Preparation method, application and application of pyridazinone compound as ubiquitin-specific protease 1 inhibitor

Abstract

The invention discloses a preparation method, application and application of a pyridazinone compound as a ubiquitin-specific protease 1 inhibitor, and particularly discloses a compound as shown in a formula (I), an optical isomer, a tautomer or pharmaceutically acceptable salt of the compound, and application of the compound as the ubiquitin-specific protease 1 inhibitor.

Description

Preparation method, application and use of pyridazinone compounds as ubiquitin-specific protease 1 inhibitors

[0001] This application claims priority to:

[0002] CN202311252269.4, application date September 25, 2023;

[0003] CN202311534440.0, application date November 16, 2023;

[0004] CN202410155795.7, application date February 2, 2024;

[0005] CN202410981590.4, application date July 19, 2024. Technical Field

[0006] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a preparation method, application and use of a pyridazinone compound as a ubiquitin-specific protease 1 inhibitor. Background Art

[0007] Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs) that regulate various cellular processes by deconjugating ubiquitin from substrates. DUBs are encoded by approximately 100 human genes and are divided into six families, the largest of which is the ubiquitin-specific protease (USP) with more than 50 members. DUBs and their substrate proteins are often dysregulated in cancer, supporting the hypothesis that targeting specific DUB family members may lead to anti-tumor activity by enhancing the activity of ubiquitination and subsequent degradation of other key proteins involved in tumor growth, survival, differentiation and maintenance of oncogenic substrates and the tumor microenvironment. USP1 is a cysteine ​​isopeptidase of the USP subfamily of DUBs. Full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593 and Asp751. USP1 deubiquitinates various cellular targets involved in different processes related to cancer. For example, USP1 deubiquitinates PCNA (proliferating cell nuclear antigen), a key protein in translesion synthesis (TLS), and FANCD2 (Fanconi anemia complementation group D2), a key protein in the Fanconi anemia (FA) pathway. Therefore, inhibiting USP1 with small molecule inhibitors has the potential to be a therapeutic approach for treating cancer and other diseases. For these reasons, there is a considerable unmet need for potent small molecule inhibitors of USP1.

[0008] Summary of the Invention

[0009] In one aspect of the present invention, the present invention provides a compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof,

[0010] in,

[0011] Selected from

[0012] when Selected from When X1 is selected from N;

[0013] when Selected from When X1 is selected from C;

[0014] X2 is selected from N and CR 2X ;

[0015] X3 selected from N and CR 3X ;

[0016] R 2X 、R 3X Each independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -OC(=O)-C 1-6 Alkyl, C 3-6 Cycloalkyl-O-, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, C 1-6 Alkylthio, -S(O)2-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)-N(H)-C 1-6 Alkyl, NRxR Y 、-C(=O)NRxR Y and-P(=O)RxR Y , said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -OC(=O)C 1-6 Alkyl, C 3-6 Cycloalkyl-O-, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkylthio, -S(O)2C1-6 Alkyl, -S(O)C 1-6 Alkyl or -S(O)N(H)-C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH;

[0017] R X 、R Y Each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0018] or, R X 、R Y Together with the nitrogen atom to which it is attached, it forms a 3-9 membered heterocyclic group or a 5-9 membered heteroaryl group, wherein the 3-9 membered heterocyclic group or the 5-9 membered heteroaryl group is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted;

[0019] R2 is selected from phenyl, naphthyl and 5-9 membered heteroaryl, wherein the phenyl, naphthyl or 5-9 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R';

[0020] R' is selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0021] L is selected from CR3R4, NR3, O, S, S(=O) and S(=O)2;

[0022] R3 and R4 are each independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH;

[0023] Or, R3, R4 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted;

[0024] Ring E is selected from 5-7 membered unsaturated heterocyclic group, C 6-14 Aryl, 5-9 membered heteroaryl, the 5-7 membered unsaturated heterocyclic group, C 6-14 Aryl, 5-9 membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R';

[0025] Ring B is selected from C 6-14 Aryl, C 3-9 Cycloalkyl, C 5-15 Bridged cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, the C 6-14 Aryl, C 3-9 Cycloalkyl, C 5-15 Bridged cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl are optionally substituted with 1, 2 or 3 R5;

[0026] R5 is selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0027] Or, two optional R5 on ring B together with the atoms to which they are attached are linked together to form C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 cycloalkyl substitution;

[0028] Optionally, R5 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NRa R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 aryl, 5-9 membered heteroaryl and 3-9 membered heterocyclyl;

[0029] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 cycloalkyl substitution;

[0030] The C 1-6 The heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, and 5-9 membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(O)-, -S(O)2- and N, and the remaining variables are as defined herein.

[0031] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0032] in,

[0033] Y1, Y2, Y3, Y4, Y5 are each independently selected from N or C(R');

[0034] R' is independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 The remaining variables are as defined in the present invention.

[0035] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0036] in,

[0037] R 2A 、R 2B 、R 2C 、R 2D 、R 2E 、R 2F 、R 2G 、R 2H 、R 2I 、R 2J 、R 2K 、R 2L 、R 2M 、R 2N 、R 2O Each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 The remaining variables are as defined in the present invention.

[0038] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0039] in,

[0040] X5, X6, X7, and X8 are each independently selected from N and CR B ;

[0041] R B Selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH, and the remaining variables are as defined herein.

[0042] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0043] in,

[0044] R 5A 、R 5B 、R 5C 、R5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NRa S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0045] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 The remaining variables are as defined herein.

[0046] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0047] in,

[0048] X5, X6, X7, T1, and T2 are each independently selected from N and CR B ;

[0049] R B Selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH;

[0050] J, K, and M are each independently selected from CR 7A R 7B NR 7A , C(=O), O, S, S(O) and S(O)2;

[0051] R 7A 、R 7B Each independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH;

[0052] Ring A is selected from C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl and 3-9 membered heterocyclic group, the C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl are optionally substituted with 1, 2 or 3 R6;

[0053] R6 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a Rb 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-

[0054] S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0055] Or, two optional R6 on ring A together with the carbon atoms to which they are attached are linked together to form C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted;

[0056] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted;

[0057] The C 1-6Heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-9 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(O)-, -S(O)2- and N, and the remaining variables are as defined herein.

[0058] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0059] in,

[0060] R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0061] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 The remaining variables are as defined herein.

[0062] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0063] in,

[0064] X 4A 、X 5A are each independently selected from N or C(R');

[0065] X 4B 、X 5B are each independently selected from O, S, N(R') or CR'R";

[0066] R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 The remaining variables are as defined in the present invention.

[0067] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0068] in,

[0069] X 4A 、X 5A 、X 6A are each independently selected from N or C(R');

[0070] X 4B 、X 5B 、X 6B are each independently selected from O, S, N(R') or CR'R";

[0071] R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 The remaining variables are as defined in the present invention.

[0072] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0073] in,

[0074] X 5B 、X 6B 、X 7B are each independently selected from O, S, N(R') or CR'R";

[0075] R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 The remaining variables are as defined in the present invention.

[0076] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0077] in,

[0078] R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0079] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 The remaining variables are as defined herein.

[0080] In some embodiments of the present invention, the structural unit Selected from

[0081] The remaining variables are as defined in the present invention.

[0082] In some embodiments of the present invention, R2 is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl and pyrazolyl, and the phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl or pyrazolyl is optionally substituted with 1, 2, 3 or 4 R';

[0083] Optionally, R' is each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0084] Optionally, R' is each independently selected from H, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -OCH3, -SCH3,

[0085] Optionally, R2 is selected from

[0086] R 2A 、R 2B 、R 2C 、R 2D 、R 2E 、R 2F 、R 2G 、R 2H 、R 2I 、R 2J 、R 2K 、R 2L 、R 2M 、R 2N 、R 2O Selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3- 9-membered cycloalkyl and 3-9-membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0087] Optionally, R2 is selected from The remaining variables are as defined in the present invention.

[0088] In some embodiments of the present invention, L is selected from NR3, CR3R4;

[0089] R3 and R4 are each independently selected from H, OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3Alkylthio, C 1-3 Alkylamino, C 2-3 Alkenyl, C 2-3 Alkynyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2 or COOH;

[0090] Optionally, R3 and R4 are each independently selected from H, OH, CN, halogen, methyl, ethyl and propyl, and the remaining variables are as defined herein.

[0091] In some embodiments of the present invention, R5 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl and 5-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0092] Optionally, R5 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR aC(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl,

[0093] R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0094] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3- 9-cycloalkyl-O-, C 6-14Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted;

[0095] Optionally, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-6 Alkyl-C(=O)N(C 1-6 Alkyl) 2, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3- 6-membered cycloalkyl, 3-6-membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6Alkylamino substitution;

[0096] Optionally, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5P Each independently selected from H, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heteroalkyl and -C 1-3 Alkyl-C(=O)N(C 1-3 Alkyl) 2, the C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-3 Alkyl-C(=O)N(C 1-3 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0097] Optionally, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 、R 5PEach independently selected from H, CN, halogen, OCH3, OCH2CH3, CF3, CHF2, CD3, methyl, ethyl,

[0098] Optionally, R5 is selected from The remaining variables are as defined in the present invention.

[0099] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, has the following structure:

[0100] in,

[0101] R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0102] R a 、R b Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3- 9-cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 The remaining variables are as defined herein.

[0103] In some embodiments of the present invention, the structural unit Selected from

[0104] R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-6 Alkyl-C(=O)N(C 1-6 Alkyl) 2, the C 1-6 Alkyl, C 1- 6 heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0105] Optionally, R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G Each independently selected from H, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6Cycloalkyl, 3-6 membered heteroalkyl and -C 1-3 Alkyl-C(=O)N(C 1- 3 alkyl) 2, the C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-3 Alkyl-C(=O)N(C 1-3 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0106] Optionally, R 6A 、R 6B 、R 6C 、R 6D 、R 6E 、R 6F 、R 6G Each independently selected from H, CN, halogen, OCH3, OCH2CH3, CF3, CHF2, CD3, methyl, ethyl,

[0107] Optionally, Selected from The remaining variables are as defined in the present invention.

[0108] In some embodiments of the present invention, J, K, and M are each independently selected from NR 7A , CR 7A R 7B , C(=O) and O;

[0109] R 7A 、R 7B Each independently selected from H, OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2- 3 alkenyl, C 2-3 Alkynyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2-3 Alkenyl, C 2-3 Alkynyl or C 3-6Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2 or COOH;

[0110] Optionally, R 7A 、R 7B are each independently selected from H, OH, CN, halogen, methyl, ethyl and propyl, and the remaining variables are as defined herein.

[0111] In some embodiments of the present invention, the structural unit Selected from

[0112] R 6A 、R 6B 、R 6C 、R 6D Each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-6 Alkyl-C(=O)N(C 1-6 Alkyl) 2, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0113] Optionally, the structural unit Selected from The remaining variables are as defined in the present invention.

[0114] In another aspect of the present invention, the present invention also provides a compound of the following formula, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, which is selected from:

[0115] In yet another aspect of the present invention, the present invention further provides the use of the aforementioned compound, its optical isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating diseases associated with USP1 activity or expression.

[0116] In some embodiments of the present invention, the above-mentioned diseases related to USP1 activity or expression are selected from cancer-related diseases and the like.

[0117] In some embodiments of the present invention, the above-mentioned cancer-related diseases are selected from bone cancer, brain cancer, soft tissue cancer, kidney cancer, bladder cancer, skin cancer, lung cancer, colon cancer, nervous system cancer, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, uterine cancer, cervical cancer, etc.

[0118] In some embodiments of the present invention, the above-mentioned bone cancer is selected from osteosarcoma, chondrosarcoma, etc.

[0119] In some embodiments of the present invention, the above-mentioned brain cancer is selected from glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, etc.

[0120] In some embodiments of the present invention, the above-mentioned soft tissue cancer is selected from rhabdoid sarcoma and the like.

[0121] In some embodiments of the present invention, the above-mentioned skin cancer is selected from melanoma and the like.

[0122] In some embodiments of the present invention, the above-mentioned lung cancer is selected from non-small cell lung cancer, etc.

[0123] Definition and Description

[0124] 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.

[0125] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, 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.

[0126] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0127] 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 these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0128] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention 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 invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0129] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and readily interconvert into each other. If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0130] The compounds of the present invention 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 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 of the present invention, whether radioactive or not, are included within the scope of this invention.

[0131] "Optional" or "optionally" means 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.

[0132] The term "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced with a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted with" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any chemically feasible.

[0133] 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 1, 2, or 3 Rs, the group may optionally be substituted with up to three Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0134] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L2 represents a single bond, it means that the structure is actually A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0135] Unless otherwise indicated, when a group bond is indicated by a dashed line When, for example, In the example, the dashed line indicates the point of attachment of the group to the rest of the molecule.

[0136] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0137] When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time Phenyl and cyclopentyl groups can be connected in the same direction as reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups 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.

[0138] Unless otherwise specified, the number of ring atoms refers to the number of atoms that make up the ring itself in a compound (such as a monocyclic compound, a paracyclic compound, a spirocyclic compound, a bridged ring compound, a cross-linked compound, a carbocyclic compound, or a heterocyclic compound) formed by atoms bonded together to form a ring. The number of ring atoms is usually defined as the number of ring members. For example, a "4-6 membered ring" refers to a "ring" with 4-6 atoms arranged around it. When a ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0139] Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms, or a combination thereof, which can represent a straight chain and / or branched alkyl group, which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specified in the specification, the alkyl group may be optionally substituted.

[0140] 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 2-6 Alkyl, etc.; it 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 such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu"), or tert-butyl ("t-Bu"), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, and the like.

[0141] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), methylene, 1,2-ethylene, 1,3-propylene, and the like.

[0142] Unless otherwise specified, the term "alkenyl" refers to a group containing a carbon-carbon sp 2 A double-bonded hydrocarbon group may represent a straight and / or branched alkenyl group, wherein a branched group refers to one or more alkyl groups such as methyl, ethyl or propyl groups attached to a straight alkenyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.

[0143] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylenyl, hexadienyl, ethenylene, propenylene, sec-butenylene, and the like.

[0144] 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, ethenylene, propenylene, and the like.

[0145] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond. It can represent a straight and / or branched alkynyl group, where a branched chain refers to one or more alkyl groups, such as methyl, ethyl, or propyl, attached to a straight alkynyl chain. It can be monovalent, divalent, or polyvalent. Unless otherwise specified in the specification, an alkynyl group may be optionally substituted.

[0146] Unless otherwise specified, the term “C 2-6 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-6 Alkynyl groups include C 2-5 、C 2-4 、C 2-3 , C2, C 2-6 , C6 and C5 alkynyl, etc. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, pentynyl, pentynylene, and the like.

[0147] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, and the like.

[0148] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the "alkyl" in the "alkyl radical" is defined as above in the present invention. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl group is C 1-20 In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1-3 Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule. Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -OCHCHCH, -OCH(CH), -CH-CH-O-CH, -NHCH, -N(CH), -NHCHCH, -N(CH)(CHCH), -CH-CH-NH-CH, -CH-CH-N(CH)-CH, -SCH, -SCHCH, -SCHCHCH, -SCH(CH), -CH-S-CH-CH, -CH-CH, -S(=O)-CH, -CH-CH-S(=O)-CH, etc.; up to two heteroatoms thereof may be consecutive, for example, -CH-NH-OCH. Unless otherwise specified in the specification, heteroalkyl groups may be optionally substituted. Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected to the rest of the molecule via an oxygen atom, wherein "alkyl" in "alkyl group" has the same meaning as described above in the present invention. Unless otherwise specified in the specification, alkoxy groups may be optionally substituted.

[0149] 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 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, and the like.

[0150] Unless otherwise specified, the term “C 1-4 "Alkoxy" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-4 Alkoxy groups include C 1-3 、C 1-2 、C 2-4 , C4 and C3 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, s-butoxy and t-butoxy), methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, and the like.

[0151] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-2 、C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy, and the like.

[0152] Unless otherwise specified, the term "amino" may be a monovalent Two-price or multi-price

[0153] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the rest of the molecule via an amino group as defined above, wherein "alkyl" in "alkyl group" has the same meaning as described above in the present invention. Unless otherwise specified in the specification, an alkylamino group may be optionally substituted.

[0154] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0155] Unless otherwise specified, the term “C 1-4 "Alkylamino" means an alkyl group containing 1 to 4 carbon atoms which is attached to the rest of the molecule via an amino group. 1-4 Alkylamino groups include C 1-3 、C 1-2 、C 2-4 , C4, C3 and C2 alkylamino, etc. 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0156] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0157] Unless otherwise specified, the term "alkylthio" refers to an alkyl group attached to the rest of the molecule via a sulfur atom, wherein "alkyl" in "alkyl group" has the same meaning as described above in the present invention. Unless otherwise specified in the specification, an alkylthio group may be optionally substituted.

[0158] Unless otherwise specified, the term “C 1-20 "Alkylthio" refers to those alkyl groups containing 1 to 20 carbon atoms which are linked to the rest of the molecule through a sulfur atom. 1-20 Alkylthio includes C 1-19 、C 1-14 、C 1-12 、C 2-6 、C 2-4 、C 15 、C10 , C8, C5 and C 20 Alkylthio, etc. 1-20 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -SCH2CH2CH2CH3, -SCH2CH2(CH3)2, -SCH2CH2CH2CH2CH3, -SCH2CH2CH2CH2CH3, -SCH2(CH2CH2CH3)(CH2CH2CH2CH3), and the like.

[0159] 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 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0160] Unless otherwise specified, the term “C 1-4 "Alkylthio" refers to those alkyl groups containing 1 to 4 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-4 Alkylthio includes C 1-3 、C 1-2 、C 2-4 , C4, C3 and C2 alkylthio, etc. 1-4 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0161] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0162] Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group composed of carbon and hydrogen atoms, which may include cyclic, spirocyclic and / or bridged ring systems. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. "C 4-6 "Cycloalkyl" means a cycloalkyl group having 4 to 6 ring carbon atoms. Similarly, "C 3-4 "Cycloalkyl" means a cycloalkyl group having 3-4 ring carbon atoms. Unless stated otherwise specifically in the specification, a cycloalkyl group may be optionally substituted.

[0163] Unless otherwise specified, “C 3-20 "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group having 3 to 20 ring carbon atoms, such as 3 to 15 ring carbon atoms, such as 3 to 6 ring carbon atoms; it can be monovalent, divalent or polyvalent. 3-20 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0164] Unless otherwise specified, “C 3-9 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 9 carbon atoms, which is a monocyclic or bicyclic system. 3-9 Cycloalkyl groups include C 3-8 、C 3-7 、C 3-6 、C 3-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-9 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0165] Unless otherwise specified, “C 3-6 "Cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3 to 6 ring carbon atoms, such as 3 to 5 ring carbon atoms, such as 3 to 4 ring carbon atoms; it can be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0166] Unless otherwise specified, “C 4-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic or bicyclic system. 4-6 Cycloalkyl groups include C 4-5 、C 5-6 , C4, C5 and C6 cycloalkyl, etc.; which may be monovalent, divalent or polyvalent. 4-6Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0167] Unless otherwise specified, the term “C 5-15 "Bridged cycloalkyl" refers to a bridged cycloalkyl group containing 5 to 15 carbon atoms, examples of which include "C 7-15 Bridged cycloalkyl" and "C 5-11 Bridged cycloalkyl". The term "C 5-15 Representative examples of "bridged cycloalkyl" include, but are not limited to, adamantanyl, noradamantyl, norbornyl (systematically named bicyclo[2.2.1]heptanyl), and cubanyl.

[0168] Unless otherwise specified, the term "heterocyclyl" refers to a non-aromatic saturated cyclic group that exists as a monocyclic, fused, spirocyclic and / or bridged ring, wherein at least one of the ring atoms is a heteroatom or heteroatom group, and the rest are carbon atoms; in some embodiments, each occurrence of the heteroatom is independently selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), the nitrogen heteroatom is optionally quaternized, and in other embodiments, each occurrence of the heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heteroatom group may be positioned at any interior position of the heterocycloalkyl group, including the position at which the heterocycloalkyl group is attached to the rest of the molecule. In some embodiments, the heterocycloalkyl group is a 3-20 membered heterocycloalkyl group; in some embodiments, the heterocycloalkyl group is a 3-10 membered heterocycloalkyl group; in other embodiments, the heterocycloalkyl group is a 3-6 membered heterocycloalkyl group. Unless stated otherwise specifically in the specification, the heterocycloalkyl group may be optionally substituted. 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 B, O, S and N or heteroatoms as described above, 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). This includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl, including the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyls, etc. Examples of 3-6 membered heterocycloalkyl groups 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 or homopiperidinyl, etc.

[0169] Unless otherwise specified, when a substituent connected to Ring A can be connected to Ring A to form a ring, it means that the substituent can be connected to any position of Ring A to form a new ring together with Ring A, including a cyclic, spirocyclic or bridged ring; wherein Ring A can be selected from the cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, etc. as described above. For example, when The R in connected to form a 6-membered ring, examples of which include but are not limited to wait.

[0170] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 、C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0171] Unless otherwise specified, the term "aryl" refers to a hydrocarbon ring system radical comprising at least one aromatic ring. In the present invention, an aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a paracyclic, spirocyclic and / or bridged ring system. Aryl groups include, but are not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, triphenylene, perylene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene and derivative groups thereof. Unless otherwise specified in the specification, an aryl group may be optionally substituted.

[0172] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, containing 1 to 3 heteroatoms; more preferably 5 or 6-membered, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like. The heteroaryl group can be attached to the rest of the molecule via a heteroatom or carbon atom. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include: etc. Non-limiting examples of heteroaryl groups also include triazine, pyridine, pyrimidine, imidazole, furan, thiophene, benzofuran, benzothiophene, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, quinoline, isoquinoline, o-naphthylene, quinoxaline, phenanthridine, primary idine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole, and derivatives thereof. Unless otherwise specifically stated in the specification, a heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio or heterocycloalkylthio.

[0173] As used herein, the term "substituted" means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a bond to a non-hydrogen atom, including but not limited to halogen atoms (e.g., F, Cl, Br, I), oxygen-containing groups (e.g., hydroxyl, alkoxy, ester groups), sulfur-containing groups (e.g., thiol, thioalkyl, sulfone, sulfonyl, sulfoxide groups), nitrogen-containing groups (e.g., amine, amide, alkylamino, dialkylamine, arylamine, aryl-alkyl-amine, diarylamine, N-oxide groups, imide, enamine groups), silicon-containing groups (e.g., trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0174] As used herein, the term "substituted" also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are replaced by a higher order bond (e.g., double bond or triple bond) of a heteroatom, such as the oxygen in carbonyl, carboxyl, and ester groups, and the nitrogen in imines, oximes, hydrazones, and nitriles. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g SO2R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、SO2R g 、-OSO2R g 、-SO2OR g , =NSO2R g With -SO2NR g R h Substituted. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2R g 、-CH2SO2NRg R h The R g With R h Identical or different, independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl." substituted " can also represent that one or more hydrogen atoms in any of the above-mentioned groups are replaced by amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxyl, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. In addition, each of the above-mentioned substituents can also be optionally replaced by one or more of the above-mentioned substituents.

[0175] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0176] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, and conformers, among others.

[0177] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0178] As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activities. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography, such as HPLC.

[0179] Stereochemical definitions and conventions may be followed in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign with which the compound rotates plane-polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

[0180] The racemic mixture can be used as such or resolved into its individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry," Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then liberating one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0181] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0182] The compounds of the present invention 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 of the present invention.

[0183] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Specific implementation method:

[0184] The present application is described in detail below by way of examples, but this does not necessarily mean that there are any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. 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 application without departing from the spirit and scope of the present application.

[0185] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0186] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker ASCEND TM -400 NMR spectrometer, the determination solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0187] MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.

[0188] HPLC analysis was performed using a Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 μm column).

[0189] Chiral HPLC analysis was performed using THARSFC X5.

[0190] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) were 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products were 0.4mm-0.5mm.

[0191] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0192] High performance liquid phase preparation used Waters2767, Waters2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0193] Chiral preparative column chromatography used Shimadzu LC20-AP and THARSFC PREP80.

[0194] The pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0195] A Biotage initiator+ microwave reactor was used for the microwave reaction.

[0196] Unless otherwise specified in the experimental examples, all reactions were carried out under an argon or nitrogen atmosphere.

[0197] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 liter.

[0198] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0199] Unless otherwise specified in the experimental examples, the reaction temperature was room temperature, ranging from 20°C to 30°C.

[0200] Example 1: Synthesis of Compound 1

[0201] Step 1: Synthesis of compound 1-2

[0202] Compound 1-1 (500 mg) was dissolved in anhydrous tetrahydrofuran (10.0 mL). The atmosphere was replaced with nitrogen. Isopropylmagnesium chloride and lithium chloride (1.3 M, 2.2 mL, 2.83 mmol) were slowly added dropwise at zero degrees Celsius. Stirring was continued for 30 minutes, and di-tert-butyl azodicarboxylate (501 mg) was added. The reaction was stirred at room temperature for 1 hour. LCMS indicated that the reaction was complete. The reaction was quenched by adding saturated aqueous ammonium chloride (10 mL). The mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. To the concentrated residue was added a 1,4-dioxane solution (4 mL) and a dioxane hydrochloride solution (4 M, 2.0 mL, 8.00 mmol). The mixture was stirred at room temperature for 16 hours. After completion of the reaction, dichloromethane (50 mL) and methanol (5 mL) were added. The mixture was filtered, and the filter cake was dried to obtain compound 1-2 (300 mg).

[0203] LC-MS (ESI) [M+H] + 181.2.

[0204] Step 2: Synthesis of Compounds 1-4

[0205] To a solution of compound 1-3 (2 g) in chloroform (20.0 mL) were added azobisisobutyronitrile (77 mg) and N-bromosuccinimide (1.84 g) in sequence, and the atmosphere was replaced with nitrogen. The reaction temperature was raised to 70° C. and stirred for 2 hours. LC-MS showed that the reaction was complete, and water (40 mL) was added. The mixture was extracted three times with dichloromethane (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (petroleum ether / ethyl acetate = 100% / 0% to 75% / 25%) to give compound 1-4 (2.4 g).

[0206] 1 H NMR (400MHz, CDCl3-d) δ7.77 (dd, J=7.3, 1.1Hz, 1H), 7.66-7.57 (m, 2H), 7.35 (s, 1H).

[0207] Step 3: Synthesis of Compounds 1-5

[0208] Compound 1-4 (200 mg) was dissolved in 1M aqueous hydrochloric acid solution (6.0 mL), the nitrogen atmosphere was replaced, and the mixture was heated to 100°C and stirred for 1 hour. After cooling naturally to room temperature, compound 1-2 (149 mg) was added, and the reaction system was heated to 100°C and stirred for 3 hours. After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by column chromatography (petroleum ether / ethyl acetate = 100% / 0% to 30% / 70%) to obtain compound 1-5 (130 mg).

[0209] LC-MS (ESI) [M+H] + 373.0.

[0210] Step 4: Synthesis of compound 1

[0211] Compound 1-5 (100 mg) was dissolved in a mixture of 2-methyltetrahydrofuran (5 mL) and water (0.5 mL). 1-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)methyl)phenyl)-4-trifluoromethylimidazole (197 mg), potassium carbonate (75 mg), and tetrakis(triphenylphosphine)palladium (15.6 mg) were added sequentially. The atmosphere was replaced with nitrogen, and the mixture was heated to 90°C and stirred for 16 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the concentrated residue was purified by reverse phase preparative (FA) to obtain compound 1 (6.57 mg).

[0212] LC-MS (ESI) [M+H] + 533.0.

[0213] 1H NMR (400MHz, CDCl3-d) δ8.62(s,1H),8.27(s,1H),7.77(t,J=7.7Hz,1H),7.66(d,J=7.3Hz,1H),7.52(t,J=8.3Hz,3H),7.33(d,J=8.1 Hz,2H),7.29(s,1H),4.91(q,J=15.6Hz,2H),3.95(s,3H),3.75(s,3H),1.80–1.69(m,1H),1.22(t,J=3.9Hz,2H),1.01–0.85(m,2H).

[0214] Example 2: Synthesis of Compound 2

[0215] Step 1: Synthesis of compound 2-2

[0216] Compound 2-1 (200 mg) and compound 1-2 (214.34 mg) were dissolved in 1M aqueous hydrochloric acid (8 mL) and stirred at 100°C for 1 hour. LCMS analysis confirmed the formation of the product. The reaction solution was poured into saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and directly spin-dried to obtain the crude product. Reverse-phase column chromatography with a water / acetonitrile ratio of 4 / 1 afforded compound 2-2 (25 mg).

[0217] LC-MS (ESI) [M+H] + 284.8.

[0218] Step 2: Synthesis of compound 2

[0219] Compound 2-2 (25 mg), compound (4-bromomethyl)phenyl-1-methyl-4-trifluoromethyl-1H-imidazole (28.06 mg), and cesium carbonate (57.16 mg) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was stirred at 60 ° C in a microwave for 1.5 hours. LCMS detected that the conversion of the raw material was complete, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to give a crude product, which was then prepared by liquid phase to give compound 2 (20 mg).

[0220] LC-MS (ESI) [M+H] + 523.2.

[0221] 1H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.68(s,1H),8.37(s,1H),7.98(d,J=1.2Hz,1H),7.76(d,J=8.0Hz,2H),7.50 (d,J=8.0Hz,2H),6.02(s,2H),3.95(s,3H),3.81(s,3H),1.87–1.83(m,1H),1.14–1.11(m,2H),1.04–1.00(m,2H).

[0222] Example 3: Synthesis of Compound 3

[0223] Step 1: Synthesis of compound 3

[0224] Compound 2-2 (50 mg), 9-bromomethyl-2-trifluoromethyl-6,7-dihydro-5H-benzimidazolo[1,2-a]azepine (60.71 mg) and cesium carbonate (114.33 mg) were dissolved in N,N-dimethylformamide (8 mL), and the reaction was stirred at 60 ° C in a microwave for 2 hours. LCMS detected that the conversion of the raw material was complete, and the reaction was quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to give a crude product, which was then prepared by liquid phase to give compound 3 (19.70 mg).

[0225] LC-MS (ESI) [M+H] + 549.0.

[0226] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.63(s,1H),8.31(s,1H),7.98(d,J=1 .2Hz,1H),7.67(d,J=7.8Hz,1H),7.35(s,1H),7.30(dd,J=8.0Hz,J=1.2Hz,1 H),5.93(s,2H),3.99(t,J=6.8Hz,2H),3.90(s,3H),2.66(t,J=6.8Hz,2H), 2.28–2.23(m,2H),1.82–1.78(m,1H),1.08–1.06(m,2H),0.99–0.94(m,2H).

[0227] Example 4: Synthesis of Compound 4

[0228] Step 1: Synthesis of compound 4

[0229] Compound 2-2 (50 mg), 2-[4-bromomethylphenyl]-1-(1-methylethyl)-4-trifluoromethyl-1H-imidazole (61.06 mg), and cesium carbonate (114.33 mg) were dissolved in N,N-dimethylformamide (3 mL), and the reaction was stirred at 60 ° C. for 2 hours. LCMS detected that the conversion of the raw material was complete, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to give a crude product, which was then prepared by liquid phase to give compound 4 (28.54 mg).

[0230] LC-MS (ESI) [M+H] + 551.3.

[0231] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.56(s,1H),8.25(s,1H),8.10(d,J=1.2Hz,1H),7.48(dd,J=6.4Hz,J=1.6Hz,2H),7.37(d,J=8.0 Hz,2H),5.90(s,2H),4.38–4.35(m,1H),3.82(s,3H),1.72–1.71(m,1H),1.31(d,J=6.4Hz,6H),1.00–0.98(m,2H),0.91–0.86(m,2H).

[0232] Example 5: Synthesis of Compound 5

[0233] Step 1: Synthesis of compound 5

[0234] Compound 2-2 (50 mg), 1-(4-bromomethyl)phenyl-5-methyl-3-trifluoromethylpyrazole (56.13 mg), and cesium carbonate (114.33 mg) were dissolved in N,N-dimethylformamide (3 mL), and the reaction was stirred at 60 ° C. for 2 hours. LCMS detected that the conversion of the raw material was complete, and the mixture was quenched with water (10 mL). The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to give a crude product, which was then prepared by liquid phase to give compound 5 (12.86 mg).

[0235] LC-MS (ESI) [M+H] + 523.2.

[0236] 1H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.56(s,1H),8.25(s,1H),7.50(d,J=8.4Hz,2H),7.41(d,J=8.8Hz,2H), 6.68(s,1H),5.91(s,2H),3.82(s,3H),2.25(s,3H),1.72–1.71(m,1H),1.00–0.98(m,2H),0.91–0.87(m,2H).

[0237] Example 6: Synthesis of Compound 6

[0238] Step 1: Synthesis of compound 6-2

[0239] Compound 6-1 (3.8 g) was dissolved in ultra-dry 1,4-dioxane (30 mL), and tributyl(1-ethoxyethylene)tin (10.04 g) and bistriphenylphosphine palladium dichloride (0.65 g) were added. The atmosphere was replaced with nitrogen and the mixture was reacted at 100°C for 2 hours. The mixture was cooled to room temperature, adjusted to pH 2 with 2N hydrochloric acid, and stirred for 30 minutes. The mixture was concentrated and purified by column chromatography (ethyl acetate / petroleum ether = 0-60%) to obtain compound 6-2 (830 mg).

[0240] LC-MS (ESI) [M+H] + 169.1.

[0241] Step 2: Synthesis of compound 6-3

[0242] Compound 6-2 (400 mg) and compound 1-2 (430 mg) were dissolved in 1N hydrochloric acid (12 mL) and reacted at 100°C for 20 minutes. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse phase column chromatography to obtain compound 6-3 (200 mg).

[0243] LC-MS (ESI) [M+H] + 299.2.

[0244] Step 3: Synthesis of compound 6

[0245] Compound 6-3 (0.05 g) was dissolved in ultra-dry tetrahydrofuran (10 mL), and 4-(1-methyl-4-trifluoromethyl)-1H-imidazole-2-phenylmethanol (0.044 g) and triphenylphosphine (0.13 g) were added. The nitrogen atmosphere was replaced and the temperature was lowered to 0°C. Diisopropyl azodicarboxylate (0.10 g) diluted with ultra-dry tetrahydrofuran was added dropwise. The temperature was slowly raised to room temperature and the reaction was allowed to proceed for 2 hours. LCMS analysis showed that the reaction was complete and the target product was generated. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse preparative purification and normal column chromatography (ethyl acetate / petroleum ether = 0-50%) to obtain compound 6 (52.85 mg).

[0246] LC-MS (ESI) [M+H] + 537.2.

[0247] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.36(s,1H),7.93(s,1H),7.70(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H), 5.96(s,2H),3.89(s,3H),3.75(s,3H),2.52(s,3H),1.83–1.74(m,1H),1.11–1.01(m,2H),1.00–0.90(m,2H).

[0248] Example 7: Synthesis of Compound 7

[0249] Step 1: Synthesis of compound 7-2

[0250] Compound 7-1 (420 mg) was dissolved in anhydrous tetrahydrofuran (20 mL) at 0°C, and phosphorus tribromide (370 mg) was slowly added dropwise. The system was naturally warmed to room temperature and reacted for 16 hours. The reaction was completed by LCMS. The system was quenched with saturated ammonium chloride (10 mL). The reaction solution was added to water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After column chromatography (ethyl acetate / petroleum ether = 35%), compound 7-2 (150 mg) was obtained.

[0251] LC-MS (ESI) [M+H] + 373.0 / 375.0.

[0252] 1H NMR (400MHz, CDCl3) δ7.27(d,J=0.9Hz,1H),4.26–4.21(m,3H),4.13(dt,J=13.4,6.7Hz,1H),3.96–3.91(m,3H),3.71(s,2H),1.45(d,J=6.7Hz,6H).

[0253] Step 2: Synthesis of compound 7

[0254] Compound 2-2 (26.26 mg), 7-2 (20 mg), and cesium carbonate (45.85 mg) were added to N,N-dimethylformamide (5 mL) and reacted at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was then purified by reverse phase column chromatography to obtain compound 7 (10.50 mg). LC-MS (ESI) [M+H] + 577.4.

[0255] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.55(s,1H),8.22(s,1H),7.92(d,J=1.4Hz,1H),5.00–4.85(m,2H),4.09(dd,J=5 .8,4.2Hz,3H),3.97–3.85(m,4H),3.82(s,3H),1.71(tt,J=8.3,4.6Hz,1H),1.31(d,J=6.6Hz,6H),1.23–0.74(m,4H).

[0256] Example 8: Synthesis of Compound 8

[0257] Step 1: Synthesis of compound 8

[0258] Compound 2-2 (70.32 mg), 2-(4-(bromomethyl)phenyl)-1-ethyl-4-(trifluoromethyl)-1H-imidazole (50 mg), and cesium carbonate (171.92 mg) were added to N,N-dimethylformamide (5 mL) and reacted at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by reverse phase column chromatography to obtain compound 8 (19.41 mg).

[0259] LC-MS (ESI) [M+H] + 537.2.

[0260] 1H NMR(400MHz, DMSO-d6)δ8.72(s,1H),8.64(s,1H),8.33(s,1H),8.04(d,J=1.4Hz,1H),7.68–7.59(m,2H),7.48–7.41(m,2H),5.98(s,2H) ,4.07(q,J=7.3Hz,2H),3.90(s,3H),1.80(tt,J=8.3,4.6Hz,1H),1.31(t,J=7.2Hz,3H),1.07(td,J=5.0,2.2Hz,2H),1.01–0.93(m,2H).

[0261] Example 9: Synthesis of Compound 9

[0262] Step 1: Synthesis of compound 9-1

[0263] Compound 2-2 (153 mg) and N-bromosuccinimide (290 mg) were dissolved in acetonitrile (40 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred at room temperature for 16 hours. The reaction was complete as determined by LCMS. The reaction solution was concentrated, and water (15 mL) was added to the concentrate. The mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with water (15 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate / petroleum ether = 22%) to obtain compound 9-1 (70 mg).

[0264] LC-MS (ESI) [M+H] + 363.0 / 365.0.

[0265] Step 2: Synthesis of compound 9-2

[0266] Compound 9-1 (170 mg), (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (120 mg), and triphenylphosphine (370 mg) were dissolved in ultra-dry tetrahydrofuran (4 mL), the atmosphere was replaced with nitrogen, and the temperature was lowered to 0°C. Subsequently, diisopropyl azodicarboxylate (290 mg) was slowly added to the system, the temperature was raised to room temperature, and the mixture was stirred for 2 hours. The reaction was detected to be complete by LCMS. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (15 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by column chromatography (ethyl acetate / petroleum ether = 30%) to obtain compound 9-2 (270 mg).

[0267] LC-MS (ESI) [M+H] + 601.0 / 603.0.

[0268] Step 3: Synthesis of compound 9

[0269] Compound 9-2 (150 mg), methylboronic acid (75 mg), potassium carbonate (100 mg), and tetrakis(triphenylphosphine)palladium (8 mg) were dissolved in 1,4-dioxane / water (10 mL / 2 mL), the atmosphere was replaced with nitrogen, and the mixture was reacted at 120°C for 16 hours. The reaction was complete as determined by LCMS. After cooling to room temperature, water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (15 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by reverse preparative chromatography and column chromatography (ethyl acetate / petroleum ether = 30%) to obtain compound 9 (6.2 mg).

[0270] LC-MS (ESI) [M+H] + 537.3.

[0271] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.64(s,1H),7.93(s,1H),7.70(d,J=8.2Hz,2H),7.43(d,J=8.3Hz,2H), 5.87(s,2H),3.89(s,3H),3.76(s,3H),2.52(s,3H),1.80–1.74(m,1H),1.09–1.03(m,2H),1.00–0.91(m,2H).

[0272] Example 10: Synthesis of Compounds 10a and 10b

[0273] Step 1: Synthesis of compounds 10a and 10b

[0274] Compound 4 (73.68 mg) was prepared by chiral SFC (column (250*25mm, 10um); mobile phase [A: carbon dioxide, B: methanol (containing 0.1%, 7M amine methanol solution)]; B%: 20% to 20%) to obtain compound 10a (retention time 2.940 minutes) (20.70 mg) and compound 10b (retention time 2.117 minutes) (19.78 mg). Retention times were determined using the following analytical method: Column: 100*3.0mm, 3um, mobile phase [A: carbon dioxide, B: methanol (containing 0.1% diethylamine)], 10% B, flow rate: 1.5mL / min, column temperature: 35℃.

[0275] Compound 10a:

[0276] LC-MS (ESI) [M+H]+ 551.4.

[0277] 1 H NMR (400MHz, CDCl3-d) δ8.69(s,1H),8.35(s,1H),8.02(s,1H),7.59(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,2H),7.41(s,1H),5 .99(s,2H),4.57–4.50(m,1H),3.99(s,3H),1.71–1.66(m,1H),1.44(d,J=8.0Hz,6H),1.34–1.34(m,2H),1.07–0.98(m,2H).

[0278] Compound 10b:

[0279] LC-MS (ESI) [M+H] + 551.4.

[0280] 1 H NMR (400MHz, CDCl3-d) δ8.70(s,1H),8.35(s,1H),8.02(s,1H),7.59(d,J=8.0Hz,2H),7.52(d,J=8.0Hz,2H),7.41(s,1H),5 .99(s,2H),4.57–4.50(m,1H),4.00(s,3H),1.73–1.67(m,1H),1.44(d,J=8.0Hz,6H),1.35–1.35(m,2H),1.06–1.01(m,2H).

[0281] Example 11: Synthesis of Compounds 11a and 11b

[0282] Step 1: Synthesis of compounds 11a and 11b

[0283] Compound 2 (1.02 g) was prepared by chiral SFC (column (250*25mm, 10mm); mobile phase [A: carbon dioxide, B: methanol (containing 0.2%, 7M ammonia methanol solution)]; B%: 20% to 20%) to obtain compound 11a (retention time 1.547 minutes) (275 mg) and compound 11b (retention time 2.145 minutes) (264 mg). Retention times were determined using the following analytical method: Column: 3 mm, mobile phase [Α: carbon dioxide, B: methanol (containing 0.3% diethylamine)], 30% B, flow rate: 1.5 mL / min, column temperature: 35°C.

[0284] Compound 11a:

[0285] LC-MS (ESI) [M+H] + 523.3.

[0286] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.63(s,1H),8.31(s,1H),7.93(d,J=1.2Hz,1H),7.74–7.63(m,2H),7.44(d,J =8.4Hz,2H),6.15–5.73(m,2H),3.90(s,3H),3.76(s,3H),1.89–1.63(m,1H),1.16–1.01(m,2H),1.03–0.87(m,2H).

[0287] Compound 11b:

[0288] LC-MS (ESI) [M+H] + 523.3.

[0289] 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.62(s,1H),8.31(s,1H),7.92(d,J=1.2Hz,1H),7.81–7.63(m,2H),7.43(d,J =8.3Hz,2H),6.06–5.88(m,2H),3.89(s,3H),3.75(s,3H),1.97–1.70(m,1H),1.16–1.01(m,2H),1.01–0.90(m,2H).

[0290] Example 12: Synthesis of Compounds 12a and 12b

[0291] Step 1: Synthesis of compounds 12a and 12b

[0292] Compound 3 (1.0 g) was prepared by chiral SFC (column The column was eluted with a column column (250 x 25 mm, 10 mm); mobile phase [A: carbon dioxide, B: methanol (containing 0.1%, 7M ammonia methanol solution)]; B%: 20% to 20%) to give compound 12a (retention time 2.907 minutes) (296.28 mg) and compound 12b (retention time 3.458 minutes) (266.44 mg). Retention times were determined using the following analytical method: Column: 3 mm, mobile phase [Α: carbon dioxide, B: methanol (containing 0.3% diethylamine)], 25% B, flow rate: 1.5 mL / min, column temperature: 35°C.

[0293] Compound 12a:

[0294] LC-MS (ESI) [M+H] + 549.4.

[0295] 1 H NMR (400MHz, DMSO-d6) δ8.71(s,1H),8.63(s,1H),8.31(s,1H),7.97(d,J=1. 0Hz,1H),7.67(d,J=7.9Hz,1H),7.35(s,1H),7.29(dd,J=8.0,1.5Hz,1H),5. 93(s,2H),3.98(t,J=6.8Hz,2H),3.90(s,3H),2.65(t,J=6.9Hz,2H),2.24(p ,J=6.8Hz,2H),1.84–1.74(m,1H),1.06(d,J=4.6Hz,2H),1.01–0.91(m,2H).

[0296] Compound 12b:

[0297] LC-MS (ESI) [M+H] + 549.3.

[0298] 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.63 (s, 1H), 8.31 (s, 1H), 7.97 (d, J = 1.0 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.35 (s, 1H), 7.29 (dd, J = 8.0, 1.5 Hz, 1H), 5.93 (s, 2H), 3.98 (t, J = 6.8 Hz, 2H), 3.90 (s, 3H), 2.65 (t, J = 6.9 Hz, 2H), 2.24 (p, J = 6.8 Hz, 2H), 1.84–1.74 (m, 1H), 1.06 (d, J = 4.6 Hz, 2H), 1.01–0.91 (m, 2H). Example 13: Synthesis of Compound 13

[0299] Step 1: Synthesis of compound 13-2

[0300] At -10°C, under nitrogen, 2,2,6,6-tetramethylpiperidine (16.14 g) was dissolved in ultra-dry tetrahydrofuran (150 mL). The temperature was lowered to -78°C, and 2.5 M n-butyllithium (45.7 mL) was slowly added. The mixture was stirred for 10 minutes, followed by the addition of compound 13-1 (6 g). The reaction was continued at -50°C for 3 hours, followed by the addition of ultra-dry N,N-dimethylformamide (16.70 g) at -78°C, and the reaction was continued for 1 hour and 30 minutes. The mixture was warmed to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (150 mL × 3). The aqueous phase was adjusted to pH 2 with concentrated hydrochloric acid, and then extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated, and purified by slurrying (ethyl acetate) to obtain compound 13-2 (4.1 g).

[0301] 1 H NMR (400MHz, DMSO-d6) δ8.76(d,J=5.0Hz,1H),8.47(d,J=6.7Hz,1H),7.80(d,J=5.0Hz,1H),6.68(d,J=5.6Hz,1H).

[0302] Step 2: Synthesis of compound 13-3

[0303] Compound 13-2 (0.5 g), compound 1-2 (0.73 g), and sodium acetate (0.66 g) were dissolved in water (20 mL), the atmosphere was purged with nitrogen, and the mixture was reacted at 105°C for 16 hours. LCMS confirmed the reaction was complete. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 0-70%) to afford compound 13-3 (0.64 g).

[0304] LC-MS (ESI) [M+H] + 330.0.

[0305] Step 3: Synthesis of compound 13

[0306] Compound 13-3 (0.38 g) and 1-methyl-2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)-4-(trifluoromethyl)-1H-imidazole (2.11 g) were dissolved in toluene (24 mL). A solution of sodium tert-butoxide (0.28 g) in water (3 mL) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (0.15 g) were added. The atmosphere was replaced with nitrogen and the reaction was carried out at 100°C for 16 hours. LCMS analysis indicated the formation of the target product. The mixture was concentrated, diluted with water (20 mL), and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by normal column chromatography before liquid chromatography to obtain compound 13 (20 mg).

[0307] LC-MS (ESI) [M+H] + 534.3.

[0308] 1 H NMR (400MHz, MeOD-d4) δ9.01(d,J=5.2Hz,1H),8.63(s,1H),8.52(s,1H),7.80(d,J=5.3Hz,1H),7.67(s,1H),7.54(d,J=8.2Hz,2H) ,7.48(d,J=8.2Hz,2H),5.04(q,J=13.6Hz,2H),3.95(s,3H),3.76(s,3H),1.87–1.80(m,1H),1.21–1.12(m,2H),1.02–0.93(m,2H).

[0309] Example 14: Synthesis of Compound 14

[0310] Step 1: Synthesis of compound 14-3

[0311] Compound 14-1 (1 g) was dissolved in 1N hydrochloric acid (10 mL) at room temperature. A mixture of sodium nitrite (0.76 g) and water (6 mL) was added at -65°C. After 30 minutes, stannous chloride (4.14 g) and 1N hydrochloric acid (6 mL) were added. The mixture was stirred at -65°C for 2 hours and then refrigerated overnight. The reaction solution was concentrated using an oil pump, and di-tert-butyl dicarbonate (4.8 g), triethylamine (4.4 g), and ethanol (20 mL) were added. The mixture was reacted at room temperature for 2 hours. The organic phase was filtered, concentrated, and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 14-3 (1.17 g).

[0312] LC-MS (ESI) [M+H] + 252.3.

[0313] Step 2: Synthesis of compound 14-4

[0314] Compound 14-3 (1.3 g) was dissolved in hydrochloric acid-dioxane (10 mL) and dichloromethane (10 mL), stirred at room temperature for 1 hour, and filtered to obtain a solid as the product, giving compound 14-4 (750 mg).

[0315] LC-MS (ESI) [M+H] + 152.3.

[0316] Step 3: Synthesis of compound 14-5

[0317] Compound 14-4 (1.07 g, 7.03 mmol) and ethyl 4-formyl-1H-pyrazole-5-carboxylate (1.18 g) were dissolved in 1N hydrochloric acid (10 mL), stirred at 100 ° C. for 1 hour, and purified by column chromatography (acetonitrile / water = 30%) to obtain compound 14-5 (886 mg).

[0318] LC-MS (ESI) [M+H] + 256.2.

[0319] Step 4: Synthesis of compound 14

[0320] Compound 14-5 (100 mg), (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (95 mg), and triphenylphosphine (290 mg) were dissolved in ultra-dry tetrahydrofuran (5 mL). Under nitrogen protection, diisopropyl azodicarboxylate (220 mg) was added and stirred at room temperature for 16 hours. LCMS analysis indicated that the reaction was complete and the desired product was generated. After concentration, the mixture was purified by liquid phase chromatography to obtain compound 14 (42.6 mg).

[0321] LC-MS (ESI) [M+H] + 494.3.

[0322] 1 H NMR (400MHz, DMSO-d6) δ8.67(dd,J=4.7,1.6Hz,1H),8.58(s,1H),8.31(s,1H),7.92(d,J=1.1Hz,1H),7.82(dd,J=7.9,1.6Hz ,1H),7.69(d,J=8.3Hz,2H),7.46–7.39(m,3H),5.96(d,J=6.8Hz,2H),3.75(s,3H),2.87–2.76(m,1H),1.12(d,J=5.6Hz,6H).

[0323] Example 15: Synthesis of Compound 15

[0324] Step 1: Synthesis of compound 15

[0325] Compound 14-5 (100 mg), 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methanol (110 mg), and triphenylphosphine (0.31 g) were dissolved in ultra-dry tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (0.24 g, 1.17 mmol) dissolved in ultra-dry tetrahydrofuran (5 mL) was added dropwise to the reaction system at 0°C. The reaction was allowed to proceed at 0°C for 1 hour. LCMS indicated the reaction was complete. The system was added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 15 (10.26 mg).

[0326] LC-MS (ESI) [M+H] + 520.3.

[0327] 1 H NMR(400MHz,DMSO-d6)δ8.67(d,J=3.4Hz,1H),8.58(s,1H),8.31(s,1H),7.9 7(s,1H),7.82(d,J=7.9Hz,1H),7.65(d,J=7.9Hz,1H),7.42(dd,J=8.0,4.7H z,1H),7.34(s,1H),7.30(d,J=8.3Hz,1H),5.93(s,2H),3.97(t,J=6.9Hz,2H ),2.87–2.77(m,1H),2.64(t,J=7.0Hz,2H),2.28–2.18(m,2H),1.13(s,6H).

[0328] Example 16: Synthesis of Compounds 16a and 16b

[0329] Step 1: Synthesis of compound 16-2

[0330] At room temperature, compound 16-1 (1 g) was dissolved in concentrated hydrochloric acid (10 ml). At -70 ° C, sodium nitrite (0.69 g) was dissolved in water (6 ml) and added dropwise to the reaction system. The reaction was carried out at -70 ° C for 0.5 hours. Stannous chloride (3.76 g) was dissolved in concentrated hydrochloric acid (6 ml) and added dropwise to the reaction system. The reaction was carried out at -70 ° C for 2 hours. LCMS showed that the reaction was complete. The system was concentrated to remove the solvent and used directly in the next step.

[0331] LC-MS (ESI) [M+H]+ 166.1.

[0332] Step 2: Synthesis of compound 16-3

[0333] Compound 16-2 (1.19 g) was dissolved in anhydrous dichloromethane (20 mL) at room temperature, and triethylamine (4.00 g) and di-tert-butyl dicarbonate (2.9 g) were added. The mixture was allowed to react at room temperature for 1 hour. LCMS confirmed the reaction was complete. The system was concentrated to dryness, added to water (60 mL), and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with water (20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound 16-3 (1.17 g).

[0334] LC-MS (ESI) [M+H] + 266.2.

[0335] Step 3: Synthesis of compound 16-4

[0336] Compound 16-3 (1.17 g) was dissolved in dichloromethane (10 mL) and a dioxane hydrochloride solution (2 mL) was added. The mixture was reacted at room temperature for 1 hour. A sample was taken and filtered. LCMS analysis showed that no starting material remained in the filtrate. The system was filtered and the filter cake was washed with dichloromethane (2 mL) to obtain the crude product 16-4 (0.67 g). LC-MS (ESI) [M+H] + 166.1.

[0337] Step 4: Synthesis of compound 16-5

[0338] Compound 16-4 (0.67 g) and ethyl 4-formyl-1H-pyrazole-5-carboxylate (1.2 g) were dissolved in hydrochloric acid (10 mL, 1 M) and reacted at 100°C for 3 hours. LCMS confirmed the reaction was complete. The pH of the system was adjusted to 8-9 with sodium carbonate, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound 16-5 (0.33 g).

[0339] LC-MS (ESI) [M+H] + 270.1.

[0340] Step 5: Synthesis of compound 16

[0341] Compound 16-5 (50.00 mg), (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (47.50 mg) and triphenylphosphine (0.15 g) were dissolved in ultra-dry tetrahydrofuran (10 ml). Diisopropyl azodicarboxylate (0.12 g) was dissolved in ultra-dry tetrahydrofuran (5 ml) and added dropwise to the reaction system at 0°C. The reaction was allowed to proceed at 0°C for 1 hour. LCMS showed that the reaction was complete. The system was added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with water (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the concentrated liquid phase obtained to give compound 16 (24.62 mg). LC-MS (ESI) [M+H] + 508.3.

[0342] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.52(d,J=4.9Hz,1H),8.33(s,1H),7.92(d,J=1.1Hz,1H),7.69(d,J=8.3Hz,2H),7. 42(d,J=8.3Hz,2H),7.30(d,J=5.4Hz,1H),5.96(s,2H),3.75(s,3H),2.74–2.62(m,1H),2.01(s,3H),1.13–1.05(m,6H).

[0343] Step 6: Synthesis of compounds 16a and 16b

[0344] Compound 16 (24.62 mg) was prepared by chiral SFC (column The column was eluted with a column column (250 x 25 mm, 10 μm); mobile phase [A: carbon dioxide, B: methanol (containing 0.1%, 7M ammonia in methanol)]; B%: 50% to 50%) to give compound 16a (retention time 0.913 minutes) (2.55 mg) and compound 16b (retention time 2.638 minutes) (2.63 mg). Retention times were determined using the following analytical method: Column: 3 mm, mobile phase [Α: carbon dioxide, B: methanol (containing 0.3% diethylamine)], 30% B, flow rate: 1.5 mL / min, column temperature: 35°C.

[0345] Compound 16a:

[0346] LC-MS (ESI) [M+H] + 508.3.

[0347] 1H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.52(d,J=4.9Hz,1H),8.33(s,1H),7.92(s,1H),7.69(d,J=8.2Hz,2H),7.42(d, J=8.2Hz,2H),7.30(d,J=4.9Hz,1H),5.96(s,2H),3.75(s,3H),2.69–2.64(m,1H),2.01(s,3H),1.09(t,J=7.2Hz,6H).

[0348] Compound 16b:

[0349] LC-MS (ESI) [M+H] + 508.3.

[0350] 1 H NMR (400MHz, DMSO-d6) δ8.63(s,1H),8.52(d,J=4.9Hz,1H),8.33(s,1H),7.92(s,1H),7.69(d,J=8.2Hz,2H),7.42(d,J= 8.2Hz,2H),7.30(d,J=5.0Hz,1H),5.96(s,2H),3.75(s,3H),2.68(t,J=6.6Hz,1H),2.01(s,3H),1.09(t,J=7.3Hz,6H).

[0351] Example 17: Synthesis of Compound 17

[0352] Step 1: Synthesis of compound 17-2

[0353] At room temperature, methyl 3-cyclopropyl-3-oxopropanoate (20 g) was dissolved in anhydrous methanol (200 mL), and sodium methoxide (53.20 g) and formamidine acetate (29.30 g) were added. The mixture was stirred at 30°C for 16 hours. The reaction was confirmed to be complete by LCMS. Acetic acid was added to the reaction solution to adjust the pH to neutral. The filtrate was filtered and concentrated under reduced pressure. The mixture was purified by column chromatography (dichloromethane / methanol = 97 / 3) to obtain compound 17-2 (12.10 g).

[0354] LC-MS (ESI) [M+H] + 137.2.

[0355] Step 2: Synthesis of compound 17-3

[0356] Compound 17-2 (12.1 g) was dissolved in phosphorus oxychloride (50 mL) and stirred at 80° C. for 3 hours. The reaction was completed as determined by LCMS. The reaction solution was concentrated and quenched by adding sodium hydroxide under ice bath. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 ml×3). The organic phases were combined, washed with water (20 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 17-3 (2.69 g).

[0357] LC-MS (ESI) [M+H] + 155.1.

[0358] Step 3: Synthesis of compound 17-4

[0359] Compound 17-3 (2.6 g), cyclopropylboronic acid (2.89 g), and anhydrous sodium carbonate (5.35 g) were dissolved in 1,4-dioxane / water (20 mL / 10 mL), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (0.36 g) was added. The nitrogen atmosphere was replaced and stirred at 130° C. for 3 hours. The reaction was completed as determined by LCMS. The reaction solution was filtered and the filtrate was added to water (20 mL). The mixture was extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with water (20 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 17-4 (855 mg).

[0360] LC-MS (ESI) [M+H] + 161.1.

[0361] Step 4: Synthesis of compound 17-5

[0362] Compound 17-4 (750 mg) was dissolved in anhydrous ethanol (10 mL), cooled to -10 ° C, and liquid bromine (2.24 g) was added dropwise to the reaction solution, stirred at -10 ° C for 3 hours. The reaction was completed as determined by LCMS. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 ml × 3), and the organic phases were combined, washed with water (20 mL), sodium thiosulfate (10 mL), and saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 17-5 (415 mg).

[0363] LC-MS (ESI) [M+H] + 239.0.

[0364] Step 5: Synthesis of compound 17-6

[0365] Compound 17-5 (388 mg), tert-butyl carbazate (260 mg), and anhydrous cesium carbonate (530 mg) were dissolved in 1,4-dioxane (20 mL), and methanesulfonic acid (2-dicyclohexylphosphine-3,6-methoxy-2,4,6-diisopropyl-1,1-biphenyl) (2-methylamino-1,1-biphenyl-2-yl) palladium (II) (75 mg) was added. The nitrogen atmosphere was replaced and stirred at 100° C. for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered and the filtrate was added to water (20 mL). The mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with water (20 mL) and saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 17-6 (278 mg).

[0366] LC-MS (ESI) [M+H] + 291.2.

[0367] Step 6: Synthesis of compound 17-7

[0368] Compound 17-6 (50 mg) was dissolved in hydrochloric acid / 1,4-dioxane (4M, 2 mL) and stirred at 25°C for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated with ethyl acetate several times to obtain compound 17-7 (32 mg).

[0369] LC-MS (ESI) [M+H] + 191.1.

[0370] Step 7: Synthesis of compound 17-8

[0371] Compound 17-7 (32 mg) and ethyl 4-formyl-1H-pyrazole-3-carboxylate (29 mg) were dissolved in hydrochloric acid (1M, 1 mL) and stirred at 110°C for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was added to water (5 mL) and extracted with ethyl acetate (5 ml × 3). The organic phases were combined, washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by reverse column chromatography (formic acid system) to obtain compound 17-8 (20 mg).

[0372] LC-MS (ESI) [M+H] + 295.1.

[0373] Step 8: Synthesis of compound 17

[0374] Compound 17-8 (65 mg), triphenylphosphine (170 mg), and (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (56 mg) were dissolved in ultra-dry tetrahydrofuran (2 mL), cooled to 0°C, and diisopropyl azodicarboxylate (130 mg) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was added to water (5 mL) and extracted with ethyl acetate (5 ml × 3). The organic phases were combined, washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a crude product, which was then purified by liquid phase preparative purification to obtain compound 17 (55.72 mg).

[0375] LC-MS (ESI) [M+H] + 533.3.

[0376] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.69(s,1H),8.34(s,1H),7.93(s,1H),7.69(d,J=8.2Hz,2H),7.4 5(d,J=8.2Hz,2H),5.98(s,2H),3.75(s,3H),1.78–1.62(m,2H),1.08–1.02(m,4H),0.98–0.93(m,4H).

[0377] Example 18: Synthesis of Compound 18

[0378] Step 1: Synthesis of compound 18

[0379] Compound 17-8 (65 mg), triphenylphosphine (170 mg), and 2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepine-9-yl)methanol (62 mg) were dissolved in ultra-dry tetrahydrofuran (2 mL), cooled to 0°C, and diisopropyl azodicarboxylate (130 mg) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was added to water (5 mL) and extracted with ethyl acetate (5 ml × 3). The organic phases were combined, washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the crude product, which was then purified by liquid phase preparative purification to obtain compound 18 (32.51 mg).

[0380] LC-MS (ESI) [M+H] + 559.3.

[0381] 1H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.70(s,1H),8.33(s,1H),7.97(d,J=1.0Hz,1H),7.66(d,J=7.9Hz,1H),7.36(s,1H),7.30(dd,J=8.0,1.5Hz ,1H),5.94(s,2H),3.97(t,J=6.7Hz,2H),2.64(t,J=6.9Hz,2H),2.23(p ,J=6.9Hz,2H),1.77–1.67(m,2H),1.09–1.02(m,4H),0.99–0.90(m,4H).

[0382] Example 19: Synthesis of Compound 19

[0383] Step 1: Synthesis of compound 19-2

[0384] At room temperature, compound 19-1 (1 g) was dissolved in dichloromethane (20 mL), and Dess-Martin periodinane (3.21 g) was added in batches. The mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by TLC (dinitrophenylhydrazine color developer, petroleum ether: ethyl acetate = 1:1). The reaction solution was added to saturated sodium bicarbonate (15 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phases were washed with water (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 19-2 (520 mg).

[0385] Step 2: Synthesis of compound 19-3

[0386] 1,1-Dibromo-3,3,3-trifluoroacetone (0.93 g) was dissolved in water (9 mL), sodium acetate (0.3 g) was added, and after nitrogen was replaced, the reaction was carried out at 100°C for 1 hour. The system was cooled to room temperature, and compound 19-2 (520 mg) was dissolved in a mixture of methanol (50 ml) and aqueous ammonia (13 ml) and added to the system. The mixture was stirred at room temperature for 40 minutes and then reacted at 100°C for 2 hours. LCMS showed that the reaction was complete. The system was concentrated to remove most of the solvent, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 20%) to obtain compound 19-3 (0.70 g).

[0387] LC-MS (ESI) [M+H] + 303.0.

[0388] Step 3: Synthesis of compound 19-4

[0389] Compound 19-3 (200 mg) was dissolved in N,N-dimethylformamide (5 mL), and iodomethane (0.094 g) and potassium carbonate (0.18 g) were added. The mixture was reacted at room temperature for 3 hours. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (ethyl acetate / petroleum ether = 16%) to obtain compound 19-4 (200 mg).

[0390] LC-MS (ESI) [M+H] + 317.0.

[0391] Step 4: Synthesis of compound 19-5

[0392] Compound 19-4 (0.18 g) was dissolved in tetrahydrofuran (20 mL). Under argon, a solution of lithium aluminum hydride in tetrahydrofuran (0.41 mL, 2.5 M, 1.03 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. LCMS confirmed the reaction was complete. Water (0.04 mL), aqueous sodium hydroxide solution (0.04 mL, 15 wt%), and water (0.12 mL) were then slowly added dropwise. The mixture was stirred for 15 minutes and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 19-5 (60 mg).

[0393] LC-MS (ESI) [M+H] + 289.0.

[0394] Step 5: Synthesis of compound 19

[0395] Compound 19-5 (50 mg) and compound 17-8 (49 mg) were dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and triphenylphosphine (130 mg) was added under argon. Diisopropyl azodicarboxylate (100 mg) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the system. The mixture was stirred at room temperature overnight. LCMS confirmed the reaction was complete. The concentrated liquid phase afforded compound 19 (12.3 mg).

[0396] LC-MS (ESI) [M+H] + 565.4.

[0397] 1H NMR(400MHz,MeOD-d4)δ8.79(s,1H),8.59(s,1H),8.20(s,1H),7.39(s,1H),4.62(s,2H),3.8 0(s,3H),2.04–1.97(m,6H),1.73–1.59(m,8H),1.23(m,2H),1.14(m,2H),1.03–0.96(m,4H).

[0398] Example 20: Synthesis of Compound 20

[0399] Step 1: Synthesis of compound 20

[0400] Compound 17-8 (50 mg), (4-(5-methoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (46 mg), and triphenylphosphine (130 mg) were dissolved in ultra-dry tetrahydrofuran (2 mL). Diisopropyl azodicarboxylate (100 mg) was added under nitrogen at zero degrees Celsius, and the mixture was stirred at room temperature for 16 hours. After concentration, the liquid phase was used to obtain compound 20 (26.0 mg).

[0401] LC-MS (ESI) [M+H] + 549.1.

[0402] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.69(s,1H),8.33(s,1H),7.62(d,J=8.6Hz,2H),7.47(d,J=8.6Hz ,2H),6.46(s,1H),5.96(s,2H),3.98(s,3H),1.75–1.65(m,2H),1.09–1.02(m,4H),0.99–0.90(m,4H).

[0403] Example 21: Synthesis of Compound 21

[0404] Step 1: Synthesis of compound 21

[0405] Compound 17-8 (50 mg), (4-(5-ethoxy-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (51 mg), and triphenylphosphine (134 mg) were dissolved in ultra-dry tetrahydrofuran (2 mL). Diisopropyl azodicarboxylate (103 mg) was added under nitrogen at zero degrees Celsius, and the mixture was stirred at room temperature for 16 hours. After concentration, the liquid phase was used to obtain compound 21 (34.0 mg).

[0406] LC-MS (ESI) [M+H]+ 563.3.

[0407] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.69(s,1H),8.33(s,1H),7.64(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H),6.45(s,1 H),5.95(s,2H),4.27(q,J=7.0Hz,2H),1.74–1.66(m,2H),1.34(t,J=7.0Hz,3H),1.09–1.02(m,4H),0.98–0.90(m,4H).

[0408] Example 22: Synthesis of Compound 22

[0409] Step 1: Synthesis of compound 22-2

[0410] At room temperature, compound 22-1 (5 g) and tert-butyl carbazate (5 g) were dissolved in 1,4-dioxane / water (50 / 10 mL). Cesium carbonate (7.44 g) and (2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)methanesulfonate palladium(II) (1.05 g) were added. The atmosphere was replaced with nitrogen and stirred at 100°C for 16 hours. LCMS confirmed the reaction was complete. Water (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (30 mL), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and purified by forward column chromatography (ethyl acetate / petroleum ether = 25%) to obtain compound 22-2 (5.22 g).

[0411] LC-MS (ESI) [M+H] + 271.1.

[0412] Step 2: Synthesis of compound 22-3

[0413] Compound 22-2 (5.22 g) was dissolved in dichloromethane (50 mL), and hydrochloric acid / dioxane (50 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was complete as determined by LCMS. The reaction solution was filtered, and the filter cake was rinsed with dichloromethane and collected to obtain compound 22-3 (3.28 g).

[0414] LC-MS (ESI) [M+H] + 172.1.

[0415] Step 3: Synthesis of compound 22-4

[0416] Compound 22-3 (3.28 g) and methyl 4-formyl-1H-pyrazole-3-carboxylate (3.32 g) were dissolved in hydrochloric acid (1 M, 44 mL) and stirred at 100°C for 20 minutes. The reaction was complete as determined by LCMS. Ethyl acetate (15 mL × 3) was added to the reaction solution for extraction. The combined organic phases were washed with water (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by reverse phase flash column (acetonitrile / water (FA) = 11%) to obtain compound 22-4 (560 mg). LC-MS (ESI) [M+H] + 275.1.

[0417] Step 4: Synthesis of compound 22

[0418] Compound 22-4 (280 mg), (4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (260 mg), and triphenylphosphine (800 mg) were dissolved in ultra-dry tetrahydrofuran (10 mL), the atmosphere was replaced with nitrogen, and the temperature was lowered to 0° C. Subsequently, diisopropyl azodicarboxylate (620 mg) was diluted and injected into the system. The mixture was warmed to room temperature and stirred for 1 hour. LCMS confirmed the completion of the reaction. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with water (15 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by forward column chromatography (ethyl acetate / petroleum ether = 30%) to obtain a crude compound, which was then purified by liquid phase chromatography to obtain compound 22 (233.1 mg).

[0419] LC-MS (ESI) [M+H] + 513.2.

[0420] 1 H NMR (400MHz, DMSO-d6) δ8.64(s,1H),8.56(s,1H),8.29(s,1H),7.92(d,J=1.1Hz,1H) ,7.71(d,J=8.3Hz,2H),7.42(d,J=8.4Hz,2H),5.94(s,2H),3.92(s,6H),3.76(s,3H).

[0421] Example 23: Synthesis of Compound 23

[0422] Step 1: Synthesis of compound 23

[0423] Compound 2-2 (121.42 mg), 2-(4-bromomethylphenyl)-1-cyclopropyl-4-trifluoromethyl-1H-imidazole (100 mg), and cesium carbonate (343.84 mg) were dissolved in N,N-dimethylformamide (5 mL) and stirred at 60°C in a microwave oven for 2 h. The reaction was quenched by adding water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 23 (25 mg).

[0424] LC-MS (ESI) [M+H] + 549.2.

[0425] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.61(s,1H),8.50(s,1H),7.90–7.85(m,3H),7.49–7.4 3(m,2H),5.72(s,2H),3.80(s,3H),3.72–3.64(m,1H),1.76–1.63(m,1H),1.04–0.80(m,8H).

[0426] Example 24: Synthesis of Compound 24

[0427] Step 1: Synthesis of compound 24

[0428] Compound 17-8 (40 mg), (4-(5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol (34.82 mg), triphenylphosphine (53.47 mg), and diisopropyl azodicarboxylate (41.22 mg, 203.87 μmol, 40.14 μL) were dissolved in tetrahydrofuran (5 mL) and reacted at room temperature for 1 hour. The reaction was quenched with water and extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 24 (6 mg) via liquid phase.

[0429] LC-MS (ESI) [M+H] + 533.3.

[0430] 1H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.70(s,1H),8.35(s,1H),7.61–7.53(m,2H),7.53–7.46(m,2H),6. 76(s,1H),6.00(s,2H),2.32(s,3H),1.79–1.63(m,2H),1.04(dq,J=5.6,2.6Hz,4H),1.00–0.90(m,4H).

[0431] Example 25: Synthesis of Compound 25

[0432] Step 1: Synthesis of compound 25

[0433] Compound 17-8 (40 mg), (4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl)methanol (38.64 mg), triphenylphosphine (53.47 mg), and diisopropyl azodicarboxylate (41.22 mg, 203.87 μmol, 40.14 μL) were dissolved in tetrahydrofuran (5 mL) and reacted at room temperature for 1 hour. The reaction was quenched with water and extracted with dichloromethane (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 25 (16 mg) via liquid phase.

[0434] LC-MS (ESI) [M+H] + 561.4.

[0435] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.70(s,1H),8.35(s,1H),8.18(d,J=1.4Hz,1H),7.57–7.52(m,2H),7.47–7.43(m ,2H),5.99(s,2H),4.50–4.34(m,1H),1.77–1.65(m,2H),1.38(d,J=6.6Hz,6H),1.08–1.01(m,4H),0.99–0.90(m,4H).

[0436] Example 26: Synthesis of Compound 26

[0437] Step 1: Synthesis of compound 26-2

[0438] At room temperature, compound 26-1 (240 mg) and compound 17-8 (360 mg) were dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and triphenylphosphine (970 mg) was added under argon. Diisopropyl azodicarboxylate (750 mg) was dissolved in tetrahydrofuran (5 mL) and added dropwise to the system. The mixture was stirred at room temperature overnight. LCMS confirmed the reaction was complete. The system was concentrated to dryness and purified by column chromatography (ethyl acetate / petroleum ether = 50%) to obtain compound 26-2 (450 mg). LC-MS (ESI) [M+H] + 469.1.

[0439] Step 2: Synthesis of compound 26-3

[0440] Compound 26-2 (0.45 g) was dissolved in tetrahydrofuran (20 mL) at 0°C. Under argon, a toluene solution of diisobutylaluminum hydride (1.92 mL, 1.5 M, 2.88 mmol) was added dropwise. The mixture was stirred at 0°C for 1 hour. LCMS confirmed the reaction was complete. Water (0.04 mL), aqueous sodium hydroxide solution (0.04 mL, 15 wt%), and water (0.12 mL) were then slowly added dropwise. The mixture was stirred for 15 minutes and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford compound 26-3 (220 mg).

[0441] LC-MS (ESI) [M+H] + 441.1.

[0442] Step 3: Synthesis of compound 26-4

[0443] Compound 26-3 (0.2 g) was dissolved in dichloromethane (20 mL), sodium carbonate (0.15 g) was added, and Dess-Martin periodinane (0.23 g) was added in batches. The mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was added with saturated sodium thiosulfate (10 mL), extracted with dichloromethane (20 mL×3), and the combined organic phases were washed with water (15 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 26-4 (70 mg).

[0444] LC-MS (ESI) [M+H] + 439.2.

[0445] Step 4: Synthesis of compound 26-5

[0446] 1,1-Dibromo-3,3,3-trifluoroacetone (45 mg) was dissolved in water (2 ml), and sodium acetate (14 mg) was added to replace the nitrogen atmosphere. The reaction was carried out at 100°C for 1 hour. The system was cooled to room temperature, and compound 26-4 (65 mg) was dissolved in a mixture of methanol (20 ml) and aqueous ammonia (4 ml) and added to the system. The mixture was stirred at room temperature for 40 minutes and then reacted at 100°C for 2 hours. LCMS showed that the reaction was complete. The system was concentrated to remove most of the solvent, and water (20 ml) was added. The mixture was extracted with ethyl acetate (20 ml × 3). The combined organic phases were washed with water (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 20%) to obtain compound 26-5 (50 mg).

[0447] LC-MS (ESI) [M+H] + 545.1.

[0448] Step 5: Synthesis of compound 26

[0449] Compound 26-5 (25 mg) was dissolved in N,N-dimethylformamide (5 mL), and iodomethane (0.0065 g) and potassium carbonate (0.013 g) were added. The mixture was reacted at room temperature for 3 hours. LCMS analysis showed that the reaction was complete. The mixture was cooled to room temperature, added to water (20 mL), and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with water (20 mL × 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by liquid phase preparative purification to obtain compound 26 (13.32 mg).

[0450] LC-MS (ESI) [M+H] + 559.2.

[0451] 1 H NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.69(s,1H),8.32(s,1H),7.74(d,J=1.1Hz,1H),5.01(s,2H),4.25 –4.15(m,3H),3.98–3.90(m,3H),3.53(s,3H),1.71–1.63(m,2H),1.08–1.01(m,4H),1.01–0.89(m,4H).

[0452] The preparation method of the reference compound KSQ-4279 is as follows (Example 143, WO2020132269A1)

[0453] Biological Examples

[0454] Experimental Example 1: USP1 / UAF1 Deubiquitination Assay (Ubiquitin Fluorophore Assay)

[0455] Prepare the USP1 / UAF1 complex: First, prepare reaction buffer (50 mM HEPES [pH 7.8], 0.5 mM EDTA, 1 mM DTT, 0.1 mg / ml BSA, and 0.01% Tween-20). Prepare the enzyme mix containing USP1 / UAF1 complex (R&D, E-568-050) in the reaction buffer to a final concentration of 0.15 nM.

[0456] 2. Prepare Ubiquitin Rhodamine 110 reaction substrate: Prepare a substrate mixture with a final concentration of 150 nM Ubiquitin Rhodamine 110 (R&D, E-555-050) in reaction buffer (50 mM HEPES [pH 7.8], 0.5 mM EDTA, 1 mM DTT, 0.1 mg / ml BSA, and 0.01% Tween-20).

[0457] 3. Compound Preparation: Dissolve the test compound in DMSO at a final concentration of 1%. Prepare the compound in DMSO at various concentrations. Set up replicates for each concentration, performing a 3-fold serial dilution for a total of 11 concentrations. Also include a corresponding vehicle control. Following dilution, dilute the compound 25-fold in reaction buffer.

[0458] 4. USP1 / UAF1 deubiquitination reaction: Add 5 μL of 4x USP1 / UAF1 complex solution and 5 μL of 4x compound to each well of the assay plate and incubate for 15 minutes. Then, add 10 μL of 2x Ubiquitin Rhodamine 110 substrate to initiate the reaction. Centrifuge, seal the plate, and incubate at 37°C for 30 minutes.

[0459] 5. After the reaction, the fluorescence value was read using a microplate reader (MD, VersaMax) with an excitation wavelength of 480 nm and an emission wavelength of 540 nm. Finally, the data were analyzed using GraphPad Prism 8 software, and the IC was calculated using the dose-response-inhibition (four-parameter) equation using GraphPad Prism software. 50 value.

[0460] The experimental results are shown in Table 1.

[0461] Table 1: IC values ​​of selected compounds in the USP1 / UAF1 deubiquitination assay 50 value

[0462] The compound of the present invention has excellent in vitro activity and can inhibit the deubiquitination activity of USP1 / UAF1 on Ubiquitin Rhodamine 110.

[0463] Test Example 2: MDA-MB-436BRCA1 Mut Cell Proliferation Inhibition Assay (MDA-MB-436BRCA1 Mut CTG Assay) Preparation of DMEM Cell Culture Medium: First, prepare DMEM cell culture medium (10% FBS, 1% Pen-Strep, 10 μg / ml Insulin). Prepare MDA-MB-436BRCA1 Mut cells: Remove MDA-MB-436 cells from liquid nitrogen, thaw in DMEM medium, and culture until the logarithmic growth phase. When cell confluence reaches greater than 80%, harvest the cells and plate 3000 cells per well in 80 μl of culture volume. Incubate overnight at 37°C, 5% CO2.

[0464] Compound Preparation: Dissolve the test compound in DMSO to a 10 mM stock solution. Dilute the stock solution 20-fold with cell culture medium and then serially dilute it 3-fold to various concentrations. Set up replicates for each concentration, for a total of 9 concentrations. Also include a vehicle control. Following dilution, dilute the compound 100-fold in 5% DMEM medium.

[0465] Drug treatment: Add 20ul of compound working solution to each well of the cell culture plate, set up a positive control and a cell-free negative control, and continue to culture for 10

[0466] d, The final concentration of DMSO in the system was 0.01%.

[0467] CTG test: according to Prepare CTG detection reagent according to the Luminescent Cell Viability Assay instructions. Add 50 μl of CTG detection reagent to each well of the cell culture plate and incubate in the dark for 15 minutes before reading the plate.

[0468] Luminescence signals were read using a microplate reader (MD, VersaMax). Data were analyzed using GraphPad Prism 8 software, and the IC was calculated using the dose-response-inhibition (four-parameter) equation using GraphPad Prism software. 50 value.

[0469] The experimental results are shown in Table 2.

[0470] Table 2. IC values ​​of selected compounds in the MDA-MB-436BRCA1 Mut cell proliferation inhibition assay 50 value

[0471] As shown in the experimental results in Table 2, the compounds of the present invention have excellent in vitro activity and can inhibit the cell proliferation process of human breast cancer cells MDA-MB-436 BRCA1 Mut.

[0472] Experimental Example 3: Pharmacokinetic Test

[0473] 1. Purpose of the experiment

[0474] CD-1 mice were used as test animals and Example 11b and Comparative Example KSQ-4279 were administered orally. The drug concentrations in plasma at different time points were determined by LC-MS / MS to study the pharmacokinetic characteristics of the compound of the present invention and the comparative example compound in mice.

[0475] 2. Experimental Plan

[0476] 2.1 Experimental drugs and animals

[0477] Experimental drugs: Example 11b and comparative example KSQ-4279;

[0478] Animals: CD-1 mice, male, 24-25 g, were purchased from Shanghai Jihui Experimental Animal Co., Ltd.

[0479] 2.2 Drug preparation

[0480] Appropriate amounts of Example 11b and Comparative Example KSQ-4279 were weighed, and appropriate amounts of 5% dimethyl sulfoxide + 10% solutol + 80% saline (5% DMSO + 10% solutol + 85% saline) were added. The mixture was vortexed and sonicated to prepare a 10 mg / mL dosing solution.

[0481] 2.3 Administration

[0482] Mice in each test compound gavage group (3 mice per group) were fasted overnight and then gavaged with the compound (dose 100 mg / kg, administration volume 10 mL / kg), and were fed 4 hours after administration.

[0483] 3. Operation

[0484] 0.2 mL of blood was collected before dosing and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing, and anticoagulated with sodium heparin. After collection, the blood samples were placed on ice and centrifuged (1500 g for 10 minutes) to separate the plasma. The collected plasma was stored at -20°C until analysis.

[0485] Determination of the test compound content in mouse plasma after oral administration by LC-MS / MS

[0486] 4. Pharmacokinetic parameter results

[0487] The pharmacokinetic parameters of Example 11b of the present invention and Comparative Example KSQ-4279 are shown in Table 3.

[0488] Table 3 Pharmacokinetic results

[0489] Conclusion: Compared with the comparative example KSQ-4279, the pharmacokinetic characteristics such as blood drug concentration and area under the curve in mice of Example 11b were significantly improved.

[0490] The above describes exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention should be included in the scope of protection of this application.

Claims

1. A compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, in, Selected from when Selected from When , X1 is selected from N; when Selected from When X1 is selected from C; X2 is selected from N and CR 2X ; X3 selected from N and CR 3X ; R 2X , R 3X Each independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -OC(=O)-C 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)-OC 1-6 Alkyl, C 1-6 Alkylthio, -S(O)2-C 1-6 Alkyl, -S(O)-C 1-6 Alkyl, -S(O)-N(H)-C 1-6 Alkyl, NRxR Y 、-C(=O)NRxR Y and-P(=O)RxR Y , the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 1-6 Alkoxy, -OC(=O)C 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, C 1-6 Alkylthio, -S(O)2C 1-6 Alkyl, -S(O)C 1-6 Alkyl or -S(O)N(H)-C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH; R X , R Y Each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; or, R X , R Y Together with the nitrogen atom to which it is attached, it forms a 3-9 membered heterocyclic group or a 5-9 membered heteroaryl group, wherein the 3-9 membered heterocyclic group or the 5-9 membered heteroaryl group is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; R2 is selected from phenyl, naphthyl and 5-9 membered heteroaryl, wherein the phenyl, naphthyl or 5-9 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R'; R' is selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; L is selected from CR3R4, NR3, O, S, S(=O) and S(=O)2; R3 and R4 are each independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 OH, NH2, halogen Element, CN, NO2, COOH substitution; Or, R3, R4 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; Ring E is selected from 5-7 membered unsaturated heterocyclic group, C 6-14 Aryl, 5-9 membered heteroaryl, the 5-7 membered unsaturated heterocyclic group, C 6-14 Aryl, 5-9 membered heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 R'; Ring B is selected from C 6-14 Aryl, C 3-9 Cycloalkyl, C 5-15 bridged cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, the C 6-14 Aryl, C 3-9 Cycloalkyl, C 5-15 The bridged cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl are optionally substituted by 1, 2 or 3 R5; R5 is selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Or, two optional R5 on ring B together with the atoms to which they are attached are linked together to form C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; Optionally, R5 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl and 3-9 membered heterocyclyl; R a , R b are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; The C 1-6 The heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, and 5-9 membered heteroaryl groups contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(O)-, -S(O)2- and N.

2. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, Y1, Y2, Y3, Y4, Y5 are each independently selected from N or C(R'); R' is independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substituted.

3. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2G , R 2H , R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O Each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substituted.

4. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, X5, X6, X7, and X8 are each independently selected from N and CR B ; R B Selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH.

5. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O , R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; R a , R b are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted.

6. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, X5, X6, X7, T1, T2 are each independently selected from N and CR B ; R B Selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH; J, K, and M are each independently selected from CR 7A R 7B NR 7A , C(=O), O, S, S(O) and S(O)2; R 7A , R 7B Each independently selected from H, OH, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH; Ring A is selected from C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl and 3-9 membered heterocyclic group, the C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl are optionally substituted by 1, 2 or 3 R6; R6 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、- S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Or, two optional R6 on ring A together with the carbon atom to which they are attached are linked together to form C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-9 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; R a , R b are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; The C 1-6 The heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 5-9 membered heteroaryl contain 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(O)-, -S(O)2- and N.

7. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O , R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; R a , R b are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl -O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted.

8. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, X 4A , X 5A are each independently selected from N or C(R'); X 4B , X 5B are each independently selected from O, S, N(R') or CR'R"; R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substituted.

9. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, X 4A , X 5A , X 6A are each independently selected from N or C(R'); X 4B , X 5B , X 6B are each independently selected from O, S, N(R') or CR'R"; R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substituted.

10. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, X 5B , X 6B , X 7B are each independently selected from O, S, N(R') or CR'R"; R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substituted.

11. The compound according to claim 1, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 12. The compound according to any one of claims 1, 4, 5, 6, 7, 8, 9 or 10, its optical isomer, tautomer or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl and pyrazolyl, wherein the phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl or pyrazolyl is optionally substituted with 1, 2, 3 or 4 R'; Optionally, R' is each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, halogen, CN, NO2, COOH, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R' is each independently selected from H, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -OCH3, -SCH3, Optionally, R2 is selected from R 2A , R 2B , R 2C , R 2D , R 2E , R 2F , R 2G , R 2H , R 2I , R 2J , R 2K , R 2L , R 2M , R 2N , R 2O Selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3- 9-membered cycloalkyl and 3-9-membered heterocyclic group, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(O)2C 1-6 Alkyl, C 3-9 Cycloalkyl-O-, 3-9 membered heterocyclyl-O-, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R2 is selected from 13. The compound according to any one of claims 1 to 10, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: L is selected from N R3, CR3R4; R3 and R4 are each independently selected from H, OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2-3 Alkenyl, C 2-3 Alkynyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2-3 Alkenyl, C 2-3 Alkynyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2 or COOH; Optionally, R3, R4 are each independently selected from H, OH, CN, halogen, methyl, ethyl and propyl.

14. The compound according to any one of claims 1-4, 8-10, its optical isomer, tautomer or a pharmaceutically acceptable salt thereof, wherein: R5 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl and 5-6 membered heterocyclyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl or 5-6 membered heteroaryl and 5-6 membered heterocyclyl are optionally substituted by 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1- 6 alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R5 is selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O , R 5P are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; R a , R b are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3- 9-cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted; Optionally, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O , R 5P are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-6 Alkyl-C(=O)N(C 1-6 Alkyl)2, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O , R 5P are each independently selected from H, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heteroalkyl and -C 1-3 Alkyl-C(=O)N(C 1-3 Alkyl)2, the C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-3 Alkyl-C(=O)N(C 1-3 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G , R 5H , R 5I , R 5J , R 5K , R 5L , R 5M , R 5N , R 5O , R 5P Each is independently selected from H, CN, halogen, OCH3, OCH2CH3, CF3, CHF2, CD3, methyl, ethyl, Optionally, R5 is selected from 15. The compound according to any one of claims 1 to 6, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, R 6A , R 6B , R 6C , R 6D , R 6E , R 6F , R 6G are each independently selected from H, CN, halogen, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b , -C 1-6 Alkyl-C(=O)NR a R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- or 5-9 membered heteroaryl-O- is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; R a , R b are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3- 9-cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O-, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, C 3-9 Cycloalkyl-O-, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl, 3-9 membered heterocyclyl-O-, C 6-14 Aryl-O- and 5-9 membered heteroaryl-O- are optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl-O-substituted.

16. The compound according to claim 6, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from R 6A , R 6B , R 6C , R 6D , R 6E , R 6F , R 6G are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-6 Alkyl-C(=O)N(C 1-6 Alkyl)2, the C 1-6 Alkyl, C 1- 6 heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R 6A , R 6B , R 6C , R 6D , R 6E , R 6F , R 6G are each independently selected from H, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heteroalkyl and -C 1-3 Alkyl-C(=O)N(C 1- 3 alkyl) 2, the C 1-3 Alkylthio, C 1-3 Alkylamino, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-3 Alkyl-C(=O)N(C 1-3 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, R 6A , R 6B , R 6C , R 6D , R 6E , R 6F , R 6G Each is independently selected from H, CN, halogen, OCH3, OCH2CH3, CF3, CHF2, CD3, methyl, ethyl, Optionally, Selected from 17. The compound according to claim 6, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, wherein: J, K, and M are each independently selected from NR 7A , CR 7A R 7B , C(=O) and O; R 7A , R 7B Each independently selected from H, OH, CN, halogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2- 3 alkenyl, C 2-3 Alkynyl and C 3-6 Cycloalkyl, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 2-3 Alkenyl, C 2-3 Alkynyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2 or COOH; Optionally, R 7A , R 7B Each is independently selected from H, OH, CN, halogen, methyl, ethyl and propyl.

18. The compound according to claim 6, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from R 6A , R 6B , R 6C , R 6D are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and -C 1-6 Alkyl-C(=O)N(C 1-6 Alkyl)2, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl-O-, 3-6 membered heterocyclyl-O-, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; Optionally, the structural unit Selected from 19. A compound of the following formula, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, selected from:

20. Use of the compound according to any one of claims 1 to 19, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease associated with USP1 activity or expression.

21. The disease associated with USP1 activity or expression according to claim 20, which is selected from cancer-related diseases.

22. The cancer-related disease according to claim 21, which is selected from bone cancer, brain cancer, soft tissue cancer, kidney cancer, bladder cancer, skin cancer, lung cancer, colon cancer, nervous system cancer, head and neck cancer, pancreatic cancer, ovarian cancer, breast cancer, uterine cancer, cervical cancer.

23. The cancer-related disease according to claim 21, which is selected from osteosarcoma, chondrosarcoma, glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, rhabdoid sarcoma, melanoma, and non-small cell lung cancer.

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