Amide compound for treating and / or preventing hepatitis virus infection

Abstract

The invention relates to amide compounds for treating and / or preventing hepatitis virus infection. Specifically, the compound provided by the invention has a structure as shown in a formula A, and the definitions of all groups and substituent groups are described in the specification. The compound has higher activity, higher selectivity, better in-vivo drug effect, better safety, better pharmacokinetic property and better druggability.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to a class of amide compounds for the treatment and / or prevention of hepatitis virus infection, their preparation methods and applications, which can effectively inhibit HBV virus replication and reduce HBV surface antigen (HBsAg). Background Technology

[0002] Hepatitis B virus (HBV) is an enveloped DNA virus belonging to the Hepadnaviridae family. Chronic hepatitis B (CHB) can progress to serious liver diseases such as liver fibrosis, cirrhosis, liver failure, and hepatocellular carcinoma (HCC). The World Health Organization estimates that 2 billion people worldwide have been infected with HBV, with approximately 300 million chronically infected individuals. Around 1.5 million new infections occur annually, and approximately 1 million people die each year from liver diseases caused by HBV infection. Chronic hepatitis B remains a serious global disease threatening human health. Although current treatments can suppress HBV replication and reduce liver damage, they cannot eliminate HBV or achieve a clinical cure.

[0003] Therefore, novel or improved drugs and treatments remain in urgent clinical need. Summary of the Invention

[0004] This invention provides a class of compounds that can effectively inhibit HBV virus replication and suppress HBsAg secretion in HBV-infected cells. Compared to similar compounds known in the art, the compounds of this invention exhibit higher activity, higher selectivity, better in vivo efficacy, better safety, superior pharmacokinetic properties, and better druggability.

[0005] The present invention also provides pharmaceutical compositions containing the said compound and methods of using the compound or composition to inhibit HBV replication and / or treat diseases related to or caused by HBV.

[0006] In a first aspect, the present invention provides a compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, said compound having the structure shown in Formula A:

[0007]

[0008] in,

[0009] R1 is selected from the following group: substituted or unsubstituted groups: C 6-10Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, halogenated and deuterated or only deuterated C 1-6 Alkyl, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyl, halogenated, and deuterated or only deuterated C 1-6 alkoxy, halogenated, and deuterated or only deuterated C 3-6 cycloalkyloxy; and / or

[0010] R1' is selected from the following groups: H, C 1-6 alkyl,

[0011] and / or

[0012] Ring A is selected from the following group, either substituted or unsubstituted: C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, halogenated and deuterated or only deuterated C 1-6 Alkyl, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyl, halogenated, and deuterated or only deuterated C 1-6 alkoxy, halogenated, and deuterated or only deuterated C 3-6 cycloalkyloxy; and / or

[0013] R' and R” are each independently selected from the following groups: hydrogen, halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, halogenated and deuterated or only deuterated C 1-6 Alkyl, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyl, halogenated, and deuterated or only deuterated C 1-6 alkoxy, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyloxy group; or R', R” and the carbon atom and / or heteroatom attached thereto form the substituted or unsubstituted group: C 3-6 Cycloalkyl groups, 5-10 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyloxy groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; and / or

[0014] R is selected from the following group:

[0015] and / or

[0016] R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, hydroxyl, halogen, cyano, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 Alkynyl; the above-mentioned alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl groups may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 Alkyl groups; and / or

[0017] Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0018] Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S; and / or

[0019] Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0020] Or R9, R 10 Together with the carbon atom it is attached to, they form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S; and / or

[0021] Ring B is absent or selected from the following group of substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy and / or

[0022] m is selected from the following groups: 0, 1, 2, 3; and / or

[0023] U is and / or

[0024] V is and / or

[0025] R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl, -(C=O)-CH2-N(C 1-6 alkyl)-(C=O)-CH(NH3Cl)-CH2-C 6-10 aryl; and / or

[0026] R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6Cycloalkyl carbonyl, halogenated C 1-6 cycloalkyl carbonyl,

[0027]

[0028] Wherein, the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, -N(C 1-6 alkyl)-(C=O)-CH(NH3Cl)-CH2-C 6-10 Aryl, -N(C 1-6 alkyl)-(C=O)-CH(NH3Cl)-CH2-C 6-10 Aryl, -O-(CH2)2-NH3Cl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; and / or

[0029] R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl, cycloalkyl, or heterocyclic alkyl is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkoxy, cyano; and / or

[0030] R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl;

[0031] R”' is selected from the following group: H,

[0032] In another preferred embodiment, the compound has the structure shown in Formula B:

[0033]

[0034] in,

[0035] R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy;

[0036] X is selected from the following group: N, NR2, O, S, CR2;

[0037] Y is selected from the following groups: N, NR3, O, S, CR3;

[0038] Z is selected from the following group: N, C;

[0039] W is selected from the following groups: N, NR4, O, S, CR4;

[0040] R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the carbon and / or nitrogen atoms attached thereto form a substituted or unsubstituted 5- to 10-membered heterocycloalkyl or heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy;

[0041] R is selected from the following group:

[0042]

[0043] R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, hydroxyl, halogen, cyano, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 The alkyne group, and the alkenyl, alkyne, alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl groups mentioned above, may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0044] Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0045] Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0046] Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0047] Or R9, R 10 Together with the carbon atom it is attached to, they form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0048] Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy

[0049] m is selected from the following group: 0, 1, 2;

[0050] U is

[0051] V is

[0052] R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0053] R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH;

[0054] R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl, cycloalkyl, or heterocyclic alkyl is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group;

[0055] R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl;

[0056] R ”’ Selected from the following group: H,

[0057]

[0058] In another preferred embodiment, R1 is selected from the following group: C (substituted or unsubstituted). 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy;

[0059] X is NR2;

[0060] Y is CR3;

[0061] Z is C;

[0062] W is CR4;

[0063] R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C.1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the nitrogen and / or carbon atom attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0064] R is selected from the following group:

[0065] R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, hydroxyl, halogen, cyano, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 The alkyne group, and the alkenyl, alkyne, alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl groups mentioned above, may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0066] Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0067] Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0068] Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0069] Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy

[0070] m is selected from the following groups: 0, 1;

[0071] U is

[0072] V is

[0073] R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0074] R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH;

[0075] R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group;

[0076] R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl;

[0077] R ”’ Selected from the following group: H,

[0078] In another preferred embodiment, R1 is selected from the following group: C (substituted or unsubstituted). 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0079] R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl;

[0080] Alternatively, R4 is selected from the following group: C 1-6 Alkyl, C3-6 A cycloalkyl group, wherein R2, R3, and the nitrogen and / or carbon atoms attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0081] R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 The alkyne group, alkyne group, alkyl group, cycloalkyl group, aryl group, and heteroaryl group may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0082] Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0083] Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S;

[0084] Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0085] Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl,

[0086] m is selected from the following groups: 0, 1;

[0087] U is

[0088] V is

[0089] R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0090] R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH;

[0091] R 15 Selected from the following group: C 1-6 Alkyl, C 3-6Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group;

[0092] R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group;

[0093] R ”’ Selected from the following group: H,

[0094] In another preferred embodiment, R1 is substituted or unsubstituted C. 6-10 aryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 alkyl;

[0095] X is NR2;

[0096] Y is CR3;

[0097] Z is C;

[0098] W is CR4;

[0099] R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the nitrogen and / or carbon atom attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0100] R is

[0101] m is selected from the following groups: 0, 1;

[0102] R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl group, C 3-6 cycloalkyl;

[0103] R”' is selected from the following group: H,

[0104] In another preferred embodiment, R1 is selected from the following group: C (substituted or unsubstituted). 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy;

[0105] X is NR2;

[0106] Y is CR3;

[0107] Z is C;

[0108] W is CR4;

[0109] R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the nitrogen and / or carbon atom attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0110] R is

[0111] R9, R 10 R 11 R 12 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0112] Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy

[0113] m is 0 or 1;

[0114] V is

[0115] R 13 It is hydrogen;

[0116] R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH;

[0117] R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group;

[0118] R”' is selected from the following group: H,

[0119] In another preferred embodiment, R1 is selected from the following group: C (substituted or unsubstituted). 6-10Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0120] R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl;

[0121] Alternatively, R4 can be selected from the following group: C 1-6 Alkyl, C 3-6 A cycloalkyl group, wherein R2, R3, and the nitrogen and / or carbon atoms attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl;

[0122] R9, R 10 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl;

[0123] R 11 R 12 It is hydrogen;

[0124] R is

[0125] Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy

[0126] m is 0 or 1;

[0127] V is

[0128] R 13 It is hydrogen;

[0129] R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH;

[0130] R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group;

[0131] R”' is selected from the following group: H,

[0132] In another preferred embodiment, the compound is selected from the group consisting of:

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140] A second aspect of the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of any of the compounds described in the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof.

[0141] In another preferred embodiment, the pharmaceutical composition further comprises a second active ingredient selected from the group consisting of interferon, nucleoside analogs, nucleotide analogs, sequence-specific oligonucleotides, nucleic acid polymers, entry inhibitors, immunomodulators, or combinations thereof.

[0142] In another preferred embodiment, the interferon is a recombinant interferon selected from the group consisting of α2b, IFN-α, PEGIFN-α-2a, or a combination thereof.

[0143] In another preferred embodiment, the nucleoside analogue is selected from the group consisting of lamivudine, telbivudine, adefovir dipivoxil, clavidine, entecavir, tenofovir alafenamide, tenofovir disoproxil fumarate, or combinations thereof.

[0144] A third aspect of the invention provides the use of any of the compounds described in the first aspect of the invention, or pharmaceutically acceptable salts, stereoisomers, solvates, isotopically labeled compounds, metabolites, or prodrugs thereof, for the preparation of a medicament for the prevention and / or treatment of hepatitis virus infection.

[0145] In another preferred embodiment, the hepatitis virus infection is selected from the group consisting of hepatitis B and hepatitis C.

[0146] In another preferred embodiment, the drug is used to treat and / or prevent HBV infection.

[0147] In another preferred embodiment, the drug is used to inhibit HBV virus replication.

[0148] In another preferred embodiment, the drug is used to inhibit the secretion of HBsAg.

[0149] In another preferred embodiment, the treatment subject is a mammal, such as a human.

[0150] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0151] Through long-term and in-depth research, the inventors unexpectedly prepared a novel compound with higher activity, higher selectivity, better in vivo efficacy, better safety, superior pharmacokinetic properties, and better drug-likeness via structural design. Based on this, the inventors completed this invention.

[0152] the term

[0153] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0154] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0155] In this invention, the term "C" 1-6 "Alkyl" refers to a straight-chain or branched alkyl group comprising 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0156] In this invention, the term "C" 2-6 "Alkenyl" refers to a straight-chain or branched alkenyl group with 2-6 carbon atoms and containing a double bond, and includes, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl groups.

[0157] In this invention, the term "C" 2-6 "Alynyl" refers to a straight-chain or branched alkynyl group with 2-6 carbon atoms and containing a triple bond, and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0158] In this invention, the term "C" 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3-6 carbon atoms on a ring, and includes, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0159] In this invention, the term "C" 1-6 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1-6 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is C16. 1-4 Alkyl group.

[0160] In this invention, the term "heterocyclic group" refers to a 5-10 member heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, including (but not limited to) the following groups:

[0161] In this invention, the terms "aromatic ring" or "aryl" have the same meaning, and are preferably "C". 6-10 "Aromatic". The term "C" 6-10 "Aryl" refers to an aromatic cyclic group with 6-10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl.

[0162] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more heteroatoms. Non-limiting examples include: furanyl, thiopheneyl, pyridyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0163] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0164] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0165] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0166] compound

[0167] This invention provides a compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, having the structure shown in Formula A:

[0168]

[0169] The groups are defined as described above.

[0170] In another preferred embodiment, in the compound, any one of rings R1, R1', R, R', R”, R”', and A is independently the corresponding group in the specific compound of the present invention.

[0171] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0172] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0173] The term "solvent complex" refers to a complex formed by the coordination of the compound of this invention with solvent molecules in a specific ratio.

[0174] Furthermore, the compounds of this invention also include prodrugs of compounds represented by Formula A. The term "prodrug" includes compounds that are themselves biologically active or inactive, and which, upon administration by an appropriate method, are metabolized or chemically reacted in the human body to form compounds of Formula A, or salts or solutions of compounds of Formula A. The prodrugs include (but are not limited to) carboxylic acid esters, carbonates, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, etc.

[0175] The embodiments of this invention specifically describe the preparation method of compound A of this invention, but these specific methods do not constitute any limitation on this invention. The compounds of this invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0176] Typically, the raw materials and reagents used in the preparation process of the compounds of the present invention can be purchased commercially unless otherwise specified.

[0177] Pharmaceutical Compositions and Administration

[0178] The present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of the compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof.

[0179] The purpose of pharmaceutical compositions is to facilitate the administration of compounds to organisms. Typically, the compounds of this invention can be formulated into suitable dosage forms with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral administration, rectal administration, topical administration, and other non-gastrointestinal administration (e.g., subcutaneous, intramuscular, intravenous, etc.). For example, suitable dosage forms for oral administration include capsules, tablets, granules, and syrups. The compounds of this invention contained in these formulations can be solid powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; water-in-oil or oil-in-water emulsions, etc. The above dosage forms can be prepared from an active compound and one or more pharmaceutically acceptable carriers using common pharmaceutical methods. A pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound. The carrier needs to be compatible with the active compound or other excipients. For solid dosage forms, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, calcium carbonate, calcium phosphate, starch, cellulose and its derivatives, glucose, sucrose, gelatin, etc. Carriers used in liquid formulations include water, physiological saline, glucose solution, vegetable oil, ethylene glycol, and polyethylene glycol. The active compound can form a solution or suspension with these carriers.

[0180] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0181] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0182] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0183] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0184] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0185] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0186] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0187] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0188] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0189] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0190] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0191] The specific method of administration and dosage form depend on the physicochemical properties of the compound itself and the severity of the disease to which it is applied.

[0192] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0193] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skills of a skilled physician.

[0194] Compared with the prior art, the present invention has the following main advantages:

[0195] (1) The compounds of the present invention have higher activity, higher selectivity, better in vivo efficacy, better safety, better pharmacokinetic properties and better drug-likeness.

[0196] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0197] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0198] Preparation of intermediate A1

[0199]

[0200] Step 1: Preparation of intermediate A1-2

[0201] Add A1-1 (25 g, 149.7 mmol, 1.0 eq) and DMSO (150 mL) to a 250 mL round-bottom flask. Add KOH (12.6 g, 224.6 mmol, 1.50 eq) in portions under ice bath conditions. Stir the reaction mixture at room temperature for 30 minutes. Add iodomethane (22.3 g, 157.2 mmol, 1.05 eq) dropwise and stir at room temperature for 4 hours. Quench the reaction mixture with water (200 mL), extract with EA (500 mL), wash the organic phase with brine (200 mL) and water (5 × 100 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give compound A1-2 (27 g, yield: 99.6%).

[0202] MS(ESI,[M+H) + m / z:=182.10

[0203] Step 2: Preparation of intermediate A1-3

[0204] Compound A1-2 (27 g, 147.5 mmol, 1.0 eq) and compound 4-fluoro-3-trifluoromethylaniline (39.6 g, 221.3 mmol, 1.5 eq) were added to a 500 mL three-necked flask. Nitrogen gas was purged, and THF (200 mL) was added using a syringe. Hexamethyldisilamide lithium (443 mL, 442.6 mmol, 3.0 eq, 1 M THF solution) was added dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction system was quenched with saturated ammonium chloride solution (150 mL), and the mixture was extracted with EA (3 × 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by slurrying with methyl tert-butyl ether to give A1-3 (42 g, yield: 89.6%).

[0205] MS(ESI,[M+H) + m / z:=315.00

[0206] Step 3: Preparation of intermediate A1-4

[0207] Add A1-3 (22 g, 70.1 mmol, 1.00 eq) and dichloromethane (200 mL) to a 500 mL three-necked round-bottom flask. Add dropwise a solution of ethyl chloroxaate (14.3 g, 105.1 mmol, 1.50 eq) in dichloromethane (60 mL) at 0 °C. Add aluminum chloride (23.3 g, 175.1 mmol, 2.50 eq) in portions. Stir overnight at room temperature. After the reaction is complete, quench the reaction mixture with water / ice. Extract the reaction solution with dichloromethane (3 × 200 mL). Combine the organic phases, wash with saturated sodium bicarbonate solution (300 mL) and water (200 mL), dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 7:3) to give A1-4 (7.8 g, yield: 26.9%).

[0208] MS(ESI,[M+H) + m / z:=416.00

[0209] Step 4: Preparation of intermediate A1

[0210] Add Al-4 (7.8 g, 18.8 mmol, 1.0 eq), lithium hydroxide (902 mg, 37.6 mmol, 2.0 eq), THF (100 mL), methanol (50 mL), and water (50 mL) to a 250 mL round-bottom flask. Stir the reaction mixture at room temperature for 2 h. After the reaction is complete, remove the organic solvent under reduced pressure, add hydrochloric acid (40 mL, 1 mol / L), and extract the mixture with EA (3 × 150 mL). Combine the organic phases, dry to anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify the residue by silica gel column chromatography (dichloromethane / methanol = 10:1) to give Al (4.28 g, yield: 59.1%).

[0211] MS(ESI,[M+H) + m / z:=387.20

[0212] 1 HNMR (400MHz, DMSO-d6) δ10.53(s,1H),8.21(dd,J=6.5,2.5Hz,1H),8.04–7.89(m,1H),7.52(t,J=9.8Hz,1H),3.60(s,3H),2.45(s,3H),2.27(s,3H).

[0213] Preparation of intermediate A2

[0214]

[0215] Step 1: Preparation of intermediate A2-2

[0216] Compound A2-1 (5.0 g, 33.51 mmol, 1.0 eq) was dissolved in DCM (50 mL), and Boc2O (7.31 g, 33.51 mmol, 1.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE / EA = 10 / 1) to give compound A2-2 (8.16 g, yield: 97%).

[0217] MS(ESI,[M+Na)) + m / z:=272.20

[0218] Step 2: Preparation of intermediate A2-3

[0219] Compound A2-2 (500 mg, 2.01 mmol, 1.0 eq) and triethylamine (244 mg, 2.41 mmol, 1.2 eq) were dissolved in DCM (5 mL). The reaction solution was cooled to 0 °C, and MsCl (253 mg, 2.21 mmol, 1.1 eq) was added dropwise. The reaction solution was heated to room temperature under a nitrogen atmosphere and stirred for 2 hours. Water (20 mL) was added, and the reaction solution was extracted with dichloromethane (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound A2-3 (583 mg, yield: 88%).

[0220] MS(ESI,[M+Na)) + m / z:350.10

[0221] Step 3: Preparation of intermediate A2-4

[0222] Compound A2-3 (450 mg, 1.37 mmol, 1.0 eq) was dissolved in DMF (5 mL), and sodium methanethiol (963 mg, 13.74 mmol, 10 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 24 / 1) to give compound A2-4 (200 mg, yield: 52%).

[0223] MS(ESI,[M+Na)) + m / z:302.10

[0224] Step 4: Preparation of intermediate A2-5

[0225] Compound A2-4 (190 mg, 0.680 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (212 mg, 2.72 mmol, 4.0 eq) and iodophenyldiacetic acid (657 mg, 2.04 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue A2-5 (200 mg, yield: 94%) was used directly in the next reaction.

[0226] MS(ESI,[M+H) + )m / z:311.20

[0227] Step 5: Preparation of intermediate A2

[0228] Compound 6 (200 mg, 0.644 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue A2 (200 mg) was used directly in the next step of the reaction.

[0229] MS(ESI,[M+H) + )m / z:211.10

[0230] Preparation of intermediate A3

[0231]

[0232] Step 1: Preparation of intermediate A3-2

[0233] Compound A3-1 (10.0 g, 95.11 mmol, 1.0 eq) was dissolved in methanol (200 mL), and Boc2O (24.9 g, 114.14 mmol, 1.2 eq) was added under ice bath conditions. The reaction solution was reacted at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound A3-2 (19.0 g, yield: 97%).

[0234] MS(ESI,[M+Na)) + )m / z:228.10

[0235] Step 2: Preparation of intermediate A3-3

[0236] Compound 2 (10.0 g, 48.72 mmol, 1.0 eq) was dissolved in DCM (200 mL), and imidazole (4.98 g, 73.08 mmol, 1.5 eq) and tert-butyldiphenylchlorosilane (12 mL, 46.28 mmol, 0.95 eq) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound A3-3 (16.0 g, yield: 74%).

[0237] MS(ESI,[M+Na)) + )m / z:466.20

[0238] Step 3: Preparation of intermediate A3-4

[0239] Compound A3-3 (10 g, 22.54 mmol, 1.0 eq) was dissolved in DCM (100 mL), and Dys-Martin reagent (11.5 g, 27.05 mmol, 1.2 eq) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane, filtered, and the filtrate was washed with saturated sodium bicarbonate aqueous solution and water. After drying with anhydrous sodium sulfate, the solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound A3-4 (8.8 g, yield: 88%).

[0240] MS(ESI,[M+Na)) + )m / z:464.20

[0241] Step 4: Preparation of intermediate A3-5

[0242] Compound A3-4 (10 g, 22.64 mmol, 1.0 eq) was dissolved in methanol (60 mL). Dimethyl (1-diazo-2-oxopropyl)phosphonate (3.76 g, 27.17 mmol, 1.2 eq) and potassium carbonate (9.57 g, 49.81 mmol, 2.2 eq) were added under ice bath conditions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 9 / 1) to give compound A3-5 (6.5 g, yield: 66%).

[0243] MS(ESI,[M+Na)) + m / z:460.20

[0244] Step 5: Preparation of intermediate A3-6

[0245] Compound A3-5 (3.4 g, 7.8 mmol, 1.0 eq) was dissolved in THF (20 mL), and 1 M tetrabutylammonium fluoride tetrahydrofuran solution (10 mL) was added. The reaction solution was reacted at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound A3-6 (1.4 g, yield: 88%).

[0246] Step 6: Preparation of intermediate A3-7

[0247] Compound A3-6 (1.4 g, 7.03 mmol, 1.0 eq) and triethylamine (3 mL, 21.08 mmol, 3.0 eq) were dissolved in dichloromethane (15 mL). The reaction solution was cooled to 0 °C, and methanesulfonyl chloride (1.05 g, 9.13 mmol, 1.3 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with DCM, washed with water, saturated citric acid solution, and water. The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound A3-7 (1.7 g, yield: 87%).

[0248] Step 7: Preparation of intermediate A3-8

[0249] Compound A3-7 (600 mg, 2.16 mmol, 1.0 eq) was dissolved in a toluene / ethanol mixture (15 mL / 15 mL), and sodium methanethiol (607 mg, 8.65 mmol, 4.0 eq) was added. The mixture was reacted at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A3-8 (496 mg, yield: 100%).

[0250] MS(ESI,[M+Na)) + )m / z:252.10

[0251] Step 8: Preparation of intermediate A3

[0252] Compound A3-8 (336 mg, 1.47 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the crude residue A3 (400 mg) was concentrated under reduced pressure and used directly in the next step of the reaction.

[0253] Preparation of intermediate A4

[0254]

[0255] Step 1: Synthesis of intermediate A4-1

[0256] Compound A1-2 (10.0 g, 55.2 mmol, 1.0 eq) and compound 3,4-difluoroaniline (10.69 g, 82.8 mmol, 1.5 eq) were added to a dry three-necked flask. Nitrogen gas was purged, and THF (150 mL) was added using a syringe. The mixture was cooled to 0 °C, and a THF solution of hexamethyldisilamide lithium (165.6 mL, 165.6 mmol, 3.0 eq, 1 M) was added dropwise. The mixture was then heated to room temperature and stirred for 16 h. After the reaction was complete, the reaction solution was poured into ice water (500 mL) and extracted with EA (3 × 200 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by slurrying with methyl tert-butyl ether to give compound A4-1 (14.0 g, yield: 91%).

[0257] MS(ESI,[M+H) + m / z:265.10

[0258] Step 2: Synthesis of intermediate A4-2

[0259] Compound A4-1 (10 g, 37.8 mmol, 1.0 eq) was dissolved in dichloromethane (130 mL), and nitrogen was purged. Ethyl chloroxaate (7.74 g, 56.7 mmol, 1.5 eq) in dichloromethane (20 mL) was added dropwise to the mixture at 0 °C. Aluminum chloride (12.6 g, 94.5 mmol, 2.5 eq) was added in portions, and the reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was quenched by adding ice water (100 mL), and extracted with dichloromethane (3 × 300 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (300 mL) and water (300 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by pulping (petroleum ether / ethyl acetate = 1:1) to give compound A4-2 (10.0 g, yield: 69%).

[0260] MS(ESI,[M+H) + )m / z:365.10

[0261] Step 3: Synthesis of intermediate A4

[0262] Compound A4-2 (1.5 g, 4.12 mmol, 1.0 eq) was dissolved in a mixed solvent (THF / MeOH / H2O = 20 / 10 / 5 mL), and LiOH (296 mg, 12.36 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 4 with saturated citric acid aqueous solution, diluted with water (30 mL), and extracted with ethyl acetate (3 × 40 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was then slurried (PE / EA = 1 / 1, 20 mL) to obtain compound A4 (1.2 g, yield: 86%).

[0263] MS(ESI,[M+H) + )m / z:337.10

[0264] Preparation of intermediate A5

[0265]

[0266] Step 1: Preparation of intermediate A5-2

[0267] Compound A5-1 (500 mg, 3.49 mmol, 1.0 eq) was dissolved in THF (10 mL), and LiAlH4 (397 mg, 10.48 mmol, 3.0 eq) was added at 0 °C. The reaction mixture was stirred at 70 °C for 16 hours. After the reaction was complete, the temperature was lowered to 0 °C, quenched with sodium sulfate decahydrate, diluted with ethyl acetate, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound A5-2 (500 mg, yield: 100%).

[0268] MS(ESI,[M+H) + m / z:130.20

[0269] Step 2: Preparation of intermediate A5-3

[0270] Compound A5-2 (500 mg, 3.87 mmol, 1.0 eq) was dissolved in DCM (10 mL), and Boc₂O (844 mg, 3.87 mmol, 1.0 eq) and triethylamine (1.17 g, 11.58 mmol, 3.0 eq) were added at 0 °C. The reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A5-3 (900 mg, yield: 100%).

[0271] MS(ESI,[M+Na)) + m / z:252.20

[0272] Step 3: Preparation of intermediate A5-4

[0273] Compound A5-3 (900 mg, 3.90 mmol, 1.0 eq) and triethylamine (1.18 g, 11.72 mmol, 3 eq) were dissolved in DCM (5 mL). The reaction mixture was cooled to 0 °C, and MsCl (537 mg, 4.68 mmol, 1.2 eq) was added dropwise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A5-4 (1.2 g, yield: 99%).

[0274] MS(ESI,[M+Na)) + )m / z:330.20

[0275] Step 4: Preparation of intermediate A5-5

[0276] Compound A5-4 (1.0 g, 3.2 mmol, 1.0 eq) was dissolved in DMF (20 mL), and sodium methanethiol (1.12 g, 16.0 mmol, 5 eq) was added. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A5-5 (0.8 g, yield: 95%).

[0277] MS(ESI,[M+Na)) + m / z:282.20

[0278] Step 5: Preparation of intermediate A5

[0279] Compound A5-5 (500 mg, 1.92 mmol) was added to an ethanol solution of hydrochloric acid (4 M, 10 mL) and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound A5 (250 mg, yield: 66%), which was directly used in the next reaction step.

[0280] MS(ESI,[M+H) + m / z:160.20

[0281] Preparation of intermediate A6

[0282]

[0283] Step 1: Preparation of intermediate A6-1

[0284] Compound A1-2 (3.1 g, 17.1 mmol, 1.0 eq) and 3-chloro-4-fluoroaniline (3.7 g, 25.7 mmol, 1.5 eq) were added to a dry three-necked flask. Nitrogen gas was purged, and THF (20 mL) was added using a syringe to obtain a reaction solution. The mixture was cooled to 0 °C, and a THF solution of hexamethyldisilamide lithium (51.3 mL, 51.3 mmol, 3.0 eq, 1 M) was added dropwise. The resulting solution was then heated to room temperature and stirred for 16 h. After the reaction was complete, the reaction solution was poured into ice water (200 mL) and extracted with EA (3 × 200 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by slurrying with methyl tert-butyl ether to obtain compound A6-1 (4.7 g, yield: 98%).

[0285] MS(ESI,[M+H) + )m / z:281.10

[0286] Step 2: Preparation of intermediate A6-2

[0287] Compound A6-1 (2.0 g, 7.1 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and nitrogen was purged. A solution of ethyl chloroxaate (1.5 g, 10.7 mmol, 1.5 eq) in dichloromethane (5 mL) was added dropwise to the mixture at 0 °C, followed by the addition of aluminum chloride (2.4 g, 17.8 mmol, 2.5 eq) in portions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with ice water (100 mL), and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 20:1) to give compound A6-2 (2.0 g, yield: 75%).

[0288] MS(ESI,[M+H) + )m / z:381.10

[0289] Step 3: Preparation of intermediate A6

[0290] Compound A6-2 (2.0 g, 5.3 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (40 / 40 / 20 mL), and lithium hydroxide (250 mg, 10.6 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed under reduced pressure. The residue was adjusted to pH 3-4 with 1 M hydrochloric acid, extracted with ethyl acetate (3 × 100 mL), and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give intermediate A6 (1.3 g, yield: 70%).

[0291] MS(ESI,[M+H) + )m / z:353.10

[0292] Preparation of intermediate A7

[0293]

[0294] Step 1: Preparation of intermediate A7-1

[0295] Compound A1-2 (3.0 g, 16.6 mmol, 1.0 eq) and 4-fluoro-3-methylaniline (3.1 g, 24.8 mmol, 1.5 eq) were added to a dry three-necked flask. Nitrogen gas was purged, and THF (20 mL) was added using a syringe. The reaction mixture was cooled to 0 °C, and a THF solution of hexamethyldisilamide lithium (49.8 mL, 49.8 mmol, 3.0 eq, 1 M) was added dropwise. The mixture was then heated to room temperature and stirred for 16 h. After the reaction was complete, the reaction mixture was poured into ice water (200 mL) and extracted with ethyl acetate (3 × 200 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by slurrying with methyl tert-butyl ether to give compound A7-1 (3.9 g, yield: 91%).

[0296] MS(ESI,[M+H) + )m / z:261.10

[0297] Step 2: Preparation of intermediate A7-2

[0298] Compound A7-1 (1.9 g, 7.30 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and nitrogen was purged. The resulting solution was cooled to 0 °C, and a solution of ethyl chloroxaate (1.5 g, 10.95 mmol, 1.5 eq) in dichloromethane (5 mL) was added dropwise. Aluminum chloride (2.4 g, 18.25 mmol, 2.5 eq) was added in portions. The reaction mixture was stirred overnight at room temperature under nitrogen. After the reaction was complete, ice water (100 mL) was added to quench the reaction, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 20:1) to give compound A7-2 (2.2 g, yield: 84%).

[0299] MS(ESI,[M+H) + )m / z:361.10

[0300] Step 3: Preparation of intermediate A7

[0301] Compound A7-2 (2.2 g, 6.1 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (40 / 40 / 20 mL), and lithium hydroxide (292 mg, 12.2 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed under reduced pressure. The residue was adjusted to pH 3-4 with 1 M hydrochloric acid, extracted with ethyl acetate (3 × 100 mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give intermediate A7 (1.9 g, yield: 94%).

[0302] MS(ESI,[M+H) + )m / z:333.20

[0303] Preparation of intermediate A8

[0304]

[0305] Step 1: Preparation of intermediate A8-1

[0306] Compound A1-2 (2.5 g, 138 mmol, 1.0 eq) and 3,4,5-trifluoroaniline (3.04 g, 207 mmol, 1.5 eq) were added to a dry 250 mL three-necked flask. Nitrogen gas was purged, and THF (50 mL) was added using a syringe. The reaction mixture was cooled to 0 °C, and hexamethyldisilamide lithium (41.4 mL, 41.4 mmol, 3.00 eq, 1 M THF solution) was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. After the reaction was complete, a saturated ammonium chloride solution (50 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3 × 200 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified and concentrated by slurrying with methyl tert-butyl ether to obtain intermediate A8-1 (3.5 g, yield: 85%).

[0307] MS(ESI,[M+H) + )m / z:283.10

[0308] Step 2: Preparation of intermediate A8-2

[0309] Compound A8-2 (2.0 g, 7.1 mmol, 1.00 eq) and dichloromethane (60 mL) were added to a 250 mL three-necked round-bottom flask to obtain a clear solution. The solution was cooled to 0 °C, and a solution of ethyl chloroxaate (1.45 g, 10.7 mmol, 1.5 eq) in dichloromethane (20 mL) was added dropwise. After the addition was complete, aluminum chloride (2.37 g, 17.75 mmol, 2.5 eq) was added in five portions, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched in a water / ice bath, and the solution was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (200 mL) and water (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified and concentrated by slurrying with petroleum ether / ethyl acetate (7:3) to obtain intermediate A8-2 (2.8 g, yield: 93%).

[0310] MS(ESI,[M+H) + )m / z:383.10

[0311] Step 3: Preparation of intermediate A8

[0312] Compound A8-2 (2.0 g, 5.2 mmol, 1.0 eq) was added to a 250 mL round-bottom flask and dissolved in tetrahydrofuran (100 mL), methanol (50 mL), and water (50 mL). Lithium hydroxide (0.25 g, 10.4 mmol, 2.0 eq) was then added, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the pH of the reaction mixture was adjusted to 2–3 with hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3 × 100 mL), the organic layers were combined, dried over anhydrous sulfate, filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate to give intermediate A8 (1.6 g, yield: 83%).

[0313] MS(ESI,[M+H) + )m / z:355.10

[0314] Preparation of intermediate A9

[0315]

[0316] Step 1: Preparation of intermediate A9-3

[0317] At -40°C, a tetrahydrofuran solution of compound A9-2 (0.5M, 279mL, 139.58mmol, 0.95eq) was added dropwise to a toluene (100mL) solution containing compound A9-1 (30.0g, 146.93mmol, 50% in toluene, 1.0eq). The reaction mixture was stirred at -40°C for 1.5 hours and then slowly heated to 0°C over 1 hour. After the reaction was completed by TLC monitoring, the reaction mixture was added to a saturated ammonium chloride aqueous solution (150mL) to quench the reaction. The mixture was extracted with ethyl acetate (2×250mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (dichloromethane) to give intermediate A9-3 (2.6g, yield: 12%).

[0318] 1 H NMR (400MHz, CDCl3) δ4.84-4.76(m,1H),4.37-4.26(m,2H),1.88-1.85(m,3H),1.37-1.31(m,3H).

[0319] Step 2: Preparation of intermediate A9-4

[0320] Compound A9-3 (2.5 g, 17.59 mmol, 1.0 eq) was dissolved in DCM (30 mL), and activated manganese dioxide (6.12 g, 70.35 mmol, 4.0 eq) was added. The reaction mixture was reacted at room temperature for 5 hours. The reaction mixture was filtered through diatomaceous earth, and the solid was washed with dichloromethane. The filtrate was concentrated under reduced pressure at 30 °C. The concentrated residue was purified by rapid silica gel column chromatography (DCM / PE = 4:6) to give compound A9-4 (1.26 g, yield: 51%).

[0321] 1 H NMR (400MHz, CDCl3) δ4.36 (q, J = 7.2Hz, 2H), 2.16 (s, 3H), 1.39 (t, J = 7.2Hz, 3H).

[0322] Step 3: Preparation of intermediate A9-6

[0323] Compound A9-5 (10 g, 41.37 mmol, 1.0 eq) and DIEA (10.96 g, 84.81 mmol, 2.05 eq) were dissolved in DCM (150 mL), cooled to 0 °C, and ethyl chloroxaate (8.47 g, 62.06 mmol, 1.5 eq) was added. The reaction mixture was heated to room temperature and stirred for 1 hour. After the reaction was complete, the reaction mixture was poured into a cooled saturated aqueous sodium bicarbonate solution, the mixture was extracted with DCM, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate A9-6 (12.04 g, yield: 95%).

[0324] MS(ESI,[M+H) + )m / z:306.10

[0325] Step 4: Preparation of intermediate A9-7

[0326] Compound A9-6 (11.0 g, 36.03 mmol, 1.0 eq) was dissolved in ethanol (100 mL), and Pd / C (2.30 g, 10 wt%) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through diatomaceous earth, washed with ethanol, and the filtrate was concentrated under reduced pressure to give compound A9-7 (7.7 g, yield: 99%).

[0327] MS(ESI,[M+H) + )m / z:216.10

[0328] Step 5: Preparation of intermediate A9-8

[0329] Compound A9-7 (3.0 g, 13.94 mmol, 1.67 eq) was dissolved in a mixed solvent (toluene / DCM = 3 / 1, 32 mL). Oxaloyl chloride (3.54 g, 27.88 mmol, 3.54 eq) was added dropwise at 0 °C, followed by one drop of DMF. The reaction mixture was then stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure to obtain the acyl chloride product (3.3 g). The acyl chloride product was dissolved in acetonitrile (32 mL), and 2,6-dimethylpyridine (4.48 g, 41.82 mmol, 5.01 eq) and compound A9-4 (1.17 g, 8.35 mmol, 1.0 eq) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with saturated aqueous solutions of ammonium chloride and sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (0-60% EA in PE) to give compound A9-8 (1.4 g, yield: 57%).

[0330] MS(ESI,[M+H) +)m / z:294.10

[0331] Step 6: Preparation of intermediate A9

[0332] Compound A9-8 (1.4 g, 4.77 mmol, 1.0 eq) was dissolved in ethanol (15 mL), and sodium hydroxide aqueous solution (4.0 M, 1.43 mL, 5.73 mmol, 1.2 eq) was added at 0 °C. The reaction mixture was stirred at 0 °C for 5 minutes. After the reaction was complete, dilute hydrochloric acid (1.0 M) was added dropwise to adjust the pH to 4. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound A9 (1.16 g, yield: 91%).

[0333] MS(ESI,[M+H) + )m / z:266.10

[0334] Preparation of intermediate A10

[0335]

[0336] Step 1: Preparation of intermediate A10-2

[0337] Compound A10-1 (2.0 g, 13.23 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and triethylamine (4.01 g, 39.6 mmol, 3 eq) was added. Boc₂O (4.32 g, 19.8 mmol, 1.5 eq) was then added under ice bath conditions. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A10-2 (3 g, yield: 90%).

[0338] MS(ESI,[M+Na)) + m / z:274.20

[0339] Step 2: Preparation of intermediate A10-3

[0340] Compound A10-2 (1.0 g, 4 mmol, 1.0 eq) and triethylamine (1.21 g, 12 mmol, 3 eq) were dissolved in DCM (20 mL). The reaction solution was cooled to 0 °C, and methanesulfonyl chloride (684 mg, 6 mmol, 1.5 eq) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with DCM, washed with water, saturated citric acid aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated to give compound A10-3 (1.2 g, yield: 91%).

[0341] MS(ESI,[M+Na)) +)m / z:352.10

[0342] Step 3: Preparation of intermediate A10-4

[0343] Compound A10-3 (1.2 g, 3.64 mmol, 1.0 eq) was dissolved in DMF (20 mL), and sodium methanethiol (1.01 g, 14.4 mmol, 4.0 eq) was added. The reaction mixture was reacted at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A10-4 (1.0 g, yield: 97%).

[0344] MS(ESI,[M+Na)) + )m / z:304.20

[0345] Step 4: Preparation of intermediate A10

[0346] Compound A10-4 (300 mg, 1.07 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain compound A10 (300 mg, crude product), which was directly used in the next step of the reaction.

[0347] MS(ESI,[M+H) + m / z:182.20

[0348] Preparation of intermediate A11

[0349]

[0350] The preparation method is the same as that for intermediate A10.

[0351] MS(ESI,[M+H) + m / z:182.10

[0352] Preparation of intermediate A12

[0353]

[0354] Step 1: Preparation of intermediate A12-2

[0355] Compound A12-1 (1.00 g, 4.21 mmol, 1.0 eq) and triethylamine (853 mg, 8.43 mmol, 2.0 eq) were dissolved in DCM (30 mL), cooled to 0 °C, and MsCl (724 mg, 6.32 mmol, 1.5 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction solution was diluted with DCM, washed with water (20 mL), citric acid aqueous solution (1 M), and water, dried over anhydrous sodium sulfate, and concentrated to give compound A12-2 (1.20 g, yield: 90%).

[0356] MS(ESI,[M+Na)) + )m / z:338.00

[0357] Step 2: Preparation of intermediate A12-3

[0358] Compound A12-2 (1.20 g, 3.80 mmol, 1.0 eq) was dissolved in a toluene / ethanol mixture (15 / 15 mL), and sodium methanethiol (1.60 g, 22.8 mmol, 6.0 eq) was added. The reaction mixture was reacted at room temperature for 4 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A12-3 (1.00 g, yield: 98%).

[0359] MS(ESI,[M+Na)) + m / z:290.10

[0360] Step 3: Preparation of intermediate A12

[0361] Compound A12-3 (1.00 g, 3.74 mmol) was dissolved in dichloromethane (10 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain residue A12 (980 mg), which was directly used in the next reaction step.

[0362] MS(ESI,[M+H) + )m / z:168.1

[0363] Preparation of intermediate A13

[0364]

[0365] The preparation method is the same as that for intermediate A12.

[0366] MS(ESI,[M+H) + m / z:168.10

[0367] Preparation of intermediate A14

[0368]

[0369] Step 1: Preparation of intermediate A14-2

[0370] Compound A14-1 (10 g, 66.6 mmol, 1.0 eq) was dissolved in methanol (150 mL), and NaBH4 (3.02 g, 79.9 mol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with dilute hydrochloric acid solution (150 mL, 1 M), and stirred at room temperature for 2 hours. Ethyl acetate was added to the reaction system for extraction (3 × 200 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound A14-2 (10.0 g, yield: 99%).

[0371] MS(ESI,[M+H-H2O)) + m / z:135.10

[0372] Step 2: Preparation of intermediate A14-3

[0373] Compound A14-2 (10 g, 65.7 mmol, 1.0 eq) was dissolved in toluene (300 mL), and TsOH·H2O (125 mg, 0.66 mmol, 0.01 eq) was added. The reaction mixture was stirred at 120 °C for 3 hours. After the reaction was completed as detected by TLC, approximately 200 mL of toluene solvent was removed by vacuum distillation. The residue was extracted with ethyl acetate, and the organic phase was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE) to give compound A14-3 (6.8 g, yield: 77%).

[0374] 1 H NMR (400MHz, CDCl3) δ7.34-7.27(m,1H),7.21-7.14(m,1H),7.02-6.91(m,1H),6.87-6.79(m,1H),6.56-6.48(m,1H),3.38(s,2H).

[0375] Step 3: Preparation of intermediate A14-5

[0376] Compound A14-3 (5.0 g, 37.3 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL), cooled to 0 °C, and (R,R)-Jacobsen's catalyst (2.37 g, 0.37 mmol, 0.1 eq) and compound A14-4 (0.64 g, 0.37 mmol, 0.1 eq) were added to the reaction solution. After the addition was complete, sodium hypochlorite solution (50 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for one hour. After the reaction was completed, dichloromethane was removed by vacuum distillation, and petroleum ether (100 mL) was added to obtain the reaction system. The mixture was stirred at room temperature for ten minutes, filtered to remove the filter cake, and the filtrate was washed with water. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 15:1) to obtain compound A14-5 (3.5 g, yield: 62%).

[0377] 1 H NMR (400MHz, CDCl3) δ7.44(dd,J=8.0,5.2Hz,1H),7.00-6.87(m,2H),4.27-4.21(m,1H),4.14-4.06(m,1H),3.26-3.15(m,1H),3.04-2.91(m,1H).

[0378] Step 4: Preparation of intermediate A14-6

[0379] Under nitrogen protection, A14-5 (6.6 g, 44 mmol, 1.0 eq) was dissolved in acetonitrile (120 mL), cooled to -40 °C, and TfOH (13.20 g, 88 mmol, 2.0 eq) was slowly added. The mixture was slowly heated to room temperature and reacted for 1 hour. Water (240 mL) was added, and the mixture was stirred for 15 minutes. Acetonitrile was removed by vacuum distillation, and the mixture was heated to 100 °C and refluxed for 3 hours. The reaction mixture was cooled to room temperature, and dichloromethane was added. The mixture was stirred for 15 minutes, and the layers were separated. The aqueous phase was washed with dichloromethane, and 100 mL of 1 M sodium hydroxide solution was added to the aqueous phase. The mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound A14-6 (8.0 g, crude product, yield: 100%).

[0380] MS(ESI,[M+H) + m / z:168.20

[0381] Step 5: Preparation of intermediate A14-7

[0382] Compound A14-6 (3.5 g, 20.9 mmol, 1.0 eq) was dissolved in DCM (50 mL), and Boc2O (13.7 g, 62.6 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE / EA = 15 / 1) to give compound A14-7 (2.6 g, yield: 44%).

[0383] MS(ESI,[M+Na)) + m / z:=290.10

[0384] Step 6: Preparation of intermediate A14-8

[0385] Compound A14-7 (2.5 g, 9.3 mmol, 1.0 eq) and triethylamine (4.7 g, 46.5 mmol, 5.0 eq) were dissolved in DCM (20 mL), cooled to 0 °C, and MsCl (3.2 g, 27.9 mmol, 3.0 eq) was added dropwise. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The solution was diluted with DCM, washed with water, citric acid aqueous solution (1 M), and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude compound A14-8 (4.0 g, yield: 100%).

[0386] MS(ESI,[M+Na)) + )m / z:368.10

[0387] Step 7: Preparation of intermediate A14-9

[0388] Sodium methanethiol (8.69 g, 124.0 mol, 10.0 eq) was dissolved in DMF / H₂O (20 / 20 mL) and reacted at 80 °C for 5 min. Compound A14-8 (4.3 g, 12.4 mmol, 1.0 eq) was added, and the reaction was allowed to proceed for 1 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 150 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 20 / 1) to give compound A14-9 (1.3 g, yield: 35%).

[0389] MS(ESI,[M+Na)) + )m / z:320.20

[0390] Step 8: Preparation of intermediate A14-10

[0391] Compound A14-9 (800 mg, 2.7 mol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (630 mg, 8.1 mol, 3.0 eq) and diacetoxyiodobenzene (3.48 g, 10.8 mol, 4.0 eq) were added sequentially. The mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give compound A14-10 (800 mg, yield: 89%).

[0392] MS(ESI,[M+H) + )m / z:329.10

[0393] Step 8: Preparation of intermediate A14

[0394] Compound A14-10 (100 mg, 0.30 mmol) was dissolved in dichloromethane (6 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the crude compound A14 (100 mg, yield: 100%) was concentrated and used directly in the next step of the reaction.

[0395] MS(ESI,[M+H) + )m / z:229.10

[0396] Preparation of intermediate A15

[0397]

[0398] Step 1: Preparation of intermediate A15-1

[0399] Compound A2-5 (200 mg 0.64 mmol, 1.0 eq) was dissolved in dioxane (5 mL), followed by the sequential addition of methylboric acid (77 mg, 1.29 mmol, 2.0 eq), pyridine (122 mg, 1.55 mmol, 2.4 eq), and anhydrous copper acetate (175 mg, 0.97 mmol, 1.5 eq). The reaction mixture was stirred at 100 °C for 2 hours under nitrogen protection. Ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (0.1% formic acid / acetonitrile / water) to give compound A15-1 (130 mg, yield: 62%).

[0400] MS(ESI,[M+H) + )m / z:325.20

[0401] Step 2: Preparation of intermediate A15

[0402] Compound A15-1 (126 mg, 0.388 mmol) was dissolved in dichloromethane (4 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the concentrated residue A15 (125 mg, yield: 100%) was used directly in the next step of the reaction.

[0403] MS(ESI,[M+H) + )m / z:225.10

[0404] Preparation of intermediate A16

[0405]

[0406] Step 1: Preparation of intermediate A16-1

[0407] Compound A14-10 (800 mg, 2.43 mmol, 1.0 eq) was dissolved in dioxane (10 mL), and compound 2 (291 mg, 4.86 mmol, 2.0 eq), pyridine (384 mg, 4.86 mmol, 2.0 eq), and Cu(OAc)2 (662 mg, 3.64 mmol, 1.5 eq) were added. The reaction mixture was stirred at 100 °C for 8 hours. After the reaction was complete, ethyl acetate was added, followed by washing with water, then saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give compound A16-1 (800 mg, yield: 96%).

[0408] MS(ESI,[M+H) + )m / z:343.10

[0409] Step 2: Preparation of intermediate A16

[0410] Compound A16-1 (100 mg, 0.292 mmol) was dissolved in dichloromethane (6 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the crude compound A16 (100 mg, yield: 100%) was concentrated and used directly in the next step of the reaction.

[0411] MS(ESI,[M+H) + m / z:243.10

[0412] Preparation of intermediate A17

[0413]

[0414] Step 1: Preparation of intermediate A17-1

[0415] Compound A5-5 (750 mg, 2.89 mmol, 1.0 eq), diacetyloxyiodobenzene (3.73 g, 11.6 mmol, 4.0 eq), and ammonium carbonate (833 mg, 8.67 mmol, 3.0 eq) were dissolved in methanol (30 mL), and the reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added, followed by water (60 mL). The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 70 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude compound 17-1 (800 mg).

[0416] MS(ESI,[M+H) + m / z:291.30

[0417] Step 2: Preparation of intermediate A17-2

[0418] Compound 17-1 (800 mg, 2.75 mmol, 1.0 eq) was dissolved in dioxane (8 mL), followed by the addition of methylboric acid (330 mg, 5.51 mmol, 2.0 eq), pyridine (523 mg, 6.61 mmol, 2.4 eq), and anhydrous copper acetate (751 mg, 4.13 mmol, 1.5 eq). The reaction mixture was stirred at 100 °C for 3 hours under nitrogen protection. Ethyl acetate (50 mL) and water (30 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude compound 17-2 (780 mg, yield: 93%).

[0419] MS(ESI,[M+H) + )m / z:305.20

[0420] Step 2: Preparation of intermediate A17

[0421] Compound 17-2 (780 mg, 2.56 mmol) was dissolved in dichloromethane (8 mL), and TFA (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the crude product A17 (780 mg, yield: 100%) was concentrated under reduced pressure and used directly in the next step of the reaction.

[0422] MS(ESI,[M+H) + m / z:205.10

[0423] Preparation of intermediate A18

[0424]

[0425] Step 1: Preparation of intermediate A18-2

[0426] Compound A18-1 (900 mg, 4.47 mmol, 1.0 eq) and triethylamine (1.36 g, 13.4 mmol, 3 eq) were dissolved in DCM (10 mL). The reaction mixture was cooled to 0 °C, and methanesulfonyl chloride (768 mg, 6.70 mmol, 1.5 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours. DCM was added, and the mixture was washed with water, a saturated citric acid solution, and water. After drying with anhydrous sodium sulfate, the solution was concentrated to give compound A18-2 (1.2 g, yield: 96%).

[0427] MS(ESI,[M+Na)) + m / z:302.10

[0428] Step 2: Preparation of intermediate A18-3

[0429] Compound A18-2 (1.2 g, 4.3 mmol, 1.0 eq) was dissolved in DMF (20 mL), and sodium methanethiol (1.51 g, 21.5 mmol, 5.0 eq) was added. The reaction mixture was reacted at room temperature for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A18-3 (1.0 g, yield: 100%).

[0430] MS(ESI,[M+Na)) + )m / z:254.20

[0431] Step 3: Preparation of intermediate A18

[0432] Compound A18-3 (300 mg, 1.30 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain intermediate A18 (200 mg, crude product), which was directly used in the next step of the reaction.

[0433] MS(ESI,[M+H) + m / z:132.20

[0434] Preparation of intermediate A19

[0435]

[0436] Step 1: Preparation of intermediate A19-2

[0437] Compound A19-1 (1.0 g, 5.34 mmol, 1.0 eq) and triethylamine (1.62 g, 16.02 mmol, 3 eq) were dissolved in DCM (50 mL). The reaction solution was cooled to 0 °C, and MsCl (1.53 g, 13.35 mmol, 2.5 eq) was added dropwise. The reaction solution was stirred at room temperature for 2 hours under a nitrogen atmosphere. Water (30 mL) was added, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A19-2 (1.3 g, yield: 92%).

[0438] MS(ESI,[M+Na)) + )m / z:288.10

[0439] Step 2: Preparation of intermediate A19-3

[0440] Compound A19-2 (1.6 g, 6.03 mmol, 1.0 eq) was dissolved in DMF (10 mL), and sodium methanethiol (4.23 g, 60.30 mmol, 10.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A19-3 (1.2 g, yield: 92%).

[0441] MS(ESI,[M+Na)) + m / z:240.10

[0442] Step 3: Preparation of intermediate A19

[0443] Compound A19-3 (300 mg, 1.38 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude brown oily product A19 (309 mg), which was directly used in the next step of the reaction.

[0444] MS(ESI,[M+H) + )m / z:118.10

[0445] Preparation of intermediate A20

[0446]

[0447] Step 1: Preparation of intermediate A20-2

[0448] Compound A20-1 (400 mg, 1.97 mmol, 1.0 eq) and TEA (398 mg, 3.94 mmol, 2.0 eq) were dissolved in DCM (5 mL). The reaction solution was cooled to 0 °C, and MsCl (338 mg, 2.95 mmol, 1.5 eq) was added dropwise. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A20-2 (550 mg, yield: 99%).

[0449] MS(ESI,[M+H) + m / z:282.10

[0450] Step 2: Preparation of intermediate A20-3

[0451] Compound A20-2 (550 mg, 1.96 mmol, 1.0 eq) was dissolved in DMF (5 mL), and sodium methanethiol (1.37 g, 19.55 mmol, 10 eq) was added. The reaction mixture was reacted at room temperature for 3 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A20-3 (456 mg, yield: 100%).

[0452] MS(ESI,[M+H) + )m / z:234.10

[0453] Step 3: Preparation of intermediate A20

[0454] Compound A20-3 (456 mg, 1.95 mmol) was dissolved in dichloromethane (10 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the crude product A20 (450 mg) obtained by concentration was directly used in the next step of the reaction.

[0455] MS(ESI,[M+H) + m / z:134.10

[0456] Preparation of intermediate A21

[0457]

[0458] Step 1: Preparation of intermediate A21-2

[0459] Compound A21-1 (500 mg, 2.1 mmol, 1.0 eq) and triethylamine (637 mg, 6.3 mmol, 3.0 eq) were dissolved in DCM (8 mL). The reaction solution was cooled to 0 °C, and MsCl (313 mg, 2.7 mmol, 1.3 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with dichloromethane (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A21-2 (650 mg, yield: 98%).

[0460] MS(ESI,[M+Na)) + )m / z:338.10

[0461] Step 2: Preparation of intermediate A21-3

[0462] Compound A21-2 (250 mg, 0.79 mmol, 1.0 eq) was dissolved in toluene / EtOH (1 / 1, 10 mL), and sodium methanethiol (222 mg, 3.2 mmol, 4.0 eq) was added. The reaction mixture was allowed to react at room temperature for 16 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A21-3 (200 mg, yield: 94%).

[0463] MS(ESI,[M+Na)) + m / z:290.10

[0464] Step 3: Preparation of intermediate A21

[0465] Compound A21-3 (200 mg, 0.75 mmol) was dissolved in dichloromethane (3 mL), and TFA (1.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the residue A21 (120 mg) was concentrated and used directly in the next step of the reaction.

[0466] MS(ESI,[M+H) + m / z:168.10

[0467] Preparation of intermediate A22

[0468]

[0469] Step 1: Preparation of intermediate A22-1

[0470] Compound A1-2 (300 mg, 1.66 mmol, 1.0 eq) and 3,4-difluoro-5-methylaniline (308 mg, 2.15 mmol, 1.3 eq) were added to a dry, anhydrous 100 mL three-necked flask. Nitrogen gas was purged, and THF (30 mL) was added. The reaction mixture was cooled to 0 °C under nitrogen protection, and a THF solution of hexamethyldisilamide lithium (5 mL, 4.97 mmol, 3.00 eq, 1 M) was added dropwise. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched with saturated ammonium chloride solution (20 mL), and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified and concentrated by slurrying with methyl tert-butyl ether to give compound A22-1 (400 mg, yield: 87%).

[0471] MS(ESI,[M+H) + )m / z:279.10

[0472] Step 2: Preparation of intermediate A22-2

[0473] Compound A22-1 (400 mg, 1.44 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL), and nitrogen was purged. The reaction mixture was cooled to 0 °C in an ice bath under nitrogen protection. A solution of ethyl chloroxaate (294 mg, 2.16 mmol, 1.5 eq) in dichloromethane (5 mL) was added dropwise, followed by the addition of aluminum chloride (479 mg, 3.59 mmol, 2.5 eq) in portions. The reaction mixture was heated to room temperature and stirred overnight under nitrogen protection. After the reaction was complete, it was quenched in ice water (50 mL) and extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound A22-2 (300 mg, yield: 55%).

[0474] MS(ESI,[M+H) + )m / z:379.10

[0475] Step 3: Preparation of intermediate A22

[0476] Compound A22-2 (300 mg, 0.79 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (10 / 5 / 5 mL), and lithium hydroxide (38 mg, 1.59 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 3-4 with 1 M hydrochloric acid, and the residue was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A22 (260 mg, yield: 94%).

[0477] MS(ESI,[M+H) + )m / z:351.10

[0478] Preparation of intermediate A23

[0479]

[0480] Step 1: Preparation of intermediate A23-2

[0481] Compound A23-1 (500 mg, 2.37 mmol, 1.0 eq) was dissolved in DMF (10 mL), and potassium carbonate (1.31 g, 9.47 mmol, 4.0 eq) and methyl iodide (840 mg, 5.92 mmol, 2.5 eq) were added. The reaction mixture was reacted at 60 °C for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to obtain compound A23-2 (300 mg, yield: 53%).

[0482] MS(ESI,[M+H) + )m / z:240.20

[0483] Step 2: Preparation of intermediate A23-3

[0484] Compound A23-2 (300 mg, 1.25 mmol, 1.0 eq), anhydrous THF (10 mL), and 4-fluoro-3-trifluoromethylaniline (225 mg, 1.25 mmol, 1.0 eq) were added to a three-necked flask. Nitrogen gas was purged, and the reaction mixture was cooled to 0 °C. A THF solution of hexamethyldisilamide lithium (2.5 mL, 2.50 mmol, 2.00 eq, 1 M) was added dropwise, and the mixture was brought to room temperature and stirred for 16 h. After the reaction was complete, the reaction mixture was poured into ice water (20 mL) and extracted with EA (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to obtain compound A23-3 (150 mg, yield: 31%).

[0485] MS(ESI,[M+H) + )m / z:387.10

[0486] Step 3: Preparation of intermediate A23

[0487] Compound A23-3 (150 mg, 0.39 mmol, 1.0 eq) was added to ethanol (5 mL) and water (0.5 mL), followed by sodium hydroxide (310 mg, 7.77 mmol, 20 eq). The reaction mixture was stirred at 80 °C for 48 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, water was added, and the pH was adjusted to 5 with 6 N hydrochloric acid solution. The mixture was then extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A23 (120 mg, yield: 86%).

[0488] MS(ESI,[M+H) + )m / z:359.10

[0489] Preparation of intermediate A24

[0490]

[0491] Step 1: Preparation of intermediate A24-1

[0492] Compound A2-5 (200 mg, 0.644 mmol, 1.0 eq) was dissolved in dioxane (5 mL), and methylboric acid (110 mg, 1.29 mmol, 2.0 eq), pyridine (122 mg, 1.55 mmol, 2.4 eq), and anhydrous copper acetate (175 mg, 0.966 mmol, 1.5 eq) were added. Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours. Ethyl acetate (20 mL) was added, and the mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give A24-1 (144 mg, yield: 63%), which was used directly in the next step of the reaction.

[0493] MS(ESI,[M+H) + )m / z:351.10

[0494] Step 2: Preparation of intermediate A24

[0495] Compound A24-1 (144 mg, 0.410 mmol) was dissolved in dichloromethane (2 mL), and TFA (4 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the residue A24 (143 mg, yield: 100%) was concentrated and used directly in the next step of the reaction.

[0496] MS(ESI,[M+H) + )m / z:251.10

[0497] Preparation of intermediate A25

[0498]

[0499] Step 1: Preparation of intermediate A25-1

[0500] Compound A2-2 (5 g, 20.1 mmol, 1.0 eq) and triethylamine (6.09 g, 60.2 mmol, 3.0 eq) were dissolved in DCM (30 mL). The reaction mixture was cooled to 0 °C under nitrogen protection, and MsCl (4.59 g, 40.1 mmol, 2 eq) was added dropwise. The mixture was then heated to room temperature and stirred for 2 hours under nitrogen atmosphere. Water (50 mL) was added, and the mixture was extracted with dichloromethane (3 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A25-1 (6.0 g, yield: 91%).

[0501] MS(ESI,[M+Na)) + m / z:350.1

[0502] Step 2: Preparation of intermediate A25-2

[0503] Compound A25-1 (1.50 g, 15.27 mmol, 10 eq) was dissolved in DMF (5 mL) and water (5 mL), and sodium isopropanethiolate (500 mg, 1.53 mmol, 1.0 eq) was added. The reaction mixture was reacted at 60 °C for 3 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A25-2 (250 mg, yield: 53%).

[0504] MS(ESI,[M+Na)) + )m / z:330.10

[0505] Step 3: Preparation of intermediate A25

[0506] Compound A25-2 (130 mg, 0.423 mmol) was dissolved in dichloromethane (5 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to obtain A25 (130 mg, yield: 100%), which was directly used in the next step of the reaction.

[0507] MS(ESI,[M+H-NH2)) + )m / z:191.10

[0508] Preparation of intermediate A26

[0509]

[0510] Step 1: Preparation of intermediate A26-1

[0511] Compound A25-2 (200 mg, 0.65 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the sequential addition of ammonium carbamate (203 mg, 2.60 mmol, 4.0 eq) and diacetoxyiodobenzene (838 mg, 2.60 mmol, 4.0 eq) at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude compound A26-1 (220 mg, yield: 100%), which was directly used in the next reaction.

[0512] MS(ESI,[M+H) + )m / z:339.10

[0513] Step 2: Preparation of intermediate A26-2

[0514] Compound A26-1 (220 mg, 0.65 mmol, 1.0 eq) was dissolved in dioxane (20 mL), followed by the sequential addition of methylboric acid (156 mg, 2.60 mmol, 4.0 eq), pyridine (247 mg, 3.12 mmol, 4.8 eq), and anhydrous copper acetate (354 mg, 1.95 mmol, 3.0 eq). The reaction mixture was stirred at 100 °C for 16 hours under oxygen protection. Ethyl acetate and water were added, and the mixture was extracted to separate the layers. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A26-2 (220 mg, yield: 96%).

[0515] MS(ESI,[M+H) + )m / z:353.20

[0516] Step 3: Preparation of intermediate A26

[0517] Compound A26-2 (200 mg, 0.62 mmol) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the obtained A26 (220 mg, yield: 100%) was concentrated and used directly in the next step of the reaction.

[0518] MS(ESI,[M+H) + )m / z:253.10

[0519] Preparation of intermediate A27

[0520]

[0521] Step 1: Preparation of intermediate A27-2

[0522] Compound A27-1 (2 g, 8.78 mmol, 1.0 eq) was dissolved in THF (50 mL), and LiAlH4 (1.0 g, 26.35 mmol, 3.0 eq) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was quenched with sodium sulfate decahydrate at 0 °C, ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to give compound A27-2 (1.4 g, yield: 97%).

[0523] MS(ESI,[M+H) + m / z:164.20

[0524] Step 2: Preparation of intermediate A27-3

[0525] Compound A27-2 (1.4 g, 8.58 mmol, 1.0 eq) was dissolved in DCM (20 mL), and Boc2O (2.8 g, 12.87 mmol, 1.5 eq) and triethylamine (2.6 g, 25.7 mmol, 3.0 eq) were added at 0 °C. The reaction solution was reacted at room temperature for 16 hours. After the reaction was completed, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A27-3 (2.1 g, yield: 93%).

[0526] MS(ESI,[M+Na)) + )m / z:286.10

[0527] Step 3: Preparation of intermediate A27-4

[0528] Compound A27-3 (2.1 g, 7.97 mmol, 1.0 eq) and triethylamine (2.41 g, 23.8 mmol, 3.0 eq) were dissolved in DCM (30 mL). The reaction solution was cooled to 0 °C, and MsCl (1.36 g, 11.9 mmol, 1.5 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A27-4 (2.5 g, yield: 92%).

[0529] MS(ESI,[M+Na)) + )m / z:364.20

[0530] Step 4: Preparation of intermediate A27-5

[0531] Compound A27-4 (500 mg, 1.46 mmol, 1.0 eq) was dissolved in DMF (20 mL), and sodium methanethiol (511 mg, 7.3 mmol, 5.0 eq) was added. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A27-5 (400 mg, yield: 93%) as a yellow liquid.

[0532] MS(ESI,[M+Na)) + )m / z:316.20

[0533] Step 5: Preparation of intermediate A27

[0534] Compound A27-5 (400 mg, 1.36 mmol) was added to dichloromethane (2 mL), followed by trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to obtain compound A27-6 (300 mg, crude product), which was directly used in the next step of the reaction.

[0535] MS(ESI,[M+H) + )m / z:194.20

[0536] Preparation of intermediate A28

[0537]

[0538] Step 1: Preparation of intermediate A28-1

[0539] Compound A27-5 (200 mg, 0.680 mmol, 1.0 eq) was dissolved in methanol (5 mL), followed by the addition of ammonium carbamate (212 mg, 2.72 mmol, 4.0 eq) and compound PIDA (656 mg, 2.03 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound A28-1 (200 mg, yield: 90%), which was directly used in the next reaction.

[0540] MS(ESI,[M+H) + )m / z:325.10

[0541] Step 2: Preparation of intermediate A28-2

[0542] Compound A28-1 (200 mg, 0.61 mmol, 1.0 eq) was dissolved in dioxane (5 mL), followed by the sequential addition of methylboric acid (73 mg, 1.22 mmol, 2.0 eq), pyridine (121 mg, 1.53 mmol, 2.5 eq), and anhydrous copper acetate (167 mg, 0.92 mmol, 1.5 eq). The reaction mixture was stirred at 100 °C for 2 hours under oxygen protection. Ethyl acetate was added, and the mixture was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain A28-2 (150 mg, yield: 72%), which was used directly in the next reaction.

[0543] MS(ESI,[M+H) + )m / z:339.20

[0544] Step 3: Preparation of intermediate A28

[0545] Compound A28-2 (150 mg, 0.44 mmol) was dissolved in dichloromethane (1 mL), and TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound A28 (150 mg, yield: 100%), which was used directly in the next step of the reaction.

[0546] MS(ESI,[M+H) + )m / z:239.20

[0547] Preparation of intermediate A29

[0548]

[0549] Step 1: Preparation of intermediate A29

[0550] Compound A27-5 (500 mg, 1.70 mmol) was dissolved in dichloromethane (2 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to obtain A29 (495 mg), which was used directly in the next step of the reaction.

[0551] MS(ESI,[M+H) + )m / z:194.10

[0552] Preparation of intermediate A30

[0553]

[0554] Step 1: Preparation of intermediate A30-3

[0555] Compound A30-1 (5.0 g, 37.3 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL). The reaction solution was cooled to 0 °C, and (S,S)-Jacobsen's catalyst (2.37 g, 0.37 mmol, 0.1 eq) and compound A30-2 (0.64 g, 0.37 mmol, 0.1 eq) were added to the reaction solution. After the addition was complete, sodium hypochlorite solution (50 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for one hour. After the reaction was completed, dichloromethane was removed by vacuum distillation, and petroleum ether (100 mL) was added. The mixture was stirred at room temperature for ten minutes, filtered, and the filtrate was washed with water. The organic phase was collected, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA = 15:1) to obtain compound A30-3 (3.5 g, yield: 62%).

[0556] 1H NMR (400MHz, CDCl3) δ7.44(dd,J=8.0,5.2Hz,1H),7.00-6.87(m,2H),4.26-4.21(m,1H),4.16-4.08(m,1H),3.26-3.15(m,1H),3.04-2.91(m,1H).

[0557] Step 2: Preparation of intermediate A30-4

[0558] Under nitrogen protection, A30-3 (3.0 g, 20.0 mmol, 1.0 eq) was dissolved in acetonitrile (80 mL), cooled to -40 °C, and TfOH (6.0 g, 40.0 mmol, 2.0 eq) was slowly added. The reaction system was slowly heated to room temperature and reacted for 1 hour. Water (160 mL) was added to the reaction system and stirred for 15 minutes. Acetonitrile was removed by vacuum distillation, the mixture was heated to 100 °C and refluxed for 3 hours, cooled to room temperature, and dichloromethane was added. The mixture was stirred for 15 minutes, and the layers were separated. The aqueous phase was washed with dichloromethane, and 1M sodium hydroxide solution (100 mL) was added to the aqueous phase. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound A30-4 (2.9 g, crude product, yield: 87%).

[0559] MS(ESI,[M+H) + m / z:168.20

[0560] Step 3: Preparation of intermediate A30-5

[0561] Compound A30-4 (2.9 g, 17.4 mmol, 1.0 eq) was dissolved in DCM (40 mL), and Boc2O (11.4 g, 52.0 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 15 / 1) to give compound A30-5 (4.0 g, yield: 86%).

[0562] MS(ESI,[M+Na)) + m / z:290.10

[0563] Step 4: Preparation of intermediate A30-6

[0564] Compound A30-5 (2.0 g, 7.48 mmol, 1.0 eq) and triethylamine (3.79 g, 37.4 mmol, 5.0 eq) were dissolved in DCM (20 mL). The reaction solution was cooled to 0 °C, and MsCl (1.29 g, 11.2 mmol, 1.5 eq) was added dropwise. The reaction solution was stirred at room temperature under a nitrogen atmosphere for 2 hours. DCM was added, and the mixture was washed with water, citric acid aqueous solution (1 M), and anhydrous sodium sulfate. The solution was then concentrated under reduced pressure to give crude compound A30-6 (2.5 g, yield: 97%).

[0565] MS(ESI,[M+Na)) + )m / z:368.10

[0566] Step 5: Preparation of intermediate A30-7

[0567] Sodium methanethiol (3.04 g, 43.4 mol, 10.0 eq) was dissolved in DMF / H₂O (10 / 10 mL) and reacted at 80 °C for 5 min. Compound A30-6 (1.5 g, 4.34 mmol, 1.0 eq) was added, and the reaction mixture was reacted at 80 °C for 1 h. Water (25 mL) was added, and the mixture was extracted with ethyl acetate (3 × 150 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 20 / 1) to give compound A30-7 (0.9 g, yield: 70%).

[0568] MS(ESI,[M+Na)) + )m / z:320.20

[0569] Step 6: Preparation of intermediate A30-8

[0570] Compound A30-7 (800 mg, 2.69 mol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (630 mg, 8.07 mol, 3.0 eq) and diacetoxyiodobenzene (3.47 g, 10.8 mol, 4.0 eq). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 5 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give compound A30-8 (800 mg, yield: 91%).

[0571] MS(ESI,[M+Na)) + )m / z:329.10

[0572] Step 6: Preparation of intermediate A30

[0573] Compound A30-8 (160 mg, 0.487 mmol) was dissolved in dichloromethane (6 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the crude compound A30 (151 mg, yield: 96%) was concentrated and used directly in the next step of the reaction.

[0574] MS(ESI,[M+H) + )m / z:229.10

[0575] Preparation of intermediate A31

[0576]

[0577] Step 1: Preparation of intermediate A31-1

[0578] Compound A30-8 (150 mg, 0.457 mmol, 1.0 eq) was dissolved in dioxane (10 mL), and methylboric acid (57 mg, 0.914 mmol, 2.0 eq), pyridine (72.3 mg, 0.914 mmol, 2.0 eq), and Cu(OAc)₂ (124 mg, 0.685 mmol, 1.5 eq) were added. Oxygen was displaced, and the reaction mixture was stirred at 100 °C for 4 hours under an oxygen atmosphere. After the reaction was complete, ethyl acetate was added, followed by washing with water, then saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentration under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to give compound A31-1 (100 mg, yield: 64%).

[0579] MS(ESI,[M+H) + )m / z:343.10

[0580] Step 1: Preparation of intermediate A31

[0581] Compound A31-1 (100 mg, 0.292 mmol) was dissolved in dichloromethane (6 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the crude compound A31 (100 mg, yield: 100%) was concentrated and used directly in the next step of the reaction.

[0582] MS(ESI,[M+H) + m / z:243.10

[0583] Preparation of intermediate A32

[0584]

[0585] Step 1: Preparation of intermediate A32-1

[0586] Compound A1-1 (2.0 g, 12.0 mmol, 1.0 eq) was dissolved in DMSO (15 mL), and KOH (1.0 g, 18.0 mmol, 1.50 eq) was added under ice bath conditions. The reaction mixture was stirred at room temperature for 30 minutes, and iodoethane (1.97 g, 12.6 mmol, 1.05 eq) was added dropwise, followed by stirring for 3 hours. The reaction mixture was quenched with water (100 mL), and EA (300 mL) was added. The mixture was washed with water (4 × 100 mL) and saturated sodium chloride solution (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound A32-1 (2.35 g, yield: 100%).

[0587] MS(ESI,[M+H) + )m / z:196.20

[0588] Step 2: Preparation of intermediate A32-2

[0589] Compound A32-1 (2.3 g, 11.8 mmol, 1.0 eq) and 3-chloro-4-fluoroaniline (2.6 g, 17.7 mmol, 1.5 eq) were added to a dry three-necked flask. Nitrogen gas was purged, and THF (20 mL) was added. The mixture was cooled to 0 °C, and a THF solution of hexamethyldisilamide lithium (35.4 mL, 35.4 mmol, 3.0 eq, 1 M) was added dropwise. The mixture was then heated to room temperature and stirred for 16 h. After the reaction was complete, the mixture was poured into ice water (150 mL), extracted with ethyl acetate (3 × 150 mL), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by slurrying with methyl tert-butyl ether to give compound A32-2 (3.0 g, yield: 86%).

[0590] MS(ESI,[M+H) + m / z:295.10

[0591] Step 3: Preparation of intermediate A32-3

[0592] Compound A32-2 (3.0 g, 10.2 mmol, 1.0 eq) was dissolved in dichloromethane (30 mL), purged with nitrogen, and cooled to 0 °C. A solution of ethyl chloroxaate (2.1 g, 15.3 mmol, 1.5 eq) in dichloromethane (6 mL) was added dropwise, followed by the addition of aluminum chloride (3.4 g, 25.5 mmol, 2.5 eq) in portions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was quenched in ice water (100 mL), extracted with dichloromethane (3 × 100 mL), and the organic phases were combined. The mixture was washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / ethyl acetate = 50:1) to give compound A32-3 (3.0 g, yield: 75%).

[0593] Step 4: Preparation of intermediate A32

[0594] Compound A32-3 (3.0 g, 7.6 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (36 / 18 / 18 mL), and lithium hydroxide (360 mg, 15.2 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 2-3 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate (3 × 100 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A32 (2.7 g, yield: 97%), which was used directly in the next step.

[0595] MS(ESI,[M+H) + )m / z:367.10

[0596] Preparation of intermediate A33

[0597]

[0598] Step 1: Preparation of intermediate A33-2

[0599] Compound A33-1 (3.0 g, 14.2 mmol, 1.0 eq) was dissolved in acetonitrile (60 mL) under nitrogen protection. The mixture was cooled to -40 °C, and TfOH (4.3 g, 28.4 mmol, 2.0 eq) was slowly added. The reaction mixture was allowed to rise to room temperature and react for 1 hour. Water (120 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes. Acetonitrile was removed by vacuum distillation, and the mixture was refluxed at 100 °C for 3 hours. After cooling to room temperature, dichloromethane was added, and the mixture was stirred for 15 minutes. The layers were separated, and the aqueous phase was washed with dichloromethane. 1 M sodium hydroxide solution (50 mL) was added to the aqueous phase, and the mixture was extracted with ethyl acetate. The ethyl acetate phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound A33-2 (1.5 g, yield: 46%).

[0600] MS(ESI,[M+H) + )m / z:228.00

[0601] Step 2: Preparation of intermediate A33-3

[0602] Compound A33-2 (5.2 g, 22.8 mmol, 1.0 eq) was dissolved in DCM (50 mL), and Boc2O (14.9 g, 68.4 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE / EA = 15 / 1) to give compound A33-3 (6.6 g, yield: 88%).

[0603] MS(ESI,[M+Na)) + m / z:350.10

[0604] Step 3: Preparation of intermediate A33-4

[0605] Compound A33-3 (6.6 g, 20.1 mmol, 1.0 eq) and triethylamine (8.4 mL, 60.3 mmol, 3.0 eq) were dissolved in DCM (40 mL) under nitrogen atmosphere. The reaction solution was cooled to 0 °C, and MsCl (1.9 mL, 24.1 mmol, 1.2 eq) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. DCM was added, and the mixture was washed with water, citric acid aqueous solution (1 M), and anhydrous sodium sulfate. The solution was then dried under reduced pressure to obtain crude compound A33-4 (8.0 g, yield: 98%).

[0606] MS(ESI,[M+Na)) + )m / z:428.00

[0607] Step 4: Preparation of intermediate A33-5

[0608] Compound A33-4 (3.0 g, 7.4 mmol, 1.0 eq) was dissolved in DMF (20 mL), and 20% sodium methanethiol aqueous solution (25.9 g, 73.84 mmol, 10.0 eq) was added. The reaction solution was reacted at 80 °C for 1 hour. After cooling to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (3 × 150 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 10 / 1) to give compound A33-5 (800 mg, yield: 30%).

[0609] MS(ESI,[M+Na)) + )m / z:380.00

[0610] Step 5: Preparation of intermediate A33-6

[0611] Compound A33-5 (400 mg, 1.12 mmol, 1.0 eq) was dissolved in dioxane (9 mL) and water (3 mL). Methylboric acid (334 mg, 5.58 mmol, 5.0 eq), potassium phosphate hydrate (771 mg, 3.35 mmol, 3.0 eq), and Pd(dppf)Cl2 (163 mg, 0.22 mmol, 0.2 mmol) were rapidly added, purging with nitrogen. The reaction mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by washing with water, then saturated sodium chloride solution, drying over anhydrous sodium sulfate, and concentrating. The residue was purified by rapid silica gel column chromatography (PE / EA = 10 / 1) to give compound A33-6 (180 mg, yield: 55%).

[0612] MS(ESI,[M+Na)) + )m / z:316.10

[0613] Step 6: Preparation of intermediate A33

[0614] Compound A33-6 (120 mg, 0.41 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give intermediate A33 (140 mg, yield: 100%), which was used directly in the next step of the reaction.

[0615] MS(ESI,[M+H-NH3)) + m / z:177.10

[0616] Preparation of intermediate A34

[0617]

[0618] Step 1: Intermediate A34-2

[0619] Compound A34-1 (2.0 g, 10.39 mmol, 1.0 eq) was dissolved in MeOH (20 mL), cooled to 0 °C, and K₂CO₃ (1.44 g, 10.39 mmol, 1.0 eq) and Boc₂O (2.27 g, 10.39 mmol, 1.0 eq) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The solution was concentrated under reduced pressure, dissolved in ethyl acetate (60 mL), and separated after adding water (40 mL). The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic phases were washed with saturated sodium chloride solution (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A34-2 (2.66 g, yield: 100%).

[0620] MS(ESI,[M+Na)) + )m / z:278.10

[0621] Step 2: Intermediate A34-3

[0622] Compound A34-2 (100 mg, 0.390 mmol, 1.0 eq) was dissolved in MeOH (3 mL), and sodium hydrosulfide (131 mg, 2.34 mmol, 6 eq) was added. The reaction mixture was reacted at 80 °C for 16 hours. The solution was concentrated under reduced pressure, dissolved in dichloromethane (20 mL), and water (15 mL) was added. The aqueous layer was extracted with dichloromethane (20 mL). The combined organic phases were washed with dilute hydrochloric acid (0.25 M, 15 mL), washed with saturated sodium chloride solution (20 mL), and dried over anhydrous sodium sulfate. After drying, the solution was concentrated under reduced pressure to give compound A34-3 (85 mg, yield: 100%).

[0623] MS(ESI,[M+Na)) + m / z:=240.10

[0624] Step 3: Intermediate A34

[0625] Compound A34-3 (85 mg, 0.391 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated to obtain A34 (84 mg, yield: 100%), which was directly used in the next step of the reaction.

[0626] MS(ESI,[M+H) + m / z:118.20

[0627] Preparation of intermediate A35

[0628]

[0629] Step 1: Preparation of intermediate A35-1

[0630] Compound A1-1 (5.0 g, 29.9 mmol, 1.0 eq) was dissolved in DMF (30 mL), and cesium carbonate (24.4 g, 74.76 mmol, 2.5 eq) was added. The reaction mixture was stirred at 80 °C for 10 minutes under a nitrogen atmosphere. Trifluoroiodoethane (37.7 g, 179.42 mmol, 6.0 eq) was added dropwise in batches over a total of 4 hours. The reaction mixture was stirred at 80 °C for 20 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EA = 30:1) to give compound A35-1 (2.5 g, yield: 34%).

[0631] MS(ESI,[M+H) + m / z:250.20

[0632] Step 2: Preparation of intermediate A35-2

[0633] Compound A35-1 (2.5 g, 10.03 mmol, 1.0 eq) was dissolved in anhydrous THF (20 mL), and 3-chloro-4-fluoroaniline (2.19 g, 15.05 mmol, 1.5 eq) was added. Under nitrogen protection, the mixture was cooled to 0 °C, and LiHMDS (30 mL, 1 M, 30.09 mmol, 3.0 eq) was added. The reaction mixture was slowly heated to room temperature and reacted for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methyl tert-butyl ether (30 mL), stirred for ten minutes, filtered, and the filter cake was dried to give compound A35-2 (730 mg, yield: 21%).

[0634] MS(ESI,[M+H) + )m / z:349.00

[0635] Step 3: Preparation of intermediate A35-3

[0636] Compound A35-2 (730 mg, 2.09 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL) under nitrogen protection and cooled to 0 °C. A solution of ethyl chloroxaate (429 mg, 3.14 mmol, 1.5 eq) in dichloromethane (3 mL) was added dropwise, followed by the addition of aluminum chloride (698 mg, 5.23 mmol, 2.50 eq) in portions. The reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched in ice water and extracted with dichloromethane (2 × 50 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 7:3) to give compound A35-3 (550 mg, yield: 59%).

[0637] MS(ESI,[M+H) + )m / z:449.10

[0638] Step 4: Preparation of intermediate A35

[0639] Compound A35-3 (550 mg, 1.23 mmol, 1.0 eq) was dissolved in THF / MeOH / H2O (5 / 3 / 3 mL), and LiOH (88 mg, 3.68 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, 1 M dilute hydrochloric acid solution was added to make the reaction mixture acidic. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A35 (440 mg, yield: 85%).

[0640] MS(ESI,[M+H) + )m / z:421.10

[0641] Preparation of intermediate A36

[0642]

[0643] Step 1: Preparation of intermediate A36-1

[0644] Compound A1-1 (2.00 g, 11.96 mmol, 1.0 eq) was dissolved in toluene (10 mL), and isopropanol (1.08 g, 17.94 mmol, 1.5 eq) and cyanomethylenetri-n-butylphosphine (1.44 g, 5.98 mmol, 0.5 eq) were added. The reaction mixture was stirred at 120 °C for 5 hours under a nitrogen atmosphere. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE) to give compound A36-1 (1.6 g, yield: 64%).

[0645] MS(ESI,[M+H) + )m / z:210.10

[0646] Step 2: Preparation of intermediate A36-2

[0647] Compound A36-1 (1.6 g, 7.64 mmol, 1.0 eq) was dissolved in anhydrous THF (25 mL), and 3-chloro-4-fluoroaniline (1.45 g, 9.94 mmol, 1.3 eq) was added. Nitrogen gas was then added, and LiHMDS (23 mL, 1 M, 23 mmol, 3.0 eq) was added at 0 °C. The reaction mixture was slowly heated to room temperature and reacted for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methyl tert-butyl ether (10 mL), stirred for ten minutes, filtered, and the filtrate was evaporated to dryness to give compound A36-2 (1.6 g, yield: 68%).

[0648] MS(ESI,[M+H) + )m / z:309.10

[0649] Step 3: Preparation of intermediate A36-3

[0650] Compound A36-2 (1.6 g, 5.18 mmol, 1.0 eq) was dissolved in DCM (20 mL) and cooled to 0 °C. Under a nitrogen atmosphere, a solution of ethyl chloroxaate (1.06 g, 7.77 mmol, 1.5 eq) in dichloromethane (5 mL) was added dropwise to the reaction mixture. Aluminum trichloride (1.73 g, 12.95 mmol, 2.5 eq) was added in portions. The reaction mixture was slowly heated to room temperature and stirred for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (DCM) to give compound A36-3 (1.2 g, yield: 57%).

[0651] MS(ESI,[M+H) + )m / z:409.10

[0652] Step 4: Preparation of intermediate A36

[0653] Compound A36-3 (1.2 g, 2.94 mmol, 1.0 eq) was dissolved in THF / MeOH / H2O (10 / 5 / 5 mL), and LiOH (141 mg, 5.87 mmol, 2.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, 1 M dilute hydrochloric acid solution was added to make the reaction mixture acidic. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A36 (850 mg, yield: 76%).

[0654] MS(ESI,[M+H) + )m / z:381.10

[0655] Preparation of intermediate A37

[0656]

[0657] Step 1: Preparation of intermediate A37-1

[0658] Compound A1-1 (5.00 g, 29.9 mmol, 1.0 eq) was dissolved in 1,4-dioxane (120 mL), and cyclopropylboronic acid (6.42 g, 74.76 mmol, 2.5 eq), copper acetate (8.15 g, 44.85 mmol, 1.5 eq), 2,2-bipyridine (7.01 g, 44.85 mmol, 1.5 eq), and sodium carbonate (7.92 g, 74.76 mmol, 2.5 eq) were added. The reaction mixture was stirred at 100 °C for 16 hours under an oxygen atmosphere. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE) to give compound A37-1 (1.40 g, yield: 23%).

[0659] MS(ESI,[M+H) + )m / z:208.10

[0660] Step 2: Preparation of intermediate A37-2

[0661] Compound A37-1 (900 mg, 4.34 mmol, 1.0 eq) was dissolved in anhydrous THF (20 mL), and 3-chloro-4-fluoroaniline (1.90 g, 13.0 mmol, 3.0 eq) was added. Nitrogen was then introduced to displace the solution, and the mixture was cooled to 0 °C. A THF solution of LiHMDS (43.4 mL, 1 M, 43.4 mmol, 10.0 eq) was added to the reaction mixture. Under nitrogen protection, the reaction mixture was slowly heated to room temperature and stirred for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in methyl tert-butyl ether (15 mL), stirred for ten minutes, filtered, and the filter cake was dried to give compound A37-2 (1.20 g, yield: 90%).

[0662] MS(ESI,[M+H) + m / z:307.40

[0663] Step 3: Preparation of intermediate A37-3

[0664] Compound A37-2 (1.78 g, 13.04 mmol, 4.0 eq) and AlCl3 (1.74 g, 13.04 mmol, 4.0 eq) were added to DCM (20 mL) under nitrogen protection. The mixture was cooled to 0 °C and stirred for half an hour. Ethyl chloroxaate (1.00 g, 3.26 mmol, 1.0 eq) was added, and the mixture was slowly heated to room temperature and stirred for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE:EA = 3:1) to give compound A37-3 (800 mg, yield: 60%).

[0665] MS(ESI,[M+H) + )m / z:407.10

[0666] Step 4: Preparation of intermediate A37

[0667] Compound A37-3 (800 mg, 1.97 mmol, 1.0 eq) was dissolved in THF / MeOH / H2O (10 / 5 / 5 mL), and LiOH (141 mg, 5.90 mmol, 3.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, 1 M dilute hydrochloric acid solution was added to bring the pH of the reaction mixture to 3. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A37 (700 mg, yield: 94%).

[0668] MS(ESI,[M+H) + )m / z:379.40

[0669] Preparation of intermediate A38

[0670]

[0671] Step 1: Preparation of intermediate A38-1

[0672] Compound A2-5 (300 mg, 0.966 mmol, 1.0 eq) and pyridine (3.9 mL) were dissolved in dichloromethane (6 mL). The reaction mixture was cooled to 0 °C under nitrogen protection, and acetic anhydride (296 mg, 2.900 mmol, 3.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. Dichloromethane (20 mL) and water (15 mL) were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with NaHCO3 aqueous solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound A38-1 (400 mg, yield >100%), which was directly used in the next reaction.

[0673] MS(ESI,[M+H) + )m / z:353.10

[0674] Step 2: Preparation of intermediate A38

[0675] Compound A38-1 (300 mg, 0.851 mmol) was dissolved in dichloromethane (3 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the crude product A38 (300 mg, yield >100%) was concentrated and used directly in the next step of the reaction.

[0676] MS(ESI,[M+H) + )m / z:253.10

[0677] Preparation of intermediate A39

[0678]

[0679] Step 1: Preparation of intermediate A39-1

[0680] Compound A2-3 (520 mg, 5.77 mmol, 1.0 eq) was dissolved in anhydrous DMF (5 mL), cooled to 0 °C, and NaH (60%, 276 mg, 6.92 mmol, 1.2 eq) was added under a nitrogen atmosphere. The mixture was stirred under a nitrogen atmosphere for 30 minutes, and then oxetane-3-thiol (2.27 g, 6.92 mmol, 1.2 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture was quenched in ice water and extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A39-1 (800 mg, yield: 43%).

[0681] MS(ESI,[M+Na)) + )m / z:344.10

[0682] Step 2: Preparation of intermediate A39-2

[0683] Compound A39-1 (800 mg, 2.49 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and ammonium carbamate (777 mg, 9.96 mmol, 4.0 eq) and diacetoxyiodobenzene (2.40 g, 7.47 mmol, 3.0 eq) were added. The reaction mixture was reacted at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A39-2 (900 mg, yield >100%), which was used directly in the next reaction.

[0684] MS(ESI,[M+H) + )m / z:353.20

[0685] Step 3: Preparation of intermediate A39

[0686] Compound A39-2 (900 mg, 2.55 mmol) was dissolved in dichloromethane (5 mL), and TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the concentrated residue (892 mg) was used directly in the next step of the reaction.

[0687] MS(ESI,[M+H) + )m / z:253.10

[0688] Preparation of intermediate A40

[0689]

[0690] Step 1: Preparation of intermediate A40-2

[0691] Compound A40-1 (5.0 g, 33.51 mmol, 1.0 eq) was dissolved in dichloromethane (60 mL), and triethylamine (10.17 g, 100.54 mmol, 3.0 eq) and triphosgene (5.0 g, 16.76 mmol, 0.5 eq) were added sequentially at -60 °C. The reaction mixture was then heated to room temperature and stirred for 1 hour. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to give compound A40-2 (5.7 g, yield: 97%).

[0692] MS(ESI,[M+H) + m / z:176.10

[0693] Step 2: Preparation of intermediate A40-3

[0694] Compound A40-2 (3.0 g, 17.12 mmol, 1.0 eq) was dissolved in a solution of sulfuric acid (4.8 mL) and trifluoroacetic acid (16.3 mL) at 0 °C. NBS (3.2 g, 17.98 mmol, 1.05 eq) was slowly added in portions at 0 °C, and the reaction mixture was stirred at 0 °C for 1.5 hours. After the reaction was complete, the mixture was added to ice water (100 mL), extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 1 / 1) to give compound A40-3 (3.0 g, yield: 69%).

[0695] MS(ESI,[M+H) + m / z:253.90

[0696] Step 3: Preparation of intermediate A40

[0697] Compound A40-3 (500 mg, 1.97 mmol, 1.0 eq) and KOH (552 mg, 9.85 mmol, 5.0 eq) were dissolved in a mixed solvent of EtOH / H2O (1 / 1, 20 mL). The reaction solution was reacted at 80 °C for 5 hours. After the reaction was complete, the mixture was extracted with ethyl acetate. The combined organic phases were extracted with dilute hydrochloric acid (1.0 M, 20 mL). The aqueous phase was adjusted to pH 14 with solid NaOH and extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A40 (419 mg, yield: 93%).

[0698] MS(ESI,[M+H) + )m / z:228.00

[0699] Preparation of intermediate A41

[0700]

[0701] Step 1: Preparation of intermediate A41-2

[0702] Compound A41-1 (6.0 g, 28.4 mmol, 1.0 eq) was dissolved in methanol (100 mL), and NaBH4 (1.6 g, 42.6 mol, 1.5 eq) was added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, ethyl acetate (200 mL) and water (200 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 100 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound A41-2 (6.0 g, yield: 99%).

[0703] MS(ESI,[M+2-H2O)) + m / z:197.00

[0704] Step 2: Preparation of intermediate A41-3

[0705] Compound A41-2 (5.5 g, 25.8 mmol, 1.0 eq) was dissolved in toluene (30 mL), and TsOH·H2O (98 mg, 0.52 mmol, 0.02 eq) was added. The reaction mixture was stirred at 115 °C for 3 hours. After the reaction was complete, ethyl acetate was added, and the mixture was washed successively with water and saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure to give compound A41-3 (4.5 g, yield: 89%).

[0706] 1 H NMR (400MHz, CDCl3) δ7.59(s,1H),7.39(dd,J=8.0,1.6Hz,1H),7.27-7.23(m,1H),6.87-6.78(m,1H),6.57-6.51(m,1H),3.38(t,J=1.6Hz,2H).

[0707] Step 3: Preparation of intermediate A41-5

[0708] Compound A41-3 (3.0 g, 15.4 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and the solution was cooled to 0 °C. (R,R)-Jacobsen's catalyst (980 mg, 1.54 mmol, 0.1 eq) and compound A41-4 (790 mg, 4.62 mmol, 0.3 eq) were added to the reaction solution. Sodium hypochlorite solution (18 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for 1 hour. After the reaction was complete, dichloromethane (40 mL) was added, followed by water (40 mL). The aqueous phase was extracted with dichloromethane (3 × 40 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain crude compound A41-5 (3.2 g, yield: 98%).

[0709] MS(ESI,[M+2)) + )m / z:211.90

[0710] Step 4: Preparation of intermediate A41

[0711] Compound A41-5 (3.2 g, 15.16 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonia (20 mL) was added. The tube was sealed, and the mixture was heated to 95 °C and stirred for 4 hours. After the reaction was complete, dichloromethane (60 mL) and water (40 mL) were added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (3 × 40 mL), and the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated to give crude compound A41 (3.3 g, yield: 95%).

[0712] MS(ESI,[M+2)) + )m / z:229.00

[0713] Preparation of intermediate A42

[0714]

[0715] Step 1: Preparation of intermediate A42-1

[0716] Compound A40-3 (10.0 g, 39.4 mmol, 1.0 eq), potassium phosphate (25.1 g, 118.1 mmol, 3.0 eq), and PMBCl (9.3 g, 59.1 mmol, 1.5 eq) were dissolved in acetonitrile (500 mL), and TBAB (1.3 g, 3.94 mmol, 0.1 eq) was added. The reaction mixture was stirred at 50 °C for 16 hours, filtered, and the filtrate was evaporated to dryness. The residue was purified by slurry mixing with petroleum ether / ethyl acetate (2:1, 60 mL) to give compound A42-1 (7.6 g, yield: 52%).

[0717] MS(ESI,[M+2)) +m / z:375.00

[0718] Step 2: Preparation of intermediate A42-2

[0719] Compound A42-1 (4.0 g, 10.7 mmol, 1.0 eq), CuI (4.1 g, 21.4 mmol, 2.0 eq), and DABCO (4.8 g, 42.8 mmol, 4.0 eq) were added to DMSO (45 mL), placed in an iron sealed container, and the air was purged with nitrogen. The mixture was stirred at 140 °C for 72 hours under sealed conditions, and the reaction solution was cooled to room temperature. Ethyl acetate (300 mL) was added, and the mixture was filtered. The filtrate was washed with saturated sodium chloride solution (3 × 100 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound A42-2 (3.0 g, yield: 82%).

[0720] MS(ESI,[M+H) + )m / z:342.10

[0721] Step 3: Preparation of intermediate A42-3

[0722] Compound A42-2 (3.0 g, 8.8 mmol, 1.0 eq) was dissolved in TFA (15 mL), and the reaction mixture was stirred at 90 °C for 3 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The pH was adjusted to 8 with a saturated sodium carbonate aqueous solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A42-3 (1.8 g, yield: 93%).

[0723] MS(ESI,[M+H) + )m / z:222.10

[0724] Step 4: Preparation of intermediate A42

[0725] Compound A42-3 (1.8 g, 8.1 mmol, 1.0 eq) was dissolved in a mixed solvent of ethanol / water (2 / 1, 150 mL), and potassium hydroxide (2.3 g, 40.5 mmol, 5.0 eq) was added. The reaction mixture was stirred at 95 °C for 6 hours. The solution was concentrated under reduced pressure and extracted with ethyl acetate (3 × 60 mL). The combined organic phases were extracted with dilute hydrochloric acid (1 M). The aqueous phases were combined, the pH was adjusted to 8 with solid sodium hydroxide, and the solution was extracted with ethyl acetate (3 × 60 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A42 (1.4 g, yield: 88%).

[0726] MS(ESI,[M+H) +)m / z:196.10

[0727] Preparation of intermediate A43

[0728]

[0729] Step 1: Preparation of intermediate A43-3

[0730] Compound A43-1 (1.00 g, 11.6 mmol, 1.0 eq) was dissolved in toluene (50 mL), and compound A43-2 (4.01 g, 11.5 mmol, 0.99 eq) was added. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 15 / 1) to give compound A43-3 (1.50 g, yield: 83%).

[0731] MS(ESI,[M+H) + m / z:157.10

[0732] Step 2: Preparation of intermediate A43

[0733] Compound A43-3 (1.0 g, 6.40 mmol, 1.0 eq) was dissolved in 1,4-dioxane (40 mL), and ammonia-methanol solution (6.4 mL, 25.6 mmol, 4 M, 4.0 eq) was added. The reaction mixture was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated to give compound A43 (1.0 g, yield: 90%).

[0734] MS(ESI,[M+H) + m / z:174.10

[0735] Preparation of intermediate A44

[0736]

[0737] Step 1: Preparation of intermediate A44-3

[0738] Compound A44-1 (2.0 g, 19.98 mmol, 1.0 eq) and compound A44-2 (6.96 g, 19.98 mmol, 1.0 eq) were dissolved in toluene (50 mL), and the reaction solution was reacted at 120 °C for 16 hours. After cooling to room temperature, toluene was removed under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound A44-3 (2.0 g, yield: 59%).

[0739] MS(ESI,[M+H) + m / z:171.10

[0740] Step 2: Preparation of intermediate A44-4

[0741] Compound A44-3 (1.5 g, 8.81 mmol, 1.0 eq) and NH3 (7.0 M in MeOH, 10 mL) were placed in a high-pressure reactor, sealed, and heated at 90 °C for 16 hours. The mixture was then concentrated under reduced pressure to obtain crude compound A44-4 (1.7 g).

[0742] Step 3: Preparation of intermediate A44

[0743] The crude compound A44-4 (1.7 g) was dissolved in EA / PE (1 / 10, 20 mL), and ethyl acetate hydrochloride solution (4.0 M, 1.5 mL) was added. The reaction mixture was stirred at room temperature for half an hour and allowed to stand for half an hour. The solid and liquid layers separated and adhered to the bottle wall. The supernatant was discarded, and the solid was dried under reduced pressure to obtain mixture A44 (100 mg, yield: 6%), which was directly used in the next reaction.

[0744] MS(ESI,[M+H) + )m / z:88.10

[0745] Preparation of intermediate A45

[0746]

[0747] Step 1: Preparation of intermediate A45-3

[0748] Compound A45-1 (1.00 g, 10.0 mmol, 1.0 eq) was dissolved in toluene (20 mL), and compound 2 (3.48 g, 10.0 mmol, 1.0 eq) was added. The reaction mixture was stirred at 120 °C for 16 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to give compound A45-3 (0.8 g, yield: 47%).

[0749] MS(ESI,[M+H) + m / z:171.20

[0750] Step 2: Preparation of intermediate A45

[0751] Compound A45-3 (0.8 g, 4.7 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonia-methanol solution (4.7 mL, 18.8 mmol, 4 M, 4.0 eq) was added. The reaction mixture was stirred at 90 °C for 16 hours in a sealed container. The mixture was then cooled to room temperature and concentrated to give compound A45 (0.8 g, crude product).

[0752] MS(ESI,[M+H) +)m / z:188.20

[0753] Preparation of intermediate A46

[0754]

[0755] Step 1: Preparation of intermediate A46-2

[0756] Cis compound A46-1 (200 mg, 1.34 mmol, 1.0 eq) was dissolved in DCM (5 mL), cooled to 0 °C under nitrogen protection, and then triethylamine (271 mg, 2.68 mmol, 2.0 eq) and Boc₂O (293 mg, 1.34 mmol, 1.0 eq) were added sequentially. The reaction mixture was reacted at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE / EA = 7 / 1) to give cis compound A46-2 (260 mg, yield: 78%).

[0757] MS(ESI,[M+Na)) + m / z:272.10

[0758] Step 2: Preparation of intermediate A46-3

[0759] Cis compound A46-2 (260 mg, 1.04 mmol, 1.0 eq) was dissolved in toluene (5 mL) under nitrogen protection. p-Nitrobenzoic acid (436 mg, 2.61 mmol, 2.5 eq), DIAD (422 mg, 2.09 mmol, 2.0 eq), and triphenylphosphine (547 mg, 2.09 mmol, 2.0 eq) were added sequentially. The reaction mixture was reacted at 100 °C for 3 hours under nitrogen protection. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 6 / 1) to give trans compound A46-3 (400 mg, yield: 96%).

[0760] MS(ESI,[M+Na)) + )m / z:421.10

[0761] Step 3: Preparation of intermediate A46-4

[0762] Trans-compound A46-3 (400 mg, 1.00 mmol, 1.0 eq) was dissolved in THF / H₂O (5 / 5 mL), and LiOH (240 mg, 10.0 mmol, 10.0 eq) was added. The reaction mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, the pH was adjusted to acidic by adding citric acid aqueous solution, and the mixture was extracted with ethyl acetate. The ethyl acetate phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude trans-compound A46-4 (230 mg, yield: 92%).

[0763] MS(ESI,[M+Na)) + m / z:272.10

[0764] Step 4: Preparation of intermediate A46

[0765] Trans compound A46-4 (230 mg, 0.922 mmol) was dissolved in dichloromethane (6 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude trans compound A46 (170 mg, yield: 75%), which was directly used in the next step of the reaction.

[0766] MS(ESI,[M+H) + m / z:150.10

[0767] Preparation of intermediate A47

[0768]

[0769] Step 1: Preparation of intermediate A47-2

[0770] Trans compound A47-1 (1.5 g, 7.04 mmol, 1.0 eq) was dissolved in DMSO (20 mL), and sodium azide (549 mg, 8.45 mmol, 1.2 eq) was added. The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was complete, the reaction mixture was cooled to room temperature. Ethyl acetate was added, and the mixture was extracted with water and saturated sodium chloride solution. After drying with anhydrous sodium sulfate, the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 4 / 1) to give cis compound A47-2 (900 mg, yield: 73%).

[0771] MS(ESI,[M+Na)) + )m / z:198.10

[0772] Step 2: Preparation of intermediate A47

[0773] Cis compound A47-2 (900 mg, 5.14 mmol, 1.0 eq) was dissolved in methanol (50 mL), and Raney Ni (200 mg) was added to displace hydrogen gas. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain cis compound A47 (600 mg, yield: 78%).

[0774] MS(ESI,[M+H) + m / z:150.10

[0775] Preparation of intermediate A48

[0776]

[0777] Step 1: Preparation of intermediate A48-3

[0778] Compound A48-1 (3.0 g, 15.4 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and (S,S)-Jacobsen's catalyst (980 mg, 1.54 mmol, 0.1 eq) and compound A48-2 (790 mg, 4.62 mmol, 0.3 eq) were added. After the addition was complete, sodium hypochlorite solution (18 mL) was slowly added to the reaction system, and the reaction was carried out at 0 °C for 1 hour. After the reaction was completed, dichloromethane (50 mL) was added, followed by water (40 mL), and the mixture was separated. The aqueous phase was extracted with dichloromethane (3 × 40 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A48-3 (1.8 g, yield: 55%).

[0779] MS(ESI,[M+H) + )m / z:211.20

[0780] Step 2: Preparation of intermediate A48

[0781] Compound A48-3 (650 mg, 3.08 mmol, 1.0 eq) was dissolved in methanol (5 mL), and ammonia (20 mL) was added. The reaction mixture was stirred at 95 °C for 16 hours in a sealed container. After the reaction was complete, the reaction mixture was diluted with dichloromethane (40 mL), and water (40 mL) was added. The aqueous phase was extracted with dichloromethane (3 × 40 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain crude compound A48 (600 mg, yield: 85%).

[0782] MS(ESI,[M+H) + )m / z:228.00

[0783] Preparation of intermediate A49

[0784]

[0785] Step 1: Preparation of intermediate A49-1

[0786] Compound A27-4 (400 mg, 1.17 mmol, 1.0 eq) was dissolved in DMF (5 mL) and water (5 mL), and sodium isopropanethiolate (1.15 g, 11.72 mmol, 10.0 eq) was added. The reaction mixture was reacted at 80 °C for 8 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A49-1 (350 mg, yield: 93%).

[0787] MS(ESI,[M+Na)) + )m / z:344.20

[0788] Step 2: Preparation of intermediate A49

[0789] Compound A49-1 (350 mg, 1.09 mmol) was added to dichloromethane (2 mL), followed by trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain crude trifluoroacetate of compound A49 (400 mg, yield: 100%), which was directly used in the next step of the reaction.

[0790] MS(ESI,[M+H) + )m / z:222.10

[0791] Preparation of intermediate A50

[0792]

[0793] Step 1: Preparation of intermediate A50-2

[0794] Compound A50-1 (900 mg, 8.73 mmol, 1.0 eq) was dissolved in methanol (10 mL), and triethylamine (2.62 g, 25.9 mmol, 3.0 eq) was added. Nitrogen gas was then introduced to displace the solution. Boc₂O (2.86 g, 13.1 mmol, 1.5 eq) was added to the reaction mixture under ice bath conditions. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A50-2 (1.8 g, yield: 100%).

[0795] MS(ESI,[M+Na)) + )m / z:226.10

[0796] Step 2: Preparation of intermediate A50-3

[0797] Compound A50-2 (1.8 g, 8.86 mmol, 1.0 eq) and triethylamine (2.67 g, 26.4 mmol, 3.0 eq) were dissolved in DCM (20 mL). The reaction solution was cooled to 0 °C under nitrogen protection, and methanesulfonyl chloride (1.51 g, 13.2 mmol, 1.5 eq) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with DCM, washed successively with water, saturated citric acid aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated to give compound A50-3 (2.0 g, yield: 80%).

[0798] MS(ESI,[M+Na)) + )m / z:304.10

[0799] Step 3: Preparation of intermediate A50-4

[0800] Sodium isopropanethiolate (500 mg, 1.78 mmol, 1.0 eq) was dissolved in DMF (5 mL) and water (5 mL), and compound A50-3 (500 mg, 1.78 mmol, 1.0 eq) was added. The reaction mixture was reacted at 60 °C for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A50-4 (450 mg, yield: 97%).

[0801] MS(ESI,[M+Na)) + )m / z:284.20

[0802] Step 4: Preparation of intermediate A50

[0803] Compound A50-4 (450 mg, 1.72 mmol) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried to obtain A50 (450 mg, yield: 100%), which was directly used in the next step of the reaction.

[0804] MS(ESI,[M+H-NH3)) + m / z:145.10

[0805] Preparation of intermediate A51

[0806]

[0807] Step 1: Preparation of intermediate A51-1

[0808] Compound A50-3 (300 mg, 1.06 mmol, 1.0 eq) was dissolved in DMF (10 mL), and sodium methanethiol (372 mg, 5.31 mmol, 5.0 eq) was added. The reaction mixture was reacted at 60 °C for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A51-1 (250 mg, yield: 100%).

[0809] MS(ESI,[M+Na)) + m / z:=256.10

[0810] Step 2: Preparation of intermediate A51

[0811] Compound A51-1 (250 mg, 1.06 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain compound A51 (250 mg, yield: 100%), which was directly used in the next step of the reaction.

[0812] MS(ESI,[M-NH2] + m / z:117.10

[0813] Preparation of intermediate A52

[0814]

[0815] Step 1: Preparation of intermediate A52-1

[0816] Compound A25-1 (3.5 g, 10.69 mmol, 1.0 eq) and potassium thioacetate (4.88 g, 42.76 mmol, 4.0 eq) were added to DMF (11 mL), and the reaction mixture was stirred at 100 °C for 3 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed with water in a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound A52-1 (3.0 g, yield: 91%).

[0817] MS(ESI,[M+Na)) + )m / z:330.10

[0818] Step 2: Preparation of intermediate A52-2

[0819] Compound A52-1 (3.0 g, 9.76 mmol, 1.0 eq) was dissolved in THF (20 mL) and water (10 mL), and LiOH (467 mg, 19.52 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed with water in a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound A52-2 (1.2 g, yield: 23%).

[0820] MS(ESI,[M+Na)) + )m / z:551.20

[0821] Step 3: Preparation of intermediate A52-3

[0822] Compound A52-2 (800 mg, 1.51 mmol, 1.0 eq) was added to a THF solution of compound 5 (1 M, 10.6 mL, 10.6 mmol, 7.0 eq) at 0 °C under nitrogen protection. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with THF, and the reaction was quenched with solid citric acid (3.0 g, 15.1 mmol, 10.0 eq). The mixture was dissolved in EA and water, and the aqueous phase was extracted with EA. The organic phases were combined, washed with water in a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound A52-3 (400 mg, yield: 87%).

[0823] MS(ESI,[M+Na)) + )m / z:328.10

[0824] Step 4: Preparation of intermediate A52

[0825] Compound A52-3 (100 mg, 0.33 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the crude compound A52 (110 mg, yield: greater than 100%) was concentrated and used directly in the next step of the reaction.

[0826] MS(ESI,[M+H-NH3)) + )m / z:189.10

[0827] Preparation of intermediate A53

[0828]

[0829] Step 1: Preparation of intermediate A53-1

[0830] Compound A52-3 (200 mg, 0.654 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (204 mg, 2.616 mmol, 4.0 eq) and PIDA (637 mg, 1.962 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, water and a saturated sodium sulfite aqueous solution were added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain A53-1 (220 mg, yield: 100%), which was used directly in the next reaction.

[0831] MS(ESI,[M+H) + )m / z:337.20

[0832] Step 2: Preparation of intermediate A53

[0833] Compound A53-1 (220 mg, 0.654 mmol) was dissolved in dichloromethane (2 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to obtain compound A53 (220 mg, yield: 100%), which was directly used in the next step of the reaction.

[0834] MS(ESI,[M+H) + )m / z:237.10

[0835] Preparation of intermediate A54

[0836]

[0837] Step 1: Preparation of intermediate A54-2

[0838] Compound A54-1 (500 mg, 1.6 mmol, 1.0 eq) was dissolved in toluene (5 mL), followed by the addition of 50% sodium hydroxide aqueous solution (5 mL), TBAB (260 mg, 0.8 mmol, 0.5 eq), and methyl iodoform (457 mg, 3.2 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound A54-2 (330 mg, yield: 63%).

[0839] MS(ESI,[M+Na)) + )m / z:346.20

[0840] Step 2: Preparation of intermediate A54-3

[0841] Compound A54-2 (330 mg, 1.02 mmol, 1.0 eq) was dissolved in methanol (4 mL), followed by the addition of ammonium carbamate (318 mg, 4.1 mmol, 4.0 eq) and diacetoxyiodobenzene (1.3 g, 4.1 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A54-3 (320 mg, yield: 89%).

[0842] MS(ESI,[M+H) + )m / z:355.20

[0843] Step 3: Preparation of intermediate A54

[0844] Compound A54-3 (320 mg, 0.9 mmol) was dissolved in dichloromethane (2 mL), and TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried to obtain compound A54 (315 mg, yield: 100%), which was directly used in the next step of the reaction.

[0845] MS(ESI,[M+H) + )m / z:255.10

[0846] Preparation of intermediate A55

[0847]

[0848] Step 1: Preparation of intermediate A55-1

[0849] The compound oxetane-3-thiol (320 mg, 3.55 mmol, 1.0 eq) was dissolved in anhydrous DMF (4 mL) and cooled to 0 °C under nitrogen protection. NaH (60% in mineral oil, 170 mg, 4.26 mmol, 1.2 eq) was added, and the reaction mixture was stirred under nitrogen atmosphere for 30 minutes. Compound A54-3 (1.19 g, 4.26 mmol, 1.2 eq) was added, and the reaction mixture was reacted at room temperature for 2.5 hours. The reaction mixture was quenched in ice water and extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A55-1 (460 mg, yield: 47%).

[0850] MS(ESI,[M+Na)) + m / z:296.20

[0851] Step 2: Preparation of intermediate A55-2

[0852] Compound A55-1 (460 mg, 1.68 mmol, 1.0 eq) was dissolved in MeOH (10 mL), and ammonium carbamate (525 mg, 6.73 mmol, 4.0 eq) and diacetoxyiodobenzene (1.63 g, 5.05 mmol, 3.0 eq) were added. The reaction mixture was reacted at room temperature for 1 hour. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with liquid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A55-2 (550 mg, yield: 100%), which was used directly in the next reaction.

[0853] MS(ESI,[M+H) + )m / z:305.20

[0854] Step 3: Preparation of intermediate A55

[0855] Compound A55-2 (550 mg, 1.68 mmol) was dissolved in dichloromethane (5 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain residue A55 (550 mg, yield: 100%), which was directly used in the next step of the reaction.

[0856] MS(ESI,[M+H) + m / z:205.10

[0857] Preparation of intermediate A56

[0858]

[0859] Step 1: Preparation of intermediate A56-1

[0860] Oxycyclobutane-3-thiol (318 mg, 3.530 mmol, 2.0 eq) was dissolved in anhydrous ethanol (4 mL), and sodium methoxide (381 mg, 7.080 mmol, 4.0 eq) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Compound A3-7 (490 mg, 1.770 mmol, 1.0 eq) was added. The reaction mixture was reacted at room temperature for 2.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A56-1 (390 mg, yield: 81%).

[0861] MS(ESI,[M+Na)) + )m / z:294.10

[0862] Step 2: Preparation of intermediate A56

[0863] Compound A56-1 (390 mg, 1.440 mmol) was dissolved in dichloromethane (3 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to obtain residue A56 (400 mg, yield: 100%), which was used directly in the next reaction step.

[0864] MS(ESI,[M+H) + m / z:172.10

[0865] Preparation of intermediate A57

[0866]

[0867] Step 1: Preparation of intermediate A57-1

[0868] Sodium ethanethiol (1.28 g, 15.3 mmol, 10.0 eq) was dissolved in DMF / H₂O (3 / 3 mL) and reacted at 60 °C for 5 min. Compound A25-1 (500 mg, 1.53 mmol, 1.0 eq) was added, and the reaction mixture was reacted at 60 °C for 16 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 20 / 1) to give compound A57-1 (400 mg, yield: 89%).

[0869] MS(ESI,[M+Na)) + )m / z:315.90

[0870] Step 2: Preparation of intermediate A57-2

[0871] Compound A57-1 (200 mg, 0.682 mol, 1.0 eq) was dissolved in methanol (4 mL), followed by the sequential addition of ammonium carbamate (106 mg, 1.36 mol, 2.0 eq) and diacetoxyiodobenzene (659 mg, 2.04 mol, 3.0 eq). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude compound A57-2 (150 mg, yield: 68%).

[0872] MS(ESI,[M+H) + m / z:325.00

[0873] Step 3: Preparation of intermediate A57

[0874] Compound A57-2 (150 mg, 0.462 mmol) was dissolved in dichloromethane (3 mL), and TFA (8 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude compound A57 (150 mg, yield: 100%), which was directly used in the next step of the reaction.

[0875] MS(ESI,[M+H) + )m / z:225.10

[0876] Preparation of intermediate A58

[0877]

[0878] Step 1: Preparation of intermediate A58-1

[0879] Mercaptoethanol (0.95 g, 12.2 mmol, 1.0 eq) was dissolved in DMF (20 mL) under a nitrogen atmosphere. The solution was heated to 0 °C, and NaH (484 mg, 12.1 mmol, 0.99 eq) was added. The mixture was stirred at room temperature for 30 minutes, and then A2-3 (4.0 g, 12.2 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give compound A58-1 (2.0 g, yield: 53%).

[0880] MS(ESI,[M+Na)) + )m / z:332.20

[0881] Step 2: Preparation of intermediate A58-2

[0882] Compound A58-1 (500 mg, 1.62 mmol, 1.0 eq) was dissolved in methanol (5 mL), followed by the addition of ammonium carbamate (378 mg, 4.85 mmol, 3.0 eq) and diacetoxyiodobenzene (1.56 g, 4.85 mmol, 3.0 eq). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A58-2 (530 mg, yield: 96%).

[0883] MS(ESI,[M+H) + )m / z:341.20

[0884] Step 3: Preparation of intermediate A58

[0885] Compound A58-2 (530 mg, 1.56 mmol) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried to obtain compound A58 (530 mg, yield: 100%), which was directly used in the next step of the reaction.

[0886] MS(ESI,[M+H) + )m / z:241.20

[0887] Preparation of intermediate A59

[0888]

[0889] Step 1: Preparation of intermediate A59-1

[0890] Compound A1-2 (1.0 g, 5.52 mmol, 1.0 eq) and 5-amino-2-fluorobenzonitrile (1.13 g, 8.28 mmol, 1.5 eq) were added to a dry three-necked flask. Nitrogen gas was purged, and THF (10 mL) was added. The mixture was cooled to 0 °C, and a THF solution of hexamethyldisilamide lithium (16.6 mL, 16.6 mmol, 3.0 eq, 1 M) was added dropwise. The reaction mixture was then stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was poured into ice water and extracted with EA. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 3 / 1) to give compound A59-1 (600 mg, yield: 40%).

[0891] MS(ESI,[M+H) + m / z:272.20

[0892] Step 2: Preparation of intermediate A59-2

[0893] Compound A59-1 (600 mg, 2.21 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), and nitrogen was introduced to replace the nitrogen atmosphere. A solution of oxaloyl chloride monoethyl ester (453 mg, 3.32 mmol, 1.5 eq) in dichloromethane (3 mL) was added at 0 °C, followed by the addition of aluminum chloride (737 mg, 5.53 mmol, 2.5 eq) in portions. The reaction mixture was stirred overnight at room temperature under nitrogen. After the reaction was complete, the reaction mixture was quenched with ice water, extracted with dichloromethane, and the organic phases were combined, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, concentrated, and the residue purified by silica gel column chromatography (PE / EA = 3 / 1) to give compound A59-2 (500 mg, yield: 61%).

[0894] MS(ESI,[M+H) +)m / z:372.10

[0895] Step 3: Preparation of intermediate A59

[0896] Compound A59-2 (500 mg, 1.35 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (10 / 5 / 5 mL), and lithium hydroxide (322 mg, 13.46 mmol, 10.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the organic solvent was removed under reduced pressure. The residue was adjusted to pH 3-4 with 1 M hydrochloric acid, extracted with ethyl acetate (3 × 100 mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A59 (400 mg, yield: 87%).

[0897] MS(ESI,[M+H) + )m / z:344.10

[0898] Preparation of intermediate A60

[0899]

[0900] Step 1: Preparation of intermediate A60-1

[0901] 3-Mercaptopropanol (1.13 g, 12.2 mmol, 1.0 eq) was dissolved in DMF (20 mL) under nitrogen atmosphere. The mixture was cooled to 0 °C under nitrogen atmosphere, and NaH (484 mg, 12.1 mmol, 0.99 eq) was added. The mixture was then slowly heated to room temperature and stirred for 30 minutes. Compound A2-3 (4 g, 12.2 mmol, 1.0 eq) was added, and the mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 2 / 1) to give compound A60-1 (2.5 g, yield: 63%).

[0902] MS(ESI,[M+Na)) + )m / z:346.20

[0903] Step 2: Preparation of intermediate A60-2

[0904] Compound A60-2 (500 mg, 1.55 mmol, 1.0 eq) was dissolved in methanol (5 mL), followed by the sequential addition of ammonium carbamate (241 mg, 3.09 mmol, 2.0 eq) and diacetoxyiodobenzene (1.49 g, 4.64 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A60-2 (400 mg, yield: 73%).

[0905] MS(ESI,[M+H) + )m / z:355.20

[0906] Step 3: Preparation of intermediate A60

[0907] Compound A60-2 (400 mg, 1.13 mmol) was dissolved in dichloromethane (3 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain compound A60 (400 mg, yield: 100%), which was directly used in the next reaction.

[0908] MS(ESI,[M+H) + )m / z:255.10

[0909] Preparation of intermediate A61

[0910]

[0911] Step 1: Preparation of intermediate A61-2

[0912] Compound A61-1 (1.0 g, 11.5 mmol, 1.0 eq) was dissolved in DCM (10 mL), and Boc2O (2.8 g, 12.7 mmol, 1.1 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM, washed with water, dried over anhydrous sodium sulfate, and concentrated to give compound A61-2 (1.9 g, yield: 88%).

[0913] MS(ESI,[M+Na)) + )m / z:210.20

[0914] Step 2: Preparation of intermediate A61-3

[0915] Compound A61-2 (1.9 g, 10.15 mmol, 1.0 eq) and triethylamine (2.6 g, 25.38 mmol, 2.5 eq) were dissolved in DCM (30 mL). Under nitrogen protection, the mixture was lowered to 0 °C, and methanesulfonyl chloride (1.4 g, 12.18 mmol, 1.2 eq) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with DCM, washed successively with water, saturated citric acid aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated to give compound A61-3 (2.4 g, yield: 89%).

[0916] MS(ESI,[M+Na)) + )m / z:288.10

[0917] Step 3: Preparation of intermediate A61-4

[0918] Sodium isopropanethiolate (3.7 g, 38.0 mmol, 10.0 eq) was dissolved in DMF (30 mL), and compound A61-3 (1.0 g, 3.8 mmol, 1.0 eq) was added. The reaction mixture was reacted at 100 °C for 3 hours. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A61-4 (0.76 g, yield: 82%).

[0919] MS(ESI,[M+Na)) + )m / z:268.20

[0920] Step 4: Preparation of intermediate A61

[0921] Compound A61-4 (350 mg, 1.43 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL), and TFA (2.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure and dried under reduced pressure to obtain compound A61 (350 mg, crude product, yield: 100%), which was directly used in the next step of the reaction.

[0922] MS(ESI,[M+H) + m / z:146.20

[0923] Preparation of intermediate A62

[0924]

[0925] Step 1: Preparation of intermediate A62-2

[0926] Compound A62-1 (3.0 g, 15.9 mmol, 1.0 eq) and triethylamine (4.8 g, 47.6 mmol, 3.0 eq) were dissolved in DCM (40 mL). The reaction solution was cooled to 0 °C under a nitrogen atmosphere, and methanesulfonyl chloride (2.2 g, 19.02 mmol, 1.2 eq) was added dropwise. The reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was diluted with DCM, washed successively with water, saturated citric acid aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated to give compound A62-2 (4.1 g, yield: 97%) as a yellow liquid.

[0927] MS(ESI,[M+Na)) + m / z:290.10

[0928] Step 2: Preparation of intermediate A62-3

[0929] Sodium isopropanethiolate (3.6 g, 37.4 mmol, 10.0 eq) was dissolved in DMF / water (1 / 1, 6 mL), and compound A62-2 (1.0 g, 3.74 mmol, 1.0 eq) was added. The reaction mixture was reacted at 100 °C for 3 hours. Water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A62-3 (0.8 g, yield: 86%).

[0930] MS(ESI,[M+Na)) + m / z:270.20

[0931] Step 3: Preparation of intermediate A62

[0932] Compound A62-3 (400 mg, 1.6 mmol, 1.0 eq) was dissolved in dichloromethane (1.5 mL), and TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure and dried under reduced pressure to obtain compound A62 (400 mg, crude product, yield: 100%), which was directly used in the next step of the reaction.

[0933] MS(ESI,[M+H) + m / z:148.20

[0934] Preparation of intermediate A63

[0935]

[0936] Step 1: Preparation of intermediate A63-1

[0937] Sodium isopropanethiolate (976 mg, 9.95 mmol, 10.0 eq) was dissolved in a mixed solvent DMF / H₂O (1 / 1, 10 mL), and stirred at 60 °C for 5 minutes. After the system became clear, compound A20-2 (280 mg, 0.995 mmol, 1.0 eq) was added, and the reaction mixture was stirred at 60 °C for 2 hours. After the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give crude compound A63-1 (300 mg, yield: 100%).

[0938] MS(ESI,[M+Na)) + )m / z:284.10

[0939] Step 2: Preparation of intermediate A63

[0940] The crude compound A63-1 (300 mg, approximately 0.995 mmol) was dissolved in dichloromethane (2 mL), and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and dried under reduced pressure to obtain the residue A63 (300 mg, yield: 100%), which was directly used in the next step of the reaction.

[0941] MS(ESI,[M+H) + m / z:162.20

[0942] Preparation of intermediate A64

[0943]

[0944] Step 1: Preparation of intermediate A64-2

[0945] Compound A64-1 (3.0 g, 15.76 mmol, 1.0 eq) and TEA (3.19 g, 31.53 mmol, 2.0 eq) were dissolved in DCM (5 mL). The reaction mixture was cooled to 0 °C under nitrogen protection, and MsCl (2.17 g, 18.92 mmol, 1.2 eq) was added dropwise. The reaction mixture was then stirred at room temperature for 2 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was diluted with DCM, washed successively with water, 0.5 M citric acid aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated to give compound A64-2 (3.0 g, yield: 71%).

[0946] MS(ESI,[M+Na)) + m / z:290.10

[0947] Step 2: Preparation of intermediate A64-3

[0948] Compound A64-2 (3.0 g, 11.17 mmol, 1.0 eq) was dissolved in toluene and ethanol (1 / 1, 40 mL), and sodium methanethiol (7.8 g, 111.7 mmol, 10 eq) was added. The reaction mixture was reacted at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A64-3 (2.0 g, yield: 81%).

[0949] MS(ESI,[M+Na)) + )m / z:242.10

[0950] Step 3: Preparation of intermediate A64

[0951] Compound A64-3 (100 mg, 0.456 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude compound A64 (100 mg, yield: 100%), which was directly used in the next step of the reaction.

[0952] MS(ESI,[M+H) + m / z:120.20

[0953] Preparation of intermediate A65

[0954]

[0955] Step 1: Preparation of intermediate A65-1

[0956] Compound A64-3 (500 mg, 2.28 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (711 mg, 9.12 mmol, 4.0 eq) and compound PIDA (2.2 g, 6.84 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain residue A65-1 (500 mg, yield: 88%), which was used directly in the next reaction.

[0957] MS(ESI,[M+H) + m / z:251.40

[0958] Step 2: Preparation of intermediate A65-2

[0959] Compound A65-1 (500 mg, 2.0 mmol, 1.0 eq) was dissolved in dioxane (10 mL), followed by the addition of methylboric acid (240 mg, 4.0 mmol, 2.0 eq), pyridine (379 mg, 4.8 mmol, 2.4 eq), and anhydrous copper acetate (544 mg, 3.0 mmol, 1.5 eq). Under nitrogen protection, the reaction mixture was stirred at 100 °C for 2 hours. The solution was diluted with ethyl acetate (20 mL), and water (10 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (0.1% formic acid / acetonitrile / water) to obtain compound A65-2 (130 mg, yield: 62%).

[0960] MS(ESI,[M+H) + )m / z:265.20

[0961] Step 3: Preparation of intermediate A65

[0962] Compound A65-2 (200 mg, 0.756 mmol) was dissolved in dichloromethane (2 mL), and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain crude compound A65 (200 mg, yield: 100%), which was directly used in the next step of the reaction.

[0963] MS(ESI,[M+H) + m / z:165.20

[0964] Preparation of intermediate A66

[0965]

[0966] Step 1: Preparation of intermediate A66-2

[0967] Compound A66-1 (500 mg, 3.63 mmol, 1.0 eq) and NEt3 (735 mg, 7.27 mmol, 2.0 eq) were dissolved in methanol (30 mL). The reaction mixture was cooled to 0 °C under a nitrogen atmosphere, and di-tert-butyl dicarbonate (793 mg, 3.63 mmol, 1.0 eq) was added dropwise. The reaction mixture was then heated to room temperature and stirred for 15 hours under a nitrogen atmosphere. Water was added, and the mixture was extracted three times with dichloromethane. The combined organic phases were washed with saturated sodium chloride solution and concentrated to give compound A66-2 (700 mg, yield: 96%).

[0968] MS(ESI,[M+Na)) + )m / z:224.10

[0969] Step 2: Preparation of intermediate A66-3

[0970] Compound A66-2 (700 mg, 3.48 mmol, 1.0 eq) and NEt3 (1.06 g, 10.43 mmol, 3.0 eq) were dissolved in DCM (30 mL). The reaction solution was cooled to 0 °C under a nitrogen atmosphere, and MsCl (797 mg, 6.96 mmol, 2.0 eq) was added dropwise. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed successively with water, citric acid (0.5 M) aqueous solution, and water, dried over anhydrous sodium sulfate, and concentrated to give compound A66-3 (850 mg, yield: 87%).

[0971] MS(ESI,[M+Na)) + m / z:302.10

[0972] Step 3: Preparation of intermediate A66-4

[0973] Compound A66-3 (400 mg, 1.43 mmol, 1.0 eq) was dissolved in DMF (5 mL), and sodium methanethiol (1 g, 14.32 mmol, 10 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. Water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, and concentrated to give compound A66-4 (210 mg, yield: 63%).

[0974] MS(ESI,[M+Na)) + m / z:254.30

[0975] Step 4: Preparation of intermediate A66-5

[0976] Compound A66-4 (200 mg, 0.86 mmol, 1.0 eq) was dissolved in methanol (8 mL), followed by the addition of ammonium carbamate (270 mg, 3.46 mmol, 4.0 eq) and diacetoxyiodobenzene (1.11 g, 3.46 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 2 hours under an oxygen atmosphere. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A66-5 (220 mg, yield: 97%).

[0977] MS(ESI,[M+H) + )m / z:263.20

[0978] Step 5: Preparation of intermediate A66-6

[0979] Compound A66-5 (220 mg, 0.84 mmol, 1.0 eq) was dissolved in dioxane (6 mL), followed by the addition of methylboric acid (201 mg, 3.35 mmol, 4.0 eq), pyridine (318 mg, 4.02 mmol, 4.8 eq), and anhydrous copper acetate (609 mg, 3.35 mmol, 4.0 eq). The mixture was stirred at 100 °C for 2 hours under oxygen protection. The reaction solution was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A66-6 (220 mg, yield: 95%).

[0980] MS(ESI,[M+H) + )m / z:277.10

[0981] Step 6: Preparation of intermediate A66

[0982] Compound A66-6 (200 mg, 0.724 mmol) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated and dried to obtain residue A66 (200 mg, yield: 100%), which was directly used in the next reaction.

[0983] MS(ESI,[M+H) + m / z:177.20

[0984] Preparation of intermediate A67

[0985]

[0986] Step 1: Preparation of intermediate A67-1

[0987] Compound A41 (3.00 g, 13.2 mmol, 1.0 eq) was dissolved in DCM (40 mL), and Boc2O (2.87 g, 13.2 mmol, 1.0 eq) was added. The reaction mixture was reacted at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by rapid silica gel column chromatography (PE / EA = 4 / 1) to give compound A67-1 (1.30 g, yield: 30%).

[0988] MS(ESI,[M+Na)) + m / z:350.10

[0989] Step 2: Preparation of intermediate A67-2

[0990] Compound A67-1 (1.30 g, 3.96 mmol, 1.0 eq) was dissolved in DCM (40 mL), and acetic anhydride (2.02 g, 19.80 mmol, 5.0 eq) and triethylamine (2.00 g, 19.80 mmol, 5.0 eq) were added. DMAP (97 mg, 0.79 mmol, 0.2 eq) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (PE / EA = 6 / 1) to give compound A67-2 (1.10 g, yield: 75%).

[0991] MS(ESI,[M+Na)) + m / z:392.00

[0992] Step 3: Preparation of intermediate A67-3

[0993] Compound A67-2 (1.0 g, 2.70 mmol, 1.0 eq) was dissolved in DMSO (10 mL), and DABCO (606 mg, 5.40 mmol, 2.0 eq) and CuI (514 mg, 2.70 mmol, 1.0 eq) were added. The reaction mixture was placed in a sealed container and stirred at 140 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (5% EA / PE) to give compound A67-3 (190 mg, yield: 21%).

[0994] 1 H NMR (400MHz, CDCl3) δ7.40-7.32(m,1H),7.24-7.12(m,2H),7.09(s,1H),5.20-5.10(m,1H),4. 83-4.67(m,1H),3.40-3.25(m,1H),2.93-2.77(m,1H),2.47(s,3H),2.09(s,3H),1.48(s,9H).

[0995] Step 4: Preparation of intermediate A67

[0996] Compound A67-3 (180 mg, 0.533 mmol) was dissolved in dichloromethane (2 mL), and HCl / EA (2 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solution was concentrated under reduced pressure to give compound A67 (140 mg, yield: 97%), which was used directly in the next step of the reaction.

[0997] MS(ESI,[M+H-NH3)) +)m / z:221.10

[0998] Preparation of intermediate A68

[0999]

[1000] Step 1: Preparation of intermediate A68-1

[1001] Compound A42-1 (2 g, 5.3 mmol, 1.0 eq) was added to dioxane (50 mL), followed by methyl acetoacetate (1.85 g, 15.9 mmol, 3.0 eq), palladium acetate (120 mg, 0.53 mmol, 0.1 eq), tBuXphos (225 mg, 0.53 mmol, 0.1 eq), and potassium phosphate (5.61 g, 26.5 mmol, 5.0 eq). The reaction mixture was reacted at 120 °C for 16 hours under nitrogen protection. After the reaction was complete, the reaction mixture was cooled to room temperature and extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound A68-1 (1.2 g, crude product).

[1002] MS(ESI,[M+H) + )m / z:368.20

[1003] Step 2: Preparation of intermediate A68-2

[1004] Compound A68-1 (1.0 g, 2.7 mmol, 1.0 eq) was added to trifluoroacetic acid (50 mL), and the reaction mixture was stirred at 80 °C for two hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by rapid silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound A68-2 (0.5 g, two-step yield: 38%).

[1005] MS(ESI,[M+H) + )m / z:248.10

[1006] Step 3: Preparation of intermediate A68-3

[1007] Compound A68-2 (0.5 g, 2.02 mmol, 1.0 eq) was dissolved in ethanol (20 mL) and water (5 mL), and potassium hydroxide (567 mg, 10.1 mmol, 5.0 eq) was added. The reaction solution was stirred at 80 °C for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound A68-3 (400 mg, crude product).

[1008] MS(ESI,[M+H) + )m / z:208.20

[1009] Step 4: Preparation of intermediate A68

[1010] Compound A68-3 (300 mg, 1.48 mmol, 1.0 eq) was dissolved in ethanol (5 mL), and hydrochloric acid-ethanol solution (5 mL, 2 M) was added. The reaction mixture was stirred at 25 °C for 6 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain compound A68 (300 mg, crude product).

[1011] MS(ESI,[M+H) + )m / z:236.10

[1012] Preparation of intermediate A69

[1013]

[1014] Step 1: Preparation of intermediate A69-2

[1015] Compound A69-1 (10.0 g, 72.38 mmol, 1.0 eq) was dissolved in methanol (80 mL), cooled to 0 °C, and sodium borohydride (5.48 g, 144.75 mmol, 2.0 eq) was added in portions. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with chloroform, cooled to 0 °C, and 2 M hydrochloric acid aqueous solution (200 mL) was slowly added. The mixture was extracted with chloroform / isopropanol (5 / 1, 3 × 250 mL), and the organic phases were combined and washed with a small amount of saturated sodium bicarbonate aqueous solution (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give compound A69-2 (6.2 g, yield: 60%).

[1016] 1 H NMR (400MHz, CDCl3) δ4.32-4.26(m,2H),2.59-2.46(m,2H),2.20-2.07(m,4H),1.77-1.68(m,4H).

[1017] Step 2: Preparation of intermediate A69-3

[1018] Compound A69-2 (4.0 g, 28.13 mmol, 1.0 eq) was dissolved in DCM (50 mL), cooled to 0 °C, and then imidazole (3.8 g, 56.26 mmol, 2.0 eq) and TBDPSCl (7.0 g, 25.32 mmol, 0.9 eq) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 7) to give compound A69-3 (3.7 g, yield: 35%).

[1019] MS(ESI,[M+H) + )m / z:381.20

[1020] Step 3: Preparation of intermediate A69

[1021] Compound A69-3 (3.70 g, 9.72 mmol, 1.0 eq) and triethylamine (3.38 mL, 24.30 mmol, 2.5 eq) were dissolved in DCM (50 mL), cooled to 0 °C, and methanesulfonyl chloride (1.13 mL, 14.58 mmol, 1.5 eq) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with dichloromethane, washed successively with water, saturated citric acid aqueous solution, and water, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give compound A69 (3.6 g, yield: 81%).

[1022] MS(ESI,[M+Na)) + )m / z:481.20

[1023] Preparation of intermediate A70

[1024]

[1025] Step 1: Preparation of intermediate A70-2

[1026] Compound A70-1 (1.0 g, 3.61 mmol, 1.0 eq) was dissolved in a mixed solution of DMF / water (15 mL / 15 mL), and sodium isopropanethiolate (3.5 g, 36.06 mmol, 10.0 eq) was added. The reaction mixture was reacted at 80 °C for 2 hours. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (2 × 60 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound A70-2 (900 mg, yield: 97%).

[1027] MS(ESI,[M+Na)) +m / z:280.10

[1028] Step 2: Preparation of intermediate A70-3

[1029] The crude compound A70-2 (630 mg, 2.45 mmol, 1.0 eq) was dissolved in DMF (8 mL), and ammonium carbamate (1.91 g, 24.48 mol, 10.0 eq) and diacetoxyiodobenzene (7.88 g, 24.48 mmol, 10.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed sequentially with saturated sodium sulfite aqueous solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to give compound A70-3 (240 mg, yield: 34%).

[1030] MS(ESI,[M+H) + )m / z:289.30

[1031] Step 3: Preparation of intermediate A70

[1032] Compound A70-3 (200 mg, 0.69 mmol, 1.0 eq) was dissolved in petroleum ether (9 mL) and ethyl acetate (6 mL). The mixture was cooled to 0 °C under a nitrogen atmosphere, and 1 mL of 2 M ethyl acetate hydrochloride solution was added. The reaction mixture was stirred at 0 °C for 3 hours, and then stirred overnight at room temperature. After the reaction was complete, the supernatant was poured off, and the lower layer, a brown oily substance adhering to the flask wall, was dried under reduced pressure at low temperature to obtain crude compound A70 (100 mg, yield: 64%), which was directly used in the next reaction.

[1033] MS(ESI,[M+H) + )m / z:189.30

[1034] Preparation of intermediate A71

[1035]

[1036] Step 1: Preparation of intermediate A71-1

[1037] Oxycyclobutane-3-thiol (318 mg, 3.530 mmol, 2.0 eq) was dissolved in anhydrous ethanol (4 mL), and sodium methoxide (381 mg, 7.080 mmol, 4.0 eq) was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. Compound A3-7 (490 mg, 1.770 mmol, 1.0 eq) was added, and the reaction was carried out at room temperature for 2.5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A71-1 (390 mg, yield: 81%).

[1038] MS(ESI,[M+Na)) + )m / z:294.10

[1039] Step 2: Preparation of intermediate A71

[1040] Compound A71-1 (390 mg, 1.440 mmol) was dissolved in dichloromethane (3 mL), and TFA (6 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure, and the residue A71 (400 mg, yield: 100%) was used directly in the next step of the reaction.

[1041] MS(ESI,[M+H) + m / z:172.10

[1042] Preparation of intermediate A72

[1043]

[1044] Step 1: Preparation of intermediate A72-2

[1045] Compound A72-1 (6 g, 40.22 mmol, 1.0 eq) was added to dichloromethane (60 mL), followed by the addition of triethylamine (12.2 g, 120.65 mmol, 3 eq) and di-tert-butyl dicarbonate (10.53 g, 48.26 mmol, 1.2 eq) at 0 °C. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the dichloromethane was diluted, washed successively with saturated citric acid aqueous solution and water, dried over anhydrous sodium sulfate, concentrated, and the residue was dried to give compound A72-2 (10 g, yield: 99%).

[1046] MS(ESI,[M+H]+)m / z:272.1

[1047] Step 2: Preparation of intermediate A72-3

[1048] Compound A72-2 (3.0 g, 12.03 mmol, 1.0 eq) and triethylamine (1.8 g, 18.05 mmol, 1.5 eq) were dissolved in DCM (30 mL). The reaction solution was cooled to 0 °C under nitrogen protection, and MsCl (1.5 g, 13.24 mmol, 1.1 eq) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed successively with saturated citric acid aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated to give compound A72-3 (3.9 g, yield: 99%).

[1049] MS(ESI,[M+H]+)m / z:350.1

[1050] Step 3: Preparation of intermediate A72-4

[1051] Sodium isopropanethiolate (3.3 g, 33.6 mmol, 10 eq) was dissolved in DMF (10 mL) and water (10 mL), and then compound A72-3 (1.1 g, 3.36 mmol, 1.0 eq) was added. The reaction mixture was reacted at 60 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 15 / 1) to give compound A72-4 (230 mg, yield: 22%).

[1052] MS(ESI,[M+H]+)m / z:330.5

[1053] Step 4: Preparation of intermediate A72-5

[1054] Compound A72-4 (230 mg, 0.75 mmol, 1.0 eq) was dissolved in methanol (15 mL), followed by the addition of ammonium carbamate (234 mg, 2.99 mmol, 4.0 eq) and iodobenzene acetate (964 mg, 2.99 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 2 hours. Then, 1 M sodium dithionite aqueous solution (15 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 20 minutes. The mixture was washed with petroleum ether (40 mL), the petroleum ether phase was discarded, and the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A72-5 (210 mg, yield: 83%).

[1055] MS(ESI,[M+H]+)m / z:339.2

[1056] Step 5: Preparation of intermediate A72

[1057] Compound A72-5 (210 mg, 0.62 mmol) was dissolved in dichloromethane (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated by rotary evaporation and dried under vacuum to obtain intermediate A72 (230 mg, yield: 100%), which was directly used in the next step of the reaction.

[1058] MS(ESI,[M+H]+)m / z:239.2

[1059] Preparation of intermediate A73

[1060]

[1061] The preparation method is the same as that for intermediate A72.

[1062] Preparation of intermediate A74

[1063]

[1064] The preparation method is the same as that for intermediate A72.

[1065] Preparation of intermediate A75

[1066]

[1067] Step 1: Preparation of intermediate A75-1

[1068] Compound A25-2 (500 mg, 1.63 mmol, 1.0 eq) was dissolved in THF (5 mL), cooled to 0 °C under a nitrogen atmosphere, and NaH (60% in kerosene, 97.3 mg, 2.43 mmol, 1.5 eq) was added. The mixture was stirred at 0 °C for 30 minutes. Then, iodomethane (460 mg, 3.24 mmol, 2.0 eq) was added to the reaction mixture, and the reaction solution was stirred at room temperature for 16 hours. After the reaction was complete, the reaction solution was quenched with water, extracted with ethyl acetate, the ethyl acetate phases were combined, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE / EA = 20 / 1) to give compound A75-1 (450 mg, yield: 86%).

[1069] MS(ESI,[M+H) + )m / z:344.2

[1070] Step 2: Preparation of intermediate A75-2

[1071] Compound A75-1 (450 mg, 1.4 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (326 mg, 4.18 mmol, 3.0 eq) and PIDA (1.8 g, 5.58 mmol, 4.0 eq). The reaction flask was left open and stirred at room temperature for 3 hours. After the reaction was complete, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain A75-2 (350 mg, yield: 70%), which was used directly in the next reaction.

[1072] MS(ESI,[M+H) + )m / z:353.2

[1073] Step 2: Preparation of intermediate A75

[1074] Compound A75-2 (350 mg, 0.644 mmol) was dissolved in dichloromethane (4 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the reaction mixture was concentrated by rotary evaporation to obtain A75 (350 mg, 100%), which was directly used in the next reaction step.

[1075] MS(ESI,[M+H) + m / z:253.2

[1076] Preparation of intermediate A76

[1077]

[1078] Step 1: Preparation of intermediate A76-2

[1079] Compound A76-1 (3.0 g, 19.6 mmol, 1.0 eq) was dissolved in dimethyl sulfoxide (20 mL), and potassium hydroxide (1.65 g, 29.3 mmol, 1.5 eq) and methyl iodoform (4.17 g, 29.3 mmol, 1.5 eq) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was poured into water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1) to give compound A76-2 (2.4 g, yield: 73%).

[1080] MS(ESI,[M+H) + m / z:168.2

[1081] Step 2: Preparation of intermediate A76-3

[1082] Compound A76-2 (1.2 g, 7.18 mmol, 1.0 eq) and 3-chloro-4-fluoroaniline (1.57 g, 10.77 mmol, 1.5 eq) were added to THF (20 mL). The mixture was lowered to 0 °C under a nitrogen atmosphere, and a THF solution of hexamethyldisilamide lithium (17.9 mL, 17.9 mmol, 2.5 eq, 1 M) was added dropwise. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was poured into ice water and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by slurrying with methyl tert-butyl ether to give compound A76-3 (1.2 g, yield: 63%).

[1083] MS(ESI,[M+H) + )m / z:267.1

[1084] Step 3: Preparation of intermediate A76-4

[1085] Compound A76-3 (1.2 g, 4.50 mmol, 1.0 eq) was dissolved in dichloromethane (20 mL). The reaction mixture was purged with nitrogen and cooled to 0 °C. A dichloromethane (5 mL) solution of oxaloyl chloride monoethyl ester (0.92 g, 6.75 mmol, 1.5 eq) was added dropwise to the mixture. Aluminum chloride (1.50 g, 11.2 mmol, 2.5 eq) was added in portions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction mixture was added to ice water and extracted with dichloromethane. The organic phases were combined, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound A76-4 (1.0 g, yield: 61%).

[1086] MS(ESI,[M+H) + )m / z:367.1

[1087] Step 4: Preparation of intermediate A76-5

[1088] Compound A76-4 (1.0 g, 2.73 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (10 mL), and N-chlorosuccinimide (364 mg, 2.73 mmol, 1.0 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2:1) to give compound A76-5 (700 mg, yield: 64%).

[1089] MS(ESI,[M+H) + )m / z:401.1

[1090] Step 5: Preparation of intermediate A76

[1091] Compound A76-5 (200 mg, 5.0 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (5 / 5 / 1, 11 mL), and lithium hydroxide (36 mg, 1.50 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, the residual mixture was diluted with water, the pH was adjusted to 3-4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A76 (180 mg, yield: 97%).

[1092] MS(ESI,[M+H) + )m / z:373.0

[1093] Preparation of intermediate A77

[1094]

[1095] The preparation method is the same as that for intermediate A76.

[1096] Preparation of intermediate A78

[1097]

[1098] Step 1: Preparation of intermediate A78-1

[1099] Compound A1-1 (3 g, 17.94 mmol, 1.0 eq) was dissolved in DMSO (20 mL). Under a nitrogen atmosphere, the mixture was cooled to 0 °C, and potassium hydroxide (1.51 g, 26.91 mmol, 1.5 eq) was added. The mixture was then brought to room temperature and stirred for 30 minutes. Deuterated iodomethane (2.73 g, 18.84 mmol, 1.05 eq) was added dropwise, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction system was quenched in water and extracted with EA. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A78-1 (2.5 g, yield: 76%).

[1100] MS(ESI,[M+H) + m / z:185.2

[1101] Step 2: Preparation of intermediate A78-2

[1102] Compound A78-1 (1.25 g, 6.78 mmol, 1.0 eq) and 3-chloro-4-fluoroaniline (1.48 g, 10.18 mmol, 1.5 eq) were added to a 100 mL three-necked flask. After purging with nitrogen, anhydrous THF (20 mL) was added using a syringe to dissolve the compound and obtain a reaction solution. Under a nitrogen atmosphere, the mixture was cooled to 0 °C, and a THF solution of hexamethyldisilamide lithium (20 mL, 20 mmol, 3.00 eq, 1 M) was added dropwise to the mixture. After the addition was complete, the reaction system was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched in water, and then extracted with ethyl acetate (3 × 500 mL). The organic layers were combined, dried with anhydrous sodium sulfate, concentrated, and the residue was slurried with methyl tert-butyl ether. The solid was dried to give compound A78-2 (1.9 g, yield: 98.7%).

[1103] MS(ESI,[M+H) + )m / z:284.2

[1104] Step 3: Preparation of intermediate A78-3

[1105] Compound A78-2 (1.5 g, 5.29 mmol, 1.0 eq) and dichloromethane (20 mL) were placed in a 100 mL three-necked round-bottom flask. Under a nitrogen atmosphere, the mixture was cooled to 0 °C, and a solution of ethyl chloroxaate (1.08 g, 7.93 mmol, 1.50 eq) in dichloromethane (10 mL) was added dropwise. Then, aluminum chloride (1.76 g, 13.22 mmol, 2.50 eq) was added in portions. The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the reaction was quenched in ice water, extracted with dichloromethane, and the organic phases were combined. The mixture was washed successively with saturated sodium bicarbonate solution (300 mL) and water (200 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was slurried with a mixed solvent (petroleum ether / ethyl acetate = 2:1). The solid was dried to give compound A78-3 (1.9 g, yield: 94%).

[1106] MS(ESI,[M+H) + )m / z:384.1

[1107] Step 4: Preparation of intermediate A78

[1108] Compound A78-3 (1.9 g, 4.95 mmol, 1.0 eq) was dissolved in tetrahydrofuran (20 mL), methanol (10 mL), and water (10 mL). Lithium hydroxide (237 mg, 9.9 mmol, 2.0 eq) was added, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 4 with dilute hydrochloric acid (1 mol / L), resulting in the precipitation of a white solid. The mixture was filtered and dried to give compound A78 (1.7 g, yield: 97%).

[1109] MS(ESI,[M+H) + )m / z:356.1

[1110] Preparation of intermediate A79

[1111]

[1112] The preparation method is the same as that for intermediate A78.

[1113] Preparation of intermediates A80-1 and A80-2

[1114]

[1115] Step 1: Preparation of intermediates A80-1 and A80-2

[1116] Compound A80 (500 mg, 2.10 mmol) was resolved by a chiral column (mobile phase: CO2 / MeOH [0.2% NH3 (7MS solution in MeOH)] = 70 / 30; flow rate: 80 g / min; column temperature: 35 °C; column: Daicel CHIRALCEL AS, 250 mm × 30 mm ID, 10 μm) to give brown oil A80-1 (100 mg, yield: 20%) and brown solid A80-2 (270 mg, yield: 54%).

[1117] A80-1: Rt = 1.409 min

[1118] MS(ESI,[M+H) + )m / z:239.1

[1119] 1H NMR (400MHz, CDCl3) δ7.41-7.39(m,1H),7.30-7.27(m,2H),7.21-7.19(m,1H),5.00(d,J =7.6Hz,1H),3.85-3.78(m,1H),3.45-3.34(m,2H),3.31-3.24(m,1H),1.47-1.44(m,6H).

[1120] A80-2: Rt = 1.593 min

[1121] MS(ESI,[M+H]+)m / z:239.1

[1122] 1H NMR (400MHz, CDCl3) δ7.38-7.35(m,1H),7.32-7.27(m,2H),7.22-7.18(m,1H),5.02(d,J =8.0Hz,1H),3.78-3.71(m,1H),3.40-3.30(m,2H),3.24-3.17(m,1H),1.45-1.41(m,6H).

[1123] Preparation of intermediate A81

[1124]

[1125] The preparation method is the same as that for intermediate A76.

[1126] Preparation of intermediate A82

[1127]

[1128] The preparation method is the same as that for intermediate A76.

[1129] Preparation of intermediate A83

[1130]

[1131] Step 1: Preparation of intermediate A83-1

[1132] Compound A76-4 (1 g, 2.73 mmol, 1.0 eq) was dissolved in anhydrous DMF (10 mL) under nitrogen protection, and NBS (970 mg, 5.45 mmol, 2.0 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE / EA = 1 / 1) to give compound A83-1 (600 mg, yield: 49%).

[1133] MS(ESI,[M+H) + m / z:445.0

[1134] Step 2: Preparation of intermediate A83

[1135] Compound A83-1 (500 mg, 1.12 mmol, 1.0 eq) and deuterated methylphenidate borate (1.63 g, 11.2 mmol, 10.0 eq) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). Potassium carbonate (465 mg, 3.36 mmol, 3.0 eq) and Pd(dppf)Cl2 (82 mg, 0.11 mmol, 0.1 eq) were then added. The reaction mixture was stirred at 100 °C for 16 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate and water, and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound A83 (400 mg, crude product).

[1136] MS(ESI,[M+H) + )m / z:384.1

[1137] Preparation of intermediate A84

[1138]

[1139] The preparation method is the same as that for intermediate A76.

[1140] Preparation of intermediate A85

[1141]

[1142] Step 1: Preparation of intermediate A85-2

[1143] Compound A85-1 (1.5 g, 9.54 mmol, 1.0 eq) was dissolved in DMSO (20 mL), followed by the addition of potassium hydroxide (0.83 g, 14.3 mmol, 1.5 eq) and methyl iodoform (2.03 g, 14.3 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to give compound A85-2 (1.5 g, yield: 91%).

[1144] MS(ESI,[M+H) + m / z:172.1

[1145] Step 2: Preparation of intermediate A85-3

[1146] Compound A85-2 (1.5 g, 8.76 mmol, 1.0 eq) and 3-chloro-4-fluoroaniline (1.91 g, 13.1 mmol, 1.5 eq) were dissolved in anhydrous THF (20 mL). After the reaction solution was cooled to 0 °C, a THF solution of LiHMDS (1.0 M, 21.9 mL, 21.9 mmol, 2.5 eq) was added dropwise. After the addition was complete, the reaction solution was heated to room temperature and stirred at room temperature for 16 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried with a mixed solvent of methyl tert-butyl ether (20 mL) and PE (20 mL) for 5 minutes, filtered, washed with PE, and dried to obtain compound A85-3 (2.2 g, yield: 92%).

[1147] MS(ESI,[M+H) + )m / z:271.1

[1148] Step 3: Preparation of intermediate A85-4

[1149] Compound A85-3 (1.2 g, 4.43 mmol, 1.0 eq) was dissolved in anhydrous DCM (50 mL). Under nitrogen protection, the reaction solution was cooled to 0 °C. Anhydrous DCM (5 mL) solution of oxaloyl chloride monoethyl ester (0.74 g, 6.65 mmol, 1.5 eq) was added dropwise to the reaction solution. AlCl3 (1.48 g, 11.08 mmol, 2.5 eq) was added in portions to the reaction solution. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was diluted with water, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A85-4 (800 mg, yield: 48%).

[1150] MS(ESI,[M+H) + )m / z:371.1

[1151] Step 4: Preparation of intermediate A85-5

[1152] Compound A85-4 (500 mg, 1.35 mmol, 1.0 eq) was dissolved in anhydrous DMF (10 mL) under nitrogen protection, followed by the addition of NBS (480 mg, 2.70 mmol, 2.0 eq). The reaction mixture was stirred at 60 °C for 1 hour. After the reaction was complete, the reaction mixture was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A85-5 (400 mg, yield: 65%).

[1153] MS(ESI,[M+H) + )m / z:445.9

[1154] Step 5: Preparation of intermediate A85

[1155] Compound A85-5 (200 mg, 0.445 mmol, 1.0 eq) and methylboronic acid (53 mg, 0.890 mmol, 2.0 eq) were dissolved in 1,4-dioxane (5 mL), followed by the addition of potassium carbonate (184 mg, 1.33 mmol, 3.0 eq) and Pd(dppf)Cl2 (32 mg, 0.0445 mmol, 0.1 eq). The reaction mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate and water, and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A85 (140 mg, yield: 88%).

[1156] MS(ESI,[M+H) + m / z:357.0

[1157] Preparation of intermediate A86

[1158]

[1159] Step 1: Preparation of intermediate A86-1

[1160] Compound A85-4 (100 mg, 0.270 mmol, 1.0 eq) was dissolved in anhydrous DMF (2 mL), and then NCS (72 mg, 0.539 mmol, 2.0 eq) was added. The reaction mixture was stirred at 60 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE / EA = 9 / 1) to give compound A86-1 (110 mg, yield: 100%).

[1161] MS(ESI,[M+H) + m / z:405.0

[1162] Step 1: Preparation of intermediate A86

[1163] Compound A86-2 (95 mg, 0.234 mmol, 1.0 eq) was dissolved in MeOH (3 mL) and THF (3 mL), followed by the addition of a 1 mL solution of LiOH (28 mg, 1.17 mmol, 5.0 eq) in water. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 2 with 1 N HCl, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound A86 (88 mg, yield: 100%). This solid was used directly in the next reaction step.

[1164] MS(ESI,[M+H) + )m / z:377.0

[1165] Preparation of intermediate A87

[1166]

[1167] Step 1: Preparation of intermediate A87-1

[1168] Compound 152a (350 mg, 0.785 mmol, 1.0 eq) and methyl fluorosulfonyl difluoroacetate (302 mg, 1.57 mmol, 2.0 eq) were dissolved in anhydrous DMF (5 mL), followed by the addition of cuprous iodide (180 mg, 0.942 mmol, 1.2 eq). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. The reaction mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound A87-1 (320 mg, yield: 94%).

[1169] MS(ESI,[M+H) + )m / z:435.1

[1170] Step 2: Preparation of intermediate A87

[1171] Compound A87-1 (160 mg, 0.368 mmol, 1.0 eq) was dissolved in a mixed solution of tetrahydrofuran / methanol / water (2 / 1 / 1 mL), and then lithium hydroxide (44 mg, 1.84 mmol, 5.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated, the residue was diluted with water, the pH was adjusted to 3-4 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A87 (120 mg, yield: 80%).

[1172] MS(ESI,[M+H) + m / z:407.0

[1173] Preparation of intermediate A88

[1174]

[1175] Step 1: Preparation of intermediate A88-1

[1176] Compound 152a (250 mg, 0.56 mmol, 1.0 eq) and cyclopropylboronic acid (241 mg, 2.8 mmol, 5.0 eq) were dissolved in anhydrous DMF (20 mL), followed by the addition of potassium carbonate (233 mg, 1.7 mmol, 3.0 eq) and Pd(dtbpf)Cl2 (36 mg, 0.056 mmol, 0.1 eq). The reaction mixture was stirred at 80 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE / EA = 6 / 1) to give compound A88-1 (120 mg, yield: 53%).

[1177] MS(ESI,[M+H) + m / z:407.1

[1178] Step 2: Preparation of intermediate A88

[1179] Compound A88-1 (120 mg, 0.29 mmol, 1.0 eq) was dissolved in methanol (9 mL), and then a solution of LiOH (21 mg, 0.88 mmol, 3.0 eq) in water (3 mL) was added. The mixture was stirred at room temperature for 2 hours. The pH of the reaction solution was adjusted to approximately 2 with 1 N HCl. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound A88 (110 mg, yield: 98%). This solid was used directly in the next reaction step.

[1180] MS(ESI,[M+H)+ )m / z:379.1

[1181] Preparation of intermediate A89

[1182]

[1183] Step 1: Preparation of intermediate A89-2

[1184] Compound A89-1 (10.0 g, 71.86 mmol, 1.0 eq) was dissolved in DMSO (50 mL), followed by the addition of potassium hydroxide (6.1 g, 107.79 mmol, 1.5 eq) and methyl iodoform (15.3 g, 107.79 mmol, 1.5 eq). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give compound A89-2 (10.2 g, yield: 93%).

[1185] MS(ESI,[M+H) + m / z:154.3

[1186] Step 2: Preparation of intermediate A89-3

[1187] Compound A89-2 (10.2 g, 66.59 mmol, 1.0 eq) and 3-chloro-4-fluoroaniline (14.5 g, 99.88 mmol, 1.5 eq) were dissolved in anhydrous THF (100 mL) under a nitrogen atmosphere. The reaction mixture was cooled to 0 °C under a nitrogen atmosphere, and a THF solution of LiHMDS (180 mL, 180 mmol, 1 M, 2.7 eq) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred at room temperature for 16 hours. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with water and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. This crude product was added to methyl tert-butyl ether (100 mL) to obtain a mixture, stirred at room temperature for 10 minutes, filtered, and the solid was washed with PE. After drying, compound A89-3 (11.6 g, yield: 69%) was obtained.

[1188] MS(ESI,[M+H) + )m / z:253.3

[1189] Step 3: Preparation of intermediate A89-4

[1190] Compound A89-3 (6.0 g, 23.75 mmol, 1.0 eq) and AlCl3 (7.9 g, 59.37 mmol, 2.5 eq) were dissolved in anhydrous DCM (150 mL) under nitrogen protection. Anhydrous DCM (40 mL) of oxaloyl chloride monoethyl ester (4.86 g, 35.62 mmol, 1.5 eq) was slowly added dropwise to the reaction mixture under nitrogen protection. After the addition was complete, the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was slowly poured into ice water. The aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound A89-4 (5.0 g, yield: 60%).

[1191] MS(ESI,[M+H) + )m / z:353.1

[1192] Step 4: Preparation of intermediate A89-5

[1193] Compound A89-4 (2.0 g, 5.67 mmol, 1.0 eq) was dissolved in acetonitrile (40 mL) under nitrogen protection, followed by the addition of Selectfluor (4.02 g, 11.34 mmol, 2.0 eq). The mixture was stirred at 80 °C for 20 min. The reaction solution was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (PE / EA = 5 / 1) to give compound A89-5 (330 mg, yield: 16%).

[1194] MS(ESI,[M+H) + )m / z:371.1

[1195] Step 5: Preparation of intermediate A89-6

[1196] Compound A89-5 (300 mg, 0.81 mmol, 1.0 eq) was dissolved in anhydrous DMF (10 mL) under nitrogen protection, followed by the addition of NBS (288 mg, 1.62 mmol, 2.0 eq). The mixture was stirred at 60 °C for 1 hour. The reaction solution was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 5 / 1) to give compound A89-6 (90 mg, yield: 25%).

[1197] MS(ESI,[M+H) + )m / z:449.3

[1198] Step 6: Preparation of intermediate A89

[1199] Compound A89-6 (80 mg, 0.18 mmol, 1.0 eq) and methylboric acid (32 mg, 0.53 mmol, 3.0 eq) were dissolved in 1,4-dioxane / water (5 / 1 mL), followed by the addition of potassium carbonate (74 mg, 0.53 mmol, 3.0 eq) and Pd(dppf)Cl2 (26 mg, 0.04 mmol, 0.2 eq). The mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction mixture was diluted with ethyl acetate and water, and the pH was adjusted to 3-4 with 1 M hydrochloric acid. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound A89 (100 mg, yield: 100%), which was used directly in the next step.

[1200] MS(ESI,[M+H) + )m / z:357.1

[1201] Preparation of intermediate A90

[1202]

[1203] Step 1: Preparation of intermediate A90-3

[1204] Compound A90-1 (5 g, 18.8 mmol, 1.0 eq) and HATU (1.07 g, 21.2 mmol, 1.5 eq) were dissolved in anhydrous DMF (50 mL). After stirring the reaction mixture for 10 minutes, DIEA (7.28 g, 56.3 mmol, 3.0 eq) and compound A90-2 (5.74 g, 37.55 mmol, 2 eq) were added. The reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound A90-3 (4 g, yield: 58%).

[1205] MS(ESI,[M+H) + )m / z:387.2

[1206] Step 2: Preparation of intermediate A90

[1207] Compound A90-3 (3 g, 8.21 mmol, 1.0 eq) was dissolved in methanol (100 mL) and water (30 mL), and then NaOH (985 mg, 24.6 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to remove methanol. The pH of the residue was adjusted to 5 with 1 N hydrochloric acid. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give compound A90 (2.5 g, yield: 90%).

[1208] MS(ESI,[M+H) + )m / z:359.1

[1209] Preparation of intermediate A91

[1210]

[1211] Step 1: Preparation of intermediate A91-1

[1212] Compound A77-5 (10.0 g, 24.9 mmol, 1.0 eq) was dissolved in anhydrous DMF (60 mL). The reaction solution was cooled to 0 °C under a nitrogen atmosphere. NaH (60%, 1.49 g, 37.4 mmol, 1.5 eq) was added to the reaction solution, and the mixture was stirred at 0 °C for 30 min. Chloromethyl sulfide (7.21 g, 74.7 mmol, 3.0 eq) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was quenched in ice water, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (PE:EA = 2:1) to give compound A91-1 (8 g, yield: 69%).

[1213] MS(ESI,[M+H) + )m / z:461.1

[1214] Step 2: Preparation of intermediate A91-2

[1215] Compound A91-1 (1.5 g, 3.25 mmol, 1.0 eq) was dissolved in methanol (15 mL) and water (2 mL), followed by the addition of lithium hydroxide (233 mg, 9.75 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to approximately 2 with saturated citric acid solution. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain crude compound A91-2 (1.4 g, yield: 99%). This crude compound was used directly in the next reaction.

[1216] MS(ESI,[M+H) + )m / z:433.0

[1217] Step 3: Preparation of intermediate A91

[1218] Compounds A91-2 (1.4 g, 3.23 mmol, 1.0 eq) and HATU (1.84 g, 4.85 mmol, 1.5 eq) were dissolved in anhydrous DMF (10 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Then, A80-2 (924 mg, 3.88 mmol, 1.2 eq) and DIEA (1.25 g, 9.69 mmol, 3.0 eq) were added, and the mixture was stirred at room temperature for 16 min. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography to give intermediate A91 (1.8 g, yield: 85%).

[1219] MS(ESI,[M+H) + )m / z:653.1

[1220] Preparation of intermediate A92

[1221]

[1222] Step 1: Preparation of intermediate A92-2

[1223] Compound A92-1 (2.0 g, 13.06 mmol, 1.0 eq) was dissolved in anhydrous DMF (15 mL). The reaction mixture was cooled to 0 °C under a nitrogen atmosphere, and NaH (60%, 522 mg, 13.06 mmol, 1.0 eq) was added. The mixture was stirred for 30 minutes, followed by the addition of compound iodomethane (4 mL, 65.28 mmol, 5.0 eq). The reaction mixture was allowed to react at room temperature for 16 hours. The reaction mixture was quenched in ice water and extracted with ethyl acetate (3 × 50 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue purified by rapid silica gel column chromatography (PE) to give compound A92-2 (1.78 g, yield: 82%).

[1224] MS(ESI,[M+H) + m / z:168.2

[1225] Step 2: Preparation of intermediate A92-3

[1226] Under a nitrogen atmosphere, compound A92-2 (1 g, 5.95 mmol, 1.0 eq) and 5-amino-2-fluorobenzonitrile (0.87 g, 6.54 mmol, 1.1 eq) were dissolved in anhydrous THF (17 mL). The reaction solution was cooled to 0 °C, and a LiHMDS THF solution (1.0 M, 14.9 mL, 14.9 mmol, 2.5 eq) was added dropwise. After the addition was complete, the reaction solution was heated to room temperature and stirred for 16 hours. Ice water (100 mL) was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with liquid and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried for 5 minutes with a mixed solvent of methyl tert-butyl ether (35 mL) and PE (10 mL), filtered, and the solid was washed with PE. After drying, compound A92-3 (0.8 g, yield: 53%) was obtained.

[1227] MS(ESI,[M+H) + )m / z:258.1

[1228] Step 3: Preparation of intermediate A92-4

[1229] Under a nitrogen atmosphere, compound A92-3 (500 mg, 1.94 mmol, 1.0 eq) was dissolved in dichloromethane (40 mL). A solution of monoethyl oxaloyl chloride (395 mg, 2.91 mmol, 1.5 eq) in dichloromethane (3 mL) was added to the reaction mixture at 0 °C. AlCl3 (649 mg, 4.84 mmol, 2.5 eq) was then added in portions, and the mixture was slowly brought to room temperature and stirred for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to obtain compound A92-4 (600 mg, yield: 85%), which was directly used in the next reaction step.

[1230] MS(ESI,[M+H) + )m / z:358.1

[1231] Step 4: Preparation of intermediate A92-5

[1232] Compound A92-4 (600 mg, 1.68 mmol, 1.0 eq) was dissolved in anhydrous DMF (10 mL) under nitrogen protection. The mixture was cooled to 0 °C, and an anhydrous DMF solution of NCS (223 mg, 1.68 mmol, 1.0 eq) (1 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The solution was diluted with ethyl acetate (20 mL), and water (15 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by rapid silica gel column chromatography (13% EA in PE) to give compound A92-5 (400 mg, yield: 61%).

[1233] MS(ESI,[M+H) + )m / z:392.0

[1234] Step 5: Preparation of intermediate A92

[1235] Compound A92-5 (200 mg, 0.51 mmol, 1.0 eq) was dissolved in methanol (3 mL), and then a solution of lithium hydroxide (86 mg, 2.04 mmol, 4.0 eq) in water (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH was adjusted to approximately 2 with 1 N HCl, and water (15 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound A92 (180 mg, 97%), which was used directly in the next step of the reaction.

[1236] MS(ESI,[M+H) + )m / z:364.0

[1237] Example 1

[1238] Compound 1-1 and Compound 1-2

[1239]

[1240] Step 1: Preparation of Compound 1

[1241] Compound A1 (225 mg, 0.582 mmol, 1.0 eq) and HATU (266 mg, 0.699 mmol, 1.2 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Then, DIEA (376 mg, 2.91 mmol, 5.0 eq) and compound A2 (179 mg, 0.582 mmol, 1.0 eq) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (15 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (MeOH / DCM = 1:12) to give compound 1 (228 mg, yield: 67%).

[1242] MS(ESI,[M+H) + )m / z:579.10

[1243] Step 2: Preparation of Compound 1-1 and Compound 1-2

[1244] Compound 1 (60 mg, 0.103 mmol) was separated by a chiral column (column: Daicel CHIRALCEL OX, 250 mm 30 mm ID, 10 μm; mobile phase: CO2 / MeOH [0.2% NH3 (7 M Solution in MeOH)] = 75 / 25; flow rate: 120 g / min; column temperature: 35 °C) to obtain compound 1-1 (13.3 mg, yield: 22%) and compound 1-2 (27.8 mg, yield: 46%).

[1245] Compound 1-1: R t =3.988min

[1246] MS(ESI,[M+H) + )m / z:579.10

[1247] 1 H NMR (400MHz, DMSO-d6): δ10.50(s,1H),9.38(d,J=8.4Hz,1H),8.20(dd,J=6.4,2.4Hz,1H),7.96-7.92(m,1H),7.50(t,J=9.6Hz,1H),7.31 -7.17(m,4H),5.84-5.80(m,1H),4.03-3.95(m,1H),3.91(s,1H),3.58(s,3H),3.46-3.34(m,2H),2.93(s,3H),2.42(s,3H),2.27(s,3H).

[1248] Compounds 1-2: R t =4.742min

[1249] MS(ESI,[M+H) + )m / z:579.10

[1250] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.42(d,J=8.4Hz,1H),8.20(dd,J=6.4,2.4Hz,1H),8.96-7.92(m,1H),7.50(t,J=9.6Hz,1H),7.33 -7.14(m,4H),5.77-5.74(m,1H),4.09-4.03(m,1H),3.83(s,1H),3.59(s,3H),3.39-3.34(m,2H),2.93(s,3H),2.43(s,3H),2.28(s,3H).

[1251] Example 2

[1252] Compound 2

[1253]

[1254] Step 1: Preparation of intermediate 2a

[1255] Compound A1 (150 mg, 0.39 mmol, 1.0 eq) and HATU (221 mg, 0.58 mmol, 1.5 eq) were dissolved in anhydrous DMF (5 mL). After stirring for 5 minutes, DIEA (502 mg, 3.9 mmol, 10.0 eq) and compound A3 (132 mg, 0.58 mmol, 1.5 eq) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 2a (170 mg, yield: 88%).

[1256] MS(ESI,[M+H) + )m / z:498.1

[1257] Step 2: Preparation of Compound 2

[1258] Compound 2a (170 mg, 0.34 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (80 mg, 1.03 mmol, 3.0 eq) and iodophenyldiacetic acid (330 mg, 1.03 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 2 (44.1 mg, yield: 24%).

[1259] MS(ESI,[M+H) + )m / z:529.20

[1260] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.84-8.75(m,1H),8.22(dd,J=6.4,2.4Hz,1H),7.98-7.94(m,1H),7.52(t,J=9. 6Hz,1H),4.22-4.20(m,1H),3.86-3.63(m,3H),3.60(s,3H),3.04-3.02(m,3H),2.41(s,3H),2.25(s,3H),1.54(s,3H).

[1261] Example 3

[1262] Compound 3-1 and Compound 3-2

[1263]

[1264] Step 1: Preparation of intermediate 3a

[1265] Compound A4 (300 mg, 0.892 mmol, 1.0 eq) and HATU (508 mg, 1.34 mmol, 1.5 eq) were dissolved in anhydrous DMF (10 mL). DIEA (345 mg, 2.67 mmol, 3.0 eq) was added, and the reaction mixture was stirred at room temperature for 10 minutes. Compound A5 (259 mg, 1.34 mmol, 1.5 eq) was then added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (50% EA / PE) to give compound 3a (300 mg, yield: 70%).

[1266] MS(ESI,[M+H) +)m / z:478.20

[1267] Step 2: Preparation of Compound 3

[1268] Compound 3a (200 mg, 0.418 mmol, 1.0 eq) was dissolved in methanol (5 mL), and ammonium carbamate (130 mg, 1.67 mmol, 4.0 eq) and PIDA (404 mg, 1.25 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by preparative separation to obtain compound 3 (100 mg, yield: 47%).

[1269] MS(ESI,[M+H) + )m / z:509.20

[1270] Step 3: Preparation of compounds 3-1 and 3-2

[1271] Compound 3 (100 mg, 0.197 mmol) was separated by a chiral column (column: Daicel CHIRALCEL OX, 250 mm 30 mm ID, 10 μm; mobile phase: CO2 / MeOH [0.2% NH3 (7 M Solution in MeOH)] = 65 / 35; flow rate: 120 g / min; column temperature: 35 °C) to obtain compound 3-1 (21.9 mg, yield: 21%) and compound 3-2 (21.6 mg, yield: 21%).

[1272] Compound 3-1:R t =1.744min

[1273] MS(ESI,[M+H) + )m / z:509.20

[1274] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.51(s,1H),7.89-7.84(m,1H),7.46-7.38(m,2H),3.83(s,1H),3.6 7(s,2H),3.59(s,3H),2.96(s,3H),2.44(s,3H),2.27-2.59(m,5H),1.87-1.75(m,2H),1.50-1.23(m,6H).

[1275] Compound 3-2:R t =1.515min

[1276] MS(ESI,[M+H) + )m / z:509.20

[1277] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.51(s,1H),7.89-7.83(m,1H),7.46-7.38(m,2H),3.83(s,1H),3.6 7(s,2H),3.59(s,3H),2.96(s,3H),2.44(s,3H),2.27-2.19(m,5H),1.85-1.75(m,2H),1.50-1.23(m,6H).

[1278] Example 4

[1279] Compound 4-1 and Compound 4-2

[1280]

[1281] Step 1: Preparation of Compound 4

[1282] Intermediate A4 (100 mg, 0.297 mmol, 1.0 eq) and HATU (135 mg, 0.356 mmol, 1.2 eq) were dissolved in anhydrous DMF (3 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Intermediate A2 (99 mg, 0.401 mmol, 1.35 eq) and DIEA (192 mg, 1.49 mmol, 5.0 eq) were added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (15 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 15 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (0.1% formic acid / acetonitrile / water) to give compound 4 (20 mg, yield: 12%).

[1283] MS(ESI,[M+H) + m / z:=529.20

[1284] Step 2: Preparation of compounds 4-1 and 4-2

[1285] Compound 4 (20 mg, 0.0378 mmol) was purified by chiral column separation (column: Daicel CHIRALCEL OJ, 250 mm 30 mm ID, 10 μm, mobile phase: CO2 / MeOH [0.2% NH3 (7 M Solution in MeOH)] = 70 / 30; flow rate: 120 g / min; column temperature: 35 °C) to give compound 4-1 (7.3 mg, yield: 36%) and compound 4-2 (2.4 mg, yield: 12%).

[1286] Compound 4-1: R t =1.830min

[1287] MS(ESI,[M+H) + m / z:=529.10

[1288] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),9.34(d,J=8.8Hz,1H),7.80-7.75(m,1H),7.35-729(m,2H),7.22-7.16(m,3H),7.12-7.10( m,1H),5.70-5.66(m,1H),4.01-3.95(m,1H),3.75(s,1H),3.51(s,3H),3.30-3.26(m,2H),2.86(s,3H),2.35(s,3H),2.19(s,3H).

[1289] Compound 4-2: R t =2.205min

[1290] MS(ESI,[M+H) + )m / z:529.20

[1291] 1 H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), 9.23 (d, J = 8.8Hz, 1H), 7.74-7.68 (m, 1H), 7.29-7.23 (m, 2H), 7.15-7.09 (m, 3H), 7.07 -7.05(m,1H),5.70-5.66(m,1H),3.89-3.83(m,1H),3.44(s,3H),3.31-3.20(m,2H),2.80(s,3H),2.28(s,3H),2.12(s,3H).

[1292] Example 5

[1293] Compound 5

[1294]

[1295] Step 1: Preparation of Compound 5

[1296] Intermediate A6 (100 mg, 0.28 mmol, 1.0 eq) was dissolved in DMF (5 mL), followed by intermediates A2 (87 mg, 0.28 mmol, 1.0 eq), HATU (162 mg, 0.43 mmol, 1.5 eq), and DIEA (183 mg, 1.4 mmol, 5.0 eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 5 (58.1 mg, yield: 38%).

[1297] MS(ESI,[M+H) + )m / z:545.10

[1298] 1 H NMR(400MHz,DMSO-d6)δ10.40-10.39(m,1H),9.47-9.42(m,1H),8.01(dd,J =6.4,2.4Hz,1H),7.66-7.56(m,1H),7.41(t,J=8.8Hz,1H),7.32-7.27(m,3H ),7.22(t,J=6.0Hz,1H),5.91-5.77(m,1H),4.22-4.13(m,1H),3.60(s,3H), 3.45-3.39(m,2H),3.09-3.04(m,3H),2.44-2.43(m,3H),2.28-2.20(m,3H).

[1299] Example 6

[1300] Compound 6

[1301]

[1302] Step 1: Preparation of Compound 6

[1303] Compound A7 (100 mg, 0.3 mmol, 1.0 eq) was dissolved in DMF (5 mL), followed by the addition of compounds A2 (111 mg, 0.36 mmol, 1.0 eq), HATU (172 mg, 0.45 mmol, 1.5 eq), and DIEA (389 mg, 3.0 mmol, 10.0 eq). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 6 (52.2 mg, yield: 33%).

[1304] MS(ESI,[M+H) + )m / z:525.20

[1305] 1 H NMR(400MHz,DMSO-d6)δ10.19-10.18(m,1H),9.44-9.37(m,1H),7.64-7.6 2(m,1H),7.52-7.49(m,1H),7.31-7.20(m,4H),7.11(t,J=9.2Hz,1H),5.86 -5.75(m,1H),4.13-3.96(m,1H),3.93-3.85(m,1H),3.59(s,3H),3.46-3. 34(m,2H),2.95(s,3H),2.44-2.43(m,3H),2.28-2.27(m,3H),2.22(s,3H).

[1306] Example 7

[1307] Compound 7

[1308]

[1309] Step 1: Preparation of Compound 7

[1310] Compound A8 (120 mg, 0.339 mmol, 1.0 eq), compound A2 (71 mg, 0.339 mmol, 1.00 eq), and HATU (258 mg, 0.677 mmol, 2.0 eq) were dissolved in DMF (3 mL), and DIEA (219 mg, 1.69 mmol, 5.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 2 h. After the reaction was complete, compound 7 (24.6 mg, yield: 13%) was purified by preparative prep-HPLC (mobile phase: acetonitrile / water / formic acid).

[1311] MS(ESI,[M+H) +)m / z:547.10

[1312] 1 H NMR(400MHz,DMSO-d6)δ10.53(s,1H),9.45-9.38(m,1H),7.65-7.61(m,2H),7.32-7.19(m,4H),5.86-5.76(m,1H),4.1 1-4.01(m,1H),3.93-3.84(m,1H),3.60(s,3H),3.41-3.36(m,2H),2.95(s,3H),2.44-2.43(m,3H),2.28-2.27(m,3H).

[1313] Example 8

[1314] Compound 8

[1315]

[1316] Step 1: Preparation of intermediate 8a

[1317] Compound A9 (329 mg, 2.26 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (6 mL). A tetrahydrofuran solution of LiHMDS (1.0 M, 6.03 mL, 6.03 mmol, 8.0 eq) was added at 0 °C. The reaction mixture was stirred at room temperature for 30 minutes. Then, 3-chloro-4-fluoroaniline (200 mg, 0.753 mmol, 1.0 eq) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the combined organic phases were washed successively with 1 M hydrochloric acid aqueous solution, brine, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain crude compound 8a (500 mg, yield >100%), which was used directly in the next reaction.

[1318] MS(ESI,[M+H) + )m / z:365.10

[1319] Step 2: Preparation of Compound 8

[1320] Under nitrogen protection, crude compound 8a (150 mg, crude product, in a ratio of 0.225 mmol, 1.0 eq) and HATU (188 mg, 0.495 mmol, 2.2 eq) were dissolved in anhydrous DMF (3 mL). The mixture was stirred at room temperature for 10 minutes, and then DIEA (532 mg, 4.11 mmol, 18.3 eq) and compound A2 (173 mg, 0.562 mmol, 2.5 eq) were added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, water was added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 8 (27.1 mg, two-step yield: 22%).

[1321] MS(ESI,[M+H) + )m / z:557.20

[1322] 1 H NMR (400MHz, DMSO-d6) δ10.02-10.01(m,1H),9.40-9.34(m,1H),7.96(dd,J=6.4,2.8Hz,1H),7.62-7.58(m,1H),7.41(t,J=9 .2Hz,1H),7.32-7.19(m,4H),5.88-5.76(m,1H),4.19-4.07(m,3H),3.47-3.31(m,3H),3.10-2.97(m,5H),2.48-2.40(m,5H).

[1323] Example 9

[1324] Compound 9

[1325]

[1326] Step 1: Preparation of intermediate 9a

[1327] Compound 3,4-difluoroaniline (292 mg, 2.259 mmol, 1.0 eq) was dissolved in anhydrous tetrahydrofuran (6 mL). LiHMDS (1.0 M in THF, 6.03 mL, 6.03 mmol, 8.0 eq) was added at 0 °C, and the reaction mixture was stirred at room temperature for 30 min. Compound A9 (200 mg, 0.753 mmol, 1.0 eq) was then added, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched in saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined. The mixture was washed twice with 1 M hydrochloric acid aqueous solution, washed with brine, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (0.1% FA / CH3CN / H2O) to give compound 9a (75 mg, yield: 28%).

[1328] MS(ESI,[M+H) + m / z:=349.10

[1329] Step 2: Preparation of Compound 9

[1330] Compound 9a (38 mg, 0.109 mmol, 1.0 eq) and HATU (50 mg, 0.131 mmol, 1.2 eq) were dissolved in anhydrous DMF (2 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. DIEA (141 mg, 1.090 mmol, 10.0 eq) and compound A2 (67 mg, 0.218 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL), and water (10 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 9 (2.0 mg, yield: 3%).

[1331] MS(ESI,[M+H) + )m / z:541.20

[1332] 1H NMR (400MHz, DMSO-d6) δ10.04 (s, 1H), 9.33 (d, J = 8.8Hz, 1H), 7.85-7.80 ( m,1H),7.44-7.40(m,2H),7.30-7.25(m,3H),7.21-7.20(m,1H),5.85-5.8 2(m,1H),4.16(t,J=7.8Hz,2H),4.06-4.00(m,1H),3.92(s,1H),3.47-3.3 3(m,2H),3.15-2.98(m,2H),2.95(s,3H),2.45(s,3H),2.44-2.38(m,2H).

[1333] Example 10

[1334] Compound 10

[1335]

[1336] Step 1: Preparation of intermediate 10a

[1337] Compound A4 (600 mg, 1.78 mmol, 1.0 eq) and HATU (1.02 g, 2.68 mmol, 1.5 eq) were dissolved in anhydrous DMF (10 mL) and stirred at room temperature for 5 minutes. Then, DIEA (2.31 g, 17.84 mmol, 10.0 eq) and compound A3 (400 mg, crude product, 2.14 mmol, 1.2 eq) were added sequentially, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 10a (600 mg, yield: 75%).

[1338] MS(ESI,[M+H) + )m / z:448.20

[1339] Step 2: Preparation of Compound 10

[1340] Compound 10a (550 mg, 1.23 mmol, 1.0 eq) was dissolved in methanol (30 mL), and ammonium carbamate (288 mg, 3.69 mmol, 3.0 eq) and diacetoxyiodobenzene (1.19 g, 3.69 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1.5 hours. After the reaction was complete, water (60 mL) was added, and the mixture was extracted with ethyl acetate (3 × 70 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give 10 (248 mg, yield: 42%).

[1341] MS(ESI,[M+H) + )m / z:479.10

[1342] 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.82-8.72(m,1H),7.87-7.82(m,1H),7.42-7.36(m,2H),4.20-4 .17(m,1H),3.83-3.62(m,3H),3.57(s,3H),3.01-3.00(m,3H),2.39(s,3H),2.21(s,3H),1.51(s,3H).

[1343] Example 11

[1344] Compound 11

[1345]

[1346] Step 1: Preparation of intermediate 11a

[1347] Compound A6 (200 mg, 0.57 mmol, 1.0 eq) and compound A3 (110 mg, 0.85 mmol, 1.5 eq) were dissolved in DMF (5 mL), and HATU (259 mg, 0.68 mmol, 1.2 eq) and DIEA (366 mg, 2.84 mmol, 5.0 eq) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and separated by adding water (20 mL). The mixture was extracted with ethyl acetate (3 × 20 mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (PE / EA = 2 / 1) to give compound 11a (230 mg, yield: 87%).

[1348] MS(ESI,[M+H) + )m / z:464.10

[1349] Step 2: Preparation of Compound 11

[1350] Compound 11a (230 mg, 0.50 mmol, 1.0 eq), diacetoxyiodobenzene (604 mg, 1.5 mmol, 3.0 eq), and ammonium carbamate (116 mg, 1.5 mmol, 3.0 eq) were dissolved in methanol (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 11 (36.6 mg, yield: 15%).

[1351] MS(ESI,[M+H) + )m / z:495.10

[1352] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.85-8.72(m,1H),8.01(dd,J=6.8,2.4Hz,1H),7.64-7.60(m,1H),7.41(t,J=9.2Hz,1H), 4.21-4.19(m,1H),3.87-3.67(m,2H),3.67-3.63(m,1H),3.59(s,3H),3.03-3.02(m,3H),2.40(s,3H),2.24(s,3H),1.53(s,3H).

[1353] Example 12

[1354] Compound 12-1 and Compound 12-2

[1355]

[1356] Step 1: Preparation of Intermediate 12

[1357] Compound A8 (200 mg, 0.56 mmol, 1.0 eq) and HATU (322 mg, 0.85 mmol, 1.5 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 minutes. DIEA (365 mg, 2.82 mmol, 5.0 eq) and crude compound A3 (80 mg, 0.62 mmol, 1.12 eq) were added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (30 mL), water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The concentrated residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 12 (200 mg, yield: 76%).

[1358] MS(ESI,[M+H) + )m / z:466.10

[1359] Step 2: Preparation of intermediates 12a-1 and 12a-2

[1360] Compound 12 (200 mg, 0.43 mmol, 1.0 eq) was purified by chiral column separation (column: Daicel CHIRALCEL OJ 250 mm 30 mm ID, mobile phase: CO2 / MeOH [0.2% NH3 (7 M Solution in MeOH)] = 90 / 10; flow rate: 80 g / min; column temperature: 35 °C) to give 12a-1 (78 mg, yield: 39%) and 12a-2 (80 mg, yield: 40%).

[1361] 12a-1:Rt=2.639min

[1362] MS(ESI,[M+H) + )m / z:466.1

[1363] 12a-2:R t =2.907min

[1364] MS(ESI,[M+H) + )m / z:466.1

[1365] Step 3: Compound 12-1

[1366] Compound 12a-1 (78 mg, 0.17 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (52 mg, 0.67 mmol, 4.0 eq) and diacetoxyiodobenzene (216 mg, 0.67 mmol, 4.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 12-1 (9.7 mg, yield: 12%).

[1367] MS(ESI,[M+H) + )m / z:497.1

[1368] 1H NMR(400MHz,DMSO-d6)δ10.53(s,1H),8.86-8.76(m,1H),7.65-7.60(m,2H),4.232-4.20(m,1 H),3.85-3.64(m,3H),3.59(s,3H),3.03-3.02(m,3H),2.41(s,3H),2.23(s,3H),1.53(s,3H).

[1369] Step 3: Preparation of compound 12-2

[1370] Compound 12a-2 (80 mg, 0.17 mmol, 1.0 eq) was dissolved in methanol (10 mL), followed by the addition of ammonium carbamate (54 mg, 0.68 mmol, 4.0 eq) and diacetoxyiodobenzene (221 mg, 0.68 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 12-2 (3.8 mg, yield: 4%).

[1371] MS(ESI,[M+H) + )m / z:497.10

[1372] 1 H NMR(400MHz,DMSO-d6)δ10.55(s,1H),8.86-8.76(m,1H),7.65-7.59(m,2H),4.22-4.20(m,1H ),3.84-3.64(m,3H),3.59(s,3H),3.03-3.02(m,3H),2.41(s,3H),2.23(s,3H),1.53(s,3H).

[1373] Example 13

[1374] Compound 13

[1375]

[1376] Step 1: Preparation of intermediate 13a

[1377] Compound A1 (300 mg, 0.78 mmol, 1.0 eq) and HATU (443 mg, 1.16 mmol, 1.5 eq) were dissolved in anhydrous DMF (5 mL). After stirring for 5 minutes, DIEA (502 mg, 3.88 mmol, 5.0 eq) and compound A10 (277 mg, 0.94 mmol, 1.2 eq) were added. The reaction mixture was stirred at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the residue was concentrated and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 13a (300 mg, yield: 70%).

[1378] MS(ESI,[M+H) + )m / z:550.10

[1379] Step 2: Preparation of Compound 13

[1380] Compound 13a (300 mg, 0.54 mmol, 1.0 eq) was dissolved in methanol (20 mL), and ammonium carbamate (170 mg, 2.18 mmol, 4.0 eq) and PIDA (527 mg, 1.64 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 13 (130 mg, yield: 41%).

[1381] MS(ESI,[M+H) + )m / z:581.20

[1382] 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.98-8.93(m 1H),8.21-8.19(m,1H),7.95-7.93(m,1H),7.52(t,J=9.6Hz,1H),7.32-7.19(m,5H),4.57-4.55(m,1H),3.83 -3.78(m,1H),3.55-3.54(m,3H),3.39-3.36(m,1H),3.26-3.19(m,1H),3.07-2.83(m,5H),2.17-2.07(m,6H).

[1383] Example 14

[1384] Compound 14

[1385]

[1386] Step 1: Preparation of intermediate 14a

[1387] Compound A1 (180 mg, 0.466 mmol, 1.0 eq) and HATU (213 mg, 0.559 mmol, 1.2 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Then, DIEA (301 mg, 2.33 mmol, 5.0 eq) and compound A12 (184 mg, 0.699 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (15 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (30% EA in PE) to give compound 14a (200 mg, yield: 80%).

[1388] MS(ESI,[M+H) + )m / z:536.10

[1389] Step 2: Preparation of Compound 14

[1390] Compound 14a (200 mg, 0.37 mmol, 1.0 eq) was dissolved in methanol (5 mL), followed by the addition of ammonium carbonate (108 mg, 1.12 mmol, 3.0 eq) and diacetoxyiodobenzene (481 mg, 1.49 mmol, 4.0 eq). The reaction mixture was stirred at room temperature for 4 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 25 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative prep-HPLC (mobile phase 0.1% trifluoroacetic acid / acetonitrile / water) to give compound 14 (21.3 mg, yield: 10%).

[1391] MS(ESI,[M+H) + )m / z:567.10

[1392] 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),9.57(d,J=8.4Hz,1H),8.19(dd,J=6.4,2.4Hz,1H),7.95-7.91(m,1H),7.54-7.46(m,3H),7.43-7.3 9(m,2H),7.35-7.27(m,1H),5.54-5.49(m,1H),4.04-3.96(m,1H),3. 88-3.82(m,2H),3.56(s,3H),3.19(s,3H),2.26(s,3H),2.11(s,3H).

[1393] Example 15

[1394] Compound 15

[1395]

[1396] Step 1: Preparation of intermediate 15a

[1397] Compound A1 (219 mg, 0.57 mmol, 1.0 eq) and HATU (432 mg, 1.14 mmol, 2.0 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 minutes. Then, DIEA (367 mg, 2.84 mmol, 5.0 eq) and crude compound A13 (240 mg, 0.90 mmol, 1.6 eq) were added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, water (20 mL) was added, and the mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (30% PE / EA) to give compound 15a (300 mg, yield: 99%).

[1398] MS(ESI,[M+H) + )m / z:536.10

[1399] Step 2: Preparation of Compound 15

[1400] Compound 15a (150 mg, 0.28 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (87 mg, 1.12 mmol, 4.0 eq) and diacetoxyiodobenzene (541 mg, 1.68 mmol, 6.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was washed with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: acetonitrile / water / 0.1% formic acid) to give compound 15 (11.3 mg, yield: 7%).

[1401] MS(ESI,[M+H) + )m / z:567.20

[1402] 1 H NMR(400MHz, DMSO-d6)δ10.47(s,1H),9.47(t,J=8.8Hz,1H),8.20-8.18(m,1H),7.95-7.92(m,1H),7.53-7.28(m,6H),5 .46-5.41(m,1H),3.87-3.69(m,2H),3.56(s,3H),3.51-3.40(m,1H),2.88-2.81(m,3H),2.26(s,3H),2.12-2.11(m,3H).

[1403] Example 16

[1404] Compound 16

[1405]

[1406] Step 1: Preparation of Compound 16

[1407] Compound A1 (100 mg, 0.26 mol, 1.0 eq) and HATU (147.26 mg, 0.3873 mmol, 1.5 eq) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes. Then, DIEA (166.85 mg, 1.291 mmol, 5.0 eq) and compound A14 (100 mg, crude product, 0.30 mmol, 1.15 eq) were added, and the reaction mixture was stirred at room temperature for 35 minutes. After the reaction was complete, the reaction mixture was purified by preparative prep-HPLC (mobile phase: acetonitrile / water / 0.1% formic acid) to give compound 16 (16.1 mg, yield: 10%).

[1408] MS(ESI,[M+H) + )m / z:597.00

[1409] 1H NMR (400MHz, DMSO-d6) δ10.47-10.46(m,1H),9.41-9.35m,1H),8.17(dd,J=6.4,2.8Hz,1H),7.94-7.83(m,1H),7.48(t,J=9.2Hz,1H),7.1 8-7.00(m,3H),5.76-5.66(m,1H),4.09-3.98(m,1H),3.56(s,3H),3.38-3.33(m,2H),2.91(s,3H),2.39-2.38(m,3H),2.24-2.23(m,3H).

[1410] Example 17

[1411] Compound 17

[1412]

[1413] Step 1: Preparation of Compound 17

[1414] Compound A4 (100 mg, 0.30 mmol, 1.0 eq) and HATU (147 mg, 0.39 mmol, 1.3 eq) were dissolved in DMF (4 mL). The reaction mixture was stirred at room temperature for 10 minutes. Then, DIEA (384 mg, 3.0 mmol, 10.0 eq) and compound A14 (116 mg, 0.36 mmol, 1.2 eq) were added, and the reaction mixture was stirred at room temperature for 50 minutes. The reaction mixture was diluted with ethyl acetate (20 mL), and separated by adding water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 17 (89.6 mg, yield: 55%).

[1415] MS(ESI,[M+H) + )m / z:547.10

[1416] 1H NMR (400MHz, DMSO-d6) δ10.43-10.42(m,1H),9.46-9.40(m,1H),7.90-7.84(m,1H),7.45-7.39(m,2H),7.24-7.08(m,3H),5.80-5.70( m,1H),4.13-4.01(m,1H),3.97-3.88(m,1H),3.60-3.59(m,3H),3.47-3.37(m,2H),2.95(s,3H),2.43-2.42(m,3H),2.27-2.26(m,3H).

[1417] Example 18

[1418] Compound 18

[1419]

[1420] Step 1: Preparation of Compound 18

[1421] Compound A1 (140 mg, 0.362 mmol, 1.0 eq) and HATU (165 mg, 0.434 mmol, 1.2 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Then, DIEA (234 mg, 1.81 mmol, 5.0 eq) and compound A15 (124 mg, 0.387 mmol, 1.07 eq) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (10 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (0.1% formic acid / acetonitrile / water) to give compound 18 (92.1 mg, yield: 42%).

[1422] MS(ESI,[M+H) + )m / z:593.20

[1423] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),9.50(t,J=8.8Hz,1H),8.22(dd,J=6.4,2.4Hz,1H),7.98-7. 94(m,1H),7.53(t,J=9.6Hz,1H),7.35-7.29(m,3H),7.26-7.24(m,1H),5.99-5.92(m,1H),4.51(br s,1H),3.61(s,3H),3.57-3.42(m,2H),3.36(s,3H),2.76-2.70(m,3H),2.44-2.43(m,3H),2.29-2.28(m,3H).

[1424] Example 19

[1425] Compound 19

[1426]

[1427] Step 1: Preparation of Compound 19

[1428] Compound A1 (100 mg, 0.26 mol, 1.0 eq) and HATU (147 mg, 0.39 mmol, 1.5 eq) were dissolved in DMF (5 mL). The reaction mixture was stirred at room temperature for 10 minutes. Then, DIEA (167 mg, 1.29 mmol, 5.0 eq) and crude compound A16 (100 mg, 0.29 mmol, 1.15 eq) were added, and the mixture was stirred at room temperature for 35 minutes. After the reaction was complete, the reaction mixture was purified by preparative prep-HPLC (mobile phase: 0.1% FA / acetonitrile / water) to give compound 19 (73.2 mg, yield: 46%).

[1429] MS(ESI,[M+H) + )m / z:611.10

[1430] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),9.42(t,J=8.8Hz,1H),8.22(dd,J=6.4,2.4Hz,1H),7.97-7.94(m,1H),7.52(t,J=9.6Hz,1H),7.25-7.08 (m,3H),5.82-5.78(m,1H),4.17-4.12(m,1H),3.60(s,3H),3.49-3.38( m,2H),2.96-2.93(m,3H),2.63-2.59(m,3H),2.42(s,3H),2.28(s,3H).

[1431] Example 20

[1432] Compound 20

[1433]

[1434] Step 1: Preparation of Compound 20

[1435] Compound A1 (100 mg, 0.26 mmol, 1.0 eq) was dissolved in DMF (5 mL), and (1S,2R)-(-)-1-amino-2-indanol (50 mg, 0.34 mmol, 1.3 eq), HATU (118 mg, 0.31 mmol, 1.2 eq), and DIEA (167 mg, 1.3 mmol, 5.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 1 hour, filtered, and the filtrate was purified by prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to obtain compound 20 (62.4 mg, yield: 47%).

[1436] MS(ESI,[M+H) + m / z:=518.10

[1437] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.57(d,J=8.8Hz,1H),8.23(dd,J=6.4,2.4Hz,1H),8.02-7.86(m,1H),7.52(t,J=10.0Hz,1H),7.31-7.13( m,4H),5.32-5.25(m,1H),5.20(d,J=4.8Hz,1H),4.55-4.46(m,1H),3.61 (s,3H),3.12-3.04(m,1H),2.92-3.84(m,1H),2.45(s,3H),2.31(s,3H).

[1438] Example 21

[1439] Compound 21

[1440]

[1441] Step 1: Preparation of Compound 21

[1442] Compound 10 (50 mg, 0.104 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL), and trimethyloxonium tetrafluoroboric acid (54 mg, 0.366 mmol, 3.5 eq) was added. The reaction mixture was stirred at room temperature for 1.5 hours. Saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (2 × 20 mL), and the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by prep-TLC (PE / EA = 1 / 5) to give compound 21 (11.5 mg, yield: 22%).

[1443] MS(ESI,[M+H) + )m / z:493.10

[1444] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),8.86-8.12(m,1H),7.89-7.84(m,1H),7.44-7.40(m,2H),3.83-3.78(m,1H ),3.73-3.68(m,2H),3.59(s,3H),3.06-3.04(m,3H),2.77-2.76(m,3H),2.40(s,3H),2.23(s,3H),1.57(s,3H).

[1445] Example 22

[1446] Compound 22

[1447]

[1448] Step 1: Preparation of Compound 22

[1449] Compound A1 (250 mg, 0.647 mmol, 1.0 eq) and HATU (369 mg, 0.970 mmol, 1.5 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Then, DIEA (418 mg, 3.24 mmol, 5.0 eq) and compound A17 (389 mg, 1.29 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (10 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 22 (77.0 mg, yield: 21%).

[1450] MS(ESI,[M+H) +)m / z:573.10

[1451] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.60(s,1H),8.24-8.16(m,1H),7.98-7.89(m,1H),7.50(t,J=9.6Hz,1H),3.71-3.60(m,2H),3.60-3.51 (m,3H),2.98(s,3H),2.59(s,3H),2.42(s,3H),2.30-2.14(m,5H),1.90 -1.80(m,1H),1.79-1.66(m,1H),1.57-1.37(m,5H),1.35-1.25(m,1H).

[1452] Example 23

[1453] Compound 23

[1454]

[1455] Step 1: Preparation of Compound 23

[1456] Compound 3b (100 mg, 0.196 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (30 mL), and trimethyloxonium tetrafluoroboric acid (87 mg, 0.590 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (2 × 30 mL). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 23 (31 mg, yield: 30%).

[1457] MS(ESI,[M+H) + )m / z:523.20

[1458] 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.61(s,1H),7.89-7.84(m,1H),7.47-7.38(m,2H),3.71-3.62(m,2H),3.59(s,3H),3.00( s,3H),2.61(s,3H),2.43(s,3H),2.32-2.17(m,5H),1.92-1.81(m,1H),1.79-1.69(m,1H),1.60-1.40(m,5H),1.37-1.26(m,1H).

[1459] Example 24

[1460] Compound 24

[1461]

[1462] Step 1: Synthesis of Compound 24

[1463] Compound A4 (140 mg, 0.416 mmol, 1.0 eq) and HATU (190 mg, 0.499 mmol, 1.2 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Compound A15 (174 mg, 0.541 mmol, 1.3 eq) and DIEA (269 mg, 2.08 mmol, 5.0 eq) were added, and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (20 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase 0.1% formic acid / acetonitrile / water) to give compound 24 (161.6 mg, yield: 71%).

[1464] MS(ESI,[M+H) + )m / z:543.20

[1465] 1 H NMR (400MHz, DMSO-d6) δ10.41 (s, 1H), 9.40 (t, J = 8.8Hz, 1H), 7.90-7.84 (m, 1H), 7.45-7.39 (m, 2H), 7.31-7.22 (m, 4H), 5.90-5. 85(m,1H),4.15-4.09(m,1H),3.60(s,3H),3.50-3.36(m,2H),2.97-2.93(m,3H),2.64-2.59(m,3H),2.43(s,3H),2.27(s,3H).

[1466] Example 25

[1467] Compound 25

[1468]

[1469] Step 1: Preparation of intermediate 25a

[1470] Compound A4 (250 mg, 0.74 mmol, 1.0 eq) and HATU (424 mg, 1.11 mmol, 1.5 eq) were dissolved in anhydrous DMF (5 mL). After stirring for 5 minutes, DIEA (480 mg, 3.72 mmol, 5.0 eq) and compound A18 (188 mg, 0.82 mmol, 1.1 eq) were added, and the reaction mixture was stirred at room temperature for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 25a (220 mg, yield: 66%).

[1471] MS(ESI,[M+H) + m / z:450.20

[1472] Step 2: Preparation of Compound 25

[1473] Compound 25a (200 mg, 0.44 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (139 mg, 1.78 mmol, 4.0 eq) and PIDA (430 mg, 1.33 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 25 (100 mg, yield: 47%).

[1474] MS(ESI,[M+H) + )m / z:481.20

[1475] 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.24(s,1H),7.90-7.84(m,1H),7.47-7.38(m,2H),3.78-3.6 8(m,3H),3.60(s,3H),2.95(s,3H),2.45(s,3H),2.36-2.31(m,4H),2.28(s,3H),1.95-1.85(m,2H).

[1476] Example 26

[1477] Compound 26

[1478]

[1479] Step 1: Preparation of intermediate 26a

[1480] Compound A4 (300 mg, 0.89 mmol, 1.0 eq) and HATU (678 mg, 1.78 mmol, 2.0 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. Then, DIEA (576 mg, 4.46 mmol, 5.0 eq) and crude compound A19 (309 mg, 1.38 mmol, 1.6 eq) were added, and the mixture was stirred at room temperature for 60 min. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (33% PE / EA) to give compound 26a (220 mg, yield: 57%).

[1481] MS(ESI,[M+H) + )m / z:436.10

[1482] Step 2: Preparation of Compound 26

[1483] Compound 26a (200 mg, 0.459 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (143 mg, 1.84 mmol, 4.0 eq) and diacetoxyiodobenzene (888 mg, 2.76 mmol, 6.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: acetonitrile / water / formic acid) to give compound 26 (100 mg, yield: 47%).

[1484] MS(ESI,[M+H) + )m / z:467.10

[1485] 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.14(s,1H),7.87-7.84(m,1H),7.44-7.40(m,2H),3.67(s ,1H),3.58(s,3H),3.50-3.34(m,2H),2.96(s,3H),2.38(s,3H),2.20(s,3H),1.13-0.82(m,4H).

[1486] Example 27

[1487] Compound 27

[1488]

[1489] Step 1: Preparation of intermediate 27a

[1490] Compound A4 (300 mg, 0.892 mmol, 1.0 eq) and HATU (407 mg, 1.07 mmol, 1.2 eq) were dissolved in anhydrous DMF (5 mL) under nitrogen protection. The reaction mixture was stirred at room temperature for 10 min. DIEA (576 mg, 4.46 mmol, 5.0 eq) and compound A20 (411 mg, 1.78 mmol, 2.0 eq) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL), and water (15 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (8% MeOH in DCM) to give compound 27a (350 mg, yield: 86%).

[1491] MS(ESI,[M+H) + )m / z:452.10

[1492] Step 2: Preparation of Compound 27

[1493] Compound 27a (350 mg, 0.775 mmol, 1.0 eq) was dissolved in methanol (10 mL), and ammonium carbamate (242 mg, 3.10 mmol, 4.0 eq) and diacetoxyiodobenzene (749 mg, 2.33 mmol, 3.0 eq) were added sequentially. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (20 mL) was added. The mixture was extracted with ethyl acetate (3 × 25 mL), and the organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase 0.1% formic acid / acetonitrile / water) to give compound 27 (210 mg, yield: 56%).

[1494] MS(ESI,[M+H) + m / z:483.20

[1495] 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),9.86(s,1H),7.94-7.83(m,1H),7.49-7.39(m,2H),4.86-4.7 5(m,2H),4.69-4.62(m,2H),4.11-3.88(m,3H),3.63(s,3H),3.04(s,3H),2.46(s,3H),2.28(s,3H).

[1496] Example 28

[1497] Compound 28

[1498]

[1499] Step 1: Preparation of Compound 28

[1500] Compound 25 (80 mg, 0.166 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (10 mL), and trimethyloxonium tetrafluoroboric acid (74 mg, 0.50 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution (20 mL) was added, and the mixture was separated. The aqueous phase was extracted with dichloromethane (2 × 20 mL), and the organic phases were combined, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by thin-layer chromatography (DCM:MeOH = 20:1) to give compound 28 (11.5 mg, yield: 14%).

[1501] MS(ESI,[M+H) + )m / z:495.20

[1502] 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.26(s,1H),7.90-7.84(m,1H),7.47-7.38(m,2H),3.76-3.67(m,2H ),3.60(s,3H),2.97(s,3H),2.62(s,3H),2.44(s,3H),2.39-2.32(m,4H),2.27(s,3H),1.94-1.86(m,2H).

[1503] Example 29

[1504] Compound 29

[1505]

[1506] Step 1: Preparation of Compound 29

[1507] Compound 26 (80 mg, 0.17 mmol, 1.0 eq) was dissolved in anhydrous dichloromethane (20 mL), and trimethyloxonium tetrafluoroboric acid (76 mg, 0.51 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added, followed by dilution with dichloromethane (20 mL) and separation. The aqueous phase was extracted with dichloromethane (3 × 30 mL). The combined organic phases were washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 29 (10.3 mg, yield: 13%).

[1508] MS(ESI,[M+H) + )m / z:481.20

[1509] 1 H NMR(400MHz,DMSO-d6)δ10.40(s,1H),9.14(s,1H),7.89-7.84(m,1H),7.44-7.38(m,2H),3.58(s,3H),3.5 1-3.38(m,2H),3.00(s,3H),2.60(s,3H),2.37(s,3H),2.19(s,3H),1.06-0.99(m,2H),0.90-0.83(m,2H).

[1510] Example 30

[1511] Compound 30

[1512]

[1513] Step 1: Preparation of intermediate 30a

[1514] Compound A21 (119 mg, 0.71 mmol, 1.2 eq) and compound A4 (200 mg, 0.59 mmol, 1.0 eq) were dissolved in DMF (5 mL), and HATU (294 mg, 0.77 mmol, 1.3 eq) and DIEA (384 mg, 2.97 mmol, 5.0 eq) were added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and separated by adding water (20 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by rapid silica gel column chromatography (DCM / EA = 4 / 1) to give compound 30a (260 mg, yield: 90%).

[1515] MS(ESI,[M+H) + )m / z:486.10

[1516] Step 2: Preparation of Compound 30

[1517] Compound 30a (260 mg, 0.54 mmol, 1.0 eq), diacetoxyiodobenzene (604 mg, 1.9 mmol, 3.5 eq), and ammonium carbamate (146 mg, 1.9 mmol, 3.5 eq) were dissolved in ethanol (10 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was concentrated, and the residue was purified by preparative prep-HPLC (mobile phase: 0.1% formic acid / acetonitrile / water) to give compound 30 (175 mg, yield: 63%).

[1518] MS(ESI,[M+H) + )m / z:517.20

[1519] 1 H NMR(400MHz,DMSO-d6)...

Claims

1. A compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, The compound has the structure shown in Formula A: in, R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, halogenated and deuterated or only deuterated C 1-6 Alkyl, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyl, halogenated, and deuterated or only deuterated C 1-6 alkoxy, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyloxy; R1' is selected from the following groups: H, C 1-6 alkyl, Ring A is selected from the following group, either substituted or unsubstituted: C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, halogenated and deuterated or only deuterated C 1-6 Alkyl, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyl, halogenated, and deuterated or only deuterated C 1-6 alkoxy, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyloxy; R' and R” are each independently selected from the following groups: hydrogen, halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy, halogenated and deuterated or only deuterated C 1-6 Alkyl, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyl, halogenated, and deuterated or only deuterated C 1-6 alkoxy, halogenated, and deuterated or only deuterated C 3-6 Cycloalkyloxy group; or R', R” and the carbon atom and / or heteroatom attached thereto form the substituted or unsubstituted group: C 3-6 Cycloalkyl groups, 5-10 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 1-6 Alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 Cycloalkyloxy groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; R is selected from the following group: R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, hydroxyl, halogen, cyano, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 Alkynyl; the above-mentioned alkenyl, alkynyl, alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl groups may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl; Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; Or R9, R 10 Together with the carbon atom it is attached to, they form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Ring B is absent or selected from the following group of substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy m is selected from the following group: 0, 1, 2, 3; U is V is R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl, -(C=O)-CH2-N(C 1-6 alkyl)-(C=O)-CH(NH3Cl)-CH2-C 6-10 Aryl; R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 Alkyl carbonyl, halogenated C 1-6 alkyl carbonyl, C 1-6 Cycloalkyl carbonyl, halogenated C 1-6 cycloalkyl carbonyl, Wherein, the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, -N(C 1-6 alkyl)-(C=O)-CH(NH3Cl)-CH2-C 6-10 Aryl, -N(C 1-6 alkyl)-(C=O)-CH(NH3Cl)-CH2-C 6-10 Aryl, -O-(CH2)2-NH3Cl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl, cycloalkyl, or heterocyclic alkyl is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group; R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl; R ”’ Selected from the following group: H, 2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, The compound has the structure shown in Formula B: in, R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy; X is selected from the following group: N, NR2, O, S, CR2; Y is selected from the following groups: N, NR3, O, S, CR3; Z is selected from the following group: N, C; W is selected from the following groups: N, NR4, O, S, CR4; R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the carbon and / or nitrogen atoms attached thereto form a substituted or unsubstituted 5- to 10-membered heterocycloalkyl or heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy; R is selected from the following group: R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, hydroxyl, halogen, cyano, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 The alkyne group, and the alkenyl, alkyne, alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl groups mentioned above, may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl; Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; Or R9, R 10 Together with the carbon atom it is attached to, they form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O, or S; the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy m is selected from the following group: 0, 1, 2; U is V is R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclic alkyl containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl, cycloalkyl, or heterocyclic alkyl is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group; R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl; R ”’ Selected from the following group: H, 3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy; X is NR2; Y is CR3; Z is C; W is CR4; R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the nitrogen and / or carbon atom attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R is selected from the following group: R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, hydroxyl, halogen, cyano, deuterium, and C. 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 The alkyne group, and the alkenyl, alkyne, alkyl, cycloalkyl, heterocycloalkyl, phenyl, aryl, and heteroaryl groups mentioned above, may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl; Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy m is selected from the following groups: 0, 1; U is V is R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group; R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl; R ”’ Selected from the following group: H, 4. The compound of claim 3, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl; Alternatively, R4 is selected from the following group: C 1-6 Alkyl, C 3-6 A cycloalkyl group, wherein R2, R3, and the nitrogen and / or carbon atoms attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R5, R6, R7, and R8 are either absent or independently selected from the following groups: hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl-substituted C 1-6 Alkyl, C 6-10 aryl, 5-10 heteroaryl groups containing 1-3 heteroatoms selected from N, O or S, C 2-6 alkenyl, C 2-6 The alkyne group, alkyne group, alkyl group, cycloalkyl group, aryl group, and heteroaryl group may optionally be further substituted by one or more groups selected from the group consisting of: hydroxyl, -COOH, halogen, cyano, deuterium, C 1-6 Alkyl, Halogenated C 1-6 alkyl; Alternatively, R5, R6, and the carbon atom they are connected to, together with / or R7, R8, and the carbon atom they are connected to, form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 Aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; Alternatively, R5, R8, and the carbon atom attached to them together form substituted or unsubstituted groups selected from the group consisting of: C 3-6 Cycloalkyl groups, 4-6 membered heterocycloalkyl groups containing 1-3 heteroatoms selected from N, O or S, C 6-10 aryl, a 5-10 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: hydroxyl, halogen, cyano, deuterium, C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, and halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl groups, halogenated 4-6-membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S; Each R9, R 10 R 11 R 12 Each of the following is independently selected: hydrogen, deuterium, and C. 1-6 Alkyl, Halogenated C 1-6 alkyl; Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, m is selected from the following groups: 0, 1; U is V is R 13 Selected from the following group: hydrogen, C 1-6 Alkyl, Halogenated C 1-6 alkyl; R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group; R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group; R ”’ Selected from the following group: H, 5. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, R1 represents C with or without substitution. 6-10 aryl, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, Halogenated C 1-6 alkyl; X is NR2; Y is CR3; Z is C; W is CR4; R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the nitrogen and / or carbon atom attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R is m is selected from the following groups: 0, 1; R 16 R 17 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl; R”' is selected from the following group: H, 6. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy; X is NR2; Y is CR3; Z is C; W is CR4; R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 Cycloalkyl; or R2, R3 and the nitrogen and / or carbon atom attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R is R9, R 10 R 11 R 12 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, a 4-7 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, nitro, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy m is 0 or 1; V is R 13 It is hydrogen; R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group; R”' is selected from the following group: H, 7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that: R1 is selected from the following group: substituted or unsubstituted groups: C 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R2, R3, and R4 are each independently selected from the following groups: hydrogen, halogen, C. 1-6 Alkyl, C 3-6 cycloalkyl; Alternatively, R4 can be selected from the following group: C 1-6 Alkyl, C 3-6 A cycloalkyl group, wherein R2, R3, and the nitrogen and / or carbon atoms attached thereto form a substituted or unsubstituted 5- to 10-membered heterocyclic alkyl group containing 1-3 heteroatoms selected from N, O, or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogens, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl; R9, R 10 Each of the following groups is selected independently: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl; R 11 R 12 It is hydrogen; R is Ring B is either unsubstituted or selected from the following group of substituent or unsubstituted groups: C 6-10 Aryl, 4-7 membered heteroaryl containing 1-3 heteroatoms selected from N, O or S, wherein the substitution refers to substitution by one or more substituents selected from the group consisting of: halogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyloxy m is 0 or 1; V is R 13 It is hydrogen; R 14 Selected from the following group: hydrogen, C 1-6 Alkyl, C 3-6 cycloalkyl, halogenated C 1-6 Alkyl, Halogenated C 3-6 cycloalkyl, C 1-6 alkyl carbonyl, wherein the C 1-6 Alkyl groups may optionally be substituted with groups selected from the group consisting of: -N(C 1-6 alkyl)-(C=O)-CH(NH2)-CH2-C 6-10 Aryl, NH2, -(C=O)-OC 1-6 Alkyl, hydroxyl, -O-(P=O)(OH)2, -COOH; R 15 Selected from the following group: C 1-6 Alkyl, C 3-6 Cycloalkyl groups, 4-6 membered heterocyclic alkyl groups containing 1-3 heteroatoms selected from N, O or S, wherein the alkyl group, cycloalkyl group, or heterocyclic alkyl group is optionally further substituted by one or more groups selected from the group consisting of: hydroxyl, halogen, C 1-6 Alkyl group, cyano group; R ”’ Selected from the following group: H, 8. A compound, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, The compounds are selected from the group consisting of:

9. A pharmaceutical composition, characterized in that, The compound comprising a pharmaceutically acceptable carrier and one or more safe and effective amounts of any of the compounds of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof.

10. Use of any compound of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopically labeled compound, metabolite, or prodrug thereof, characterized in that, Used to prepare a drug for the prevention and / or treatment of hepatitis virus infection.

Images