Preparation method, application and application of nitrogen-containing heterocyclic compound as ubiquitin-specific protease 1 inhibitor

Abstract

The invention discloses a preparation method, application and application of a nitrogen-containing heterocyclic compound serving as a ubiquitin-specific protease 1 inhibitor, and particularly discloses a compound shown in a formula (I), an optical isomer 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. 2023107705638 filed on June 27, 2023 and Chinese Patent Application No. 2024101496050 filed on February 1, 2024. This application cites the entire 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 a nitrogen-containing heterocyclic 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), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

[0005]

[0006] in,

[0007] X1 is selected from N and CR 1X ;

[0008] X2 is selected from N and CR 2X ;

[0009] X3 selected from N and CR3X ;

[0010] X4 selected from N and CR 4X ;

[0011] R1, R 1X , R 2X , R 3X , R 4X Each independently selected from H, OH, CN, F, Cl, Br, I, NRxR Y 、-C(=O)NRxR Y 、-P(=O)RxR Y , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(=O)2C 1-6 Alkyl and -S(=O)N(H)-C 1-6 Alkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(=O)2C 1-6 Alkyl or -S(=O)N(H)-C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH;

[0012] or, R 3X , R 4X Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 OH, NH2, halogen, CN, C 1-6Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl substitution;

[0013] Rx, R Y Each independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, -C(=O)C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, -C(=O)C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0014] or, R X , R Y Together with the nitrogen atom to which it is attached, it forms a 3-9 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-9 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl substitution;

[0015] R2 is selected from phenyl, naphthyl and 5-6 membered heteroaryl, wherein the phenyl, naphthyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R';

[0016] R' is independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0017] L is selected from CR3R4, NR3, O, S, S(=O) and S(=O)2;

[0018] R3 and R4 are each independently selected from H, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, CN, NO2, COOH;

[0019] 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 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-6 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;

[0020] X5, X6, X7, T1, T2 are each independently selected from N and CR 5X ;

[0021] R 5X Selected from H, OH, CN, F, Cl, Br, I, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl and C3-6 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, F, Cl, Br, I, CN, NO2, COOH;

[0022] J, K, and M are each independently selected from CR 6A R 6B NR 6A , O, S, S(=O), S(=O)(=NH) and S(=O)2;

[0023] R 6A , R 6B Each independently selected from H, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, CN, NO2, COOH;

[0024] Ring A is selected from C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 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 R5;

[0025] R5 is selected from H, D, CN, F, Cl, Br, I, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NR a C(=O)R b 、-

[0026] 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

[0027] Base, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl or -O-5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 or, two optional R5 on ring A together with the carbon atom to which they are attached form C 3-6Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-6 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;

[0028] R a , R b Each independently selected from H, D, CN, F, Cl, Br, I, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl 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;

[0029] The C 1-6 The heteroalkyl, 3-9 membered heterocyclyl, 5-9 membered heterocyclyl, 5-6 membered heterocyclyl, 5-9 membered heteroaryl, 5-6 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.

[0030] In some embodiments of the present invention, the compound represented by formula (I), its optical isomer or a pharmaceutically acceptable salt thereof, has a structure as shown below:

[0031]

[0032] in,

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

[0034] R' is independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, 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, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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.

[0035] In some embodiments of the present invention, the compound represented by formula (I), its optical isomer or a pharmaceutically acceptable salt thereof, has a structure as shown below:

[0036]

[0037] in,

[0038] 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, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, 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, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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.

[0039] In some embodiments of the present invention, the compound represented by formula (I), its optical isomer or a pharmaceutically acceptable salt thereof, has a structure as shown below:

[0040]

[0041] in,

[0042] R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G Each independently selected from H, D, CN, F, Cl, Br, I, -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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl, the -C(=O)Ra 、-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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl or -O-5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution;

[0043] R a , R b Each independently selected from H, D, CN, F, Cl, Br, I, 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 -O-5-9 membered heteroaryl, 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, C6-14 Aryl, 5-9 membered heteroaryl, 3-9 membered heterocyclic group, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl 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.

[0044] In some embodiments of the present invention, the structural unit Selected from

[0045] The remaining variables are as defined in the present invention.

[0046] In some embodiments of the present invention, R1, R 1X , R 2X , R 3X , R 3Y , R 4X Each independently selected from H, CN, F, Cl, Br, NRxR Y 、-C(=O)NRxR Y 、-P(=O)RxR Y , C 1-3 Alkyl, -OC 1-3 Alkyl, -OC(=O)C 1-3 Alkyl, -C(=O)C 1-3 Alkyl, -C(=O)OC 1-3 Alkyl, -SC 1-3 Alkyl, -S(=O)2C 1-3 Alkyl and -S(=O)N(H)-C 1-3 Alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -OC(=O)C 1-3 Alkyl, -C(=O)C 1-3 Alkyl, -C(=O)OC 1-3 Alkyl, -SC 1-3 Alkyl, -S(=O)2C 1-3 Alkyl or -S(=O)N(H)-C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH, and the remaining variables are as defined herein.

[0047] In some embodiments of the present invention, R 3X , R 4X Together with the carbon atom to which it is attached, it forms C3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 The remaining variables are as defined herein.

[0048] In some embodiments of the present invention, Rx, R Y Each independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl and -C(=O)C 1-3 Alkyl, the C 1-3 Alkyl or -C(=O)C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, and the remaining variables are as defined herein.

[0049] In some embodiments of the present invention, R X , R Y Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 The remaining variables are as defined herein.

[0050] In some embodiments of the present invention, the structural unit Selected from

[0051] The remaining variables are as defined in the present invention.

[0052] In some embodiments of the present invention, R2 is selected from phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl and pyrazolyl, and the phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrrolyl or pyrazolyl is optionally substituted with 1, 2, 3 or 4 R', and the remaining variables are as defined in the present invention.

[0053] In some embodiments of the present invention, R' is independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 The remaining variables are as defined herein.

[0054] In some embodiments of the present invention, R' is independently selected from H, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -SCH3, The remaining variables are as defined in the present invention.

[0055] In some embodiments of the present invention, R2 is selected from

[0056] 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, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C 1-6Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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.

[0057] In some embodiments of the present invention, R2 is selected from

[0058] The remaining variables are as defined in the present invention.

[0059] In some embodiments of the present invention, 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, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3Alkoxy, C 1-3 Alkylthio or C 1-3 The remaining variables are as defined herein.

[0060] In some embodiments of the present invention, 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, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -SCH3,

[0061] The remaining variables are as defined in the present invention.

[0062] In some embodiments of the present invention, L is selected from CR3R4, R3 and R4 are each independently selected from H, OH, CN, F, Cl, Br, I, 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 The cycloalkyl group is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2 or COOH, and the remaining variables are as defined herein.

[0063] In some embodiments of the present invention, R3 and R4 are each independently selected from H, D, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl, and the remaining variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the structural unit Selected from R 5A , R5B , R 5C , R 5D , R 5E , R 5F , R 5G Each independently selected from H, D, CN, F, Cl, Br, I, 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 The alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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.

[0065] In some embodiments of the present invention, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G Each independently selected from H, D, CN, F, Cl, Br, I, 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 1-3The alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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.

[0066] In some embodiments of the present invention, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G Each independently selected from H, D, CN, F, Cl, Br, I, OCH3, OCH2CH3, CF3, CHF2, CD3, methyl, ethyl, The remaining variables are as defined in the present invention.

[0067] In some embodiments of the present invention, Selected from The remaining variables are as defined in the present invention.

[0068] In some embodiments of the present invention, J, K, and M are each independently selected from CR 6A R 6B and O, and the remaining variables are as defined in the present invention.

[0069] In some embodiments of the present invention, R 6A , R 6B Each independently selected from H, OH, CN, F, Cl, Br, I, 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 The cycloalkyl group is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2 or COOH, and the remaining variables are as defined herein.

[0070] In some embodiments of the present invention, R 6A , R 6BEach is independently selected from H, D, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl, and the remaining variables are as defined herein.

[0071] In some embodiments of the present invention, the structural unit Selected from R 5A , R 5B , R 5C , R 5D Each independently selected from H, D, CN, F, Cl, Br, I, 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 The alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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.

[0072] In some embodiments of the present invention, the structural unit Selected from The remaining variables are as defined in the present invention.

[0073] In another aspect of the present invention, the present invention also proposes a compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] 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.

[0080] 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.

[0081] 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.

[0082] In some embodiments of the present invention, the above-mentioned bone cancer is selected from osteosarcoma, chondrosarcoma, etc.

[0083] In some embodiments of the present invention, the above-mentioned brain cancer is selected from glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, etc.

[0084] In some embodiments of the present invention, the above-mentioned soft tissue cancer is selected from rhabdoid sarcoma and the like.

[0085] In some embodiments of the present invention, the above-mentioned skin cancer is selected from melanoma and the like.

[0086] In some embodiments of the present invention, the above-mentioned lung cancer is selected from non-small cell lung cancer and the like.

[0087] Definition and Description

[0088] 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.

[0089] As in the present invention, the phrase "at least one" used when referring to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in the list of elements, but does not necessarily include at least one of each element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that there may be optionally elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers, whether related or unrelated to those specifically identified elements.

[0090] 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.

[0091] The term "pharmaceutically acceptable salt" refers to salts of compounds of the invention, prepared from compounds of the invention having specific substituents with relatively nontoxic acids or bases. When the compounds of the 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 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, and 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.

[0092] 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 acids or bases are prepared by reacting with a stoichiometric amount of appropriate base or acid.

[0093] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, formulation aid or carrier commonly used with therapeutic agents in the art, which together constitute a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration used and is compatible with the other ingredients of the formulation. The pharmaceutically acceptable carrier is suitable for the formulation used.

[0094] Since the compounds of the present disclosure are inhibitors of USP1 protein, the present disclosure provides a method for inhibiting USP1 protein, the method comprising contacting USP1 protein or a composition comprising USP1 protein with one or more compounds of the present disclosure.

[0095] Since the compounds of the present disclosure are inhibitors of USP1 proteins, a variety of diseases, disorders or conditions mediated by USP1 proteins can be treated by employing the compounds. Thus, the present disclosure generally relates to a method for treating a disease, disorder or condition in an animal suffering from or at risk of a condition responsive to inhibition of USP1 proteins, the method comprising administering to the animal an effective amount of one or more compounds of the present disclosure.

[0096] The present disclosure further relates to a method of inhibiting USP1 protein in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one compound of the present disclosure.

[0097] As used herein, "USP1" and "ubiquitin-specific protease 1" refer to any native polypeptide or polynucleotide encoding USP1. The term "USP1" encompasses "full-length" unprocessed USP1 polypeptides as well as any form of USP1 resulting from processing within the cell (e.g., removal of the signal peptide). The term also encompasses naturally occurring variants of USP1, such as those encoded by splice variants and allelic variants. The USP1 polypeptides described herein may be derived from a variety of sources, such as isolated from a human tissue type or from another source, or produced by recombinant or synthetic methods. Human USP1 sequences are known and include, for example, sequences publicly available as UniProt No. 094782 (including isoforms). As used herein, the term "human USP1 protein" refers to a USP1 protein comprising an amino acid sequence as shown in SEQ ID NO: 1 in U.S. Provisional Patent Application No. 62 / 857,986, filed on June 6, 2019.

[0098] USP1 is a deubiquitinase that acts as part of a complex with UAF1. The "deubiquitinase activity" of USP1 includes its ability to deubiquitinate as part of the USP1-UAF1 complex.

[0099] The term "specific binding" to a protein or a domain of a protein is a well-known term in the art, and methods for determining the specific binding achieved are also well-known in the art. A molecule is considered to exhibit "specific binding" or "preferential binding" if it reacts or associates with a particular protein or a domain of a protein more frequently, more quickly, for a longer period of time, and / or with a higher affinity than it reacts or associates with an alternative protein or domain. It should be understood that a molecule that specifically or preferentially binds to a first protein or domain may or may not specifically or preferentially bind to a second protein or domain. Therefore, "specific binding" or "preferential binding" does not necessarily require (but may include) exclusive binding. In general, but not necessarily, reference to binding means preferential binding. For example, a USP1 inhibitor that specifically binds to USP1, UAF1, and / or a USP1-UAF1 complex may not bind to other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (USP46-UAF1), or may bind to other deubiquitinating enzymes, other USP proteins, or other UAF1 complexes (e.g., USP46-UAF1) with lower affinity than it binds to USP1.

[0100] As used herein, the terms "cancer" and "tumor" refer to or describe a physiological condition in which a population of cells in a mammal is characterized by unregulated cell growth. The terms encompass solid cancers and blood / lymphoid cancers. Examples of cancer include, but are not limited to, cancers with defects in DNA damage repair pathways. Other examples of cancer include, but are not limited to, ovarian cancer, breast cancer (including triple-negative breast cancer), non-small cell lung cancer (NSCLC), and osteosarcoma. The cancer may be BRCA1 or BRCA2 wild type. The cancer may also be BRCA1 or BRCA2 mutant. The cancer may also be a PARP inhibitor-resistant or refractory cancer, or a PARP inhibitor-resistant or refractory BRCA1 or BRCA2 mutant cancer.

[0101] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, and each case of R has an independent option. For example, if a group is substituted with 1, 2, or 3 R's, the group may optionally be substituted with 1 or 2 or 3 R's, and each case of R' has an independent option. 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.

[0102] 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.

[0103] When the group bond is marked with a dotted line When, for example, In the examples, the dashed line represents the point of attachment of the group to the rest of the molecule.

[0104] The term "substituted" or "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" or "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.

[0105] 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 L1 represents a single bond, it means that the structure is actually

[0106] 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.

[0107] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is -CH2O-, in which case -CH2O- can connect phenyl and cyclopentyl in the same direction as the reading order 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.

[0108] The term "halogen" refers to fluorine, chlorine, bromine, iodine.

[0109] The term "deuterium" is also called heavy hydrogen or hydrogen-2. It is a stable isotope of hydrogen, and its element symbol is usually D or 2 H.

[0110] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0111] 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 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0112] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 , C 1-3 , C 3-4 and C 2-3 Alkyl, etc.; it can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-4 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0113] 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, piperyl, hexadienyl, and the like.

[0114] 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 C2-3 The alkenyl group may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to wait.

[0115] Unless otherwise specified, “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 C 2-3 , C 2-4 , C 2-5 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 5-6 , C6, C5, C4, C3 and C2 alkynyl. 2-6 Examples of alkynyl groups include, but are not limited to wait.

[0116] 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 wait.

[0117] The term "heteroalkyl" by itself or in combination with another term refers to 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. 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 1-6 In other embodiments, the heteroalkyl group is C 1-3Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is a customary expression to refer to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(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, -SCH(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2-S-CH3, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3.

[0118] 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, and the like.

[0119] 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 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0120] 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. 1-6Alkylamino 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, -NHCH(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0121] 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 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, and the like.

[0122] 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. 1-6 Alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0123] 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 , C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0124] 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.

[0125] Unless otherwise specified, “C 3-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic or bicyclic system. 3-6 Cycloalkyl includes C 3-5 , C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0126] Unless otherwise specified, the term "3-9 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 3 to 9 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur atoms are independently optionally oxidized (i.e., C=O, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, cyclic and bridged rings. In addition, with respect to the "3-9 membered heterocyclic group", heteroatoms can occupy the connection position of the heterocyclic group with the rest of the molecule. The 3-9 membered heterocyclic group includes 3-8, 3-7, 3-6, 3-5, 3-4, 4-5, 4-6, 4-7, 4-8, 4-9, 5-6, 5-7, 5-8, 5-9, 6-7, 6-8, 6-9, 7-8, 3, 4, 5, 6, 7, 8 and 9 membered heterocyclic groups. Examples of 3-9 membered heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, 1,3-dioxolane, 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.

[0127] Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., C=O, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spirocyclic, fused and bridged rings. In addition, with respect to the "3-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected to the rest of the molecule. The 3-6 membered heterocyclic group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocyclic groups, etc. Examples of 3-6 membered heterocyclic 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 or hexahydropyridazinyl, etc.

[0128] Unless otherwise specified, the term "5-6 membered heterocyclyl" by itself or in combination with other terms means a saturated or partially unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", a heteroatom may occupy the position where the heterocyclic group is connected to the rest of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups, etc. Examples of 5-6 membered heterocyclic groups include, but are not limited to, 1,3-dioxolane, 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.

[0129] Unless otherwise specified, the terms "5-9 membered heteroaromatic ring" and "5-9 membered heteroaryl" are used interchangeably in the present invention. The term "5-9 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 9 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. 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). The 5-9 membered heteroaryl group may be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-9 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered and 6 membered heteroaryl groups. Examples of the 5-9 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl) oxazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzoxazolyl, indolyl (including 5-indolyl, etc.), isoquinolyl (including 1-isoquinolyl and 5-isoquinolyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolyl and 6-quinolyl, etc.).

[0130] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" of the present invention can be used interchangeably, and the term "5-6 membered heteroaryl" means a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl) and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0131] Unless otherwise specified, the term “C 6-14 "Aryl" by itself or in combination with other terms refers to a monocyclic or bicyclic aromatic ring system having six to fourteen carbon atoms, respectively. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthrenyl, anthryl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl. The aryl group may be selected from phenyl or theanyl group. The aryl group may be phenyl.

[0132] 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, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring and 6-10-membered ring, etc.

[0133] 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.

[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] 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.

[0136] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0137] 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.

[0138] 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.

[0139] The racemic mixture can be used as such or resolved into the individual isomers. To obtain stereochemicalPure compounds or mixtures enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), 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.

[0140] The compounds of the present invention may exist in specific tautomers. Unless otherwise specified, the term "tautomer" or "tautomeric form" means that at room temperature, different functional group isomers are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (such as in solution), the chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as prototropic tautomers) include interconversions carried out by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valence tautomers) include interconversions carried out by the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one.

[0141] 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( 14C). 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.

[0142] "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.

[0143] 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.

[0144] The solvent used in the present invention is commercially available.

[0145] Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0146] The compounds disclosed in the present invention may have one or more chiral centers, each of which independently has an R configuration or an S configuration. The chiral centers of some of the compounds disclosed in the present invention are marked with *R, *S, R*, or S*, indicating that the absolute configuration of the chiral center of the compound has not been identified, but the compound has been chirally resolved and the chiral center is a chiral center of a single configuration, the compound is a single configuration enantiomer monomer, or a single configuration diastereoisomer monomer, or a diastereoisomer mixture with a single configuration of the chiral center (for example: other chiral center configurations have not been resolved). When the absolute configuration (R configuration, or S configuration) of the chiral center of the compounds disclosed in the present invention has not been identified, such compounds can be identified according to their corresponding retention time (R configuration) under corresponding chromatographic column conditions (for example, chromatographic column model, chromatographic column filling material, chromatographic column size, mobile phase, etc.). T ) for confirmation.

[0147] The present invention is explained in more detail in the following examples. However, it should be understood that these examples are for illustrating the present invention and are not intended to limit the scope of the present invention in any way. The experimental methods in the following examples, if no specific conditions are specified, are usually based on the conventional conditions of this type of reaction, or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and weight parts. Unless otherwise stated, the ratio of liquid is volume ratio.

[0148] 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

[0149] 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.

[0150] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0151] 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)

[0152] MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.

[0153] HPLC determination was performed using Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5μm column)

[0154] Chiral HPLC analysis was performed using THARSFC X5.

[0155] 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.

[0156] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0157] High performance liquid phase preparation used Waters2767, Waters2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0158] Chiral preparative column chromatography used Shimadzu LC20-AP and THARSFC PREP80.

[0159] The pressurized hydrogenation reaction uses a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0160] The microwave reaction was carried out using a Biotage initiator+ type microwave reactor.

[0161] Unless otherwise specified in the experimental examples, the reactions were carried out under argon or nitrogen atmosphere.

[0162] 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.

[0163] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0164] Unless otherwise specified in the experimental examples, the reaction temperature is room temperature, ranging from 20°C to 30°C.

[0165] Example 1: Synthesis of Compound 1

[0166]

[0167] Step 1: Synthesis of compound 1-2

[0168] Under ice bath, compound 1-1 (1 g) was added to 1,4-dioxane / water (10 / 1 mL), and 4-cyclopropyl-6-methoxypyrimidine-5-boric acid (1.64 g), potassium phosphate (2.76 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (621 mg) and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (551 mg) were added. The reaction solution was stirred at 100°C for 16 hours, the reaction solution was added to water, extracted with ethyl acetate, the organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column to obtain compound 1-2 (700 mg).

[0169] LC-MS(ESI)[M+H] + 268.2.

[0170] Step 2: Synthesis of Compound 1-3

[0171] Under ice bath, compound 1-2 (44 g) was added to N,N-dimethylformamide (500 mL), and N-bromosuccinimide (32.3 g) was added. The reaction solution was stirred at room temperature overnight. LC-MS showed that the reaction was successful. Water was added, and ethyl acetate was extracted. The organic phases were combined and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column to obtain compound 1-3 (31.8 g).

[0172] LC-MS(ESI)[M+H] + 346.0.

[0173] Step 3: Synthesis of Compound 1-4

[0174] Compound 1-3 (5.00 g), selective fluorine reagent (7.67 g) and sodium bicarbonate (6.05 g) were dissolved in acetonitrile (75 mL), and the reaction was carried out at 80 ° C in a microwave for 15 minutes. LCMS detected that the raw material was completely converted, and water was added to quench, ethyl acetate (2*20 mL) was extracted, and water (2*20 mL) was washed. The organic phase was dried over anhydrous sodium sulfate. The crude compound 1-4 was separated and purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1), and compound 1-4 (560 mg) was obtained by secondary separation and purification by column chromatography (petroleum ether / ethyl acetate = 8 / 1).

[0175] LCMS (ESI) m / z (M+H) + 366.0.

[0176] Step 4: Synthesis of compound 1

[0177] Compound 1-4 (60 mg), 9-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazole[1,2-d][1,4]oxazepine (71.4 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12.0 mg) and potassium phosphate (69.9 mg) were dissolved in toluene (3 mL) / water (0.3 mL), and the reaction was reacted at 100°C in a microwave for 2 hours. LCMS detected that the raw material was completely converted, and water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL*3), and the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by liquid phase preparation to obtain compound 1 (20.5 mg).

[0178] LCMS (ESI) m / z (M+H) + 552.0.

[0179] 1H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.71(s,1H),8.23(d,J=8.4Hz,1H),7.96(d,J=8.0Hz,1H),7.04(dd,J=8.4Hz,J=1.6Hz,1H),6 .96(s,1H),6.91(d,J=1.2Hz,1H),4.44(s,4H),4.32(s,2H),3.87(s,3H),1.84-1.80(m,1H),1.06-1.03(m,2H),0.91-0.86(m,2H).

[0180] Example 2: Synthesis of Compound 2

[0181]

[0182] Step 1: Preparation of compound 2-1

[0183] Compound 1-3 (500 mg), 9-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazole[1,2-a]azepine (623 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (105.58 mg) and potassium phosphate (612.40 mg) were dissolved in toluene (15 mL) / water (2 mL), and the reaction was carried out at 100° C. for 16 hours. LCMS detected that the raw material was completely converted. The reaction solution was directly spin-dried and mixed, and separated and purified by column chromatography (petroleum ether / ethyl acetate=1 / 1) to obtain compound 2-1 (300 mg).

[0184] LCMS (ESI) m / z (M+H) + 532.2.

[0185] Step 2: Preparation of compound 2-2

[0186] Compound 2-1 (300 mg) was dissolved in acetonitrile (15 mL), N-bromosuccinimide (100 mg) was added at room temperature, and the reaction was carried out at 25°C for 0.5 hours. LCMS detected that the raw material was completely converted, and the mixture was quenched with water, extracted with ethyl acetate (2*20 mL), washed with water (2*20 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain compound 2-2 (340 mg).

[0187] LCMS (ESI) m / z (M+H) + 610.2.

[0188] Step 3: Preparation of compound 2

[0189] Compound 2-2 (140 mg), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium (II) (19.6 mg), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (22.2 mg) and sodium tert-butoxide (44.0 mg) were dissolved in The reaction was stirred at 100°C for 16 hours in methanol (1 mL) / 1,4-dioxane (10 mL) / water (1 mL). LCMS detected that the raw material was completely converted. Water (10 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was purified by liquid phase preparation to obtain compound 2 (22.9 mg).

[0190] LCMS (ESI) m / z (M+H) + 562.2.

[0191] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.68(s,1H),7.97(d,J=0.4Hz,1H),7.59(d,J=7.6Hz,1H),7.27-7.22(m,2H),6.68(s,1H),4.32(s,2 H),3.98-3.93(m,5H),3.86(s,3H),2.62(t,J=6.8Hz,2H),2.22(t,J=6.8Hz,2H),1.83-1.81(m,1H),1.05-1.01(m,2H),0.88-0.85(m,2H).

[0192] Example 3: Synthesis of Compound 3

[0193]

[0194] Step 1: Preparation of compound 3

[0195] Compound 2-2 (130 mg) was added to an autoclave of methanol (5 mL) / acetonitrile (5 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15.0 mg) and triethylamine (64 mg) were added. Carbon monoxide was filled into the autoclave to 2 standard atmospheric pressures, and the reaction kettle was stirred at 100°C for 24 hours. LCMS detected that the raw material was completely converted. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1 / 1) to obtain a crude compound 3 (100 mg). Compound 3 (61.4 mg) was obtained by liquid phase preparation and purification.

[0196] LCMS (ESI) m / z (M+H) + 590.0.

[0197] 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),8.74(s,1H),7.97(s,1H),7.60(d,J=8.0Hz,1H),7.43(s,1H),7.32-7.24(m,2H),4.42(s,2H),3.97(t, J=8.0Hz,2H),3.90(s,3H),3.86(s,3H),2.62(t,J=8.0Hz,2H),2.28-2.18(m,2H),1.89-1.81(m,1H),1.09-1.02(m,2H),0.88-0.80(m,2H).

[0198] Example 4: Synthesis of Compound 4

[0199]

[0200] Step 1: Preparation of compound 4

[0201] Compound 2-2 (50 mg), tributyl (1-ethoxyvinyl) stannane (44 mg), bistriphenylphosphine palladium dichloride (12 mg) were dissolved in ultra-dry 1,4-dioxane (3 mL), nitrogen was replaced, and stirred at 100 ° C for 2 hours. No raw material remained after LCMS detection. The reaction solution was cooled to room temperature, and dilute hydrochloric acid (3 mL, 2 mol / L) was added, and the reaction was carried out at room temperature for 30 minutes. LCMS detection showed that the reaction was complete. Water (10 mL) was added to the reaction solution, and ethyl acetate was extracted (10 mL × 3). The organic phases were combined, washed with water (10 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to prepare compound 4 (10.079 mg).

[0202] LCMS (ESI) m / z (M+H) + 574.3.

[0203] 1 H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 8.73 (s, 1H), 7.96 (d, J = 1.1Hz, 1H), 7.60 (t, J = 3.9Hz, 2H), 7.31-7.23(m,2H),4.43(s,2H),3.96(t,J=6.7Hz,2H),3.86(s,3H), 2.65-2.57(m,5H),2.26-2.16(m,2H),1.86- 1.79(m,1H),1.07-1.02(m,2H),0.87-0.79(m,2H).

[0204] Example 5: Synthesis of Compound 5

[0205]

[0206] Step 1: Synthesis of compound 5-1

[0207] Compound 1-3 (130 mg), 9-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)-2-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (162.83 mg) were dissolved in toluene (3 mL), water (0.3 mL) mixed solution, then potassium phosphate (159.42 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (27.25 mg) were added, nitrogen was replaced three times, and microwave reaction was performed at 100°C for 3.5 hours. Purification by column chromatography (petroleum ether: ethyl acetate = 0-80%) gave compound 5-1 (200 mg, crude product).

[0208] LCMS (ESI) m / z (M+H) + 534.2.

[0209] Step 2: Synthesis of compound 5-2

[0210] Compound 5-1 (180 mg) was dissolved in acetonitrile (5 mL), and then N-bromosuccinimide (60.05 mg) was added and reacted at 25° C. for 1 hour. LCMS showed that the main peak was the desired product. Part of the solvent was concentrated, and then dichloromethane (30 ml) and water (30 ml) were added for extraction three times. The sample was spin-dried and purified by column chromatography (petroleum ether: ethyl acetate = 0-80%) to obtain compound 5-2 (130 mg).

[0211] LCMS (ESI) m / z (M+H) + 612.2.

[0212] Step 3: Synthesis of compound 5-3

[0213] Compound 5-2 (60 mg) was dissolved in 1-butyl-3-methylimidazolium tetrafluoroborate (0.01 mL), N,N-dimethylformamide (3 mL), followed by the addition of vinyl butyl ether (49.07 mg), triethylamine (49.57 mg, 68.33 μL), 1,3-bis(diphenylphosphino)propane (8.08 mg) and palladium acetate (2.22 mg), nitrogen was replaced three times, and microwave reaction was performed at 100°C for 3 hours. Water (35 ml) and dichloromethane (40 ml) were added and extracted three times, washed once with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and dried by spin drying, mixed, and purified by column chromatography (petroleum ether: ethyl acetate = 0-60%) to obtain 50 mg of crude compound 5-3, and 15 mg of solid was obtained by liquid phase preparation. 1HNMR confirmed that the product was vinyl butyl ether.

[0214] 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 8.71 (s, 1H), 8.23 ​​(d, J = 8.0Hz, 1H), 7.94 (s, 1 H),7.24(s,1H),7.04(d,J=8.0Hz,1H),6.90(s,1H),4.81(d,J=4.0Hz,1H),4.44(s, 4H),4.38(s,1H),4.32(s,2H),3.93(t,J=8.0Hz,2H),3.87(s,3H),1.87-1.76(m,3 H),1.53-1.40(m,2H),1.07-1.01(m,2H),0.96(t,J=8.0Hz,3H),0.91-0.83(m,2H).

[0215] Step 4: Synthesis of compound 5

[0216] Compound 5-3 (15 mg) was dissolved in dioxane (5 mL), and then hydrochloric acid (865.86 μg, 0.5 mL) was added and stirred at room temperature of 25°C for 15 minutes. Then triethylamine was added to adjust the pH to about 7, and part of the solvent was concentrated. Then water (30 ml) and dichloromethane (30 ml) were added to extract three times, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. Then compound 5 (8.8 mg) was prepared by liquid phase.

[0217] LCMS (ESI) m / z (M+H) + 576.0.

[0218] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.74(s,1H),8.26(d,J=12.0Hz,1H),7.95(d,J=4.0Hz,1H),7.61(s,1H),7.08(d,J=8.0,1 H),6.94(s,1H),4.45(s,4H),4.38(s,2H),3.88(s,3H),2.61(s,3H),1.89-1.77(m,1H),1.10-1.03(m,2H),0.91-0.82(m,2H).

[0219] Biological Examples

[0220] Experimental Example 1: USP1 / UAF1 deubiquitination assay (Ubiquitin Fluorophore Assay)

[0221] 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.

[0222] 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).

[0223] 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.

[0224] 4. USP1 / UAF1 deubiquitination reaction: Add 5uL 4x USP1 / UAF1 complex solution to each well of the test plate and incubate with 5uL 4x compound for 15 minutes, then add 10uL 2x Ubiquitin Rhodamine 110 reaction substrate to initiate the reaction. Centrifuge, seal the plate, and incubate at 37°C for 30 minutes. 5. After the reaction, use an ELISA reader (MD, VersaMax) to read the fluorescence value with an excitation wavelength of 480nm and an emission wavelength of 540nm. Finally, use GraphPad Prism 8 software to analyze the data, and use the dose-response-inhibition (four-parameter) equation to calculate the IC using GraphPadPrism software. 50 value.

[0225] The experimental results are shown in Table 1.

[0226] Table 1: IC values ​​of selected compounds in USP1 / UAF1 deubiquitination assay 50 value

[0227] Compound No. <![CDATA[IC 50 (nM)]]> Example 2 23.25 Example 3 36.00 Example 4 68.96 Example 5 362.8

[0228] The representative compounds of the present invention have excellent in vitro activity and can inhibit the deubiquitinating activity of USP1 / UAF1 on UbiquitinRhodamine 110.

[0229] 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), an optical isomer thereof or a pharmaceutically acceptable salt thereof, in, X1 is selected from N and CR 1X ; X2 is selected from N and CR 2X ; X3 selected from N and CR 3X ; X4 selected from N and CR 4X ; R1, R 1X , R 2X , R 3X , R 4X Each independently selected from H, OH, CN, F, Cl, Br, I, NRxR Y 、-C(=O)NRxR Y 、-P(=O)RxR Y , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(=O)2C 1-6 Alkyl and -S(=O)N(H)-C 1-6 Alkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC(=O)C 1-6 Alkyl, -OC 3-6 Cycloalkyl, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -SC 1-6 Alkyl, -S(=O)2C 1-6 Alkyl or -S(=O)N(H)-C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH; or, R 3X , R 4X Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 Aryl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-6 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; Rx, R Y Each independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C(=O)C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl and 3-9 membered heterocyclic group, the C 1-6 Alkyl, C(=O)C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 The cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylamino substitution; or, R X , R Y Together with the nitrogen atom to which it is attached, it forms a 3-9 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-9 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl substitution; R2 is selected from phenyl, naphthyl and 5-6 membered heteroaryl, wherein the phenyl, naphthyl or 5-6 membered heteroaryl is optionally substituted with 1, 2, 3, 4 or 5 R'; R' is independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, 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, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, 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, F, Cl, Br, I, 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 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-6 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; X5, X6, X7, T1, T2 are each independently selected from N and CR 5X ; R 5X Selected from H, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, CN, NO2, COOH; J, K, and M are each independently selected from CR 6A R 6B NR 6A , O, S, S(=O), S(=O)(=NH) and S(=O)2; R 6A , R 6B Each independently selected from H, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, CN, NO2, COOH; Ring A is selected from C 3-9 Cycloalkyl, C 6-14 Aryl, 5-9 membered heteroaryl, 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 R5; R5 is selected from H, D, CN, F, Cl, Br, I, -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 Base, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl or -O-5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 A 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 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 3-9 membered heterocyclic group, C 6-14 The aryl or 5-6 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 Each independently selected from H, D, CN, F, Cl, Br, I, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl 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, 5-9 membered heteroaryl, 5-6 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.

2. The compound according to claim 1, its optical isomer or a 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, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, 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, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 or a 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, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, 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, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 or a pharmaceutically acceptable salt thereof, whose structure is shown below, in, R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G Each independently selected from H, D, CN, F, Cl, Br, I, -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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl or -O-5-9 membered heteroaryl is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 Each independently selected from H, D, CN, F, Cl, Br, I, 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 -O-5-9 membered heteroaryl, 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, -O-3-9 membered heterocyclic group, -OC 6-14 Aryl and -O-5-9 membered heteroaryl 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.

5. The compound according to any one of claims 1 to 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 6. The compound according to any one of claims 1 to 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R1, R 1X , R 2X , R 3X , R 3Y , R 4X Each independently selected from H, CN, F, Cl, Br, NRxR Y 、-C(=O)NRxR Y 、-P(=O)RxR Y , C 1-3 Alkyl, -OC 1-3 Alkyl, -OC(=O)C 1-3 Alkyl, -C(=O)C 1-3 Alkyl, -C(=O)OC 1-3 Alkyl, -SC 1-3 Alkyl, -S(=O)2C 1-3 Alkyl and -S(=O)N(H)-C 1-3 Alkyl, the C 1-3 Alkyl, -OC 1-3 Alkyl, -OC(=O)C 1-3 Alkyl, -C(=O)C 1-3 Alkyl, -C(=O)OC 1-3 Alkyl, -SC 1-3 Alkyl, -S(=O)2C 1-3 Alkyl or -S(=O)N(H)-C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH; or, R 3X , R 4X Together with the carbon atom to which it is attached, it forms C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl, the C 3-6 Cycloalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl substitution.

7. The compound according to any one of claims 1 to 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Rx, R Y Each independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl and -C(=O)C 1-3 Alkyl, the C 1-3 Alkyl or C(=O)C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 H, OH, CN, F, Cl, Br, I, CN, NO2, COOH; or, R X , R Y Together with the nitrogen atom to which it is attached, it forms a 3-6 membered heterocyclic group or a 5-6 membered heteroaryl group, wherein the 3-6 membered heterocyclic group or the 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl substitution.

8. The compound according to claim 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 9. The compound according to claim 1 or 4, its optical isomer 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, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 Alkylamino substitution; Optionally, R' is each independently selected from H, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -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 Each independently selected from H, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, 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, -OC 3-9 Cycloalkyl, -O-3-9 membered heterocyclic group, C 3-9 Cycloalkyl or 3-9 membered heterocyclic group is optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 10. The compound according to claim 9, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: 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, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, -S(=O)2C 1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups are optionally substituted by 1, 2 or 3 D, OH, CN, F, Cl, Br, I, CN, NO2, COOH, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio or C 1-3 Alkylamino substitution; Optionally, 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, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -SCH3, 11. The compound according to any one of claims 1 to 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: L is selected from CR3R4, R3 and R4 are each independently selected from H, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, CN, NO2 or COOH; Optionally, R3, R4 are each independently selected from H, D, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl.

12. The compound according to claim 1, 2 or 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from R 5A , R 5B , R 5C , R 5D , R 5E , R 5F , R 5G Each independently selected from H, D, CN, F, Cl, Br, I, 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 The alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 Each independently selected from H, D, CN, F, Cl, Br, I, 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 The alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 Each independently selected from H, D, CN, F, Cl, Br, I, -OCH3, -OCH2CH3, CF3, CHF2, CD3, methyl, ethyl, Optionally, Selected from 13. The compound according to any one of claims 1 to 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: J, K, and M are each independently selected from CR 6A R 6B and O; R 6A , R 6B Each independently selected from H, OH, CN, F, Cl, Br, I, 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, F, Cl, Br, I, CN, NO2 or COOH; Optionally, R 6A , R 6B Each is independently selected from H, D, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl.

14. The compound according to any one of claims 1 to 4, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from R 5A , R 5B , R 5C , R 5D Each independently selected from H, D, CN, F, Cl, Br, I, 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 The alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, F, Cl, Br, I, 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 15. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

16. Use of the compound according to any one of claims 1 to 15, 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. 17 . The disease associated with USP1 activity or expression according to claim 16 , which is selected from cancer-related diseases.

18. The cancer-related disease according to claim 17, 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.

19. The cancer-related disease according to claim 17, which is selected from osteosarcoma, chondrosarcoma, glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, rhabdoid sarcoma, melanoma, and non-small cell lung cancer.

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