Preparation method and application of aza five-membered aromatic fused ring compound as ubiquitin-specific protease 1 inhibitor and application of aza five-membered aromatic fused ring compound

Abstract

The invention discloses a preparation method, application and application of an aza five-membered aromatic fused ring compound serving as a ubiquitin-specific protease 1 inhibitor, and particularly discloses a compound shown in a formula (I), an optical isomer, a tautomer or pharmaceutically acceptable salt of the compound and application of the compound serving as the ubiquitin-specific protease 1 inhibitor. # imgabs0 #

Description

[0001] This application claims the priority of Chinese patent application No. 2023112858436 filed on September 28, 2023 and Chinese patent application No. 202410149653X filed on February 1, 2024. This application cites the full text of the above Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and in particular, relates to a preparation method, application and use of an aza-five-membered aromatic fused ring compound as a ubiquitin-specific protease 1 inhibitor. Background Art

[0003] 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 antitumor activity by enhancing ubiquitination and subsequently degrading the activity of other key proteins involved in tumor growth, survival, differentiation and maintenance of oncogenic substrates and 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, inhibition of USP1 with small molecule inhibitors has the potential to become a therapeutic approach for the treatment of cancer and other diseases. For the above reasons, there is a considerable unmet need for potent small molecule inhibitors of USP1. Summary of the invention

[0004] 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,

[0005]

[0006] in,

[0007] A is selected from O, S and Se;

[0008] Selected from

[0009] X1 is selected from N and C;

[0010] When X1 is selected from N, the structural unit Selected from

[0011] When X1 is selected from C, the structural unit Selected from

[0012] 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';

[0013] 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;

[0014] L is selected from CR3R4, NR3, O, S, S(=O) and S(=O)2;

[0015] 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;

[0016] 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, C6-14 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;

[0017] 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';

[0018] Ring B is selected from C 6-14 Aryl, C 3-9 Cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, the C 6-14 Aryl, C 3-9 Cycloalkyl, 5-9 membered heteroaryl, 3-9 membered heterocyclyl are optionally substituted by 1, 2 or 3 R5;

[0019] 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, -OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 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- 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;

[0020] 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 6-14Aryl 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 -OC 3-6 Cycloalkyl substitution;

[0021] 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, -OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl and 3-9 membered heterocyclyl;

[0022] 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, C3-9 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;

[0023] The C 1-6 Heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, 5-9 membered heteroaryl, 5-9 membered heteroaryl contains 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.

[0024] 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:

[0025]

[0026] in,

[0027] Y1, Y2, Y3, Y4, Y5 are each independently selected from N or C(R');

[0028] 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 The remaining variables are as defined herein.

[0029] 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:

[0030]

[0031] in,

[0032] 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 The remaining variables are as defined herein.

[0033] 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:

[0034]

[0035] in,

[0036] X5, X6, X7, and X8 are each independently selected from N and CR B ;

[0037] RB 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.

[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]

[0040] in,

[0041] 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 Rb , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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;

[0042] 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, OC 3-9Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, -3-9 membered heterocyclic group, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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 The remaining variables are as defined herein.

[0043] 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:

[0044]

[0045] in,

[0046] Ring F is selected from a 5- to 7-membered saturated or unsaturated heterocyclic group, wherein the 5- to 7-membered saturated or unsaturated heterocyclic group is optionally substituted by 1, 2 or 3 R B replace;

[0047] X5, X6, X7, T1, T2 are each independently selected from N and CR B ;

[0048] 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;

[0049] Ring A is selected from C 3-9 Cycloalkyl, C 6-14Aryl, 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;

[0050] 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 、-

[0051] 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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)NRa R b , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-9 Cycloalkyl, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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;

[0052] 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 -OC 3-6 Cycloalkyl substitution;

[0053] 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14Aryl 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;

[0054] The C 1-6 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, and the remaining variables are as defined in the present invention.

[0055] 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:

[0056]

[0057] in,

[0058] 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;

[0059] 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 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.

[0060] 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:

[0061]

[0062] in,

[0063] R4A Selected from O or NH;

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

[0065] 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 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 The remaining variables are as defined herein.

[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]

[0069] in,

[0070] R 4A Selected from O or NH;

[0071] X 4A , X 5A , X 6A are each independently selected from N or C(R');

[0072] X 5B , X 6B are each independently selected from O, S, N(R') or CR'R";

[0073] R', R" are each independently selected from H, OH, CN, halogen, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-9Cycloalkyl-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 The remaining variables are as defined herein.

[0074] 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:

[0075]

[0076] in,

[0077] R 4A Selected from O or NH;

[0078] X 5B , X 6B , X 7B are each independently selected from O, S, N(R') or CR'R";

[0079] 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 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, wherein 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 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;

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

[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 3-9Cycloalkyl-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 substitution;

[0087] Optionally, R2 is selected from

[0088]

[0089] The remaining variables are as defined in the present invention.

[0090] In some embodiments of the present invention, L is selected from NR3, CR3R4;

[0091] 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;

[0092] 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.

[0093] 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 、-NRa 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 and 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;

[0094] 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, C1-6 Heteroalkyl,

[0095] 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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;

[0096] 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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 3-6Cycloalkyl 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 5P are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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;

[0098] 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 1-3Alkylthio, C 1-3 Alkylamino, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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;

[0099] 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,

[0100] Optionally, R5 is selected from

[0101] The remaining variables are as defined in the present invention.

[0102] In some embodiments of the present invention, the structural unit Selected from

[0103] R 6A , R 6B , R 6C , R 6Dare each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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 The remaining variables are as defined herein.

[0104] In some embodiments of the present invention, the structural unit Selected from

[0105] 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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;

[0106] 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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;

[0107] 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,

[0108] Optionally, Selected from The remaining variables are as defined in the present invention.

[0109] 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;

[0110] R 7A , R 7BEach 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;

[0111] 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.

[0112] In some embodiments of the present invention, the structural unit Selected from

[0113] R 6A , R 6B , R 6C , R 6D are each independently selected from H, CN, halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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;

[0114] Optionally, the structural unit Selected from

[0115] The remaining variables are as defined in the present invention.

[0116] In another aspect of the present invention, the present invention also proposes a compound of the following formula, its optical isomers, tautomers or pharmaceutically acceptable salts thereof, which is selected from:

[0117]

[0118]

[0119]

[0120]

[0121] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating a disease associated with USP1 activity or expression.

[0122] In some embodiments of the present invention, the above-mentioned diseases related to USP1 activity or expression level are selected from cancer-related diseases and the like.

[0123] 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.

[0124] In some embodiments of the present invention, the above-mentioned bone cancer is selected from osteosarcoma, chondrosarcoma, etc.

[0125] In some embodiments of the present invention, the above-mentioned brain cancer is selected from glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, etc.

[0126] In some embodiments of the present invention, the above-mentioned soft tissue cancer is selected from rhabdoid sarcoma and the like.

[0127] In some embodiments of the present invention, the above-mentioned skin cancer is selected from melanoma and the like.

[0128] In some embodiments of the present invention, the above-mentioned lung cancer is selected from non-small cell lung cancer and the like.

[0129] Definition and Description

[0130] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0131] 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 humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0132] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention and 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 a pure solution or 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 a solution or 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, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; 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, etc.; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0133] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in the form of free acid or base are prepared by reacting with a suitable base or acid in a stoichiometric amount.

[0134] 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. All of these isomers and their mixtures are included within the scope of the present invention.

[0135] 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 can rapidly interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of 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.

[0136] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0137] "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.

[0138] The term "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.

[0139] 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 be optionally substituted with up to three Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0140] 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 ("-") not between two letters or symbols indicates the point of attachment of a substituent. 1-6 Alkylcarbonyl - refers to a C- 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.

[0141] Unless otherwise indicated, when a group bond is indicated by a dash When, for example, In the figure, the dashed line indicates the point of attachment of the group to the rest of the molecule.

[0142] When the substituent is listed without indicating the atom through which it is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0143] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect phenyl and cyclopentyl groups 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.

[0144] Unless otherwise specified, the number of atoms on the ring refers to the number of atoms that constitute 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, a heterocyclic compound) in which atoms are bonded to form a ring. The number of atoms on the ring is usually defined as the number of members of the ring. 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.

[0145] Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight chain and / or branched alkyl group, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specifically stated in the specification, an alkyl group may be optionally substituted.

[0146] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to 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 may 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-pentylidene, 1,6-hexylidene, and the like.

[0147] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to 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 may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3Examples 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.

[0148] 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 chain and / or branched alkenyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight chain alkenyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.

[0149] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a straight 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. 2-6 Alkenyl includes 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.

[0150] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a straight 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 The alkenyl group may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, ethenylene, propenylene, and the like.

[0151] 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, which may represent a straight and / or branched alkynyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight alkynyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkynyl group may be optionally substituted.

[0152] Unless otherwise specified, the term “C 2-6 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-6 Alkynyl groups include C2-5 , 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.

[0153] Unless otherwise specified, “C 2-3 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can 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.

[0154] 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 is C 1-20 In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1-3Heteroalkyl. A heteroatom or heteroatom group may be located at any internal position of a 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, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, etc.; up to two heteroatoms thereof may be consecutive, for example, -CH2-NH-OCH3. 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 the "alkyl" in the "alkyl group" is as defined above in the present invention. Unless otherwise specified in the specification, alkoxy groups may be optionally substituted.

[0155] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, 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), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy and the like.

[0156] 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 includes C 1-3 , C 1-2 , C 2-4 , 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), methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, and the like.

[0157] 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. 1-3 Alkoxy includes 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.

[0158] Unless otherwise specified, the term "amino" may be monovalent - NH2, divalent Or multiple price

[0159] 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" is as defined above in the present invention. Unless otherwise specifically stated in the specification, the alkylamino group may be optionally substituted.

[0160] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through an amino group. 1-6 Alkylamino groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , 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.

[0161] Unless otherwise specified, the term “C 1-4 "Alkylamino" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule through 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.

[0162] Unless otherwise specified, the term “C 1-3 "Alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through 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.

[0163] Unless otherwise specified, the term "alkylthio" refers to an alkyl group connected to the rest of the molecule via a sulfur atom, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, alkylthio may be optionally substituted.

[0164] Unless otherwise specified, the term “C 1-20 "Alkylthio" refers to those alkyl groups containing 1 to 20 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-20 Alkylthio includes C 1-19 , C 1-14 , C 1-12 , C 2-6 , C 2-4 , C 15 , C 10 , 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.

[0165] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-6Alkylthio 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.

[0166] Unless otherwise specified, the term “C 1-4 "Alkylthio" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached 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.

[0167] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached 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.

[0168] 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 cyclo, spiro 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.

[0169] 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 may be monovalent, divalent or polyvalent.3-20 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0170] 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 includes 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 include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0171] Unless otherwise specified, “C 3-6 "Cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3-6 ring carbon atoms, such as 3-5 ring carbon atoms, such as 3-4 ring carbon atoms; it can be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0172] 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. 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0173] Unless otherwise specified, the term "heterocyclyl" refers to a non-aromatic saturated cyclic group that exists in 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 located at any interior position of the heterocycloalkyl, including the position at which the heterocycloalkyl is attached to the rest of the molecule. In some embodiments, the heterocycloalkyl is a 3-20 membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 3-10 membered heterocycloalkyl; in other embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl 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). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, paracyclic 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 that may occupy the connection position of the heterocycloalkyl with the rest of the molecule. The 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, 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.

[0174] 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, spiro or bridged ring; wherein ring A can be selected from 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.

[0175] 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 9-12 Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0176] Unless otherwise specified, the term "aryl" refers to a hydrocarbon ring system group containing at least one aromatic ring. In the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a paracyclic, spirocyclic and / or bridged ring system. The aryl group includes, but is not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, triphenylene, perylene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene and derivative groups thereof. Unless otherwise specifically stated in the specification, the aryl group can be optionally substituted.

[0177] 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. Heteroaryl is preferably 5 to 10 yuan, containing 1 to 3 heteroatoms; more preferably 5 yuan or 6 yuan, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. Heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples 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, furanofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primary dine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole, and derivatives thereof. Unless otherwise specifically stated in the specification, the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio or heterocycloalkylthio.

[0178] The term "substituted" as used in the present invention 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 with a non-hydrogen atom, wherein the non-hydrogen atom includes but is not limited to halogen atoms (e.g., F, Cl, Br, I), oxygen atom-containing groups (e.g., hydroxyl, alkoxy, ester groups), sulfur atom-containing groups (e.g., thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, sulfoxide groups), nitrogen atom-containing groups (e.g., amine groups, amide groups, alkylamino groups, dialkylamine groups, arylamine groups, aryl-alkyl-amine groups, diarylamine groups, N-oxide groups, imide groups, enamine groups), silicon atom-containing groups (e.g., trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups) and other heteroatoms in various other groups.

[0179] The term "substituted" as used herein 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 (such as a double bond or a triple bond) of a heteroatom, such as oxygen in carbonyl, carboxyl and ester groups, and 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 S02R h 、-OC(=O)NR g Rh 、-OR g 、-SR g 、-SOR g 、SO2R g 、-OSO2R g 、-SO2OR g ,

[0180] =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 、-CH2SO2NR g R h The R g With R h Identical or different, independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, 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 mean 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, alkoxy, alkylamino, alkylthio, 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.

[0181] 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 may 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.

[0182] The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.

[0183] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0184] The term "diastereomer" as used herein refers to stereoisomers having 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 by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0185] 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. In 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 of the rotation of plane polarized light by the compound, 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. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may 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.

[0186] The racemic mixture can be used in its own form or split into individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by splitting. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared 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 freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers 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.

[0187] The term "tautomer" or "tautomeric form" as used herein 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 proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0188] 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 embodiments of the present invention.

[0189] 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. DETAILED DESCRIPTION

[0190] The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. 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.

[0191] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0192] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker ASCEND TM -400 NMR spectrometer, the solvents used for determination were deuterated sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD, the internal standard was tetramethylsilane (TMS)

[0193] MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.

[0194] HPLC determination was performed using Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5μm column)

[0195] Chiral HPLC analysis was performed using THARSFC X5.

[0196] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) had a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products was 0.4mm-0.5mm.

[0197] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0198] High performance liquid phase preparation used Waters 2767, Waters 2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0199] Chiral preparative column chromatography used Shimadzu LC20-AP and THARSFC PREP80.

[0200] The pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0201] The microwave reaction was carried out using a Biotage initiator+ type microwave reactor.

[0202] Unless otherwise specified in the experimental examples, the reactions were carried out under argon or nitrogen atmosphere.

[0203] 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.

[0204] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0205] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20°C to 30°C.

[0206] Example 1: Synthesis of Compound 1

[0207]

[0208] Step 1: Synthesis of compound 1-2

[0209] Compound 1-1 (1.8 g, 9.09 mmol) was dissolved in ultra-dry tetrahydrofuran (30 mL), nitrogen was replaced, the temperature was lowered to -20 °C, lithium bis(trimethylsilyl)amide (11.82 mL, 11.82 mmol, 1M in THF) was slowly added, stirred for 20 min, N-chlorosuccinimide (1.46 g, 10.91 mmol) was added, stirred for 20 min, and the temperature was raised to room temperature for 3 hours. TLC spot plate showed that most of the raw materials reacted completely to generate new products (LCMS no signal), water (20 mL) was added to quench the reaction, and ethyl acetate (20 mL × 3) was used for extraction, the organic phase was washed with water (20 mL), saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1 / 10) to obtain compound 1-2 (1.353 g, yield: 64.03%, colorless oil).

[0210] 1 H NMR (400MHz, CDCl3-d) δ7.67 (dd, J=8.0, 0.9Hz, 1H), 7.62 (dd, J=8.1, 0.9Hz, 1H), 7.36 (t, J=8.0Hz, 1H).

[0211] Step 2: Synthesis of Compound 1-3

[0212] Compound 1-2 (1.65 g, 7.10 mmol) and 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (2.06 g, 10.65 mmol) were dissolved in tetrahydrofuran (20 mL) and water (10 mL), and cesium carbonate (6.94 g, 21.30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.29 g, 0.35 mmol) were added, and nitrogen was replaced, and the mixture was reacted at 80°C for 16 hours. The reaction was completed by LCMS detection, and the target product was generated. Cool to room temperature, add water (10 mL), extract with ethyl acetate (20 mL×3), wash the organic phase with water (10 mL) and saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (petroleum ether / ethyl acetate=5 / 1) to obtain compound 1-3 (0.354 g, yield: 14.41%, gray solid).

[0213] LC-MS(ESI)[M+H] + 346.0 / 348.0.

[0214] Step 3: Synthesis of compound 1

[0215] Compound 1-3 (83 mg, 0.24 mmol), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)methyl)phenyl)-4-trifluoromethylimidazole (60 mg, 0.16 mmol), dissolved in toluene / water (8 mL / 1.6 mL), added potassium phosphate (68 mg, 0.32 mmol), 1,1-bis(diphenylphosphino)diferronichloridopalladium (12 mg, 0.016 mmol), replaced nitrogen, reacted at 90 ° C overnight. LCMS detected that the reaction was complete and the target product was generated. Cooled to room temperature, added water (10 mL), extracted with ethyl acetate (20 mL×3), the organic phase was washed with water (10 mL), saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated and liquid phase prepared compound 1 (25.92 mg, yield: 31.30%). LC-MS(ESI)[M+H] + 505.9.

[0216] 1H NMR (400MHz, DMSO-d6) δ8.79(s,1H),7.90(s,1H),7.78-7.71(m,1H),7.65(d,J=6.5Hz,2H),7.46(d,J=6.8Hz,2H), 7.43-7.36(m,2H),4.33(s,2H),3.95(s,3H),3.75(s,3H),2.29-2.13(m,1H),1.17-1.08(m,2H),1.07-0.94(m,2H).

[0217] Example 2: Synthesis of Compound 2

[0218]

[0219] Step 1: Synthesis of compound 2-1

[0220] Compound 1-3 (1 g, 2.89 mmol), (tributyltinyl)methanol (1.86 g, 5.78 mmol), tetrakistriphenylphosphine palladium (330 mg, 0.29 mmol) were added to dioxane (10 mL), and the reaction solution was reacted at 100° C. for 2 hours. The reaction solution was directly spin-dried and purified by column chromatography (ethyl acetate / petroleum ether=1 / 1) to obtain compound 2-1 (0.5 g, yield: 58%, yellow oil).

[0221] LC-MS(ESI)[M+H] + 298.2.

[0222] Step 2: Synthesis of compound 2-2

[0223] Compound 2-1 (500 mg, 1.68 mmol) was dissolved in tetrahydrofuran, phosphorus tribromide (1.36 g, 5.04 mmol) was slowly added dropwise under ice bath, and the reaction solution was stirred at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride, the organic phases were concentrated and purified by column chromatography (ethyl acetate / petroleum ether=1 / 1) to obtain compound 2-2 (400 mg, yield: 66%, yellow solid).

[0224] LC-MS (ESI) [M+3H] + 362.1.

[0225] Step 3: Synthesis of compound 2-3

[0226] Compound 2-2 (300 mg, 0.83 mmol), bis-pinacol borate (420 mg, 1.66 mmol), potassium acetate (240 mg, 2.49 mmol) and ditriphenylphosphine palladium dichloride (120 mg, 0.17 mmol) were added to dioxane (5 ml). The reaction solution was stirred at 100 ° C for 16 hours under nitrogen protection. The reaction solution was filtered, water was added to the organic phase, and it was extracted with ethyl acetate. The organic phase was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 2-3 (300 mg, yield: 62%, yellow solid).

[0227] LC-MS(ESI)[M+H] + 408.2.

[0228] Step 4: Synthesis of compound 2

[0229] Compound 2-3 (100 mg, 0.25 mmol), 2-bromo-5-(1-methyl-4-trifluoromethyl)-1H-imidazol-2-yl)pyridine (100 mg, 0.33 mmol), potassium phosphate (110 mg, 0.5 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (39 mg, 0.05 mmol) were added to a mixed solution of toluene (2 mL) and water (0.2 mL), and the reaction solution was stirred at 100° C. for 16 hours. Water was added to the reaction solution, extracted twice with ethyl acetate, washed with saturated sodium chloride aqueous solution, the organic phase was concentrated, purified by TLC large plate (ethyl acetate / petroleum ether=1 / 4), and then purified by liquid phase preparation to obtain compound 2 (1.42 mg, yield: 1.1%).

[0230] LC-MS(ESI)[M+H] + 507.3.

[0231] 1 H NMR (400MHz, MeOD-d4) δ8.78(d,J=1.8Hz,1H),8.67(s,1H),8.07(dd,J=8.1,2.3Hz,1H),7.75-7.69(m,2H),7.54(d,J=8.1Hz,1H),7.42 (dd,J=7.0,4.4Hz,2H),4.56(s,2H),3.98(s,3H),3.79(s,3H),2.14(d,J=3.7Hz,1H),1.23-1.20(m,2H),1.02(dt,J=12.0,3.7Hz,2H).

[0232] Biological Examples

[0233] Test Example 1: USP1 / UAF1 deubiquitination assay (Ubiquitin Fluorophore Assay)

[0234] 1. Prepare 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), and use the reaction buffer to prepare a final concentration of 0.15 nM USP1 / UAF1 complex (R&D, E-568-050) enzyme mixture.

[0235] 2. Prepare Ubiquitin Rhodamine 110 reaction substrate: Use 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) to prepare a substrate mixture with a final concentration of 150 nM Ubiquitin Rhodamine 110 (R&D, E-555-050).

[0236] 3. Compound preparation: The test compound is dissolved in DMSO, and the final concentration of DMSO is 1%. The compound is prepared with DMSO to different concentrations, and duplicate wells are set for each concentration, with 3-fold gradient dilution, a total of 11 concentrations, and corresponding solvent controls are set at the same time. After dilution, the compound is diluted 25 times with reaction buffer.

[0237] 4. USP1 / UAF1 deubiquitination reaction: Add 5uL 4x USP1 / UAF1 complex solution and 5uL 4x compound to each well of the test plate and incubate for 15 minutes, then add 10uL 2x Ubiquitin Rhodamine 110 reaction substrate to start the reaction. Centrifuge, seal the plate, and incubate at 37°C for 30 minutes.

[0238] 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.

[0239] The experimental results are shown in Table 1.

[0240] Table 1: IC values ​​of selected compounds in USP1 / UAF1 deubiquitination assay 50 value

[0241] Compound No. <![CDATA[Luciferase IC 50 (nM)]]> Example 1 17.68 Example 2 33.50

[0242] As shown in the experimental results in Table 1, the compounds of the present invention have excellent in vitro activity and can inhibit the deubiquitinating activity of USP1 / UAF1 on Ubiquitin Rhodamine110.

[0243] The exemplary embodiments of the present invention are described above. It should be understood that the protection scope of the present application is not limited to the above exemplary embodiments. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the present application.

Claims

1. A compound represented by formula (I), its optical isomers, tautomers or pharmaceutically acceptable salts thereof, in, A is selected from O, S and Se; Selected from and X1 is selected from N and C; When X1 is selected from N, the structural unit Selected from When X1 is selected from C, the structural unit Selected from 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 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, NO2, COOH; 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 -OC 3-6 Cycloalkyl substitution; 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, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, the C 6-14 Aryl, C 3-9 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, -OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 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- 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 Heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, 5-9 membered heteroaryl, 5-9 membered heteroaryl contains 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, -3-9 membered heterocyclic group, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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.

6. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, Ring F is selected from a 5- to 7-membered saturated or unsaturated heterocyclic group, wherein the 5- to 7-membered saturated or unsaturated heterocyclic group is optionally substituted by 1, 2 or 3 R B replace; 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; 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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 -OC 3-6 Cycloalkyl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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; 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 6, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, 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.

8. The compound according to claim 1, its optical isomer, tautomer or pharmaceutically acceptable salt thereof, whose structure is shown below, in, R 4A Selected from O or NH; X 4A , X 5A are each independently selected from N or C(R'); 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, R 4A Selected from O or NH; X 4A , X 5A , X 6A are each independently selected from N or C(R'); 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, R 4A Selected from O or NH; 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 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 NR3, 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 and 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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, OC 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, 3-9 membered heterocyclic group-O-, -OC 6-14 Aryl 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; 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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 claim 6, its optical isomers, tautomers or pharmaceutically acceptable salts 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, 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.

Images