yl)propanamido)-5- oxohexanoate
MS: m/z 401 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.16 (s, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.52 (s, 1H), 5.22 (s, 1H), 5.02 (dt, J = 12.3, 6.3 Hz, 1H), 4.67-4.56 (m, 1H), 4.52-4.38 (m, 2H), 4.35-4.19 (m, 1H), 2.97- 2.88 (m, 1H), 2.33-2.20 (m, 1H), 2.19-2.07 (m, 1H), 2.01-1.86 (m, 1H), 1.29- 1.22 (m, 6H).


 


20




isopropyl (S)-6- diazo-2-((S)-2-(4- fluorophenyl)-2- hydroxyacetamido)- 5-oxohexanoate
MS: m/z 366 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.52 (t, J = 6.1 Hz, 2H), 7.09 (td, J = 8.8, 3.0 Hz, 2H), 5.06 (s, 1H), 5.00 (dq, J = 12.9, 6.4 Hz, 1H), 4.38 (td, J = 9.5, 5.0 Hz, 1H), 2.56-2.32 (m, 2H), 2.30-2.14 (m, 1H), 2.12- 1.89 (m, 1H), 1.27-1.09 (m, 6H).


 


21




isopropyl (S)-6- diazo-2-(2-((4- fluorobenzyl)oxy) acetamido)-5- oxohexanoate
MS: m/z 380 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 2H), 7.06 (t, J = 8.4 Hz, 2H), 5.13-4.98 (m, 1H), 4.67-4.48 (m, 3H), 4.06-3.87 (m, 2H), 2.57-2.30 (m, 2H), 2.31-1.85 (m, 2H), 1.32-1.19 (m, 6H).


 


22




isopropyl (S)-2- ((S)-3-(7-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
426


 


23




isopropyl (S)-2- ((S)-3-(6-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
426


 


24




isopropyl (S)-2- ((S)-3-(5-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
426


 


25




isopropyl (S)-2- ((S)-3-(4-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
426


 


26




isopropyl (S)-2- ((S)-3-(6-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
440


 


27




isopropyl (S)-2- ((S)-3-(6-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
440


 


28




isopropyl (S)-2- ((S)-3-(5-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
440


 


29




isopropyl (S)-2- ((S)-3-(4-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
440


 


30




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(6- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
431


 


31




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(5- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
431


 


32




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(4- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
431


 


33




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(6- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
445


 


34




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(5- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
445


 


35




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(4- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
445


 


36




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(7- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate
445


 


37




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1- methyl-1H- imidazol-4- yl)propanamido)-5- oxohexanoate
380


 


38




isopropyl (2S)-6- diazo-2-(2- hydroxy-3-(1H- indol-3-yl)-2- methylpropanamido)- 5-oxohexanoate
415


 


39




isopropyl (S)-6- diazo-2-((S)-3-(6- fluoro-1H-indol-3- yl)-2- hydroxypropanamido)- 5- oxohexanoate
419


 


40




isopropyl (S)-6- diazo-2-((S)-3-(5- fluoro-1H-indol-3- yl)-2- hydroxypropanamido)- 5- oxohexanoate
419


 


41




isopropyl (S)-6- diazo-2-((S)-3-(4- fluoro-1H-indol-3- yl)-2- hydroxypropanamido)- 5- oxohexanoate
419


 


42




isopropyl (S)-6- diazo-2-((S)-3-(7- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate
433


 


43




isopropyl (S)-6- diazo-2-((S)-3-(6- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate
433


 


44




isopropyl (S)-6- diazo-2-((S)-3-(5- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate
433


 


45




isopropyl (S)-6- diazo-2-((S)-3-(4- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate
433


 


46




isopropyl (S)-2- ((S)-3-(7-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
435


 


47




isopropyl (S)-2- ((S)-3-(6-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
435


 


48




isopropyl (S)-2- ((S)-3-(5-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
435


 


49




isopropyl (S)-2- ((S)-3-(4-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
435


 


50




isopropyl (S)-2- ((S)-3-(7-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
449


 


51




isopropyl (S)-2- ((S)-3-(6-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
449


 


52




isopropyl (S)-2- ((S)-3-(5-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
449


 


53




isopropyl (S)-2- ((S)-3-(4-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
449


 


54




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(7- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
415


 


55




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(6- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
415


 


56




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(5- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
415


 


57




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(4- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
415


 


58




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(7- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
429


 


59




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(6- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
429


 


60




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(5- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
429


 


61




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(4- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
429


 


62




isopropyl (S)-6- diazo-2-((S)-3-(7- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5-oxohexanoate
444


 


63




isopropyl (S)-6- diazo-2-((S)-3-(6- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5- oxohexanoate
444


 


64




isopropyl (S)-6- diazo-2-((S)-3-(5- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5- oxohexanoate
444


 


65




isopropyl (S)-6- diazo-2-((S)-3-(4- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5- oxohexanoate
444


 


66




isopropyl (S)-6- diazo-2-((S)-3-(7- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate
458


 


67




isopropyl (S)-6- diazo-2-((S)-3-(6- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate
458


 


68




isopropyl (S)-6- diazo-2-((S)-3-(5- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate
458


 


69




isopropyl (S)-6- diazo-2-((S)-3-(4- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate
458


 


70




S-isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanethioate
MS: 417 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.63 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.01 (m, 1H), 5.24 (s, 1H), 4.44 (t, J = 4.8 Hz, 1H), 4.31 (m, 1H), 3.60-3.47 (m, 1H), 3.26-3.17 (m, 2H), 2.11 (s, 1H), 2.03-1.87 (m, 1H), 1.66 (m, 2H), 1.28 (m, 3H), 1.27 (d, J = 2.6 Hz, 3H).


 


71




isopropyl (S)-6- diazo-2-((S)-2- ethoxypropanamido)- 5-oxohexanoate
MS: 314 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.39 (dd, J = 9.0, 4.9 Hz, 1H), 3.84 (q, J = 6.8 Hz, 1H), 3.66-3.45 (m, 2H), 2.43 (s, 2H), 2.27-1.92 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.28-1.21 (m, 9H).


 


72




isopropyl (S)-6- diazo-2-((S)-2- isopropoxypropanamido)- 5- oxohexanoate
328


 


73




isopropyl (S)-2- ((S)-2- cyclopropoxypropanamido)- 6-diazo-5- oxohexanoate
326


 


74




isopropyl (S)-6- diazo-2-(2- hydroxyacetamido)- 5-oxohexanoate
MS: 272 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.02 (dt, J = 12.5, 6.2 Hz, 1H), 4.44 (dd, J = 8.7, 5.1 Hz, 1H), 4.01 (s, 2H), 2.44 (s, 2H), 2.30-1.95 (m, 2H), 1.26 (d, J = 6.2 Hz, 6H).


 


75




isopropyl (S)-2-(2- cyclopropoxyacetamido)- 6-diazo-5- oxohexanoate
312


 


76




isopropyl (S)-6- diazo-2-((S)-2- hydroxybutanamido)- 5-oxohexanoate
300


 


77




isopropyl (S)-6- diazo-2-((S)-2- methoxybutanamido)- 5-oxohexanoate
MS: 314 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 5.02 (dt, J = 12.3, 6.3 Hz, 1H), 4.41 (dd, J = 9.3, 4.8 Hz, 1H), 3.62- 3.55 (m, 1H), 3.41 (s, 3H), 2.44 (s, 2H), 2.27-1.91 (m, 2H), 1.86-1.59 (m, 2H), 1.26 (dd, J = 6.1, 3.4 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H).


 


78




isopropyl (S)-6- diazo-2-((S)-2- ethoxybutanamido)- 5-oxohexanoate
328


 


79




isopropyl (S)-6- diazo-2-((S)-2- isopropoxybutanamido)- 5- oxohexanoate
342


 


80




isopropyl (S)-2- ((S)-2- cyclopropoxybutanamido)- 6-diazo-5- oxohexanoate
340


 


81




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3- methylbutanamido)- 5-oxohexanoate
MS: 314 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.80 (s, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.39 (dd, J = 8.7, 5.1 Hz, 1H), 3.86 (d, J = 3.8 Hz, 1H), 2.43 (s, 2H), 2.25-1.91 (m, 3H), 1.30- 1.21 (m, 6H), 1.01 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).


 


82




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3- methylbutanamido)- 5-oxohexanoate
MS: 328 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.02 (dt, J = 12.5, 6.2 Hz, 1H), 4.41 (dd, J = 9.2, 4.9 Hz, 1H), 3.41 (s, 3H), 3.38 (d, J = 5.2 Hz, 1H), 2.45 (s, 2H), 2.26-2.14 (m, 1H), 2.06-1.92 (m, 2H), 1.26 (dd, J = 6.1, 3.8 Hz, 6H), 0.98 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H).


 


83




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3- methylbutanamido)- 5-oxohexanoate
342


 


84




isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-3- methylbutanamido)- 5-oxohexanoate
356


 


85




isopropyl (S)-2- ((S)-2- cyclopropoxy-3- methylbutanamido)- 6-diazo-5- oxohexanoate
354


 


86




isopropyl (S)-6- diazo-2-((2S,3R)-2- hydroxy-3- methylpentanamido)- 5-oxohexanoate
328


 


87




isopropyl (S)-6- diazo-2-((2S,3R)-2- methoxy-3- methylpentanamido)- 5-oxohexanoate
342


 


88




isopropyl (S)-6- diazo-2-((2S,3R)-2- ethoxy-3- methylpentanamido)- 5-oxohexanoate
356


 


89




isopropyl (S)-6- diazo-2-((2S,3R)-2- isopropoxy-3- methylpentanamido)- 5-oxohexanoate
370


 


90




isopropyl (S)-2- ((2S,3R)-2- cyclopropoxy-3- methylpentanamido)- 6-diazo-5- oxohexanoate
368


 


91




isopropyl (S)-6- diazo-2-((S)-2- hydroxypentanamido)- 5-oxohexanoate
314


 


92




isopropyl (S)-6- diazo-2-((S)-2- methoxypentanamido)- 5- oxohexanoate
328


 


93




isopropyl (S)-6- diazo-2-((S)-2- ethoxypentanamido)- 5-oxohexanoate
342


 


94




isopropyl (S)-6- diazo-2-((S)-2- isopropoxypentanamido)- 5- oxohexanoate
356


 


95




isopropyl (S)-2- ((S)-2- cyclopropoxypentanamido)- 6-diazo-5- oxohexanoate
354


 


96




isopropyl (S)-6- diazo-2-((S)-2- methoxy-4- methylpentanamido)- 5-oxohexanoate
342


 


97




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-4- methylpentanamido)- 5-oxohexanoate
356


 


98




isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-4- methylpentanamido)- 5-oxohexanoate
370


 


99




isopropyl (S)-2- ((S)-2- cyclopropoxy-4- methylpentanamido)- 6-diazo-5- oxohexanoate
368


 


100




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3,3- dimethylbutanamido)- 5-oxohexanoate
328


 


101




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3,3- dimethylbutanamido)- 5-oxohexanoate
342


 


102




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3,3- dimethylbutanamido)- 5-oxohexanoate
356


 


103




isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-3,3- dimethylbutanamido)- 5-oxohexanoate
370


 


104




isopropyl (S)-2- ((S)-2- cyclopropoxy-3,3- dimethylbutanamido)- 6-diazo-5- oxohexanoate
368


 


105




isopropyl (S)-6- diazo-2-((S)-2- hydroxyhexanamido)- 5-oxohexanoate
328


 


106




isopropyl (S)-6- diazo-2-((S)-2- methoxyhexanamido)- 5-oxohexanoate
342


 


107




isopropyl (S)-6- diazo-2-((S)-2- ethoxyhexanamido)- 5-oxohexanoate
356


 


108




isopropyl (S)-6- diazo-2-((S)-2- isopropoxyhexanamido)- 5- oxohexanoate
370


 


109




isopropyl (S)-2- ((S)-2- cyclopropoxyhexanamido)- 6-diazo-5- oxohexanoate
368


 


110




isopropyl (S)-2- ((S)-2-cyclopentyl- 2- hydroxyacetamido)- 6-diazo-5- oxohexanoate
340


 


111




isopropyl (S)-2- ((S)-2-cyclopentyl- 2- methoxyacetamido)- 6-diazo-5- oxohexanoate
354


 


112




isopropyl (S)-2- ((S)-2-cyclopentyl- 2- ethoxyacetamido)- 6-diazo-5- oxohexanoate
368


 


113




isopropyl (S)-2- ((S)-2-cyclopentyl- 2- isopropoxyacetamido)- 6-diazo-5- oxohexanoate
382


 


114




isopropyl (S)-2- ((S)-2-cyclopentyl- 2- cyclopropoxyacetamido)- 6-diazo-5- oxohexanoate
380


 


115




isopropyl (S)-2- ((S)-3-cyclopentyl- 2- hydroxypropanamido)- 6-diazo-5- oxohexanoate
354


 


116




isopropyl (S)-2- ((S)-3-cyclopentyl- 2- methoxypropanamido)- 6-diazo-5- oxohexanoate
368


 


117




isopropyl (S)-2- ((S)-3-cyclopentyl- 2- ethoxypropanamido)- 6-diazo-5- oxohexanoate
382


 


118




isopropyl (S)-2- ((S)-3-cyclopentyl- 2- isopropoxypropanamido)- 6-diazo-5- oxohexanoate
396


 


119




isopropyl (S)-2- ((S)-3-cyclopentyl- 2- cyclopropoxypropanamido)- 6-diazo-5- oxohexanoate
394


 


120




isopropyl (S)-2- ((S)-2-cyclohexyl- 2- hydroxyacetamido)- 6-diazo-5- oxohexanoate
354


 


121




isopropyl (S)-2- ((S)-2-cyclohexyl- 2- methoxyacetamido)- 6-diazo-5- oxohexanoate
368


 


122




isopropyl (S)-2- ((S)-2-cyclohexyl- 2- ethoxyacetamido)- 6-diazo-5- oxohexanoate
382


 


123




isopropyl (S)-2- ((S)-2-cyclohexyl- 2- isopropoxyacetamido)- 6-diazo-5- oxohexanoate
396


 


124




isopropyl (S)-2- ((S)-2-cyclohexyl- 2- cyclopropoxyacetamido)- 6-diazo-5- oxohexanoate
394


 


125




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-2- phenylacetamido)- 5-oxohexanoate
376


 


126




isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-2- phenylacetamido)- 5-oxohexanoate
390


 


127




isopropyl (S)-2- ((S)-2- cyclopropoxy-2- phenylacetamido)- 6-diazo-5- oxohexanoate
388


 


128




isopropyl (S)-6- diazo-2-((S)-2-(4- fluorophenyl)-2- methoxyacetamido)- 5-oxohexanoate
380


 


129




isopropyl (S)-2- ((S)-2-(4- chlorophenyl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
396


 


130




isopropyl (S)-2- ((S)-2-(4- chlorophenyl)-2- hydroxyacetamido)- 6-diazo-5- oxohexanoate
382


 


131




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(4- methoxyphenyl) acetamido)-5- oxohexanoate
378


 


132




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(4- methoxyphenyl) acetamido)-5- oxohexanoate
392


 


133




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(4- hydroxyphenyl) acetamido)-5- oxohexanoate
364


 


134




isopropyl (S)-6- diazo-2-((S)-2-(4- hydroxyphenyl)-2- methoxyacetamido)- 5-oxohexanoate
378


 


135




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(p- tolyl)acetamido)-5- oxohexanoate
362


 


136




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(p- tolyl)acetamido)-5- oxohexanoate
376


 


137




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3- phenylpropanamido)- 5-oxohexanoate
390


 


138




isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-3- phenylpropanamido)- 5-oxohexanoate
404


 


139




isopropyl (S)-2- ((S)-2- cyclopropoxy-3- phenylpropanamido)- 6-diazo-5- oxohexanoate
402


 


140




isopropyl (S)-6- diazo-2-((S)-3-(4- fluorophenyl)-2- hydroxypropanamido)- 5- oxohexanoate
380


 


142




isopropyl (S)-6- diazo-2-((S)-3-(4- fluorophenyl)-2- methoxypropanamido)- 5- oxohexanoate
394


 


143




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(4- fluorophenyl) propanamido)-5- oxohexanoate
408


 


144




isopropyl (S)-6- diazo-2-((S)-3-(4- fluorophenyl)-2- isopropoxypropanamido)- 5- oxohexanoate
422


 


145




isopropyl (S)-2- ((S)-2- cyclopropoxy-3-(4- fluorophenyl) propanamido)-6-diazo-5- oxohexanoate
420


 


146




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(4- hydroxyphenyl) propanamido)-5- oxohexanoate
378


 


147




isopropyl (S)-6- diazo-2-((S)-3-(4- hydroxyphenyl)-2- methoxypropanamido)- 5- oxohexanoate
392


 


148




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(4- hydroxyphenyl) propanamido)-5- oxohexanoate
406


 


149




isopropyl (S)-6- diazo-2-((S)-3-(4- hydroxyphenyl)-2- isopropoxypropanamido)- 5- oxohexanoate
420


 


150




isopropyl (S)-2- ((S)-2- cyclopropoxy-3-(4- hydroxyphenyl) propanamido)-6-diazo- 5-oxohexanoate
418


 


151




isopropyl (S)-6- diazo-2-(1- hydroxycyclobutane- 1-carboxamido)- 5-oxohexanoate
312


 


152




isopropyl (S)-6- diazo-2-(1- methoxycyclobutane- 1-carboxamido)- 5-oxohexanoate
326


 


153




isopropyl (S)-6- diazo-2-(3- hydroxyoxetane-3- carboxamido)-5- oxohexanoate
314


 


154




isopropyl (S)-6- diazo-2-(3- methoxyoxetane-3- carboxamido)-5- oxohexanoate
328


 


155




isopropyl (S)-6- diazo-2-(1- hydroxycyclopentane- 1-carboxamido)- 5-oxohexanoate
326


 


156




isopropyl (S)-6- diazo-2-(1- methoxycyclopentane- 1-carboxamido)- 5-oxohexanoate
340


 


157




isopropyl (2S)-6- diazo-2-(3- hydroxytetrahydrofuran- 3- carboxamido)-5- oxohexanoate
328


 


158




isopropyl (2S)-6- diazo-2-(3- methoxytetrahydrofuran- 3- carboxamido)-5- oxohexanoate
342


 


159




isopropyl (S)-6- diazo-2-(1- hydroxycyclohexane- 1-carboxamido)- 5-oxohexanoate
340


 


160




isopropyl (S)-6- diazo-2-(1- methoxycyclohexane- 1-carboxamido)- 5-oxohexanoate
354


 


161




isopropyl (S)-6- diazo-2-(4- hydroxy-1- methylpiperidine-4- carboxamido)-5- oxohexanoate
355


 


162




isopropyl (S)-6- diazo-2-(4- methoxy-1- methylpiperidine-4- carboxamido)-5- oxohexanoate
369


 


163




isopropyl (2S)-6- diazo-5-oxo-2- (tetrahydrofuran-2- carboxamido) hexanoate
312


 


164




isopropyl (2S)-6- diazo-5-oxo-2- (tetrahydro-2H- pyran-2- carboxamido) hexanoate
326


 


165




isopropyl (2S)-6- diazo-2- (hexahydro-1H- cyclopenta[c]furan- 1-carboxamido)-5- oxohexanoate
352


 


166




isopropyl (S)-2-(2- (cyclopropylmethoxy) acetamido)-6- diazo-5- oxohexanoate
MS: 326 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 5.02 (dt, J = 12.5, 6.3 Hz, 1H), 4.44 (dd, J = 8.8, 5.0 Hz, 1H), 4.09- 3.89 (m, 2H), 3.40 (d, J = 6.9 Hz, 2H), 2.45 (s, 2H), 2.11 (ddq, J = 37.1, 14.6, 7.3 Hz, 2H), 1.34-1.20 (m, 6H), 1.12 (tt, J = 12.4, 6.2 Hz, 1H), 0.56 (d, J = 8.0 Hz, 2H), 0.26 (d, J = 3.7 Hz, 2H).


 


167




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- phenylpropanamido)- 5-oxohexanoate
MS: 362 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.62-7.56 (m, 2H), 7.35- 7.28 (m, 2H), 7.28-7.22 (m, 1H), 4.93 (dt, J = 12.5, 6.3 Hz, 1H), 4.31 (dd, J = 8.9, 5.1 Hz, 1H), 2.42 (s, 2H), 2.29- 1.94 (m, 2H), 1.75 (s, 3H), 1.13 (dd, J = 19.5, 6.3 Hz, 6H).


 


168




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- phenylpropanamido)- 5-oxohexanoate
MS: 362 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.63-7.58 (m, 2H), 7.37- 7.30 (m, 2H), 7.28-7.23 (m, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.29 (dd, J = 9.2, 4.5 Hz, 1H), 2.29-2.09 (m, 3H), 1.99-1.87 (m, 1H), 1.73 (s, 3H), 1.24 (dd, J = 6.2, 3.2 Hz, 5H).


 


169




isopropyl (S)-2- ((S)-2-(2- cyanoacetoxy)-3- (7-fluoro-1H-indol- 3-yl)propanamido)- 6-diazo-5- oxohexanoate
MS: 486 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.47-7.35 (m, 1H), 7.24- 7.13 (m, 1H), 6.93 (td, J = 7.8, 4.0 Hz, 1H), 6.84-6.72 (m, 1H), 5.36 (s, 1H), 5.07- 4.91 (m, 1H), 4.43-4.32 (m, 1H), 4.43-4.19 (m, 2H), 4.32- 4.19 (m, 1H), 3.23-3.09 (m, 2H), 2.12-1.60 (m, 4H), 1.27-1.13 (m, 6H).


 


170




isopropyl (S)-6- diazo-2-((S)-3-(7- fluoro-1H-indol-3- yl)-2- (isobutyryloxy) propanamido)-5- oxohexanoate
489


 


171




1-methylpiperidin- 4-yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate
355


 


172




isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydrofuran-2- carboxamido)hexanoate
MS: 312 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.83 (s, 1H), 5.01 (dt, J = 12.6, 6.2 Hz, 1H), 4.38-4.27 (m, 2H), 4.07-3.97 (m, 1H), 3.93-3.82 (m, 1H), 2.43 (s, 2H), 2.31-2.12 (m, 2H), 2.07- 1.83 (m, 4H), 1.29-1.23 (m, 6H).


 


173




isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydro-2H- pyran-2- carboxamido)hexanoate
326


 


174




isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydrofuran-3- carboxamido)hexanoate
MS: 312 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 5.00 (dt, J = 12.5, 6.2 Hz, 1H), 4.32 (dd, J = 9.1, 5.2 Hz, 1H), 3.97- 3.90 (m, 1H), 3.91-3.74 (m, 3H), 3.14-3.03 (m, 1H), 2.44 (s, 2H), 2.22-2.06 (m, 3H), 2.00-1.88 (m, 1H), 1.25 (dd, J = 6.2, 4.1 Hz, 6H).


 


175




isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydro-2H- pyran-3- carboxamido)hexanoate
326


 


176




isopropyl (S)-6- diazo-2-(3- methoxy-2- oxopropanamido)- 5-oxohexanoate
314


 


177




isopropyl (S)-6- diazo-2-(3- hydroxy-2- oxopropanamido)- 5-oxohexanoate
300


 


178




cyclobutyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
MS: 312 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 5.04-4.91 (m, 1H), 4.49-4.29 (m, 1H), 3.76 (p, J = 6.8 Hz, 1H), 3.44- 3.34 (m, 3H), 2.51-2.29 (m, 4H), 2.25-1.98 (m, 4H), 1.88- 1.76 (m, 1H), 1.73-1.62 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H).


 


179




cyclopentyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
MS: 326 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.27-5.07 (m, 1H), 4.43- 4.30 (m, 1H), 3.76 (p, J = 6.6 Hz, 1H), 3.46-3.34 (m, 3H), 2.57-2.34 (m, 2H), 2.26- 2.12 (m, 1H), 2.06-1.93 (m, 1H), 1.94-1.82 (m, 2H), 1.81- 1.56 (m, 6H), 1.34 (d, J = 6.8 Hz, 3H).


 


180




2-(pyrrolidin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
355


 


181




(pivaloyloxy)methyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate
372


 


182




isopentyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
MS: 328 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 4.48-4.36 (m, 1H), 4.17 (dt, J = 6.6, 4.3 Hz, 2H), 3.76 (p, J = 6.8 Hz, 1H), 3.45- 3.33 (m, 3H), 2.51-2.37 (m, 2H), 2.28-2.15 (m, 1H), 2.07- 1.93 (m, 1H), 1.71 (dt, J = 13.4, 6.7 Hz, 1H), 1.62-1.49 (m, 2H), 1.37-1.29 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H).


 


183




isopropyl (S)-6- diazo-2-(3- hydroxypropanamido)- 5- oxohexanoate
MS: 286 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.00 (dt, J = 12.7, 6.5 Hz, 1H), 4.37 (dd, J = 9.0, 5.1 Hz, 1H), 3.81 (dd, J = 10.2, 5.3 Hz, 2H), 2.55-2.37 (m, 4H), 2.22-2.08 (m, 1H), 1.99- 1.83 (m, 1H), 1.37-1.17 (m, 6H).


 


184




isopropyl (S)-6- diazo-2-((S)-3- hydroxybutanamido)- 5-oxohexanoate
MS: 286 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.00 (dt, J = 12.5, 6.2 Hz, 1H), 4.35 (dd, J = 8.6, 5.2 Hz, 1H), 4.14 (dd, J = 12.6, 6.3 Hz, 1H), 2.50-2.28 (m, 4H), 2.15 (td, J = 13.6, 6.9 Hz, 1H), 1.93 (td, J = 15.2, 7.9 Hz, 1H), 1.25 (d, J = 6.2 Hz, 6H), 1.21 (d, J = 6.1 Hz, 3H).


 


185




isopropyl (S)-6- diazo-2-(3- methoxypropanamido)- 5- oxohexanoate
MS: 300 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.00 (dt, J = 12.4, 6.2 Hz, 1H), 4.36 (dd, J = 8.9, 5.1 Hz, 1H), 3.70-3.55 (m, 2H), 3.33 (s, 3H), 2.58-2.35 (m, 4H), 2.14 (td, J = 13.5, 7.2 Hz, 1H), 1.91 (td, J = 15.1, 7.8 Hz, 1H), 1.30-1.20 (m, 6H).


 


186




isopropyl (S)-6- diazo-2-((S)-3- methoxybutanamido)- 5-oxohexanoate
314


 


187




isopropyl (S)-6- diazo-2-((S)-3- hydroxy-2- methylpropanamido)- 5-oxohexanoate
MS: 300 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 5.00 (dt, J = 12.4, 6.3 Hz, 1H), 4.34 (dd, J = 8.7, 5.1 Hz, 1H), 3.73- 3.63 (m, 1H), 3.56-3.45 (m, 1H), 2.56 (dd, J = 13.6, 6.7 Hz, 1H), 2.44 (s, 2H), 2.22- 2.08 (m, 1H), 2.02-1.88 (m, 1H), 1.25 (d, J = 6.2 Hz, 6H), 1.11 (d, J = 6.9 Hz, 3H).


 


188




isopropyl (S)-6- diazo-2-((S)-3- methoxy-2- methylpropanamido)- 5-oxohexanoate
MS: 314 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 5.00 (dt, J = 12.5, 6.3 Hz, 1H), 4.33 (dd, J = 9.0, 5.2 Hz, 1H), 3.53 (dd, J = 9.3, 8.1 Hz, 1H), 3.38- 3.33 (m, 1H), 3.33 (s, 3H), 2.68 (dd, J = 13.4, 7.1 Hz, 1H), 2.43 (s, 2H), 2.25-2.08 (m, 1H), 2.02-1.86 (m, 1H), 1.25 (dd, J = 6.2, 2.7 Hz, 6H), 1.10 (d, J = 7.0 Hz, 3H).


 


189




isopropyl (S)-6- diazo-2-((S)- oxetane-2- carboxamido)-5- oxohexanoate
MS: 298 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 5.12-4.98 (m, 2H), 4.83-4.64 (m, 2H), 4.45 (dd, J = 9.2, 4.9 Hz, 1H), 3.11- 2.95 (m, 1H), 2.70-2.55 (m, 1H), 2.45 (s, 2H), 2.30- 2.18 (m, 1H), 2.10-1.94 (m, 1H), 1.31-1.27 (m, 6H).


 


190




isopropyl (S)-6- diazo-2-((2S,3R)-3- hydroxy-2- methylbutanamido)- 5-oxohexanoate
314


 


191




isopropyl (S)-6- diazo-2-((2S,3R)-3- methoxy-2- methylbutanamido)- 5-oxohexanoate
328


 


192




isopropyl (S)-6- diazo-2-((2R,3R)- 3-hydroxy-2- methylbutanamido)- 5-oxohexanoate
314


 


193




isopropyl (S)-6- diazo-2-((2R,3R)- 3-methoxy-2- methylbutanamido)- 5-oxohexanoate
328


 


194




isopropyl (S)-6- diazo-2-((2R,3S)-3- hydroxy-2- methylbutanamido)- 5-oxohexanoate
314


 


195




isopropyl (S)-6- diazo-2-((2R,3S)-3- methoxy-2- methylbutanamido)- 5-oxohexanoate
328


 


196




isopropyl (S)-6- diazo-2-((R)-3- hydroxybutanamido)- 5-oxohexanoate
300


 


197




isopropyl (S)-6- diazo-2-((2S,3S)-3- hydroxy-2- methylbutanamido)- 5-oxohexanoate
314


 


198




isopropyl (S)-6- diazo-2-((2S,3S)-3- methoxy-2- methylbutanamido)- 5-oxohexanoate
328


 


199




isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydrofuran-2- carboxamido)hexanoate
312


 


200




isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydro-2H- pyran-2- carboxamido)hexanoate
326


 


201




isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydrofuran-3- carboxamido)hexanoate
MS: 312 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 4.99 (dt, J = 12.5, 6.2 Hz, 1H), 4.32 (dd, J = 9.1, 5.2 Hz, 1H), 3.99- 3.93 (m, 1H), 3.91-3.84 (m, 1H), 3.83-3.74 (m, 2H), 3.14- 2.98 (m, 1H), 2.45 (s, 2H), 2.21-2.06 (m, 3H), 1.93 (dt, J = 14.4, 7.5 Hz, 1H), 1.24 (dd, J = 6.2, 4.3 Hz, 6H).


 


202




isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydro-2H- pyran-3- carboxamido)hexanoate
326


 


203




isopropyl (S)-6- diazo-2-((R)-3- methoxybutanamido)- 5-oxohexanoate
314


 


204




isopropyl (S)-6- diazo-5-oxo-2-((R)- 3,3,3-trifluoro-2- methoxypropanamido) hexanoate
354


 


205




isopropyl (S)-6- diazo-5-oxo-2-((R)- 3,3,3-trifluoro-2- hydroxypropanamido) hexanoate
340


 


206




isopropyl (S)-6- diazo-5-oxo-2-((S)- 3,3,3-trifluoro-2- methoxypropanamido) hexanoate
354


 


207




isopropyl (S)-6- diazo-5-oxo-2-((S)- 3,3,3-trifluoro-2- hydroxypropanamido) hexanoate
340


 


208




isopropyl (S)-6- diazo-2-((R)- oxetane-2- carboxamido)-5- oxohexanoate
MS: 298 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.85 (s, 1H), 5.09-4.96 (m, 2H), 4.80-4.60 (m, 2H), 4.43 (dd, J = 9.0, 5.0 Hz, 1H), 3.11- 2.97 (m, 1H), 2.70-2.56 (m, 1H), 2.50 (s, 2H), 2.35- 2.19 (m, 1H), 2.17-1.99 (m, 1H), 1.26 (d, J = 6.3 Hz, 6H).


 


209




isopropyl (S)-6- diazo-2-(oxetane-3- carboxamido)-5- oxohexanoate
298


 


210




isopropyl (S)-6- diazo-2-((R)-3- hydroxy-2- methylpropanamido)- 5-oxohexanoate
300


 


211




isopropyl (S)-6- diazo-5-oxo-2- (tetrahydro-2H- pyran-4- carboxamido)hexanoate
326


 


212




isopropyl (2S)-6- diazo-5-oxo-2- ((1S)-tetrahydro- 1H,3H-furo[3,4- c]furan-1- carboxamido)hexanoate
354


 


213




isopropyl (2S)-6- diazo-5-oxo-2- ((1R)-tetrahydro- 1H,3H-furo[3,4- c]furan-1- carboxamido)hexanoate
354


 


214




isopropyl (S)-2- ((S)-2-cyano-2- hydroxyacetamido)- 6-diazo-5- oxohexanoate
297


 


215




isopropyl (S)-2- ((S)-2-cyano-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
311


 


216




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3- oxobutanamido)-5- oxohexanoate
328


 


217




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3- oxobutanamido)-5- oxohexanoate
314


 


218




isopropyl (S)-6- diazo-2-((R)-3- methoxy-2- methylpropanamido)- 5-oxohexanoate
MS: 298 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.78 (s, 1H), 5.00 (dt, J = 12.5, 6.3 Hz, 1H), 4.36 (dd, J = 9.5, 4.9 Hz, 1H), 3.52 (t, J = 9.1 Hz, 1H), 3.35-3.32 (m, 4H), 2.74-2.59 (m, 1H), 2.45 (s, 2H), 2.23-2.08 (m, 1H), 1.98-1.82 (m, 1H), 1.25 (dd, J = 6.1, 4.7 Hz, 6H), 1.08 (d, J = 7.0 Hz, 3H).


 


219




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiazol-4- yl)acetamido)-5- oxohexanoate
367


 


220




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(thiazol- 4-yl)acetamido)-5- oxohexanoate
355


 


221




isopropyl (S)-2- ((R)-2-cyano-2- hydroxyacetamido)- 6-diazo-5- oxohexanoate
297


 


222




isopropyl (S)-2- ((R)-2-cyano-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
311


 


223




isopropyl (S)-6- diazo-2-((R)-2- methoxy-3- oxobutanamido)-5- oxohexanoate
328


 


224




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-3- oxobutanamido)-5- oxohexanoate
314


 


225




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiazol-4- yl)acetamido)-5- oxohexanoate
369


 


226




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(thiazol- 4-yl)acetamido)-5- oxohexanoate
355


 


227




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate
351


 


228




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate
351


 


229




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate
337


 


230




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate
337


 


231




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate
353


 


232




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate
339


 


233




isopropyl (S)-6- diazo-2-((S)-2- (furan-2-yl)-2- methoxyacetamido)- 5-oxohexanoate
352


 


234




isopropyl (S)-6- diazo-2-((S)-2- (furan-3-yl)-2- methoxyacetamido)- 5-oxohexanoate
352


 


235




isopropyl (S)-6- diazo-2-((S)-2- (furan-2-yl)-2- hydroxyacetamido)- 5-oxohexanoate
338


 


236




isopropyl (S)-6- diazo-2-((S)-2- (furan-3-yl)-2- hydroxyacetamido)- 5-oxohexanoate
338


 


237




isopropyl (S)-2- ((S)-2-(1H- imidazol-4-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
352


 


238




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- imidazol-4- yl)acetamido)-5- oxohexanoate
338


 


239




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate
351


 


240




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate
351


 


241




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate
337


 


242




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate
337


 


243




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate
353


 


244




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate
339


 


245




isopropyl (S)-6- diazo-2-((R)-2- (furan-2-yl)-2- methoxyacetamido)- 5-oxohexanoate
352


 


246




isopropyl (S)-6- diazo-2-((R)-2- (furan-3-yl)-2- methoxyacetamido)- 5-oxohexanoate
352


 


247




isopropyl (S)-6- diazo-2-((R)-2- (furan-2-yl)-2- hydroxyacetamido)- 5-oxohexanoate
338


 


248




isopropyl (S)-6- diazo-2-((R)-2- (furan-3-yl)-2- hydroxyacetamido)- 5-oxohexanoate
338


 


249




isopropyl (S)-2- ((R)-2-(1H- imidazol-4-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
352


 


250




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- imidazol-4- yl)acetamido)-5- oxohexanoate
338


 


251




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate
368


 


252




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate
368


 


253




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate
354


 


254




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate
354


 


255




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiazol-2- yl)acetamido)-5- oxohexanoate
369


 


256




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(thiazol- 2-yl)acetamido)-5- oxohexanoate
355


 


257




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate
366


 


258




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate
352


 


259




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate
366


 


260




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate
352


 


261




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate
353


 


262




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate
339


 


263




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate
366


 


264




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate
352


 


265




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate
353


 


266




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate
339


 


267




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate
368


 


268




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate
368


 


269




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate
354


 


270




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate
354


 


271




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiazol-2- yl)acetamido)-5- oxohexanoate
369


 


272




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(thiazol- 2-yl)acetamido)-5- oxohexanoate
355


 


273




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate
366


 


274




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate
352


 


275




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiazol-5- yl)acetamido)-5- oxohexanoate
369


 


276




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(thiazol- 5-yl)acetamido)-5- oxohexanoate
355


 


277




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1- methyl-1H- imidazol-5- yl)acetamido)-5- oxohexanoate
366


 


278




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1- methyl-1H- imidazol-5- yl)acetamido)-5- oxohexanoate
352


 


279




isopropyl (S)-2- ((R)-2-(1H- imidazol-2-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
352


 


280




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- imidazol-2- yl)acetamido)-5- oxohexanoate
338


 


281




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(oxazol- 5-yl)acetamido)-5- oxohexanoate
353


 


282




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(oxazol- 5-yl)acetamido)-5- oxohexanoate
339


 


283




isopropyl (S)-2- ((S)-2-(1H- imidazol-5-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
352


 


284




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- imidazol-5- yl)acetamido)-5- oxohexanoate
338


 


285




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate
363


 


286




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate
349


 


287




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate
364


 


288




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate
350


 


289




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate
364


 


290




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate
350


 


291




isopropyl (S)-6- diazo-2-((S)-2-(3- fluoropyridin-4-yl)- 2- methoxyacetamido)- 5-oxohexanoate
381


 


292




isopropyl (S)-6- diazo-2-((S)-2-(3- fluoropyridin-4-yl)- 2- hydroxyacetamido)- 5-oxohexanoate
367


 


293




isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-2-yl)- 2- methoxyacetamido)- 5-oxohexanoate
381


 


294




isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-2-yl)- 2- hydroxyacetamido)- 5-oxohexanoate
367


 


295




isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-3-yl)- 2- methoxyacetamido)- 5-oxohexanoate
381


 


296




isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-3-yl)- 2- hydroxyacetamido)- 5-oxohexanoate
367


 


297




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate
393


 


298




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate
379


 


299




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate
393


 


300




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate
379


 


301




isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate
393


 


302




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate
379


 


303




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate
393


 


304




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate
379


 


305




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate
393


 


306




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate
379


 


307




isopropyl (S)-2- ((R)-2-(1H- imidazol-5-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate
352


 


308




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- imidazol-5- yl)acetamido)-5- oxohexanoate
338


 


309




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate
363


 


310




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate
349


 


311




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate
364


 


312




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate
350


 


313




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate
364


 


314




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate
350


 


315




isopropyl (S)-6- diazo-2-((R)-2-(3- fluoropyridin-4-yl)- 2- methoxyacetamido)- 5-oxohexanoate
381


 


316




isopropyl (S)-6- diazo-2-((R)-2-(3- fluoropyridin-4-yl)- 2- hydroxyacetamido)- 5-oxohexanoate
367


 


317




isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-2-yl)- 2- methoxyacetamido)- 5-oxohexanoate
381


 


318




isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-2-yl)- 2- hydroxyacetamido)- 5-oxohexanoate
367


 


319




isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-3-yl)- 2- methoxyacetamido)- 5-oxohexanoate
381


 


320




isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-3-yl)- 2- hydroxyacetamido)- 5-oxohexanoate
367


 


321




isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate
393


 


322




isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate
379


 


323




tert-butyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
314


 


324




phenyl (S)-6-diazo- 2-((S)-2- methoxypropanamido)- 5- oxohexanoate
334


 


325




benzyl (S)-6-diazo- 2-((S)-2- methoxypropanamido)- 5- oxohexanoate
348


 


326




cyclohexyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
340


 


327




cycloheptyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
354


 


328




cyclooctyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
368


 


329




cyclooctyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
368


 


330




tert-butyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
314


 


331




phenyl (S)-6-diazo- 2-((R)-2- methoxypropanamido)- 5- oxohexanoate
334


 


332




benzyl (S)-6-diazo- 2-((R)-2- methoxypropanamido)- 5- oxohexanoate
348


 


333




cyclohexyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
340


 


334




cycloheptyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
354


 


335




1-methylpiperidin- 4-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)- 5- oxohexanoate
355


 


336




pyridin-4-yl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
335


 


337




pyridin-4-ylmethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
349


 


338




tetrahydro-2H- pyran-4-yl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
342


 


339




1-methylpiperidin- 4-yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate
355


 


340




(R)-oxepan-4-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
356


 


341




(S)-oxepan-4-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
356


 


342




oxocan-5-yl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
370


 


343




pyridin-4-yl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
335


 


344




pyridin-4-ylmethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)- 5- oxohexanoate
349


 


345




tetrahydro-2H- pyran-4-yl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
342


 


346




1-methylpiperidin- 4-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)- 5- oxohexanoate
355


 


347




(R)-oxepan-4-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)- 5- oxohexanoate
356


 


348




(S)-oxepan-4-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)- 5- oxohexanoate
356


 


349




oxocan-5-yl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate
370


 


350




trifluoromethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
326


 


351




2,2,2-trifluoroethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
340


 


352




(S)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate
354


 


353




3,3,3- trifluoropropyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
354


 


354




(S)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
368


 


355




1,1,1-trifluoro-2- methylpropan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
368


 


356




4,4,4-trifluoro-2- methylbutan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
382


 


357




cyanic (S)-6-diazo- 2-((S)-2- methoxypropanamido)- 5-oxohexanoic anhydride
283


 


358




cyanomethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
297


 


359




(S)-1-cyanoethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
311


 


360




2-cyanoethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
311


 


361




1-cyanopropan-2-yl (2S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate
325


 


362




2-cyanopropan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
325


 


363




1-cyano-2- methylpropan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate
339


 


364




hydroxymethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
288


 


365




methoxymethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
302


 


366




ethoxymethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
316


 


367




isopropoxymethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
330


 


368




cyclopropoxymethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
328


 


369




cyclobutoxymethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
342


 


370




trifluoromethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
326


 


371




2,2,2-trifluoroethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
340


 


372




(S)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
354


 


373




(R)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
354


 


374




(R)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
368


 


375




(R)-1-cyanoethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
311


 


376




(R)-1-cyanopropan- 2-yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
325


 


377




(R)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
354


 


378




3,3,3- trifluoropropyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
354


 


379




(S)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
368


 


380




(R)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
368


 


381




1,1,1-trifluoro-2- methylpropan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
368


 


382




4,4,4-trifluoro-2- methylbutan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
382


 


383




cyanic (S)-6-diazo- 2-((R)-2- methoxypropanamido)- 5-oxohexanoic anhydride
283


 


384




cyanomethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
297


 


385




(S)-1-cyanoethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
311


 


386




(R)-1-cyanoethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
311


 


387




2-cyanoethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
311


 


388




(S)-1-cyanopropan- 2-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
325


 


389




(R)-1-cyanopropan- 2-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
325


 


390




2-cyanopropan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
325


 


391




1-cyano-2- methylpropan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
339


 


392




hydroxymethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
288


 


393




methoxymethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
302


 


394




ethoxymethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
316


 


395




isopropoxymethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
330


 


396




cyclopropoxymethy (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
328


 


397




cyclobutoxymethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
342


 


398




2-(pyrrolidin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
355


 


399




2-methoxyethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
316


 


400




2-ethoxyethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
330


 


401




2-isopropoxyethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
344


 


402




2-aminoethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
301


 


403




2- (methylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
315


 


404




2- (dimethylamino)ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
329


 


405




2-(ethylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
329


 


406




2- (isopropylamino)ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
343


 


407




2- (cyclopropylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
341


 


408




2- (cyclobutylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
355


 


409




2- (cyclopentylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
369


 


410




2- (cyclohexylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
383


 


411




2-(azetidin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
341


 


412




2-(piperidin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
369


 


413




2-(azepan-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
383


 


414




2-(azocan-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
397


 


415




2-morpholinoethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
371


 


416




2- (phenylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
377


 


417




2-(pyridin-4- ylamino)ethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
378


 


418




2- (benzylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate
391


 


419




2-((pyridin-4- ylmethyl)amino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
392


 


420




2-(4- methylpiperazin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
384


 


421




2-methoxyethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
316


 


422




2-ethoxyethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
330


 


423




2-isopropoxyethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
344


 


424




2-aminoethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
301


 


425




2- (methylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
315


 


426




2- (dimethylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
329


 


427




2-(ethylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
329


 


428




2- (isopropylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
343


 


429




2- (cyclopropylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
341


 


430




2- (cyclobutylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
355


 


431




2- (cyclopentylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
369


 


432




2- (cyclohexylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
383


 


433




2-(azetidin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
341


 


434




2-(piperidin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
369


 


435




2-(azepan-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
383


 


436




2-(azocan-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
397


 


437




2-morpholinoethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
371


 


438




2- (phenylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
377


 


439




2-(pyridin-4- ylamino)ethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
378


 


440




2- (benzylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate
391


 


441




2-((pyridin-4- ylmethyl)amino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate
392


 


442




2-(4- methylpiperazin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate
384


 


443




isopropyl (S)-6- diazo-2-((S)-2- methoxy-4- (methylthio) butanamido)-5- oxohexanoate
MS: 360 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 7.23- 7.04 (m, 1H), 5.26 (s, 1H), 5.11-4.95 (m, 1H), 4.58- 4.44 (m, 1H), 3.86-3.68 (m, 1H), 3.50-3.35 (m, 3H), 2.64- 2.50 (m, 2H), 2.40 (s, 2H), 2.26-2.15 (m, 1H), 2.10- 2.05 (m, 3H), 2.06-1.86 (m, 3H), 1.29-1.19 (m, 6H).


 


444




isopropyl (S)-6- diazo-2-(2- hydroxy-2- methylpropanamido)- 5-oxohexanoate
MS: 300 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.33 (dd, J = 8.7, 5.1 Hz, 1H), 2.43 (s, 2H), 2.29-2.11 (m, 1H), 2.10- 1.90 (m, 1H), 1.36 (d, J = 3.3 Hz, 6H), 1.26 (dd, J = 6.2, 2.9 Hz, 6H).


 


445




methyl (S)-6-diazo- 2-((S)-2-methoxy- 4- (methylthio) butanamido)-5- oxohexanoate
332


 


446




methyl (S)-6-diazo- 2-((S)-2-hydroxy- 3-(1H-indol-3- yl)propanamido)-5- oxohexanoate
MS: 373 (M + H)+ 1H NMR (400 MHz, CD3OD) δ 7.61 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.11-7.03 (m, 1H), 7.03-6.94 (m, 1H), 5.23 (s, 1H), 4.38 (t, J = 4.9 Hz, 1H), 4.32-4.22 (m, 1H), 3.67 (s, 3H), 3.25-3.12 (m, 2H), 1.96- 1.84 (m, 1H), 1.81-1.60 (m, 3H).


 


447




methyl (S)-6-diazo- 2-((S)-2-hydroxy- 3- methylbutanamido)- 5-oxohexanoate
MS: 286 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 4.46 (dd, J = 8.5, 5.1 Hz, 1H), 3.87 (d, J = 3.4 Hz, 1H), 3.73 (s, 3H), 2.54-2.33 (m, 2H), 2.29-2.14 (m, 1H), 2.15- 1.92 (m, 2H), 1.01 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).


 


448




methyl (S)-6-diazo- 2-(2- isopropoxyacetamido)-5- oxohexanoate
MS: 286 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 4.50 (dd, J = 8.7, 5.0 Hz, 1H), 4.05-3.88 (m, 2H), 3.74 (s, 3H), 3.72- 3.66 (m, 1H), 2.45 (s, 2H), 2.31-2.15 (m, 1H), 2.13- 1.92 (m, 1H), 1.30-1.15 (m, 6H).


 


449




(S)-6-diazo-2-((S)- 2- hydroxypropanamido)- 5-oxohexanoic acid
244


 


450




cyclopropyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
MS: 298 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 4.44-4.29 (m, 1H), 4.15 (dt, J = 8.8, 2.8 Hz, 1H), 3.82-3.70 (m, 1H), 3.42- 3.34 (m, 3H), 2.44 (s, 2H), 2.28-2.10 (m, 1H), 2.06- 1.91 (m, 1H), 1.35-1.31 (m, 3H), 0.78-0.63 (m, 4H).


 


451




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate
MS: 415 (M + H)+, 1H NMR (400 MHz, CDCl3) δ 8.12- 8.00 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.17-7.05 (m, 3H), 6.92- 6.83 (m, 1H), 4.96 (dt, J = 12.6, 6.3 Hz, 1H), 4.76 (s, 1H), 4.46-4.34 (m, 1H), 4.00- 3.92 (m, 1H), 3.50-3.41 (m, 3H), 3.29-3.19 (m, 2H), 1.94-1.69 (m, 2H), 1.70- 1.59 (m, 2H), 1.21-1.16 (m, 6H).


 


452




isopropyl (S)-6- diazo-2-(2- isopropoxyacetamido)-5- oxohexanoate
MS: 314 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 5.02 (dt, J = 12.5, 6.3 Hz, 1H), 4.42 (dd, J = 8.7, 5.0 Hz, 1H), 4.03-3.87 (m, 2H), 3.70 (dt, J = 12.2, 6.1 Hz, 1H), 2.44 (s, 2H), 2.27-2.14 (m, 1H), 2.10-1.93 (m, 1H), 1.26 (dd, J = 6.3, 2.1 Hz, 6H), 1.22 (dd, J = 6.1, 3.4 Hz, 6H).


 


453




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
MS: 429 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.57 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.1 Hz, 1H), 7.08-6.99 (m, 2H), 5.26 (s, 1H), 4.26-4.18 (m, 1H), 3.96 (t, J = 5.0 Hz, 1H), 3.75 (s, 3H), 3.48 (s, 3H), 3.22-3.16 (m, 2H), 1.95- 1.83 (m, 1H), 1.80-1.61 (m, 3H), 1.22 (dd, J = 8.6, 6.3 Hz, 6H).


 


454




isopropyl (S)-6- diazo-2-((R)-2- methoxy-3-(1- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate
MS: 429 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.55 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.06-6.99 (m, 2H), 5.49 (s, 1H), 4.94 (dt, J = 12.5, 6.2 Hz, 1H), 4.21-4.09 (m, 1H), 3.94 (t, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.37 (s, 3H), 3.13 (ddd, J = 34.8, 14.5, 6.4 Hz, 2H), 2.06-1.85 (m, 3H), 1.82-1.69 (m, 1H), 1.20 (dd, J = 8.8, 6.3 Hz, 6H).


 


456




methyl (S)-6-diazo- 2-((S)-2-hydroxy- 2- phenylacetamido)- 5-oxohexanoate
MS: 320 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.53- 7.43 (m, 2H), 7.42-7.22 (m, 3H), 5.05 (s, 1H), 4.45 (dd, J = 8.9, 4.8 Hz, 1H), 3.71 (s, 3H), 2.33 (s, 2H), 2.27-2.12 (m, 1H), 2.07-1.91 (m, 1H).


 


457




methyl (S)-6-diazo- 2-((S)-2-methoxy- 2- phenylacetamido)- 5-oxohexanoate
MS: 334 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 7.47- 7.42 (m, 2H), 7.40-7.32 (m, 3H), 5.57 (s, 1H), 4.68 (s, 1H), 4.44 (dd, J = 9.4, 4.8 Hz, 1H), 3.71 (s, 3H), 3.42 (s, 3H), 2.32 (s, 2H), 2.26-2.12 (m, 1H), 2.05-1.97 (m, 1H).


 


458




methyl (S)-6-diazo- 2-(2- methoxyacetamido)- 5-oxohexanoate
MS: 258 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.82 (s, 1H), 4.50 (dd, J = 8.8, 5.0 Hz, 1H), 3.93 (d, J = 4.0 Hz, 2H), 3.73 (s, 3H), 3.43 (s, 3H), 2.44 (s, 2H), 2.30-2.16 (m, 1H), 2.11-1.93 (m, 1H).


 


459




S-isopropyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate
MS: 316 (M + H)+, 1H NMR (400 MHz, CD3OD) δ 5.81 (s, 1H), 4.51 (dd, J = 9.9, 4.6 Hz, 1H), 3.80 (q, J = 6.7 Hz, 1H), 3.59 (dt, J = 13.7, 6.9 Hz, 1H), 3.44 (s, 3H), 2.43 (s, 2H), 2.31-2.16 (m, 1H), 2.04- 1.87 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.9 Hz, 6H).


 


460




(S)-6-diazo-2-((S)- 2-methoxy-4- (methylthio) butanamido)-5- oxohexanoic acid
318


 


461




isopropyl (2S)-2-(2- acetoxy-3-(1H- indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
442


 


462




isopropyl (2S)-2-(2- (2-cyanoacetoxy)- 3-(1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
467


 


463




isopropyl (2S)-6- diazo-2-(2- ((dimethylglycyl) oxy)-3-(1H-indol-3- yl)propanamido)-5- oxohexanoate
486


 


464




isopropyl (2S)-2-(3- (1H-indol-3-yl)-2- (2-(2- oxopyrrolidin-1- yl)acetoxy)propanamido)- 6-diazo-5- oxohexanoate
526


 


465




isopropyl (2S)-6- diazo-2-(2- hydroxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate
400


 


466




isopropyl (S)-6- diazo-2-((S)-2-(2- hydroxyethoxy)-3- (1H-indol-3- yl)propanamido)-5- oxohexanoate
444


 


467




isopropyl (S)-2- ((S)-2-(2- acetamidoethoxy)- 3-(1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
486


 


468




isopropyl (S)-2- ((S)-2-(2- cyanoethoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
454


 


469




isopropyl (S)-2- ((S)-2- (cyanomethoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
439


 


470




isopropyl (S)-6- diazo-2-((S)-2-(2- (dimethylamino)-2- oxoethoxy)-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate
486


 


471




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(2- (methylamino)-2- oxoethoxy)propanamido)- 6-diazo-5- oxohexanoate
472


 


472




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(2- oxopropoxy)propanamido)- 6-diazo-5- oxohexanoate
457


 


473




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-((tetrahydro- 2H-pyran-4- yl)oxy)propanamido)- 6-diazo-5- oxohexanoate
485


 


474




isopropyl (S)-2- ((S)-2-(3-amino-3- oxopropoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate
472


 


475




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(3- (methylamino)-3- oxopropoxy)propanamido)- 6-diazo-5- oxohexanoate
486


 


476




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate
428


 


477




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1H- pyrrolo[3,2- b]pyridin-3- yl)propanamido)-5- oxohexanoate
415


 


478




isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1H- pyrrolo[2,3- b]pyridin-3- yl)propanamido)-5- oxohexanoate
415


 


479




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1- methyl-1H- pyrrolo[3,2- b]pyridin-3- yl)propanamido)-5- oxohexanoate
415


 


480




isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1- methyl-1H- pyrrolo[2,3- b]pyridin-3- yl)propanamido)-5- oxohexanoate
415


 


481




isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(7-fluoro- 1H-indol-3- yl)propanamido)-5- oxohexanoate
447


 


482




isopropyl (S)-6- diazo-2-((S)-3-(7- fluoro-1H-indol-3- yl)-2- isopropoxypropanamido)- 5- oxohexanoate
461


 


483




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- phenoxypropanamido)- 6-diazo-5- oxohexanoate
477


 


484




isopropyl (2S)-2-(3- (1H-indol-3-yl)-2- ((methylglycyl) oxy)propanamido)-6- diazo-5- oxohexanoate
472


 


485




isopropyl (2S)-6- diazo-2-(2- (glycyloxy)-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate
457


 


486




isopropyl (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate
303


 


487




(S)-6-diazo-2-((S)- 2-(methoxy- d3)propanamido)- 5-oxohexanoic acid
261


 


488




methyl (S)-6-diazo- 2-((S)-2-(methoxy- d3)propanamido)- 5-oxohexanoate
275


 


489




ethyl (S)-6-diazo-2- ((S)-2-(methoxy- d3)propanamido)- 5-oxohexanoate
289


 


490




S-isopropyl (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanethioate
319


 


491




isopropyl (S)-6- diazo-2-((S)-2- (methoxy-d3)-4- (methylthio) butanamido)-5- oxohexanoate
363


 


492




methyl-d3 (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
275


 


493




ethyl-2,2,2-d3 (S)- 6-diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate
289


 


494




isopropyl (S)-6- diazo-2-(2-(ethoxy- 2,2,2- d3)acetamido)-5- oxohexanoate
303


 


495




isopropyl (S)-6- diazo-2-(2-(ethoxy- d5)acetamido)-5- oxohexanoate
305


 


496




ethyl-d5 (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
291


 


497




propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
307


 


498




propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- hydroxypropanamido)-5- oxohexanoate
293


 


499




propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- hydroxy-3- methylbutanamido)- 5-oxohexanoate
321


 


500




propan-2-yl-d7 (S)- 6-diazo-2-(2- ethoxyacetamido)- 5-oxohexanoate
307


 


501




S-(propan-2-yl-d7) (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanethioate
323


 


502




propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- methoxy-4- (methylthio) butanamido)-5- oxohexanoate
367


 


503




methyl-d3 (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate
278


 


504




ethyl-2,2,2-d3 (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate
292


 


505




ethyl-d5 (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate
294


 


506




propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate
310


 


507




propan-2-yl-d7 (S)- 6-diazo-2-(2- (ethoxy-2,2,2- d3)acetamido)-5- oxohexanoate
310


 


508




S-(propan-2-yl-d7) (S)-6-diazo-2-((S)- 2-(methoxy- d3)propanamido)- 5-oxohexanethioate
326


 


509




propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- (methoxy-d3)-4- (methylthio) butanamido)-5- oxohexanoate
370


 


510




propan-2-yl-d7 (S)- 6-diazo-2-(2- (ethoxy- d5)acetamido)-5- oxohexanoate
312


 


511




methyl 6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate-2-d
273


 


512




ethyl 6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate-2-d
287


 


513




isopropyl 6-diazo- 2-((S)-2- methoxypropanamido)-5- oxohexanoate-2-d
301


 


514




isopropyl 6-diazo- 2-(2- ethoxyacetamido)- 5-oxohexanoate-2- d
301


 


515




S-isopropyl 6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate- 2-d
317


 


516




isopropyl 6-diazo- 2-((S)-2-methoxy- 4-(methylthio) butanamido)-5- oxohexanoate-2-d
361


 


517




isopropyl 6-diazo- 2-((S)-2- hydroxypropanamido)-5- oxohexanoate-2-d
287


 


518




isopropyl 6-diazo- 2-((S)-2-hydroxy- 3- methylbutanamido)- 5-oxohexanoate-2- d
315


 


519




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate
309


 


520




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-(2- (ethoxy-2,2,2- d3)acetamido)-5- oxohexanoate
309


 


521




S-(propan-2-yl- 1,1,1,3,3,3-d6) (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanethioate
325


 


522




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- (methoxy-d3)-4- (methylthio) butanamido)-5- oxohexanoate
369


 


523




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-(2- (ethoxy- d5)acetamido)-5- oxohexanoate
311


 


524




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- hydroxypropanamido)-5- oxohexanoate
292


 


525




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- hydroxy-3- methylbutanamido)- 5-oxohexanoate
320


 


526




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-(methoxy- d3)propanamido)- 5-oxohexanoate
306


 


527




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- (2-(ethoxy-2,2,2- d3)acetamido)-5- oxohexanoate
306


 


528




S-(propan-2-yl- 1,1,1-d3) (2S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanethioate
322


 


529




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-(methoxy- d3)-4- (methylthio) butanamido)-5- oxohexanoate
366


 


530




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- (2-(ethoxy- d5)acetamido)-5- oxohexanoate
308


 


531




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2- hydroxypropanamido)-5- oxohexanoate
289


 


532




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-hydroxy-3- methylbutanamido)- 5-oxohexanoate
317


 


533




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate
306


 


534




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-(2- ethoxyacetamido)- 5-oxohexanoate
306


 


535




S-(propan-2-yl- 1,1,1,3,3,3-d6) (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate
322


 


536




propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- methoxy-4- (methylthio) butanamido)-5- oxohexanoate
366


 


537




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate
303


 


538




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- (2- ethoxyacetamido)- 5-oxohexanoate
303


 


539




S-(propan-2-yl- 1,1,1-d3) (2S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate
319


 


540




propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-methoxy-4- (methylthio) butanamido)-5- oxohexanoate
363


 


541




methyl (S)-6-diazo- 2-((S)-2- (methylthio) propanamido)-5- oxohexanoate
288


 


542




ethyl (S)-6-diazo-2- ((S)-2- (methylthio) propanamido)-5- oxohexanoate
302


 


543




isopropyl (S)-6- diazo-2-((S)-2- (methylthio) propanamido)-5- oxohexanoate
316


 


544




isopropyl (S)-6- diazo-2-((S)-2- mercaptopropanamido)-5- oxohexanoate
302


 


545




isopropyl (S)-6- diazo-2-((S)-2- mercapto-3- methylbutanamido)- 5-oxohexanoate
330


 


546




isopropyl (S)-6- diazo-2-(2- (ethylthio)acetamido)- 5-oxohexanoate
316


 


547




S-isopropyl (S)-6- diazo-2-((S)-2- (methylthio) propanamido)-5- oxohexanethioate
332


 


548




isopropyl (S)-2- ((S)-2,4- bis(methylthio) butanamido)-6-diazo-5- oxohexanoate
376


 


549




isopropyl (S)-6- diazo-2-((S)-2- (ethylthio)-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate
445


 


550




isopropyl (S)-2- ((S)-2-(acetylthio)- 4- (methylthio)butanamido)- 6-diazo-5- oxohexanoate
404


 


551




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- (methylthio)propanamido)- 6-diazo-5- oxohexanoate
431


 


552




isopropyl (S)-6- diazo-2-(2- (isopropylthio) acetamido)-5- oxohexanoate
330


 


553




isopropyl (S)-6- diazo-2-((S)-2- (methylthio)-3- phenylpropanamido)- 5-oxohexanoate
392


 


554




isopropyl (S)-6- diazo-2-((S)-2- (methylthio)-2- phenylacetamido)- 5-oxohexanoate
378


 


555




isopropyl (S)-6- diazo-2-((S)-2- (methylthio) butanamido)-5- oxohexanoate
330


 


556




isopropyl (S)-6- diazo-2-((S)-3- methyl-2- (methylthio) butanamido)-5- oxohexanoate
344


 


557




cyclopentyl (S)-6- diazo-2-((S)-2- (methylthio) propanamido)-5- oxohexanoate
342


 


558




isopropyl (S)-6- diazo-5-oxo-2-((S)- thietane-2- carboxamido) hexanoate
314


 


559




methyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate
304


 


560




ethyl (2S)-6-diazo- 2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate
318


 


561




isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate
332


 


562




isopropyl (2S)-6- diazo-2-(2- (ethylsulfinyl) acetamido)-5- oxohexanoate
332


 


563




S-isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanethioate
348


 


564




isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl)-4- (methylthio) butanamido)-5- oxohexanoate
392


 


565




isopropyl (2S)-6- diazo-2-((2S)-2- (ethylsulfinyl)-3- (1H-indol-3- yl)propanamido)-5- oxohexanoate
461


 


566




isopropyl (2S)-2- ((2S)-3-(1H-indol- 3-yl)-2- (methylsulfinyl) propanamido)-6-diazo- 5-oxohexanoate
447


 


567




isopropyl (2S)-6- diazo-2-(2- (isopropylsulfinyl) acetamido)-5- oxohexanoate
346


 


568




isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl)-3- phenylpropanamido)- 5-oxohexanoate
408


 


569




isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl)-2- phenylacetamido)- 5-oxohexanoate
394


 


570




isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) butanamido)-5- oxohexanoate
346


 


571




isopropyl (2S)-6- diazo-2-((2S)-3- methyl-2- (methylsulfinyl) butanamido)-5- oxohexanoate
360


 


572




cyclopentyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate
358


 


573




methyl (S)-6-diazo- 2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate
320


 


574




ethyl (S)-6-diazo-2- ((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate
334


 


575




isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate
348


 


576




isopropyl (S)-6- diazo-2-(2- (ethylsulfonyl) acetamido)-5- oxohexanoate
348


 


577




S-isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanethioate
364


 


578




isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl)-4- (methylthio) butanamido)-5- oxohexanoate
408


 


579




isopropyl (S)-6- diazo-2-((S)-2- (ethylsulfonyl)-3- (1H-indol-3- yl)propanamido)-5- oxohexanoate
477


 


580




isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- (methylsulfonyl) propanamido)-6- diazo-5- oxohexanoate
463


 


581




isopropyl (S)-6- diazo-2-(2- (isopropylsulfonyl) acetamido)-5- oxohexanoate
362


 


582




isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl)-3- phenylpropanamido)- 5-oxohexanoate
424


 


583




isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl)-2- phenylacetamido)- 5-oxohexanoate
410


 


584




isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) butanamido)-5- oxohexanoate
362


 


585




isopropyl (S)-6- diazo-2-((S)-3- methyl-2- (methylsulfonyl) butanamido)-5- oxohexanoate
376


 


586




cyclopentyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate
374









Synthesis of Control Compounds
Compound 60 of WO2017023774 (named “reference compound A”) was obtained according to the synthesis route and operation steps of compound 60 in Page 124 of WO2017023774.
Compound 25 of WO2017023774 (named “reference compound 1”) was obtained according to the synthesis route and operation steps of compound 25 in Page 100-101 of WO2017023774.
Compound 9 of WO2017023774 (named “reference compound 2”) was obtained according to the synthesis route and operation steps of compound 9 in Page 87-88 of WO2017023774.
Compound 47 of WO2017023774 (named “reference compound 3”) was obtained according to the synthesis route and operation steps of compound 47 in Page 115-116 of WO2017023774.
Example 7 Plasma Stability of Different Species
Reference compound A, reference compound 1, reference compound 2, compound 2, compound 3, compound 81, compound 443, compound 459 were provided for assay of plasma stability of compounds in different species, and they were shown as below:




For metabolic stability, plasma from dog, monkey, swine and human were used. For stability, prodrugs (1 μM) were spiked in respective solutions and incubated in an orbital shaker at 37° C. 50 μL aliquots of the mixture in duplicate were removed, and the reaction quenched by addition of four times the volume of ice cold acetonitrile spiked with the internal standard (Dexamethasone 100 ng/mL). The samples were vortexed for 30 s and centrifuged at 15000 g for 5 min. 100 μL of the supernatant was diluted with 100 μL of water and transferred to the 0.6 mL plastic tubes on 96-well plate. Prodrug disappearance was monitored over time using a liquid chromatography and tandem mass spectrometry (LC-MS/MS).
For LC-MS/MS, prodrugs were analyzed on a ExionLC AD HPLC system coupled to REF Triple Quad 5500+ mass spectrometer with an ESI interface on an Phenomenex Kinetex 5 m C18 100A (2.1*50) mm UPLC column. The autosampler was temperature controlled and was operated at 4° C. The mobile phase used for the chromatographic separation was composed of acetonitrile/water containing 0.10% formic acid and will run at a flow rate of 0.6 mL/min for 3.5 min using gradient elution. The column effluent was monitored using TSQ Vantage triple-quadrupole mass-spectrometric detector, equipped with an electrospray probe set in the positive ionization mode. Samples were introduced into the ionization source through a heated nebulized probe (400° C.). Disappearance of prodrugs will be measured from ratio of peak areas of analyte to IS.
For quantification of compound remaining, disappearance of prodrugs was measured from ratio of peak areas of analyte to IS.
FIG. 1 shows the plasma stability of compounds after incubation for 4 hours in the presence of dog, monkey, swine and human plasma. The data show that the Reference compound A, compound 2, compound 3, compound 81, compound 443, compound 459 was substantially intact in the presence of the dog, monkey, swine and human plasma for 4 hours, while few of reference compound 1 and reference compound 2 remained in such conditions.
Example 8 Stability of Liver Microsomes of Different Species
Reference compound A, reference compound 1, reference compound 2, and compound 2, compound 3, compound 81, compound 443, compound 459 were provided for assay of stability of liver microsomes in different species.
For metabolic stability, microsomes from human, monkey, dog, rat and mouse were used. For stability, prodrugs (1 μM) were spiked in each microsomes matrix and incubated in an orbital shaker at 37° C. Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45 and 60 min. The reaction was stopped by the addition of 4 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 2 μM ketoprofen). Samples were centrifuged at 3, 220 g for 40 minutes. Aliquot of 100 μL of the supernatant was mixed with 100 μL of ultra-pure H2O and then used for LC-MS/MS analysis.
For LC-MS/MS, prodrugs were analyzed on an API 4000 instrument from AB Inc (Canada) with an ESI interface coupled to Shimadzu LC system on an Waters XSelect HSS T3 C18, 2.5 m, 2.1×30 mm column. The mobile phase used for the chromatographic separation was composed of Phase A: water (0.1% formic acid); Phase B: acetonitrile (0.1% formic acid) and will run at a flow rate of 1.0 mL/min for 1.0 min using gradient elution. Samples was introduced into the ionization source through a heated nebulized probe (500° C.). Disappearance of prodrugs will be measured from ratio of peak areas of analyte to IS.
For data analysis, peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t1/2) was determined from the slope value:

in vitro t1/2=−(0.693/k)

Conversion of the in vitro t1/2 (min) into the in vitro intrinsic clearance (in vitro CLint, in μL/min/mg protein) was done using the following equation (mean of duplicate determinations):



 
  
   in
   ⁢
      
   vitro
   ⁢
      
   
    CL
    int
   
  
  =
  
   
    0.693
    
     t
     
      1
      /
      2
     
    
   
   ×
   
    
     volume
     ⁢
        
     of
     ⁢
         
     incubation
     ⁢
        
     
      (
      µL
      )
     
    
    
     amount
     ⁢
        
     of
     ⁢
        
     
      proteins
      ⁢
      
         
        
      
      (
      mg
      )
     
    
   
  
 



Table 1 shows the in vitro intrinsic clearance of compounds after incubation for 60 minutes in the presence of human, monkey, dog, rat and mouse liver microsomes.







TABLE 1







In vitro Clint (μL/min/mg protein) of Test Compounds in Different 


Species of Liver Microsomes 












Compounds 
Human 
Monkey 
Dog 
Rat 
Mouse















Reference Compound 1 
95.34 
167.25 
63.64 
123.55 
114.88 


Reference Compound 2 
110.42 
280.56 
50.25 
437.21 
125.68 


Reference Compound A 
118.61 
393.20 
60.41 
95.16 
152.92 


Compound 2 
43.44 
31.78 
12.70 
62.43 
67.14 


Compound 3 
124.33 
46.39 
10.90 
49.47 
71.15 


Compound 81 
16.82 
25.97 
5.49 
268.83 
60.81 


Compound 443 
73.52 
179.92 
81.89 
238.84 
407.55 


Compound 459 
18.88 
130.50 
9.57 
114.96 
71.74









Example 9 Examination on the Anti-Tumor Efficacy in MC38 Syngeneics in C57BL/6 Mouse
Reference compound A, compound 2, compound 3, compound 81, compound 443, compound 459 were provided for the anti-tumor Efficacy in MC38 Syngeneics in C57BL/6 mouse.
Animal species: Mus musculus; Strain: C57BL/6; Age: 6-8 weeks; Sex: female.
The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37° C., 5% CO2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50% Matrigel at a density of 1×107 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 1×106 cells in 0.1 mL of PBS containing 50% Matrigel for tumor development.
The treatments were started when the mean tumor size reached 79-118 mm3 (average tumor size 96 mm3). Each group contained 8 tumor bearing mice. Group 1 was treated with Vehicle (10% DMSO+90% Saline), S.C., QD. Group 2 was given treatments with reference compound A at 2 μmol/kg, S.C., QD. Group 3 was given treatments with compound 2 at 2 μmol/kg, S.C., QD. The administration of test articles in each study group was shown in the following Table 2.
In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.











TABLE 2







Dose 




Group 
Compound 
(μmol/kg) 
Dosing Route 
Schedule







1 
Vehicle 
2 
S.C. 
QD × 16 


2 
Reference compound A 
2 
S.C. 
QD × 26 


3 
Compound 2 
2 
S.C. 
QD × 26









Body Weight

The results of the body weight changes in the tumor-bearing mice are shown in Table 3, FIG. 2.







TABLE 3







The body weight changes (%) of the mice in different groups 











Dose 
BW(g) (Mean ± SEM) 
BW Change 











Compound 
(μmol/kg) 
Beginning (D6) 
End (D21) 
(%)














Vehicle 
2 
21.9 ± 0.4 
24.9 ± 0.4 
+13.6 


Reference 
2 
21.9 ± 0.3 
22.5 ± 0.4 
+2.8 


Compound A 






Compound 2 
2 
21.7 ± 0.2 
22.4 ± 0.2 
+ 3.3









Tumor Volumes

The results of tumor sizes in different groups at different time points post tumor inoculation are shown in Table 4 and FIG. 3. The tumor growth inhibition is summarized in Table 5. The result showed that the other treatment groups showed significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed). All data was analyzed using SPSS 22.0 software.







TABLE 4







Mean tumor volume in the different treatment groups










Dose
TV (mm3) (Mean ± SEM)
















Compound
(μmol/kg)
D6
D10
D14
D18
D21
D25
D28
D31





Vehicle
2
96 ± 4
354 ± 17
909 ± 42
1732 ± 114
2778 ± 188





Reference
2
96 ± 4
148 ± 6
196 ± 25
 297 ± 48
 399 ± 74
680 ± 143
928 ± 153
1358 ± 213


compound A











Compound 2
2
96 ± 4
141 ± 9
140 ± 10
 180 ± 13
 263 ± 32
381 ± 55
496 ± 62
 617 ± 56
















TABLE 5







Anti-tumor activity of test compounds in MC38 syngeneic model 













Dose 
TV (mm3) at D21 
T/C 
TGI 
Pvalue 


Compound 
(μmol/kg) 
(Mean ± SEM) 
(%) 
(%) 
(vs. Vehicle)





Vehicle 
2 
2778 ± 188 
—
—
—


Reference 
2 
399 ± 74 
14.4 
85.6 
0.000 


Compound A 







Compound 2 
2 
263 ± 32 
9.5 
90.5 
0.000









Example 10 Examination on the Anti-Tumor Efficacy in MC38 Model in CES1c −/− Mouse
Reference compound A and compound 2 obtained from example 2 were provided for the anti-tumor Efficacy in MC38 model in CES1c −/− mouse.
Animal species: Mus musculus; Strain: C57BL/6-Ces1cemISmoc; Age: 6-8 weeks; Sex: female. (Shanghai Model Organisms). The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37° C., 5% CO2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50% Matrigel at a density of 1×107 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 1×106 in 0.1 mL of PBS containing 50% Matrigel for tumor development.
The treatments were started when the mean tumor size reached 52-132 mm3 (average tumor size 95 mm3). Each group contained 5 tumor bearing mice. Group 1 was treated with Vehicle (10% DMSO+90% Saline), S.C., QD(Subcutaneous injection, quaque die). Group 2 was given treatments with reference compound A at 2 μmol/kg, S.C., QD. Group 3 was given treatments with compound 2 at 2 μmol/kg, S.C., QD. The administration of test articles in each study group was shown in the following Table 6.
In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.











TABLE 6







Dose 




Group 
Compound 
(μmol/kg) 
Dosing Route 
Schedule







1 
Vehicle 
2 
S.C. 
QD × 21 


2 
Reference compound A 
2 
S.C. 
QD × 21 


3 
Compound 2 
2 
S.C. 
QD × 21









Body Weight

Group treated with reference compound A showed some body weight loss, but the group treated with vehicle and the group treated with compound 2 were well-tolerated by the tumor-bearing mice. The results of the body weight changes in the tumor-bearing mice are shown in Table 7, FIG. 4.







TABLE 7







The body weight changes (%) of the mice in different groups 











Dose 
BW(g) (Mean ± SEM) 
BW Change 











Compound 
(μmol/kg) 
Beginning (D6) 
End (D26) 
(%)














Vehicle 
2 
18.0 ± 0.3 
20.3 ± 0.3 
+12.8 


Reference 
2 
19.2 ± 0.2 
17.6 ± 0.9 
−8.3 


Compound A 






Compound 2 
2 
19.1 ± 0.3 
19.5 ± 0.3 
+2.4









Tumor Volumes

The results of tumor sizes in different groups at different time points post tumor inoculation are shown in Table 8 and FIG. 5. The tumor growth inhibition is summarized in Table 9. The result showed that all treatment groups showed significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed). All data was analyzed using SPSS 22.0 software.







TABLE 8







Mean tumor volume in the different treatment groups










Dose
TV (mm3) (Mean ± SEM)















Compound
(μmol/kg)
D6
D9
D12
D15
D20
D23
D26





Vehicle
2
95 ± 13
259 ± 13
275 ± 22
448 ± 29
825 ± 85
1300 ± 242
2234 ± 413


Reference Compound A
2
95 ± 6
275 ± 33
147 ± 5
195 ± 23
196 ± 33
 183 ± 33
 274 ± 81


Compound 2
2
95 ± 11
193 ± 20
103 ± 15
131 ± 21
169 ± 19
 219 ± 21
 313 ± 35
















TABLE 9







Anti-tumor activity of test compounds in MC38 syngeneic model 













Dose 
TV (mm3) at D26 
T/C 
TGI 
P value 


Compound 
(μmol/kg) 
(Mean ± SEM) 
(%) 
(%) 
(vs. Vehicle)





Vehicle 
2 
2234 ± 413 
—
—
—


Reference 
2 
274 ± 81 
12.3 
87.7 
0.046 


Compound A 







Compound 2 
2 
313 ± 35 
14.0 
86.0 
0.052









Example 11 Examination on the Anti-Tumor Efficacy in MC38 Model in C57BL/6 Mouse
Compound 2, compound 3, compound 81, compound 443 and compound 459 were provided for the anti-tumor Efficacy in MC38 model in C57BL/6 mouse.
Animal species: Mus musculus; Strain: C57BL/6; Age: 6-8 weeks; Sex: female. The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37° C., 5% CO2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50% Matrigel at a density of 1×107 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 1×106 cells in 0.1 mL of PBS containing 50% Matrigel for tumor development.
The treatments were started when the mean tumor size reached 82-129 mm3 (average tumor size 102 mm3). Each group contained 6 tumor bearing mice. Group 1 was treated with Vehicle (10% DMSO+90% Saline), S.C., QD. Group 2 was given treatments with compound 2 at 2 μmol/kg, S.C., QD. Group 3 was given treatments with compound 81 at 2 μmol/kg, S.C., QD. Group 4 was given treatments with compound 443 at 2 μmol/kg, S.C., QD. Group 5 was given treatments with compound 459 at 2 μmol/kg, S.C., QD. Group 6 was given treatments with compound 3 at 2 μmol/kg, S.C., QD. The administration of test articles in each study group was shown in the following Table 10.
In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.











TABLE 10





Group 
Compound 
Dose (μmol/kg) 
Dosing Route 
Schedule







1 
Vehicle 
2 
S.C. 
QD × 15 


2 
Compound 2 
2 
S.C. 
QD × 15 


3 
Compound 81 
2 
S.C. 
QD × 15 


4 
Compound 443 
2 
S.C. 
QD × 15 


5 
Compound 459 
2 
S.C. 
QD × 15 


6 
Compound 3 
2 
S.C. 
QD × 15









Body Weight

The results of the body weight changes in the tumor-bearing mice are shown in Table 11, FIG. 6.







TABLE 11







The body weight changes (%) of the mice in different groups 











Dose 
BW(g) (Mean ± SEM) 
BW Change 











Compound 
(μmol/kg) 
Beginning (D6) 
End (D20) 
(%)














Vehicle 
2 
19.9 ± 0.5 
23.6 ± 0.8 
+18.6 


Compound 2 
2 
19.8 ± 0.2 
21.1 ± 0.3 
+6.4 


Compound 81 
2 
19.8 ± 0.3 
20.2 ± 0.5 
+1.9 


Compound 443 
2 
19.9 ± 0.6 
22.3 ± 0.5 
+11.9 


Compound 459 
2 
19.9 ± 0.3 
21.1 ± 0.5 
+6.3 


Compound 3 
2 
19.9 ± 0.5 
21.5 ± 0.4 
+7.8









Tumor Volumes

The results of tumor sizes in different groups at different time points post tumor inoculation are shown in Table 12 and FIG. 7. The tumor growth inhibition is summarized in Table 13. The result showed that the other treatment groups showed significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed). All data was analyzed using SPSS 22.0 software.







TABLE 12







Mean tumor volume in the different treatment groups










Dose
TV (mm3) (Mean ± SEM)













Compound
(μmol/kg)
D6
D10
D13
D17
D20





Vehicle
2
102 ± 5
451 ± 37
810 ± 114
1537 ± 216
2331 ± 369


Compound 2
2
102 ± 7
167 ± 17
257 ± 51
 306 ± 43
 407 ± 33


Compound 81
2
102 ± 6
141 ± 9
124 ± 10
 176 ± 13
 112 ± 22


Compound 443
2
102 ± 6
152 ± 25
267 ± 65
 384 ± 95
 500 ± 119


Compound 459
2
102 ± 5
148 ± 22
183 ± 30
 281 ± 65
 275 ± 59


Compound 3
2
102 ± 6
145 ± 16
169 ± 9
 215 ± 27
 233 ± 31
















TABLE 13







Anti-tumor activity of test compounds in MC38 syngeneic model 













Dose 
TV (mm3) at D21 
T/C 
TGI 
P value 


Compound 
(μmol/kg) 
(Mean ± SEM) 
(%) 
(%) 
(vs. Vehicle)





Vehicle 
2 
2331 ± 369 
—
—
—


Compound 2 
2 
407 ± 33 
17.5 
82.5 
0.022 


Compound 81 
2 
112 ± 22 
4.8 
95.2 
0.012 


Compound 443 
2 
 500 ± 119 
21.5 
78.5 
0.023 


Compound 459 
2 
275 ± 59 
11.8 
88.2 
0.016 


Compound 3 
2 
233 ± 31 
10.0 
90.0 
0.015