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

Abstract

Relates to a nitrogen-containing heterocyclic compound serving as an ubiquitin-specific protease 1 inhibitor, and a preparation method and application thereof, in particular to 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

Preparation method, application and use of nitrogen-containing heterocyclic compounds as ubiquitin-specific protease 1 inhibitors

[0001] The present invention claims the following priority:

[0002] 1) Application number CN 202210952786.1, application date August 9, 2022;

[0003] 2) Application number CN 202310878446.3, application date July 17, 2023. Technical Field

[0004] The present invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a preparation method, application and use of a nitrogen-containing heterocyclic compound as a ubiquitin-specific protease 1 inhibitor. Background Art

[0005] Ubiquitination is a reversible process involving a family of deubiquitinating enzymes (DUBs) that regulate various cellular processes by deconjugating ubiquitin from substrates. DUBs are encoded by approximately 100 human genes and are divided into six families, the largest of which is the ubiquitin-specific protease (USP) with more than 50 members. DUBs and their substrate proteins are often dysregulated in cancer, supporting the hypothesis that targeting specific DUB family members may lead to anti-tumor activity by enhancing the activity of ubiquitination and subsequent degradation of other key proteins involved in tumor growth, survival, differentiation and maintenance of oncogenic substrates and the tumor microenvironment. USP1 is a cysteine ​​isopeptidase of the USP subfamily of DUBs. Full-length human USP1 consists of 785 amino acids, including a catalytic triad consisting of Cys90, His593 and Asp751. USP1 deubiquitinates various cellular targets involved in different processes related to cancer. For example, USP1 deubiquitinates PCNA (proliferating cell nuclear antigen), a key protein in translesion synthesis (TLS), and FANCD2 (Fanconi anemia complementation group D2), a key protein in the Fanconi anemia (FA) pathway. Therefore, inhibiting USP1 with small molecule inhibitors has the potential to be a therapeutic approach for treating cancer and other diseases. For these reasons, there is a considerable unmet need for potent small molecule inhibitors of USP1.

[0006] Summary of the Invention

[0007] 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,

[0008] in,

[0009] X1 is selected from N and CR 1X ;

[0010] X2 is selected from N and CR 2X ;

[0011] X3 selected from N and CR 3X ;

[0012] X4 selected from N and CR 4X ;

[0013] R1, R 1X 、R 2X 、R 3X 、R 4X 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, C 3-6 Cycloalkyl and -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH;

[0014] 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 or 3 R';

[0015] R' is 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 groups, 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;

[0016] 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;

[0017] X5, X6, X7, and X8 are each independently selected from N and CR X ;

[0018] R X 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] 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 、C1-6 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, said -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;

[0020] Or, wherein the two optional substituents on R5 together with the carbon atoms 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 Aryl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 cycloalkyl substitution;

[0021] 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 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;

[0022] The C 1-6 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.

[0023] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers or pharmaceutically acceptable salts thereof, has the following structure:

[0024] in,

[0025] Y1, Y2, Y3, Y4, Y5 are each independently selected from N or C(R');

[0026] 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 groups, 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 in the present invention.

[0027] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers or pharmaceutically acceptable salts thereof, has the following structure:

[0028] in,

[0029] 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 groups, the C 1-6 Alkyl, C 1-6 Heteroalkyl, -S(=O)2C 1-6 Alkyl, -OC 3-9Cycloalkyl, -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 in the present invention.

[0030] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers or pharmaceutically acceptable salts thereof, has the following structure:

[0031] Among them, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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 6-14Aryl, 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, said -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;

[0032] 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, C2-6 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 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.

[0033] In some embodiments of the present invention, the structural unit Selected from The remaining variables are as defined in the present invention.

[0034] In some embodiments of the present invention, the structural unit Selected from The remaining variables are as defined in the present invention.

[0035] In some embodiments of the present invention, R1, R 1X 、R 2X 、R 3X 、R 4X 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, C 3-6 Cycloalkyl and -OC 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, C 3-6 Cycloalkyl or -OC 3-6 The cycloalkyl 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.

[0036] In some embodiments of the present invention, R1, R 1X 、R2X 、R 3X 、R 4X are each independently selected from H, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl, and the remaining variables are as defined herein.

[0037] 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.

[0038] 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, 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, 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 in the present invention.

[0039] In some embodiments of the present invention, R' is independently selected from H, CN, methyl, ethyl, -OCH3, -OCH2CH3, -OCD3, -OCHF2, -OCH3, -SCH3, The remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, R2 is selected from R 2A 、R 2B 、R 2C 、R 2D 、R 2E 、R 2F 、R2G 、R 2H 、R 2I 、R 2J 、R 2K 、R 2L 、R 2M 、R 2N 、R 2O 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 groups, 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 in the present invention.

[0041] In some embodiments of the present invention, R2 is selected from The remaining variables are as defined in the present invention.

[0042] 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)2C1-3 Alkyl, -OC 3-6 Cycloalkyl, -O-3-6 membered heterocyclic group, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, 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 in the present invention.

[0043] 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, -OCH3, -SCH3, The remaining variables are as defined in the present invention.

[0044] In some embodiments of the present invention, 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 2-3Alkenyl, 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.

[0045] 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.

[0046] In some embodiments of the present invention, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl and 5-6 membered heterocyclyl are 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 In some embodiments of the present invention, R5 is selected from H, D, CN, F, Cl, Br, I, -C(=O)R a 、-C(=O)OR b 、-NR a R b 、-NRa C(=O)R b 、-NR a C(=O)NR a R b 、-S(O)2NR a R b 、-C(=O)NR a R b 、-S(O)2R a 、-NR a S(O)2R b 、-C 1-6 Alkyl-C(=O)NR a R b 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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 2-6Alkynyl, 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, said -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;

[0047] 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 6-14Aryl, 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 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, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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 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 1-6Alkylthio or C 1-6 The remaining variables are as defined in the present invention.

[0049] In some embodiments of the present invention, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、 R 5O 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 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 in the present invention.

[0050] In some embodiments of the present invention, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R5N 、R 5O 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.

[0051] In some embodiments of the present invention, R5 is selected from The remaining variables are as defined in the present invention.

[0052] In another aspect of the present invention, the present invention also provides a compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from:

[0053] In yet another aspect of the present invention, the present invention further provides the use of the aforementioned compound, its optical isomers or pharmaceutically acceptable salts thereof in the preparation of drugs for treating diseases associated with USP1 activity or expression.

[0054] In some embodiments of the present invention, the above-mentioned diseases related to USP1 activity or expression are selected from cancer-related diseases and the like.

[0055] 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.

[0056] In some embodiments of the present invention, the above-mentioned bone cancer is selected from osteosarcoma, chondrosarcoma, etc.

[0057] In some embodiments of the present invention, the above-mentioned brain cancer is selected from glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, etc.

[0058] In some embodiments of the present invention, the above-mentioned soft tissue cancer is selected from rhabdoid sarcoma and the like.

[0059] In some embodiments of the present invention, the above-mentioned skin cancer is selected from melanoma and the like.

[0060] In some embodiments of the present invention, the above-mentioned lung cancer is selected from non-small cell lung cancer, etc.

[0061] Definition and Description

[0062] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0063] As used herein, the phrase "at least one" 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 elements other than the elements specifically identified in the list of elements to which the phrase "at least one" refers may optionally be present, whether related or unrelated to those specifically identified elements.

[0064] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0065] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine) and organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0066] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0067] "Pharmaceutically acceptable carrier" refers to a non-toxic solid, semi-solid, or liquid filler, diluent, encapsulating material, formulation aid, or vehicle commonly used in the art with therapeutic agents to form a "pharmaceutical composition" for administration to a subject. A pharmaceutically acceptable carrier is non-toxic to the recipient at the dosage and concentration employed and is compatible with the other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation being employed.

[0068] 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.

[0069] Because the compounds of the present disclosure are inhibitors of USP1 proteins, various diseases, disorders, or conditions mediated by USP1 proteins can be treated by employing the compounds. Accordingly, the present disclosure generally relates to a method for treating a disease, disorder, or condition responsive to or at risk of inhibiting USP1 proteins in an animal, the method comprising administering to the animal an effective amount of one or more compounds of the present disclosure.

[0070] The present disclosure further relates to a method of inhibiting USP1 protein in an animal in need thereof, comprising administering to the animal a therapeutically effective amount of at least one compound of the present disclosure.

[0071] 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 can be derived from a variety of sources, such as isolated from human tissue types 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 the amino acid sequence set forth in SEQ ID NO: 1 in U.S. Provisional Patent Application No. 62 / 857,986, filed June 6, 2019.

[0072] USP1 is a deubiquitinating enzyme that acts as part of a complex with UAF1. The "deubiquitinating enzyme activity" of USP1 includes its ability to deubiquitinate as part of the USP1-UAF1 complex.

[0073] The term "specific binding" to a protein or protein domain is a well-known term in the art, and methods for determining specific binding 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 protein domain 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 will 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. Thus, "specific binding" or "preferential binding" does not necessarily require (but can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding. For example, a USP1 inhibitor that specifically binds to USP1, UAF1, and / or the 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.

[0074] As used herein, the terms "cancer" and "tumor" refer to or describe the physiological condition in which a population of cells in a mammal is characterized by unregulated cell growth. The terms encompass both 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.

[0075] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0076] A hyphen ("-") that is not between two letters or symbols indicates the site of attachment of a substituent. For example, C 1-6 Alkylcarbonyl - refers to a C-alkyl group attached to the rest of the molecule through a carbonyl group. 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0077] When the group valence bond is marked with a dotted line When, for example, In the example, the dashed line represents the point of attachment of the group to the rest of the molecule. When, for example, In the example, the dotted line represents a single bond or does not exist, which also means Represents a single bond or double bond

[0078] The term "substituted" or "substituted with" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted with" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be any based on chemical practicability.

[0079] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 R's, the group may optionally be substituted with 1, 2, or 3 R's, with each occurrence of R' being an independent choice. Furthermore, combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds.

[0080] 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

[0081] When the substituents listed do not specify through which atom they are connected to the substituted group, such substituents can be bonded through any atom thereof. For example, a pyridyl substituent can be connected to the substituted group through any carbon atom on the pyridine ring.

[0082] When the listed linking groups do not specify their linking direction, their 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 reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0083] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0084] 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.

[0085] Unless otherwise specified, the number of atoms in a ring is generally defined as the ring member number, for example, a "3-6 membered ring" refers to a "ring" having 3-6 atoms arranged around it.

[0086] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to represent a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as CH3), divalent (-CH2-) or polyvalent (such as ). C 1-6 Examples of alkyl groups include, but are not limited to, CH3, wait.

[0087] Unless otherwise specified, the term “C 1-4 "Alkyl" is used to represent 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.

[0088] Unless otherwise specified, “C 2-6"Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl groups include C 2-4 、C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperyl, hexadienyl, and the like.

[0089] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 Alkenyl groups can be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to wait.

[0090] Unless otherwise specified, “C 2-6 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-6 Alkynyl groups include C 2- 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.

[0091] Unless otherwise specified, “C 2-3 "Alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to wait.

[0092] The term "oxo" refers to an oxygen atom doubly bonded to a carbon atom or another element, including a nitrogen atom of a pyridine ring, to form a pyridine N-oxide. For example, the term "oxo 5-6 membered heteroaryl" includes but is not limited to

[0093] The term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched chain 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 group is C 1-6 In other embodiments, the heteroalkyl group is C 1-3 Heteroalkyl. The heteroatom or heteroatom group may be located at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule, but the term "alkoxy" is used conventionally 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 can be consecutive, for example, -CH2-NH-OCH3.

[0094] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, and the like.

[0095] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. The C 1-3 Alkoxy groups include C 1-3 、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.

[0096] Unless otherwise specified, the term “C 1-6 "Alkylamino" means an alkyl group containing 1 to 6 carbon atoms which is attached to the rest of the molecule via an amino group. 1-6 Alkylamino groups include C 1-4 、C 1-3 、C 1-2 、C 2-6 、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.

[0097] Unless otherwise specified, the term “C 1-3 "Alkylamino" means an alkyl group containing 1 to 3 carbon atoms which is attached to the rest of the molecule via an amino group. 1-3 Alkylamino groups include C 1-3 、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.

[0098] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are linked to the rest of the molecule via a sulfur atom.1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2, and the like.

[0099] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are linked to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 、C 1-2 、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.

[0100] 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 ring system. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0101] 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 ring systems, wherein bicyclic ring systems include 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 to 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.

[0102] 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 ring systems, wherein the bicyclic ring system includes 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. 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.

[0103] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 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). 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 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.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0104] Unless otherwise specified, the term “C 6-14 "Aryl" by itself or in combination with other terms means a monocyclic or bicyclic aromatic ring system having six to fourteen carbon atoms. Non-limiting exemplary aryl groups include phenyl (abbreviated "Ph"), naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene, and fluorenyl. The aryl group may be selected from phenyl or theanyl group. The aryl group may be phenyl.

[0105] 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 、C3-12 、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, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 5-10-membered ring, a 6-7-membered ring, a 6-8-membered ring, a 6-9-membered ring and a 6-10-membered ring, etc.

[0106] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[0107] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0108] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g., enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0109] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are contemplated by the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0110] As used herein, the term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, and conformers, among others.

[0111] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0112] As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, or biological activities. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis and chromatography, such as HPLC.

[0113] Stereochemical definitions and conventions can 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, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of 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. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

[0114] The racemic mixture can be used as such or resolved into its individual isomers. Resolution can yield a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry," Vol. 6, Wiley Interscience, 1971) and include physical methods such as chromatography using chiral adsorbents. Individual isomers can be prepared in chiral form from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then liberating one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0115] The compounds of the present invention may exist in specific forms. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers with different functional groups that are in dynamic equilibrium at room temperature and can quickly convert into each other. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions that occur through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0116] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds of the present invention,

[0117] Whether radioactive or not, they are all within the scope of the present invention.

[0118] "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.

[0119] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0120] The solvent used in the present invention is commercially available.

[0121] Compounds are named according to the conventional nomenclature in the art or using Software naming, commercially available compounds use supplier catalog names.

[0122] 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 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, and 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, the configuration of other chiral centers has not been resolved). When the absolute configuration (R configuration or S configuration) of the chiral center of the compound disclosed in the present invention has not been identified, such compounds can be identified based on 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 ) to confirm.

[0123] The present invention is explained in more detail in the following examples. However, it should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention in any way. The experimental methods in the following examples, unless otherwise specified, generally follow conventional conditions for such reactions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. Unless otherwise stated, liquid ratios are by volume.

[0124] 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

[0125] The present application is described in detail below by way of examples, but this does not necessarily mean that there are any adverse limitations on the present application. The present application has been described in detail herein, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0126] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0127] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker ASCEND TM -400 NMR spectrometer, the solvents for determination were deuterated sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD, the internal standard was tetramethylsilane (TMS)

[0128] MS was determined using Agilent 6110, Agilent 1100, Agilent 6120, and Agilent 6125B liquid chromatography-mass spectrometers.

[0129] HPLC determination was performed using a Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50 mm, 3.5 μm column).

[0130] Chiral HPLC analysis was performed using THARSFC X5.

[0131] The thin layer chromatography silica gel plate used was Yantai Qingdao GF254 silica gel plate. The specifications of the silica gel plate used in thin layer chromatography (TLC) were 0.15mm-0.2mm, and the specifications used for thin layer chromatography separation and purification products were 0.4mm-0.5mm.

[0132] Column chromatography generally uses Qingdao Marine Silica Gel 200-300 mesh silica gel as the carrier.

[0133] High performance liquid phase preparation used Waters2767, Waters2545, and Chuangxin Hengtong LC3000 preparative chromatographs.

[0134] Chiral preparative column chromatography used Shimadzu LC20-AP and THARSFC PREP80.

[0135] The pressurized hydrogenation reaction used a Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0136] A Biotage initiator+ microwave reactor was used for the microwave reaction.

[0137] Unless otherwise specified in the experimental examples, all reactions were carried out under argon or nitrogen atmosphere.

[0138] 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.

[0139] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1 liter.

[0140] Unless otherwise specified in the experimental examples, the reaction temperature was room temperature, ranging from 20°C to 30°C.

[0141] Example 1: Synthesis of Compound 1

[0142] Step 1: Synthesis of compound 1-2

[0143] To a solution of compound 1-1 (5.00 g, 22.2 mmol) in tetrahydrofuran (200 mL) was added dropwise a solution of p-methoxyphenylmagnesium bromide in tetrahydrofuran (1.00 mol / L, 29.0 mL, 29.0 mmol) under an ice bath. The reaction mixture was stirred at room temperature for 16 hours. LCMS indicated completion of the reaction. Under an ice bath, saturated aqueous ammonium chloride (50 mL) was slowly added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford compound 1-2 (5.02 g, yield: 67.8%) as a yellow solid.

[0144] LC-MS (ESI) [M+H] + 333.2 / 335.2.

[0145] Step 2: Synthesis of Compounds 1-3

[0146] To a solution of compound 1-2 (5.02 g, 15.0 mmol) in dichloromethane (50 mL) was added boron trifluoride etherate (47.0 wt%, 8.52 g, 59.1 mmol) and triethylsilane (5.23 g, 45.0 mmol) sequentially under ice. The reaction mixture was stirred at room temperature for 16 hours. LCMS indicated completion of the reaction. Under ice, the reaction mixture was quenched by the slow addition of saturated aqueous sodium bicarbonate (50 mL). The mixture was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 1-3 (4.05 g, 84.7% yield, as a yellow solid).

[0147] LC-MS (ESI) [M+H] + 317.2 / 319.2.

[0148] Step 3: Synthesis of Compounds 1-4

[0149] To a solution of compound 1-3 (2.00 g, 6.31 mmol) in dichloromethane (20 mL) was added a dichloromethane solution of boron tribromide (1.00 mol / L, 12.3 mL, 12.3 mmol) under ice. The reaction mixture was stirred at room temperature for 16 hours. LCMS indicated the reaction was complete. Under ice, methanol (10 mL) was slowly added to the reaction mixture to quench the reaction. The mixture was concentrated under reduced pressure, and dichloromethane (10 mL) was added to the residue. The mixture was filtered to obtain a filter cake, compound 1-4 (1.83 g, yield: 95.7%), as a yellow solid.

[0150] LC-MS (ESI) [M+H] + 303.2 / 305.2.

[0151] Step 4: Synthesis of Compounds 1-5

[0152] To a mixture of compound 1-4 (1.80 g, 5.94 mmol), 4-cyclopropyl-6-methoxy-5-boronic acid pyrimidine (prepared by the method of reference WO2020132269A1, 1.38 g, 7.12 mmol), potassium carbonate (1.64 g, 11.9 mmol), and tetrakistriphenylphosphine palladium (686 mg, 0.593 mmol) was added a 1,4-dioxane / water mixture (20 / 4 mL). Under a nitrogen atmosphere, the reaction system was stirred at 100°C for 16 hours. LCMS indicated the reaction was complete. Cool to room temperature, and water (50 mL) was added. Extraction was performed with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 1-5 (1.24 g, yield: 56.1%, yellow solid).

[0153] LC-MS (ESI) [M+H] + 373.2.

[0154] Step 5: Synthesis of Compounds 1-6

[0155] To a solution of compound 1-5 (600 mg, 1.61 mmol) in dichloromethane (6 mL) was added pyridine (3.33 mL, 73.9 mmol) and trifluoromethanesulfonic anhydride (908 mg, 3.22 mmol) sequentially under ice. The reaction was stirred at room temperature for 16 hours. LCMS indicated the reaction was complete. Water (150 mL) was slowly added to the reaction solution to quench the reaction, and the mixture was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to afford compound 1-6 (350 mg, yield: 43.1%) as a yellow solid.

[0156] LC-MS (ESI) [M+H] + 505.0.

[0157] Step 6: Synthesis of Compounds 1-7

[0158] To a mixture of compound 1-6 (350 mg, 0.694 mmol), pinacol boronate (352 mg, 1.39 mmol), potassium phosphate (442 mg, 2.08 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (66.0 mg, 0.139 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (66.0 mg, 0.069 mmol) was added 1,4-dioxane (5 mL). Under a nitrogen atmosphere, the reaction system was stirred at 100°C for 16 hours. LCMS indicated the reaction was complete. The mixture was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 1-7 (200 mg, yield: 59.8%, yellow solid).

[0159] LC-MS (ESI) [M+H] + 483.2.

[0160] Step 7: Synthesis of Compound 1

[0161] To a mixture of compound 1-7 (200 mg, 0.499 mmol), 2-chloro-1-isopropyl-4-trifluoromethylimidazole (prepared by the method of reference WO2020132269A1, 128 mg, 0.600 mmol), potassium phosphate (212 mg, 0.999 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.0 mg, 98.3 μmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (40.0 mg, 50.8 μmol) was added a 1,4-dioxane / water mixed solvent (6 / 1 mL). Under a nitrogen atmosphere, the reaction system was stirred at 100°C for 16 hours. LCMS showed the reaction was complete. The mixture was cooled to room temperature, and water (30 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to obtain compound 1 (27.6 mg, yield: 12.5%).

[0162] LC-MS (ESI) [M+H] + 533.2.

[0163] 1H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.53(s,1H),8.16(s,1H),7.81(d,J=9.1Hz,1H),7.74(s,1H),7.52(d,J=8.1Hz, 2H),7.44(m,3H),4.51-4.36(m,3H),3.81(s,3H),1.78-1.69(m,1H),1.39(d,J=6.6Hz,6H),1.01(m,2H),0.79(m,2H).

[0164] Example 2: Synthesis of Compound 2

[0165] Step 1: Synthesis of compound 2-2

[0166] Under ice bath, compound 2-1 (1 g, 6.51 mmol) was added to 1,4-dioxane / water (10 / 1 mL), and 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (1.64 g, 8.47 mmol), potassium phosphate (2.76 g, 13.02 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (621 mg, 1.302 mmol) and chloro(2-dicyclohexylphosphino- The reaction solution was stirred at 100° C. for 16 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column to obtain compound 2-2 (700 mg, yield: 40%, yellow solid).

[0167] LC-MS (ESI) [M+H] + 268.2.

[0168] Step 2: Synthesis of compound 2-3

[0169] Under ice bath, compound 2-2 (44 g, 165 mmol) was added to N,N-dimethylformamide (500 mL), and N-bromosuccinimide (32.3 g, 181 mmol) was added. The reaction solution was stirred at room temperature overnight. LC-MS showed that the reaction was successful. Water was added and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column to obtain compound 2-3 (31.8 g, yield: 56%, yellow solid).

[0170] LC-MS (ESI) [M+H] + 346.0.

[0171] Step 3: Synthesis of compound 2

[0172] Intermediate 2-3 (50 mg, 144.43 μmol), 1-(1-methylethyl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]-4-trifluoromethylimidazole (62.64 mg, 158.88 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10.57 mg, 14.44 μmol), and potassium phosphate (61.24 mg, 288.87 μmol) were dissolved in toluene (2 mL) / water (0.1 mL). The reaction was stirred in a microwave oven at 100°C for 2 hours. LCMS analysis confirmed the formation of the product. The sample was directly spin-dried and separated by column chromatography using petroleum ether / ethyl acetate = 3 / 1 to obtain the product. Liquid phase chromatography gave compound 2 (10.30 mg, 13.37% yield).

[0173] LC-MS (ESI) [M+H] + 534.2.

[0174] 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.70(s,1H),8.15(d,J=1.2Hz,1H),7.47(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.10(d,J=4.8Hz,1 H),7.05(d,J=4.4Hz,1H),4.46-4.39(m,3H),3.87(s,3H),1.81-1.76(m,1H),1.38(d,J=6.8Hz,6H),1.06-1.02(m,2H),0.88-0.84(m,2H).

[0175] Example 3: Synthesis of Compound 3

[0176] Step 1: Synthesis of compound 3

[0177] Under ice bath, compound 2-3 (4.32 g, 12.53 mmol), pinacol boron ester (6.4 g, 25.06 mmol), 1-(3-bromomethyl)phenyl-5-methyl-3-trifluoromethylpyrazole (4.0 g, 12.53 mmol), potassium phosphate (4.96 g, 25.06 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.11 g, 2.50 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6',-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (0.96 g, The reaction mixture was stirred for 1 h at room temperature for 1 h. The reaction mixture was stirred for 1 h. The resulting mixture was stirred for 1 h. The resulting mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h. The mixture was stirred for 1 h.

[0178] LCMS (ESI) [M+H] + 506.4.

[0179] 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),9.01(s,1H),8.66(s,1H),7.94(s,1H ),7.84(s,1H),7.56(d,J=7.8Hz,1H),7.36-7.27(m,2H),4.14(s,2H),3.96( t,J=6.7Hz,2H),3.82(s,3H),2.61(t,J=6.9Hz,2H),2.28-2.15(m,2H),1.58 (dt,J=12.6,4.1Hz,1H),1.02(d,J=3.8Hz,2H),0.81(dd,J=7.9,3.1Hz,2H).

[0180] Example 4: Synthesis of Compound 4

[0181] Step 1: Synthesis of compound 4-2

[0182] Compound 4-1 (25 g, 48.3 mmol) was dissolved in dichloromethane (20 mL), N,N-dimethylformamide dimethyl acetal (90 mL) and N,N-dimethylformamide (90 mL) were added, and the resulting mixture was heated at 90 ° C for 1 hour and then at 125 ° C for 2 hours. The mixture was cooled to 25 ° C and then poured into water (450 mL). The solution was extracted with ethyl acetate (3*150 mL). The combined organic layer was washed with water (150 mL) and saturated sodium chloride aqueous solution (150 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The dark oil obtained by slurrying with ether / hexane (5 / 1) gave compound 4-2 (20 g, yield: 53.32%, orange solid).

[0183] LCMS (ESI) [M+H] + 208.0.

[0184] Step 2: Synthesis of compound 4-3

[0185] Compound 4-2 (15 g, 72 mmol) was added to tetrahydrofuran / water (60 mL / 60 mL), and sodium periodate (45 g, 216 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. After the reaction, it was directly concentrated, extracted with ethyl acetate (3*100 mL), washed with brine, dried and spin-dried, and column chromatography was performed to obtain compound 4-3 (1.5 g, yield: 12.47%, yellow solid).

[0186] LCMS (ESI) [M+H] + 166.0.

[0187] Step 3: Synthesis of compound 4-4

[0188] 3,3-Dibromo-1,1,1-trifluoropropane-2-one (2.44 g, 9 mmol) was added to water (15 mL), and sodium acetate (1.5 g, 9 mmol) was slowly added under ice bath. The reaction solution was stirred at 100 ° C for 2 hours. A solution of compound 4-3 (1.5 g, 9 mmol) in ammonium hydroxide and methanol was slowly added to the reaction solution. The mixture was reacted at room temperature for 40 minutes and then heated to 100 ° C for 2 hours. Water (3*10 mL) and ethyl acetate (3*10 mL) were added to the reaction solution for extraction. The organic phase was dried and purified by column chromatography to obtain compound 4-4 (400 mg, yield: 17.23%, white solid).

[0189] LCMS (ESI) [M+H] + 258.0.

[0190] Step 4: Synthesis of compound 4-5

[0191] Compound 4-4 (400 mg, 1.56 mmol) was added to ethanol (1 mL). Sodium hydroxide (12 mg, 7.8 mmol) / water (4 mL) was added under ice-cooling. The reaction was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. 1 M hydrochloric acid (5 mL) was added to the reaction solution, and ethyl acetate (3 x 10 mL) was added for extraction. The organic phase was dried to give crude compound 4-5 (350 mg, crude, white solid). This was directly carried to the next step without purification.

[0192] LCMS (ESI) [M+H] + 259.0.

[0193] Step 5: Synthesis of Compounds 4-6

[0194] Compound 4-5 (0.35 g, 1.36 mmol) was added to N,N-dimethylformamide (5 mL), and isopropyl iodide (921 mg, 5.42 mmol) and cesium carbonate (1.5 g, 4.42 mmol) were added. The reaction solution was stirred at 100 ° C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with water (3*50 mL) and ethyl acetate (3*50 mL). The organic phase was dried, filtered, and spin-dried. The sample was purified by column chromatography to obtain compound 4-6 (300 mg, yield: 64.64%, yellow oil).

[0195] LCMS (ESI) [M+H] + 343.0.

[0196] Step 6: Synthesis of Compounds 4-7

[0197] Compound 4-6 (300 mg, 0.876 mmol) was added to tetrahydrofuran (10 mL). Sodium borohydride (100 mg, 2.62 mmol) was slowly added at 0°C. The reaction solution was stirred at 0°C for 30 minutes. LCMS indicated the reaction was complete. The reaction solution was quenched with methanol and extracted with ethyl acetate (3*10 mL) and water (3*10 mL). The organic phase was dried to obtain crude compound 4-7 (250 mg, crude, white solid). This was directly used in the next step without purification.

[0198] LCMS (ESI) [M+H] + 287.0.

[0199] Step 7: Synthesis of Compounds 4-8

[0200] Compound 4-7 (100 mg, 0.34 mmol) was added to tetrahydrofuran (10 mL). Phosphorus tribromide (283.68 mg, 1.05 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction mixture was extracted with water (3 x 10 mL) and ethyl acetate (3 x 10 mL). The organic phase was dried, filtered, and spin-dried. Column chromatography afforded compound 4-8 (35 mg, 99.65% yield) as a white solid.

[0201] LCMS (ESI) [M+H] + 349.0.

[0202] Step 8: Synthesis of compound 4

[0203] Compound 4-8 (35 mg, 0.1 mmol) was added to 1,4-dioxane / water (2 / 0.2 mL), compound 2-3 (52 mg, 0.15 mmol), bipyraclostrobin (50.6 mg, 0.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (9.5 mg, 0.02 mmol), potassium phosphate (63 mg, 0.3 mmol) and (2-dicyclohexylphosphino) were added. --2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium (8.46 mg, 0.01 mmol), nitrogen was replaced, and the reaction solution was stirred at 100°C for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with ethyl acetate (3*10 mL) and water (3*10 mL). The organic phase was dried and spin-dried to dryness, and compound 4 (1 mg, yield: 1.86%) was prepared by liquid phase.

[0204] LCMS (ESI) [M+H] + 536.4.

[0205] 1 H NMR(400MHz,MeOD-d4)δ9.10(s,2H),8.68(s,1H),8.60(s,1H),8.00(s,1H),7.14(q,J=4.6Hz,2H),5.66-5.5 3(m,1H),4.70(s,2H),3.90(s,3H),1.76(s,1H),1.49(d,J=6.7Hz,6H),1.15-1.07(m,2H),0.90-0.85(m,2H).

[0206] Example 5: Synthesis of Compound 5

[0207] Step 1: Synthesis of compound 5-2

[0208] Compound 5-1 (2 g, 13.02 mmol), compound 2-1 (3.79 g, 19.53 mmol), potassium phosphate (5.53 g, 26.04 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.24 g, 2.60 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6',-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) ( 1.10 g, 1.30 mmol) was dissolved in a mixed solvent of 1,4-dioxane: water = 5:1 (20 ml) and heated to 100 ° C. and refluxed for 12 hours. LCMS showed that the reaction was complete. After cooling to room temperature, ethyl acetate and water were added to the reaction solution and extracted three times. The organic phase was washed with saturated sodium chloride aqueous solution, dried, and the sample was purified by normal phase column (petroleum ether: ethyl acetate = 100% / 0 to 60 / 40%) to give compound 5-2 (1.5 g, yield: 75%, yellow solid).

[0209] LCMS (ESI) [M+H] + 296.3.

[0210] Step 2: Synthesis of compound 5-3

[0211] Compound 5-2 (1.5 g, 5.61 mmol) was added to N,N-dimethylformamide (10 ml). A solution of N-bromosuccinimide (0.89 g, 5.05 mmol) in N,N-dimethylformamide (5 ml) was added dropwise under an ice bath at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. LCMS indicated the reaction was complete. The mixture was extracted three times with ethyl acetate and water, washed three times with saturated sodium chloride solution, and the organic phase was concentrated. A mixed solvent of petroleum ether:ethyl acetate (5:1) (2 ml) was added and slurried to give compound 5-3 (1.4 g, yield: 95%) as an off-white solid.

[0212] LCMS (ESI) [M+H] + 374.2.

[0213] Step 3: Synthesis of compound 5

[0214] Compound 5-3 (2 g, 13.02 mmol), 1-(3-bromomethyl)phenyl-5-methyl-3-trifluoromethylpyrazole (3.79 g, 13.02 mmol), potassium phosphate (5.53 g, 26.04 mmol), bipinacol boronate (6.59 g, 26.04 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.24 g, 2.60 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6',-triisopropyl-1,1'-biphenyl) (2'-Amino-1,1'-biphenyl-2-yl)palladium(II) (1.10 g, 1.30 mmol) was dissolved in a mixed solvent of 1,4-dioxane:water = 5:1 (200 ml), heated to 100°C and refluxed for 12 hours. LCMS showed that the reaction was complete. After cooling to room temperature, ethyl acetate and water were added to the reaction solution and extracted three times. The organic phase was washed with saturated aqueous sodium chloride solution, dried, and the sample was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100% / 0 to 70 / 30%) to give compound 5 (1.5 g, yield: 75%).

[0215] LCMS (ESI) [M+H] + 534.5.

[0216] 1 H NMR(400MHz,DMSO-d6)δ11.82(s,1H),9.01(s,1H),8.66(s,1H),7.94(s,1H ),7.84(s,1H),7.56(d,J=7.8Hz,1H),7.36-7.27(m,2H),4.14(s,2H),3.96( t,J=6.7Hz,2H),3.82(s,3H),2.61(t,J=6.9Hz,2H),2.28-2.15(m,2H),1.58 (dt,J=12.6,4.1Hz,1H),1.02(d,J=3.8Hz,2H),0.81(dd,J=7.9,3.1Hz,2H).

[0217] Example 6: Synthesis of Compound 6

[0218] Step 1: Synthesis of compound 6-2

[0219] Compound 2-3 (0.10 g, 288.87 μmol) was dissolved in acetonitrile (10 mL) and a selective fluorine reagent (0.15 g, 423.42 μmol) was added. The reaction was allowed to proceed at 70°C for 2 hours. LCMS indicated product formation. Seven parallel batches were successfully prepared. Successful batches were combined, water (100 mL) was added, and extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined and washed with saturated brine (100 mL). Drying was performed over sodium sulfate, filtering, and spin drying. The product was then flushed out through a column using ethyl acetate / petroleum ether (1 / 2). Compound 6-2 (0.075 g, yield: 71.29%) was obtained as a pale yellow oil.

[0220] LCMS (ESI) [M+H] + 364.0.

[0221] Step 2: Synthesis of compound 6

[0222] At room temperature, compound 6-2 (75 mg, 205.95 μmol) was dissolved in toluene (5 mL) / water (1 mL) with 1-(1-methylethyl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]-4-trifluoromethylimidazole (81.19 mg, 205.95 μmol), potassium phosphate (87.43 mg, 411.89 μmol), and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (15.07 mg, 20.59 μmol). The atmosphere was purged with nitrogen three times. The reaction was incubated at 90°C for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, spin-dried, and sent to alkaline liquid phase for purification to obtain compound 6 (13.98 mg, yield: 12.31%).

[0223] LCMS (ESI) [M+H] + 552.3.

[0224] 1 H NMR (400MHz, MeOD-d4) δ9.02(s,1H),8.52(s,1H),7.80(q,J=1.3Hz,1H),7.38(s,4H),6.68(s,1H),4.42(p,J=6.7 Hz,1H),4.36(s,2H),3.85(s,3H),1.81-1.69(m,1H),1.34(d,J=6.7Hz,6H),1.09-1.02(m,2H),0.86-0.74(m,2H).

[0225] Example 7: Synthesis of Compound 7

[0226] Step 1: Synthesis of compound 7

[0227] Compound 6-2 (10.44 g, 28.67 mmol) was dissolved in toluene (500 mL) / water (50 mL) at room temperature. 5-Methyl-1-[4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]-3-trifluoromethylpyrazole (21.0 g, 57.35 mmol), sodium tert-butoxide (8.26 g, 86.02 mmol), and [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (4.67 g, 7.17 mmol) were added. The atmosphere was replaced with nitrogen three times. The reaction was allowed to proceed at 100°C for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and spin-dried. The crude product was separated by column chromatography using petroleum ether / ethyl acetate = 5 / 1. The crude product was slurried with petroleum ether, brushed on a silica gel column, and lyophilized to obtain compound 7 (8.14 g, yield: 54.23%).

[0228] LCMS (ESI) [M+H] + 524.0.

[0229] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.70(s,1H),7.49(d,J=8.4Hz,2H),7.43(d,J=8.4Hz,2H),6.96(s,1H), 6.72(s,1H),4.42(s,2H),3.87(s,3H),2.31(s,3H),1.84-1.80(m,1H),1.06-1.02(m,2H),0.89-0.85(m,2H).

[0230] Example 8: Synthesis of Compound 8

[0231] Step 1: Synthesis of compound 8-2

[0232] Compound 2 (250 mg, 468.56 μmol) was dissolved in acetonitrile (10 mL). N-bromosuccinimide (83.40 mg, 468.56 μmol) was added at room temperature, and the reaction was stirred at room temperature for 0.5 hours. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (5 / 1) afforded compound 8-2 (200 mg, 69.69% yield, as a yellow solid).

[0233] LCMS (ESI) [M+H] + 612.2.

[0234] Step 2: Synthesis of compound 8

[0235] At room temperature, compound 8-2 (180 mg, 293.91 μmol), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium (II) (25.10 mg, 29.39 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (28.45 mg, 58.78 μmol) and sodium tert-butoxide (56. 43 mg, 587.81 μmol) was dissolved in methanol (0.8 mL) / 1,4-dioxane (10 mL) / water (1 mL). The reaction was stirred in a microwave at 100°C for 2 hours. LCMS showed complete conversion of the starting material. The product was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to give the crude product, which was then prepared from the liquid phase to obtain compound 8 (71.47 mg, yield: 43.15%).

[0236] LCMS (ESI) [M+H] + 563.2.

[0237] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.66(s,1H),8.17(d,J=0.8Hz,1H),7.48(d,J=8.4Hz,2H),7.40(d,J=8.0Hz,2H),6.72(s,1H),4.44- 4.41(m,1H),4.37(s,2H),3.94(s,3H),3.87(s,3H),1.84-1.81(m,1H),1.39-1.37(d,J=6.8Hz,6H),1.05-1.01(m,2H),0.89-0.85(m,2H).

[0238] Example 9: Synthesis of Compound 9

[0239] Step 1: Synthesis of compound 9

[0240] To a 50 mL autoclave were added compound 8-2 (450 mg, 0.73 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (53 mg, 0.073 mmol), and triethylamine (220 mg, 2.19 mmol). The mixture was dissolved in 12 mL of methanol:12 mL of acetonitrile. The autoclave was sealed, and carbon monoxide gas was introduced. The reaction was carried out at 100°C for 48 hours. After the reaction was completed, the mixture was extracted three times with water (40 mL) and dichloromethane (30 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified on silica gel (petroleum ether:ethyl acetate = 0-50%) to afford compound 9 (424 mg, yield: 97.54%).

[0241] LC-MS (ESI) [M+H] + 592.3.

[0242] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.66(s,1H),8.17(d,J=0.8Hz,1H),7.48(d,J=8.4Hz,2H),7.40(d,J=8.0Hz,2H),6.72(s,1H),4.44- 4.41(m,1H),4.37(s,2H),3.94(s,3H),3.87(s,3H),1.84-1.81(m,1H),1.39-1.37(d,J=6.8Hz,6H),1.05-1.01(m,2H),0.89-0.85(m,2H).

[0243] Example 10: Synthesis of Compound 10

[0244] Step 1: Synthesis of compound 10-2

[0245] Compound 2-3 (230 mg, 0.664 mmol), 1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)methylphenyl)-4-trifluoromethylimidazole (267.62 mg, 0.730 mmol), palladium dichloride {[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride} (48.57 mg, 66.44 μmol), and potassium phosphate (281.70 mg, 1.33 mmol) were dissolved in toluene (3 mL) / water (0.3 mL). The reaction was stirred in a microwave oven at 100°C for 2 hours. LCMS confirmed the formation of the product. The reaction was quenched with water, extracted with ethyl acetate (2*50 mL), washed with water (2*50 mL), and the organic phase dried over anhydrous sodium sulfate. Column chromatography separation with petroleum ether / ethyl acetate = 1 / 1 gave compound 10-2 (150 mg, yield: 44.66%), yellow solid.

[0246] LCMS (ESI) [M+H] + 506.2.

[0247] Step 2: Synthesis of compound 10-3

[0248] Compound 10-2 (150 mg, 0.296 mmol) was dissolved in acetonitrile (10 mL). N-bromosuccinimide (52.81 mg, 0.296 mmol) was added at room temperature, and the reaction was stirred at room temperature for 0.5 hours. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (5 / 1) afforded compound 10-3 (120 mg, 69.20% yield, as a yellow solid).

[0249] LCMS (ESI) [M+H] + 584.2.

[0250] Step 3: Synthesis of compound 10

[0251] Compound 10-3 (120 mg, 205.34 μmol), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium (II) (17.54 mg, 20.53 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (19.88 mg, 41.07 μmol) and sodium tert-butoxide (39.43 mg, 410.68 μmol) were dissolved in methanol (0.5 μmol) at room temperature. mL) / 1,4-dioxane (3 mL) / water (0.3 mL), the reaction was stirred in a microwave at 100°C for 2 hours. LCMS detection showed complete conversion of the starting material, and 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, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was then prepared by liquid phase to obtain compound 10 (26.46 mg, yield: 24.06%).

[0252] LCMS (ESI) [M+H] + 536.2.

[0253] 1H NMR (400MHz, DMSO-d6) δ9.02(s,1H),8.67(s,1H),7.91(d,J=1.2Hz,1H),7.62(d,J=8.0Hz,2H),7.38(d,J=8.0Hz,2H),6. 68(s,1H),4.34(s,1H),3.92(s,3H),3.86(s,3H),3.73(s,3H),1.84-1.81(m,1H),1.03-1.01(m,2H),0.88-0.85(m,2H).

[0254] Example 11: Synthesis of Compound 11

[0255] Step 1: Synthesis of compound 11

[0256] Compound 10-3 (175 mg, 299.46 μmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 1,3-bis(diphenylphosphino)propane (24.70 mg, 59.89 μmol), triethylamine (60.60 mg, 598.92 μmol, 83.53 μL), diethylene glycol monovinyl ether (79.15 mg, 598.92 μmol), and palladium acetate (4.99 mg, 29.95 μmol). The atmosphere was purged with nitrogen three times. The reaction was microwaved at 100°C for 3 hours. The reaction was quenched with water, and the mixture was extracted three times with water (40 mL) and dichloromethane (50 mL). The mixture was washed once with saturated brine (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried. Purification on silica gel (petroleum ether:ethyl acetate = 0-100%; dichloromethane:methanol = 0-10%) afforded 150 mg of a yellow crude compound, which was then subjected to liquid phase purification to afford compound 11 (18.44 mg, yield: 11.25%).

[0257] LC-MS (ESI) [M+H] + 548.0.

[0258] 1 H NMR (400MHz, MeOD-d4) δ9.72(s,1H),8.67(s,1H),7.71(s,1H),7.62(d,J=8.2Hz,2H),7.57(s,1H),7.51(d,J=8.2Hz ,2H),4.54(s,2H),3.97(s,3H),3.79(s,3H),2.66(s,3H),1.89-1.78(m,1H),1.21-1.16(m,2H),0.96-0.89(m,2H).

[0259] Example 12: Synthesis of Compound 12

[0260] Step 1: Synthesis of compound 12-2

[0261] Compound 7 (200 mg, 382.06 μmol) was added to water (2 mL) / trifluoroacetic acid (2 mL) and reacted at 80°C for 16 hours. LCMS showed that the conversion of the starting material was complete. The reaction solution was spin-dried, diluted with ethyl acetate and saturated sodium bicarbonate, and the extract was dried and spin-dried to give the target product, crude compound 12-2 (160 mg, yield: 82.20%), as an orange-red oil.

[0262] LCMS (ESI) [M+H] + 510.2.

[0263] Step 2: Synthesis of compound 12

[0264] Compound 12-2 (150 mg, 294.43 μmol) was added to dioxane (60 mL), and potassium hydroxide (165.19 mg, 2.94 mmol) was added and stirred for 10 minutes. Diethyl bromofluoromethylphosphonate (393.07 mg, 1.47 mmol) was then added and the reaction was carried out in a microwave oven at 80°C for 30 minutes. LCMS detection showed that the raw material was completely converted. The mixture was diluted with ethyl acetate and saturated aqueous citric acid solution, extracted and separated, and concentrated to obtain compound 12 (24.6 mg, yield: 14.98%).

[0265] LCMS (ESI) [M+H] + 560.2.

[0266] 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.84(s,1H),7.84(t,J=71.5Hz,1H),7.57-7.37(m,4H),7.04(s,1H) ,6.74(s,1H),4.44(s,2H),2.32-2.28(m,3H),1.98(dt,J=8.1,3.7Hz,1H),1.19-1.08(m,2H),0.99(dt,J= 8.2,3.4Hz,2H).

[0267] Example 13: Synthesis of Compound 13

[0268] Step 1: Synthesis of compound 13-2

[0269] Compound 6 (240 mg, 435.15 μmol) was added to water (3 mL) / trifluoroacetic acid (3 mL) and reacted at 80°C for 12 hours. LCMS detected that the raw material was completely converted. The reaction solution was spin-dried, diluted with ethyl acetate and saturated sodium bicarbonate, and the extract was dried and spin-dried to obtain the target product, crude compound 13-2 (230 mg, crude, brown oil).

[0270] LCMS (ESI) [M+H] + 538.3.

[0271] Step 2: Synthesis of compound 13

[0272] Compound 13-2 (200 mg, 372.09 μmol) was added to dioxane (10 mL), and potassium hydroxide (207.76 mg, 3.72 mmol) was added and stirred for 10 minutes. Diethyl bromofluoromethylphosphonate (496.73 mg, 1.86 mmol) was then added and the reaction was carried out in a microwave oven at 80°C for 30 minutes. LCMS detection showed that the raw material was completely converted. The mixture was diluted with ethyl acetate and saturated aqueous citric acid solution, extracted and separated, and concentrated to obtain compound 13 (30.15 mg, yield: 13.79%).

[0273] LCMS (ESI) [M+H] + 588.3.

[0274] 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.85(s,1H),8.18(d,J=1.4Hz,1H),7.93(d,J=71.5Hz,1H),7.50-7.39(m,4H),7.05( s,1H),4.43(s,2H),1.98(td,J=8.0,4.1Hz,1H),1.38(d,J=6.6Hz,6H),1.12(p,J=3.6Hz,2H),0.98(dt,J=8.2,3.4Hz,2H).

[0275] Example 14: Synthesis of Compound 14

[0276] Step 1: Synthesis of compound 14

[0277] Compound 10-3 (200 mg, 0.342 mmol), potassium methyltrifluoroborate (68.70, 0.684 mmol), {[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)} (25.02 mg, 0.034 mmol) and potassium carbonate (94.52 mg, 684.47 μmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL). The reaction was stirred in a microwave at 100°C for 2 hours. LCMS detection showed that the raw material was completely converted. The mixture was quenched with water (10 mL) and 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 then prepared by liquid phase to obtain compound 14 (31.49 mg, yield: 17.71%).

[0278] LCMS (ESI) [M+H] + 520.2.

[0279] 1 H NMR (400MHz, DMSO-d6) δ9.21(s,1H),8.69(s,1H),7.92(d,J=1.2Hz,1H),7.62(d,J=8.0Hz,2H),7.39(d,J=8.4Hz,2H),6. 83(s,1H),4.37(s,1H),3.87(s,3H),3.74(s,3H),2.44(s,3H),1.80-1.78(m,1H),1.05-1.02(m,2H),0.89-0.86(m,2H).

[0280] Example 15: Synthesis of Compound 15

[0281] Step 1: Synthesis of compound 15-2

[0282] Compound 10 (170 mg, 317.45 μmol) was added to water (20 mL) / trifluoroacetic acid (20 mL) and reacted at 80°C for 16 hours. LCMS detected that the raw material was completely converted. The reaction solution was spin-dried, diluted with ethyl acetate and saturated sodium bicarbonate, and the extract was dried and spin-dried to obtain the target product, crude compound 15-2 (165 mg, crude, brown oil).

[0283] LCMS (ESI) [M+H] + 522.2.

[0284] Step 2: Synthesis of compound 15

[0285] Compound 15-2 (1165 mg, 316 μmol) was added to dioxane (20 mL), and potassium hydroxide (177.52 mg, 3.16 mmol) was added and stirred for 10 minutes. Diethyl bromofluoromethylphosphonate (675.83 mg, 2.53 mmol) was then added and the reaction was carried out at 90° C. for 3 hours. LCMS detection showed that the raw material was completely converted. The mixture was diluted with ethyl acetate and saturated aqueous citric acid solution, extracted and separated, and concentrated to obtain compound 15 (35.25 mg, yield: 19.49%).

[0286] LCMS (ESI) [M+H] + 572.2.

[0287] 1 H NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.82(s,1H),8.01-7.66(m,2H),7.61(d,J=8.0Hz,2H),7.41(d,J=8.0Hz,2H ),6.75(s,1H),4.37(s,2H),3.85(s,3H),3.74(s,3H),1.98-1.98(m,1H),1.12-1.09(m,2H),1.00-0.97(m,2H).

[0288] Example 16: Synthesis of Compound 16

[0289] Step 1: Synthesis of Compound 16

[0290] Compound 9 (30 mg, 50.71 μmol) was dissolved in a mixture of methanol (3 mL) / tetrahydrofuran (3 mL) / water (1 mL), followed by the addition of sodium hydroxide (8.11 mg, 202.85 μmol) and the reaction at 50°C for 4 hours. The solvent was partially concentrated, and the mixture was extracted three times with water (40 mL) and dichloromethane (40 mL). The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 16 (12.12 mg, 41.36% yield) via liquid phase purification.

[0291] LCMS (ESI) [M+H] + 578.2.

[0292] 1H NMR (400MHz, DMSO-d6) δ9.60(s,1H),8.73(s,1H),8.17(s,1H),7.52-7.37(m,5H),4.45(s,2H),4.44-4. 39(m,1H),3.87(s,3H),1.89-1.77(m,1H),1.39(d,J=4.0Hz,6H),1.10-1.02(m,2H),0.90-0.81(m,2H).

[0293] Example 17: Synthesis of Compound 17

[0294] Step 1: Synthesis of Compound 17

[0295] Compound 16 (70 mg, 121.20 μmol) and dimethylamine hydrochloride (39.53 mg, 484.80 μmol) were dissolved in N,N-dimethylformamide (6 mL). Triethylamine (36.36 mg, 606.00 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68.59 mg, 181.80 μmol) were then added. The reaction was allowed to react at 20°C for 3 hours. The reaction was quenched with water, and then extracted three times with water (40 mL) and dichloromethane (40 mL). The organic phases were combined and washed once with saturated brine (50 mL). The combined organic phases were then spin-dried to dryness. Compound 17 (26.52 mg, 36.19% yield) was obtained via liquid phase extraction.

[0296] LCMS (ESI) [M+H] + 605.4.

[0297] 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.72(s,1H),8.17(s,1H),7.48(d,J=8.0Hz,2H),7.42(d,J=8.0 Hz,2H),7.36(s,1H),4.51-4.36(m,3H),3.87(s,3H),3.14(s,6H),1.87- 1.76(m,1H),1.38(d,J=8.0Hz,6H),1.10-1.00(m,2H),0.90-0.81(m,2H).

[0298] Example 18: Synthesis of Compound 18

[0299] Step 1: Synthesis of Compound 18

[0300] Compound 16 (60 mg, 103.89 μmol) and methylamine hydrochloride (28.05 mg, 415.54 μmol) were dissolved in N,N-dimethylformamide (6 mL). Triethylamine (10.51 mg, 103.89 μmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (58.79 mg, 155.83 μmol) were then added. The reaction was stirred at 20°C for 3 hours. The reaction was quenched with water, and then extracted three times with water (40 mL) and dichloromethane (40 mL). The organic phases were combined, washed once with saturated brine (50 mL), and dried by spin drying. Compound 18 (33.47 mg, 54.55% yield) was obtained by liquid phase purification.

[0301] LCMS (ESI) [M+H] + 591.4.

[0302] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.73(s,1H),8.46(d,J=1.0Hz,1H),8.18(s,1H),7.51(d,J=8.0Hz 2H),7.43(d,J=8.0Hz,2H),7.40(s,1H),4.50-4.39(m,3H),3.88(s,3H),2.80(d,J=4.0 Hz,3H),1.88-1.79(m,1H),1.40(d,J=8.0Hz,6H),1.11-1.03(m,2H),0.93-0.82(m,2H).

[0303] Example 19: Synthesis of Compound 19

[0304] Step 1: Synthesis of Compound 19

[0305] Compound 16 (80 mg, 138.51 μmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (78.39 mg, 207.77 μmol) and triethylamine (84.10 mg, 831.09 μmol). The reaction was allowed to proceed at 25°C for 30 minutes, followed by the addition of azetidine (31.63 mg, 554.06 μmol) and the reaction was allowed to proceed at 50°C for 16 hours. The reaction proceeded slowly. The reaction was quenched with water, followed by extraction three times with water (50 mL) and dichloromethane (50 mL), washed once with saturated brine, and the combined organic phases were spin-dried and purified on silica gel (dichloromethane:methanol = 0-10%) to afford 30 mg of the crude product. Compound 19 (6.51 mg, 7.62% yield) was then prepared via liquid phase chromatography.

[0306] LCMS (ESI) [M+H] + 617.4.

[0307] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),8.72(s,1H),8.17(d,J=1.2Hz,1H),7.47(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),7.36(s,1H),4.54-4.3 9(m,5H),4.15-4.05(m,2H),3.86(s,3H),2.36-2.30(m,2H),1.84-1.7 4(m,1H),1.38(d,J=8.0Hz,6H),1.08-0.99(m,2H),0.89-0.76(m,2H).

[0308] Example 20: Synthesis of Compound 20

[0309] Step 1: Synthesis of Compound 20

[0310] Compound 16 (30 mg, 51.94 μmol) and ethanolamine (4.12 mg, 67.53 μmol) were dissolved in N,N-dimethylformamide (4 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (29.39 mg, 77.91 μmol) and triethylamine (10.51 mg, 103.89 μmol, 14.49 μL). The mixture was allowed to react at 25°C for 4 hours. The reaction was quenched with water, and the mixture was extracted three times with water (30 mL) and dichloromethane (40 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. Compound 20 (16.65 mg, 51.65% yield) was obtained directly from the liquid phase.

[0311] LCMS (ESI) [M+H] + 621.0.

[0312] 1H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.73(s,1H),8.49(t,J=8.0Hz,1H),8.18(d,J =4.0Hz,1H),7.51(d,J=8.0Hz,2H),7.47(s,1H),7.43(d,J=8.0Hz,2H),4.76(t,J= 4.0Hz,1H),4.52-4.38(m,3H),3.88(s,3H),3.51(q,J=4.0Hz,2H),3.37-3.34(m,2 H),1.87-1.79(m,1H),1.40(d,J=8.0Hz,6H),1.09-1.01(m,2H),0.92-0.84(m,2H).

[0313] Example 21: Synthesis of Compound 21

[0314] Step 1: Synthesis of compound 21-2

[0315] Compound 8-2 (10.0 g, 16.33 mmol), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium (II) (1.39 g, 1.63 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (1.58 mg, 3.27 mmol) and sodium tert-butoxide (3.13 g, 32.66 mm ol) was dissolved in methanol (20 mL) / 1,4-dioxane (200 mL) / water (20 mL), and the reaction was stirred at 100 ° C. for 16 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). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to give a crude product, which was purified by column chromatography using petroleum ether / ethyl acetate = 1 / 3 to give compound 21-2 (500 mg, crude product, dark red solid).

[0316] LCMS (ESI) [M+H] + 550.2.

[0317] Step 2: Synthesis of Compound 21

[0318] Compound 21-2 (100 mg, 181.97 μmol) was dissolved in acetic anhydride (5 mL), and sodium hydroxide (8.73 mg, 218.36 mol) was added. The mixture was reacted at 100°C in a microwave oven for 30 minutes. LCMS analysis showed that most of the raw materials were completely converted. The reaction solution was directly filtered and concentrated to dryness to obtain compound 21 (46 mg, yield: 42.73%).

[0319] LCMS (ESI) [M+H] + 592.0.

[0320] 1 H NMR (400MHz, DMSO-d6) δ9.20(s,1H),8.71(s,1H),8.19-8.15(m,1H),7.49(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),6.94(s,1H),4.43(d,J=4.8 Hz,3H),3.88(s,3H),2.37(s,3H),1.82(tt,J=8.2,4.6Hz,1H),1.39(d,J=6.7Hz,6H),1.05(dt,J=4.5,3.0Hz,2H),0.89(dt,J=8.2,3.4Hz,2H).

[0321] Example 22: Synthesis of Compound 22

[0322] Step 1: Synthesis of Compound 22

[0323] Compound 16 (50 mg, 86.57 μmol) was dissolved in a mixture of tert-butanol (2.5 mL) and toluene (2.5 mL). Diphenylphosphoryl azide (71.47 mg, 259.72 μmol) and triethylamine (43.80 mg, 432.86 μmol) were then added. The mixture was reacted at 65°C for 3 hours and then at 100°C for 1.5 hours. The mixture was directly spin-dried and purified by wet loading (petroleum ether:ethyl acetate = 0-100%) to afford compound 22 (3.2 mg, 5.70% yield).

[0324] LCMS (ESI) [M+H] + 649.4.

[0325] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.32(s,1H),8.69(s,1H),8.17(s,1H),7.48(d,J=8.0Hz,2H),7.41(d,J=8.0Hz,2H),7.11(s,1H),4 .49-4.40(m,1H),4.37(s,2H),3.88(s,3H),1.88-1.77(m,1H),1.50(s,9H),1.38(d,J=4.0Hz,6H),1.08-1.01(m,2H),0.92-0.85(m,2H).

[0326] Example 23: Synthesis of Compound 23

[0327] Step 1: Synthesis of compound 23-2

[0328] Compound 22 (40 mg, 61.66 μmol) was dissolved in trifluoroacetic acid (1 mL) / dichloromethane (3 mL) and reacted at room temperature for 2 hours. LCMS analysis showed that the conversion of the starting material was complete. The reaction solution was directly spin-dried to obtain the target product, crude compound 23-2 (30 mg, yield: 88.69%, brown viscous oil).

[0329] LCMS (ESI) [M+H] + 549.0.

[0330] Step 2: Synthesis of Compound 23

[0331] Compound 23-2 (30 mg, 54.69 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30.95 mg, 82.03 μmol), N,N-diisopropylethylamine (21.20 mg, 164.07 μmol, 28.58 μL), and acetic acid (6.57 mg, 109.38 μmol) were dissolved in dichloromethane (5 mL) and reacted at room temperature for 2 hours. LCMS detection showed that the main peak was the target molecular weight, indicating complete conversion of the raw materials. The reaction solution was diluted with water and ethyl acetate, extracted, and the organic phase was concentrated to dryness to obtain compound 23 (3 mg, yield: 9.29%).

[0332] LCMS (ESI) [M+H] + 591.2.

[0333] 1H NMR (400MHz, DMSO-d6) δ10.49(s,1H),9.37(s,1H),8.70(s,1H),8.16(d,J=1.5Hz,1H),7.48(d,J=8.3Hz,2H),7.41(d,J=8.3Hz,2H),7.18(s,1 H),4.56-4.33(m,3H),3.88(s,3H),2.12(s,3H),1.82(tt,J=8.4,4.6Hz,1H),1.38(d,J=6.6Hz,6H),1.04(p,J=3.7Hz,2H),0.94-0.83(m,2H).

[0334] Example 24: Synthesis of Compound 24

[0335] Step 1: Synthesis of Compound 24-6

[0336] Compound 24-5 (16.9 g, 94.84 mmol) and sodium acetate (5.19 g, 94.84 mmol) were dissolved in water (29.9 mL) and heated to 100°C under reflux for 1 hour. The mixture was then cooled to room temperature. 3,3-Dibromo-1,1,1-trifluoro-2-propanone (10 g, 94.84 mmol) was dissolved in a mixture of methanol (279.9 mL) and aqueous ammonia (65.9 mL). The mixture was added to the reaction mixture and stirred at room temperature for 40 minutes. The mixture was then heated to 100°C under reflux for 2 hours. LCMS indicated the reaction was complete. The reaction mixture was cooled to room temperature and water was slowly added to the reaction mixture. A large amount of solid precipitated from the reaction mixture, which was filtered and dried to obtain compound 24-6 (9 g, 90% yield, as a yellow solid).

[0337] LCMS (ESI) [M+H] + 285.1.

[0338] Step 2: Synthesis of compound 24-7

[0339] Compound 24-6 (9 g, 31.66 mmol), isopropanol (5.4 g, 94.98 mmol), and triphenylphosphine (18 g, 63.32 mmol) were added to tetrahydrofuran (100 mL). Diisopropyl azodicarboxylate (14.4 g, 63.32 mmol) was added dropwise at 0°C and stirred at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction solution was poured into ice water (1500 mL) and extracted with ethyl acetate (1500 mL). The organic phase was dried and passed through a column (petroleum ether:ethyl acetate = 100% / 0 to 50% / 50%) to afford compound 24-7 (6 g, 66% yield, as a white solid).

[0340] LCMS (ESI) [M+H]+ 327.1.

[0341] Step 3: Synthesis of Intermediate 24-8

[0342] Compound 24-7 (6 g, 18.38 mmol) was dissolved in a mixture of tetrahydrofuran (70 mL) and water (35 mL). Sodium hydroxide (3.67 g, 91.9 mmol) was added and allowed to react at room temperature for 12 hours. LCMS indicated the reaction was complete. The reaction solution was quenched with water (100 mL) and extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (petroleum ether:ethyl acetate = 100% / 0 to 50% / 50%) to afford intermediate 24-8 (1 g, 37% yield, as a white solid).

[0343] LCMS (ESI) [M+H] + 313.0.

[0344] Step 4: Synthesis of Compound 24-2

[0345] Compound 24-1 (1 g, 5.43 mmol), 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (1.69 g, 8.70 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (909.82 mg, 1.09 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (1.01 g, 2.17 mmol) and potassium phosphate (3.46 g, 16.30 mmol) were dissolved in a mixed solution of dioxane (16 mL) and water (4 mL), nitrogen was replaced three times, and the reaction was carried out at 60 ° C for 12 hours. The mixture was cooled to room temperature, and part of the solvent was concentrated. Ethyl acetate (30 mL) was added, and the mixture was washed with water (15 mL*2) and saturated brine (15 mL*2) in sequence. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified on silica gel to obtain compound 24-2 (0.8 g, 3.16 mmol, yield: 58.12%, light yellow solid).

[0346] LCMS (ESI) [M+H] + 253.6.

[0347] Step 5: Synthesis of compound 24-3

[0348] Compound 24-2 (0.3 g, 1.18 mmol) was dissolved in methanol (5 mL), followed by the addition of Raney nickel (69.53 μg, 1.18 mmol). The mixture was allowed to react at 25°C for 2 hours. The reaction mixture was filtered and dried to afford compound 24-3 (0.3 g, 98.43% yield, yellow solid). This was used directly in the next step without further purification.

[0349] LCMS (ESI) [M+H] + 257.6.

[0350] Step 6: Synthesis of compound 24-4

[0351] Compound 24-3 (0.3 g, 1.17 mmol), intermediate 24-8 (436.95 mg, 1.40 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (886.69 mg, 2.33 mmol), and N,N-diisopropylethylamine (301.39 mg, 2.33 mmol, 406.19 μL) were dissolved in dichloromethane (10 mL) and reacted at 25°C for 12 hours. The filtrate was directly purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 0-80%) to obtain compound 24-4 (0.2 g, yield: 31.10%), as a pale yellow solid.

[0352] LCMS (ESI) [M+H] + 551.8.

[0353] Step 7: Synthesis of compound 24

[0354] Compound 24-4 (0.2 mg, 362.61 μmol) was dissolved in phosphorus oxychloride (10 mL) and reacted at 90°C for 12 hours. After cooling to room temperature, the reaction mixture was added to ice water (20 mL), and the pH was adjusted to alkaline with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. Liquid phase preparation afforded the target compound 24 (22.47 mg, 11.61% yield).

[0355] LCMS (ESI) [M+H] + 534.2.

[0356] 1H NMR (400MHz, DMSO-d6) δ9.15(d,J=1.6Hz,1H),8.66(s,1H),8.52(t,J=1.3Hz,1H),8.16(m,1H),7.89(d,J=0.9Hz,1H),7.51(d,J=8. 3Hz,2H),7.45(d,J=8.3Hz,2H),4.56(s,2H),4.43m,1H),3.83(s,3H),1.91(m,1H),1.38(d,J=6.6Hz,7H),1.04(m,2H),0.88(m,2H).

[0357] Example 25: Synthesis of Compound 25

[0358] Step 1: Synthesis of compound 25

[0359] Compound 10-3 (200 mg, 0.342 mmol), copper chloride (46.01 mg, 342.24 μmol), and cesium carbonate (333.97 mg, 1.03 mmol) were dissolved in ethylene glycol (10 mL) and reacted at 140°C for 3 hours. LCMS analysis revealed product formation. The sample was directly spin-dried and separated by column chromatography using a PE / EA (1 / 4) ratio to afford the crude product. Compound 25 (38.02 mg, 19.64% yield) was then prepared by liquid chromatography (alkaline method).

[0360] LCMS (ESI) [M+H] + 566.0.

[0361] 1 H NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.68(s,1H),7.92(d,J=0.8Hz,1H),7.63(d,J=8.4Hz,2H),7.39(d,J=8.0Hz,2H),6.70(s,1H),4.92(t, J=5.2Hz,1H),4.35(s,2H),4.17(t,J=4.8Hz,2H),3.87(s,3H),3.76-3.72(m,5H),1.82-1.82(m,1H),1.04-1.02(m,2H),0.89-0.86(m,2H).

[0362] Example 26: Synthesis of Compound 26

[0363] Step 1: Synthesis of Compound 26

[0364] Compound 8-2 (300 mg, 0.489 mmol), bis(triphenylphosphine)palladium dichloride (68.70 mg, 0.098 mmol), and triethylamine (148.75 mg, 1.47 mmol) were dissolved in 12 mL of isopropanol:acetonitrile. The mixture was sealed in an autoclave, and CO gas was introduced. The reaction was carried out at 100°C for 48 hours. After the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by liquid phase purification to obtain compound 26 (67.72 mg, yield: 22.31%), as a yellow solid.

[0365] LCMS (ESI) [M+H] + 620.0.

[0366] 1 H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.73(s,1H),8.17(d,J=1.2Hz,1H),7.49-7.41(m,5H),5.23-5.17(m,1H) ,4.46-4.39(m,3H),3.87(s,3H),1.86-1.83(m,1H),1.39-1.36(m,12H),1.07-1.03(m,2H),0.87-0.82(m,2H).

[0367] Example 27: Synthesis of Compound 27

[0368] Step 1: Synthesis of Compound 27

[0369] Compound 8-2 (300 mg, 0.489 mmol), bis(triphenylphosphine)palladium dichloride (68.70 mg, 0.098 mmol), and triethylamine (148.75 mg, 1.47 mmol) were dissolved in 12 mL:12 mL of ethanol and acetonitrile, and the mixture was sealed in an autoclave. CO gas was introduced and the reaction was carried out at 100°C for 48 hours. After the reaction, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by liquid phase preparative purification to obtain compound 27 (19.77 mg, yield: 6.66%).

[0370] LCMS (ESI) [M+H] + 606.4.

[0371] 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 8.66 (s, 1H), 8.10 (d, J = 1.2Hz, 1H), 7.44-7.35 (m, 5H), 4.39-4.37 (m, 2H), 4.39-4. 30(m,1H),4.29-4.27(m,2H),3.80(s,3H),1.77-1.77(m,1H),1.32-1.28(m,9H),0.99-0.97(m,2H),0.79-0.76(m,2H).

[0372] Example 28: Synthesis of Compound 28

[0373] Step 1: Synthesis of compound 28-2

[0374] Compound 8-2 (100 mg, 163.28 μmol) was dissolved in toluene (5 mL), followed by the addition of zinc cyanide (95.87 mg, 816.40 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (13.67 mg, 16.33 μmol). The atmosphere was purged with nitrogen three times and microwave-treated at 125°C for 4 hours. The mixture was then directly purified on silica gel (petroleum ether:ethyl acetate = 0-100%) to afford the target compound 28-2 (90 mg, 98.68% yield, as a yellow solid).

[0375] LCMS (ESI) [M+H] + 559.3.

[0376] Step 2: Synthesis of Compound 28

[0377] Compound 28-2 (45 mg, 80.56 μmol) was dissolved in a mixture of water (1 mL) and dimethyl sulfoxide (3 mL). Sodium hydroxide (32.22 mg, 805.65 μmol) and hydrogen peroxide (2.74 mg, 80.56 μmol, 0.5 mL) were then added and allowed to react at 25°C for 3 minutes. The reaction was quenched by the addition of sodium thiosulfate solution, followed by extraction three times with dichloromethane (40 mL) and water (40 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and purified on silica gel (DCM:MeOH = 0-15%) to afford the crude product. Liquid phase purification was then performed to afford compound 28 (3.95 mg, 8.49% yield).

[0378] LCMS (ESI) [M+H] + 577.3.

[0379] 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),8.73(s,1H),8.18(s,1H),7.98(s,1H),7.51(s,1H),7.48(d,J=12.0Hz,2H),7.42(d,J=8.0Hz ,2H),7.37(s,1H),4.53-4.39(m,3H),3.88(s,3H),1.90-1.79(m,1H),1.39(d,J=4.0Hz,6H),1.10-1.01(m,2H),0.92-0.82(m,2H).

[0380] Example 29: Synthesis of Compound 29

[0381] Step 1: Synthesis of Compound 29

[0382] Compound 3 (70 mg, 138.48 μmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of N-chlorosuccinimide (20.34 mg, 152.33 μmol) and the reaction was allowed to react at 25°C for 30 minutes. The mixture was extracted three times with water (40 mL) and dichloromethane (30 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was purified on silica gel (petroleum ether:ethyl acetate = 0-50%) to afford compound 29 (11.62 mg, 15.54% yield).

[0383] LCMS (ESI) [M+H] + 540.2.

[0384] 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.72(s,1H),7.49(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H),7.19(s,1H), 6.74(s,1H),4.44(s,2H),3.87(s,3H),2.31(s,3H),1.87-1.78(m,1H),1.10-1.02(m,2H),0.90-0.84(m,2H).

[0385] Example 30: Synthesis of Compound 30

[0386] Step 1: Synthesis of compound 30-2

[0387] Compound 3 (500 mg, 0.989 mmol) was dissolved in acetonitrile (20 mL). N-bromosuccinimide (1.76 g, 0.989 mmol) was added at room temperature and the reaction was stirred for 1 hour. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (5 / 1) afforded compound 30-2 (390 mg, 0.667 mmol, 67.47% yield, as a yellow solid).

[0388] LCMS (ESI) [M+H] + 584.2.

[0389] Step 2: Synthesis of compound 30

[0390] Compound 30-2 (140 mg, 239.57 μmol), [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]methanesulfonate palladium (II) (20.46 mg, 23.96 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl (23.19 mg, 47.91 μmol) and sodium tert-butoxide (46 mg) were added. , 479.13 μmol) was dissolved in methanol (0.5 mL) / 1,4-dioxane (2 mL) / water (0.5 mL), and the reaction was stirred 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, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was prepared by liquid phase to obtain compound 30 (15.31 mg, yield: 11.93%).

[0391] LCMS (ESI) [M+H] + 536.2.

[0392] 1 H NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.61(s,1H),7.41(d,J=8.4Hz,2H),7.35(d,J=8.4Hz,2H),6.67-6.64(m,2H ),4.31(s,2H),3.87(s,3H),3.80(s,3H),2.24(s,3H),1.76-1.73(m,1H),0.98-0.94(m,2H),0.83-0.78(m,2H).

[0393] Example 31: Synthesis of Compound 31

[0394] Step 1: Synthesis of compound 31

[0395] Compound 29 (200 mg, 370.41 μmol) was dissolved in toluene (5 mL), followed by the addition of zinc cyanide (260.97 mg, 2.22 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (31.02 mg, 37.04 μmol). The atmosphere was purged with nitrogen three times, and the mixture was microwaved at 130°C for 2 hours. The mixture was extracted three times with water (40 mL) and dichloromethane (30 mL), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The crude product was then purified on silica gel (petroleum ether:ethyl acetate = 0-50%) to afford compound 31 (11.915 mg, 36.11% yield) via liquid phase chromatography.

[0396] LCMS (ESI) [M+H] + 531.2.

[0397] 1 H NMR (400MHz, DMSO-d6) δ9.63(s,1H),8.74(s,1H),7.63(s,1H),7.49(d,J=8.0Hz,2H),7.44(d,J=8.0Hz,2H), 6.75(s,1H),4.48(s,2H),3.87(s,3H),2.31(s,3H),1.91-1.80(m,1H),1.10-1.01(m,2H),0.91-0.81(m,2H).

[0398] Example 32: Synthesis of Compound 32

[0399] Step 1: Synthesis of compound 32

[0400] Compound 31 (20 mg, 37.70 μmol) was dissolved in a mixture of water (1 mL) and tetrahydrofuran (3 mL), followed by the addition of sodium hydroxide (9.05 mg, 226.20 μmol) and the reaction at 60°C for 3 hours. The solvent was partially concentrated, and the mixture was extracted three times with water (30 mL) and dichloromethane (40 mL). The organic phases were combined, dried, and liquid phase extraction yielded compound 32 (10.48 mg, 50.68% yield).

[0401] LCMS (ESI) [M+H ]+ 549.2.

[0402] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.73(s,1H),7.97(s,1H),7.52(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.44(s,1H), 7.37(s,1H),6.75(s,1H),4.45(s,2H),3.87(s,3H),2.33(s,3H),1.87-1.79(m,1H),1.09-1.02(m,2H),0.92-0.85(m,2H).

[0403] Example 33: Synthesis of Compound 33

[0404] Step 1: Synthesis of compound 33

[0405] Compound 31 (78 mg, 147.03 μmol) was dissolved in dimethyl sulfoxide (2 mL) / water (1 mL) / tetrahydrofuran (3 mL) / methanol (3 mL), followed by the addition of barium hydroxide (125.96 mg, 735.15 μmol). The mixture was then microwaved at 93°C for 4 hours. The mixture was extracted three times with water (40 mL) and dichloromethane (40 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The resulting mixture was then subjected to liquid phase purification to afford compound 33 (8.21 mg, 10.16% yield).

[0406] LCMS (ESI) [M+H] + 550.2.

[0407] 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),9.61(s,1H),8.73(s,1H),7.48(q,J=8.0Hz,4H),7.39(s,1H),6.75 (s,1H),4.46(s,2H),3.87(s,3H),2.32(s,3H),1.88-7.78(m,1H),1.09-1.02(m,2H),0.91-0.81(m,2H).

[0408] Example 34: Synthesis of Compound 34

[0409] Step 1: Synthesis of compound 34

[0410] Compound 30-2 (40 mg, 0.068 mmol) was added to a methanol / acetonitrile (10 / 10 mL) autoclave, along with palladium dichloride {[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride} (9.9 mg, 0.013 mmol) and triethylamine (20.64 mg, 0.204 mmol). The autoclave was filled with carbon monoxide to 2 standard atmospheres and stirred at 100°C for 48 hours. LCMS indicated the reaction was complete, and the reaction solution was directly dried by column chromatography. The organic phase was dried by column chromatography (petroleum ether / ethyl acetate = 100% / 0% to 40% / 60%) to afford the final product, compound 34 (8.48 mg, 21.20% yield).

[0411] LCMS (ESI) [M+H] + 563.9.

[0412] 1 H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.73(s,1H),7.51-7.44(m,5H),6.74(s,1H),4.47(s,2H), 3.89(s,3H),3.86(s,3H),2.31(s,3H),1.84-1.82(m,1H),1.07-1.04(m,2H),0.88-0.84(m,2H).

[0413] Example 35: Synthesis of Compound 35

[0414] Step 1: Synthesis of compound 35

[0415] Compound 33 (45 mg, 81.89 μmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of triethylamine (16.57 mg, 163.78 μmol), diethylamine hydrochloride (20.03 mg, 245.68 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46.34 mg, 122.84 μmol). The mixture was allowed to react at 25°C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with water (40 mL) and dichloromethane (50 mL). The mixture was washed once with saturated brine, and the combined organic phases were spin-dried to dryness. Compound 35 (42.18 mg, 89.33% yield) was obtained via liquid phase purification.

[0416] LCMS (ESI) [M+H] + 577.3.

[0417] 1H NMR(400MHz,DMSO-d6)δ9.39(s,1H),8.72(s,1H),7.51-7.43(m,4H),7.35(s,1H),6.74(s,1H),4.47(s ,2H),3.86(s,3H),3.14(s,6H),2.31(s,3H),1.88-1.76(m,1H),1.09-1.02(m,2H),0.92-0.82(m,2H).

[0418] Example 36: Synthesis of Compound 36

[0419] Step 1: Synthesis of compound 36

[0420] Compound 33 (45 mg, 81.89 μmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of triethylamine (9.83 mg, 163.78 μmol), methylamine hydrochloride (16.59 mg, 245.68 μmol), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46.34 mg, 122.84 μmol). The mixture was allowed to react at 25°C for 16 hours. The reaction was quenched with water, and the mixture was extracted three times with water (40 mL) and dichloromethane (50 mL). The mixture was washed once with saturated brine, and the combined organic phases were spin-dried to dryness. Compound 36 (36.77 mg, 79.82% yield) was obtained via liquid phase purification.

[0421] LCMS (ESI) [M+H] + 563.2.

[0422] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.73(s,1H),8.45(d,J=4.0Hz,1H),7.52(d,J=8.0Hz,2H),7.46(d,J=8.0Hz,2H),7.38(s,1H), 6.76(s,1H),4.45(s,2H),3.88(s,3H),2.80(d,J=4.0Hz,3H),2.33(s,3H),1.88-1.79(m,1H),1.09-1.03(m,2H),0.92-0.85(m,2H).

[0423] Example 37: Synthesis of Compound 37

[0424] Step 1: Synthesis of compound 37-2

[0425] Compound 37-1 (10 g, 48.1 mmol) and 1,1,1-trifluoro-5-methylhexane-2,4-dione (13.0 g, 72.2 mmol) were added to hexafluoroisopropanol (65 mL), and a solution of triethylamine (10 g, 96.2 mmol) in hexafluoroisopropanol (40 mL) was slowly added dropwise under an ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly added to ice water (300 mL) and extracted with ethyl acetate (3*100 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product compound 37-2 (15 g, crude product, yellow oil).

[0426] LCMS (ESI) [M+H] + 313.1.

[0427] Step 2: Synthesis of compound 37-3

[0428] Compound 37-2 (15 g, 48.3 mmol) was dissolved in tetrahydrofuran (65 mL), and diisobutylaluminum hydride (130 mL, 1.5 M toluene solution) was slowly added dropwise under ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly quenched by adding saturated aqueous ammonium chloride solution (500 mL), filtered, and the filtrate was extracted with ethyl acetate (3*200 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound 37-3 (10 g, yield: 79%, yellow oil).

[0429] LCMS (ESI) [M+H] + 285.2.

[0430] Step 3: Synthesis of compound 37-4

[0431] Compound 37-3 (500 mg, 1.76 mmol) was dissolved in tetrahydrofuran (10 mL) and phosphorus tribromide (1.43 g, 5.28 mmol) was added. The mixture was allowed to react overnight at room temperature. LCMS confirmed the complete reaction of the starting material to yield the desired product. The reaction solution was concentrated and diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated sodium bicarbonate (20 mL*2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1:5) to afford compound 37-4 (420 mg, 68.7% yield, as a yellow solid).

[0432] LCMS (ESI) [M+H] + 347.0 / 349.0.

[0433] Step 4: Synthesis of Compound 37

[0434] Compound 37-4 (150.4 mg, 0.43 mmol) and compound 2-3 (100 mg, 0.29 mmol) were dissolved in dioxane and water (10 mL / 1 mL), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (13.8 mg, 0.029 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)] palladium (II) (22.8 mg, 0.029 mmol) and potassium phosphate (184.6 mg, 0.87 mmol) were added to replace argon, and the reaction was carried out at 100°C for 16 hours. The reaction was confirmed to be complete by LCMS. Water (10 mL) was added for dilution, and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), and concentrated under reduced pressure to obtain compound 37 (82 mg, yield 31.7%).

[0435] LCMS (ESI) [M+H] + 534.1.

[0436] 1 H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.70(s,1H),7.43(s,4H),7.11(d,J=4.6Hz,1H),7.05(d,J=4.6Hz,1H),6.80(s,1H),4.47(s,2 H),3.86(s,3H),2.96-2.89(m,1H),1.82-1.75(m,1H),1.13-1.10(m,6H),1.04(dd,J=7.5,3.0Hz,2H),0.87(dd,J=8.1,3.2Hz,2H).

[0437] Example 38: Synthesis of Compound 38

[0438] Step 1: Synthesis of compound 38-2

[0439] Compound 38-1 (500 mg, 1.74 mmol) was dissolved in tetrahydrofuran (5 mL) and phosphorus tribromide (1.39 g, 5.22 mmol) was added. The mixture was allowed to react overnight at room temperature. LCMS confirmed the complete reaction of the starting material to yield the desired product. The reaction solution was concentrated and diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated sodium bicarbonate (20 mL*2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 10) to yield compound 38-2 (300 mg, 49.22% yield, as a yellow solid).

[0440] LCMS (ESI) [M+H] + 349.0 / 351.0.

[0441] Step 2: Synthesis of compound 38

[0442] Compound 38-2 (100 mg, 0.30 mmol) and compound 2-3 (100 mg, 0.30 mmol) were dissolved in dioxane / water (5 mL / 0.5 mL), and bis(pinacolato)diboron (152 mg, 0.6 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14 mg, 0.03 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-( 2′-amino-1,1′-biphenyl)] palladium(II) (23 mg, 0.03 mmol) and phosphoric acid (190 mg, 0.90 mmol) were added to replace argon and reacted at 100°C for 16 hours. The reaction was confirmed to be complete by LCMS. Water (10 mL) was added for dilution and the mixture was extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), and concentrated under reduced pressure to obtain compound 38 (12.26 mg, yield: 7.84%).

[0443] LCMS (ESI) [M+H] + 536.3.

[0444] 1H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.70 (s, 1H), 7.56 (d, J = 8.6Hz, 2H), 7. 39(d,J=8.6Hz,2H),7.10(d,J=4.6Hz,1H),7.04(d,J=4.5Hz,1H),6.43(s,1 H),4.42(s,2H),4.26(q,J=7.0Hz,2H),3.85(d,J=5.6Hz,3H),1.80-1.74(m ,1H),1.33(t,J=7.0Hz,3H),1.06-1.01(m,2H),0.86(dd,J=8.0,3.2Hz,2H).

[0445] Example 39: Synthesis of Compound 39

[0446] Step 1: Synthesis of compound 39

[0447] Compound 10-3 (30 mg, 0.051 mmol) was dissolved in N,N-dimethylformamide (5 mL). Potassium phosphate (13 mg, 0.061 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.8 mg, 0.0031 mmol), palladium acetate (0.57 mg, 0.0026 mmol), and dimethylphosphine oxide (4.5 mg, 0.057 mmol) were added. The atmosphere was replaced with nitrogen and the mixture was reacted at 120°C for 5 hours. LCMS analysis indicated the reaction was complete, yielding the desired product. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse preparative method to afford compound 39 (22.73 mg, 76.3% yield).

[0448] LCMS (ESI) [M+H] + 582.1.

[0449] 1 H NMR (400MHz, MeOD-d4) δ9.57(s,1H),8.66(s,1H),7.69(s,1H),7.60(d,J=8.1Hz,2H),7.49(d,J=8.1Hz,2H),7.32(d,J=5.3Hz,1H), 4.53(s,2H),3.96(d,J=9.2Hz,3H),3.77(s,3H),1.95(s,3H),1.92(s,3H),1.88-1.80(m,1H),1.20-1.15(m,2H),0.95-0.88(m,2H).

[0450] Example 40: Synthesis of Compound 40

[0451] Step 1: Synthesis of Compound 40-2

[0452] Compound 40-1 (1.0 g, 4.97 mmol) was dissolved in N,N-dimethylformamide (20 mL), and lithium bromide (475 mg, 5.469 mmol) was added. Phosphorus tribromide (1.43 g, 5.27 mmol) was then slowly added dropwise at zero degrees Celsius. The reaction mixture was allowed to react overnight at room temperature with a plate monitor until the reaction was complete. The reaction solution was concentrated, diluted with water (10 mL), and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to afford compound 40-2 (441 mg, 33.9% yield, yellow liquid).

[0453] 1 H NMR (400MHz, CDCl3-d) δ7.86-7.79 (m, 2H), 7.71 (d, J = 7.9Hz, 1H), 4.51 (s, 2H).

[0454] Step 2: Synthesis of Compound 40

[0455] Compound 40-2 (300 mg, 1.136 mmol) and compound 2-3 (590 mg, 1.704 mmol) were dissolved in dioxane / water (10 mL / 1 mL), and bis(pinacolato)diboron (575 mg, 2.272 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (162 mg, 0.341 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2- (2′-amino-1,1′-biphenyl)] palladium (II) (89 mg, 0.114 mmol) and phosphoric acid (723 mg, 3.408 mmol) were added to replace argon and reacted at 100°C for 16 hours. The reaction was confirmed to be complete by LCMS. Water (10 mL) was added for dilution and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), and concentrated under reduced pressure to obtain compound 40 (69.25 mg, yield: 13.5%).

[0456] LCMS (ESI) [M+H] + 451.0.

[0457] 1H NMR (400MHz, DMSO-d6) δ9.25(s,1H),8.70(s,1H),8.08(d,J=8.0Hz,1H),7.94(s,1H),7.69(d,J=7.8Hz,1H),7.10(dd,J= 11.6,4.6Hz,2H),4.58(s,2H),3.83(s,3H),1.73-1.65(m,1H),1.03(dt,J=7.4,3.5Hz,2H),0.82(td,J=6.5,3.4Hz,2H).

[0458] Example 41: Synthesis of Compound 41

[0459] Step 1: Synthesis of compound 41-2

[0460] Under ice bath, compound 41-1 (7 g, 35 mmol) and compound 2-1 (2.71 g, 17 mmol) were added to 1,4-dioxane / water (70 / 14 mL), potassium phosphate (7.54 g, 35 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.69 g, 3.55 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl) were added. -isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (1.50 g, 1.77 mmol), 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, and concentrated. The residue was purified by silica gel column to obtain compound 41-2 (4.67 g, yield: 97%, yellow oily liquid).

[0461] LC-MS (ESI) [M+H] + 271.2.

[0462] Step 2: Synthesis of compound 41-3

[0463] Under ice bath, compound 41-2 (4.67 g, 17 mmol) was added to N,N-dimethylformamide (40 mL), and N-bromosuccinimide (2.77 g, 15 mmol) was added. The reaction solution was stirred at room temperature overnight. LC-MS showed that the reaction was successful. Water was added and the mixture was extracted with ethyl acetate. 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 chromatography to obtain compound 41-3 (4.64 g, yield: 77%, yellow solid).

[0464] LC-MS (ESI) [M+H] + 349.1 / 351.1.

[0465] Step 3: Synthesis of compound 41

[0466] Compound 41-3 (50 mg, 0.144 mmol), 5-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylphenyl)-3-trifluoromethylpyrazole (146 mg, 0.40 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (23 mg, 0.04 mmol), and sodium tert-butoxide (41 mg, 0.42 mmol) were dissolved in toluene (9 mL) / water (1 mL). The reaction was stirred at 100°C for 16 hours. LCMS analysis confirmed the formation of the product. The reaction solution was concentrated under reduced pressure, and the residue was isolated and purified by reverse-phase column chromatography (A: formic acid, B: acetonitrile) to obtain the target compound 41 (36 mg, 50% yield).

[0467] LC-MS (ESI) [M+H] + 509.2.

[0468] 1 H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.70(s,1H),7.48(d,J=8.5Hz,2H),7.43(d,J=8.6Hz,2H),7.11(d,J=4.5Hz ,1H),7.05(d,J=4.5Hz,1H),6.73(s,1H),4.46(s,2H),2.31(s,3H),1.79(s,1H),1.05(s,2H),0.90-0.83(m,2H).

[0469] Example 42: Synthesis of Compound 42

[0470] Step 1: Synthesis of compound 42-2

[0471] Compound 41-3 (1 g, 2.86 mmol) was dissolved in acetonitrile (16 mL) under an ice bath, followed by the addition of a selective fluorine reagent (1.6 g, 0.48 mmol) and sodium bicarbonate (1.2 g, 14.32 mmol). The atmosphere was replaced with nitrogen, and the reaction mixture was microwaved at 80°C for 20 minutes. LCMS indicated the reaction was complete. Water (20 mL) was added for dilution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography to afford compound 42-2 (213 mg, 20% yield, brown oil).

[0472] LC-MS (ESI) [M+H] +367.0 / 369.0.

[0473] Step 2: Synthesis of compound 42

[0474] To a solution of compound 42-2 (70 mg, 0.19 mmol) and 5-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)-3-trifluoromethylpyrazole (195 mg, 0.53 mmol) in water (1 mL) / extra-dry toluene (9 mL) at room temperature were added sodium tert-butoxide (55 mg, 0.57 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (31 mg, 0.05 mmol). The atmosphere was replaced with nitrogen, and the reaction mixture was stirred at 100°C for 16 hours. LCMS indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by liquid phase preparative purification to afford compound 42 (24 mg, 24% yield).

[0475] LC-MS (ESI) [M+H] + 527.1.

[0476] 1 H NMR (400MHz, DMSO-d6) δ9.32(s,1H),8.70(s,1H),7.49(d,J=8.5Hz,2H),7.43(d,J=8.5Hz,2H),6.98(s,1H ),6.74(s,1H),4.42(s,2H),2.31(s,3H),1.82(s,1H),1.06(d,J=8.4Hz,2H),0.88(dd,J=7.9,3.2Hz,2H).

[0477] Example 43: Synthesis of Compound 43

[0478] Step 1: Synthesis of compound 43-2

[0479] Compound 43-1 (100 mg, 0.53 mmol) was dissolved in acetone (10 mL) under an ice bath. Sodium iodide (1.59 g, 10.64 mmol) and trifluoroacetic acid (303 mg, 2.66 mmol) were added at 0°C and the reaction was stirred at 0°C to room temperature for 2 hours. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with dichloromethane (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. The crude product 43-2 (100 mg, yield: 67.28%) was obtained by direct spin drying as a yellow solid.

[0480] LCMS (ESI) [M+H] + 279.9.

[0481] Step 2: Synthesis of compound 43-3

[0482] Compound 43-2 (135 mg, 0.483 mmol) and trifluoromethyl(1,10-phenanthroline)copper(I) (226.62 mg, 724.60 μmol) were dissolved in N,N-dimethylformamide (10 mL) under ice and stirred at 50°C for 24 hours. LCMS analysis showed no product formation. The reaction was then heated to 80°C and stirred for 2 hours. LCMS analysis confirmed product formation. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 99 / 1 afforded compound 43-3 (38 mg, 35.50% yield, as a yellow solid). H NMR and NF NMR spectra confirmed the product.

[0483] 1 H NMR (400MHz, DMSO-d6) δ8.57 (dd, J=1.2Hz, J=1.2Hz, 1H), 7.39-7.34 (m, 2H).

[0484] 19 FNMR(400MHz,DMSO-d6)δ-67.44ppm.

[0485] Step 3: Synthesis of compound 43-4

[0486] On ice, compound 43-3 (38 mg, 0.171 mmol), 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (94.72 mg, 0.343 mmol), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (15.98 mg, 34.30 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (14.34 mg, 17.15 μmol), and potassium phosphate (72.72 mg, 0.343 mmol) were dissolved in water (0.1 mL) / 1,4-dioxane (2 mL). The reaction was stirred in a microwave at 80°C for 2 hours. LCMS confirmed the formation of the product. The sample was directly spin-dried and separated by column chromatography using petroleum ether / ethyl acetate = 10 / 1 to obtain compound 43-4 (30 mg, yield: 52.17%, yellow solid).

[0487] LCMS (ESI) [M+H] + 336.0.

[0488] Step 4: Synthesis of compound 43-5

[0489] Compound 43-4 (30 mg, 89.48 μmol) was dissolved in acetonitrile (10 mL). N-bromosuccinimide (15.93 mg, 89.48 μmol) was added at room temperature, and the reaction was stirred at room temperature for 16 hours. LCMS confirmed the formation of the product. The product was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (10 / 1) afforded compound 43-5 (30 mg, 80.95% yield, as a yellow solid).

[0490] LCMS (ESI) [M+H] + 414.0.

[0491] Step 5: Synthesis of compound 43

[0492] Compound 43-5 (30 mg, 72.43 μmol), 1-(1-methylethyl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]-4-trifluoromethylimidazole (28.56 mg, 72.43 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.30 mg, 7.24 μmol), and potassium phosphate (30.71 mg, 144.86 μmol) were dissolved in toluene (2 mL) / water (0.1 mL). The reaction was stirred in a microwave oven at 100°C for 2 hours. LCMS analysis confirmed the formation of the product. The sample was directly spin-dried and separated by column chromatography using petroleum ether / ethyl acetate = 3 / 1 to obtain the product. Liquid phase preparation (alkaline method) afforded compound 43 (9.43 mg, 21.64% yield).

[0493] LCMS (ESI) [M+H] + 602.2.

[0494] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.16(d,J=0.8Hz,1H),7.48(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),7.36-7.34(m,2H),4. 53(s,2H),4.46-4.39(m,1H),3.86(s,3H),1.92-1.87(m,1H),1.39(s,3H),1.37(s,3H),1.08-1.06(m,2H),0.88-0.84(m,2H).

[0495] Example 44: Synthesis of Compound 44

[0496] Step 1: Synthesis of compound 44

[0497] Compound 43 (140 mg, 232.73 μmol) was added to tetrahydrofuran (10 mL), followed by iodomethane (991.45 mg, 6.98 mmol), sodium hydride (279.25 mg, 6.98 mmol), and lithium bis(trimethylsilyl)amide (1.17 g, 6.98 mmol). The reaction mixture was stirred at 70°C for 5 hours. Water was added, the mixture was washed with ethyl acetate, and dried by spin drying. Compound 44 (1.8 mg, 1.26% yield) was obtained by an alkaline liquid phase method.

[0498] LCMS (ESI) [M+H] + 616.5.

[0499] 1 H NMR (400MHz, DMSO-d6) δ8.73 (s, 1H), 8.16 (d, J = 1.5Hz, 1H), 7.50-7.46 (m, 3H ),7.42(d,J=8.3Hz,2H),7.39(dt,J=4.9,1.9Hz,1H),4.91(q,J=7.1Hz,1H),4 .42(p,J=6.5Hz,1H),3.84(s,3H),2.00(d,J=7.6Hz,1H),1.79(d,J=7.3Hz,3 H), 1.39 (dd, J = 6.7, 3.1Hz, 6H), 1.03 (t, J = 4.5Hz, 2H), 0.85 (q, J = 6.1Hz, 2H).

[0500] Example 45: Synthesis of Compound 45

[0501] Step 1: Synthesis of compound 45

[0502] Compound 43-5 (30 mg, 72.43 μmol), 5-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)-3-trifluoromethylpyrazole (31.83 mg, 86.92 μmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (5.30 mg, 7.24 μmol), and potassium phosphate (46.07 mg, 217.30 μmol) were dissolved in toluene (5 mL) / water (2 mL) and reacted at 100°C for 12 hours. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. Compound 45 (9.33 mg, yield: 22.46%) was obtained via liquid phase preparation.

[0503] LCMS (ESI) [M+H] + 574.3.

[0504] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),7.52-7.43(m,4H),7.35(s,2H),6.74(s,1H),4 .55(s,2H),3.88(s,3H),2.31(s,3H),1.90(m,1H),1.07(m,2H),0.94-0.80(m,2H).

[0505] Example 46: Synthesis of Compound 46

[0506] Step 1: Synthesis of compound 46-2

[0507] On ice, compound 2-1 (2.0 g, 13.02 mmol), (2-isopropylphenyl)boronic acid (4.27 g, 26.05 mmol), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (1.21 g, 2.60 mmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (181.07 mg, 216.59 μmol), and potassium phosphate (5.52 g, 26.50 mmol) were dissolved in 1,4-dioxane (100 mL) / water (10 mL). The reaction was stirred at 70°C for 16 hours. LCMS confirmed the formation of the product. The reaction mixture was quenched with water, extracted with ethyl acetate (2*50 mL), washed with water (2*50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 10 / 1 afforded compound 46-2 (2.9 g, yield: 93.84%), as a yellow solid.

[0508] LC-MS (ESI) [M+H] + 238.2.

[0509] Step 2: Synthesis of compound 46-3

[0510] Compound 46-2 (2.5 g, 10.54 mmol) was dissolved in acetonitrile (30 mL) under an ice bath. N-bromosuccinimide (1.88 g, 10.54 mmol) was added at room temperature and stirred for 10 minutes. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 10 / 1 afforded compound 46-3 (2.2 g, yield: 66.04%) as a yellow solid.

[0511] LCMS (ESI) [M+H] + 316.0.

[0512] Step 3: Synthesis of compound 46-4

[0513] Compound 46-3 (1.0 g, 3.16 mmol), a selective fluorine reagent (1.79 g, 5.06 mmol), and sodium bicarbonate (1.33 g, 15.81 mmol) were dissolved in acetonitrile (12 mL) under an ice bath and stirred in a microwave oven at 80°C for 15 minutes. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 100 / 1 afforded compound 46-4 (200 mg, yield: 18.92%), as a yellow oil.

[0514] LCMS (ESI) [M+H] + 334.0.

[0515] Step 4: Synthesis of compound 46

[0516] Compound 46-4 (200.78 mg, 600.79 μmol), 5-methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)-3-trifluoromethylpyrazole (440 mg, 1.20 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (97.78 mg, 0.150 mmol), and sodium tert-butoxide (173.03 mg, 1.80 mmol) were dissolved in toluene (20 mL) / water (2 mL). The reaction was stirred in a microwave oven at 100°C for 16 hours. LCMS confirmed the formation of the product. The reaction was quenched with water, extracted with ethyl acetate (2*50 mL), washed with water (2*50 mL), and the organic phase dried over anhydrous sodium sulfate. The crude product was separated by column chromatography using petroleum ether / ethyl acetate = 5 / 1, and then subjected to liquid phase preparation (alkaline method) to obtain compound 46 (72.88 mg, yield: 24.58%).

[0517] LCMS (ESI) [M+H] + 494.2.

[0518] 1H NMR (400MHz, DMSO-d4) δ9.31 (s, 1H), 7.55-7.53 (m, 1H), 7.51-7.45 (m, 4H), 7.39 (d, J = 8.4Hz, 2H), 7.30-7.27 (m,1H),6.93(s,1H),6.74(s,1H),4.45(s,2H),3.39-3.36(s,1H),2.31(s,3H),1.13-1.11(d,J=6.4Hz,6H).

[0519] Example 47: Synthesis of Compound 47

[0520] Step 1: Synthesis of compound 47-2

[0521] At room temperature, compound 47-1 (0.1 g, 384.50 μmol) was dissolved in tetrahydrofuran (10 mL), and sodium borohydride (29.09 mg, 769.00 μmol) was added. The reaction was allowed to react at room temperature for 3 hours. LCMS indicated the reaction was complete. The product was then directly spin-dried to give crude compound 47-2 (0.1 g, crude, white solid).

[0522] LCMS (ESI) [M+H] + 228.2.

[0523] Step 2: Synthesis of compound 47-3

[0524] To compound 47-2 (0.7 g, 3.07 mmol) suspended in toluene (5 mL) at room temperature was added manganese dioxide (802.00 mg, 9.22 mmol). The reaction was allowed to proceed at 100°C for 16 hours, with LCMS indicating completion. The mixture was filtered, and the filter cake was washed with ethyl acetate (30 mL). The filtrate was collected and purified by column chromatography (methanol / dichloromethane = 5 / 95) to afford compound 47-3 (0.14 g, 20.18% yield, as a pale yellow solid).

[0525] LCMS (ESI) [M+H] + 226.2.

[0526] Step 3: Synthesis of compound 47-4

[0527] To compound 47-3 (0.12 g, 531.84 μmol) in dioxane (5 mL) / water (1 mL) was added 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (123.81 mg, 638.21 μmol), potassium phosphate (338.68 mg, 1.60 mmol), and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (90.03 mg, 106.37 μmol) at room temperature. The mixture was reacted at 70°C for 3 hours. The mixture was filtered, and the filter cake was washed with ethyl acetate (20 mL). The filtrate was collected, dried, and filtered through a column with ethyl acetate / petroleum ether (1 / 3) to flush out the product. Compound 47-4 (0.16 g, yield: 88.65%) was obtained as a pale yellow solid.

[0528] LCMS (ESI) [M+H] + 340.2.

[0529] Step 4: Synthesis of compound 47-5

[0530] Compound 47-4 (0.11 g, 324.15 μmol) was dissolved in dichloromethane (5 mL) at room temperature, and N-bromosuccinimide (57.69 mg, 324.15 μmol) was added. The reaction was allowed to react at room temperature for 1 hour. LCMS indicated the reaction was complete, and the product was directly purified by column chromatography to afford compound 47-5 (0.11 g, 81.14% yield, as a pale yellow solid).

[0531] LCMS (ESI) [M+H] + 418.2.

[0532] Step 5: Synthesis of compound 47

[0533] Compound 47-5 (0.20 g, 478.19 μmol) was dissolved in toluene (5 mL) and water (1 mL). 5-Methyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)-3-trifluoromethylpyrazole (235.43 mg, 573.83 μmol), potassium phosphate (304.51 mg, 1.43 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (61.75 mg, 95.64 μmol) were added. The mixture was allowed to react at room temperature for 16 hours. LCMS indicated the reaction was complete. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and spin-dried. The product was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 47 (109.91 mg, yield: 37.95%).

[0534] LC-MS (ESI) [M+H] + 578.2.

[0535] 1 H NMR (400MHz, DMSO-d6) δ9.40(s,1H),8.72(s,1H),7.52(s,1H),7.48-7.43(m,2H),7.40(d,J=8.Hz,2H),6.73(s,1H),4.76(s,2H),4.36(q,J=7. 1Hz,2H),3.88(s,3H),2.29(s,3H),1.85(tt,J=8.3,4.6Hz,1H),1.33(t ,J=7.1Hz,3H),1.05(dq,J=6.2,3.5Hz,2H),0.87(dt,J=8.2,3.4Hz,2H).

[0536] Example 48: Synthesis of Compound 48

[0537] Step 1: Synthesis of compound 48

[0538] Compound 47 (0.045 g, 77.91 μmol) was dissolved in methanol (4 mL) / water (1 mL). Lithium hydroxide monohydrate (22.58 mg, 389.57 μmol) was added and the mixture was reacted at 50°C for 3 hours. The pH was adjusted to 5-6 with 1N hydrochloric acid. Liquid phase preparative purification afforded compound 48 (10.46 mg, 24.43% yield).

[0539] LC-MS (ESI) [M+H] + 550.2.

[0540] 1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.71(s,1H),7.46(s,1H),7.44-7.39(m,4H),6.73(s,1H), 4.78(s,2H),3.87(s,3H),2.28(s,3H),1.88-1.75(m,1H),1.13-1.00(m,2H),0.91-0.81(m,2H).

[0541] Example 49: Synthesis of Compound 49

[0542] Step 1: Synthesis of compound 49

[0543] Compound 47-5 (0.20 g, 478.19 μmol) was dissolved in toluene (5 mL) / water (1 mL). 1-Isopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)methyl)phenyl)-4-trifluoromethylimidazole (235.43 mg, 573.83 μmol), potassium phosphate (304.51 mg, 1.43 mmol), and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (61.75 mg, 95.64 μmol) were added. The mixture was allowed to react at room temperature for 16 hours. LCMS indicated the reaction was complete. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and spin-dried. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 49 (109.91 mg, yield: 37.95%).

[0544] LC-MS (ESI) [M+H] + 606.0.

[0545] 1 H NMR (400MHz, DMSO-d6) δ9.40(s,1H),8.72(s,1H),8.14(d,J=1.4Hz,1H),7.52(s,1H),7.47-7.41(m,2H),7.37(d,J=8.3Hz,2H),4.75(s,2H),4 .46-4.28(m,3H),3.88(s,3H),1.90-1.78(m,1H),1.37(d,J=6.6Hz,6H) ,1.33(t,J=7.1Hz,3H),1.06(dd,J=7.3,3.8Hz,2H),0.89-0.79(m,2H).

[0546] Example 50: Synthesis of Compound 50

[0547] Step 1: Synthesis of compound 50-2

[0548] Compound 50-1 (1.8 g, 5.88 mmol), 4,4,5,5-tetramethyl-2-[(4,4,5,-5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]-1,3,2-dioxaborolan (3.15 g, 11.76 mmol), bis(tri-tert-butylphosphine)palladium (300.51 mg, 588.08 μmol), and potassium hydroxide (659.89 mg, 11.76 mmol) were dissolved in water (2 mL) / dioxane (8 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at room temperature for 16 hours. LCMS analysis showed that the conversion of the starting material was complete. The reaction solution was directly mixed and passed through a column (petroleum ether:ethyl acetate = 5:1) to obtain compound 50-2 (1.2 g, yield: 84.60%, yellow solid).

[0549] LC-MS (ESI) [M+H] + 242.0.

[0550] Step 2: Synthesis of compound 50-3

[0551] Compound 50-2 (1.7 g, 7.05 mmol), N-bromosuccinimide (1.25 g, 7.05 mmol), and benzoyl peroxide (435.66 mg, 7.05 mmol) were dissolved in carbon tetrachloride (20 mL). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 16 hours. LCMS analysis showed that the conversion of the starting materials was complete. The reaction solution was directly mixed and filtered through a column (petroleum ether:ethyl acetate = 4:1) to obtain compound 50-3 (1 g, yield: 44.33%, yellow solid).

[0552] LC-MS (ESI) [M+H] + 319.8.

[0553] Step 3: Synthesis of compound 50-4

[0554] Compound 50-3 (500 mg, 1.562 mmol) and compound 2-3 (811 mg, 2.343 mmol) were dissolved in dioxane and water (20 mL / 2 mL), and dipinacol boronate (790 mg, 3.124 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (223 mg, 0.469 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (123 mg, 0.156 mmol) and potassium phosphate (993 mg, 4.686 mmol) were added. The argon atmosphere was replaced and the reaction was carried out at 100 ° C for 16 hours. LCMS detection showed that the reaction of the raw materials was complete to produce the target product. The reaction solution was concentrated and diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), and the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 50-4 (200 mg, yield: 25.3%, yellow solid).

[0555] LC-MS (ESI) [M+H] + 507.0.

[0556] Step 4: Synthesis of compound 50-5

[0557] Compound 50-4 (180 mg, 0.355 mmol) was dissolved in acetonitrile (10 mL) and N-bromosuccinimide (57 mg, 0.320 mmol) was added. The mixture was allowed to react overnight at room temperature. LCMS confirmed the complete reaction of the starting material to yield the desired product. The reaction solution was concentrated, diluted with water (10 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1 / 1) to afford compound 50-5 (155 mg, 74.5% yield, as a yellow solid).

[0558] LC-MS (ESI) [M+H] + 584.9 / 586.9.

[0559] Step 5: Synthesis of compound 50

[0560] Compound 50-5 (50 mg, 0.085 mmol) was dissolved in dioxane and water (10 mL / 1 mL), and [3,6-dimethoxy-2′,4′,6′-tri(1-methylethyl)[1,1′-biphenyl]-2-yl]bis(1,1-dimethylethyl)phosphine (8 mg, 0.017 mmol), tert-BuBrettPhos-Pd-G3, [(2-di-tert-butylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl) ... (2′-amino-1,1′-biphenyl)] palladium (II) methanesulfonate (7 mg, 0.008 mmol), sodium tert-butoxide (16 mg, 0.171 mmol) and methanol (1 mL) were added to replace argon and reacted at 100°C for 16 hours. The reaction was confirmed to be complete by LCMS. Water (10 mL) was added for dilution and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), and concentrated under reduced pressure to obtain compound 50 (7.97 mg, yield: 17.4%).

[0561] LC-MS (ESI) [M+H] + 536.9.

[0562] 1 H NMR(400MHz,MeOD-d4)δ8.88(s,1H),8.61(s,1H),7.72(d,J=8.3Hz,2H),7.52(d,J=8.3Hz,2H),6.64(s,1H), 4.46(s,2H),4.05(s,3H),4.00(s,3H),3.95(s,3H),1.90-1.81(m,1H),1.18-1.10(m,2H),0.96-0.88(m,2H).

[0563] Example 51: Synthesis of Compound 51

[0564] Step 1: Synthesis of compound 51-2

[0565] Compound 10-2 (470 mg, 0.93 mmol) was dissolved in acetonitrile (8 mL), and N-iodosuccinimide (210 mg, 0.93 mmol) and trifluoroacetic acid (530 mg, 0.53 mmol) were added. The reaction was stirred at room temperature for 30 minutes. LCMS confirmed the complete reaction of the starting material to produce the desired product. The reaction solution was concentrated and added to water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by normal column chromatography (petroleum ether / ethyl acetate = 1 / 1). After concentration, compound 51-2 (200 mg, yield: 34.07%) was obtained as a yellow solid.

[0566] LCMS (ESI) [M+H] + 631.7.

[0567] Step 2: Synthesis of compound 51-3

[0568] Compound 51-2 (150 mg, 0.238 mmol) was dissolved in toluene / acetone (4 / 2 mL) and sodium thiomethoxide (23 mg, 0.333 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.029 mmol), and tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol) were added. The argon atmosphere was replaced and the reaction was carried out at 90°C for 16 hours. LCMS analysis confirmed the complete reaction of the starting materials to produce the desired product. The reaction solution was concentrated and diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was purified by column chromatography (ethyl acetate / petroleum ether = 1:1) to afford compound 51-3 (130 mg, 99.2% yield, as a yellow solid).

[0569] LCMS (ESI) [M+H] + 551.9.

[0570] Step 3: Synthesis of compound 51

[0571] Compound 51-3 (60 mg, 0.108 mmol) was dissolved in ethanol (2 mL), and iodophenyl diacetic acid (420 mg, 1.305 mmol) was added. The mixture was reacted at 40°C for 16 hours. The reaction was confirmed to be complete by LCMS, and compound 51 (7 mg, yield: 11.3%) was prepared by liquid phase chromatography.

[0572] LCMS (ESI) [M+H] + 567.9.

[0573] 1H NMR (400MHz, DMSO-d6) δ9.58(s,1H),8.73(s,1H),7.92(s,1H),7.65(d,J=8.2Hz,2H),7.43(d,J=10.1Hz,3H),4.4 6(s,2H),3.88(s,4H),3.75(s,4H),3.03(s,3H),1.84(d,J=4.3Hz,1H),1.06(s,2H),0.88(dd,J=7.7,3.1Hz,2H).

[0574] Example 52: Synthesis of Compound 52

[0575] Step 1: Synthesis of compound 52-2

[0576] Compound 43-1 (1.0 g, 5.32 mmol) and iron acetylacetonate (331.89 mg, 939.75 μmol) were dissolved in tetrahydrofuran (30 mL) and stirred at 0°C for 0.5 hours. LCMS confirmed the formation of the product. The mixture was quenched with water, extracted with ethyl acetate (2 x 100 mL), washed with saturated ammonium chloride (2 x 100 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (95 / 5) afforded compound 52-2 (626 mg, 70.23% yield, as a yellow solid). The product was identified by two-dimensional nuclear magnetic resonance spectroscopy.

[0577] LCMS (ESI) [M+H] + 168.0.

[0578] 1 H NMR (400MHz, DMSO-d6) δ8.11-8.10(m,1H),7.21-7.20(m,1H),7.03-7.02(m,1H),2.68(s,3H).

[0579] Step 2: Synthesis of compound 52-3

[0580] Compound 52-2 (500 mg, 2.98 mmol), 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (823.82 mg, 2.98 mmol), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (278.05 mg, 596.68 μmol), (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium methanesulfonate (249.41 mg, 298.34 μmol), and potassium phosphate (1.26 g, 5.97 mmol) were dissolved in water (0.4 mL) / dioxane (8 mL). The reaction was stirred in a microwave at 80°C for 2 hours. LCMS confirmed the formation of the product. The sample was directly spin-dried and separated by column chromatography using petroleum ether / ethyl acetate = 3 / 1 to obtain compound 52-3 (520 mg, yield: 61.96%, yellow solid).

[0581] LCMS (ESI) [M+H] + 282.2.

[0582] Step 3: Synthesis of compound 52-4

[0583] Compound 52-3 (120 mg, 426.57 μmol) was dissolved in acetonitrile (10 mL). N-bromosuccinimide (75.92 mg, 426.57 μmol) was added at room temperature, and the reaction was stirred at room temperature for 16 hours. LCMS analysis indicated product formation. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (10 / 1) afforded compound 52-4 (80 mg, 52.06% yield, as a yellow solid).

[0584] LCMS (ESI) [M+H] + 359.6.

[0585] Step 4: Synthesis of compound 52

[0586] Compound 52-4 (80 mg, 222.09 μmol), 1-(1-methylethyl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]-4-trifluoromethylimidazole (87.56 mg, 222.09 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.25 mg, 22.21 μmol), and potassium phosphate (94.17 mg, 444.19 μmol) were dissolved in toluene (2 mL) / water (0.1 mL). The reaction was stirred in a microwave oven at 100°C for 2 hours. LCMS analysis confirmed the formation of the product. The sample was directly spin-dried and separated by column chromatography using petroleum ether / ethyl acetate = 3 / 1 to obtain the product. Liquid phase preparation (alkaline method) afforded compound 52 (8.9 mg, 7.32% yield).

[0587] LCMS (ESI) [M+H] + 548.2.

[0588] 1 H NMR (400MHz, DMSO-d6) δ8.69(s,1H),8.15(d,J=1.2Hz,1H),7.46(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.16(d,J=4.8Hz,1H),6.97(d,J=4 .4Hz,1H),4.44-4.40(m,3H),3.86(s,3H),2.69(s,3H),1.76-1.73(m ,1H),1.38(s,3H),1.37(s,3H),1.05-1.01(m,2H),0.87-0.83(m,2H).

[0589] Example 53: Synthesis of Compound 53

[0590] Step 1: Synthesis of compound 53

[0591] Compound 2 (15 mg, 28.11 μmol) was dissolved in tetrahydrofuran (5 mL). Sodium hydride (33.73 mg, 1.41 mmol) was added at room temperature. The reaction was stirred at room temperature for 1 hour. Iodomethane (199.61 mg, 1.41 mmol) was added and stirred at room temperature for 1 hour. LCMS analysis showed that starting material remained, but no product. The reaction was heated to 60°C and stirred for 7 hours. LCMS analysis showed that the product was formed. The product / starting material ratio was 2:1. Liquid phase preparation (alkaline method) gave compound 53 (2.06 mg, yield: 13.38%).

[0592] LCMS (ESI) [M+H] + 548.2.

[0593] 1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.68(s,1H),8.15(d,J=0.8Hz,1H),7.46(d,J=7.6Hz ,2H),7.38(d,J=8.0Hz,2H),7.18(d,J=4.8Hz,1H),7.12(d,J=4.4Hz,1H),4.84-4.82(m,1 H),4.44-4.40(m,1H),3.82(s,3H),1.75(d,J=7.2Hz,3H),1.71-1.67(m,1H),1.38(d,J=2 .8Hz,3H),1.37(d,J=3.2Hz,3H),1.00-0.97(m,2H),0.85-0.80(m,1H),0.76-0.74(m,1H).

[0594] Example 54: Synthesis of Compound 54

[0595] Step 1: Synthesis of compound 54-2

[0596] Compound 54-1 (10 g, 30.12 mmol) was dissolved in triethylamine (100 mL), followed by the addition of cuprous iodide (573 mg, 3.01 mmol) and bistriphenylphosphine palladium dichloride (633 mg, 0.903 mmol). The argon atmosphere was displaced, the temperature was raised to 80°C, and the mixture was stirred for 10 minutes. Trimethylsilylene (4.14 g, 42.16 mmol) was then added, and the mixture was stirred at 80°C for 16 hours. LCMS confirmed the reaction was complete. The reaction solution was concentrated and added to water (80 mL). Extraction was performed with ethyl acetate (100 mL x 3). The organic phases were combined, washed with water (100 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to afford the crude product of compound 54-2 (7.8 g, crude, yellow oil).

[0597] LCMS (ESI) [M+H] + 351.2.

[0598] Step 2: Synthesis of compound 54-3

[0599] At room temperature, compound 54-2 (3 g, 8.56 mmol) was dissolved in methanol (30 mL), potassium carbonate (2.37 g, 17.12 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered and concentrated, added to water (10 mL), and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated, and purified by forward flash column (petroleum ether / ethyl acetate = 10 / 1) to give compound 54-3 (1.76 g, yield: 74.0%, yellow oil).

[0600] LCMS (ESI) [M+H] + 279.1.

[0601] Step 3: Synthesis of compound 54-4

[0602] Compound 54-3 (500 mg, 1.796 mmol) was dissolved in chloroform (15 mL), and aqueous hydrobromic acid solution (3.02 g, 17.96 mmol, 48% aqueous solution) was added to replace argon. The mixture was stirred at 60°C for 4 hours. The reaction was confirmed to be complete by LCMS. Sodium hydroxide solution (2 mol / L) was added to the reaction solution under ice bath to adjust the pH to alkaline. Water (5 mL) was added thereto, and the mixture was extracted with dichloromethane (10 mL*3). The organic phases were combined, washed with water (5 mL), washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated, and purified by reverse flash column (ammonia / acetonitrile system) to obtain compound 5-4 (150 mg, yield: 23.33%, white solid).

[0603] LCMS (ESI) [M+H] + 359.0 / 361.0.

[0604] Step 4: Synthesis of compound 54-5

[0605] Compound 54-4 (36.47 mg, 0.101 mmol), compound 5-3 (38 mg, 0.101 mmol), bipinacol boronic acid ester (51.38 mg, 0.203 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (14.50 mg, 30.46 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (8.59 mg, 10.15 μmol), and potassium phosphate (43.05 mg, 0.203 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL) and the reaction was stirred in a microwave at 100°C for 16 hours. LCMS analysis showed the product was produced. The reaction mixture was quenched with water, extracted with ethyl acetate (2*50 mL), washed with water (2*50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 3 / 1 afforded compound 54-5 (30 mg, yield: 51.51%), as a yellow solid.

[0606] LCMS (ESI) [M+H] + 574.0.

[0607] Step 5: Synthesis of compound 54-6

[0608] Compound 54-5 (30 mg, 0.052 mmol) was dissolved in methanol (10 mL). Palladium on carbon (12.70 mg, 0.105 mmol) was added at room temperature and allowed to react for 0.5 h. LCMS analysis confirmed the formation of the product. Filtration afforded the crude product 54-6 (30 mg, 99.30% yield, yellow solid). This product was directly used in the next step without purification.

[0609] LCMS (ESI) [M+H] + 578.0.

[0610] Step 6: Synthesis of compound 54

[0611] Compound 54-6 (30 mg, 51.94 μmol) was dissolved in dichloromethane (10 mL). Manganese dioxide (63.08 mg, 519.35 μmol) was added at room temperature and stirred for 0.5 hours. LCMS analysis confirmed the formation of the product. The crude product was filtered and then purified by liquid chromatography to afford compound 54 (8.06 mg, 26.96% yield).

[0612] LCMS (ESI) [M+H] + 576.2.

[0613] 1H NMR (400MHz, DMSO-d6) δ9.23 (s, 1H), 8.64 (s, 1H), 8.15 (s, 1H), 7.46 (d, J = 8.4Hz, 2H), 7.3 7(d,J=8.4Hz,2H),7.16(d,J=4.8Hz,1H),7.12(d,J=4.8Hz,1H),5.34-5.27(m,1H),4.89- 4.82(m,1H),4.42(dd,J=13.3,6.6Hz,1H),1.74(d,J=7.2Hz,3H),1.67(t,J=3.9Hz,1H),1 .38(dd,J=6.6,1.4Hz,6H),1.13(dd,J=12.3,6.2Hz,6H),0.99(s,2H),0.86-0.71(m,2H).

[0614] Example 55: Synthesis of Compound 55

[0615] Step 1: Synthesis of compound 55-2

[0616] Compound 2-2 (580 mg, 2.17 mmol) was dissolved in trifluoroacetic acid (5 mL) / water (2 mL) and the reaction was stirred at 100°C for 72 hours. LCMS analysis confirmed the formation of the product. The crude product, compound 55-2 (500 mg, crude, brown oil), was obtained by spin drying.

[0617] LC-MS (ESI) [M+H] + 253.6.

[0618] Step 2: Synthesis of compound 55-3

[0619] Compound 55-2 (500 mg, 1.97 mmol) was dissolved in 1,4-dioxane (50 mL) at room temperature. Diethyl bromofluoromethylphosphonate (2.64 g, 9.87 mmol) and potassium hydroxide (1.11 g, 19.74 mmol) were added at room temperature. The reaction was stirred at 25°C for 72 hours. LCMS analysis confirmed the formation of the product. The reaction was stopped and filtered. The filtrate was then dried and the sample was separated by column chromatography using petroleum ether / ethyl acetate = 10 / 1 to obtain compound 55-3 (172 mg, yield: 28.73%) as a yellow solid.

[0620] LC-MS (ESI) [M+H] + 304.2.

[0621] Step 3: Synthesis of compound 55-4

[0622] Compound 55-3 (142 mg, 468.24 μmol) was dissolved in acetonitrile (10 mL). N-bromosuccinimide (83.84 mg, 468.24 μmol) was added at room temperature, and the reaction was stirred at room temperature for 20 minutes. LCMS analysis indicated product formation. The mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL), washed with water (2 x 50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate (10 / 1) afforded compound 55-4 (131 mg, 73.21% yield, as a yellow solid).

[0623] LCMS (ESI) [M+3H] + 382.0.

[0624] Step 4: Synthesis of compound 55-5

[0625] Compound 55-4 (131 mg, 0.342 mmol), compound 54-4 (246.25 mg, 685.57 mmol), pinacol diboronate (173.45 mg, 0.685 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (61.50 mg, 102.84 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II) (29.00 mg, 34.28 μmol), and potassium phosphate (145.34 mg, 0.685 mmol) were dissolved in 1,4-dioxane (10 mL) / water (1 mL) and the reaction was stirred in a microwave at 100°C for 16 hours. LCMS analysis indicated the product was formed. The reaction mixture was quenched with water, extracted with ethyl acetate (2*50 mL), washed with water (2*50 mL), and dried over anhydrous sodium sulfate. Column chromatography with petroleum ether / ethyl acetate = 3 / 1 afforded compound 55-5 (120 mg, yield: 60.20%), as a yellow oil.

[0626] LCMS (ESI) [M+H] + 582.2.

[0627] Step 5: Synthesis of compound 55-6

[0628] Compound 55-5 (120 mg, 0.206 mmol) was dissolved in methanol (10 mL). Palladium on carbon (50.12 mg, 0.412 mmol) was added at room temperature and allowed to react for 0.5 h. LCMS analysis confirmed the formation of the product. Filtration afforded the crude product, compound 55-6 (120 mg, 99.31% yield, as a yellow solid). This product was carried on to the next step without purification.

[0629] LCMS (ESI) [M+H]+ 586.2.

[0630] Step 6: Synthesis of compound 55

[0631] Compound 55-6 (120 mg, 204.93 μmol) was dissolved in dichloromethane (10 mL). Manganese dioxide (248.89 mg, 2.05 mmol) was added at room temperature and stirred for 0.5 hours. LCMS analysis revealed product formation. The crude product was filtered and then purified by liquid chromatography to yield compound 55 (37.83 mg, 31.63% yield).

[0632] LCMS (ESI) [M+H] + 584.2.

[0633] 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 8.30 (s, 1H), 8.16 (d, J = 1.2Hz, 1H), 7.99- 7.63(s,1H),7.47-7.40(m,2H),7.23(d,J=4.8Hz,1H),7.18(d,J=4.4Hz,1H),4 .86-4.83(m,1H),4.44-4.40(m,1H),1.87-1.83(m,1H),1.76(d,J=7.2Hz,3H), 1.38(d,J=6.8Hz,6H),1.08-1.07(m,2H),0.96-0.91(m,1H),0.88-0.84(m,1H).

[0634] Example 56: Synthesis of Compound 56

[0635] Step 1: Synthesis of compound 56-2

[0636] Compound 55-1 (10 g, 37.01 mmol) was added to N,N-dimethylformamide (100 mL), and bromocyclobutane (15 g, 111 mmol) and cesium carbonate (36 g, 111 mmol) were added. The reaction solution was stirred at 100°C overnight. LCMS showed that the reaction was complete. The reaction solution was added to water (500 mL) and extracted with ethyl acetate (200 mL*3). The organic phases were combined and washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The organic phase was concentrated (petroleum ether:ethyl acetate = 0-20%) to give compound 56-2 (7.5 g, yield: 64%, yellow solid).

[0637] LC-MS (ESI) [M+H] + 325.0.

[0638] Step 2: Synthesis of compound 56-3

[0639] Compound 56-2 (7.5 g, 23 mmol) was dissolved in tetrahydrofuran (75 mL) at room temperature, and diisobutylaluminum hydride (70 mL, 1.5 M solution in toluene) was slowly added dropwise under ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly quenched by adding saturated aqueous ammonium chloride (500 mL), filtered, and the filtrate was extracted with ethyl acetate (3*200 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound 56-3 (5 g, yield: 73%, yellow oil).

[0640] LC-MS (ESI) [M+H] + 297.1.

[0641] Step 3: Synthesis of compound 56-4

[0642] Boron tribromide (2.74 g, 10.14 mmol) was added to a solution of compound 56-3 (1 g, 3.38 mmol) in tetrahydrofuran (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 3 hours. Sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by normal phase column chromatography (petroleum ether:ethyl acetate = 20%) to afford compound 56-4 (1 g, yield: 82%) as a white solid.

[0643] LCMS (ESI) [M+H] + 358.8.

[0644] Step 4: Synthesis of compound 56-5

[0645] Compound 56-4 (1 g, 2.78 mmol), potassium acetate (820 mg, 8.35 mmol), pinacol diboron (850 mg, 3.34 mmol), and bistriphenylphosphine palladium dichloride (195 mg, 0.28 mmol) were added to 1,4-dioxane (50 mL). The reaction mixture was stirred at 80°C under nitrogen for 2 hours. The reaction mixture was concentrated and purified by normal phase column chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound 56-5 (910 mg, 80% yield, as a white solid).

[0646] LCMS (ESI) [M+H] + 407.0.

[0647] Step 5: Synthesis of compound 56-6

[0648] Compound 56-5 (281.64 mg, 693.28 μmol) and compound 2-3 (200 mg, 577.73 μmol) were dissolved in a mixture of toluene (5 mL) and water (1 mL). Potassium phosphate (245.26 mg, 1.16 mmol) and 1,1'-bis(diphenylphosphinoferrocenedichloropalladium) (37.30 mg, 51.41 μmol) were then added. The atmosphere was purged with nitrogen three times and microwaved at 100°C for 3 hours. The mixture was then purified directly on silica gel (petroleum ether:ethyl acetate = 0-80%) to afford compound 56-6 (210 mg, 66.63% yield, as a yellow solid).

[0649] LCMS (ESI) [M+H] + 546.3.

[0650] Step 6: Synthesis of compound 56-7

[0651] Compound 56-6 (190 mg, 348.27 μmol) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of N-bromosuccinimide (74.38 mg, 417.92 μmol) and trifluoroacetic acid (3.97 mg, 34.83 μmol). The mixture was reacted at 30°C for 1 hour. The mixture was extracted three times with water (100 mL) and dichloromethane (60 mL). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was then purified on silica gel (petroleum ether:ethyl acetate = 0-90%) to afford compound 56-7 (170 mg, 78.17% yield, as a yellow solid).

[0652] LCMS (ESI) [M+H] + 624.3.

[0653] Step 7: Synthesis of compound 56

[0654] Compound 56-7 (170 mg, 0.272 mmol) was added to an autoclave containing methanol and acetonitrile (10 / 10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (40.8 mg, 0.0545 mmol) and triethylamine (82 mL, 0.816 mmol) were also added. The autoclave was filled with carbon monoxide to 2 standard atmospheres and stirred at 100°C for 48 hours. LCMS indicated the reaction was complete. The reaction solution was directly dried by spin drying. The crude product was purified by a forward column (petroleum ether:ethyl acetate = 0-40%) to obtain the crude product, which was then purified by liquid phase chromatography to obtain compound 56 (22.28 mg, 31.83% yield).

[0655] LCMS (ESI) [M+H] + 604.4.

[0656] 1 H NMR(400MHz,DMSO-d6)δ9.65(s,1H),8.74(s,1H),8.29(s,1H),7.50-7.41(m,5H),4.79-4.67(m,1H),4.46(s,2H),3.9 0(s,3H),3.88(s,3H),2.44-2.32(m,4H),1.89-1.81(m,1H),1.78-1.60(m,2H),1.11-1.03(m,2H),0.90-0.82(m,2H).

[0657] Example 57: Synthesis of Compound 57

[0658] Step 1: Synthesis of Compound 57-2

[0659] Compound 57-1 (10 g, 48.1 mmol) and 1-cyclopropyl-4,4,4-trifluorobutane-1,3-dione (13.0 g, 72.2 mmol) were added to hexafluoroisopropanol (65 mL), and a solution of triethylamine (10 g, 96.2 mmol) in hexafluoroisopropanol (40 mL) was slowly added dropwise under an ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly added to ice water (300 mL) and extracted with ethyl acetate (3*100 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product compound 57-2 (15 g, crude product, yellow oil).

[0660] LCMS (ESI) [M+H] + 311.1.

[0661] Step 2: Synthesis of Compound 57-3

[0662] Compound 57-2 (15 g, 48.3 mmol) was dissolved in tetrahydrofuran (65 mL), and diisobutylaluminum hydride (130 mL, 1.5 M toluene solution) was slowly added dropwise under ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly quenched by adding saturated aqueous ammonium chloride (500 mL), filtered, and the filtrate was extracted with ethyl acetate (3*200 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound 57-3 (10 g, yield: 79%, yellow oil).

[0663] LCMS (ESI) [M+H] + 283.2.

[0664] Step 3: Synthesis of Compound 57-4

[0665] Compound 57-3 (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (15 mL) in a three-necked flask. The atmosphere was replaced with nitrogen, and phosphorus tribromide (1439 mg, 5.32 mmol) was added dropwise. The reaction was allowed to react at room temperature for 16 hours, leading to completion. The mixture was quenched with saturated sodium carbonate solution and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed, and the solvent was concentrated. The residue was isolated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 0-1%) to afford compound 57-4 (0.5 g, 82.1% yield, as a yellow solid).

[0666] LCMS (ESI) [M+H] + 345.0 / 347.0.

[0667] Step 4: Synthesis of Compound 57

[0668] Compound 57-4 (480 mg, 1.4 mmol) was dissolved in a mixed solution of dioxane / water (24 / 2.4 mL), and compound 2-3 (482.88 mg, 1.4 mmol), pinacol diboron (706.56 mg, 2.8 mmol), potassium phosphate (894.72 mg, 4.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (63.2 mg, 0.14 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (106.56 mg, 0.14 mmol) were added, and the reaction was carried out at 100 ° C under argon protection for 16 hours. After completion of the reaction, water was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL*3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica, petroleum ether / ethyl acetate = 0% to 50%) to obtain compound 57 (100 mg, yield: 13.4%).

[0669] LCMS (ESI) [M+H] + 532.4.

[0670] 1H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.70(s,1H),7.56(d,J=8.4Hz,2H),7.45(d,J=8.5Hz,2H),7.11(d,J=4.6Hz,1H),7.05(d,J=4.5Hz,1 H),6.61(s,1H),4.46(s,2H),3.87(s,3H),1.83-1.74(m,2H),1.07-.02(m,2H),0.97-0.91(m,2H),0.89-0.84(m,2H),0.83-0.78(m,2H).

[0671] Example 58: Synthesis of Compound 58

[0672] Step 1: Synthesis of Compound 58-2

[0673] Compound 58-1 (10 g, 48.1 mmol) and 1,1,1-trifluorohexane-2,4-dione (12.1 g, 72.2 mmol) were added to hexafluoroisopropanol (65 mL), and a solution of triethylamine (10 g, 96.2 mmol) in hexafluoroisopropanol (40 mL) was slowly added dropwise under an ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly added to ice water (300 mL) and extracted with ethyl acetate (3*100 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product compound 58-2 (15 g, crude product, yellow oil).

[0674] LCMS (ESI) [M+H] + 299.0.

[0675] Step 2: Synthesis of compound 58-3

[0676] Compound 58-2 (14 g, 47.0 mmol) was dissolved in tetrahydrofuran (65 mL), and diisobutylaluminum hydride (125 mL, 1.5 M toluene solution) was slowly added dropwise under ice bath. The reaction solution was stirred at room temperature overnight. LCMS showed that the reaction was complete. The reaction solution was slowly quenched by adding saturated aqueous ammonium chloride solution (500 mL), filtered, and the filtrate was extracted with ethyl acetate (3*200 mL). The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to obtain compound 58-3 (10 g, yield: 79%, yellow oil).

[0677] LCMS (ESI) [M+H] + 271.1.

[0678] Step 3: Synthesis of compound 58-4

[0679] Compound 58-3 (600 mg, 2.22 mmol) was dissolved in ultra-dry tetrahydrofuran (8 mL), the atmosphere was replaced with argon, and the mixture was cooled to 0°C in an ice bath. Phosphorus tribromide (1.8 g, 6.67 mmol) was added dropwise, and the mixture was naturally warmed to room temperature and stirred for 16 hours. LCMS confirmed the reaction was complete. Water (15 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL), saturated sodium carbonate solution (20 mL), and saturated brine (10 mL), dried over anhydrous sodium sulfate, and purified by forward flash column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound 58-4 (380 mg, yield: 51.56%) as a yellow solid.

[0680] LCMS (ESI) [M+H] + 333.0 / 335.0.

[0681] Step 4: Synthesis of Compound 58

[0682] Compound 58-4 (250 mg, 0.75 mmol), compound 2-3 (260 mg, 0.75 mmol), bis(boronic acid) pinacol ester (380 mg, 1.5 mmol), potassium phosphate (475 mg, 2.25 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (10 mg, 0.075 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15 mg, 0.075 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL) and stirred at 100 ° C for 16 hours under argon protection. The reaction was confirmed to be complete by LCMS. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 58 (22.6 mg, yield: 5.81%).

[0683] LCMS (ESI) [M+H] + 520.4.

[0684] 1H NMR (400MHz, DMSO-d6) δ9.24(s,1H),8.70(s,1H),7.49-7.39(m,4H),7.11(d,J=4.5Hz,1H),7.05(d,J=4.6Hz,1H),6.77(s,1H), 4.46(s,2H),3.87(s,3H),2.62(q,J=7.5Hz,2H),1.83-1.74(m,1H),1.13(t,J=7.5Hz,3H),1.08-1.02(m,2H),0.91-0.81(m,2H).

[0685] Example 59: Synthesis of Compound 59

[0686] Step 1: Synthesis of Compound 59-2

[0687] Compound 59-1 (100 mg, 0.52 mmol), tributylstannane (170 mg, 0.52 mmol), cuprous iodide (20 mg, 0.10 mmol), bistriphenylphosphine palladium dichloride (73 mg, 0.10 mmol), and triethylamine (100 mg, 0.52 mmol) were added to tetrahydrofuran (1 mL) and stirred at 70°C for 16 hours. Saturated potassium fluoride solution was added to the reaction solution, and after stirring for 1 hour, the solution was filtered through celite and extracted with ethyl acetate. The organic phase was concentrated and then purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100% / 0 to 80 / 20%) to afford compound 59-2 (20 mg, 77% yield, as a yellow solid).

[0688] LCMS (ESI) [M+H] + 153.0.

[0689] Step 2: Synthesis of Compound 59-3

[0690] Compound 59-2 (6 g, 39.33 mmol) was added to N,N-dimethylformamide (60 mL). Triethylamine (31.7 g, 313.73 mmol) and cuprous iodide (7.5 g, 39.22 mmol) were added to the reaction mixture. The reaction mixture was stirred at 130°C under nitrogen for 16 hours. Ethyl acetate was added to the reaction mixture, filtered, and washed three times with water. The organic phase was dried over anhydrous sodium sulfate and concentrated. The product was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100% / 0 to 80 / 20%) to afford compound 59-3 (900 mg, 15% yield, as a yellow solid).

[0691] LCMS (ESI) [M+H] + 153.0.

[0692] Step 3: Synthesis of Compound 59-4

[0693] Compound 59-3 (700 mg, 4.58 mmol), 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (1.1 g, 5.49 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium (II) (387 mg, 0.46 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (218 mg, 0.46 mmol), potassium phosphate (2.9 g, 13.73 mmol) were dissolved in water (0.7 mL) / 1,4-dioxane (7 mL) and stirred at 100°C for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was purified by normal phase column chromatography (petroleum ether:ethyl acetate = 100% / 0 to 70 / 30%) to give compound 59-4 (90 mg, yield: 40%, yellow solid).

[0694] LCMS (ESI) [M+H] + 266.9.

[0695] Step 4: Synthesis of Compound 59-5

[0696] Compound 59-4 (20 mg, 0.08 mmol) and N-bromosuccinimide (13 mg, 0.08 mmol) were added to N,N-dimethylformamide (0.5 mL). After stirring at room temperature for 1 hour, sodium sulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated and washed three times with water. After concentration, compound 59-5 (20 mg, yield: 77%) was obtained by normal phase column chromatography.

[0697] LCMS (ESI) [M+3H] + 347.0.

[0698] Step 5: Synthesis of Compound 59

[0699] Compound 59-5 (20 mg, 0.06 mmol), 2-(4-bromomethyl)phenyl-1-isopropyl-4-trifluoromethyl-1H-imidazole (24 mg, 0.07 mmol), bis(boronic acid)pinacol ester (29 mg, 0.12 mmol), potassium phosphate (86 mg, 0.40 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (7 mg, 0.01 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (11 mg, 0.01 mmol) were dissolved in 1,4-dioxane / water (0.5 mL / 0.05 mL) and stirred at 100 °C for 16 hours under argon protection. The reaction was confirmed to be complete by LCMS. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic phases were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 59 (5 mg, yield: 15%).

[0700] LCMS (ESI) [M+H] + 533.2.

[0701] 1 H NMR (400MHz, DMSO-d6) δ8.92(d,J=1.4Hz,1H),8.62(s,1H),8.27(s,1H),8.16(d,J=1.1Hz,1H),7.50(d,J=8.2Hz,2H),7.40(d,J=8.2Hz,2H ),6.92(q,J=4.2Hz,2H),4.42(s,3H),3.79(s,3H),1.94-.83(m,1H),1.38(d,J=6.6Hz,6H),1.03-0.91(m,2H),0.83(dd,J=8.0,3.1Hz,2H).

[0702] Example 60: Synthesis of Compound 60

[0703] Step 1: Synthesis of Compound 60-2

[0704] Compound 54-4 (180 mg, 0.50 mmol) was added to 1,4-dioxane / water (10 / 1 mL), and compound 2-3 (172 mg, 0.55 mmol), bipinacol boronate (46 mg, 1 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47 mg, 0.1 mmol), potassium phosphate (318 mg, 1.5 mmol) and methanesulfonic acid (2-dicyclohexylphosphino-2',4',6' -tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (42 mg, 0.05 mmol), nitrogen was replaced, and the reaction solution was stirred at 100°C for 16 hours. LCMS showed that the reaction was complete. Water and ethyl acetate were added to the reaction solution for extraction. The organic phase was dried and passed through a column (petroleum ether / ethyl acetate = 100% / 0% to 40% / 60%) to obtain compound 60-2 (100 mg, yield: 36.58%, yellow solid).

[0705] LCMS (ESI) [M+H] + 208.0.

[0706] Step 2: Synthesis of Compound 60-3

[0707] Compound 60-2 (100 mg, 0.02 mol) was added to tetrahydrofuran / water (2 ml / 0.5 mL), potassium osmate (0.02 g, 0.002 mmol) was added, and sodium periodate (238 mg, 0.08 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with water and ethyl acetate. The organic phase was dried and purified by column chromatography with petroleum ether / ethyl acetate = 1 / 1 to obtain compound 60-3 (0.06 g, yield: 59.78%), as a white solid.

[0708] LCMS (ESI) [M+H] + 548.0.

[0709] Step 3: Synthesis of Compound 60

[0710] Compound 60-3 (60 mg, 0.10 mol) was added to [bis(2-methoxyethyl)amine]sulfur trifluoride (3 mL), and the reaction solution was stirred at 70° C. for 16 hours. LCMS showed that the reaction was complete. The reaction solution was extracted with sodium bicarbonate and ethyl acetate, and the organic phase was dried to obtain compound 60 (3.49 mg, yield: 5.73%).

[0711] LCMS (ESI) [M+H] + 570.0.

[0712] 1H NMR (400MHz, MeOD-d4) δ9.27(s,1H),8.60(s,1H),7.94(s,1H),7.75(d,J=8.2Hz,2H),7.65(d,J=8.2Hz,2H),7.38(d,J=4.8Hz,1H),7.19(d,J=4 .6Hz,1H),4.53(dt,J=13.4,6.7Hz,1H),3.88(s,3H),1.75-1.64(m,1H),1.45(d,J=6.6Hz,6H),1.11-1.06(m,2H),0.83(dd,J=7.8,3.1Hz,2H).

[0713] Example 61: Synthesis of Compound 61

[0714] Step 1: Synthesis of Intermediate 61-9

[0715] Compound 61-8 (3 g, 14 mmol) was added to tetrahydrofuran (20 mL), and n-butyllithium (1.8 g, 17.5 mmol) was slowly added dropwise at -78°C. The reaction solution was stirred at -78°C for 30 minutes, and hexachloroethane (3.7 g, 28 mmol) was added. The temperature was slowly raised to room temperature and stirred overnight. The reaction solution was slowly added to saturated aqueous ammonium chloride solution (150 mL), and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column with petroleum ether / ethyl acetate = 3 / 1 to obtain intermediate 61-9 (0.7 g, yield: 19.55%, colorless liquid).

[0716] LCMS (ESI) [M+H] + 213.0.

[0717] Step 2: Synthesis of compound 61-2

[0718] Compound 61-1 (1 g, 7.69 mmol) and 2-bromomalondialdehyde (1.2 g, 7.69 mmol) were dissolved in isopropanol (10 mL) and dimethyl sulfoxide (5 mL). The reaction mixture was stirred at 100°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (ethyl acetate / petroleum ether = 0% / 100 to 20% / 80%) to obtain compound 61-2 (390 mg, yield: 29%), as a yellow solid.

[0719] LCMS (ESI) [M+H] + 182.0.

[0720] Step 3: Synthesis of compound 61-3

[0721] Compound 61-2 (370 mg, 2.03 mmol) was added to tetrahydrofuran (4 mL), and p-methoxyphenylmagnesium bromide (457 mg, 2.03 mmol) was slowly added dropwise under ice bath. The reaction solution was stirred at room temperature for 1 hour. Saturated ammonium chloride was slowly added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (ethyl acetate / petroleum ether = 0% / 100 to 50% / 50%) to obtain compound 61-3 (190 mg, yield: 32%, yellow oil).

[0722] LCMS (ESI) [M+H] + 289.9.

[0723] Step 4: Synthesis of compound 61-4

[0724] Compound 61-3 (510 mg, 1.76 mmol) was dissolved in dichloromethane (10 mL), and triethylsilyl hydrochloride (408 mg, 3.52 mmol) was added to the reaction solution. The reaction solution was stirred at 0°C for 10 minutes, and trifluoroacetic acid (1.2 g, 10.55 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, quenched with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, and the combined solution was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (ethyl acetate / petroleum ether = 0% / 100 to 30% / 70%) to obtain compound 61-4 (224 mg, 46% yield, as a white solid).

[0725] LCMS (ESI) [M+H] + 273.9.

[0726] Step 5: Synthesis of Compound 61-5

[0727] Compound 61-4 (430 mg, 1.57 mmol) was added to dichloromethane (20 mL), and boron tribromide (3.14 mL, 3.14 mmol) was slowly added under ice bath. The reaction solution was stirred at room temperature for 16 hours. Methanol was slowly added to the reaction solution to quench the reaction. After quenching, the solution was directly concentrated, dichloromethane was added, and the solution was filtered to obtain compound 61-5 (337 mg, yield: 82%, yellow solid).

[0728] LCMS (ESI) [M+H] + 259.9.

[0729] Step 6: Synthesis of Compound 61-6

[0730] Compound 61-5 (510 mg, 1.96 mmol), 4-cyclopropyl-6-methoxypyrimidine-5-boronic acid (457 mg, 2.35 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium (II) (166 mg, 0.2 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (94 mg, 0 .2mmol), potassium phosphate (1.2g, 5.9mmol) was dissolved in water (0.5mL) / 1,4-dioxane (5mL), and the reaction solution was stirred at 80°C for 16 hours. The reaction solution was added to water and extracted with ethyl acetate. The organic phases were combined and washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column (ethyl acetate / petroleum ether = 0% / 100 to 100% / 0%) to give compound 61-6 (530mg, yield: 72%, yellow oil).

[0731] LCMS (ESI) [M+H] + 374.0.

[0732] Step 7: Synthesis of Compound 61-7

[0733] Compound 61-6 (530 mg, 1.42 mmol) was added to dichloromethane (6 mL), and pyridine (561 mg, 7.10 mmol) and trifluoromethanesulfonic anhydride (601 mg, 2.13 mmol) were added under ice-cooling. The reaction solution was stirred at room temperature for 16 hours, then added to water (150 mL), extracted with dichloromethane, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on a silica gel column (ethyl acetate / petroleum ether = 0% / 100 to 50% / 50%) to obtain compound 61-7 (510 mg, yield: 71%), as a yellow-brown solid.

[0734] LCMS (ESI) [M+H] + 505.9.

[0735] Step 8: Synthesis of Compound 61

[0736] Compound 61-7 (270 mg, 0.53 mmol) was added to 1,4-dioxane (5 mL), and dipinacol boronate (173 mg, 1.07 mmol), 61-9 (114 mg, 0.53 mmol), potassium phosphate (340 mg, 1.60 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (26 mg, 0.05 mmol), and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (42 mg, 0.05 mmol) were dissolved in dioxane (5 mL). The reaction solution was stirred at 100° C. for 16 hours, added to water, extracted with ethyl acetate, and the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by liquid phase preparative method to obtain compound 61 (96.91 mg, yield: 34%).

[0737] LCMS (ESI) [M+H] + 534.3.

[0738] 1 H NMR (400MHz, MeOD-d4) δ9.34(s,1H),8.71(s,1H),8.63(s,1H),7.98(s,1H),7.94(s,1H),7.56(d,J=8.2Hz,2H),7.51(d,J=8.2Hz ,2H),4.60-4.44(m,3H),3.88(s,3H),1.84(dt,J=12.8,4.1Hz,1H),1.45(d,J=6.7Hz,6H),1.19-1.08(m,2H),0.97-0.85(m,2H).

[0739] Example 62: Synthesis of Compound 62

[0740] Step 1: Synthesis of Intermediate 62-2

[0741] Compound 62-1 (2.0 g, 7.24 mmol) was dissolved in 1,4-dioxane (100 mL) / water (20 mL). Compound 61-9 (1.69 g, 7.97 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (1.06 g, 1.45 mmol), and potassium phosphate (4.61 g, 21.73 mmol) were added. The nitrogen atmosphere was replaced three times and the reaction was carried out at 80°C for 16 hours. Water (20 mL) was added and the mixture was washed with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and dried by spin drying. Purification by column chromatography with ethyl acetate / petroleum ether = 1 / 3 to obtain compound 62-2 (1 g, yield: 42.31%) as a light yellow oily liquid.

[0742] LC-MS (ESI) [M+H] + 327.2.

[0743] Step 2: Synthesis of Compound 62-3

[0744] Compound 62-2 (1.0 g, 3.06 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to -60°C, and lithium hexamethyldisilazane (1 M, 10.00 mmol, 10.00 mL) and N-fluorobisbenzenesulfonamide (2.90 g, 9.19 mmol) were added. The reaction was allowed to react at -60°C for 2 hours. LCMS indicated completion of the reaction. Hydrolysis was predominantly observed. The reaction was quenched by adding methanol (10 mL). The product was then spin-dried and purified by reverse phase chromatography using acetonitrile / water / formic acid (60 / 40 / 0.03) to afford compound 62-3 (0.18 g, 16.21% yield, as a pale yellow oil).

[0745] LCMS (ESI) [M+H] + 363.0.

[0746] Step 3: Synthesis of Compound 62-4

[0747] Compound 62-3 (0.18 g, 496.83 μmol) was dissolved in methanol (5 mL) / water (1 mL), and lithium hydroxide monohydrate (41.70 mg, 993.67 μmol) was added. The mixture was reacted at 50°C for 16 hours. Formic acid was added to adjust the pH to 4, and the mixture was directly spin-dried. The mixture was then purified by reverse phase chromatography using acetonitrile / water / formic acid (60 / 40 / 0.03) to afford compound 62-4 (0.14 g, 80.91% yield, as a pale yellow solid).

[0748] LCMS (ESI) [M+H] + 349.0.

[0749] Step 4: Synthesis of Compound 62-5

[0750] Compound 62-4 (270.72 mg, 777.33 μmol), compound 24-8 (0.2 g, 777.33 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (591.13 mg, 1.55 mmol), and N,N-diisopropylethylamine (200.93 mg, 1.55 mmol, 270.79 μL) were dissolved in dichloromethane (10 mL) and reacted at 25°C for 12 hours. The reaction solution was directly separated and purified by column chromatography (silica gel, ethyl acetate / petroleum ether = 0-80%) to obtain compound 62-5 (0.2 g, yield: 43.79%), as a yellow solid.

[0751] LCMS (ESI) [M+H] + 587.8.

[0752] Step 5: Synthesis of Compound 62

[0753] Compound 62-5 (0.07 g, 119.14 μmol) and phosphorus pentoxide (50.73 mg, 357.42 μmol) were dissolved in phosphorus oxychloride (5 mL) and reacted at 115°C for 5 hours. After cooling to room temperature, the reaction mixture was adjusted to an alkaline pH with saturated sodium bicarbonate and extracted with ethyl acetate (20 mL x 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 afford the crude product. Liquid phase preparation afforded compound 62 (8.33 mg, 12.28% yield).

[0754] LCMS (ESI) [M+H] + 570.2.

[0755] 1 H NMR (400MHz, DMSO-d6) δ9.39(d,J=1.6Hz,1H),8.68(s,1H),8.59(s,1H),8.26(d,J=1.5Hz,1H),8.02(d,J=0.9Hz,1H),7.84(d ,J=8.4Hz,2H),7.78(d,J=8.3Hz,2H),4.54(m,1H),3.87(s,3H),1.94(m,1H),1.44(d,J=6.7Hz,7H),1.07(m,2H),0.91(m,2H).

[0756] Example 63: Synthesis of Compound 63

[0757] Step 1: Synthesis of Compound 63-2

[0758] Compound 63-1 (500 mg, 2.87 mmol) and 4-cyclopropyl-6-methoxy-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyrimidine (793.56 mg, 2.87 mmol) were dissolved in a mixed solvent of water (2 mL) and dioxane (10 mL). Sodium carbonate (597.97 mg, 5.75 mmol) and 1,1'-bis(diphenylphosphinoferrocenepalladium) dichloride (208.54 mg, 287.38 μmol) were then added. The atmosphere was purged with nitrogen three times and the reaction was continued at 80°C for 4 hours. Ethyl acetate (30 mL) was added, and the mixture was dried over water (30 mL x 3) and anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on silica gel (petroleum ether:ethyl acetate = 0-50%) to afford compound 63-2 (600 mg, yield: 72.57 g, as a white solid).

[0759] LCMS (ESI) [M+H] + 287.6.

[0760] Step 2: Synthesis of compound 63-3

[0761] Compound 63-2 (400 mg, 1.39 mmol) was dissolved in THF (10 mL) and cooled to 0°C. Methylmagnesium bromide (497.36 mg, 4.17 mmol) and ferric triacetylacetonate (196.41 mg, 556.13 μmol) were then added and allowed to react at 0°C for 3 hours. The reaction was quenched with water, and ethyl acetate (30 mL) was added. The mixture was washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on silica gel (petroleum ether:ethyl acetate = 0-15%) to afford compound 63-3 (290 mg, yield: 78.04%) as a yellow solid.

[0762] LCMS (ESI) [M+H] + 268.2.

[0763] Step 3: Synthesis of compound 63-4

[0764] Compound 63-3 (290 mg, 1.08 mmol) was dissolved in isopropanol (8 mL), and Raney nickel (63.68 mg, 1.08 mmol) was added. The hydrogen atmosphere was replaced three times and the mixture was reacted at 25°C for 20 hours. The mixture was filtered and the filtrate was dried to give compound 63-4 (290 mg, crude product, green oil).

[0765] LCMS (ESI) [M+H] + 271.8.

[0766] Step 4: Synthesis of Compound 63-5

[0767] Compound 63-4 (333.79 mg, 1.07 mmol) was dissolved in dichloromethane (10 mL), followed by the addition of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (483.90 mg, 1.28 mmol) and triethylamine (270.39 mg, 2.67 mmol). The mixture was allowed to react at 25°C for 30 minutes, followed by the addition of compound 24-8 (290 mg, 1.07 mmol), and then at 25°C for 4 hours. The reaction was quenched with water, and the mixture was washed with dichloromethane (30 mL) and water (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified on silica gel (petroleum ether:ethyl acetate = 0-100%) to afford compound 63-5 (210 mg, yield: 34.74%) as a brown solid.

[0768] LCMS (ESI) [M+H] + 566.0.

[0769] Step 5: Synthesis of Compound 63

[0770] Compound 63-5 (100 mg, 176.81 μmol) was dissolved in phosphorus oxychloride (5 mL) and reacted at 100°C for 4 hours. After cooling to room temperature, water was slowly added to quench the reaction. The pH was then adjusted to approximately 7 with saturated aqueous sodium carbonate. Ethyl acetate (30 mL) was then added, followed by washing with water (40 mL x 3), drying over anhydrous sodium sulfate, filtering, and the filtrate was concentrated under reduced pressure and dried directly to liquid phase to afford compound 63 (21.25 mg, 21.95% yield).

[0771] LCMS (ESI) [M+H] + 548.2.

[0772] 1 H NMR (400MHz, DMSO-d6) δ8.65(s,1H),8.38(s,1H),8.16(s,1H),7.91(s,1H),7.50(d,J=8.0Hz,2H),7.43(d,J=8.0Hz,2H),4.54(s, 2H),4.49-4.34(m,1H),3.82(s,3H),2.65(s,3H),1.94-1.82(m,1H),1.38(d,J=8.0Hz,6H),1.06-1.00(m,2H),0.91-0.81(m,2H).

[0773] Example 64: Synthesis of Compound 64

[0774] Step 1: Synthesis of Compound 64-2

[0775] Compound 24 (60.00 mg, 112.46 μmol) and manganese dioxide (97.76 mg, 1.12 mmol) were added to 1,2-dichloroethane (5 mL), and the reaction mixture was stirred at 25°C for 12 hours. The reaction mixture was filtered and dried to give compound 64-2 (45 mg, yield: 73.08%) as a colorless oil.

[0776] LCMS (ESI) [M+H] + 274.6.

[0777] Step 2: Synthesis of Compound 64

[0778] Sodium borohydride (4.84 mg, 127.85 μmol) was added to a mixture of compound 64-2 (35 mg, 63.92 μmol) in tetrahydrofuran (5 mL) at -40°C. The reaction mixture was stirred at -40°C for 0.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were spin-dried and subjected to liquid phase preparation (acid method) to afford compound 64 (8.24 mg, 23.46% yield).

[0779] LCMS (ESI) [M+H] + 550.2.

[0780] 1 H NMR(400MHz,DMSO-d6)δ9.18(d,J=1.6Hz,1H),8.66(s,1H),8.44(t,J=1.2Hz,1 H),8.18(d,J=1.4Hz,1H),7.86(s,1H),7.58(q,J=8.3Hz,4H),6.69(d,J=4.9Hz ,1H),6.41(d,J=4.5Hz,1H),4.47(p,J=6.6Hz,1H),3.84(s,3H),1.89(tt,J=8. 3,4.6Hz,1H),1.40(d,J=6.6Hz,6H),1.04(d,J=4.8Hz,2H),0.95-0.80(m,2H).

[0781] Example 65: Synthesis of Compound 65

[0782] Step 1: Synthesis of Compound 65-2

[0783] Compound 65-1 (250.00 mg, 1.36 mmol), (4,6-diethoxypyrimidin-5-yl)boric acid (460.91 mg, 2.17 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium (II) (170.59 mg, 203.81 μmol), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (189.95 m, 407.62 μmol) were added to 1,4-dioxane (10 mL) / water (2 mL), and the reaction mixture was stirred at 80°C for 2 hours. The reaction solution was poured into water, extracted with ethyl acetate, dried, spin-dried, and passed through a column with petroleum ether:ethyl acetate = 1:1 to obtain compound 65-2 (300 mg, yield: 81.39%, colorless oily liquid).

[0784] LCMS (ESI) [M+H] + 272.4.

[0785] Step 2: Synthesis of Compound 65-3

[0786] Compound 65-2 (280.00 mg, 1.03 mmol) and nickel (460.91 mg, 2.17 mmol) were added to isopropanol (10 mL) / tetrahydrofuran (2 mL) at 25°C. The hydrogen atmosphere was replaced, and the reaction mixture was stirred at 25°C for 12 hours. The mixture was filtered and dried to give compound 65-3 (250 mg, yield: 87.98%) as a colorless oil.

[0787] LCMS (ESI) [M+H] + 276.4.

[0788] Step 3: Synthesis of compound 65-4

[0789] At 25°C, triethylamine (275.67 mg, 2.72 mmol) was added to a mixture of compound 64-1 (250.00 mL, 908.08 μmol) in dichloromethane (15 mL). The pH of the reaction solution was adjusted to alkaline. 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (513.89 mg, 1.36 mmol) and compound 24-8 (283.58 mg, 908.08 μmol) were then added sequentially. Under nitrogen, the reaction mixture was stirred at 25°C for 2 hours. The organic solvent was removed by concentration under reduced pressure to obtain a crude product. The crude product was then purified by column chromatography using a dichloromethane:methanol ratio of 10:1 to afford compound 65-4 (470 mg, 90.87% yield, as a white solid). Ms is not shown.

[0790] Step 4: Synthesis of Compound 65

[0791] Compound 65-4 (470 mg, 825.17 μmol) was added to acetonitrile (10 mL) at 25°C, followed by phosphorus oxychloride (1 mL). The reaction mixture was stirred at 80°C for 2 hours. The reaction solution was added dropwise to saturated sodium bicarbonate, extracted with ethyl acetate, dried, and spin-dried to obtain compound 65 (70.68 mg, yield: 15.53%).

[0792] LCMS (ESI) [M+H] + 552.6.

[0793] 1 H NMR (400MHz, DMSO-d6) δ9.09(d,J=1.6Hz,1H),8.53(s,1H),8.41(t,J=1.3Hz,1H),8.16(d,J=1.4Hz,1H),7.85(d,J=0.9Hz,1H),7.52-7. 48(m,2H),7.43(d,J=8.2Hz,2H),4.55(s,2H),4.42(p,J=6.7Hz,1H),4.35(q,J=7.0Hz,4H),1.38(d,J=6.6Hz,6H),1.16(t,J=7.0Hz,6H).

[0794] Example 66: Synthesis of Compound 66

[0795] Step 1: Synthesis of Compound 66-2

[0796] Compound 65-1 (407.86 mg, 1.63 mmol), 1-isopropyl-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (407.86 mg, 1.63 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (136.47 mg, 163.05 μmol), 2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (151.96 mg, 326.10 μmol) and potassium phosphate (460.89 mg, 2.17 mmol) were added to dioxane (1.2 mL) / water (0.2 mL), and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 80°C for 4 hours. The reaction solution was directly mixed and purified by column chromatography (petroleum ether:ethyl acetate = 3:1) to obtain compound 66-2 (220 mg, yield: 89.06%, white solid).

[0797] LCMS (ESI) [M+H] +228.2.

[0798] Step 2: Synthesis of Compound 66-3

[0799] At 25°C, compound 66-2 (200 mg, 880.03 μmol) and Raney nickel (51.65 mg, 880.03 μmol) were added to tetrahydrofuran (2 mL) / isopropanol (6 mL), and the mixture was replaced with hydrogen three times. The mixture was reacted at 25°C for 16 hours. The reaction solution was directly filtered and dried to obtain compound 66-3 (200 mg, crude product, yellow oil).

[0800] LCMS (ESI) [M+H] + 232.4.

[0801] Step 3: Synthesis of Compound 66-4

[0802] At 25 ° C, compound 66-3 (200 mg, 864.69 μmol), 24-8 (270.03 mg, 864.69 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (391.47 mg, 1.04 mmol), N,N-diisopropylethylamine (223.51 mg, 1.73 mmol, 301.23 μL) were added to dichloromethane (10 mL) and reacted at 25 ° C for 16 hours. LCMS detection showed that the reaction was completely converted. The reaction solution was directly mixed and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 66-4 (320 mg, yield: 70.41%, yellow solid).

[0803] LCMS (ESI) [M+H] + 526.8.

[0804] Step 4: Synthesis of Compound 66

[0805] At 25°C, compound 66-4 (100 mg, 190.27 μmol) was added to acetonitrile (5 mL), and phosphorus oxychloride (29.17 mg, 190.27 μmol, 2 mL) was added. The reaction was stirred at 80°C for 16 hours. LCMS detection showed that the reaction was completely converted. The reaction solution was directly concentrated and liquid phase was used to prepare compound 66 (33 mg, yield: 34.17%).

[0806] LCMS (ESI) [M+H] + 508.4.

[0807] 1H NMR (400MHz, DMSO-d6) δ9.17(d,J=1.5Hz,1H),8.36(t,J=1.3Hz,1H),8.16(d,J=1.4Hz,1H),7.92(d,J=0.9Hz,1H),7.50(d,J=8.2Hz,2H),7.4 5(d,J=8.3Hz,2H),7.38(s,1H),4.76-4.65(m,1H),4.62(s,2H),4.46- 4.34(m,1H),1.90(s,3H),1.38(d,J=6.6Hz,6H),1.34(d,J=6.5Hz,6H).

[0808] Example 67: Synthesis of Compound 67

[0809] Step 1: Synthesis of Compound 67-2

[0810] Compound 65-1 (600 mg, 3.26 mmol), (2-isopropylphenyl)boronic acid (1.07 g, 6.52 mmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropyloxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl) palladium (II) (409.42 mg, 489.15 μmol), potassium phosphate (1.38 g, 6.52 mmol) were added. ), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (455.89 mg, 978.30 μmol) was dissolved in dioxane (1.2 mL) / water (0.2 mL), replaced with nitrogen three times, and reacted at 80°C for 4 hours. The reaction solution was directly mixed and purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound 67-2 (600 mg, yield: 82.41%, white solid).

[0811] LCMS (ESI) [M+H] + 223.8.

[0812] Step 2: Synthesis of Compound 67-3

[0813] At 25°C, compound 67-2 (200 mg, 895.77 μmol) and Raney nickel (52.58 mg, 895.77 μmol) were added to tetrahydrofuran (2 mL) / isopropyl alcohol (6 mL), and the mixture was replaced with hydrogen three times. The mixture was reacted at 25°C for 16 hours. The reaction solution was directly filtered and dried to obtain compound 67-3 (200 mg, yield: 98.23%, transparent oil).

[0814] LCMS (ESI) [M+H] + 228.4.

[0815] Step 3: Synthesis of Compound 67-4

[0816] At 25 ° C, compound 67-3 (200 mg, 879.88 μmol), 24-8 (274.77 mg, 879.88 μmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (398.34 mg, 1.06 mmol), N,N-diisopropylethylamine (227.44 mg, 1.76 mmol, 306.52 μL) were added to dichloromethane (10 mL) and reacted at 25 ° C for 16 hours. LCMS detection showed that the reaction conversion was complete. The reaction solution was directly mixed and purified by column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound 67-4 (300 mg, yield: 65.37%, colorless transparent oil).

[0817] LCMS (ESI) [M+H] + 522.8.

[0818] Step 4: Synthesis of Compound 67

[0819] At 25°C, compound 67-4 (100 mg, 191.73 μmol) was added to acetonitrile (5 mL), and phosphorus oxychloride (293.98 mg, 1.92 mmol, 1 mL) was added. The reaction was carried out at 80°C for 16 hours. LCMS detection showed that the reaction was completely converted. The reaction solution was directly concentrated and liquid phase was used to prepare compound 67 (34 mg, yield: 35.22%).

[0820] LCMS (ESI) [M+H] + 504.4

[0821] 1 H NMR (400MHz, DMSO-d6) δ9.14(d,J=1.6Hz,1H),8.35(d,J=1.3Hz,1H),8.16(d,J=1.3Hz,1H),7.92(s,1H),7.50(d,J=8.2Hz,2H),7.43(d ,J=7.9Hz,4H),7.32-7.24(m,2H),4.61(s,2H),4.49-4.39(m,1H),3.11(p,J=6.8Hz,1H),1.38(d,J=6.6Hz,6H),1.11(d,J=6.8Hz,6H).

[0822] Example 68: Synthesis of Compound 68

[0823] Step 1: Synthesis of Compound 68-2

[0824] Compound 65-1 (72.58 mg, 394.49 μmol) and 4-cyclopropyl-6-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)pyrimidine (120 mg, 394.49 μmol) were dissolved in a water (1 mL) / dioxane (5 mL) mixed solution, and then sodium carbonate (62.72 mg, 591.73 μmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (25.47 mg, 39.45 μmol) were added, nitrogen was replaced three times, and the reaction was carried out at 80 ° C for 3 hours. The solvent was partially concentrated, and then water (30 mL) and dichloromethane (40 mL) were added and extracted three times. The mixture was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and spin-dried. The sample was purified by column chromatography (petroleum ether: ethyl acetate = 0-30%) to give compound 68-2 (70 mg, yield: 63.08%, yellow solid).

[0825] LCMS (ESI) [M+H] + 282.2.

[0826] Step 2: Synthesis of Compound 68-3

[0827] Compound 68-2 (50 mg, 177.74 μmol) was dissolved in isopropanol (5 mL) at 25°C, followed by the addition of Raney nickel (208.64 mg, 3.55 mmol). The hydrogen atmosphere was replaced three times, and the mixture was allowed to react at 20°C for 16 hours. LCMS indicated the reaction was complete, and the mixture was filtered and the filtrate was dried to afford compound 68-3 (40 mg, 78.87% yield, as a green solid).

[0828] LCMS (ESI) [M+H] + 285.6.

[0829] Step 3: Synthesis of Compound 68-4

[0830] At 25 ° C, compound 68-3 (40 mg, 140.18 μmol) and compound 24-8 (48.15 mg, 154.20 μmol) were dissolved in dichloromethane (5 mL), and then 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.95 mg, 210.27 μmol) and N,N-diisopropylethylamine (90.59 mg, 700.91 μmol) were added and reacted at 20 ° C for 16 hours. The reaction was quenched by adding water, and then extracted three times with water (30 mL) and dichloromethane (40 mL), washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, spin-dried, and purified on silica gel (petroleum ether: ethyl acetate = 0-100%; dichloromethane: methanol = 0-10%) to give compound 68-4 (56 mg, yield: 68.92%, colorless oil).

[0831] LCMS (ESI) [M+H] + 580.0.

[0832] Step 4: Synthesis of Compound 68

[0833] Compound 68-4 (50 mg, 86.26 μmol) was dissolved in acetonitrile (2 mL) at 25°C, followed by the addition of phosphorus oxychloride (13.23 mg, 86.26 μmol, 2 mL). The mixture was reacted at 90°C for 3 hours. The crude product was then concentrated and purified on silica gel (dichloromethane:methanol = 0-15%). Liquid phase preparation afforded compound 68 (19.41 mg, 40.07% yield).

[0834] LCMS (ESI) [M+H] + 562.0.

[0835] 1 H NMR(400MHz,DMSO-d6)δ9.15(d,J=4.0Hz,1H),8.62(s,1H),8.50(s,1H),8 .16(s,1H),7.89(s,1H),7.49(d,J=8.0Hz,2H),7.42(d,J=8.0Hz,2H),5.35 -5.22(m,1H),4.57(s,2H),4.48-4.36(m,1H),1.95-1.84(m,1H),1.38(d, J=8.0Hz,6H),1.13(d,J=4.0Hz,6H),1.06-1.01(m,2H),0.91-0.84(m,2H).

[0836] The preparation method of the reference compound KSQ-4279 is as follows (Example 143, WO2020132269A1)

[0837] Biological Examples

[0838] Experimental Example 1: USP1 / UAF1 Deubiquitination Assay (Ubiquitin Fluorophore Assay)

[0839] Prepare the USP1 / UAF1 complex: First, prepare reaction buffer (50 mM HEPES [pH 7.8], 0.5 mM EDTA, 1 mM DTT, 0.1 mg / ml BSA, and 0.01% Tween-20). Prepare the enzyme mix containing USP1 / UAF1 complex (R&D, E-568-050) in reaction buffer to a final concentration of 0.15 nM.

[0840] 2. Prepare Ubiquitin Rhodamine 110 reaction substrate: Prepare a substrate mixture with a final concentration of 150 nM Ubiquitin Rhodamine 110 (R&D, E-555-050) in reaction buffer (50 mM HEPES [pH 7.8], 0.5 mM EDTA, 1 mM DTT, 0.1 mg / ml BSA, and 0.01% Tween-20).

[0841] 3. Compound Preparation: Dissolve the test compound in DMSO at a final concentration of 1%. Prepare the compound in DMSO at various concentrations. Set up replicates for each concentration, performing a 3-fold serial dilution for a total of 11 concentrations. Also include a corresponding vehicle control. Following dilution, dilute the compound 25-fold in reaction buffer.

[0842] 4. USP1 / UAF1 deubiquitination reaction: Add 5 μL of 4x USP1 / UAF1 complex solution to each well of the assay plate and incubate with 5 μL of 4x compound for 15 minutes. Then, add 10 μL of 2x Ubiquitin Rhodamine 110 substrate to initiate the reaction. Centrifuge, seal the plate, and incubate at 37°C for 30 minutes.

[0843] 5. After the reaction, the fluorescence value was read using a microplate reader (MD, VersaMax) with an excitation wavelength of 480 nm and an emission wavelength of 540 nm. Finally, the data were analyzed using GraphPad Prism 8 software, and the IC was calculated using the dose-response-inhibition (four-parameter) equation using GraphPad Prism software. 50 value.

[0844] The experimental results are shown in Table 1.

[0845] Table 1: IC values ​​of selected compounds in the USP1 / UAF1 deubiquitination assay 50 value

[0846] The compound of the present invention has excellent in vitro activity and can inhibit the deubiquitination activity of USP1 / UAF1 on Ubiquitin Rhodamine 110.

[0847] Test Example 2: Pharmacokinetic Test

[0848] 1. Experimental Purpose

[0849] ICR mice were used as test animals and Example 10, Example 11 and KSQ-4279 were administered orally. The drug concentrations in plasma at different time points were determined by LC-MS / MS to study the pharmacokinetic characteristics of the compounds of the present invention and the comparative example compounds in mice.

[0850] 2. Experimental plan

[0851] 2.1 Experimental drugs and animals

[0852] Experimental drugs: Example 10, Example 11 and KSQ-4279;

[0853] Animals: ICR mice, male, 20-30 g, were purchased from Shanghai Jihui Biotechnology Co., Ltd.

[0854] 2.2 Drug preparation

[0855] Weigh an appropriate amount of Example 10, add an appropriate amount of 5% DMSO + 10% Solutol + 85% Saline, vortex and sonicate to prepare a 1 mg / mL clear solution. Weigh an appropriate amount of Example 11, add an appropriate amount of 5% DMSO + 10% Solutol + 85% Saline, vortex and sonicate to prepare a 1 mg / mL clear solution. Weigh an appropriate amount of KSQ-4279, add an appropriate amount of 5% DMSO + 10% Solutol + 85% Saline, vortex and sonicate to prepare a 1 mg / mL clear solution.

[0856] 2.3 Administration

[0857] ICR mice in the intravenous and oral gavage groups (3 mice in each group) were fasted overnight and then gavaged with each test compound (IV, 1 mg / kg, 5 mL / kg; PO, 10 mg / kg, 10 mL / kg), and were fed 4 hours after administration.

[0858] 3. Operation

[0859] Approximately 0.03 mL of blood was collected intraorbitally and anticoagulated with sodium heparin before and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing. Blood samples were placed on ice and centrifuged to separate plasma (1500 g for 10 minutes). Collected plasma was stored at -60 to -80°C until analysis.

[0860] The levels of the test compounds in mouse plasma after intravenous and oral administration were determined by LC-MS / MS.

[0861] 4. Pharmacokinetic parameter results

[0862] The pharmacokinetic parameters of Example 10, Example 11 and KSQ-4279 of the present invention are shown in Table 2.

[0863] Table 2 Pharmacokinetic results

[0864] Conclusion: Compared with KSQ-4279, compounds 10 and 11 showed significant improvement in plasma concentration and area under the curve, and showed good pharmacokinetic characteristics in animals.

[0865] The above describes exemplary embodiments of the present invention. It should be understood that the scope of protection of this application is not limited to the above exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention should be included in the scope of protection of this application.

Claims

1. A compound represented by formula (I), 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, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and -OC 3-6 Cycloalkyl, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH; 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 or 3 R'; R' is 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 groups, 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; 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; X5, X6, X7, and X8 are each independently selected from N and CR X ; R X 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; 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, 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, said -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, wherein the two optional substituents on R5 together with the carbon atoms 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 Aryl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 OH, NH2, halogen, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl or -OC 3-6 cycloalkyl substitution; 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 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; The C 1-6 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 groups, 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 groups, 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 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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, said -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 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.

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 Optionally, the structural unit Selected from 6. The compound according to claim 1 or 5, its optical isomer or a pharmaceutically acceptable salt thereof, wherein R1, R 1X 、R 2X 、R 3X 、R 4X 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, C 3-6 Cycloalkyl and -OC 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, C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 OH, NH2, F, Cl, Br, I, CN, NO2, COOH; Optionally, R1, R 1X 、R 2X 、R 3X 、R 4X Each is independently selected from H, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl.

7. 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 groups, 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, -OCH3, -SCH3, Optionally, R2 is selected from R 2A 、R 2B 、R 2C 、R 2D 、R 2E 、R 2F 、R 2G 、R 2H 、R 2I 、R 2J 、R 2K 、R 2L 、R 2M 、R 2N 、R 2O Selected from H, OH, CN, 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 groups, 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 8. The compound according to claim 3 or 7, 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 groups, 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, -OCH3, -SCH3, 9. The compound according to any one of claims 1 to 4, its optical isomers or pharmaceutically acceptable salts thereof, wherein: 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 and R4 are each independently selected from H, D, OH, CN, F, Cl, Br, I, methyl, ethyl and propyl.

10. The compound according to claim 1, 2 or 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl and 5-6 membered heterocyclic group, the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, 5-6 membered heteroaryl and 5-6 membered heteroaryl and 5-6 membered heterocyclyl are 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, 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, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Heteroalkyl, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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, said -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, -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 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; Optionally, R 5A 、R 5B 、R 5C 、R 5D 、R 5E 、R 5F 、R 5G 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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-membered cycloalkyl, 3-6-membered heterocyclic group or -C 1-6 Alkyl-C(=O)N(C 1-6 alkyl)2 is optionally substituted with 1, 2 or 3 D, OH, CN, 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 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O 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 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 、R 5H 、R 5I 、R 5J 、R 5K 、R 5L 、R 5M 、R 5N 、R 5O Each independently selected from H, D, CN, F, Cl, Br, I, OCH3, OCH2CH3, CF3, CHF2, CD3, methyl, ethyl, Optionally, R5 is selected from 11. A compound of the following formula, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

12. Use of the compound according to any one of claims 1 to 11, its optical isomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating diseases associated with USP1 activity or expression. 13 . The disease associated with USP1 activity or expression according to claim 12 , which is selected from cancer-related diseases.

14. The cancer-related disease according to claim 13, 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, and cervical cancer.

15. The cancer-related disease according to claim 13, which is selected from osteosarcoma, chondrosarcoma, glioma, glioblastoma, astrocytoma, medulloblastoma, meningioma, rhabdoid sarcoma, melanoma, and non-small cell lung cancer.

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