Substituted purinone derivatives useful as ubiquitin-specific protease inhibitors

Abstract

The present disclosure relates to substituted purinone derivatives useful as ubiquitin-specific protease inhibitors, in particular to compounds represented by formula (I), isomers thereof, or pharmaceutically acceptable salts thereof. # imgabs0 #

Description

Substituted purinone derivatives as ubiquitin-specific protease inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority and benefits of Chinese Patent Application No. 202211106114.5 filed with the State Intellectual Property Office of China on September 9, 2022 and Chinese Patent Application No. 202311120629.5 filed with the State Intellectual Property Office of China on August 31, 2023, the contents disclosed in which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to substituted purinone derivatives useful as ubiquitin-specific protease inhibitors, and particularly to compounds represented by formula (I), isomers thereof, or pharmaceutically acceptable salts thereof. Background Art

[0004] USP1 (ubiquitin specific peptidase 1) is a member of the deubiquitinating enzyme family. USP1 and its cofactor, UAF1 (USP1-associated factor 1), form the USP1-UAF1 complex, which deubiquitinates two key proteins in the FA and TLS pathways, Ub-FANCD2 and Ub-PCNA, thereby activating DNA cross-link repair and promoting cancer cell survival. USP1 is highly expressed in a variety of human tumors and is closely associated with tumor development and progression, garnering widespread attention as a therapeutic target.

[0005] Genome-wide knockout studies using CRISPR technology have shown that USP1 is synthetically lethal when combined with BRCA1 / 2 mutations or other homologous recombination repair deficiencies (HRD). Mechanistically, USP1 and PARP are key regulatory proteins in the DNA cross-link damage and single-strand damage repair pathways, respectively. The two complement each other to promote DNA damage repair and prevent the generation of cytolethal double-strand breaks. Therefore, USP1 is an important target with great clinical value in the field of DNA damage repair.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound represented by formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] X 1 and X 2 are independently selected from C(R 1 ) or N;

[0010] X 3 、X 4 、X 5 and X 6 are independently selected from C(R 5 ) or N;

[0011] Each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents;

[0012] or R on two adjacent carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C 5-7 Cycloalkenyl, 5-7 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl;

[0013] L is selected from -(C(R 3 R 4 )) m -、-O-、-S-、-N(R 9 )-, -S(O)- or -S(O)2-;

[0014] R 2 Selected from C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group or C 5-7 Cycloalkenyl, the C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group and C 5-7 Cycloalkenyl is optionally independently substituted with one or more R 2a replace;

[0015] Each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents;

[0016] or R3 and R 4 Together with the carbon atom to which they are attached, they form a carbonyl group;

[0017] or R 3 and R 4 and the carbon atoms to which they are commonly attached together form a C optionally substituted with one or more substituents 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0018] or R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R 4 and R 4 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl;

[0019] R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally independently substituted by one or more R 6a replace;

[0020] R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents;

[0021] or R 7 and R 8 and the carbon atoms to which they are commonly attached together form a C optionally substituted with one or more substituents 3-8 Cycloalkyl, 3-8 membered heterocyclic group or C 3-8 cycloalkenyl;

[0022] R 9 Selected from hydrogen or C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with one or more substituents;

[0023] Each R 2a and R 6a are independently selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents;

[0024] m is selected from 1, 2 or 3.

[0025] In some embodiments of the present disclosure, the "substituted by 1 or more" are each independently selected from substituted by 1, 2, 3, 4, 5 or 6.

[0026] In some embodiments of the present disclosure, the "substituted by 1 or more" are each independently selected from substituted by 1, 2, 3, 4 or 5.

[0027] In some embodiments of the present disclosure, the "substituted by 1 or more" are each independently selected from substituted by 1, 2, 3 or 4.

[0028] In some embodiments of the present disclosure, the "substituted by 1 or more" are each independently selected from substituted by 1, 2 or 3.

[0029] In some embodiments of the present disclosure, the "substituted by 1 or more" are each independently selected from substituted by 1 or 2.

[0030] In some embodiments of the present disclosure, X 1 and X 2 At least one of them is selected from C(R 1 ).

[0031] In some embodiments of the present disclosure, X 1 and X 2 One of the C(R 1 ), and the other is selected from N.

[0032] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ).

[0033] In some embodiments of the present disclosure, X 1 Selected from N.

[0034] In some embodiments of the present disclosure, X 1 Selected from C(R 1 ), X 2Selected from C(R 1 ).

[0035] In some embodiments of the present disclosure, X 1 Selected from N, X 2 Selected from C(R 1 ).

[0036] In some embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0037] In some embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0038] In some embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0039] In some embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are optionally substituted independently with one or more substituents.

[0040] In some embodiments of the present disclosure, each R 1 and R 5 Each of the groups is independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are optionally substituted independently with one or more substituents.

[0041] In some embodiments of the present disclosure, each R 1 and R 5 are each optionally independently substituted with one or more groups selected from halogen, OH, CN or NH2.

[0042] In some embodiments of the present disclosure, each R 1 and R 5 are each optionally independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0043] In some embodiments of the present disclosure, each R 1 and R 5Each of the groups is independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, and isoxazolidinyl are optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0044] In some embodiments of the present disclosure, each R 1 and R 5 Each of the groups is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl is optionally substituted independently by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0045] In some embodiments of the present disclosure, each R 1 and R 5 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0046] In some embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, -F, -CN, methyl, methoxy, trifluoromethyl or trifluoromethoxy.

[0047] In some embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, -F or CN.

[0048] In some embodiments of the present disclosure, each R 1 are each independently selected from -F.

[0049] In some embodiments of the present disclosure, each R 1 are each independently selected from hydrogen.

[0050] In some embodiments of the present disclosure, X1 Selected from CH, X 2 Selected from CH.

[0051] In some embodiments of the present disclosure, X 1 Selected from N, X 2 Selected from CH.

[0052] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH.

[0053] In some embodiments of the present disclosure, X 1 Selected from C(CN), X 2 Selected from CH.

[0054] In some embodiments of the present disclosure, X 3 、X 4 、X 5 and X 6 At least 2 of them are selected from C(R 5 ).

[0055] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ).

[0056] In some embodiments of the present disclosure, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ).

[0057] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ).

[0058] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from N, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ).

[0059] In some embodiments of the present disclosure, X 3 Selected from N, X4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ).

[0060] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), X 5 Selected from N, X 6 Selected from C(R 5 ).

[0061] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), X 6 Selected from N.

[0062] In some embodiments of the present disclosure, X 3 Selected from N, X 4 Selected from C(R 5 ), X 5 Selected from N, X 6 Selected from C(R 5 ).

[0063] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from N, X 5 Selected from C(R 5 ), X 6 Selected from N.

[0064] In some embodiments of the present disclosure, each R 5 are each independently selected from hydrogen or -F.

[0065] In some embodiments of the present disclosure, each R 5 are independently selected from H.

[0066] In some embodiments of the present disclosure, X 3 Selected from CH, X 4 Selected from CH.

[0067] In some embodiments of the present disclosure, X 5 Selected from CH, X 6 Selected from CH.

[0068] In some embodiments of the present disclosure, X 3 Selected from CH, X 4 Selected from CH, X 5 Selected from CH, X 6 Selected from CH.

[0069] In some embodiments of the present disclosure, X 3 Selected from CH, X 4 Selected from N, X 5 Selected from CH, X 6 Selected from CH.

[0070] In some embodiments of the present disclosure, X 3 Selected from CH, X 4 Selected from CH, X 5 Selected from CH, X 6 Selected from C(F).

[0071] In some embodiments of the present disclosure, X 3 Selected from N, X 4 Selected from CH, X 5 Selected from CH, X 6 Selected from CH.

[0072] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), and X 3 and X 4 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0073] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), and X 3 and X 4 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2. 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0074] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R5 ), and X 3 and X 4 R on two carbon atoms 5 and the carbon atom to which it is attached form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, 2,5-dihydro-furanyl, 2,3-dihydro-furanyl, 2,5-dihydro-thienyl, 2,3-dihydro-thienyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0075] In some embodiments of the present disclosure, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), and X 3 and X 4 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl group, which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0076] In some embodiments of the present disclosure, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), and X 5 and X 6 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0077] In some embodiments of the present disclosure, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), and X 5 and X 6 R on two carbon atoms 5Together with the carbon atom to which it is attached, it forms a C optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2. 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0078] In some embodiments of the present disclosure, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), and X 5 and X 6 R on two carbon atoms 5 and the carbon atom to which it is attached form a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, 2,5-dihydro-furanyl, 2,3-dihydro-furanyl, 2,5-dihydro-thienyl, 2,3-dihydro-thienyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 3,4- dihydro-2H-pyranyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-thiopyranyl, 3,6-dihydro-2H-thiopyranyl, 3,4-dihydro-2H-1,4-oxazinyl, 3,4-dihydro-2H-1,4-thiazinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0079] In some embodiments of the present disclosure, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), and X 5 and X 6 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 2,3-dihydro-pyrrolyl, phenyl, pyrrolyl, pyrazolyl, pyridinyl or pyrimidinyl group, which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0080] In some embodiments of the present disclosure, L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -N(R 9 )-.

[0081] In some embodiments of the present disclosure, R 9 is selected from hydrogen, methyl, ethyl or isopropyl.

[0082] In some embodiments of the present disclosure, R 9 Selected from hydrogen.

[0083] In some embodiments of the present disclosure, L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -NH-.

[0084] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-or-C(R 3 R 4 )-C(R 3 R 4 )-.

[0085] In some embodiments of the present disclosure, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0086] In some embodiments of the present disclosure, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0087] In some embodiments of the present disclosure, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0088] In some embodiments of the present disclosure, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Alkoxy groups are optionally substituted independently with one or more substituents.

[0089] In some embodiments of the present disclosure, each R 3 and R 4 Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally substituted independently by one or more substituents.

[0090] In some embodiments of the present disclosure, each R 3 and R 4 Optionally independently substituted with one or more groups selected from halogen, OH, CN or NH2.

[0091] In some embodiments of the present disclosure, each R 3 and R 4 They are independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally independently substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0092] In some embodiments of the present disclosure, each R 3 and R 4 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.

[0093] In some embodiments of the present disclosure, each R 3 are independently selected from hydrogen, each R 4are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.

[0094] In some embodiments of the present disclosure, each R 3 Each R is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl. 4 are each independently selected from hydrogen.

[0095] In some embodiments of the present disclosure, each R 3 are independently selected from hydrogen, each R 4 are independently selected from hydrogen, methyl or ethyl.

[0096] In some embodiments of the present disclosure, each R 3 Each R is independently selected from hydrogen, methyl or ethyl, 4 are each independently selected from hydrogen.

[0097] In some embodiments of the present disclosure, each R 3 are independently selected from methyl, each R 4 are independently selected from methyl; or each R 3 are independently selected from hydrogen, each R 4 are independently selected from hydrogen; or each R 3 are independently selected from hydrogen, each R 4 is selected from methyl; each R 3 are independently selected from methyl, each R 4 are independently selected from hydrogen; or each R 3 are independently selected from hydrogen, each R 4 Each R is independently selected from ethyl; or 3 are independently selected from ethyl, each R 4 are each independently selected from hydrogen.

[0098] In some embodiments of the present disclosure, R 3 and R 4 and the carbon atoms to which they are commonly attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with one or more substituents.

[0099] In some embodiments of the present disclosure, R 3 and R 4and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl group which is optionally substituted with one or more substituents.

[0100] In some embodiments of the present disclosure, R 3 and R 4 and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0101] In some embodiments of the present disclosure, R 3 and R 4 The substituent formed by the carbon atoms to which they are attached is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0102] In some embodiments of the present disclosure, R 3 and R 4 Together with the carbon atoms to which they are commonly attached, they form a cyclopropyl, oxetanyl or azetidinyl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0103] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-C(R 3 R 4 )-, R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R 4 and R 4 Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl group, which may be optionally substituted with one or more substituents.

[0104] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-C(R 3 R 4 )-, R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R4 and R 4 Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl group which is optionally substituted with one or more substituents.

[0105] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-C(R 3 R 4 )-, R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R 4 and R 4 The substituent, together with the carbon atom to which it is attached, is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0106] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-C(R 3 R 4 )-, R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R 4 and R 4 Together with the carbon atom to which it is attached, it forms a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0107] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-C(R 3 R 4 )-, R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R 4 and R 4 Together with the carbon atom to which it is attached, it forms a cyclobutyl, oxetanyl or azetidinyl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0108] In some embodiments of the present disclosure, L is selected from -O-, -S-, -NH-, -CH2-, -CH(CH3)-, -CH2CH2-, -CH(F)-, -CH(Cl)-, -CH(Br)-, -CH(I)-, -CH(CN)-, -CH(CF3)-, -CH(OH)-, -CH(NH2)-, -C(O)-, -CH(CH3)CH2-, -CH(F)CH2-, -CH(Cl)CH2-, -CH(Br)CH2-, -CH(I)CH2-, -CH(CN)CH2-, -CH(CF3)CH2-, -CH(OH)CH2-, -CH(NH2)CH2-,

[0109] In some embodiments of the present disclosure, L is selected from -O-, -S-, -NH-, -CH2-, -CH(CH3)-, -CH2CH2-, -C(O)-,

[0110] In some embodiments of the present disclosure, L is selected from -CH2-, -CH(CH3)- or

[0111] In some embodiments of the present disclosure, L is selected from -CH2-.

[0112] In some embodiments of the present disclosure, L is selected from -C(R 3 R 4 )-or-C(R 3 R 4 )-C(R 3 R 4 )-, each carbon atom may be a chiral carbon atom, existing in the form of a (R) or (S) single enantiomer or in the form enriched in one enantiomer.

[0113] In some embodiments of the present disclosure, R 2 Selected from C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group or C 5-6 Cycloalkenyl, the C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a replace.

[0114] In some embodiments of the present disclosure, R 2 Selected from C 3-6Cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group or C 5-6 Cycloalkenyl, the C 3-6 Cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a replace.

[0115] In some embodiments of the present disclosure, R 2 Selected from C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group or C 5-6 Cycloalkenyl, the C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a replace.

[0116] In some embodiments of the present disclosure, R 2 Selected from C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms, 5-6 membered heterocyclic group containing 1-3 N atoms or C 5-6 Cycloalkenyl, the C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms, 5-6 membered heterocyclic group containing 1-3 N atoms and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a replace.

[0117] In some embodiments of the present disclosure, R 2 is selected from cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclopentenyl or cyclohexenyl, the cyclopentyl , cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclopentenyl and cyclohexenyl are optionally independently replaced by one or more R 2a replace.

[0118] In some embodiments of the present disclosure, R 2is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein the phenyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally independently replaced by one or more R 2a replace.

[0119] In some embodiments of the present disclosure, R 2 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl or pyrimidinyl, wherein the phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl and pyrimidinyl groups are optionally independently replaced by one or more R 2a replace.

[0120] In some embodiments of the present disclosure, R 2 is selected from phenyl, pyrazolyl, pyridinyl or pyrimidinyl, wherein the phenyl, pyrazolyl, pyridinyl and pyrimidinyl are optionally independently replaced by one or more R 2a replace.

[0121] In some embodiments of the present disclosure, R 2 is selected from pyrimidinyl, said pyrimidinyl being optionally substituted by one or more R 2a replace.

[0122] In some embodiments of the present disclosure, R 2 Selected from The R 2 Optionally independently represented by one or more R 2a replace.

[0123] In some embodiments of the present disclosure, R 2 Selected from The R 2 Optionally independently represented by one or more R 2a replace.

[0124] In some embodiments of the present disclosure, R 2 Selected from The R 2 Optionally, one or more R 2a replace.

[0125] In some embodiments of the present disclosure, each R 2a and R 6a are independently selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0126] In some embodiments of the present disclosure, each R 2a and R 6a are independently selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0127] In some embodiments of the present disclosure, each R 2a and R 6a are independently selected from halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0128] In some embodiments of the present disclosure, each R 2a and R 6a are independently selected from halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl and 3-6 membered heterocyclyl groups are optionally substituted independently with one or more substituents.

[0129] In some embodiments of the present disclosure, each R 2a and R6a Each of the groups is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl or isoxazolidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl and isoxazolidinyl is optionally substituted independently with one or more substituents.

[0130] In some embodiments of the present disclosure, each R 2a and R 6a Each of the groups is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl are optionally substituted independently by one or more substituents.

[0131] In some embodiments of the present disclosure, R 2a and R 6a are each optionally independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0132] In some embodiments of the present disclosure, each R 2a and R 6a Each of the groups is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl are optionally and independently substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0133] In some embodiments of the present disclosure, each R 2a and R 6a Each is independently selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy and cyclopropyl are optionally independently substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0134] In some embodiments of the present disclosure, R 2aSelected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,

[0135] In some other embodiments of the present disclosure, R 2a Selected from -CD3, -CH3, isopropyl, methoxy or

[0136] In some embodiments of the present disclosure, R 2a Selected from methyl, isopropyl, methoxy or

[0137] In some embodiments of the present disclosure, R 2a Selected from isopropyl, methoxy or

[0138] In some embodiments of the present disclosure, R 2 Selected from

[0139] In some embodiments of the present disclosure, R 2 Selected from

[0140] In some embodiments of the present disclosure, R 2 Selected from

[0141] In some embodiments of the present disclosure, R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally independently substituted by one or more R 6a replace.

[0142] In some embodiments of the present disclosure, R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally independently substituted by one or more R 6a replace.

[0143] In some embodiments of the present disclosure, R 6 Selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally independently substituted by one or more R 6a replace.

[0144] In some embodiments of the present disclosure, R 6 Selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally independently substituted by one or more R 6a replace.

[0145] In some embodiments of the present disclosure, R 6 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally independently substituted by one or more R 6a replace.

[0146] In some embodiments of the present disclosure, R 6 Selected from C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms or 5-6 membered heterocyclic group containing 1-3 N atoms, the C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl containing 1-3 N atoms and 5-6 membered heterocyclic group containing 1-3 N atoms are optionally independently substituted by one or more R6a replace.

[0147] In some embodiments of the present disclosure, R 6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, the cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally independently replaced by one or more R 6a replace.

[0148] In some embodiments of the present disclosure, R 6 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl, wherein the phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazole ring, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl and pyridazinyl are optionally independently replaced by one or more R 6a replace.

[0149] In some embodiments of the present disclosure, R 6 is selected from phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl or pyrimidinyl, wherein the phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl and pyrimidinyl are optionally independently replaced by one or more R 6a replace.

[0150] In some embodiments of the present disclosure, R 6 is selected from pyrazolyl or imidazolyl, wherein the pyrazolyl and imidazolyl are optionally independently substituted with one or more R 6a replace.

[0151] In some embodiments of the present disclosure, R 6 Selected from

[0152] The R 6 Optionally independently represented by one or more R 6a replace.

[0153] In some embodiments of the present disclosure, R 6 Selected from The R 6 Optionally independently represented by one or more R 6a replace.

[0154] In some embodiments of the present disclosure, R 6 Selected from The R 6 Optionally independently represented by one or more R 6a replace.

[0155] In some embodiments of the present disclosure, R 6a Selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,

[0156] In some other embodiments of the present disclosure, R 6a Selected from -CD3, deuterium atom, -CH3, isopropyl, trifluoromethyl,

[0157] In some embodiments of the present disclosure, R 6a Selected from methyl, isopropyl, trifluoromethyl,

[0158] In some embodiments of the present disclosure, R 6a is selected from isopropyl or trifluoromethyl.

[0159] In some embodiments of the present disclosure, R 6 Selected from

[0160] In some embodiments of the present disclosure, R 6 Selected from

[0161] In some embodiments of the present disclosure, R 6 Selected from

[0162] In some embodiments of the present disclosure, R 6 Selected from

[0163] In some embodiments of the present disclosure, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0164] In some embodiments of the present disclosure, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0165] In some embodiments of the present disclosure, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0166] In some embodiments of the present disclosure, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl or C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 Alkoxy groups are optionally substituted independently with one or more substituents.

[0167] In some embodiments of the present disclosure, R 7 and R 8 Each is independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally substituted independently by one or more substituents.

[0168] In some embodiments of the present disclosure, R 7 and R 8 are each optionally independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0169] In some embodiments of the present disclosure, R 7 and R 8 They are independently selected from hydrogen, halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, and the methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy are optionally independently substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0170] In some embodiments of the present disclosure, R 7 and R 8 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0171] In some embodiments of the present disclosure, R 7 and R 8 Each is independently selected from -F, -Cl, -Br, -I, methyl, methoxy or trifluoromethyl.

[0172] In some embodiments of the present disclosure, R 7 and R 8 are each independently selected from methyl.

[0173] In some embodiments of the present disclosure, R 7 and R 8 and the carbon atoms to which they are commonly attached together form a C optionally substituted with one or more substituents 3-6 Cycloalkyl, 3-6 membered heterocyclic group or C 3-6 Cycloalkenyl.

[0174] In some embodiments of the present disclosure, R 7 and R 8and the carbon atoms to which they are commonly attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group which is optionally substituted with one or more substituents.

[0175] In some embodiments of the present disclosure, R 7 and R 8 and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with one or more substituents.

[0176] In some embodiments of the present disclosure, R 7 and R 8 and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0177] In some embodiments of the present disclosure, R 7 and R 8 Together with the carbon atoms to which they are commonly attached, they form a cyclopropyl, cyclobutyl or tetrahydropyranyl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0178] In some embodiments of the present disclosure, R 7 and R 8 and the carbon atoms to which they are commonly attached together form a group optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2

[0179] In some embodiments of the present disclosure, R 7 and R 8 The substituents formed by the carbon atoms to which they are attached are optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0180] In some embodiments of the present disclosure, R 7 and R 8 and their commonly connected carbon atoms together to form

[0181] In some embodiments of the present disclosure, R7 and R 8 and their commonly connected carbon atoms together to form

[0182] In some embodiments of the present disclosure, the "hetero" is each independently selected from oxygen, sulfur and nitrogen heteroatoms, wherein the nitrogen atom is optionally quaternized or oxidized to N(O), and the sulfur atom is optionally oxidized to S(O) or S(O)2.

[0183] In some embodiments of the present disclosure, the "hetero" is each independently selected from oxygen, sulfur, and nitrogen heteroatoms, wherein the sulfur heteroatom is optionally oxidized to S(O) or S(O)2.

[0184] In some embodiments of the present disclosure, m is selected from 1.

[0185] In some embodiments of the present disclosure, the R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 6a 、R 7 、R 8 or R 9 Optionally substituted with one or more substituents selected from the group consisting of -OH, -SH, halogen, -NH2, nitro, nitroso, -CN, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, a carboxaldehyde group, an imine group, an alkyl group, a halo-alkyl group, a cycloalkyl group, a halo-cycloalkyl group, an alkenyl group, a halo-alkenyl group, a cycloalkenyl group, a halo-cycloalkenyl group, an alkynyl group, a halo-alkynyl group, a cycloalkynyl group, a halo-cycloalkynyl group, a heteroalkyl group, a halo - heteroalkyl group, alkoxy group, alkylthio group, aryl group, aryloxy group, arylthio group, aralkyl group, arylalkoxy group, arylalkylthio group, heteroaryl group, heteroaryloxy group, heteroarylthio group, heteroaralkyl group, heteroarylalkoxy group, heteroarylalkylthio group, heterocyclyl group, heterocyclyloxy group, heterocyclylthio group, heterocyclylalkyl group, heterocyclylalkoxy group, heterocyclylalkylthio group, acyl group, acyloxy group, carbamate group, amide group, urea group, epoxy group and ester group, etc.

[0186] In some embodiments of the present disclosure, the compound represented by formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) is selected from the compound represented by formula (I-1),

[0187] Among them, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I);

[0188] R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as either a (R) or (S) single enantiomer or enriched in one enantiomer.

[0189] In some embodiments of the present disclosure, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I-2)

[0190] in,

[0191] X 4 selected from CH or N;

[0192] X 1 、X 2 、R 2 , L and R 6 The compound is defined as shown in formula (I).

[0193] In some embodiments of the present disclosure, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I-3)

[0194] in,

[0195] X 4 selected from CH or N;

[0196] X 1 、R 2 , L and R 6 The compound is defined as shown in formula (I).

[0197] In some embodiments of the present disclosure, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I-4)

[0198] in,

[0199] X 4 selected from CH or N;

[0200] X 1 、R 2 、R 3 、R 4 and R 6As defined by the compound shown in formula (I);

[0201] R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as either a (R) or (S) single enantiomer or enriched in one enantiomer.

[0202] In some embodiments of the present disclosure, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I-5)

[0203] in,

[0204] X 4 selected from CH or N;

[0205] Y 1 、Y 2 and Y 3 are independently selected from CH or N;

[0206] X 1 、R 3 、R 4 、R 6 and R 2a As defined by the compound shown in formula (I);

[0207] R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as either a (R) or (S) single enantiomer or enriched in one enantiomer.

[0208] In some embodiments of the present disclosure, Y 1 Selected from N.

[0209] In some embodiments of the present disclosure, Y 1 and Y 3 All are selected from N.

[0210] In some embodiments of the present disclosure, Y 1 、Y 2 and Y 3 All are selected from CH.

[0211] In some embodiments of the present disclosure, Y 1 Selected from N, Y 2 and Y 3 All are selected from CH.

[0212] In some embodiments of the present disclosure, Y 1 and Y 3 All selected from N, Y 2 Selected from CH.

[0213] In some embodiments of the present disclosure, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I-6)

[0214] in,

[0215] X 4 selected from CH or N;

[0216] Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5);

[0217] X 1 、R 3 、R 4 、R 2a and R 6a As defined by the compound shown in formula (I);

[0218] R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as either a (R) or (S) single enantiomer or enriched in one enantiomer.

[0219] In some embodiments of the present disclosure, the compound of formula (I), its isomer or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I-7)

[0220] in,

[0221] X 4 selected from CH or N;

[0222] Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5);

[0223] X 1 、R 3 、R 4 、R 2a and R 6a As defined by the compound shown in formula (I);

[0224] R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as either a (R) or (S) single enantiomer or enriched in one enantiomer.

[0225] Some other embodiments of the present disclosure are formed by any combination of the above variables.

[0226] On the other hand, the present disclosure also provides a compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof,

[0227] On the other hand, the present disclosure also provides a compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof,

[0228] On the other hand, the present disclosure also provides a pharmaceutical composition containing a therapeutically or prophylactically effective amount of the compound of the present disclosure, its isomers or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition of the present disclosure further comprises a pharmaceutically acceptable excipient.

[0229] On the other hand, the present disclosure also provides the use of the compound, its isomer or pharmaceutically acceptable salt or pharmaceutical composition thereof in the preparation of a drug for treating or preventing diseases associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0230] On the other hand, the present disclosure also provides a method for treating or preventing a disease associated with the inhibition of ubiquitin-specific protease 1 (USP1), comprising administering a therapeutically or prophylactically effective amount of a compound of the present disclosure, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal (preferably a human) in need of such treatment or prevention.

[0231] On the other hand, the present disclosure also provides use of the compound, its isomer, or pharmaceutically acceptable salt, or pharmaceutical composition thereof in treating or preventing diseases associated with inhibition of ubiquitin-specific protease 1 (USP1).

[0232] In another aspect, the present disclosure also provides the compound of the present disclosure, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating or preventing diseases associated with the inhibition of ubiquitin-specific protease 1 (USP1).

[0233] On the other hand, in some embodiments of the present disclosure, the disease associated with inhibition of ubiquitin-specific protease 1 (USP1) is selected from tumors or cancers (eg, breast cancer).

[0234] Technical Effects

[0235] The compounds disclosed herein are novel inhibitors of ubiquitin-specific protease 1 (USP1), exhibiting potent inhibitory effects on USP1 signaling. These compounds exhibit potent inhibitory effects in vitro and in vivo, including, but not limited to, potent inhibition of in vitro enzyme and cell activity, good liver microsomal stability, favorable pharmacokinetic properties, and robust in vivo efficacy. These compounds are promising candidates for development as novel USP1 inhibitors.

[0236] Related definitions

[0237] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0238] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0239] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure, which are prepared by reacting the compounds of the present disclosure with relatively nontoxic acids or bases. When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in a neat solution or a suitable inert solvent. When the compounds of the present disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in a neat solution or a suitable inert solvent. Certain specific compounds of the present disclosure contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0240] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of the two.

[0241] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure.

[0242] [Corrected 12.09.2023 according to Rule 26] Unless otherwise specified, use a solid wedge key and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicates the relative configuration of a stereocenter.

[0243] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety, in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions by reorganization of some bonding electrons.

[0244] The compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure.

[0245] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0246] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or unsubstituted, and unless otherwise specified, the type and number of substituents can be any on the basis of chemical achievable.

[0247] The term "substituent" as used herein includes all substituents mentioned herein, for example, including the term "C 1-12 Alkyl", "C 1-12 Alkoxy", "C 1-12 Alkylthio", "C 2-12 Alkenyl", "C 2-12 Alkynyl", "halogen", "C 3-12 Cycloalkyl", "C 3-12 Cycloalkenyl", "3-6 membered heterocycloalkyl", "C 6-10The term "substituent" refers to a "5- to 10-membered heteroaryl", a "5- to 10-membered heteroaryl", a "3- to 12-membered heterocyclyl" and other related groups, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include deuterium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, carboxaldehyde, imine, alkyl, halo-alkyl, cycloalkyl, halo-cycloalkyl, alkenyl, halo-alkenyl, cycloalkenyl, halo- Cycloalkenyl, alkynyl, halo-alkynyl, cycloalkynyl, halo-cycloalkynyl, heteroalkyl, halo-heteroalkyl, alkoxy, alkylthio, aryl, aryloxy, arylthio, aralkyl, arylalkoxy, arylalkylthio, heteroaryl, heteroaryloxy, heteroarylthio, heteroaralkyl, heteroarylalkoxy, heteroarylalkylthio, heterocyclyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylene, heterocyclylalkoxy, heterocyclylalkylthio, acyl, acyloxy, carbamate group, amide The present invention also includes but is not limited to: alkyl, alkyl, alkylamino ... )2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0248] In some embodiments herein, the substituent is selected from deuterium, hydroxyl, thiol, halogen, amino, nitro, nitroso, cyano, azide, sulfoxide, sulfone, sulfone, sulfonamide, carboxyl, aldehyde, imine, C 1-12 Alkyl, halo-C 1-12 Alkyl, 3-12 membered cycloalkyl, halogenated 3-12 membered cycloalkyl, C 2-12 Alkenyl, halo-C 2-12 Alkenyl, 3-12 membered cycloalkenyl, halogenated 3-12 membered cycloalkenyl, C 2-12 Alkynyl, halo-C 2-12 Alkynyl, 8-12 membered cycloalkynyl, halogenated 8-12 membered cycloalkynyl, C 1-12 Heteroalkyl, halo-C 1-12 Heteroalkyl, C 1-12 Alkoxy, C 1-12Alkylthio, 6-10 membered aryl, 6-10 membered aryloxy, 6-10 membered arylthio, 6-10 membered arylC 1-12 Alkylene, 6-10 membered aryl C 1-12 Alkoxy, 6-10 membered aryl C 1-12 alkylthio, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroarylthio, 5-10 membered heteroarylalkylene, 5-10 membered heteroarylalkoxy, 5-10 membered heteroarylalkylthio, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, 3-12 membered heterocyclylC 1-12 Alkylene, 3-12 membered heterocyclic group C 1-12 Alkoxy, 3-12 membered heterocyclic group C 1-12 Alkylthio, C 1-12 Acyl, C 1-12 Acyloxy, carbamate group, C 1-12 Amide group, urea group, epoxy group, C 2-12 Ester group, oxo and thio, etc., the substituent is optionally substituted by one or more substituents selected from the following: oxo, hydroxy, amino, nitro, halogen, cyano, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, halogenated C 1-12 Alkoxy, C 1-12 Alkylamino, di-C 1-12 Alkylamino, halogenated C 1-12 Alkylamino, halogenated di-C 1-12 Alkylamino, carboxyl, -C(O)OC 1-12 Alkyl, -OC(O)-C 1-12 Alkyl, -C(O)NH2, -C(O)NH-C 1-12 Alkyl, -C(O)N(C 1-12 Alkyl)2, -NHC(O)-C 1-12 Alkyl, -C(O)-C 1-12 Alkyl, -S(O)-C 1-12 Alkyl, -S(O)2-C 1-12 Alkyl, -S(O)2NH2, -S(O)2NH-C 1-12 Alkyl, -S(O)2N(C 1-12 alkyl) 2, 3-12 membered cycloalkyl, 3-12 membered cycloalkyl C 1-12 Alkylene, 3-12 membered cycloalkyloxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic group C 1-12 Alkylene, 3-12 membered heterocyclyloxy, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkylC 1-12Alkylene, 3-12 membered heterocycloalkyloxy, 5-10 membered heteroaryl, 5-10 membered heteroarylC1-12 alkylene, 5-10 membered heteroaryloxy, 6-10 membered aryl, 6-10 membered arylC 1-12 an alkylene group or a 6- to 10-membered aryloxy group.

[0249] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0250] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0251] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0252] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0253] Unless otherwise specified, the term “C 1-12 "Alkyl" by itself or as part of another substituent refers to a straight or branched chain saturated hydrocarbon group consisting of 1 to 12 carbon atoms. 1-12 The alkyl group can be C 1-6 Alkyl or C 1-3 Unless otherwise specified, the term "C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like.

[0254] Unless otherwise specified, the term “C 1-12 "Alkylene" by itself or as part of another substituent means a straight or branched divalent hydrocarbon radical consisting of 1 to 12 carbon atoms, including those having 1 to 12, 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. For example, the term "C 1-6 "Alkylene" refers to an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2- or -CH2CH(CH3)-), butylene (-CH2CH2CH2CH2-, -CH2CH(CH3)CH2- or -CH2CH2CH(CH3)-), and the like. The alkylene group is optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, amino, nitro, halogen, cyano, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl, or aryloxy.

[0255] Unless otherwise specified, the term “C 1-12 "Alkoxy" refers to an alkyl group containing 1 to 12 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-12 The alkoxy group can be C 1-6 Alkoxy or C 1-3 Unless otherwise specified, the term "C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy and tert-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0256] Unless otherwise specified, the term “C 1-12 "Alkylthio" refers to those alkyl groups containing 1 to 12 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-12 Alkylthio can be C 1-6 Alkylthio or C 1-3 Unless otherwise specified, the term "C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, isobutylthio, sec-butylthio and tert-butylthio), pentylthio (including n-pentylthio, isopentylthio and neopentylthio), hexylthio and the like.

[0257] Unless otherwise specified, “C 2-12 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-12 Alkenyl can be C2-6 Alkenyl, C 2-3 Alkenyl or C 2-3 Alkenyl. 2-4 Alkenyl groups include C 2-3 , C4, C3 and C2 alkenyl, etc.; the C 2-4 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-4 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, butadienyl, and the like. Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0258] Unless otherwise specified, “C 2-12 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 12 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-12 Alkynyl groups include C 2-6 、C 2-3 , C4, C3 and C2 alkynyl, etc. It can be monovalent, divalent or polyvalent. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, and the like.

[0259] The term "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0260] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0261] Unless otherwise specified, “C 3-12 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, which is a monocyclic or bicyclic ring system. 3-12 Cycloalkyl groups include C 3-8 、C 3-6 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-12 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, and the like.

[0262] Unless otherwise specified, the term “C 3-12 "Cycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic hydrocarbon group consisting of 3 to 12 ring atoms containing at least one carbon-carbon double bond, which can be monovalent, divalent or polyvalent. 3-12 Cycloalkenyl groups include C 3-6 Cycloalkenyl, C 5-6 Cycloalkenyl, etc. 3-6 Examples of cycloalkenyl groups include, but are not limited to

[0263] Unless otherwise specified, the term "5-7 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 7 ring atoms containing at least one carbon-carbon double bond, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S, N or Se, and the rest being carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings, and any ring of the system is non-aromatic. It can be monovalent, divalent or polyvalent. In addition, with respect to the "5-7 membered heterocycloalkenyl", a heteroatom can occupy the position at which the heterocycloalkenyl group is connected to the rest of the molecule. The 5-7 membered heterocycloalkenyl group includes a 5-6 membered heterocycloalkenyl group. Examples of 5-6 membered heterocycloalkenyl groups include but are not limited to

[0264] Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). It is a monocyclic ring system. In addition, with respect to the "3-6 membered heterocycloalkyl", a heteroatom may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 3-membered, 4-membered, 5-membered and 6-membered heterocycloalkyls, etc. Examples of 3-6 membered heterocycloalkyls include, but are not limited to, oxirane, thiirane, aziridine, azetidinyl, oxetanyl, thiinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrothiophene 1,1,-dioxide-3-yl, tetrahydrothiophene 1,1,-dioxide-2-yl, tetrahydrofuranyl (including alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl.

[0265] Unless otherwise specified, the term “C 6-10 "Aryl" refers to a cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated π electron system, which can be a monocyclic, fused bicyclic or fused tricyclic ring system, in which each ring is aromatic. It can be monovalent, divalent or polyvalent. 6-10 Aryl includes C9, C 10 and C6 aryl. 6-10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, etc.).

[0266] Unless otherwise specified, the term "5-10 membered heteroaryl" refers to a cyclic group consisting of 5 to 10 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 of the ring atoms are heteroatoms independently selected from O, S, N or Se, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). It can be monovalent, divalent or polyvalent. The 5-10 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. The 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups. Examples of the 5-10 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4- thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0267] The term "3-12 membered heterocyclic radical" refers to a non-aromatic ring that is fully saturated or partially undersaturated (but not fully unsaturated heteroaromatic) and can exist as a monocycle, a bridged ring or a spirocycle. Unless otherwise indicated, the heterocycle is typically a 3 to 12 membered ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulphur, oxygen and / or nitrogen. Non-limiting examples of heterocyclic radicals include but are not limited to oxiranyl, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl etc. The heterocyclyl group is optionally substituted with one or more of the following groups: oxo, hydroxy, amino, nitro, halo, cyano, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylamino, dialkylamino, haloalkylamino, halodialkylamino, carboxyl, -C(O)O-alkyl, -OC(O)-alkyl, -C(O)NH2, -C(O)NH-alkyl, -C(O)N(alkyl)2, -NHC(O)-alkyl, -C(O)-alkyl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)2NH2, -S(O)2NH-alkyl, -S(O)2N(alkyl)2, cycloalkyl, cycloalkyloxy, heterocyclyl, heterocyclyloxy, heterocycloalkyl, heterocycloalkyloxy, heteroaryl, heteroaryloxy, aryl or aryloxy. The 3-12 membered heterocycloalkyl group includes 3-8 membered, 3-6 membered, 4-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl groups. Examples of “3- to 12-membered heterocycloalkyl” and “3- to 6-membered heterocycloalkyl” include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.

[0268] The term "treating" means administering a compound or formulation of the present disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0269] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0270] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0271] The term "prevention" means administering a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0272] The term "therapeutically or prophylactically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, or (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure that constitutes a "therapeutically or prophylactically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.

[0273] The therapeutic or preventive dose of the disclosed compounds may be based on, for example, the specific use for treatment or prevention, the mode of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the disclosed compounds in the pharmaceutical composition may not be fixed and depends on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. In certain embodiments, the dosage range is from about 0.001 mg / kg to about 1000 mg / kg body weight / day. The dosage is likely to depend on such variables, such as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0274] The word "comprise" or "comprises" and its English variations such as comprises or comprising should be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0275] A "pharmaceutical composition" refers to a composition containing one or more compounds described herein, their isomers, or pharmaceutically acceptable salts thereof, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and thereby exert its biological activity.

[0276] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, for example.

[0277] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art.

[0278] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0279] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0280] The raw materials or intermediates used in the embodiments of the present disclosure can be obtained from commercial sources or prepared by methods of the prior art.

[0281] An important consideration in synthetic route planning in the art is the selection of appropriate protecting groups for reactive functional groups (such as the amino group in the present disclosure). For example, reference may be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc.

[0282] In some embodiments, some of the compounds disclosed herein can be prepared by those skilled in the art of organic synthesis by referring to the following routes:

[0283] in,

[0284] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 , L, R 2 、R 6 、R 7 and R 8 As described above for the compound of formula (I);

[0285] Y is selected from halogen, -OH, methylsulfonyloxy, benzenesulfonyloxy or p-toluenesulfonyloxy.

[0286] In some embodiments of the present application, Y is selected from -Cl, -Br, -I, -OH, methylsulfonyloxy or p-toluenesulfonyloxy.

[0287] In some embodiments of the present application, Y is selected from -Cl.

[0288] For the sake of clarity, the present disclosure is further illustrated with examples, but the examples do not limit the scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification. DETAILED DESCRIPTION

[0289] The present disclosure is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0290] Preparation Example 1

[0291] Compound A-1 (3.2 g) was dissolved in tetrahydrofuran (100 mL). Under nitrogen, diisopropylamine (4.01 g) was added at -20°C, followed by n-butyllithium (2.4 M in n-hexane, 31.2 mL), and stirred for half an hour. The temperature was raised to 0°C, stirred for 30 minutes, and 1,2-dibromoethane (10.64 g) was added dropwise. The mixture was transferred to room temperature and stirred overnight. Saturated aqueous ammonium chloride was added, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Filtered, concentrated, and purified by column chromatography to obtain 740 mg of compound 1-1.

[0292] MS (ESI, [M+H] + )m / z:196.07.

[0293] 1 H NMR (500MHz, DMSO-d6) δ11.94(s,1H),8.13(d,J=1.5Hz,1H),1.83(q,J=4.0Hz,2H),1.62(q,J=4.0Hz,2H).

[0294] Preparation Example 2

[0295] Compound A-2 (500 mg) was dissolved in tetrahydrofuran (15 mL). Under nitrogen protection, diisopropylamine (0.63 g) was added at -20 ° C. Then, n-butyl lithium (2.4 M in n-hexane, 4.9 mL) was added and stirred for half an hour. The temperature was raised to 0 ° C. After stirring for 30 minutes, 1,2-dibromoethane (1.67 g) was added dropwise. The mixture was transferred to room temperature and stirred overnight. Saturated aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution in turn and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was added to petroleum ether (30 mL) and slurried. Filtered to obtain 0.4 g of compound 2-1.

[0296] MS (ESI, [M+H] + )m / z:195.07.

[0297] 1 H NMR (500MHz, DMSO-d6) δ11.19(s,1H),7.92(s,1H),6.95(s,1H),1.75(q,J=3.9Hz,2H),1.55(q,J=3.9Hz,2H).

[0298] Example 1

[0299] Step 1: Preparation of intermediate 1-2

[0300] Intermediate 1-1 (680 mg), B-1 (1.5 g), potassium carbonate (1.4 g), and N,N-dimethyldiamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 1.5 g of Intermediate 1-2.

[0301] MS (ESI, [M+H] + )m / z:550.15.

[0302] 1 H NMR(500MHz,DMSO-d6)δ8.24(s,1H),8.16(d,J=1.4Hz,1H),7.85–7.72(m,2H),7.46(d,J=8.2Hz,2H),5.40(s,2H) ,5.01(s,2H),3.63–3.50(m,2H),1.96-1.94(m,2H),1.76-1.73(m,2H),0.82(dd,J=8.6,7.4Hz,2H),-0.09(s,9H).

[0303] Step 2: Preparation of intermediate 1-3

[0304] Intermediate 1-2 (700 mg), C-1 (494 mg), cesium carbonate (1.24 g), tetrakistriphenylphosphine palladium (147 mg), dioxane (10 mL), and water (0.5 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.49 g of Intermediate 1-3.

[0305] MS (ESI, [M+H] + )m / z:664.40.

[0306] 1 H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.46(s,1H),8.16(s,1H),7.76(d,J=7.9Hz,2H),7.50(d,J=7.9Hz,2H),5.38(s,2H),5.04(s,2H) ,3.85(s,3H),3.56(t,J=8.1Hz,2H),1.98(q,J=4.2Hz,2H),1.82–1.69(m,3H),1.03(t,J=3.6Hz,2H),0.86-0.81(m,4H),-0.09(s,9H).

[0307] Step 3: Preparation of intermediate 1-4

[0308] Intermediate 1-3 (400 mg) and tetrahydrofuran (5 mL) were mixed, and triethylsilane (0.96 mL) and trifluoroacetic acid (7.43 mL) were added sequentially. The mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate was added to adjust the pH to neutral, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.13 g of intermediate 1-4.

[0309] MS (ESI, [M+H] + )m / z:534.31.

[0310] 1 H NMR (500MHz, DMSO-d6) δ13.18(s,1H),8.67(s,1H),8.45(s,1H),7.92–7.89(m,3H),7.45(d,J=8.2Hz,2H),5.00(s ,2H),3.85(s,3H),1.99-1.97(m,2H),1.76-1.74(m,2H),1.73–1.70(m,1H),1.04-1.02(m,2H),0.86-0.83(m,2H).

[0311] Step 4: Preparation of compound 1

[0312] Intermediate 1-4 (110 mg), cesium carbonate (336 mg), and N,N-dimethylformamide (5 mL) were mixed, and isopropyl iodide (140 mg) was added. The mixture was stirred at 80°C for 16 hours. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by column chromatography to obtain 0.031 g of compound 1.

[0313] MS (ESI, [M+H] +)m / z:576.37.

[0314] 1 H NMR (500MHz, CDCl3) δ8.66(s,1H),8.15(s,1H),7.62(d,J=8.0Hz,2H),7.48(d,J=8.1Hz,2H),7.40(d,J=1.3Hz,1H),5.11(s,2H),4.53 (h,J=6.7Hz,1H),3.95(s,3H),1.93(q,J=4.3Hz,2H),1.78-1.72(m,3H),1.44(d,J=6.7Hz,6H),1.25–1.22(m,2H),0.90-0.87(m,2H).

[0315] Example 2

[0316] Step 1: Preparation of intermediate 2-1

[0317] Intermediate 1-1 (200 mg), B-2 (309 mg), potassium carbonate (424 mg), and N,N-dimethylformamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to yield 0.36 g of Intermediate 2-1.

[0318] MS (ESI, [M+H] + )m / z:434.25.

[0319] 1 H NMR(500MHz,DMSO-d6)δ8.25(s,1H),7.56(d,J=8.5Hz,2H),7.50(d,J=8.5Hz,2H),6.7 5(s,1H),5.03(s,2H),2.41–2.31(m,3H),1.96(q,J=4.1Hz,2H),1.75(q,J=4.0Hz,2H).

[0320] Step 2: Preparation of compound 2

[0321] Intermediate 2-1 (200 mg), compound C-1 (179 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (32.6 mg), tripotassium phosphate (294 mg), dioxane (10 mL), and water (0.1 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.064 g of compound 2.

[0322] MS (ESI, [M+H]+ )m / z:548.23.

[0323] 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.47(s,1H),7.60–7.47(m,4H),6.75(s,1H),5.06(s,2H),3.84(s,3H),2.3 2(s,3H),1.99(q,J=4.0Hz,2H),1.76(q,J=3.9Hz,2H),1.72-1.69(m,1H),1.04-1.01(m,2H),0.85–0.83(m,2H).

[0324] Example 3

[0325] Step 1: Preparation of intermediate 3-1

[0326] Intermediate 1-1 (100 mg), B-3 (154 mg), potassium carbonate (212 mg), and N,N-dimethylformamide (5 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to yield 0.15 g of compound 3-1.

[0327] MS (ESI, [M+H] + )m / z:434.25.

[0328] 1 H NMR (500MHz, DMSO-d6) δ8.25(s,1H),7.93(s,1H),7.71(d,J=8.3Hz,2H),7.46(d,J=8.3Hz ,2H),5.02(s,2H),3.77(s,3H),1.96(dd,J=8.2,4.1Hz,2H),1.75(dd,J=8.1,3.9Hz,2H).

[0329] Step 2: Preparation of compound 3

[0330] Intermediate 3-1 (150 mg), C-2 (150 mg), tris(dibenzylideneacetone)dipalladium (33 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (31 mg), tripotassium phosphate (220 mg), dioxane (7 mL), and water (2 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.06 g of compound 3.

[0331] MS (ESI, [M+H] +)m / z:519.21.

[0332] 1 H NMR (500MHz, DMSO-d6) δ8.62(d,J=3.4Hz,1H),8.48(s,1H),7.98(d,J=7.6Hz,1H),7.92(s,1H),7.70(d,J=8.0Hz,2H),7.46(d,J=8.0Hz,2H),7 .38–7.27(m,1H),5.08(s,2H),3.76(s,3H),3.63(dt,J=13.2,6.6Hz,1H),1.99(d,J=3.8Hz,2H),1.77(d,J=3.8Hz,2H),1.13(d,J=6.7Hz,6H).

[0333] Example 4

[0334] Step 1: Preparation of compound 4

[0335] Intermediate 2-1 (130 mg), C-2 (99 mg), tris(dibenzylideneacetone)dipalladium (27.4 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (28.5 mg), tripotassium phosphate (191 mg), dioxane (7 mL), and water (0.5 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.02 g of compound 4.

[0336] MS (ESI, [M+H] + )m / z:519.30.

[0337] 1 H NMR (500MHz, DMSO-d6) δ8.62(dd,J=4.7,1.8Hz,1H),8.48(s,1H),7.98(dd,J=7.8,1.9Hz,1H),7.56(d,J=8.3Hz,2H),7.51(d,J=8.3Hz,2H),7.32(dd, J=7.8,4.7Hz,1H),6.74(s,1H),5.10(s,2H),3.62(p,J=6.7Hz,1H),2.32( s, 3H), 1.99 (q, J = 4.1Hz, 2H), 1.78 ( q, J = 4.0Hz, 2H), 1.12 ( d, J = 6.6Hz, 6H).

[0338] Example 5

[0339] Step 1: Preparation of intermediate 5-1

[0340] Intermediate 1-1 (100 mg), B-4 (155 mg), potassium carbonate (141 mg), and N,N-dimethylformamide (2 mL) were mixed and reacted at room temperature overnight. Water and ethyl acetate were added, and the aqueous phase was separated and extracted with ethyl acetate. The mixture was washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to obtain 185 mg of Intermediate 5-1.

[0341] MS (ESI, [M+H] + )m / z:435.27.

[0342] 1 HNMR (500MHz, DMSO-d6): δ8.66(d,J=1.5Hz,1H),8.24(s,1H),8.06(d,J=8.0Hz,1H),7.99(s,1H),7 .88(dd,J1=8.3Hz,J2=2.3Hz,1H),5.04(s,2H),4.07(s,3H),1.96-1.94(m,2H),1.76-1.74(m,2H).

[0343] Step 2: Preparation of compound 5

[0344] Intermediate 5-1 (150 mg), C-3 (113 mg), tris(dibenzylideneacetone)dipalladium (32 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (33 mg), tripotassium phosphate (220 mg), dioxane (5 mL), and water (1 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 1 hour. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 38 mg of compound 5.

[0345] MS (ESI, [M+H] + )m / z:519.33.

[0346] 1 H NMR (500MHz, DMSO-d6): δ8.66(s,1H),8.45(s,1H),8.06(d,J=8.5Hz,1H),7.98(s,1H),7.87(d,J=7.5Hz,1H),7.53(d,J=7.5Hz,1H),7.43-7.40 (m,2H),7.27(t,J=6.5Hz,1H),5.10(s,2H),4.06(s,3H),3.46-3.41(m, 1H), 1.97 (d, J = 3.5Hz, 2H), 1.76 (d, J = 3.5Hz, 2H), 1.08 (d, J = 7.0Hz, 6H).

[0347] Example 6

[0348] Step 1: Preparation of intermediate 6-1

[0349] Intermediate 2-1 (350 mg), Intermediate B-5 (599 mg), potassium carbonate (746 mg), and N,N-dimethylformamide (10 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to obtain 0.46 g of Intermediate 6-1.

[0350] MS (ESI, [M+H] + )m / z:461.26.

[0351] 1 H NMR(500MHz,DMSO-d6)δ8.16(d,J=1.4Hz,1H),8.02(s,1H),7.56(d,J=8.3Hz,2H),7.47(dd,J=8.3,1.9Hz,2H),7 .35(s,1H),5.09(s,2H),4.49–4.43(m,1H),1.89(q,J=4.0Hz,2H),1.70(q,J=3.9Hz,2H),1.39(d,J=6.7Hz,6H).

[0352] Step 2: Preparation of compound 6

[0353] Intermediate 6-1 (150 mg), C-1 (126 mg), tris(dibenzylideneacetone)dipalladium (29.8 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (31.0 mg), tripotassium phosphate (138 mg), dioxane (7 mL), and water (0.7 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated, and the crude product was purified by column chromatography to yield 65 mg of compound 6.

[0354] MS (ESI, [M+H] + )m / z:575.29.

[0355] 1H NMR(500MHz,DMSO-d6)δ8.62(s,1H),8.29(s,1H),8.23–8.12(m,1H),7.59–7.54(m,2H),7.49(d,J=7.9Hz,2H),7.33(s,1H),5.09(s,2H),4.4 3(p,J=6.7Hz,1H),3.77(s,3H),1.92(q,J=4.0Hz,2H),1.72(q,J=3.8Hz,3H),1.39(d,J=6.5Hz,6H),0.99(t,J=3.6Hz,2H),0.85–0.75(m,2H).

[0356] Example 7

[0357] Step 1: Preparation of intermediate 7-1

[0358] Intermediate 1-1 (200 mg), B-6 (480 mg), potassium carbonate (424 mg), and N,N-dimethylformamide (5 mL) were mixed and stirred at 80°C for 1 hour. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to yield 0.42 g of Intermediate 7-1.

[0359] MS (ESI, [M+H] + )m / z:476.26.

[0360] 1 HNMR(500MHz,DMSO-d6)δ1HNMR(500MHz,DMSO-d6)δ8.23(s,1H),8.17(d,J=0.9Hz,1H),7.56–7.51(m,4H),5.7 5(q,J=7.2Hz,1H),4.47(dt,J=13.3,6.7Hz,1H),1.94-1.93(m,5H),1.74–1.70(m,2H),1.40(d,J=6.6Hz,6H).

[0361] Step 2: Preparation of compound 7

[0362] Intermediate 7-1 (370 mg), C-1 (800 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (100 mg), potassium phosphate (400 mg), dioxane (15 mL), and water (3 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.28 g of compound 7.

[0363] MS (ESI, [M+H]+ )m / z:590.15.

[0364] 1 H NMR (500MHz, DMSO-d6) δ8.66(s,1H),8.45(s,1H),8.17(s,1H),7.54(q,J=8.5Hz,4H),5.80(t,J=7.2Hz,1H),4.44(dt,J=13.3,6.6Hz, 1H), 3.84 (s, 3H), 1.96 (dd, J = 14.2, 5.7Hz, 5H), 1.81–1.64 (m, 3H), 1.39 (d, J = 6.6Hz, 6H), 1.25 (t, J = 5.8Hz, 2H), 1.02 (d, J = 4.3Hz, 2H).

[0365] Example 8

[0366] Step 1: Preparation of intermediate 8-1

[0367] Intermediate 1-1 (100 mg), B-7 (171 mg), potassium carbonate (141 mg), and N,N-dimethylformamide (2 mL) were mixed and reacted at room temperature for 2 hours. Water and ethyl acetate were added, and the aqueous phase was separated and extracted with ethyl acetate. The mixture was washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to obtain 155 mg of Intermediate 8-1.

[0368] MS (ESI, [M+H] + )m / z:463.25.

[0369] 1 HNMR(500MHz,DMSO-d6)δ8.85(d,J=2.0Hz,1H),8.24-8.23(m,2H),8.03(d,J=8.5Hz,1H),7.90(dd,J1=8.3Hz ,J2=2.3Hz,1H),5.75-5.69(m,1H),5.05(s,2H),1.96-1.94(m,2H),1.76-1.74(m,2H),1.44(d,J=6.5Hz,6H).

[0370] Step 2: Preparation of compound 8

[0371] Intermediate 8-1 (150 mg), (2-isopropylpyridin-3-yl)boronic acid (107 mg), tris(dibenzylideneacetone)dipalladium (30 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (31 mg), tripotassium phosphate (206 mg), dioxane (5 mL), and water (1 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 73 mg of compound 8.

[0372] MS (ESI, [M+H] + )m / z:548.25.

[0373] 1 H NMR (500MHz, DMSO-d6): δ8.67(d,J=1.5Hz,1H),8.62(dd,J1=4.8Hz,J2=1.8Hz,1H),8.49(s,1 H),8.23(s,1H),8.04(d,J=8.5Hz,1H),7.98(dd,J1=8.3Hz,J2=1.8Hz,1H),7.90(dd,J1=8.3Hz ,J2=2.3Hz,1H),7.33(dd,J1=7.5Hz,J2=2.3Hz,1H),5.75-5.70(m,1H),5.12(s,2H),3.63-3. 57(m,1H),2.00-1.98(m,2H),1.80-1.77(m,2H),1.44(d,J=6.5Hz,6H),1.10(d,J=7.0Hz,6H).

[0374] Example 9

[0375] Step 1: Preparation of intermediate 9-1

[0376] Intermediate 1-1 (120 mg), B-8 (225 mg), potassium carbonate (265 mg), and N,N-dimethylformamide (3 mL) were mixed and stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to yield 0.22 g of Intermediate 9-1.

[0377] MS (ESI, [M+H] + )m / z:480.26.

[0378] 1H NMR (500MHz, DMSO-d6) δ8.25(s,1H),8.24(s,1H),7.54(t,J=7.7Hz,1H),7.38(d,J=10.7Hz,1H),7.29(d,J=9.4Hz,1H),5 .05(s,2H),4.15(dt,J=13.2,6.5Hz,1H),1.96(dd,J=8.2,4.1Hz,2H),1.76(dd,J=8.1,3.9Hz,2H),1.35(d,J=6.6Hz,6H).

[0379] Step 2: Preparation of compound 9

[0380] Intermediate 9-1 (180 mg), C-1 (500 mg), 4-triphenylphosphine palladium (50 mg), cesium carbonate (320 mg), dioxane (7 mL), and water (2 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.11 g of compound 9.

[0381] MS (ESI, [M+H] + )m / z:594.22.

[0382] 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.47(s,1H),8.23(s,1H),7.52(t,J=7.7Hz,1H ),7.39(d,J=10.3Hz,1H),7.30(d,J=7.9Hz,1H),5.07(s,2H),4.11(dt,J=13.2,6.5 Hz,1H),3.83(s,3H),1.99(dd,J=8.0,4.0Hz,2H),1.77(dd,J=7.9,3.8Hz,2H),1.72 (td,J=8.0,4.1Hz,1H),1.34(d,J=6.6Hz,6H),1.10–0.96(m,2H),0.86–0.80(m,2H).

[0383] Example 10

[0384] Step 1: Preparation of intermediate 10-1

[0385] Intermediate 1-1 (200 mg), B-5 ​​(371 mg), potassium carbonate (47.7 mg), dioxane (424 mg), and N,N-dimethylacetamide (10 mL) were mixed and heated to 80°C under a nitrogen atmosphere with stirring for 1 hour. The mixture was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 371 mg of Intermediate 10-1.

[0386] MS (ESI, [M+H] + )m / z:462.27.

[0387] 1 H NMR (500MHz, DMSO-d6) δ8.24(s,1H),8.16(d,J=0.8Hz,1H),7.55(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),5.02(s ,2H),4.46(hept,J=6.5Hz,1H),1.96(dd,J=8.2,4.1Hz,2H),1.75(dd,J=8.1,3.9Hz,2H),1.39(d,J=6.6Hz,6H).

[0388] Step 2: Preparation of compound 10

[0389] Intermediate 10-1 (100 mg), C-4 (108 mg), potassium phosphate (69 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (15 mg), dioxane (10 mL), and water (0.5 mL) were mixed and heated to 100°C under a nitrogen atmosphere with stirring for 4 hours. The mixture was extracted with ethyl acetate, and the organic phase was washed sequentially with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 25 mg of compound 10.

[0390] MS (ESI, [M+H] + )m / z:550.23.

[0391] 1H NMR (500MHz, DMSO-d6) δ8.46(s,1H),8.15(s,1H),7.55(d,J=8.2Hz,2H),7.46(d,J=8.2Hz,2H),7.36(s,1H),5.34–5.24(m,1H),5.09(s,2 H), 4.47–4.38 (m, 1H), 2.12 (s, 3H), 1.98 (dd, J = 8.0, 4.0Hz, 2H), 1.78 (dd, J = 7.9, 3.8Hz, 2H), 1.38 (d, J = 6.6Hz, 6H), 1.29 (d, J = 6.6Hz, 6H).

[0392] Example 11

[0393] Step 1: Preparation of intermediate 11-1

[0394] Intermediate 3-1 (250 mg), B-5 ​​(400 mg), potassium carbonate (600 mg), and N,N-dimethylformamide (6 mL) were mixed and stirred at room temperature for 2 hours. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to yield 0.44 g of Intermediate 11-1.

[0395] MS (ESI, [M+H] + )m / z:464.18.

[0396] 1 H NMR (500MHz, DMSO-d6) δ8.53(s,1H),8.17(s,1H),7.56(d,J=8.2Hz,2H),7.43(d,J=8.3 Hz, 2H), 4.95 (s, 2H), 4.47 (dt, J = 13.3, 6.6Hz, 1H), 1.43 (s, 6H), 1.40 (d, J = 6.6Hz, 6H).

[0397] Step 2: Preparation of compound 11

[0398] Intermediate 11-1 (220 mg), C-1 (200 mg), tetrakis(triphenylphosphine)palladium (50 mg), cesium carbonate (420 mg), dioxane (5 mL), and water (1 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring for 2 hours. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 0.06 g of compound 11.

[0399] MS (ESI, [M+H] + )m / z:578.31.

[0400] 1H NMR (500MHz, DMSO-d6) δ8.75(s,1H),8.65(s,1H),8.17(s,1H),7.53(d,J=8.2Hz,2H),7.43(d,J=8.2Hz,2H),4.98(s,2H),4.44(dt,J= 13.3, 6.6Hz, 1H), 3.84 (s, 3H), 1.77–1.68 (m, 1H), 1.48 (s, 6H), 1.39 (d, J = 6.6Hz, 6H), 1.04–0.98 (m, 2H), 0.81 (dt, J = 11.5, 3.3Hz, 2H).

[0401] Example 12

[0402] Step 1: Preparation of intermediate 12-2

[0403] Compound 12-1 (50 g), (E)-1-ethoxyvinyl-2-boronic acid pinacol ester (36.4 g), lithium hydroxide monohydrate (23.10 g), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (13.4 g), and N,N-dimethylformamide (500 mL) were mixed. Under nitrogen, the mixture was heated to 80°C for 2 hours. The mixture was filtered through celite, and the filtrate was diluted with water and ethyl acetate. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 32 g of intermediate 12-2.

[0404] MS: (ESI, [M+H] + )m / z:217.27.

[0405] 1 H NMR (500MHz, DMSO-d6) δ7.78(s,1H),7.04(d,J=12.7Hz,1H),6.36(s,2H),5.78(d,J=12.7Hz,1H),3.93(q,J=7.0Hz,2H),1.26(t,J=7.0Hz,3H).

[0406] Step 2: Preparation of intermediate 12-3

[0407] Intermediate 12-2 (2.5 g) was dissolved in methanol (50 mL), and hydrochloric acid (9.27 mL) was added dropwise. The reaction was stirred at 70°C for 2 hours. The mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate solution was added dropwise under an ice bath to adjust the pH to neutral. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated to obtain 1.7 g of intermediate 12-3.

[0408] MS: (ESI, [M+H] + )m / z:171.04.

[0409] 1 H NMR (500MHz, DMSO-d6) δ12.38(s,1H),8.51(d,J=1.5Hz,1H),7.60(d,J=3.2Hz,1H),6.73(t,J=3.3Hz,1H).

[0410] Step 3: Preparation of intermediate 12-4

[0411] Intermediate 12-3 (1.0 g) was dissolved in tert-butanol (50 mL), and pyridinium tribromide (4.69 g) was added portionwise. The mixture was stirred in an oil bath at 40°C overnight. The solvent was evaporated under reduced pressure, and the mixture was diluted with water and ethyl acetate. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated to obtain 1.6 g of intermediate 12-4.

[0412] MS: (ESI, [MH] - )m / z:340.75.

[0413] 1 H NMR(500MHz,DMSO-d6)δ12.68(s,1H),8.49(s,1H).

[0414] Step 4: Preparation of intermediate 12-5

[0415] Intermediate 12-4 (1.5 g) was dissolved in tetrahydrofuran (10 mL), and zinc powder (1.4 g) was added. Glacial acetic acid (5 mL) was added dropwise under ice-cooling. The mixture was stirred for 30 minutes and then filtered through celite. The filtrate was diluted with water and ethyl acetate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 540 mg of Intermediate 12-5.

[0416] MS: (ESI, [M+H] + )m / z:187.1

[0417] 1 H NMR (500MHz, DMSO-d6) δ11.62(s,1H),7.96(d,J=1.0Hz,1H),3.67(d,J=1.1Hz,2H).

[0418] Step 5: Preparation of intermediate 12-6

[0419] Intermediate 12-5 (0.5 g) was dissolved in tetrahydrofuran (5 mL). Under nitrogen, lithium diisopropylamide (2 M in tetrahydrofuran, 8 mL) was added dropwise at -20°C. After stirring for 1 hour, a solution of vinyl sulfate (1.0 g) in tetrahydrofuran (5 mL) was added dropwise. The mixture was transferred to room temperature and stirred overnight. The reaction was quenched by adding saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Filtered, concentrated, and purified by silica gel column chromatography to yield 35 mg of Intermediate 12-6.

[0420] MS: (ESI, [M+H] + )m / z:213.13

[0421] 1 H NMR (500MHz, DMSO-d6) δ11.83(s,1H),7.84(s,1H),1.82(q,J=3.9Hz,2H),1.61(q,J=3.9Hz,2H).

[0422] Step 6: Preparation of intermediate 12-7

[0423] Intermediate 12-6 (40 mg), B-5 ​​(85 mg), potassium carbonate (78 mg), and N,N-dimethylformamide (6 mL) were mixed and stirred at room temperature overnight. The mixture was extracted with ethyl acetate, washed sequentially with water and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtered and concentrated, the crude product was purified by column chromatography to yield 64 mg of Intermediate 12-7.

[0424] MS (ESI, [M+H] + )m / z:479.24.

[0425] 1 H NMR (500MHz, DMSO-d6) δ8.17(d,J=1.3Hz,1H),7.96(s,1H),7.57(d,J=8.3Hz,2H),7.41(d,J=8.0Hz,2H) ,5.16(s,2H),4.46(p,J=6.7Hz,1H),1.98(q,J=4.0Hz,2H),1.78(q,J=4.0Hz,2H),1.40(d,J=6.6Hz,6H).

[0426] Step 7: Preparation of compound 12

[0427] Intermediate 12-7 (55 mg), C-1 (67 mg), tris(dibenzylideneacetone)dipalladium (15 mg), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (15 mg), cesium carbonate (112 mg), dioxane (5 mL), and water (1 mL) were mixed and heated to 90°C under a nitrogen atmosphere with stirring overnight. The mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain 20 mg of compound 12.

[0428] MS (ESI, [M+H] + )m / z:593.29.

[0429] 1 H NMR (500MHz, CDCl3) δ8.64 (s, 1H), 7.98 (d, J = 1.1Hz, 1H), 7.52-7.48 (m, 4H), 7.4 0(d,J=1.3Hz,1H),5.28-5.14(m,2H),4.53(hept,J=6.7Hz,1H),3.90(s,3H),1. 98-1.96(m,2H),1.83-1.79(m,2H),1.70-1.65(m,1H),1.44(dd,J=6.7,1.5Hz,6 H),1.28-1.23(m,1H),1.18-1.13(m,1H),0.96-0.91(m,1H),0.86-0.80(m,1H).

[0430] Test Example 1: In vitro cell proliferation inhibitory activity

[0431] 1.1 MDA-MB-436 cell proliferation inhibitory activity assay

[0432] Take MDA-MB-436 cells that are in good growth state, collect them into centrifuge tubes, and adjust the cell density to 10 4 Cells were inoculated into 96-well plates (100 μL / well) at 400 μL / mL and cultured overnight in a cell culture incubator. Compounds were added using a nanoliter pipette to a final concentration of 1000 nM to 0.457 nM in duplicate wells, with a control set. After 7 days of culture in a cell culture incubator, the detection reagent CCK-8 (manufacturer: Tongren Chemical, 10 μL / well) was added. After incubation in a cell culture incubator for 2 hours, the absorbance was measured at 450 nm using an Envision microplate reader. Four-parameter analysis was performed, and a dose-effect curve was fitted to calculate the IC. 50 .

[0433] The experimental results are shown in Table 1, where A represents: 0nM<IC 50 ≤50nM; B represents: 50nM<IC 50 ≤100nM; C represents: 100nM<IC50 ≤1000nM; D represents: 1000nM<IC 50 .

[0434] Table 1 MDA-MB-436 cell proliferation inhibitory activity

[0435] Test Example 2: In vitro enzymatic inhibition activity

[0436] 2.1 USP1 / UAF1 enzyme inhibitory activity assay

[0437] USP1 / UAF1 protein solution (concentration 10nM) was added to the test wells at 10μl per well. Different compounds dissolved in DMSO were added to the test wells using a nanoliter pipette to make the final concentration of the compound range from 1000nM to 0.24nM. Two replicate wells were used, and a control was also set up. After the above system was incubated at room temperature for 30 minutes, Ub-Rhodamine (concentration 300nM) was added to the test wells at 10μl per well. After reacting at room temperature for 90 minutes, the plate was read on a PerkinElmer Envision multi-function microplate reader (Ex.490nm / Em.520nm), and the IC was calculated using a four-parameter fit. 50 .

[0438] The experimental results are shown in Table 2, where A represents: 0nM<IC 50 ≤50nM; B represents: 50nM<IC 50 ≤100nM; C represents: 100nM<IC 50 ≤1000nM; D represents: 1000nM<IC 50 .

[0439] Table 2 USP1 / UAF1 enzymatic inhibitory activity

[0440] The compounds disclosed herein have good USP1 / UAF1 enzyme inhibitory activity.

[0441] Test Example 3: In vitro liver microsome metabolic stability

[0442] The liver microsome incubation sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml), test compound and NADPH. + The MgCl2 solution was incubated at 37°C and 300 rpm for 1 hour. The 0-hour sample was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.5 mg / ml), and the test compound. The sample was added to an acetonitrile solution containing an internal standard for protein precipitation, and the supernatant was prepared and diluted for LC / MS / MS analysis.

[0443] The experimental results are shown in Table 3.

[0444] Table 3 In vitro metabolic stability of liver microsomes

[0445] The disclosed compounds have good in vitro liver microsomal stability.

[0446] Test Example 4: Determination of in vivo pharmacokinetic properties

[0447] ICR mice weighing 18-22 g were acclimated for 3-5 days and then randomly divided into groups of 9 mice each. The test compound solution was orally administered at a dose of 10 mg / kg.

[0448] Blood was collected from the eye socket at 15 min, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h to prepare the plasma samples to be tested.

[0449] 30 μL of plasma sample to be tested and standard curve sample were taken, and acetonitrile solution containing internal standard was added to obtain protein precipitation to obtain supernatant, which was diluted and used for LC / MS / MS determination.

[0450] The non-compartmental model was used to fit the pharmacokinetic parameters.

[0451] The compounds disclosed herein have good pharmacokinetic properties in vivo.

Claims

1. A compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, in, X 1 and X 2 are independently selected from C(R 1 ) or N; X 3 、X 4 、X 5 and X 6 are independently selected from C(R 5 ) or N; Each R 1 and R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents; or R on two adjacent carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C 5-7 Cycloalkenyl, 5-7 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; L is selected from -(C(R 3 R 4 )) m -、-O-、-S-、-N(R 9 )-, -S(O)- or -S(O)2-; R 2 Selected from C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group or C 5-7 Cycloalkenyl, the C 3-12 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclic group and C 5-7 Cycloalkenyl is optionally independently substituted with one or more R 2a replace; Each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents; or R 3 and R 4 Together with the carbon atom to which they are attached, they form a carbonyl group; or R 3 and R 4 and the carbon atoms to which they are commonly attached together form a C optionally substituted with one or more substituents 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; or R on two adjacent carbon atoms 3 and R 3 、R 3 and R 4 、R 4 and R 3 、R 4 and R 4 Together with the carbon atom to which it is attached, it forms a C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl; R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally independently substituted by one or more R 6a replace; R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents; or R 7 and R 8 and the carbon atoms to which they are commonly attached together form a C optionally substituted with one or more substituents 3-8 Cycloalkyl, 3-8 membered heterocyclic group or C 3-8 cycloalkenyl; R 9 Selected from hydrogen or C 1-12 Alkyl, the C 1-12 The alkyl group is optionally substituted with one or more substituents; Each R 2a and R 6a are independently selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Alkylthio, -COC 1-12 Alkyl, -OC(O)C 1-12 Alkyl, -C(O)OC 1-12 Alkyl, -OC(O)OC 1-12 Alkyl, -SO2C 1-12 Alkyl, -NHSO2C 1-12 Alkyl, -N(C 1-12 Alkyl)SO2C 1-12 Alkyl, -SO2NH2, -SO2NHC 1-12 Alkyl, -SO2N(C 1-12 Alkyl)2, -CONH2, -CONHC 1-12 Alkyl, -CON(C 1-12 Alkyl)2, -NHCOC 1-12 Alkyl, -N(C 1-12 Alkyl)COC 1-12 Alkyl, C 3-12 Cycloalkyl, C 3-12 Cycloalkenyl, C 6-10 Aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl are optionally substituted independently with one or more substituents; m is selected from 1, 2 or 3.

2. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 At least one of them is selected from C(R 1 ); preferably, X 1 and X 2 One of the C(R 1 ), and the other is selected from N.

3. The compound of formula (I) according to claim 2, its isomer or pharmaceutically acceptable salt thereof, wherein: Each R 1 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently by one or more substituents; preferably, each R 1 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently by one or more substituents; further preferably, each R 1 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

4. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: X 3 、X 4 、X 5 and X 6 At least 2 of them are selected from C(R 5 ); preferably, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ); or preferably, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ).

5. The compound of formula (I) according to claim 4, its isomer or pharmaceutically acceptable salt thereof, wherein: Each R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently by one or more substituents; preferably, each R 5 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently by one or more substituents; further preferably, each R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents; or X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), and X 3 and X 4 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C 5-6 Cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; preferably, X 3 Selected from C(R 5 ), X 4 Selected from C(R 5 ), and X 3 and X 4 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2. 5-6 Cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; or X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), and X 5 and X 6 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C 5-6 Cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl; preferably, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), and X 5 and X 6 R on two carbon atoms 5 Together with the carbon atom to which it is attached, it forms a C optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2. 5-6 cycloalkenyl, 5-6 membered heterocycloalkenyl, phenyl or 5-6 membered heteroaryl.

6. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -N(R 9 )-; preferably, L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -NH-.

7. The compound of formula (I) according to claim 6, its isomer or pharmaceutically acceptable salt thereof, wherein: Each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently by one or more substituents; preferably, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently by one or more substituents; further preferably, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents; Or, R 3 and R 4 and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with one or more substituents; preferably, R 3 and R 4 and the carbon atom to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl group which is optionally substituted with one or more substituents.

8. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: R 2 Selected from C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group or C 5-6 Cycloalkenyl, the C 3-8 Cycloalkyl, phenyl, naphthyl, 5-10 membered heteroaryl, 3-8 membered heterocyclic group and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a Substituted; preferably, R 2 Selected from C 3-6 Cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group or C 5-6 Cycloalkenyl, the C 3-6 Cycloalkyl, phenyl, naphthyl, 5-9 membered heteroaryl, 3-6 membered heterocyclic group and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a Substituted; further preferably, R 2 Selected from C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group or C 5-6 Cycloalkenyl, the C 5-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group and C 5-6 Cycloalkenyl is optionally independently substituted with one or more R 2a replace.

9. The compound of formula (I) according to claim 8, its isomer or pharmaceutically acceptable salt thereof, wherein: R 2a Selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently by one or more substituents; preferably, R 2a Selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents; further preferably, R 2a Selected from halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

10. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally independently substituted by one or more R 6a Substituted; preferably, R 6 Selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally independently substituted by one or more R 6a Substituted; further preferably, R 6 Selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally independently substituted by one or more R 6a replace.

11. The compound of formula (I) according to claim 10, its isomer or pharmaceutically acceptable salt thereof, wherein: R 6a Selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently by one or more substituents; preferably, R 6a Selected from halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents; further preferably, R 6a Selected from halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

12. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl or 3-8 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -COC 1-6 Alkyl, -OC(O)C 1-6 Alkyl, -C(O)OC 1-6 Alkyl, -OC(O)OC 1-6 Alkyl, -SO2C 1-6 Alkyl, -NHSO2C 1-6 Alkyl, -N(C 1-6 Alkyl)SO2C 1-6 Alkyl, -SO2NH2, -SO2NHC 1-6 Alkyl, -SO2N(C 1-6 Alkyl)2, -CONH2, -CONHC 1-6 Alkyl, -CON(C 1-6 Alkyl)2, -NHCOC 1-6 Alkyl, -N(C 1-6 Alkyl)COC 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkenyl, phenyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl are optionally substituted independently by one or more substituents; preferably, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -SH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -COC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl, -OC(O)OC 1-3 Alkyl, -SO2C 1-3 Alkyl, -NHSO2C 1-3 Alkyl, -N(C 1-3 Alkyl)SO2C 1-3 Alkyl, -SO2NH2, -SO2NHC 1-3 Alkyl, -SO2N(C 1-3 Alkyl)2, -CONH2, -CONHC 1-3 Alkyl, -CON(C 1-3 Alkyl)2, -NHCOC 1-3 Alkyl, -N(C 1-3 Alkyl)COC 1-3 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclic group are optionally substituted independently by one or more substituents; further preferably, R 7 and R 8 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, -SO2NH2, -CONH2, C 3-6 Cycloalkyl, C 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents; or R 7 and R 8 and the carbon atoms to which they are commonly attached together form a C optionally substituted with one or more substituents 3-6 Cycloalkyl, 3-6 membered heterocyclic group or C 3-6 Cycloalkenyl; preferably, R 7 and R 8 and the carbon atoms to which they are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl; further preferably, R 7 and R 8 and the carbon atoms to which they are commonly attached together form a cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl or morpholinyl group which is optionally substituted with one or more substituents.

13. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound of formula (I-1), in, X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、R 2 、R 3 、R 4 and R 6 The compound represented by formula (I) as claimed in claim 1 is defined as follows; Or the compound represented by formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound represented by formula (I-2), in, X 4 selected from CH or N; X 1 、X 2 、R 2 , L and R 6 The compound represented by formula (I) as claimed in claim 1 is defined as follows; Or the compound represented by formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound represented by formula (I-3), in, X 4 selected from CH or N; X 1 、R 2 , L and R 6 The compound represented by formula (I) as claimed in claim 1 is defined as follows; Or the compound represented by formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound represented by formula (I-4), in, X 4 selected from CH or N; X 1 、R 2 、R 3 、R 4 and R 6 The compound represented by formula (I) as claimed in claim 1 is defined as follows; R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as a (R) or (S) single enantiomer or enriched in one enantiomer; Or the compound represented by formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound represented by formula (I-5), in, X 4 selected from CH or N; Y 1 、Y 2 and Y 3 are independently selected from CH or N; X 1 、R 3 、R 4 、R 6 and R 2a The compound represented by formula (I) as claimed in claim 1 is defined as follows; R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as a (R) or (S) single enantiomer or enriched in one enantiomer; Or the compound represented by formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound represented by formula (I-6), in, X 4 selected from CH or N; Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5); X 1 、R 3 、R 4 、R 2a and R 6a The compound represented by formula (I) as claimed in claim 1 is defined as follows; R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as a (R) or (S) single enantiomer or enriched in one enantiomer; Or the compound represented by formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, selected from the compound represented by formula (I-7), in, X 4 selected from CH or N; Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5); X 1 、R 3 、R 4 、R 2a and R 6a The compound represented by formula (I) as claimed in claim 1 is defined as follows; R 3 、R 4 The attached carbon atom may be a chiral carbon atom, existing as either a (R) or (S) single enantiomer or enriched in one enantiomer.

14. A compound of the formula:

15. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound according to any one of claims 1 to 14, its isomer or a pharmaceutically acceptable salt thereof.

16. Use of the compound according to any one of claims 1 to 14, its isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing diseases associated with inhibition of ubiquitin-specific protease 1 (USP1).

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