Carbonyl fused heterocyclic derivatives as ubiquitin-specific protease inhibitors

Abstract

The invention provides a carbonyl fused heterocyclic derivative used as a ubiquitin-specific protease inhibitor, and particularly relates to a compound as shown in a formula (I), and an isomer or pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Carbonyl-fused heterocyclic derivatives as ubiquitin-specific protease inhibitors

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the priority and benefits of Chinese Patent Application No. 202211144812.4 filed with the State Intellectual Property Office of China on September 20, 2022, Chinese Patent Application No. 202310690391.3 filed with the State Intellectual Property Office of China on June 9, 2023, and Chinese Patent Application No. 202311161323.4 filed with the State Intellectual Property Office of China on September 8, 2023, and the contents disclosed in said applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure belongs to the field of medicinal chemistry and relates to carbonyl-fused heterocyclic derivatives used 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] X1 and X 2 are independently selected from C(R 1 ) or N;

[0010] X 3 Selected from C(R 1 )2、C(=Z)、N(R 7 ), S or O;

[0011] X 4 、X 5 、X 6 and X 7 are independently selected from C(R 5 ) or N;

[0012] Each R 1 and R 5 are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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;

[0013] Z is selected from O, S or N (R 8 );

[0014] or X 2 and X 3 are linked to each other to form a 5-7 membered ring which is optionally substituted with one or more substituents;

[0015] 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;

[0016] L is selected from -(C(R 3 R 4 )) m -、-O-、-S-、-N(R 9 )-, -S(O)- or -S(O)2-;

[0017] R 2 Selected from C 3-12 Cycloalkyl, C 6-10Aryl, 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;

[0018] Each R 3 and R 4 are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 1-12Alkylthio, -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;

[0019] 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;

[0020] 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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;

[0021] Each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 3-12Cycloalkyl or 3-12 membered heterocyclic group, said -NH2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 3-12 The cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents;

[0022] Each R 2a and R 6a are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 1-12 Alkylthio, -COC1-12 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;

[0023] m is selected from 1, 2 or 3;

[0024] The condition is that X 1 When N, X 3 Not for NH.

[0025] In some embodiments of the present disclosure, X 1 and X 2 At least one of them is selected from C(R 1 ).

[0026] In some embodiments of the present disclosure, X 3 Selected from C(=O), N(R 7 ), S or O.

[0027] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from C(=O), N(R 7 ), S or O.

[0028] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from N(R 7 ).

[0029] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from S.

[0030] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from O.

[0031] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from C(R 1 )2.

[0032] In some embodiments of the present disclosure, X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from C(=O), N(R 7 ), S or O.

[0033] In some embodiments of the present disclosure, X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from N(R 7 ).

[0034] In some embodiments of the present disclosure, X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from S.

[0035] In some embodiments of the present disclosure, X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from O.

[0036] In some embodiments of the present disclosure, X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from C(R 1 )2.

[0037] In some embodiments of the present disclosure, X 1 Selected from C(R 1 ), X2 Selected from C(R 1 );X 3 Selected from C(=O), N(R 7 ), S or O.

[0038] In some embodiments of the present disclosure, X 1 Selected from C(R 1 ), X 2 Selected from C(R 1 );X 3 Selected from C(R 1 )2.

[0039] In some embodiments of the present disclosure, X 1 Selected from C(R 1 ), X 2 Selected from C(R 1 );X 3 Selected from N(R 7 ).

[0040] In some embodiments of the present disclosure, X 1 Selected from C(R 1 ), X 2 Selected from C(R 1 );X 3 Selected from S.

[0041] In some embodiments of the present disclosure, X 1 Selected from C(R 1 ), X 2 Selected from C(R 1 );X 3 Selected from O.

[0042] In other embodiments of the present disclosure, the "one or more" described in the present disclosure is selected from 1, 2, 3, 4, 5 or 6.

[0043] In other embodiments of the present disclosure, the "one or more" described in the present disclosure is selected from 1, 2 or 3.

[0044] 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 1-12 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)C1-12 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.

[0045] 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 1-6 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 and 3-8 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0046] 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, 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)OC1-3 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.

[0047] 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 3-6 Cycloalkenyl, phenyl, 5-6 membered heteroaryl and 3-6 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0048] In other embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -NH2, -NHC 1-3Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Deuterated 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 1-3 Deuterated alkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, C 1-3 Alkoxy, C 1-3 Deuterated 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.

[0049] In other embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -NH2, -NHC 1-3 Alkyl, -N(C 1-3 Alkyl)2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 Deuterated alkoxy, the C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 1-3 Alkoxy or C 1-3 Deuterated alkoxy groups are optionally substituted independently with one or more substituents.

[0050] In other embodiments of the present disclosure, each R 1 and R 5 are independently selected from hydrogen, deuterium, halogen, C 1-3 Alkyl or C 1-3 Deuterated alkyl, the C 1-3 Alkyl or C 1-3 Deuterated alkyl groups are optionally substituted independently with one or more substituents.

[0051] 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.

[0052] 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.

[0053] In other embodiments of the present disclosure, each R 1 and R 5 Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2.

[0054] In some embodiments of the present disclosure, each R 1 and R 5 Optionally independently substituted with one or more groups selected from halogen, OH, CN or NH2.

[0055] In some embodiments of the present disclosure, each R 1 and R 5 Optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0056] 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.

[0057] 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.

[0058] In some embodiments of the present disclosure, each R 1 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, ethyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0059] In some embodiments of the present disclosure, each R 1 are independently selected from hydrogen, -F, methyl, ethyl or CN.

[0060] In other embodiments of the present disclosure, each R 1 Each is independently selected from hydrogen, -F, methyl, -CD3, ethyl, -CD2CD3 or CN.

[0061] In some embodiments of the present disclosure, each R 1 are each independently selected from hydrogen or -F.

[0062] In some embodiments of the present disclosure, each R 1 are each independently selected from -F.

[0063] In some embodiments of the present disclosure, Z is selected from O or S.

[0064] In some embodiments of the present disclosure, Z is selected from O.

[0065] In some embodiments of the present disclosure, X 2 and X 3 are connected to each other to form a 5-7 membered ring optionally substituted by one or more substituents, wherein the 5-7 membered ring is selected from 5-7 membered heterocycloalkenyl, C 5-7 cycloalkenyl, phenyl or 5-6 membered heteroaryl.

[0066] In some embodiments of the present disclosure, X 2 and X 3 are connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein X 3 The ring atoms at the indicated positions are N atoms.

[0067] In some embodiments of the present disclosure, X 2 and X 3 are connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein X 2 The ring atoms in the indicated positions are C atoms.

[0068] In some embodiments of the present disclosure, X 2 and X 3 are connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein X 2 The ring atoms at the indicated positions are C atoms, X 3 The ring atoms at the indicated positions are N atoms.

[0069] In some embodiments of the present disclosure, X 2 and X 3 are connected to each other to form a 5-7 membered ring optionally substituted by one or more substituents, wherein the 5-7 membered ring is selected from: 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, phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.

[0070] In some embodiments of the present disclosure, X 2 and X 3They are connected to each other to form a 5-7 membered ring which is optionally substituted by one or more substituents, wherein the 5-7 membered ring is selected from: 1,2,3,4-tetrahydro-pyridinyl, cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl, 1,2,3,6-tetrahydropyridinyl, phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl.

[0071] In some embodiments of the present disclosure, X 2 and X 3 Connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein the substituents are 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.

[0072] In some embodiments of the present disclosure, X 2 and X 3 They are connected to each other to form a 5-7 membered ring which is optionally substituted by 1, 2 or 3 substituents selected from halogen, OH, CN or NH2.

[0073] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3Selected from N(R 7 ), and X 2 R on 1 and X 3 R on 7 Together with the carbon atom and the nitrogen atom to which it is attached, it forms a 5-7 membered heterocycloalkenyl or 5-membered heteroaryl group which is optionally substituted by one or more substituents.

[0074] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2, and X 2 R on 1 and X 3 An R on 1 and the carbon atom to which it is attached together form a C optionally substituted with one or more substituents 5-7 cycloalkenyl or 5-7 membered heterocycloalkenyl.

[0075] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2, and X 2 R on 1 and X 3 The two R's on 1 Together with the carbon atom to which it is attached, it forms a phenyl group or a 5-6 membered heteroaryl group which is optionally substituted with one or more substituents.

[0076] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from N(R 7 ), and X 2 R on 1 and X 3 R on 7 Together with the carbon atom and the nitrogen atom to which it is attached, it forms a 5-6 membered heterocycloalkenyl or 5 membered heteroaryl group which is optionally substituted by one or more substituents.

[0077] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ),X 3 Selected from N(R 7 ), and X 2 R on 1 and X 3 R on 7and the substituent formed by the carbon atom and nitrogen atom to which it is attached are optionally substituted by one or more of the following substituents: 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.

[0078] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from N(R 7 ), and X 2 R on 1 and X 3 R on 7 Together with the carbon atom and the nitrogen atom to which it is attached, it forms a 5-6 membered heterocycloalkenyl or 5 membered heteroaryl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0079] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ),X 3 Selected from N(R 7 ), and X 2 R on 1 and X 3 R on7 and the carbon atom and the nitrogen atom to which it is attached together form a 2,3-dihydro-pyrrolyl, 1,2,3,4-tetrahydro-pyridyl, 1,2-dihydro-pyridyl, 1,4-dihydro-pyridyl, pyrrolyl, pyrazolyl or imidazolyl group optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0080] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ),X 3 Selected from N(R 7 ), and X 2 R on 1 and X 3 R on 7 Together with the carbon atom and the nitrogen atom to which it is attached, it forms a 1,2,3,4-tetrahydro-pyridyl group optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0081] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2, and X 2 R on 1 and X 3 An R on 1 and the carbon atom to which it is attached together form a C optionally substituted with one or more substituents 5-6 Cycloalkenyl or 5-6 membered heterocycloalkenyl.

[0082] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2, and X 2 R on 1 and X 3 An R on 1 The substituent formed together with the carbon atom to which it is attached is optionally substituted with one or more of the following substituents: 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 1-12Alkyl, -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.

[0083] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2,X 2 R on 1 and X 3 An R on 1 and the carbon atoms to which they are attached together form a C optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2 5-6 Cycloalkenyl or 5-6 membered heterocycloalkenyl.

[0084] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2,X 2 R on 1 and X 3 An R on 1 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 or 3,6-dihydro-2H-thiopyranyl which is optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0085] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2,X 2 R on 1 and X 3 An R on 1 Together with the carbon atom to which it is attached, it forms a cyclopentenyl, cyclohexenyl, 2,5-dihydro-pyrrolyl or 1,2,3,6-tetrahydropyridinyl group which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0086] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2,X 2 R on 1 and X 3 The two R's on 1 and the carbon atom to which it is attached together form a phenyl group or a 5-6 membered heteroaryl group optionally substituted by one or more substituents; the substituents are selected from the following: 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 6-10aryl, 5-10 membered heteroaryl or 3-12 membered heterocyclic group.

[0087] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2,X 2 R on 1 and X 3 The two R's on 1 and the carbon atom to which it is attached form phenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl, which are optionally substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0088] In some embodiments of the present disclosure, X 2 Selected from C(R 1 ), X 3 Selected from C(R 1 )2,X 2 R on 1 and X 3 The two R's on 1 Together with the carbon atom to which it is attached, it forms phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl or pyrimidinyl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0089] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from NH.

[0090] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from N(NH2).

[0091] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from N(CH3).

[0092] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from N(CH2CH3).

[0093] In some embodiments of the present disclosure, X 1 Selected from C(F), X2 Selected from CH, X 3 Selected from

[0094] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from N(CD3).

[0095] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from N(CD2CD3).

[0096] In some embodiments of the present disclosure, X 1 Selected from N, X 2 Selected from CH, X 3 Selected from S.

[0097] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from C(=O).

[0098] In some embodiments of the present disclosure, X 1 Selected from CH, X 2 Selected from CH, X 3 Selected from S.

[0099] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from S.

[0100] In some embodiments of the present disclosure, X 1 Selected from CH, X 2 Selected from CH, X 3 Selected from O.

[0101] In some embodiments of the present disclosure, X 1 Selected from C(F), X 2 Selected from CH, X 3 Selected from O.

[0102] In some embodiments of the present disclosure, the structural unit for

[0103] In some embodiments of the present disclosure, the structural unit for

[0104] In some embodiments of the present disclosure, X 4 、X 5 、X 6 and X 7 At least 2 of them are selected from C(R 5 ).

[0105] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ).

[0106] In some embodiments of the present disclosure, X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ).

[0107] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ).

[0108] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from N, X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ).

[0109] In some embodiments of the present disclosure, X 4 Selected from N, X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ).

[0110] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), X 6 Selected from N, X 7 Selected from C(R 5 ).

[0111] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), X 6 Selected from C(R 5 ), X 7 Selected from N.

[0112] In some embodiments of the present disclosure, X 4 Selected from N, X 5 Selected from C(R 5 ), X 6 Selected from N, X 7 Selected from C(R 5 ).

[0113] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from N, X 6 Selected from C(R 5 ), X 7 Selected from N.

[0114] In other embodiments of the present disclosure, each R 5 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted independently with one or more substituents.

[0115] In some embodiments of the present disclosure, each R 5 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0116] In other embodiments of the present disclosure, each R 5 Each is independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl, CD3, methoxy, -OCD3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy.

[0117] In some embodiments of the present disclosure, each R 5 are each independently selected from hydrogen or -F.

[0118] In some embodiments of the present disclosure, each R 5 are independently selected from H.

[0119] In some embodiments of the present disclosure, X 4 Selected from CH, X 5 Selected from CH.

[0120] In some embodiments of the present disclosure, X 6 Selected from CH, X 7 Selected from CH.

[0121] In some embodiments of the present disclosure, X 4 Selected from CH, X 5 Selected from CH, X 6 Selected from CH, X 7 Selected from CH.

[0122] In some embodiments of the present disclosure, X 4 Selected from CH, X 5 Selected from N, X 6 Selected from CH, X 7 Selected from CH.

[0123] In some embodiments of the present disclosure, X 4 Selected from CH, X 5 Selected from CH, X 6 Selected from CH, X 7 Selected from C(F).

[0124] In some embodiments of the present disclosure, X 4 Selected from NH, X 5 Selected from CH, X 6 Selected from CH, X 7 Selected from CH.

[0125] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), and X 4 and X 5 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.

[0126] In some embodiments of the present disclosure, X 4 Selected from C(R5 ), X 5 Selected from C(R 5 ), and X 4 and X 5 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.

[0127] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), and X 4 and X 5 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.

[0128] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), and X 4 and X 5 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.

[0129] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), and X4 and X 5 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.

[0130] In some embodiments of the present disclosure, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ), and X 4 and X 5 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.

[0131] In some embodiments of the present disclosure, X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ), and X 6 and X 7 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.

[0132] In some embodiments of the present disclosure, X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ), and X 6 and X 7 R on two carbon atoms 5Together 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.

[0133] In some embodiments of the present disclosure, L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -N(R 7 )-.

[0134] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, said -NH2, C 1-12 Alkyl, C 1-12 Alkoxy, C 3-12 The cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents.

[0135] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, said -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents.

[0136] In other embodiments of the present disclosure, each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, said -NH2, C 1-6 Deuterated alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 3-6The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents.

[0137] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, said -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents.

[0138] In other embodiments of the present disclosure, each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-3 Deuterated alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, said -NH2, C 1-3 Deuterated alkyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents.

[0139] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Each is independently selected from hydrogen, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, said -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, optionally substituted independently with one or more substituents.

[0140] In other embodiments of the present disclosure, each R 7 、R 8 or R9 Each is independently selected from hydrogen, -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiophene, The -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, optionally substituted independently with one or more substituents.

[0141] In other embodiments of the present disclosure, each R 7 、R 8 or R 9 Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2.

[0142] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Optionally independently substituted with one or more groups selected from halogen, OH, CN or NH2.

[0143] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 each independently selected from hydrogen, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, said -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropyloxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0144] In other embodiments of the present disclosure, each R 7 、R 8or R 9 Each is independently selected from hydrogen, -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, said -NH2, methyl, -C D3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, tetrahydropyranyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl are optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0145] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Each is independently selected from hydrogen, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl, and the -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl are optionally independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0146] In other embodiments of the present disclosure, each R 7 、R 8 or R 9 Each is independently selected from hydrogen, -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropyloxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl, and the -NH2, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropyloxy, cyclopropyl, cyclobutyl, oxetanyl, thietanyl or azetidinyl are optionally independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0147] In some embodiments of the present disclosure, each R 7 、R 8 or R 9Each is independently selected from hydrogen, -NH2, methyl, ethyl or cyclopropyl.

[0148] In other embodiments of the present disclosure, each R 7 、R 8 or R 9 Each is independently selected from hydrogen, -NH2, methyl, ethyl, -CD2CD3, cyclopropyl or -CD3.

[0149] In other embodiments of the present disclosure, R 7 Selected from -CD3 or -CD2CD3.

[0150] In other embodiments of the present disclosure, R 7 Selected from -CD3.

[0151] In other embodiments of the present disclosure, R 7 is selected from hydrogen or methyl.

[0152] In other embodiments of the present disclosure, R 7 Selected from methyl.

[0153] In some embodiments of the present disclosure, each R 7 、R 8 or R 9 Selected from hydrogen.

[0154] In some embodiments of the present disclosure, L is selected from -(C(R 3 R 4 )) m -, -O-, -S- or -NH-.

[0155] 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 )-.

[0156] 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 1-12 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)C1-12 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.

[0157] 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 2-6 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 and 3-8 membered heterocyclyl are optionally substituted independently with one or more substituents.

[0158] 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, -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)OC1-3 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.

[0159] 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(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.

[0160] In other embodiments of the present disclosure, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 Deuterated alkoxy, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 Deuterated alkoxy groups are optionally substituted independently with one or more substituents.

[0161] 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.

[0162] 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.

[0163] In other embodiments of the present disclosure, each R 3 and R 4 Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] In some embodiments of the present disclosure, each R 3 are independently selected from hydrogen, each R 4 are independently selected from hydrogen, -F, -Cl, -Br, -I, -CN, methyl or ethyl.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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 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.

[0172] 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.

[0173] In some embodiments of the present disclosure, R 3 and R4 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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 R3 、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 with one or more substituents.

[0179] 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.

[0180] 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.

[0181] 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.

[0182] 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-,

[0183] In some embodiments of the present disclosure, L is selected from -O-, -S-, -NH-, -CH2-, -CH(CH3)-, -CH2CH2-, -C(O)-,

[0184] In some embodiments of the present disclosure, L is selected from -CH2-, -CH(CH3)- or

[0185] In some embodiments of the present disclosure, L is selected from -CH2-.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] In some embodiments of the present disclosure, R 2is selected from phenyl, pyrrolyl, pyrazolyl, 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.

[0193] 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.

[0194] In some embodiments of the present disclosure, R 2 is selected from pyrimidinyl, said pyrimidinyl being optionally independently substituted with one or more R 2a replace.

[0195] In some embodiments of the present disclosure, R 2 Selected from The R 2 Optionally independently represented by one or more R 2a replace.

[0196] In some embodiments of the present disclosure, R 2 Selected from The R 2 Optionally independently represented by one or more R 2a replace.

[0197] In some embodiments of the present disclosure, R 2 Selected from The R 2 Optionally independently represented by one or more R 2a replace.

[0198] In some embodiments of the present disclosure, each R 2a and R 6a 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 1-12Alkyl, -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.

[0199] In some embodiments of the present disclosure, each R 2a and R 6aare 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 2-6 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, -NHCOC1-6 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.

[0200] 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, -SO2C1-3 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.

[0201] 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.

[0202] In other 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 Deuterated alkyl, C 1-3 Alkoxy, C 1-3Deuterated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 The cycloalkyl or 3-6 membered heterocyclyl is optionally substituted independently with one or more substituents.

[0203] 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.

[0204] 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, 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.

[0205] 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.

[0206] In other embodiments of the present disclosure, each R 2a and R 6aOptionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2.

[0207] In some embodiments of the present disclosure, each R 2a and R 6a Optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0208] In some embodiments of the present disclosure, R 2a is 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 independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0209] In some embodiments of the present disclosure, R 2a is selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy or cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy and cyclopropyl are optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0210] In some embodiments of the present disclosure, R 2a Selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,

[0211] In some embodiments of the present disclosure, R 2a Selected from methyl, isopropyl, methoxy or

[0212] In some embodiments of the present disclosure, R 2a Selected from isopropyl, methoxy or

[0213] In some embodiments of the present disclosure, R 2 Selected from

[0214] In some embodiments of the present disclosure, R 2 Selected from

[0215] In some embodiments of the present disclosure, R 2 Selected from

[0216] In some embodiments of the present disclosure, 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 1-12Alkyl, -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.

[0217] 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, -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)OC1-6 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.

[0218] 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 1-3 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 3-6Cycloalkenyl, 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.

[0219] In some embodiments of the present disclosure, 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 1-3Alkylthio, -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.

[0220] In other embodiments of the present disclosure, R 6 Selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R 6a replace.

[0221] 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.

[0222] 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.

[0223] 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 3-6Cycloalkyl, 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 R 6a replace.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] In some embodiments of the present disclosure, R 6 Selected from The R 6 Optionally independently represented by one or more R 6a replace.

[0229] In some embodiments of the present disclosure, R 6 Selected from The R 6 Optionally independently represented by one or more R 6a replace.

[0230] In some embodiments of the present disclosure, R 6 Selected from The R 6 Optionally independently represented by one or more R 6a replace.

[0231] In some embodiments of the present disclosure, R 6a is 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 independently substituted with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0232] In some embodiments of the present disclosure, R 6a is selected from halogen, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl or oxetanyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl and oxetanyl are optionally substituted independently with 1, 2 or 3 groups selected from halogen, OH, CN or NH2.

[0233] In other embodiments of the present disclosure, R 6a Selected from halogen, methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropyloxy, cyclopropyl or oxetanyl, wherein the methyl, -CD3, ethyl, -CD2CD3, isopropyl, -CH(CD3)2, methoxy, -OCD3, ethoxy, -OCD2CD3, isopropyloxy, cyclopropyl or oxetanyl are optionally substituted independently with 1, 2 or 3 groups selected from F, Cl, Br, I, OH, CN or NH2.

[0234] In some embodiments of the present disclosure, R 6a Selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy,

[0235] In other embodiments of the present disclosure, R6a Selected from -F, -Cl, -Br, -I, methyl, -CD3, isopropyl, methoxy, -OCD3, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2CF3, -CF2CF3,

[0236] In some embodiments of the present disclosure, R 6a Selected from methyl, isopropyl, difluoromethyl, trifluoromethyl,

[0237] In other embodiments of the present disclosure, R 6a Selected from methyl, -CD3, isopropyl, difluoromethyl, trifluoromethyl,

[0238] In other embodiments of the present disclosure, R 6a Selected from methyl, isopropyl, difluoromethyl, trifluoromethyl, In some other embodiments of the present disclosure, R 6a is selected from methyl, isopropyl or trifluoromethyl.

[0239] In other embodiments of the present disclosure, R 6a Selected from methyl, isopropyl, trifluoromethyl or

[0240] In some embodiments of the present disclosure, R 6 Selected from

[0241] In other embodiments of the present disclosure, R 6 Selected from

[0242] In some embodiments of the present disclosure, R 6 Selected from

[0243] In other embodiments of the present disclosure, R 6 Selected from

[0244] In some embodiments of the present disclosure, R 6 Selected from

[0245] In other embodiments of the present disclosure, R 6 Selected from

[0246] In some embodiments of the present disclosure, R 6 Selected from

[0247] 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.

[0248] 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.

[0249] In some embodiments of the present disclosure, m is selected from 1.

[0250] 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),

[0251] Among them, X 1 、X 3 、X 4 、X 5 、X 6 、X 7 、R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I);

[0252] 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.

[0253] 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)

[0254] in,

[0255] X 5 selected from CH or N;

[0256] X 1 、X 3 、R 2 、R3 、R 4 and R 6 As defined by the compound shown in formula (I);

[0257] 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.

[0258] 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)

[0259] in,

[0260] X 5 selected from CH or N;

[0261] X 3 、R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I);

[0262] 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.

[0263] 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)

[0264] in,

[0265] X 5 selected from CH or N;

[0266] R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I);

[0267] 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.

[0268] 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)

[0269] in,

[0270] X 5 selected from CH or N;

[0271] Y 1 、Y 2 and Y 3 are independently selected from CH or N;

[0272] X 3 、R 3 、R 4 、R 6 and R 2a As defined by the compound shown in formula (I);

[0273] 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.

[0274] In some embodiments of the present disclosure, Y 1 Selected from N.

[0275] In some embodiments of the present disclosure, Y 1 and Y 3 All are selected from N.

[0276] In some embodiments of the present disclosure, Y 1 Selected from N, Y 2 and Y 3 All are selected from CH.

[0277] In some embodiments of the present disclosure, Y 1 and Y 3 All selected from N, Y 2 Selected from CH.

[0278] 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)

[0279] in,

[0280] X 5 selected from CH or N;

[0281] Y 1 、Y 2and Y 3 As defined by the compound shown in formula (I-5);

[0282] X 3 、R 2a 、R 3 、R 4 and R 6a As defined by the compound shown in formula (I);

[0283] 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.

[0284] 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)

[0285] in,

[0286] X 5 selected from CH or N;

[0287] Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5);

[0288] X 3 、R 2a 、R 3 、R 4 and R 6a As defined by the compound shown in formula (I);

[0289] 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.

[0290] Some other embodiments of the present disclosure are formed by any combination of the above variables.

[0291] On the other hand, the present disclosure also provides a compound of the following formula, an isomer thereof, or a pharmaceutically acceptable salt thereof,

[0292] 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.

[0293] 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).

[0294] 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.

[0295] 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).

[0296] 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).

[0297] 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).

[0298] Technical Effects

[0299] 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.

[0300] Related definitions

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] 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 key Indicates the relative configuration of a stereocenter.

[0307] 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.

[0308] 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.

[0309] 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.

[0310] 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.

[0311] 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 6-10"aryl", "5-10 membered heteroaryl", "3-12 membered heterocyclyl" and other related groups, and corresponding non-limiting or exemplary groups, wherein some non-limiting examples of the "substituent" include a deuterium atom, a hydroxyl group, a thiol group, a halogen, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone 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, 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 group The present invention also includes but is not limited to: a deuterium atom, an oxo group, a hydroxyl group, an amino group, a nitro group, a halogen group, a cyano group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, an alkylamino group, a dialkylamino group, a halogenated alkylamino group, a halogenated dialkylamino group, a carboxyl group, a -C (O) O-alkyl group, a -OC (O) -alkyl group, a -C (O) NH2, a -C (O) NH-alkyl group, a -C (O) N (alkyl) group, a halogenated alkoxy ...alkoxy group, a halogenated alkylamino group, a halogenated dialkylamino group, a 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, cycloalkylalkylene, cycloalkyloxy, heterocyclyl, heterocyclylalkylene, heterocyclyloxy, heterocycloalkyl, heterocycloalkylalkylene, heterocycloalkyloxy, heteroaryl, heteroarylalkylene, heteroaryloxy, aryl, arylalkylene or aryloxy.

[0312] In some embodiments herein, the substituent is selected from a deuterium atom, a hydroxyl group, a sulfhydryl group, a halogen group, an amino group, a nitro group, a nitroso group, a cyano group, an azide group, a sulfoxide group, a sulfone group, a sulfonamide group, a carboxyl group, an aldehyde group, an imine group, a 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 groups, oxo and thio groups, etc., wherein the substituents are optionally substituted by one or more substituents selected from the following: deuterium atoms, oxo, hydroxyl, 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.

[0313] 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.

[0314] 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.

[0315] When the listed linking groups do not specify their linking direction, their 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.

[0316] 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.

[0317] 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.

[0318] Unless otherwise specified, the term “C 1-12 "Deuterated alkyl" refers to the above-mentioned "C 1-12 Any number and position of H atoms in the "alkyl" are replaced by deuterium atoms. 1-12 Deuterated alkyl can be C 1-6 Deuterated alkyl or C 1-3 Deuterated alkyl. Examples of deuterated alkyl include, but are not limited to, -CH2D, -CHD2, wait.

[0319] 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.

[0320] 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.

[0321] 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.

[0322] 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 C 2-6 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.

[0323] 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.

[0324] The term "halogen," by itself or as part of another substituent, means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0325] Unless otherwise specified, C n-n+m or C n -C n+mAny 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 9-12 Similarly, 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.

[0326] Unless otherwise specified, the term "ring" refers to substituted or unsubstituted cycloalkyl, heterocyclyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The so-called ring includes a monocyclic, linked, spirocyclic, fused or bridged ring. The number of atoms in the ring is usually defined as the number of ring members, for example, "5- to 7-membered ring" means 5 to 7 atoms arranged around. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Therefore, "5- to 7-membered ring" includes, for example, phenyl, pyridine and piperidinyl; the term "ring" also includes a ring system containing at least one ring, each of which "ring" independently meets the above definition.

[0327] 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 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.

[0328] 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

[0329] 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

[0330] 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.

[0331] 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.).

[0332] 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.).

[0333] 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.

[0334] 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:

[0335] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0336] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0337] 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.

[0338] 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.

[0339] The therapeutic or prophylactic dose of the disclosed compounds may depend, for example, on the specific use for treatment or prevention, the manner in which the compound is administered, the patient's health and condition, 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. For example, the disclosed compounds may be provided in a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and extent 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.

[0340] 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".

[0341] 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.

[0342] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients.

[0343] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, making dragees, grinding methods, emulsifying methods, freeze-drying methods, and the like.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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:

[0349] in,

[0350] X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 , L, R 2 and R 6 As described above for the compound of formula (I);

[0351] Y is selected from halogen, -OH, methylsulfonyloxy, phenylsulfonyloxy or p-toluenesulfonyloxy.

[0352] In some embodiments of the present application, Y is selected from -Cl, -Br, -I, -OH, methylsulfonyloxy or p-toluenesulfonyloxy.

[0353] In some embodiments of the present application, Y is selected from -Cl.

[0354] 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:

[0355] in,

[0356] X 1 、X 2 、X 4 、X 5 、X 6 、X 7 , L, R 2 、R 6 and R 7 As described above for the compound of formula (I), X is selected from halogen.

[0357] In some embodiments of the present application, X is selected from -Cl, -Br, and -I.

[0358] In some embodiments of the present application, X is selected from -I.

[0359] 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

[0360] 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.

[0361] Example 1

[0362] Step 1: Preparation of intermediate 1-2

[0363] To a 100 mL single-necked flask, 1-1 (1 g), tert-butyl carbamate (0.612 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.192 g), tris(dibenzylideneacetone)dipalladium (0.218 g), cesium carbonate (3.10 g), and 1,4-dioxane (20 mL) were added in sequence. The mixture was reacted at 85°C under nitrogen for 6 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain intermediate 1-2 (0.8 g).

[0364] 1H NMR (500MHz, DMSO-d6) δ10.00 (s, 1H), 8.30 (d, J = 2.3Hz, 1H), 7.99 (dd, J = 10.9, 2.2Hz, 1H), 1.49 (s, 9H).

[0365] MS (ESI, [M+H] + )m / z:247.20.

[0366] Step 2: Preparation of intermediate 1-3

[0367] At -78°C, a 2.5M solution of n-butyllithium in tetrahydrofuran (3.99 mL) was slowly added dropwise to a solution of Intermediate 1-2 (0.8 g) and N,N,N',N'-tetramethylethylenediamine (1.13 g) in tetrahydrofuran (10 mL). The mixture was heated to -20°C and stirred for 1.5 hours. The temperature was lowered to -78°C, and a solution of iodine (2.47 g) in tetrahydrofuran (5 mL) was slowly added to the system. The mixture was allowed to warm to room temperature and reacted for 3 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution (20 mL), extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography to obtain Intermediate 1-3 (0.7 g).

[0368] 1 H NMR (500MHz, DMSO-d6) δ9.08(s,1H),8.16(s,1H),1.47(s,9H).

[0369] MS (ESI, [M+H] + )m / z:373.03.

[0370] Step 3: Preparation of intermediate 1-4

[0371] To a 50 mL single-necked flask, intermediate 1-3 (0.70 g), intermediate A-1 (0.528 g), tris(dibenzylideneacetone)dipalladium (0.172 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.13 g), cesium carbonate (1.84 g), and 1,4-dioxane (15 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen for 12 hours. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain intermediate 1-4 (0.4 g).

[0372] 1 H NMR (500MHz, DMSO-d6) δ11.84(s,1H),7.96(s,1H),7.92(d,J=1.3Hz,1H),7.75-7.70(m,2H),7.41(d,J=8.0Hz,2H),5.17(s,2H),3.77(s,3H).

[0373] MS (ESI, [M+H] + )m / z:426.24.

[0374] Step 4: Preparation of compound 1

[0375] To a 35 mL microwave tube were added Intermediate 1-4 (0.4 g), Intermediate B-1 (0.365 g), potassium phosphate (0.399 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.179 g), tris(dibenzylideneacetone)dipalladium (0.172 g), 1,4-dioxane (20 mL), and water (1 mL). Under nitrogen protection, the reaction mixture was heated to 130°C in a microwave oven for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain Compound 1 (0.33 g).

[0376] 1 H NMR (500MHz, DMSO-d6) δ11.77(s,1H),8.66(s,1H),8.26(d,J=1.3Hz,1H),7.92(d,J=1.4Hz,1H),7.73-7.69(m,2H),7.42(d,J=8.1Hz,2H ),5.18(s,2H),3.80(s,3H),3.76(s,3H),1.71-1.65(m,1H),1.09-1.04(m,1H),0.97-0.93(m,1H),0.92-0.87(m,1H),0.82-0.77(m,1H).

[0377] HRMS (ESI) m / z [M+H] + :540.1774.

[0378] Example 2

[0379] Preparation of compound 2:

[0380] A solution of potassium hydroxide (0.042 g, 0.741 mmol) in water (1 mL) was added dropwise to a solution of compound 1 (0.1 g), tetrabutylammonium bromide (0.006 g) and 2,4-dinitrophenylhydroxylamine (0.148 g) in dichloromethane (5 mL), and the mixture was reacted at 40°C for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain compound 2 (0.03 g).

[0381] 1H NMR(500MHz, DMSO-d6)δ8.66(s,1H),8.35(d,J=1.1Hz,1H),7.92(d,J=1.3Hz,1H),7.73-7.69(m,2H),7.44-7.40(m,2H),5.66(s,2H), 5.23(s,2H),3.80(s,3H),3.75(s,3H),1.69-1.64(m,1H),1.10-1.05(m,1H),0.99-0.94(m,1H),0.92-0.87(m,1H),0.84-0.78(m,1H).

[0382] HRMS (ESI) m / z [M+H] + :555.1886.

[0383] Example 3

[0384] Preparation of compound 3:

[0385] 60% sodium hydroxide (0.006 g) was added to a solution of compound 1 (0.060 g) in N,N-dimethylformamide (3 mL) at 0°C and allowed to react for 30 minutes. Iodomethane (0.024 g) was added to the reaction solution, and the mixture was allowed to warm to room temperature and react for 40 minutes. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound 3 (0.048 g).

[0386] 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.47(s,1H),7.92(s,1H),7.70(d,J=7.9Hz,2H),7.42(d,J=7.9Hz,2H), 5.22(s,2H),3.80(s,3H),3.75(s,3H),3.50(s,3H),1.71-1.61(m,1H),1.35-1.21(m,2H),1.05-0.98(m,2H).

[0387] HRMS (ESI) m / z [M+H] + :554.1935.

[0388] Example 4

[0389] Step 1: Preparation of intermediate 2-4

[0390] To a 50 mL single-necked flask, intermediate 1-3 (0.3 g), intermediate A-2 (0.251 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.093 g), tris(dibenzylideneacetone)dipalladium (0.074 g), cesium carbonate (0.787 g), and 1,4-dioxane (15 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen for 12 hours. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain intermediate 2-4 (0.125 g).

[0391] 1 H NMR(500MHz,DMSO-d6)δ11.85(s,1H),8.17(s,1H),7.96(s,1H),7.57(d,J=8.5Hz, 2H), 7.43 (d, J = 8.5Hz, 2H), 5.18 (s, 2H), 4.50-4.42 (m, 1H), 1.39 (d, J = 6.5Hz, 6H).

[0392] MS (ESI, [M+H] + )m / z:454.21.

[0393] Step 2: Preparation of compound 4

[0394] To a 25 mL single-necked flask, intermediate 2-4 (0.10 g, 0.220 mmol), intermediate B-1 (0.085 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.042 g), potassium phosphate (0.140 g), tris(dibenzylideneacetone)dipalladium (0.040 g), 1,4-dioxane (5 mL), and water (0.25 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain compound 4 (0.068 g).

[0395] 1 H NMR (500MHz, DMSO-d6) δ11.77(s,1H),8.66(s,1H),8.27(s,1H),8.16(s,1H),7.56(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),5.19(s,2H),4.47-4 .41(m,1H),3.80(s,3H),1.71-1.65(m,1H),1.38(d,J=6.5Hz,6H),1.11 -1.05(m,1H),0.97-0.93(m,1H),0.91-0.85(m,1H),0.83-0.76(m,1H).

[0396] HRMS (ESI) m / z [M+H] + :568.2097.

[0397] Example 5

[0398] Step 1: Preparation of intermediate 3-4

[0399] To a 50 mL single-necked flask, intermediate 1-3 (0.40 g), intermediate A-3 (0.34 g), tris(dibenzylideneacetone)dipalladium (0.10 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.074 mg), cesium carbonate (1.05 g), and 1,4-dioxane (15 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen for 12 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain intermediate 3-4 (0.21 g).

[0400] 1 H NMR (500MHz, DMSO-d6) δ11.85(s,1H),8.63(d,J=2.2Hz,1H),8.23(d,J=1.3Hz,1H),8.07-8.02(m, 1H), 7.95 (s, 1H), 7.85 (dd, J = 8.3, 2.3Hz, 1H), 5.76-5.68 (m, 1H), 5.20 (s, 2H), 1.44 (d, J = 6.7Hz, 6H).

[0401] MS (ESI, [M+H] + )m / z:455.22.

[0402] Step 2: Preparation of compound 6

[0403] To a 35 mL microwave tube were added Intermediate 3-4 (0.2 g), Intermediate B-1 (0.171 g), potassium phosphate (0.187 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.084 g), tris(dibenzylideneacetone)dipalladium (0.081 g), 1,4-dioxane (20 mL), and water (1 mL). Under nitrogen protection, the reaction mixture was heated to 130°C in a microwave oven for 2 hours. The solvent was evaporated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography to obtain compound 6 (0.15 g).

[0404] 1H NMR (500MHz, DMSO-d6) δ11.79(s,1H),8.66(s,1H),8.63(d,J=2.2Hz,1H),8.26(d,J =1.3Hz,1H),8.23(d,J=1.3Hz,1H),8.04(d,J=8.2Hz,1H),7.85(dd,J=8.3,2.3Hz,1 H),5.74-5.67(m,1H),5.22(s,2H),3.79(s,3H),1.71-1.65(m,1H),1.43(d,J=6.7H z,6H),1.09-1.05(m,1H),0.97-0.93(m,1H),0.89-0.85(m,1H),0.81-0.77(m,1H).

[0405] HRMS (ESI) m / z [M+H] + :569.2043.

[0406] Example 6

[0407] Preparation of compound 6:

[0408] To a 25 mL single-necked flask, intermediate 3-4 (0.050 g), intermediate B-2 (0.055 g), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (0.021 g), potassium phosphate (0.070 g), tris(dibenzylideneacetone)dipalladium (0.020 g), 1,4-dioxane (2.5 mL), and water (0.125 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen for 1 hour. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain compound 6 (0.035 g).

[0409] 1 H NMR (500MHz, DMSO-d6) δ11.84(s,1H),8.66-8.62(m,1H),8.32-8.28(m,1H),8.24-8.21(m,1H),8.02(d,J=5Hz,1H),7.87-7.82 (m,1H),7.36(s,1H),5.73-5.65(m,1H),5.23(s,2H),4.38-4.29(m,1H),1.81(s,3H),1.42(d,J=5Hz,6H),1.25(d,J=5Hz,6H).

[0410] HRMS (ESI) m / z [M+H] + :543.2245.

[0411] Example 7

[0412] Preparation of compound 7:

[0413] 60% sodium hydroxide (0.005 g) was added to a solution of compound 6 (0.050 g) in N,N-dimethylformamide (1 mL) at 0°C, and the mixture was reacted at 0°C for 30 minutes. Iodomethane (0.019 g) was added to the reaction solution, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound 7 (0.035 g).

[0414] 1 H NMR(500MHz,DMSO-d6)δ8.67(s,1H),8.63(d,J=2.2Hz,1H),8.47(d,J=1.2Hz,1H), 8.24-8.22(m,1H),8.04(d,J=8.3Hz,1H),7.86(dd,J=8.3,2.3Hz,1H),5.73-5.67( m,1H),5.27(s,2H),3.79(s,3H),3.50(s,3H),1.69-1.64(m,1H),1.43(d,J=6.7Hz ,6H),1.10-1.05(m,1H),0.98-0.93(m,1H),0.90-0.85(m,1H),0.81-0.76(m,1H).

[0415] HRMS (ESI) m / z [M+H] + :583.2206.

[0416] Example 8

[0417] Preparation of compound 8:

[0418] 60% sodium hydroxide (0.007 g) was added to a solution of compound 6 (0.080 g) in N,N-dimethylformamide (2 mL) at 0°C, and the mixture was reacted at 0°C for 30 minutes. Ethyl iodide (0.033 g) was added to the reaction solution, and the mixture was allowed to react at room temperature for 2 hours. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain compound 7 (0.04 g).

[0419] 1H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.63(d,J=2.1Hz,1H),8.54(d,J=1.2Hz,1H),8.23(d, J=1.3Hz,1H),8.04(d,J=8.3Hz,1H),7.85(dd,J=8.3,2.3Hz,1H),5.73-5.67(m,1H),5.26(s ,2H),4.03(q,J=7.1Hz,2H),3.79(s,3H),1.71-1.65(m,1H),1.43(d,J=6.7Hz,6H),1.34(t ,J=7.2Hz,3H),1.10-1.05(m,1H),0.97-0.93(m,1H),0.91-0.87(m,1H),0.81-0.77(m,1H).

[0420] HRMS (ESI) m / z [M+H] + :597.2357.

[0421] Example 9

[0422] Step 1: Preparation of intermediate 4-4

[0423] To a 50 mL single-necked flask, intermediate 1-3 (0.3 g), intermediate A-4 (0.226 g), cesium carbonate (0.787 g), tris(dibenzylideneacetone)dipalladium (0.074 g), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (0.056 g), and 1,4-dioxane (15 mL) were added in sequence. The mixture was reacted at 100°C under nitrogen for 12 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain intermediate 4-4 (0.086 g).

[0424] 1 H NMR (500MHz, DMSO-d6) δ11.82(s,1H),7.96(s,1H),7.60-7.54(m,2H),7.47(d,J=8.2Hz,2H),6.75(s,1H),5.19(s,2H),2.33(s,3H).

[0425] MS (ESI, [M+H] + )m / z:426.18.

[0426] Step 2: Preparation of compound 9

[0427] To an 8 mL microwave tube, intermediate 4-4 (0.050 g), intermediate B-1 (0.091 g), tris(dibenzylideneacetone)dipalladium (0.054 g), potassium phosphate (0.075 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.050 g), 1,4-dioxane (3 mL), and water (0.15 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 130°C in a microwave oven for 2 hours. The solvent was evaporated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain compound 9 (0.040 g).

[0428] 1 H NMR (500MHz, DMSO-d6) δ11.78(s,1H),8.66(s,1H),8.26(d,J=1.3Hz,1H),7.60-7.54(m,2H),7.46(d,J =8.3Hz,2H),6.75(s,1H),5.20(s,2H),3.80(s,3H),2.32(s,3H),1.72-1.62(m,1H),0.99-0.81(m,4H).

[0429] HRMS (ESI) m / z [M+H] + :540.1767.

[0430] Example 10

[0431] Preparation of compound 10:

[0432] To an 8 mL microwave tube were added intermediate 3-4 (0.050 g), intermediate B-3 (0.036 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.021 g), potassium phosphate (0.070 g), tris(dibenzylideneacetone)dipalladium (0.020 g), 1,4-dioxane (3 mL), and water (0.15 mL). Under nitrogen protection, the reaction mixture was heated to 130°C in a microwave oven for 2 hours. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain compound 10 (0.011 g).

[0433] 1H NMR (500MHz, DMSO-d6) δ11.77(s,1H),8.66–8.56(m,2H),8.29-8.19(m,2H),8.03(d,J=8.2Hz,1H),7.89-7.79(m,1H),7.68-7. 58(m,1H),7.34-7.24(m,1H),5.75-5.650(m,1H),5.21(s,2H),2.89-2.79(m,1H),1.43(d,J=6.7Hz,6H),1.03(d,J=6.6Hz,6H).

[0434] HRMS (ESI) m / z [M+H] + :540.2148.

[0435] Example 11

[0436] Step 1: Preparation of Intermediate 11-2

[0437] To a 50 mL single-necked flask, intermediate 11-1 (0.40 g), N,N-dimethylformamide (8 mL), intermediate A-5 (0.72 g), and potassium carbonate (0.82 g) were added in sequence. The mixture was heated to 40°C for 3 hours. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was separated and purified on a silica gel column to obtain intermediate 11-2 (0.65 g).

[0438] 1 H NMR (500MHz, DMSO-d6) δ8.37(s,1H),8.17(s,1H),7.55(d,J=8.2Hz,2H),7.45(d,J=8 .2Hz,2H),6.88(s,2H),5.12(s,2H),4.46(hept,J=6.6Hz,1H),1.39(d,J=6.6Hz,6H).

[0439] MS (ESI, [M+H] + )m / z:435.17.

[0440] Step 2: Preparation of Intermediate 11-3

[0441] To a 30 mL microwave tube, add Intermediate 11-2 (0.20 g), N,N-dimethylformamide (12 mL), iodine (1.23 g), cuprous iodide (8.77 mg), and isoamyl nitrite (0.27 g). Microwave heating at 120°C was performed for 1 hour. The reaction solution was poured into a saturated sodium sulfite solution (100 mL) and extracted with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain Intermediate 11-3 (0.2 g).

[0442] 1 H NMR(500MHz,DMSO-d6)δ8.71(s,1H),8.17(s,1H),7.56(d,J=8.2Hz,2H),7.47(d ,J=8.2Hz,2H),5.17(s,2H),4.46(dt,J=13.2,6.6Hz,1H),1.40(d,J=6.6Hz,6H).

[0443] MS (ESI, [M+H] + )m / z:546.03.

[0444] Step 3: Preparation of compound 11

[0445] To a 10 mL single-necked flask, intermediate 11-3 (0.15 g), intermediate B-1 (0.11 g), 1,4-dioxane (2 mL), water (0.2 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.026 g), potassium phosphate (0.18 g), and tris(dibenzylideneacetone)dipalladium (0.025 g) were added in sequence. Under nitrogen protection, the mixture was heated to 100°C for 3 hours. The reaction solution was cooled to room temperature and poured into water (100 mL). The resulting solution was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain compound 11 (65 mg).

[0446] 1 H NMR(500MHz,DMSO-d6)δ9.11(s,1H),8.69(s,1H),8.17(s,1H),7.52(dd,J=23.5,8.2Hz,4H),5.24(s,2H),4.43(dt ,J=13.3,6.6Hz,1H),3.86(s,3H),1.81–1.73(m,1H),1.39(d,J=6.7Hz,6H),1.06–1.02(m,2H),0.86–0.79(m,2H).

[0447] HRMS (ESI) m / z [M+H] + :568.1749.

[0448] Example 12

[0449] Step 1: Preparation of intermediate 12-2

[0450] In a 100 mL single-necked flask, add intermediate 12-1 (1.0 g), tetrahydrofuran (20 mL), and aqueous ammonia (1 mL) sequentially under ice. Warm the mixture to room temperature and react for 2 hours. Concentrate the reaction mixture, add 50 mL of water, and stir vigorously for 10 minutes. Filter with suction, wash the filter cake with 10 mL of water, and dry to obtain intermediate 12-2 (1.5 g).

[0451] 1 H NMR (500MHz, DMSO-d6) δ 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.50 ( d, J = 18.9 Hz, 2H), 8.05 ( dd, J = 8.4, 1.5 Hz, 1H), 7.85 ( dd, J = 8.5, 4.2 Hz, 1H).

[0452] MS (ESI, [M+H] + )m / z:181.06.

[0453] Step 2: Preparation of intermediate 12-3

[0454] To a 100 mL single-necked flask, under ice-cooling, were added intermediate 12-2 (1.0 g), ethanol (10 mL), and trifluoroacetic acid (0.43 mL). Platinum oxide (0.38 g) was added under nitrogen, and the atmosphere was replaced with hydrogen. The reaction mixture was then hydrogenated overnight. The reaction solution was filtered through a pad of celite, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography to afford intermediate 12-3 (0.51 g).

[0455] 1 H NMR (500MHz, DMSO-d6) δ7.00 (s, 1H), 3.26–3.16 (m, 2H), 2.60 (t, J = 6.4Hz, 2H), 1.87–1.77 (m, 2H).

[0456] MS (ESI, [M+H] + )m / z:185.11.

[0457] Step 3: Preparation of intermediate 12-4

[0458] Under ice, intermediate 12-3 (100 mg), tetrahydrofuran (5 mL), and triphosgene (96 mg) were added to a 10 mL reaction flask in sequence. The mixture was naturally warmed to room temperature and stirred for 1 hour. Imidazole (737 mg) was added, stirred at room temperature for 5 minutes, and then heated to 70°C for 1.5 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, the layers were separated, and the organic phase was concentrated. The resulting crude product was separated and purified by silica gel column chromatography to obtain intermediate 12-4 (85 mg).

[0459] 1 H NMR (500MHz, DMSO-d6) δ7.65 (s, 1H), 3.73 (t, J = 5.7Hz, 2H), 2.79 (t, J = 6.1Hz, 2H), 2.16–2.07 (m, 2H).

[0460] MS (ESI, [M+H] + )m / z:211.11.

[0461] Step 4: Preparation of intermediate 12-5

[0462] A mixture of Intermediate 12-4 (50 mg, 0.237 mmol), Intermediate A-6 (78 mg), potassium carbonate (98 mg, 0.712 mmol), and N,N-dimethylformamide (2 mL) was stirred at room temperature for 4 hours. The reaction solution was poured into saturated sodium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was concentrated, and the resulting crude product was separated and purified by silica gel column chromatography to obtain Intermediate 12-5 (67 mg).

[0463] 1 H NMR(500MHz,DMSO-d6)δ7.95–7.91(m,1H),7.74–7.69(m,2H),7.49–7.45(m,2H),5. 08(s,2H),3.84–3.80(m,2H),3.76(s,3H),2.84(t,J=6.0Hz,2H),2.21–2.11(m,2H).

[0464] MS (ESI, [M+H] + )m / z:449.26.

[0465] Step 5: Preparation of compound 12

[0466] To a 10 mL microwave tube, intermediate 12-5 (50.0 mg), intermediate B-3 (92 mg), tris(dibenzylideneacetone)dipalladium (51.0 mg), potassium phosphate (70.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.8 mg), 1,4-dioxane (2 mL), and water (0.04 mL) were added sequentially. Under nitrogen protection, the mixture was heated to 130°C in a microwave oven for 2 hours. The reaction solution was concentrated, and the crude product was separated and purified by silica gel column chromatography to obtain compound 12 (25 mg).

[0467] 1 H NMR (500MHz, DMSO-d6) δ8.63–8.53(m,1H),7.91(d,J=9.6Hz,2H),7.70(d,J=8.3Hz,2H),7.51(d,J=8.2Hz,2H),7.34–7.24(m,1H),5 .12(s,2H),3.88(t,J=5.6Hz,2H),3.75(s,3H),3.62–3.52(m,1H),2.92(t,J=6.0Hz,2H),2.28–2.18(m,2H),1.16(d,J=6.7Hz,6H).

[0468] HRMS (ESI) m / z [M+H] + :534.2234.

[0469] Example 13

[0470] To a 10 mL microwave tube were added intermediate 12-5 (50.0 mg), intermediate B-1 (43.2 mg), tris(dibenzylideneacetone)dipalladium (51.0 mg, 0.056 mmol), potassium phosphate (70.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.8 mg), 1,4-dioxane (3 mL), and water (0.15 mL). The reaction mixture was heated to 130°C under a nitrogen atmosphere for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 13 (60 mg).

[0471] 1H NMR(500MHz,DMSO-d6)δ8.64(s,1H),7.92(s,1H),7.70–7.64(m,2H),7.52–7.46(m,2H),5.11(s,2H) ,3.89–3.86(m,2H),3.83(s,3H),3.75(s,3H),2.91(t,J=6.0Hz,2H),2.27–2.17(m,2H),1.7–1.6(m, 1H),1.07–0.97(m,2H),0.84(s,2H).

[0472] HRMS (ESI) m / z [M+H] + :563.2130.

[0473] Example 14

[0474] To a 10 mL microwave tube, intermediate 12-5 (50.0 mg), intermediate B-2 (55.7 mg), tris(dibenzylideneacetone)dipalladium (51.0 mg), potassium phosphate (70.9 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.8 mg), 1,4-dioxane (3 mL), and water (0.15 mL) were added sequentially. Under a nitrogen atmosphere, the mixture was heated to 130°C in a microwave oven for 2 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 14 (34 mg).

[0475] 1 H NMR (500MHz, DMSO-d6) δ7.92(d,J=1.3Hz,1H),7.76–7.65(m,2H),7.52(d,J=8.2Hz,2H),7.33(s,1H),5.26–5.16(m,1H),5. 12(s,2H),3.88(t,J=5.6Hz,2H),3.75(s,3H),2.90(t,J=6.0Hz,2H),2.27–2.17(m,2H),2.12(s,3H),1.33(d,J=6.6Hz,6H).

[0476] HRMS (ESI) m / z [M+H] + :537.2339.

[0477] Example 15

[0478] Sodium hydroxide (11.12 mg) was added to a solution of compound 9 (100 mg) in N,N-dimethylformamide (1 mL) at 0°C. After the addition, the mixture was kept at 0°C for 30 minutes. Deuterated iodomethane (28.2 mg) was added to the reaction solution, and the mixture was reacted at 0°C. After the reaction was completed, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to obtain 77 mg of compound 15.

[0479] HRMS (ESI) m / z [M+H] + :557.1737.

[0480] 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.47(s,1H),7.56(d,J=8.5Hz,2H),7.47(d,J=8.4Hz,2H),6.75(s,1H),5.24(s,2H), 3.80(s,3H),2.31(s,3H),1.69–1.62(m,1H),1.11-1.04(m,1H),0.99-0.93(m,1H),0.93-0.86(m,1H),0.84-0.77(m,1H).

[0481] Example 16

[0482] Sodium hydroxide (8.46 mg, 60% dispersion in mineral oil) was added to a solution of compound 4 (80 mg) in N,N-dimethylformamide (1 mL) at 0°C. The reaction mixture was maintained at 0°C for 30 minutes. Deuterated iodomethane (21.45 mg) was added to the reaction solution and the mixture was allowed to return to room temperature for reaction. After the reaction was complete, the reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 98:2) to obtain 45 mg of compound 16.

[0483] HRMS (ESI) m / z [M+H] + :585.2446.

[0484] 1H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.47(s,1H),8.17(s,1H),7.56(d,J=8.5Hz,2H),7.44(d,J=8.5Hz,2H),5.23(s,2H),4.46-4.38(m, 1H),3.80(s,3H),1.71-1.62(m,1H),1.39(d,J=6.5Hz,6H),1.11-1.05(m,1H),0.98-0.94(m,1H),0.92-0.86(m,1H),0.83-0.76(m,1H).

[0485] Example 17

[0486] Step 1: Synthesis of Intermediate 17-1

[0487] Mix (4-bromophenyl)hydrazine (24.07 g) and hexafluoroisopropanol (300 ml), add ethyl 2,4-dioxovalerate (18.5 g) under ice-cooling, and stir at room temperature for 12 hours. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 90:10) to obtain 27.8 g of Intermediate 17-1.

[0488] MS (ESI): m / z = 309.08 [M+H] + .

[0489] 1 H NMR (500MHz, DMSO-d6) δ7.79-7.74(m,2H),7.59-7.53(m,2H),6.77(s,1H),4.29(q,J=7.1Hz,2H),2.34(s,3H),1.29(t,J=7.1Hz,3H).

[0490] Step 2: Synthesis of intermediate 17-2

[0491] Intermediate 17-1 (10 g), methanol (40 ml), water (20 ml), and lithium hydroxide hydrate (6.79 g) were mixed and stirred at room temperature for 12 hours. The reaction mixture was concentrated to remove the methanol, and the residue was diluted with ethyl acetate (50 ml). The pH was adjusted to 6 with saturated aqueous citric acid. The organic phase was directly concentrated to obtain 8.9 g of Intermediate 17-2.

[0492] MS (ESI): m / z = 281.18 [M+H] +

[0493] 1H NMR (500MHz, DMSO-d6) δ12.81(br,1H),7.76(d,J=8.8Hz,2H),7.55(d,J=8.8Hz,2H),6.72(s,1H),2.34(s,3H).

[0494] Step 3: Synthesis of intermediate 17-3

[0495] Intermediate 17-2 (6 g) and dichloromethane (60 ml) were mixed, the reaction mixture was cooled to 0°C, and N,O-dimethylhydroxylamine hydrochloride (2.29 g), 4-methylmorpholine (2.38 g), and 3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-amine hydrochloride (4.50 g) were added. The mixture was stirred at room temperature for 3 hours. The pH of the reaction mixture was adjusted to 5-6 with 1 M dilute hydrochloric acid, and dichloromethane (100 mL) was added for extraction. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 6.4 g of Intermediate 17-3.

[0496] MS (ESI): m / z = 324.05 [M+H] + .

[0497] 1 H NMR (500MHz, DMSO-d6) δ7.75(d,J=8.7Hz,2H),7.56(d,J=8.7Hz,2H),6.66(s,1H),3.73(s,3H),3.34(s,3H),2.36(s,3H).

[0498] Step 4: Synthesis of intermediate 17-4

[0499] At 0°C, under a nitrogen atmosphere, 3M methylmagnesium bromide (7.77 mL) was slowly added dropwise to a solution of Intermediate 17-3 (6.3 g, 19.43 mmol) in tetrahydrofuran (50 mL). After complete addition, the mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was poured into saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to yield 5.4 g of Intermediate 17-4.

[0500] MS (ESI): m / z = 279.08 [M+H] + .

[0501] 1H NMR (500MHz, DMSO-d6) δ7.77(d,J=8.8Hz,2H),7.58(d,J=8.7Hz,2H),6.72(s,1H),2.49(s,3H),2.35(s,3H).

[0502] Step 5: Synthesis of Intermediate 17-5

[0503] Intermediate 17-4 (1.6 g) and 1,2-dichloroethane (40 mL) were mixed and cooled to 0°C. N,N-diethyl-1,1,1-trifluoro-14-sulfonamide (7.39 g) and triethylamine trihydrofluoride (4.62 g) were added dropwise. After the addition was complete, the temperature was raised to 70°C and stirred for 12 hours. The reaction mixture was poured into water (20 mL), the pH was adjusted to 7-8 with saturated sodium bicarbonate, and ethyl acetate (100 mL) was added for extraction. The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 0.72 g of Intermediate 17-5.

[0504] MS (ESI): m / z = 301.04 [M+H] + .

[0505] 1 H NMR (500MHz, DMSO-d6) δ7.76-7.71(m,2H),7.55-7.51(m,2H),6.53(s,1H),2.34(s,3H),1.99(t,J=18.8Hz,3H).

[0506] Step 6: Synthesis of Intermediate 17-6

[0507] Intermediate 17-5 (1.5 g), zinc powder (39.1 mg), 1,1'-bis(diphenylphosphino)ferrocene (276 mg), tris(dibenzylideneacetone)palladium (228 mg), zinc cyanide (360 mg), and N,N-dimethylacetamide (10 mL) were mixed and reacted at 150°C for 12 h under a nitrogen atmosphere. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to obtain 800 mg of Intermediate 17-6.

[0508] MS (ESI): m / z = 248.22 [M+H] + .

[0509] Step 7: Synthesis of Intermediate 17-7

[0510] Intermediate 17-6 (770 mg) and tetrahydrofuran (5 mL) were mixed, and 2.5 M lithium aluminum hydride (2.49 mL) was added under ice-cooling. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography to obtain 720 mg of Intermediate 17-7.

[0511] MS (ESI): m / z = 252.25 [M+H] + .

[0512] Step 8: Synthesis of Intermediate 17-8

[0513] Intermediate 17-7 (300 mg), tris(dibenzylideneacetone)dipalladium (109 mg), cesium carbonate (1167 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (138 mg), tert-butyl (6-chloro-5-fluoro-4-iodopyridin-3-yl)carbamate (445 mg), and 1,4-dioxane (5 mL) were mixed and reacted at 100°C under a nitrogen atmosphere for 12 hours. The reaction solution was directly concentrated, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 300 mg of intermediate 17-8.

[0514] MS (ESI): m / z = 422.22 [M+H] + .

[0515] 1 H NMR (500MHz, DMSO-d6) δ7.96 (s, 1H), 7.56-7.52 (m, 2H), 7.44 (d, J = 8.5Hz, 2H), 6.50 (s, 1H), 5.17 (s, 2H), 2.31 (s, 3H), 1.97 (t, J = 18.8Hz, 3H).

[0516] Step 9: Synthesis of Intermediate 17-9

[0517] Intermediate 17-8 (300 mg), potassium phosphate (453 mg), (4-cyclopropyl-6-methoxypyrimidin-5-yl)boronic acid (276 mg), tris(dibenzylideneacetone)dipalladium (65.1 mg), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (67.8 mg), 1,4-dioxane (5 mL), and water (0.25 mL) were mixed and reacted at 100°C under a nitrogen atmosphere for 1 hour. The reaction solution was directly concentrated, and the resulting crude product was separated and purified by silica gel column chromatography to obtain 70 mg of intermediate 17-9.

[0518] MS (ESI): m / z = 536.22 [M+H]+ .

[0519] 1 H NMR (500MHz, DMSO-d6) δ11.77(s,1H),8.65(s,1H),8.26(s,1H),7.52(d,J=6 .4Hz,2H),7.43(d,J=8.5Hz,2H),6.50(s,1H),5.18(s,2H),3.80(s,3H),2.3 0(s,3H),1.97(t,J=18.8Hz,3H),1.66(td,J=8.1,4.0Hz,1H),1.06(ddd,J=7 .5,4.7,2.5Hz,1H),0.99-0.92(m,1H),0.92-0.84(m,1H),0.84-0.76(m,1H).

[0520] Step 10: Synthesis of compound 17

[0521] At 0°C, sodium hydroxide (11 mg) was slowly added to a solution of intermediate 17-9 (100 mg) in N,N-dimethylformamide (3 mL). After the addition was complete, the mixture was kept at 0°C for 30 minutes. Deuterated iodomethane (28 mg) was added to the reaction solution, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine, dried, and concentrated. The resulting crude product was separated and purified by silica gel column chromatography to obtain 42 mg of compound 17.

[0522] HRMS (ESI) m / z [M+H] + :553.2368.

[0523] 1 H NMR(500MHz,DMSO-d6)δ8.66(s,1H),8.47(s,1H),7.52(d,J=8.5Hz,2H),7.44(d,J=8.4Hz,2H),6.50(s,1H),5.27-5.19(m,2H),3.80(s,3H),2.30 (d,J=8.9Hz,3H),1.97(t,J=18.8Hz,3H),1.65(td,J=8.0,4.1Hz,1H),1. 11-1.04(m,1H),0.99-0.93(m,1H),0.92-0.86(m,1H),0.83-0.77(m,1H).

[0524] Test Example 1: In vitro cell proliferation inhibitory activity

[0525] 1.1 MDA-MB-436 cell proliferation inhibitory activity assay

[0526] 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 .

[0527] The experimental results are shown in Table 1, where A represents: 0nM<IC 50 ≤50nM; B represents: 50nM<IC 50 ≤100nM; C represents: 100nM<IC 50 ≤1000nM; D represents: 1000nM<IC 50 .

[0528] Table 1 MDA-MB-436 cell proliferation inhibitory activity

[0529] Test Example 2: In vitro enzymatic inhibition activity

[0530] 2.1 USP1 / UAF1 enzyme inhibitory activity assay

[0531] 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 .

[0532] 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 .

[0533] Table 2 USP1 / UAF1 enzymatic inhibitory activity

[0534] The disclosed compounds have good USP1 / UAF1 enzyme inhibitory activity.

[0535] Test Example 3: In vitro CYP450 enzyme inhibition activity

[0536] The human liver microsome incubation system was prepared by mixing PBS buffer (pH 7.4), liver microsome solution (0.2 mg / ml), a mixed CYP450 specific substrate, the test compound, and an NADPH+MgCl2 solution, and incubating at 37°C and 300 rpm for 0.5 hours. A positive control group and a negative control group were also set up. The positive control group replaced the test compound with a specific inhibitor in the above system, while the negative control group replaced the test compound with a solvent in the above system. After incubation, the sample was added with an acetonitrile solution containing an internal standard to prepare a supernatant for protein precipitation. After dilution, the supernatant was used to determine the metabolites of the specific substrate by LC / MS / MS. The inhibition rate was calculated using the formula (1 – (test group / negative control group)) × 100%. The disclosed compounds have low inhibitory effects on CYP450 enzymes in vitro.

[0537] Test Example 4: Pharmacokinetics in mice

[0538] 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.

[0539] 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.

[0540] 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.

[0541] The compounds disclosed herein have good pharmacokinetic properties.

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 Selected from C(R 1 )2、C(=Z)、N(R 7 ), S or O; X 4 、X 5 、X 6 and X 7 are independently selected from C(R 5 ) or N; Each R 1 and R 5 are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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; Z is selected from O, S or N (R 8 ); or X 2 and X 3 are linked to each other to form a 5-7 membered ring which is optionally substituted 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, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 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; 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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; Each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 3-12 Cycloalkyl or 3-12 membered heterocyclic group, said -NH2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 1-12 Alkoxy, C 1-12 Deuterated alkoxy, C 3-12 The cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents; Each R 2a and R 6a are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -SH, -COOH, -NH2, -NHC 1-12 Alkyl, -N(C 1-12 Alkyl)2, C 1-12 Alkyl, C 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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 1-12 Deuterated alkyl, C 2-12 Alkenyl, C 2-12 Alkynyl, C 1-12 Alkoxy, C 1-12 Deuterated 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; provided that, X 1 When N, X 3 Not for NH.

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 ), X 3 Selected from C=O, N(R 7 ), S or O; preferably, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from C=O, N(R 7 ), S or O; or X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from C=O, N(R 7 ), S or O; or X1 is selected from C(R1), X2 is selected from C(R1); X3 is selected from C=O, N(R7), S or O; further preferably, X 2 Selected from C(R 1 ), X 1 Select from N;X 3 Selected from N(R 7 ); or X 2 Selected from N, X 1 Selected from C(R 1 );X 3 Selected from N(R 7 ); or X 1 Selected from C(R 1 ), X 2 Selected from C(R 1 );X 3 Selected from N(R 7 ).

3. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: X 2 and X 3 are connected to each other to form a 5-7 membered ring optionally substituted by one or more substituents, wherein the 5-7 membered ring is selected from 5-7 membered heterocycloalkenyl, C 5-7 Cycloalkenyl, phenyl or 5-6 membered heteroaryl; preferably, X 2 and X 3 are connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein X 3 The ring atoms at the positions shown are N atoms; further preferably, X 2 and X 3 are connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein X 2 The ring atoms at the positions shown are C atoms; most preferably, X 2 and X 3 are connected to form a 5-7 membered ring optionally substituted by one or more substituents, wherein X 2 The ring atoms at the indicated positions are C atoms, X 3 The ring atoms at the indicated positions are N atoms.

4. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: X 4 、X 5 、X 6 and X 7 At least 2 of them are selected from C(R 5 ); preferably, X 4 Selected from C(R 5 ), X 5 Selected from C(R 5 ); or preferably, X 6 Selected from C(R 5 ), X 7 Selected from C(R 5 ).

5. The compound of formula (I) according to any one of claims 2 or 4, its isomer or a pharmaceutically acceptable salt thereof, wherein: Each R 1 and R 5 are independently selected from hydrogen, deuterium, halogen, -CN, -OH, -NH2, -NHC 1‐3 Alkyl, -N(C 1‐3 Alkyl)2, C 1‐3 Alkyl, C 1‐3 Deuterated alkyl, C 1‐3 Alkoxy or C 1‐3 Deuterated alkoxy, the C 1‐3 Alkoxy, C 1‐3 Deuterated alkoxy, C 1‐3 Alkoxy or C 1‐3 Deuterated alkoxy is optionally substituted independently by one or more substituents; preferably, each R 1 and R 5 Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2; preferably, each R 1 Each is independently selected from hydrogen, -F, methyl, -CD3, ethyl, -CD2CD3 or CN; Or, preferably, each R 5 are independently selected from hydrogen or -F.

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, -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 by one or more substituents; preferably, each R 3 and R 4 are independently selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 Deuterated alkoxy, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy or C 1-3 Deuterated alkoxy is optionally substituted independently by one or more substituents; preferably, each R 3 and R 4 Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2; 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 1, its isomer or pharmaceutically acceptable salt thereof, wherein: R 6 Selected from hydrogen, halogen, -CN, -OH, -NH2, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy, C 3-6 Cycloalkyl, phenyl, 5-6 membered heteroaryl or 3-6 membered heterocyclic group are optionally independently substituted by one or more R 6a Substituted; preferably, 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.

10. The compound of formula (I) according to any one of claims 8 or 9, its isomer or a pharmaceutically acceptable salt thereof, wherein: Each R 2a and R 6a are independently selected from halogen, -CN, -OH, -NH2, C 1‐3 Alkyl, C 1‐3 Deuterated alkyl, C 1‐3 Alkoxy, C 1‐3 Deuterated alkoxy, C 3‐6 Cycloalkyl or 3-6 membered heterocyclic group, said C 1‐3 Alkyl, C 1‐3 Deuterated alkyl, C 1‐3 Alkoxy, C 1‐3 Deuterated alkoxy, C 3‐6 Cycloalkyl or 3-6 membered heterocyclic group is optionally substituted independently by one or more substituents; preferably, each R 2a and R 6a Each of the following groups is independently selected from halogen, -CN, -OH, -NH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl or azetidinyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl and azetidinyl are optionally substituted independently with one or more substituents; preferably, each R 2a and R 6a Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2; Or, R 2a Selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, Or, R 6a Selected from -F, -Cl, -Br, -I, methyl, isopropyl, methoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 11. The compound of formula (I) according to claim 1, its isomer or pharmaceutically acceptable salt thereof, wherein: Each R 7 、R 8 or R 9 Each independently selected from hydrogen, -NH2, C 1‐3 Deuterated alkyl, C 1‐3 Alkyl, C 1‐3 Alkoxy, C 1‐3 Deuterated alkoxy, C 3‐6 Cycloalkyl or 3-6 membered heterocyclic group, said -NH2, C 1‐3 Deuterated alkyl, C 1‐3 Alkyl, C 1‐3 Alkoxy, C 1‐3 Deuterated alkoxy, C 3‐6 Cycloalkyl or 3-6 membered heterocyclic group is optionally substituted by one or more substituents; preferably, each R 7 、R 8 or R 9 Optionally independently substituted with one or more groups selected from halogen, deuterium, OH, CN or NH2; preferably, each R 7 、R 8 or R 9 Each is independently selected from hydrogen, -NH2, methyl, ethyl, -CD2CD3, cyclopropyl or -CD3.

12. 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 3 、X 4 、X 5 、X 6 、X 7 、R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I); 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-2), in, X 5 selected from CH or N; X 1 、X 3 、R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I); 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-3), in, X 5 selected from CH or N; X 3 、R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I); 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-4), in, X 5 selected from CH or N; R 2 、R 3 、R 4 and R 6 As defined by the compound shown in formula (I); 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 5 selected from CH or N; Y 1 、Y 2 and Y 3 are independently selected from CH or N; X 3 、R 3 、R 4 、R 6 and R 2a As defined by the compound shown in formula (I); 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 5 selected from CH or N; Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5); X 3 、R 2a 、R 3 、R 4 and R 6a As defined by the compound shown in formula (I); 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 5 selected from CH or N; Y 1 、Y 2 and Y 3 As defined by the compound shown in formula (I-5); X 3 、R 2a 、R 3 、R 4 and R 6a As defined by the compound shown in formula (I); 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.

13. A compound of the formula:

14. A pharmaceutical composition comprising a therapeutically or prophylactically effective amount of the compound according to any one of claims 1 to 13, its isomer or a pharmaceutically acceptable salt thereof.

15. Use of the compound according to any one of claims 1 to 13, its isomer or 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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