Compounds as WRN helicase inhibitors

Abstract

This invention discloses a compound represented by formula (I) and its pharmaceutically acceptable salts. Specifically, this invention discloses a series of compounds as WRN helicase inhibitors. [Formula 1] TIFF2026512828000250.tif40156

Description

Detailed description of the invention

[0001] This invention claims the following priority: Application number CN2023103018345, application date: March 24, 2023; Application number: CN202311004828X, Filing date: August 09, 2023; Application number CN2023110500915, filing date: August 18, 2023; Application number CN2024102950619, application date: March 14, 2024.

[0002] [Technical field] The present invention relates to a compound represented by formula (I) and its pharmaceutically acceptable salts, and more specifically, to a series of compounds as WRN helicase inhibitors.

[0003] [Background technology] The human genome contains numerous short tandem repeat sequences, known as "microsatellites." These repeating DNA regions are prone to slip errors during replication and therefore heavily rely on the MMR (mismatch repair) system for repair. Abnormalities in the MMR system lead to dMMR (mismatch repair deficiency), which prevents the recognition and repair of microsatellite replication errors, resulting in MSI (microsatellite instability-high / deficient mismatch repair) mutations. This can induce frameshift mutations, leading to abnormalities in tumor-related genes and potentially promoting cancer development and progression. In 2017, immune checkpoint inhibitors (ICIs) were approved for the treatment of high-frequency microsatellite instability-high / deficient mismatch repair (MSI-H / dMMR) tumors, making MSI-H / dMMR the first "pan-cancer" tumor marker. High-frequency microsatellite instability (MSI-H) cancer cells depend on WRN (Werner syndrome RecQ helicase) helicase activity. Inhibiting WRN induces DNA double-strand breaks, activating the DNA damage response and further inducing apoptosis and cell cycle arrest. Conventional treatments for dMMR (mismatch repair deficiency) / MSI-H type cancer include targeted therapy, chemotherapy, and immunotherapy. The clinical efficacy of targeted therapy and chemotherapy is limited by drug resistance and toxicity, and furthermore, approximately half of immunotherapy patients do not show a positive response to immune checkpoint inhibitors. 45-60% of MSI-H cancer patients do not respond to immunotherapy, highlighting the urgent need to address primary and secondary resistance issues in targeted therapy, chemotherapy, and immunotherapy. In 2019, Harvard University and the Broad Institute at MIT analyzed two databases, Achilles and drive, to evaluate the dependence of each cell line on different targets. Their findings revealed that the activity of the RecQ DNA helicase WRN is essential in vivo and in vitro in dMMR / MSI-H type cell lines, while MSS cells can survive independently of WRN. In the MSI-H model, WRN knockout induces double-strand DNA breaks, selectively promoting apoptosis and cell cycle arrest.This tumor suppression mechanism differs from that of targeted drugs (which suppress cancer cell-specific oncogenic changes) and immunotherapy (which suppresses immune evasion and resistance). In 2021, Dr. Mathew J. Garnett's research group at the Wellcome Sanger Institute demonstrated, using a PDX model, that WRN inhibitors could be a second- or third-line monotherapy for dMMR patients. In dMMR tumors, tumor mutagenesis is negatively correlated with immune checkpoint inhibition response, but WRN sensitivity is unrelated to mutational burden. Due to the difference in mechanism of action, combination therapy with checkpoint inhibitors, chemotherapy, or targeted therapy and WRN inhibitors may suppress cross-resistance and promote tumor eradication. Furthermore, because the lack of DNA repair modulates new antigen structures and increases mutational burden, enhancing the immune response, WRN inhibition may also synergistically interact with immunotherapy. Therefore, WRN could be an important target for monotherapy or in combination therapy with targeted drugs, chemotherapy, and immunotherapy for dMMR / MSI-H tumors.

[0004] MSI-H tumors occur in multiple locations, with the highest incidence in endometrial cancer (31%), colorectal adenocarcinoma (20%), and gastric cancer (19%). Approximately 325,000 new MSI-H tumors are diagnosed annually in the United States and approximately 300,000 in China, indicating significant market value for drug development. In mismatch repair normal (MSS) tumors, deletion (or reduction) of WRN expression does not affect tumor cell proliferation. In mismatch repair deficiency (MSI-H) tumors, simultaneous deletion (or reduction) of WRN expression leads to an increased accumulation of double-strand breaks in cellular DNA, causing the cell cycle to arrest in the G1 or G2 / M phase, leading to tumor cell death. This is known as synthetic lethality. The development of WRN helicase inhibitors could be one effective treatment for MSI-H cancer.

[0005] [Overview of the prefecture] In one aspect of the present invention, a compound represented by formula (I), an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[0006] [ka]

[0007] Here, ring A is selected from phenyl or 5- to 10-membered heteroaryl, and the phenyl and 5- to 10-membered heteroaryl are optionally substituted with 1, 2, or 3 R

[0008] , , , , b3 , 3-20 , b1 ,

[0009] , t , , b2 , b1 , , , 6-20 , , t , , b2 , , b1 , b3 , b1 ; ring B is selected from C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C 6-20 aryl, or 5- to 20-membered heteroaryl; ring C is selected from C 6-20 aryl or 5- to 20-membered heteroaryl; ring D is selected from C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, 4- to 20-membered heterocycloalkenyl, C 6-20 aryl or 5- to 20-membered heteroaryl; ring E is selected from C 3-20 cycloalkyl, 5- to 20-membered heterocycloalkyl, C 6-20 aryl or 5- to 20-membered heteroaryl; L1 is a single bond, -N(R b1 ), -N(R b1 )C(=O)-, -O-, -S-, -(CR b2 R b3 ) t -, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or 3-20 26>

[0008]

Chemical formula

[0009] L2 is a single bond, -N(R b1 ), -N(R b1 )C(=O)-, -O-, -S-, -(CR b2 R b3 ) t -, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or

[0010] [ka] Selected from;

[0011] R1 is independently H, F, Cl, Br, OH, N(R) b4 )2, CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Selected from aryl or 5-20 member heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Aryl and 5-20 member heteroaryls are optionally substituted with 1, 2, or 3 R atoms; Alternatively, two R1s may combine with each other to form a single C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Forming aryl or 5-20 member heteroaryl groups;

[0012] [ka] teeth

[0013] [ka] Selected from,

[0014] [ka] teeth

[0015] [ka] Selected from;

[0016] or,

[0017]

Chem.

[0018]

Chem.

[0019]

Chem.

[0020]

Chem.

[0021]

Chem.

[0022]

Chem.

[0023]

Chem.

[0024]

Chem.

[0025]

Chem.

[0026]

Chem.

[0027] If selected from, R2 is H, F, Cl, Br, OH, N(R b4 )2, CN, SF5, CHO, COOH, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, C 2-20 Alkenil, C 2-20 Alkinyl, 3-20 member heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 member heterocycloalkenyl, C 6-20 Selected from aryl or 5-20 member heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, C 2-20 Alkenil, C 2-20 Alkinyl, 3-20 member heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 member heterocycloalkenyl, C 6-20 Aryl and 5-20 member heteroaryls are optionally substituted with 1, 2, or 3 R atoms;

[0028] [ka] but

[0029] [ka] If selected from, R2 will be selected from O or S;

[0030] R3 and R4 are independently H, F, Cl, Br, OH, and N(R) b4 )2, CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Selected from cycloalkyl or 3-20 member heterocycloalkyl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3- to 20-membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms; Alternatively, R3 and R4 are bonded to each other to form a C 3-20 cycloalkyl or 3- to 20-membered heterocycloalkyl, and the C 3-20 cycloalkyl or 3- to 20-membered heterocycloalkyl is optionally substituted with one, two or three Rs; R5 is independently selected from H, F, Cl, Br, OH, N(R b4 )2, SF5, CN, CHO, C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and the C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl and 5- to 20-membered heteroaryl are optionally substituted with one, two or three Rs; Alternatively, two R5s are bonded to each other to form a C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and the C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 4-20 cycloalkenyl, 4- to 20-membered heterocycloalkenyl, C 6-20 aryl and 5- to 20-membered heteroaryl are optionally substituted with one, two or three Rs; R6 is independently selected from H, F, Cl, Br, OH, N(R b4 )2, CN, C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and the C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20Cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl and 5- to 20-membered heteroaryl are each optionally substituted with one, two or three Rs; alternatively, two Rs6 are joined to each other to form one C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and the C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl and 5- to 20-membered heteroaryl are each optionally substituted with one, two or three Rs; R7 is each independently H, F, Cl, Br, OH, N(R b4 )2, CN, C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl or 5- to 20-membered heteroaryl, and the C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, 3- to 20-membered heterocycloalkyl, C 6-20 aryl and 5- to 20-membered heteroaryl are each optionally substituted with one, two or three Rs; R8 is H, C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, or 3- to 20-membered heterocycloalkyl, and the C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, and 3- to 20-membered heterocycloalkyl are each optionally substituted with one, two, or three Rs; R a is each independently H, F, Cl, Br, OH, NH2, CN, C 1-20 alkyl, C 1-20 heteroalkyl, C 3-20 cycloalkyl, or 3- to 20-membered heterocycloalkyl, and the C 1-20 alkyl, C 1-20 heteroalkyl, C3-20 Cycloalkyls and 3- to 20-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; R b1 H, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Selected from aryl or 5-20 member heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Aryls and 5- to 20-membered heteroaryls can be optionally substituted with 1, 2, or 3 Rs; R b2 , R b3 These are H, F, Cl, Br, OH, NH2, CN, and C, respectively, independently. 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Selected from cycloalkyl or 3-20 member heterocycloalkyl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyls and 3- to 20-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; Alternatively, R b2 and R b3 They combine with each other, C 3-20 Forming cycloalkyl or 3-20 member heterocycloalkyl groups; R b4 These are H and C, respectively, independently. 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Selected from aryl or 5-20 member heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20Aryls and 5- to 20-membered heteroaryls can be optionally substituted with 1, 2, or 3 Rs; m, n, p, q, and t are each independently selected from 0, 1, 2, or 3; R is independently H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH.

[0031] [ka] , C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Selected from aryl or 5-20 member heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 member heterocycloalkyl, C 6-20 Aryl and 5-20 member heteroaryls are optionally substituted with 1, 2, or 3 R';

[0032] R' is H, F, Cl, Br, I, OH, NH2, CH3, CF3, C2H5, CN, SF5, CHO, COOH or

[0033] [ka] Selected from;

[0034] Said C 1-6 Heteroalkyl, C 1-20 Heteroalkyls, 3-20 membered heterocycloalkyls, 4-20 membered heterocycloalkenyls, 5-20 membered heteroaryls, or 5-10 membered heteroaryls contain one, two, or three heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, and N.

[0035] In some embodiments of the present invention, ring A is selected from phenyl or a 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl have 1, 2, or 3 R a It is arbitrarily replaced by; Ring B is C 3-6 Cycloalkyl, 5-6 member heterocycloalkyl, C 5-6 Cycloalkenyl, 5-6 member heterocycloalkenyl, C 6-10 Selected from aryl or 5-10 member heteroaryl; Ring C is C 6-10 Selected from aryl or 5-10 member heteroaryl; Ring D is C 3-6 Cycloalkyl, 5-6 member heterocycloalkyl, 5-6 member heterocycloalkenyl, C 6-10 Selected from aryl or 5-10 member heteroaryl; Ring E is C 3-6 Cycloalkyl, 5-6 member heterocycloalkyl, C 6-10 Selected from aryl or 5-10 member heteroaryl; L1 is a single bond, -N(R b1 )-, -O-, -S-, -C(R b2 )2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or

[0036] [ka] Selected from;

[0037] L2 is a single bond, -N(R b1 )-, -O-, -S-, -C(R b2 )2-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2- or

[0038] [ka] Selected from;

[0039] R aThese are H, F, Cl, Br, OH, NH2, CN, and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; R b1 H, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; R b2 These are H, F, Cl, Br, OH, NH2, CN, and C, respectively, independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; R1 independently contains H, F, Cl, Br, OH, NH2, CN, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyls and 3- to 6-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; Alternatively, two R1s may combine with each other to form a single C 4-6 Forming cycloalkyl or 4-6 member heterocycloalkyl groups;

[0040] [ka] teeth

[0041] [ka] Selected from,

[0042] [ka] teeth

[0043] [ka] Selected from;

[0044] or,

[0045] [ka] teeth

[0046] [ka] Selected from,

[0047] [ka] teeth

[0048] [ka] Selected from;

[0049] [ka] but

[0050] [ka] If selected from, T is selected from C;

[0051] [ka] but

[0052] [ka] If selected from, T is selected from N or CH;

[0053] [ka] but

[0054] [ka] If selected from the following, R2 is H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyls and 3- to 6-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms;

[0055] [ka] but

[0056] [ka] If selected from, R2 will be selected from O or S;

[0057] R3 and R4 are independently H, F, Cl, Br, OH, NH2, CN, and C, respectively. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyls and 3- to 6-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; Alternatively, R3 and R4 may be coupled to each other, C 3-6 Forming a cycloalkyl or 3-6 member heterocycloalkyl, the C 3-6 The cycloalkyl or 3- to 6-membered heterocycloalkyl may optionally be substituted with 1, 2, or 3 R atoms; R5 consists of H, F, Cl, Br, OH, NH2, SF5, CN, HC(=O)-, and C, each independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; Alternatively, two R5s can combine to form one C 4-6 Forming a cycloalkyl or 4-6 member heterocycloalkyl, the C 4-6 Cycloalkyl and 4- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; R6 consists of H, F, Cl, Br, OH, NH2, CN, and C, each independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; Alternatively, two R6s may combine with each other to form a single C 4-6 Forming a cycloalkyl or 4-6 member heterocycloalkyl, the C 4-6Cycloalkyl and 4- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; R7 consists of H, F, Cl, Br, OH, NH2, CN, and C, each independently. 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; R8 is H, C 1-6 Alkyl, C 3-6 Selected from cycloalkyl or 3-6 member heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 3- to 6-membered heterocycloalkyl groups may be optionally substituted with 1, 2, or 3 R atoms; m, n, p, and q are each independently selected from 0, 1, 2, or 3; R is independently H, F, Cl, Br, I, OH, NH2, CN, COOH.

[0058] [ka] , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio and C 1-6 Selected from alkylaminos, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio or C 1-6 Alkylaminos are optionally substituted with 1, 2, or 3 R'; R' is selected from F, Cl, Br, I, OH, NH2, and CH3;

[0059] Said C 1-6Heteroalkyls, 5-6 membered heterocycloalkyls, 5-6 membered heterocycloalkenyls, 5-6 membered heteroaryls, or 5-10 membered heteroaryls contain one, two, or three heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2-, and N.

[0060] In some aspects of the present invention, R is independently H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH,

[0061] [ka] , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkylthio, -C 1-6 Alkyl-C 1-6 Alkylamino, C 1-6 alkyl-OH, C 1-6 Alkyl-NH2, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Selected from cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiopyranil,

[0062] Said C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkylthio, -C 1-6 Alkyl-C 1-6 Alkylamino, C 1-6 alkyl-OH, C 1-6 Alkyl-NH2, -C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperinidyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiopyranil are optionally substituted with 1, 2, or 3 R' values, and the other variables are as defined in this invention.

[0063] In some aspects of the present invention, R is independently H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH,

[0064] [ka] , CH3, CF3, CHF2, CH2F, CF2Cl, CF2Br, CF2I,

[0065] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0066] In some aspects of the present invention, R is H, F, Cl, Br, OH, NH2, COOH,

[0067] [ka] , Ho, CF3, CHF2, CH2F,

[0068] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0069] In some aspects of the present invention, ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl, or 1H-pyrrolyl, wherein phenyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl, and 1H-pyrrolyl have 1, 2, or 3 R a This can be optionally substituted by the other variables, and the other variables are as defined in this invention.

[0070] In some aspects of the present invention, ring A is

[0071] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0072] In some aspects of the present invention, R a These are H, F, Cl, Br, OH, NH2, CN, Me, each independently.

[0073] [ka] Selected from, the Me,

[0074] [ka] R is optionally substituted with one, two, or three Rs, and the other variables are as defined in this invention.

[0075] In some aspects of the present invention, R a These are H, F, Cl, Br, OH, NH2, CN, Me, CF3, each independently.

[0076] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0077] In some aspects of the present invention, ring A is

[0078] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0079] In some aspects of the present invention,

[0080] [ka] but

[0081] [ka] If selected from the following, R2 is H, F, Cl, Br, OH, NH2, CN, SF5, CHO, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6Cycloalkyl, 3-6 member heterocycloalkyl, C 4-6 Cycloalkenyl, 4-6 member heterocycloalkenyl, C 6-10 Selected from aryl or 5-10 member heteroaryl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, C 4-6 Cycloalkenyl, 4-6 member heterocycloalkenyl, C 6-10 The aryl and 5- to 10-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs, and the other variables are as defined in this invention.

[0082] In some aspects of the present invention,

[0083] [ka] but

[0084] [ka] If selected from, R2 is H, F, Cl, Br, OH, NH2, CN, Me,

[0085] [ka] Selected from, the Me,

[0086] [ka] R can be optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0087] In some aspects of the present invention, R2 is H, F, Cl, Br, OH, NH2, CN, Me, CF3,

[0088] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0089] In some aspects of the present invention, structural units

[0090] [ka] teeth

[0091] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0092] In some aspects of the present invention, structural units

[0093] [ka] teeth

[0094] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0095] In some aspects of the present invention, R1 is independently H, F, Cl, Br, OH, NH2, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkylthio, -C 1-6 Alkyl-C 1-6 Alkylamino, C 1-6 alkyl-OH, C 1-6 Alkyl-NH2, C1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Selected from cycloalkyl-S(=O)2- or 3- to 6-membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-6 Alkyl-C 1-6 Alkoxy, -C 1-6 Alkyl-C 1-6 Alkylthio, -C 1-6 Alkyl-C 1-6 Alkylamino, C 1-6 alkyl-OH, C 1-6 Alkyl-NH2, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-OC(=O)-, C 1-6 Alkyl-OC(=O)-C 1-6 Alkyl, -NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-NH-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-S(=O)2-, C 1-6 Alkyl-S(=O)2-C 1-6 Alkyl, -NH-S(=O)2-C1-6 Alkyl, C 1-6 Alkyl-NH-S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkyl-S(=O)2- and 3- to 6-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms, and the other variables are as defined in this invention.

[0096] In some aspects of the present invention, R1 is independently H, F, Cl, Br, OH, NH2, CN, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-OC(=O)-, C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, or C 3-6 Selected from cycloalkyl-S(=O)2-, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, C 1-3 Alkyl-C(=O)-, C 1-3 Alkyl-OC(=O)-, C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl and C 3-6 The cycloalkyl-S(=O)2- is optionally substituted with 1, 2, or 3 R atoms, and the other variables are as defined in this invention.

[0097] In some aspects of the present invention, R1 is independently H, F, Cl, Br, OH, NH2, CN, Me,

[0098] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0099] In some aspects of the present invention, R1 is independently H, F, Cl, Br, OH, NH2, CN, Me,

[0100] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0101] In some embodiments of the present invention, ring B is cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxynyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, tetrahydro-2H-pyranyl Selected from 5,6-dihydro-2H-pyran-2-keto, phenyl, pyridyl, pyrrolidinyl, 2-oxa-6-azaspiro[3,3]heptanyl, 1,1-dioxo-3,6-dihydro-2H-thiopyranyl, oxepinyl, azetidinyl, 2-oxa-7-azaspiro[4.4]nonanyl, or hexahydro-1H-flo[3,4-c]pyrrolyl, with other variables as defined herein.

[0102] In some aspects of the present invention, ring B is selected from cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxynyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyran-2-keto, phenyl, pyridyl, or pyrrolidinyl, with other variables as defined in the present invention.

[0103] In some aspects of the present invention, structural units

[0104] [ka] teeth,

[0105] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0106] In some aspects of the present invention, structural units

[0107] [ka] teeth,

[0108] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0109] In some aspects of the present invention, R5 is independently H, F, Cl, Br, OH, NH2, CN, SF5, CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, or C 3-6 Selected from heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, and C 3-6 Heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms; Alternatively, two R5s can combine to form one C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, C 4-10 Cycloalkenyl, 4-10 member heterocycloalkenyl, C 6-10 Forming an aryl or a 5-10 member heteroaryl, the C 3-6Cycloalkyl, 3-6 member heterocycloalkyl, C 4-10 Cycloalkenyl, 4-10 member heterocycloalkenyl, C 6-10 The aryl and 5- to 10-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs, and the other variables are as defined in this invention.

[0110] In some aspects of the present invention, R5 is independently H, F, Cl, Br, OH, NH2, CN, SF5, CHO, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, or C 3-6 Selected from heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, C 3-6 Cycloalkyl, and C 3-6 Heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R atoms; Alternatively, two R5s can combine to form one C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, C 4-10 Cycloalkenyl, 4-10 member heterocycloalkenyl, C 6-10 Forming an aryl or a 5-10 member heteroaryl, the C 3-6 Cycloalkyl, 3-6 member heterocycloalkyl, C 4-10 Cycloalkenyls, 4-10 member heterocycloalkenyls, and C 6-10 The aryl is optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0111] In some aspects of the present invention, R5 is independently H, F, Cl, Br, OH, NH2, CN, SF5, Me, CHO,

[0112] [ka] Selected from, the Me,

[0113] [ka] This can be arbitrarily replaced with one, two, or three Rs;

[0114] Alternatively, two R5s may be combined with each other.

[0115] [ka] Forms the above

[0116] [ka] R can be optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0117] In some aspects of the present invention, R5 is independently H, F, Cl, Br, OH, NH2, CN, SF5, Me, HC(=O)-,

[0118] [ka] Selected from, the Me,

[0119] [ka] R can be optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0120] In some aspects of the present invention, R5 is independently H, F, Cl, Br, OH, NH2, SF5, CN, Me, CF3, CHO,

[0121] [ka] Selected from;

[0122] Alternatively, two R5s may be combined with each other.

[0123] [ka] The following is formed, and the other variables are as defined in this invention.

[0124] In some aspects of the present invention, R5 is independently H, F, Cl, Br, OH, NH2, SF5, CN, Me, CF3, HC(=O)-,

[0125] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0126] In some aspects of the present invention, ring C is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or thienyl, and other variables are as defined in the present invention.

[0127] In some aspects of the present invention, structural units

[0128] [ka] teeth,

[0129] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0130] In some aspects of the present invention, structural units

[0131] [ka] teeth,

[0132] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0133] In some aspects of the present invention, R6 is independently H, F, Cl, Br, OH, NH2, CN, Me,

[0134] [ka] Selected from, the Me,

[0135] [ka] R can be optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0136] In some aspects of the present invention, R6 is independently H, F, Cl, Br, OH, NH2, CN, Me, CF3,

[0137] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0138] In some aspects of the present invention, ring D is

[0139] [ka] Selected from;

[0140] T1, T2, T3, and T4 are each independently selected from N or CH; X1, X2, X3, and X4 are each independently selected from single bonds or CH2; X5 and X6 are independently selected from a single bond, CH2, or CH2CH2, and X5 and X6 are not simultaneously selected from a single bond; X7, X8, X9, X 10 Each of these is independently a single bond, NH, O, S, CH2 or

[0141] [ka] Selected from X7, X8, X9, X 10 Up to three of these are selected simultaneously from the single bonds;

[0142] L a is C 1-6 Alkyl, C 2-6 Alkenyl or C 1-6 Selected from heteroalkyl groups, the C 1-6 Alkyl and C 1-6 The heteroalkyl group is optionally substituted with 1, 2, or 3 R atoms, and the other variables are as defined herein.

[0143] In some aspects of the present invention, ring D is

[0144] [ka] The following are selected, and the other variables are as defined herein. In some aspects of the present invention, ring D is

[0145] [ka] The following are selected, and the other variables are as defined herein.

[0146] In some aspects of the present invention, ring D is selected from piperidinyl, piperazinyl, or 1,2,3,6-tetrahydropyridyl, and other variables are as defined herein.

[0147] In some aspects of the present invention, structural units

[0148] [ka] teeth,

[0149] [ka] The following are selected, and the other variables are as defined herein.

[0150] In some aspects of the present invention, structural units

[0151] [ka] teeth

[0152] [ka] The following are selected, and the other variables are as defined herein. In some aspects of the present invention, R7 is independently H, F, Cl, Br, OH, NH2, CN, Me,

[0153] [ka] Selected from, the Me,

[0154] [ka] R is optionally replaced by one, two, or three Rs, and the other variables are as defined herein.

[0155] In some aspects of the present invention, R7 is independently H, F, Cl, Br, OH, NH2, CN, Me, CF3,

[0156] [ka] The variables are selected from the above, and the other variables are as defined in this invention. In some aspects of the present invention, ring E is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, or thienyl, and other variables are as defined in the present invention.

[0157] In some aspects of the present invention, structural units

[0158] [ka] teeth,

[0159] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0160] In some aspects of the present invention, structural units

[0161] [ka] teeth,

[0162] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0163] In some aspects of the present invention, R3 and R4 are independently H, F, Cl, Br, OH, NH2, CN, Me,

[0164] [ka] Selected from, the Me,

[0165] [ka] R can be optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0166] In some aspects of the present invention, R3 and R4 are independently H, F, Cl, Br, OH, NH2, CN, Me, CF3,

[0167] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0168] In some aspects of the present invention, R8 is H, Me,

[0169] [ka] Selected from, the Me,

[0170] [ka] R can be optionally replaced with one, two, or three Rs, and the other variables are as defined in this invention.

[0171] In some aspects of the present invention, R8 is H, Me, CF3,

[0172] [ka] The variables are selected from the above, and the other variables are as defined in this invention.

[0173] The present invention also provides compounds of the following formulas selected from the following, their optical isomers, or pharmaceutically acceptable salts thereof:

[0174] [ka] TIFF2026512828000107.tif226170TIFF2026512828000108.tif244170TIFF2026512828000109.tif246170TIFF2026512828000110.tif221170 TIFF2026512828000111.tif222170TIFF2026512828000112.tif250170TIFF2026512828000113.tif250170TIFF2026512828000114.tif206170

[0175] In another embodiment of the present invention, the present invention further provides pharmaceutical compositions. In some aspects of the present invention, the pharmaceutical composition comprises the aforementioned compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. In some embodiments of the present invention, the pharmaceutical composition further comprises a medicinal additive.

[0176] In another embodiment of the present invention, the present invention further provides the use of the compound, its optical isomers, its pharmaceutically acceptable salts, or the pharmaceutical composition in the manufacture of a pharmacopoeia for the treatment of tumor-related diseases.

[0177] The object of the present invention is to provide compounds as WRN inhibitors, or their stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic, and intermediates thereof, as well as methods for their manufacture, and their use in the manufacture of therapeutic agents for high-frequency microsatellite instability tumor-related diseases.

[0178] In some embodiments of the present invention, the tumor-related disease is one or more solid tumor-related diseases. The compounds of the present invention can be used alone or in combination with other chemotherapeutic agents, targeted therapies, or immunotherapies to treat a wide variety of tumors, particularly malignant tumors with high microsatellite instability (MSI), or malignant tumors with mismatch repair deficiency (dMMR), or high levels of (TA)n This method is applied to malignant tumors in which repetitive sequences are detected, including, but not limited to, colorectal cancer, gastric cancer, endometrial cancer, and ovarian cancer.

[0179] Definition and explanation Unless otherwise specified, the following terms and phrases used herein shall have the meanings set forth below. Where a particular term or phrase is not specifically defined, it should not be considered uncertain or unclear, but rather understood according to its usual meaning. Where a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0180] As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form suitable for contact with human and animal tissues, within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and with a reasonable benefit-to-risk ratio.

[0181] "Pharmacologically acceptable salts" refer to salts of the compounds of the present invention, which are prepared from a relatively non-toxic acid or base and a compound having a specific substituent discovered in the present invention. If the compounds of the present invention contain a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts, or similar salts. If the compounds of the present invention contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts (e.g., hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate ion, phosphoric acid, monohydrogen phosphate ion, dihydrogen phosphate ion, sulfuric acid, bisulfate ion, hydroiodic acid, phosphorous acid, etc.) and organic acid salts (e.g., 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, methanesulfonic acid, and similar acids), as well as salts of amino acids (e.g., arginine) and salts of organic acids such as glucuronic acid. Since certain compounds of the present invention contain basic and acidic functional groups, they can be converted into either a base or an acid addition salt.

[0182] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds having acidic or basic groups by conventional chemical methods. Generally, these salts are prepared by reacting these compounds in free acidic or basic form with a stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture thereof.

[0183] The compounds of the present invention may exist in the form of specific geometric isomers or stereoisomers. The present invention envisions all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and other mixtures such as racemic mixtures thereof and mixtures enriched with enantiomers or diastereomers, all of which fall within the scope of the present invention. Substituents such as alkyl groups may have additional chiral carbon atoms. All of these isomers and mixtures thereof are within the scope of the present invention.

[0184] Unless otherwise specified, the term "tautomer" or "tautomer form" refers to the dynamic equilibrium state at room temperature where different functional isomers rapidly convert to one another. When tautomerism is possible (e.g., in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversion by proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversion by rearrangement of bonded electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypento-3-en-2-one.

[0185] The compounds of the present invention may contain atomic isotopes in unnatural ratios in one or more atoms constituting the compound. For example, the compound can be labeled with a radioactive isotope, such as tritium. 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14Examples include C). Furthermore, it is possible to form deuterated pharmaceuticals by substituting hydrogen with deuterium. Since the bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon, deuterated pharmaceuticals have advantages over non-deuterated pharmaceuticals, such as reduced side effects, improved drug stability, enhanced efficacy, and extended biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0186] "Optional" or "optional" means that the event or state described below may occur but is not mandatory, and the description includes both cases in which the event or state occurs and cases in which it does not occur. The term "substituted by..." means that one or more hydrogen atoms on a particular atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the particular atom is normal and the substituted compound is stable. The term "optionally substituted by..." means that substitution is optional, and unless otherwise specified, the type and number of substituents are arbitrary to the extent that is chemically feasible.

[0187] If any variable (e.g., R) appears multiple times in the composition or structure of a compound, its definition in each case is independent. Therefore, for example, if a group is substituted by one, two, or three Rs, that group can be substituted by up to three Rs, and the selection of Rs in each case is independent. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound. For example,

[0188] [ka] teeth

[0189] [ka] These are some of the options that can be selected.

[0190] If either variable is selected from a single bond, it indicates that the two connected groups are directly bonded, for example,

[0191] [ka] In this case, if L2 represents a single bond, then the structure is actually

[0192] [ka] This indicates that. A hyphen ("-") without a space between two letters or symbols indicates the bonding position of a substituent. For example, C 1-6 Alkylcarbonyl- is a carbonyl group that is attached to the rest of the molecule via a carbonyl group. 1-6 This refers to alkyl groups. However, the hyphen "-" may be omitted if the bonding position of the substituent is obvious to those skilled in the art, for example, in the case of halogen substituents.

[0193] Unless otherwise specified, the valence bonds of the base are indicated by a dotted line.

[0194] [ka] If the phrase is attached, for example,

[0195] [ka] In this diagram, the dotted line indicates that the base is a bonding point with other parts of the molecule.

[0196] If, in the enumerated substituents, it is not specified which atom it bonds to the group it is substituted through, the substituent can bond through any atom; for example, if a pyridyl group acts as a substituent, it can bond to the group it is substituted through any carbon atom of the pyridine ring.

[0197] If the direction of bonding is not specified for a listed linking group, the bonding direction is arbitrary. For example,

[0198] [ka] In this case, the linking group L

[0199] [ka] If that is the case,

[0200] [ka] The phenyl group and cyclopentyl group are bonded in the same direction as the reading order from left to right.

[0201] [ka] It can also be constructed by combining elements in the reverse direction of the reading order from left to right.

[0202] [ka] It is also possible to construct such a combination. The combination of the linking group, substituent, and / or variant thereof is permissible only if such a combination results in a stable compound.

[0203] Unless otherwise specified, the number of atoms constituting a ring refers to the number of atoms that make up the ring itself in compounds obtained by bonding atoms in a ring (monocyclic compounds, fused ring compounds, spiro compounds, bridged ring compounds, cross-linked compounds, carbocyclic compounds, heterocyclic compounds, etc.). The number of atoms constituting a ring is usually defined as the number of members in the ring; for example, a "4- to 6-membered ring" refers to a "ring" in which 4 to 6 atoms are arranged in a ring. If the ring is substituted with substituents, the atoms included in the substituents are not included in the ring constituent atoms. Unless otherwise specified, benzene refers to a 6-membered ring, naphthalene to a 10-membered ring, and thiophene to a 5-membered ring.

[0204] Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group comprising a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atom, a quaternary carbon atom, or a combination thereof, and can mean linear and / or segmented alkyl groups, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Unless otherwise specified in the specification, alkyl groups may be optionally substituted.

[0205] Unless otherwise specified, the term "C" 1-20 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 20 carbon atoms in a linear or branched chain. 1-20 Alkyl is C 1-19 , C 1-15 , C 1-10 , C 1-5 , C 1-4 , C 2-20 , C 2-12 , C 2-6 It may contain alkyl groups, etc.; it may be monovalent (methyl, etc.), divalent (methylene, etc.), or polyvalent (methine, etc.). C 1-20 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, sec-butyl, n-pentyl, n-hexyl, 1-methylhexyl, n-nonyl, n-decyl, adamantyl, n-undecyl, n-dodecyl, 2-ethyldodecyl, 2-butyldodecyl, n-eicosyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,7-heptylene, 1,8-octylene, 1,9-nonylene, 1,10-decylene, 1,12-dodecylene, 1,14-tetradecylene, 1,16-hexadecylene, 1,18-octadecylene, and 1,20-eicosilene.

[0206] Unless otherwise specified, the term "C" 1-6 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 6 carbon atoms in a linear or branched chain. 1-6 Alkyl is C 1-5 , C 1-4 , C 2-6It may contain alkyl groups, etc.; it may be monovalent (methyl, etc.), divalent (methylene, etc.), or polyvalent (methine, etc.). C 1-6 Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or tert-butyl ("t-Bu"), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, and 1,6-hexylene.

[0207] Unless otherwise specified, the term "C" 1-3 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 3 carbon atoms in a linear or branched chain. 1-3 Alkyl is C 1-2 and C 2-3 It may contain alkyl groups, etc.; it may be monovalent (methyl, etc.), divalent (methylene, etc.), or polyvalent (methine, etc.). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), methylene, 1,2-ethylene, and 1,3-propylene.

[0208] Unless otherwise specified, the term "alkenyl" means at least one unsaturated site, i.e., carbon-carbon sp. 2 This refers to a hydrocarbon group having a double bond, meaning a linear and / or branched alkenyl, where branched means that one or more alkyl groups, such as methyl, ethyl, or propyl, are bonded to the linear alkenyl chain. This may be monovalent, divalent, or polyvalent. Unless otherwise specified in the specification, the alkenyl may be optionally substituted.

[0209] Unless otherwise specified, "C 2-20"Alkenyl" refers to a linear or branched hydrocarbon group having at least one carbon-carbon double bond, with the number of carbon atoms ranging from 2 to 20, and the carbon-carbon double bond can be located at any position on the group. 2-20 Alkenil is C 2-19 , C 2-15 , C 2-10 , C 2-5 , C 2-4 , C 3-20 , C 4-12 , C 5-6 Contains alkenyls, etc.; may be monovalent, divalent, or polyvalent. 2-20 Examples of alkenyls include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbuto-2-enyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, octenyl, decenyl, n-undecenyl, vinylidene, alilidene, second-butylidene, and 2-methylbutylidene.

[0210] Unless otherwise specified, "C 2-6 "Alkenyl" refers to a linear or branched hydrocarbon group having at least one carbon-carbon double bond, the number of carbon atoms being 2 to 6, and the carbon-carbon double bond can be located at any position on the group. 2-6 Alkenil is C 2-4 , C 2-3 , including C4, C3 and C2 alkenyls; may be monovalent, divalent or polyvalent. 2-6 Examples of alkenyls include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadinyl, hexadienyl, vinylidene, alilidene, and second-butylidene.

[0211] Unless otherwise specified, "C 2-3 "Alkenyl" refers to a linear or branched hydrocarbon group having at least one carbon-carbon double bond, the number of carbon atoms being 2 to 3, and the carbon-carbon double bond can be located at any position on the group. 2-3 Alkenyls include C3 and C2 alkenyls; the C 2-3The alkenyl may be monovalent, divalent, or polyvalent. 2-3 Examples of alkenyls include, but are not limited to, ethenyl, propenyl, vinylidene, and arylidene.

[0212] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group having at least one unsaturated site, i.e., a carbon-carbon sp triple bond, and can represent linear and / or branched alkynyl groups, where branched means that one or more alkyl groups (such as methyl, ethyl, or propyl) are bonded to the linear alkynyl chain. This may be monovalent, divalent, or polyvalent. Unless otherwise specified in the specification, alkynyl may be optionally substituted.

[0213] Unless otherwise specified, the term "C" 2-20 The term "alkynyl" is used to represent a linear or branched hydrocarbon group consisting of 2 to 20 carbon atoms, which contains at least one carbon-carbon triple bond, and the carbon-carbon triple bond may be at any position in the group. 2-20 Alkinyl is C 2-19 , C 2-15 , C 2-10 , C 2-5 , C 2-4 , C 3-20 , C 4-12 , C 5-6 Contains alkynyl, etc.; this may be monovalent, divalent, or polyvalent. 2-20 Examples of alkynyls include, but are not limited to, ethinyl, propynyl, ethindiyl, propindiyl, pentynyl, pentindiyl, 1-butynyl, butadiinyl, cyclopropylethynyl, and 3-methyl-2-pentindiyl.

[0214] Unless otherwise specified, the term "C" 2-6 The term "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, where the carbon-carbon triple bond may be at any position in the group. It may be monovalent, divalent, or polyvalent. 2-6 Alkinyl is C2-5 , C 2-4 , C 2-3 , C2, C 2-6 , including C6 and C5 alkynyls. 2-6 Examples of alkynyls include, but are not limited to, ethinyl, propynyl, ethindiyl, propindiyl, pentinyl, and pentindiyl.

[0215] Unless otherwise specified, "C 2-3 The term "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, where the carbon-carbon triple bond may be at any position in the group. It may be monovalent, divalent, or polyvalent. 2-3 Alkynnyls include C3 and C2 alkynyls. 2-3 Examples of alkynyls include, but are not limited to, ethinyl, propynyl, ethinylene, and propindiyl.

[0216] Unless otherwise specified, the term “heteroalkyl” means, alone or in combination with other terms, a stable linear or branched alkyl or composition thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatomic group, where “alkyl” in “alkylatomic group” is as defined above in the present invention. In some embodiments, the heteroatom is selected from B, O, N, and S, where the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In other embodiments, the heteroatomic group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-20 It is a heteroalkyl; in some forms, the heteroalkyl is C 1-6 It is a heteroalkyl; in other embodiments, the heteroalkyl is C 1-3It is a heteroalkyl group. Heteroatoms or heteroatomic groups can be arranged in any internal position of the heteroalkyl, including the bond position of the alkyl to the rest of the molecule. Examples of heteroalkyls include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, etc.; up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3. Unless otherwise specified in the specification, heteroalkyls may be optionally substituted. Unless otherwise specified, the term "alkoxy" means an alkyl group that is bonded to the rest of the molecule via an oxygen atom, where "alkyl" in "alkyl" is as defined above in this invention. Unless otherwise specified in the specification, alkoxy groups may be optionally substituted.

[0217] Unless otherwise specified, the term "C" 1-20 "Alkoxy" refers to an alkyl group containing 1 to 20 carbon atoms bonded to the rest of the molecule via an oxygen atom. 1-20 Alkoxy is C 1-19 , C 1-10 , C 1-5 , C 2-20 , C 2-8 , including C6, C5 and C4 alkoxys. 1-20Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, n-hexyloxy, 1-methylhexyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, 2-ethyldodecyloxy, n-eicosyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, heptyleneoxy, dodecyleneoxy, etc.

[0218] Unless otherwise specified, the term "C" 1-6 "Alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms bonded to the rest of the molecule via an oxygen atom. 1-6 Alkoxy is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , including C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, etc.

[0219] Unless otherwise specified, the term "C" 1-4 "Alkoxy" refers to an alkyl group containing 1 to 4 carbon atoms bonded to the rest of the molecule via an oxygen atom. 1-4 Alkoxy is C 1-3 , C 1-2 , C 2-4 , including C4 and C3 alkoxys. 1-6Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, etc.

[0220] Unless otherwise specified, the term "C" 1-3 "Alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms bonded to the rest of the molecule via an oxygen atom. 1-3 Alkoxy is C 1-2 , C 2-3 , including C3 and C2 alkoxy, etc. 1-3 Examples of alkoxys include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, and propyleneoxy.

[0221] Unless otherwise specified, the term "amino" is monovalent.

[0222] [ka] , divalent

[0223] [ka] or polyvalent

[0224] [ka] That's fine. Unless otherwise specified, the term "alkylamino" refers to an alkyl group linked to the rest of the molecule via the amino group as defined above, and "alkyl" in the term "alkyl" is as defined above in this invention. Unless otherwise specifically indicated in the specification, alkylaminos may be optionally substituted.

[0225] Unless otherwise specified, the term "C" 1-20"Alkylamino" refers to an alkyl group containing 1 to 20 carbon atoms linked to the rest of the molecule via an amino acid. 1-20 Alkylamino is C 1-19 , C 1-14 , C 1-12 , C 2-6 , C 2-4 , C 15 , C 10 , C8, C5 and C 20 Contains alkylaminos, etc. 1-20 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, -NHCH2CH2CH2CH2CH2CH3, -NHCH2CH2CH2CH2CH2CH2CH3, -N(CH2CH2CH3)(CH2CH2CH2CH3), etc.

[0226] Unless otherwise specified, the term "C" 1-6 "Alkylamino" represents an alkyl group containing 1 to 6 carbon atoms linked to the rest of the molecule via an amino acid. 1-6 Alkylamino is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , including C6, C5, C4, C3 and C2 alkylaminos, etc. 1-6 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0227] Unless otherwise specified, the term "C" 1-4 "Alkylamino" refers to an alkyl group containing 1 to 4 carbon atoms linked to the rest of the molecule via an amino acid. 1-4 Alkylamino is C 1-3 , C 1-2 , C 2-4Includes C4, C3, and C2 alkylaminos, etc. 1-4 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc. Unless otherwise specified, the term "C" 1-3 "Alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms linked to the rest of the molecule via an amino acid. 1-3 Alkylaminos include C 1-2 C includes C3, C2 alkylaminos, etc. 1-3 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, and -NHCH2(CH3)2.

[0228] Unless otherwise specified, the term “alkylthio” refers to an alkyl group bonded to the rest of the molecule via a sulfur atom, where “alkyl” in “alkyl” follows the definition set forth herein. Unless otherwise specified in the specification, alkylthio may be optionally substituted.

[0229] Unless otherwise specified, the term "C" 1-20 "Alkylthio" refers to an alkyl group containing 1 to 20 carbon atoms bonded to the rest of the molecule via a sulfur atom. 1-20 Alkylthio contains C 1-19 , C 1-14 , C 1-12 , C 2-6 , C 2-4 , C 15 , C 10 , C8, C5, C 20 It contains alkylthio, etc. 1-20Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -SCH2CH2CH2CH3, -SCH2CH2(CH3)2, -SCH2CH2CH2CH2CH3, -SCH2CH2CH2CH2CH2CH3, and -SCH2(CH2CH2CH3)(CH2CH2CH2CH3).

[0230] Unless otherwise specified, the term "C" 1-6 "Alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms bonded to the rest of the molecule via a sulfur atom. 1-6 Alkylthio contains C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 This includes C6, C5, C4, C3, C2 alkylthio, etc. 1-6 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, and -SCH2(CH3)2.

[0231] Unless otherwise specified, the term "C" 1-4 "Alkylthio" refers to an alkyl group containing 1 to 4 carbon atoms bonded to the rest of the molecule via a sulfur atom. 1-4 Alkylthio contains C 1-3 , C 1-2 , C 2-4 This includes C4, C3, and C2 alkylthios. 1-4 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, and -SCH2(CH3)2.

[0232] Unless otherwise specified, the term "C" 1-3 "Alkylthio" refers to an alkyl group containing 1 to 3 carbon atoms bonded to the rest of the molecule via a sulfur atom. 1-3 Alkylthio contains C 1-3 , C 1-2 and C3 alkylthio, etc. 1-3Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, and -SCH2(CH3)2.

[0233] Unless otherwise specified, the term “cycloalkyl” refers to a stable, non-aromatic monocyclic or polycyclic saturated hydrocarbon group consisting of carbon and hydrogen atoms, which may include fused rings, spirocyclic rings, and / or bridged rings. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decahydronaphthalenyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and others. 4-6 "Cycloalkyl" refers to a cycloalkyl group having 4 to 6 ring carbon atoms. Similarly, "C 3-4 "Cycloalkyl" refers to a cycloalkyl group having 3 to 4 cyclic carbon atoms. Unless otherwise specified in the specification, cycloalkyl groups may be optionally substituted.

[0234] Unless otherwise specified, "C 3-20 "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group having 3 to 20 cyclic carbon atoms (for example, 3 to 15 cyclic carbon atoms, and even more, for example, 3 to 6 cyclic carbon atoms), and may be monovalent, divalent, or polyvalent. 3-20 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0235] Unless otherwise specified, "C 3-6 "Cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3 to 6 cyclic carbon atoms (for example, 3 to 5 cyclic carbon atoms, and even more, for example, 3 to 4 cyclic carbon atoms), and may be monovalent, divalent, or polyvalent. 3-6 Examples of cycloalkyl compounds include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0236] Unless otherwise specified, "C 4-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, and is monocyclic and bicyclic. 4-6 Cycloalkyls include C 4-5 , C 5-6 This includes C4, C5, and C6 cycloalkyl groups, and may be monovalent, divalent, or polyvalent. 4-6 Examples of cycloalkyl compounds include, but are not limited to, cyclobutyl, cyclopentyl, and cyclohexyl.

[0237] Unless otherwise specified, the term "heterocycloalkyl" refers to a non-aromatic saturated cyclic group having a monocyclic, fused, spirocyclic, and / or bridged ring structure in which at least one ring atom is a heteroatom or heteroatomic group and the rest are carbon atoms, in some embodiments the heteroatom is independently selected from B, O, N, and S on a case-by-case basis, where the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)). p(where p is 1 or 2), the nitrogen atom may be optionally quaternized, and in other embodiments, the heteroatomic group is each independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heteroatomic group may be located at any internal position of the heterocycloalkyl, including the bonding position between the heterocycloalkyl and the rest of the molecule. In some embodiments, the heterocycloalkyl is a 3- to 20-membered heterocycloalkyl, in some embodiments, the heterocycloalkyl is a 3- to 10-membered heterocycloalkyl, and in other embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. Unless otherwise specified in the specification, the heterocycloalkyl may be optionally substituted. Unless otherwise specified, the term "3-6 membered heterocycloalkyl" alone or in combination with other terms refers to a saturated cyclic group consisting of 3 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms or the aforementioned heteroatom groups independently selected from B, O, S, and N, and the remainder are carbon atoms, provided that the nitrogen atom may optionally be quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p(where p is 1 or 2). This includes monocyclic and bicyclic systems, with bicyclic systems including spiro rings, fused rings, and bridge rings. Furthermore, with respect to the "3-6 membered heterocycloalkyls," the heteroatom or heteroatomic group may be located in any internal position of the heterocycloalkyl, or it may occupy a bonding position between the heterocycloalkyl and the rest of the molecule. The 3-6 membered heterocycloalkyls include 5-6 membered, 4-membered, 5-membered, and 6-membered heterocycloalkyls, and so on. Examples of 3- to 6-membered heterocycloalkyls include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl, tetrahydrothien-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl, 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), dioxanyl, dithiopyranyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiadinyl, hexahydropyridazinyl, homopiperadinyl, or homopiperidinyl.

[0238] Unless otherwise specified, the term "cycloalkenyl" in this invention refers to a stable, non-aromatic monocyclic or polycyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, and one or more carbon-carbon sp² groups. 2 They may have a double bond and include fused rings, spiro rings and / or bridging ring systems. Monocyclic cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]hept-2-enyl. Unless otherwise specified in the specification, cycloalkenyls may be optionally substituted. 3-7"Cycloalkenyls" include C3, C4, C5, C6, and C7 cycloalkenyls. Examples of cycloalkenyls include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0239] Unless otherwise specified, the term "heterocycloalkenyl" in this invention refers to a cyclic alkenyl comprising multiple heteroatoms or heteroatomic groups, in some forms in which the heteroatoms are independently selected from B, O, N, and S in each occurrence, and the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2), the nitrogen atom is optionally quaternized, and in other embodiments, the heteroatom group is independently selected for each occurrence 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)-. "5-6 heterocycloalkenyl" alone or in combination with other terms represents an unsaturated cyclic group consisting of 5-6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from B, O, S and N or the aforementioned heteroatoms, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O) p (where p is 1 or 2). An example of a heterocycloalkenyl is,

[0240] [ka] This includes, but is not limited to, the heterocycloalkenyls. Unless otherwise specified in the specification, heterocycloalkenyls may be optionally substituted.

[0241] Unless otherwise specified, when a substituent bonded to ring A can link with ring A to form a ring, it means that the substituent can bond to any position on ring A and form a new ring (including a fused ring, spiro ring, or bridge ring) together with ring A, where ring A can be selected from the aforementioned cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, etc. For example,

[0242] [ka] The R inside

[0243] [ka] When linked to form a 6-membered ring, the embodiment is

[0244] [ka] This includes, but is not limited to, the following.

[0245] Unless otherwise specified, C n~n+m or C n ~C n+m This refers to any specific example containing n to n+m carbon atoms, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , C 12 This includes any range from n to n+m, for example C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , C 9-12This includes, for example, n-membered to n+m-membered rings, which refer to rings with n to n+m ring atoms. For example, 3-12 membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings, as well as any range from n to n+m. For example, 3-2 membered rings include 3-6 membered rings, 3-9 membered rings, 5-6 membered rings, 5-7 membered rings, 6-7 membered rings, 6-8 membered rings, 6-10 membered rings, etc.

[0246] Unless otherwise specified, the term "aryl" refers to a hydrocarbon cyclic group having at least one aromatic ring. In this invention, aryl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and may include fused rings, spiro-rings, and / or bridged ring systems. Aryl includes, but is not limited to, benzene, naphthalene, anthracene, fluoranthan, phenanthrene, benzophenanthrene, perylene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene, and their derivative groups. Unless otherwise specified, aryl may be optionally substituted.

[0247] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic system having 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, and 5 to 20 ring atoms. The heteroaryl group is preferably a 5 to 10-membered ring having 1 to 3 heteroatoms, more preferably a 5 or 6-membered ring having 1 to 3 heteroatoms. Non-limiting examples include pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, and pyrazinyl. The heteroaryl can be bonded to the remainder of the molecule via heteroatoms or carbon atoms. The heteroaryl may be fused with an aryl, heterocyclyl, or cycloalkyl ring, where the ring linked to the parent structure is a heteroaromatic ring. Non-limiting examples include:

[0248] [ka] These include, among others. Non-exclusive examples of heteroaryls further include triazines, pyridines, pyrimidines, imidazoles, furans, thiophenes, benzofurans, benzothiophenes, indoles, carbazoles, pyrroloimidazoles, pyrrolopyrroles, thienopyrroles, thienopyrroles, furanopyrroles, furanofurans, thienofurans, benzoisoxazoles, benzoisothiazoles, benzimidazoles, quinolines, isoquinolines, phthalazines, quinoxalines, phenanthidines, perimidines, quinazolines, quinazolinones, dibenzothiophenes, dibenzofurans, carbazoles, and their derivatives. Unless otherwise specified in the specification, heteroaryls may be substituted or unsubstituted, and if substituted, the substituent is preferably selected from one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

[0249] As used in this invention, the term "substituted" means that in any of the above-mentioned groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is substituted by bonding with a non-hydrogen atom, and such non-hydrogen atom includes, but is not limited to, halogen atoms (e.g., F, Cl, Br, I), oxygen-containing groups (e.g., hydroxy, alkoxy, ester groups), sulfur-containing groups (e.g., thiol, thioalkyl, sulfone, sulfonyl, sulfinyl), nitrogen-containing groups (e.g., amine, amide, alkylamino, dialkylamino, arylamino, aryl-alkyl-amino, diarylamino, N-oxide, imide, enamine), silicon-containing groups (e.g., trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl), and other heteroatoms in various other groups.

[0250] As used in this invention, the term "substituted" also means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), one or more hydrogen atoms are substituted by a higher-order bond of the heteroatom (e.g., a double or triple bond), such as oxygen in carbonyl, carboxyl, and ester groups, and nitrogen in imines, oximes, hydrazones, and nitriles. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are substituted by -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h -OC(=O)NRg R h , -OR g , -SR g -SOR g SO2R g , -OSO2R g , -SO2OR g ,=NSO2R g , or -SO2NR g R h This means that it is replaced by -C(=O)R. "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by -C(=O)R g , -C(=O)OR g -C(=O)NR g R h ,-CH2SO2R g -CH2SO2NR g R h This also means that it is replaced by the aforementioned R g and R h These may be the same or different, and are independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. "Substituted" further means that one or more hydrogen atoms in any of the above groups are substituted with amino, cyano, hydroxy, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, and heteroaryl-alkyl. Furthermore, each of the above substituents may be optionally replaced with one or more of the above substituents.

[0251] Those skilled in the art should understand that, since some compounds of formula (I) contain one or more chiral centers, two or more stereoisomers may exist. Therefore, the compounds of the present invention may exist in the form of a single stereoisomer (e.g., an enantiomer, a diastereomer) and mixtures thereof in any ratio (e.g., a racemate), and, where appropriate, in the form of tautomers and geometric isomers thereof. As used herein, the term "stereoisomer" refers to a compound that has the same chemical composition but differs in the spatial arrangement of its atoms or groups. Stereoiomers include enantiomers, diastereomers, and conformational isomers.

[0252] As used herein, the term "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. 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 point, boiling point, spectroscopic properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical methods such as electrophoresis or chromatography, including HPLC.

[0253] Many organic compounds exist in optically active forms, meaning they have the ability to rotate the plane of polarization 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 with respect to the chiral center of the molecule. The prefixes d and l or (+) and (-) are used to indicate the direction in which the compound rotates plane-polarized light, with (-) or l indicating that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical to each other except that they are mirror images. Certain stereoisomers are also called enantiomers, and mixtures of such isomers are generally called enantiomer mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and is produced when stereoselectivity or stereospecificity does not manifest in a chemical reaction or method. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that do not exhibit optical activity.

[0254] Racemic mixtures can be used as is or separated into single isomers. Separation yields stereochemically pure compounds or mixtures enriched with one or more isomers. Methods for separating isomers are well known and include physical methods such as chromatography using chiral adsorbents. Single isomers in chiral form can be prepared from chiral precursors. Alternatively, to chemically separate a single isomer from a mixture, a non-pairing salt can be formed with a chiral acid (e.g., a single enantiomer of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), the salt can be fractionally crystallized, and one or both of the separated bases can be liberated. By repeating this step as needed, one or two isomers substantially free of the other isomer can be obtained, i.e., desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.5% by weight. Alternatively, as is well known to those skilled in the art, a method can be employed in which a racemic mixture is covalently bonded to a chiral compound (chiral auxiliary) to obtain a non-diastereomer.

[0255] As used herein, the term "tautomer" or "tautomer" refers to structural isomers with different energies that are interconvertible across low-energy barriers. For example, proton tautomers (also called proton-transfer tautomers) involve interconversion via proton transfer, with keto-enol and imine-enamine isomerization being examples. Valence tautomers involve interconversion via rearrangement of bonding electrons. The compounds of the present invention can be prepared by various synthesis methods well known to those skilled in the art, including, but not limited to, the following specific examples, embodiments combining them with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0256] Technical and scientific terms used herein that are not specifically defined have the meanings generally understood by a person ordinary in the art to which this invention pertains. [Specific implementation details] The present application will be described in detail below through examples, but this does not mean any limitation to the present application. Although the present application has already been described in detail in this specification and specific examples have been disclosed, it will be obvious to those skilled in the art that various modifications and improvements can be made to specific embodiments of the present application without departing from the spirit and scope of the present application.

[0257] Example 1: Synthesis of Compound 1

[0258] [ka]

[0259] Step 1: Preparation of Compounds 1-2 Compound 1-1 (1.00 g, 5.81 mmol) and triphosgene (1.72 g, 5.81 mmol) were dissolved in ultra-dried tetrahydrofuran (50 mL). Triethylamine (2.35 g, 23.2 mmol) was added dropwise to the reaction system under an ice bath and nitrogen stream. After the addition was complete, the reaction system was stirred for a further 1 hour under an ice bath. Then, 4-amino-1-tert-butoxycarbonylpiperidine (2.02 g, 10.1 mmol) was added. The mixture was allowed to rise naturally to room temperature and stirred for 16 hours. Completion of the reaction was confirmed by LC-MS. The reaction was quenched with saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (70 mL x 3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by reverse-phase column chromatography (water / acetonitrile = 3 / 2) to obtain compound 1-2 (1.94 g, yield: 84.0%). LC-MS(ESI) [M+H] + 399.1.

[0260] Step 2: Preparation of Compounds 1-3 Under a nitrogen atmosphere, potassium tert-butoxide (1.35 g, 12.0 mmol) was added to a solution of compound 1-2 (800 mg, 2.01 mmol) in ultra-dried tetrahydrofuran (10 mL). The reaction system was stirred at 60°C for 2 hours. Completion of the reaction was confirmed by LC-MS. The mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 1-3 (338 mg, yield: 47.8%). LC-MS(ESI)[M+H] + 297.0.

[0261] Step 3: Preparation of Compounds 1-4 Under a nitrogen atmosphere, N-bromosuccinimide (132 mg, 0.743 mmol) was added to a 10 mL solution of compound 1-3 (238 mg, 0.675 mmol) in acetonitrile. The reaction system was stirred at room temperature for 3 hours. Completion of the reaction was confirmed by LC-MS. After concentration under reduced pressure, the residue was purified by reverse-phase column chromatography (water / acetonitrile = 1 / 1) to obtain compound 1-4 (212 mg, yield: 72.9%). LC-MS(ESI)[M+H] + 374.9 / 376.9.

[0262] Step 4: Preparation of Compounds 1-5 Under an ice bath and nitrogen atmosphere, N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (202 mg, 0.556 mmol) and N,N-diisopropylethylamine (120 mg, 0.927 mmol) were sequentially added to a solution of compound 1-4 (200 mg, 0.464 mmol) in N,N-dimethylformamide (5 mL). The reaction system was stirred in an ice bath for 2 hours. Completion of the reaction was confirmed by LC-MS. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (40 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 = 2 / 1) to obtain compound 1-5 (203 mg, yield: 65.7%). LC-MS(ESI)[M+H-56] + 609.9 / 611.9.

[0263] Step 5: Preparation of Compounds 1-6 Compound 1-5 (467 mg, 0.700 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-group)-3,6-dihydro-2H-pyran (177 mg, 0.840 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (14.0 mg, 0.070 mmol), and sodium carbonate (223 mg, 2.10 mmol) were dissolved in 1,4-dioxane / water (10 / 1 mL). The reaction system was stirred at 80°C for 4 hours. Completion of the reaction was confirmed by LC-MS. After dilution with water (30 mL), the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated saline solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 1-6 (303 mg, yield 70.5%). LC-MS(ESI)[M+H] + 670.2.

[0264] Step 6: Preparation of Compounds 1-7 At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compounds 1-6 (118 mg, 176 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS. The mixture was concentrated under reduced pressure to obtain the crude product of compounds 1-7 (120 mg). This crude product was used directly in the next reaction. LC-MS(ESI)[M+H] + 570.4.

[0265] Step 7: Preparation of Compounds 1-8 At room temperature, 120 mg of the crude products of compounds 1-7, 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid (51.5 mg, 211 μmol), and N,N-diisopropylethylamine (68.1 mg, 527 μmol) were dissolved in 10 mL of dichloromethane, to which O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (79.5 mg, 211 μmol) was added. The reaction system was stirred at room temperature for 4 hours. Completion of the reaction was confirmed by LC-MS. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 1-8 (120 mg, 2-step total yield: 85.6%). LC-MS(ESI)[M+H] + 796.2.

[0266] Step 8: Preparation of Compound 1 Under ice water bath and nitrogen gas protection, a solution of compounds 1-8 (100 mg, 126 μmol) in dichloromethane (5 mL) was added dropwise with a solution of boron maleate chloride dichloromethane (1.00 mol / L, 251 μL, 251 μmol). The reaction system was stirred at room temperature for 3 hours. Completion of the reaction was confirmed by LC-MS. After quenching with water (10 mL), the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain compound 1 (36.0 mg, yield: 40.6%). LC-MS(ESI)[M+H] + 706.2.

[0267] 1HNMR(400MHz,DMSO-d6)δ10.36(s,1H),10.18(s,1H),8.56(s,1H),8.06(d,J=8.5Hz,1H),7.98(d,J=2 .1Hz,1H),7.73(dd,J=9.0,2.1Hz,1H),6.64(dd,J=3.1,1.6Hz,1H),5.09(s,1H),4.96(d,J=5.1Hz,2H) ,4.63(d,J=12.8Hz,1H),4.25(d,J=2.9Hz,2H),3.81(t,J=5.4Hz,2H),3.56(d,J=13.2Hz,1H),3.16(t, J=12.9Hz,1H),2.89(s,1H),2.55(s,4H),2.43(s,3H),1.73(d,J=12.0Hz,1H),1.56(d,J=11.9Hz,1H).

[0268] Example 2: Synthesis of Compound 2

[0269] [ka]

[0270] Step 1: Preparation of Compound 2-2 Compound 2-1 (800 mg, 1.86 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (469 mg, 2.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (136 mg, 186 μmol), and cesium carbonate (1.82 g, 5.58 mmol) were dissolved in 1,4-dioxane / water (30 / 5 mL). The reaction system was stirred at 100 °C for 12 hours. Completion of the reaction was confirmed by LC-MS. After cooling the reaction system to room temperature, it was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 2-2 (750 mg, yield: 93.1%). LC-MS(ESI)[M+H] + 378.0.

[0271] Step 2: Preparation of Compounds 2-3 Under a nitrogen atmosphere, N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (629 mg, 1.73 mmol) and N,N-diisopropylethylamine (448 mg, 3.46 mmol) were sequentially added to a solution of compound 2-2 (750 mg, 1.73 mmol) in N,N-dimethylformamide (5 mL). The reaction system was stirred at 40°C for 4 hours. Completion of the reaction was confirmed by LC-MS. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 2-3 (770 mg, yield 66.5%). LC-MS(ESI)[M+H-56] + 612.8.

[0272] Step 3: Preparation of Compounds 2-4 At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compound 2-3 (400 mg, 598 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS. The mixture was concentrated under reduced pressure to obtain the crude product of compound 2-4 (340 mg). This crude product was used directly in the next reaction. LC-MS(ESI)[M+H] + 569.0.

[0273] Step 4: Preparation of Compounds 2-5 At room temperature, 340 mg of the crude product of compound 2-4, 175 mg (717 μmol) of 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid, and 312 μL (1.79 μmol) of N,N-diisopropylethylamine were added to a solution of dichloromethane (10 mL) with 232 mg (717 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. The reaction system was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 2-5 (450 mg, 2-step total yield: 94.7%). LC-MS(ESI)[M+H] + 795.2.

[0274] Step 5: Preparation of Compound 2 Under ice water bath and nitrogen gas protection, a solution of compound 2-5 (350 mg, 440 μmol) in dichloromethane (10 mL) was added dropwise with a solution of boron maleate dichloromethane chloride (1.00 mol / L, 880 μL, 880 μmol). The reaction system was stirred at room temperature for 3 hours. Completion of the reaction was confirmed by LC-MS. After quenching with water (10 mL), the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain compound 2 (85.0 mg, yield: 27.4%). LC-MS(ESI)[M+H] + 705.0.

[0275] 1HNMR(400MHz,DMSO-d6)δ10.20(d,J=17.6Hz,2H),8.56(s,1H),8.10(d,J=8.6Hz,1H),7.97(d,J=2.1Hz,1H ),7.72(dd,J=8.7,2.2Hz,1H),7.46(s,1H),6.52(s,1H),5.04(d,J=17.4Hz,3H),4.62(d,J=12.8Hz,1H),4. 24(d,J=3.2Hz,2H),3.81(t,J=5.4Hz,2H),3.55(d,J=13.2Hz,1H),3.13(t,J=12.9Hz,1H),2.86(t,J=12.9 Hz,1H),2.62-2.53(m,2H),2.48-2.44(m,2H),2.43(s,3H),1.72(d,J=11.9Hz,1H),1.55(d,J=12.1Hz,1H).

[0276] Example 3: Synthesis of Compound 3

[0277] [ka]

[0278] Step 1: Preparation of Compound 3-2 Compound 3-1 (2.50 g, 13.5 mmol) and trisphosgene (1.40 g, 4.72 mmol) were dissolved in dichloromethane (25 mL). Triethylamine (4.10 g, 40.5 mmol) was added dropwise to the reaction system under an ice bath and nitrogen atmosphere. After the addition was complete, the reaction system was stirred for a further 1 hour under an ice bath. Subsequently, 4-amino-1-tert-butoxycarbonylpiperidine (2.52 g, 12.58 mmol) was added. After raising the temperature to room temperature, the reaction was allowed to proceed for 4 hours. Completion of the reaction was confirmed by LC-MS. The reaction was quenched with water (100 mL) and extracted with dichloromethane (70 mL x 3). The organic phases were combined and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 3-2 (2.60 g, yield: 51.7%). LC-MS(ESI)[M+H-56] + 356.2.

[0279] Step 2: Preparation of Compound 3-3 Under a nitrogen atmosphere, tert-butoxypotassium (2.13 g, 18.9 mmol) was added to a solution of compound 3-2 (2.60 g, 6.32 mmol) in ultra-dried tetrahydrofuran (30 mL). The reaction system was stirred at 60 °C for 6 hours. Completion of the reaction was confirmed by LC-MS. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-3 (1.10 g, yield: 47.6%). LC-MS(ESI)[M+H-56] + 310.4.

[0280] Step 3: Preparation of Compounds 3-4 Under ice water cooling and a nitrogen atmosphere, N-bromosuccinimide (487 mg, 2.74 mmol) was added to a solution of compound 3-3 (1.00 g, 2.74 mmol) in dichloromethane (20 mL). The reaction system was stirred in an ice water bath for 1 hour. Completion of the reaction was confirmed by LC-MS. Water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (70 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-4 (950 mg, yield: 78.1%). LC-MS(ESI)[M+H-56] + 388.0 / 390.0.

[0281] Step 4: Preparation of Compounds 3-5 Compounds 3-4 (900 mg, 2.03 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (511 mg, 2.43 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (148 mg, 202 μmol), and cesium carbonate (1.98 g, 6.08 mmol) were dissolved in 1,4-dioxane / water (10 / 3 mL). The reaction system was stirred at 100 °C for 12 hours. Completion of the reaction was confirmed by LC-MS. After cooling the reaction system to room temperature, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (70 mL x 3). The combined organic phases were washed with saturated saline solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-5 (300 mg, yield: 33.1%). LC-MS(ESI)[M+H-56] + 392.2.

[0282] Step 5: Preparation of Compounds 3-6 Under an ice bath and nitrogen stream, N-[2-chloro-4-(trifluoromethyl)phenyl]-2-iodoacetamide (211 mg, 581 μmol) and N,N-diisopropylethylamine (150 mg, 1.16 mmol) were sequentially added to a solution of compound 3-5 (260 mg, 581 μmol) in N,N-dimethylformamide (5 mL). The reaction system was stirred at 40°C for 3 hours. Completion of the reaction was confirmed by LC-MS. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound 3-6 (250 mg, yield 63.0%). LC-MS(ESI)[M+H-56] + 627.2.

[0283] Step 6: Preparation of Compounds 3-7 At room temperature, trifluoroacetic acid (2 mL) was added to a solution of compound 3-6 (250 mg, 366 μmol) in dichloromethane (10 mL). The reaction system was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS. The mixture was concentrated under reduced pressure to obtain the crude product of compound 3-7 (250 mg). This crude product was used directly in the next reaction. LC-MS(ESI)[M+H] + 583.2.

[0284] Step 7: Preparation of Compounds 3-8 At room temperature, 250 mg of the crude product of compound 3-7, 105 mg (429 μmol) of 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid, and 55.4 mg (429 μmol) of N,N-diisopropylethylamine were added to a 10 mL solution of dichloromethane. 162 mg (429 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate was added. The reaction system was stirred at room temperature for 12 hours. Completion of the reaction was confirmed by LC-MS. The solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 3-8 (200 mg, 2-step total yield: 67.6%). LC-MS(ESI)[M+H] + 809.4.

[0285] Step 8: Preparation of Compound 3 Under ice water bath and nitrogen gas protection, a solution of compound 3-8 (100 mg, 123 μmol) in dichloromethane (10 mL) was added dropwise with a solution of boron maleate dichloromethane chloride (1.00 mol / L, 247 μL, 247 μmol). The reaction system was stirred at room temperature for 2 hours. Completion of the reaction was confirmed by LC-MS. After quenching with water (20 mL), the mixture was extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to obtain compound 3 (13.6 mg, yield: 15.3%). LC-MS(ESI)[M+H] + 719.2.

[0286] 1 HNMR(400MHz,DMSO-d6)δ10.33(s,1H),10.18(s,1H),8.56(s,1H),8.06(d,J=8.5Hz,1H),7.97(d,J=2.1Hz,1H) ,7.73(dd,J=8.8,2.1Hz,1H),6.04-5.92(m,1H),5.06(s,1H),4.88(d,J=3.6Hz,2H),4.63(d,J=12.9Hz,1H),4. 21(m,2H),3.78(t,J=5.4Hz,2H),3.56(d,J=13.3Hz,1H),3.13(t,J=12.9Hz,1H),2.86(t,J=12.7Hz,1H),2.59( d,J=13.6Hz,1H),2.45(s,3H),2.43(s,3H),2.36-2.30(m,3H),1.70(d,J=12.0Hz,1H),1.53(d,J=12.0Hz,1H).

[0287] Example 4: Synthesis of Compound 4

[0288] [ka]

[0289] Step 1: Preparation of Compound 4-2 Starting materials 4-1 (3.80 g, 33.31 mmol) and PMBCl (7.85 g, 49.97 mmol) were dissolved in DMF (40.0 mL), and potassium carbonate (6.90 g, 49.97 mmol) was added at room temperature. The reaction system was stirred at 60 °C for 5 hours, then cooled, and the reaction was quenched with water (50 mL). 40 mL of a mixed solvent of petroleum ether and ethyl acetate (5:1) was added, and the mixture was stirred for 5 minutes. After filtration, the cake was washed with a mixed solvent of petroleum ether and ethyl acetate (5:1) to obtain compound 4-2 (3.90 g), with a yield of 50%.

[0290] Step 2: Preparation of Compound 4-3 Compound 4-2 (3.40 g, 14.52 mmol) was dissolved in a methanol-water mixed solvent (40 mL, 3:1), iron powder (2.44 g, 43.55 mmol) and ammonium chloride (3.92 g, 72.58 mmol) were added, and the reaction system was stirred at 70°C for 2 hours, then cooled. The suspension was filtered through diatomaceous earth, the filtrate was concentrated to dryness under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated brine, separated, dried, and the solvent was removed using a rotary evaporator to obtain compound 4-3 (2.55 g). The yield was 86.0%. LC-MS(ESI)[M+H] + : 205.2.

[0291] Step 3: Preparation of Compound 4-4 Compound 4-3 (2 g, 9.79 mmol), 4-(1-methoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3.5 g, 11.13 mmol), and TsOH (168.44 mg, 979.30 μmol) were dissolved in EtOH (35 mL), and the reaction system was heated to 100°C and stirred for 12 hours. TLC showed the disappearance of the starting materials. Water was directly added to the reaction system to quench the reaction, the product was extracted with ethyl acetate, the organic phase was washed with aqueous sodium carbonate solution, liquid-liquid-liquid, dried, and concentrated to dryness under reduced pressure to obtain compound 4-4 (4.91 g). The residue was used directly in the next step. The yield of the crude product was 100%. LC-MS(ESI)[M+H] + : 501.2.

[0292] Step 4: Preparation of Compounds 4-5 Compound 4-4 (4 g, 7.99 mmol) was dissolved in diphenyl ether:dichloromethane (5 mL, 4:1) and slowly added dropwise to diphenyl ether (43 mL) preheated to an internal temperature of 220°C. After the addition was complete, the reaction system was stirred at 220°C for 4.5 minutes. After cooling the reaction system to room temperature, the reaction was directly quenched with cyclohexane, the solid was filtered and washed with cyclohexane to obtain compound 4-5 (1.1 g), with a yield of 29.4%. LC-MS(ESI)[M+H] + : 469.2.

[0293] Step 5: Preparation of Compounds 4-6 Compound 4-5 (1 g, 2.13 mmol) was dissolved in DMF (7 mL), and ethyl bromide (712.84 mg, 4.27 mmol) and cesium carbonate (2.10 g, 6.40 mmol) were added. After addition, the reaction system was stirred at room temperature for 2 hours. The reaction system was directly quenched with water, the product was extracted with ethyl acetate, the organic phase was liquid-liquid separated, dried, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-6 (0.27 g) in yield of 22.9%. LC-MS(ESI)[M+H] + :555.2.

[0294] Step 6: Preparation of Compounds 4-7 Compound 4-6 (170 mg, 306.51 μmol) was dissolved in DCM (2 mL), and TFA (1 mL) was added at room temperature. After addition, the reaction system was stirred at room temperature for 0.5 hours. Disappearance of the starting material was confirmed by TLC. The reaction system was directly concentrated under reduced pressure and dried. The residue was used directly in the next step, and the yield of the crude product was 100%. LC-MS(ESI)[M+H] + :455.2.

[0295] Step 7: Preparation of Compounds 4-8 Compound 4-7 (150 mg, 330.02 μmol) was dissolved in TFA (2 mL), and TfOH (0.05 mL) was added. After addition, the reaction system was stirred at room temperature for 10 minutes. Disappearance of the starting material was confirmed by TLC. The reaction system was directly concentrated under reduced pressure and dried. The residue was used directly in the next step, and the yield of the crude product was 100%. LC-MS(ESI)[M+H] + :335.2.

[0296] Step 8: Preparation of Compounds 4-9 Compound 4-8 (200 mg, 598.13 μmol) and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (146.09 mg, 598.13 μmol) were dissolved in DMF (3.96 mL). DIEA (773.05 mg, 5.98 mmol, 1.04 mL) and HATU (293.36 mg, 777.58 μmol) were added, and the reaction system was stirred at room temperature for 2 hours. The reaction system was directly quenched with water, the by-products were extracted with ethyl acetate, the aqueous phase was washed with citrate, and then extracted with ethyl acetate. The organic phase was separated, dried, and concentrated to dryness under reduced pressure. The residue was purified by HPLC to obtain compound 4-9 (110 mg) in 32.83% yield. LC-MS(ESI)[M+H] + :561.2.

[0297] Step 9: Preparation of Compounds 4-10 Compound 4-9 (16 mg, 28.54 μmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid (12.78 mg, 99.89 μmol), and PhenCuPPh3Br (6.70 mg, 11.42 μmol) were dissolved in DMSO (1 mL). After addition, the reaction system was heated to 90°C under air ball protection and stirred for 3 hours. The reaction system was directly quenched with water, the product was extracted with ethyl acetate, the organic phase was separated, dried, and concentrated to dryness under reduced pressure. The residue was purified using a medium-pressure preparative column (DCM:MeOH = 10:1) to obtain compound 4-10 (11 mg) in 59.88% yield. LC-MS (ESI) [M+H] + :643.2.

[0298] Step 10: Preparation of Compounds 4-11 Compound 4-10 (17 mg, 26.45 μmol) was dissolved in a mixed solvent of water (1.5 mL), MeOH (1.5 mL), and THF (1.5 mL). NaOH (10.58 mg, 264.51 μmol) was added, and the reaction system was stirred at room temperature for 0.25 hours. The pH was adjusted to 4.0 with 3N hydrochloric acid, the product was extracted with ethyl acetate, and the organic phase was separated, dried, and concentrated to obtain crude product 4-11 (16 mg). The yield of the crude product was 100%. LC-MS (ESI) [M+H] + :615.2.

[0299] Step 11: Preparation of Compounds 4-12 Compound 4-11 (16 mg, 26.05 μmol), 2-chloro-4-trifluoromethylaniline (15.20 mg, 78.17 μmol), and pyridine (20.37 mg, 261 μmol) were dissolved in DCM (0.5 mL). Phosphoryl chloride (20.29 mg, 130 μmol) was added, and the reaction system was stirred at room temperature for 0.5 hours. After confirming the product spot by TLC, the reaction system was quenched with water, the product was extracted with ethyl acetate, the organic phase was liquid-liquid-liquid-dried, and concentrated to dryness under reduced pressure. The residue was purified by preparative column chromatography (dichloromethane:methanol = 10:1) to obtain compound 4-12 (16 mg) with a yield of 77.88%. LC-MS(ESI)[M+H] + :792.2.

[0300] Step 12: Preparation of Compound 4 Compound 4-12 (18 mg, 22.75 μmol) was dissolved in DCM (2 mL), and boron trichloride (180.00 μL, 1 N) was added at room temperature. After the addition, the reaction system was stirred at room temperature for 0.25 hours. The reaction system was directly quenched with methanol, and the residue was purified by preparative HPLC to obtain crude compound 4 product (10.63 mg, including isomers). Crude product 4 was further purified by SFC (column: ChiralPak AD, 250 × 30 mm ID, 10 μm; mobile phase [A: carbon dioxide, B: isopropanol (containing 0.1% aqueous ammonia)]; B%: 40%, flow rate: 150 mL / min, column temperature: 38 °C, wavelength: 220 nm, cycle time: ~5 min) to obtain compound 4 (4.11 mg), yielding a yield of 38.66% (retention time of target product: 0.788 min, analytical method: column: ChiralPak AD, 50 × 4.6 mm ID, 3 μm, mobile phase [A: carbon dioxide, B: isopropanol (containing 0.05% DEA)], 40% B, flow rate: 3 mL / min, column temperature: 35 °C). LC-MS(ESI)[M+H]+:702.2.

[0301] 1HNMR(400MHz,Methanol-d4)δ8.31(s,1H),8.04(d,J=8.8Hz,1H),7.74-7.68(m,1H), 7.55-7.47(m,1H),6.79-6.73(m,1H),5.29(s,2H),4.30-4.22(m,2H),3.94-3.85(m,2 H),3.84-3.72(m,2H),3.42-3.28(m,1H),3.10-2.95(m,3H),2.81(s,3H),2.71-2.60 (m,1H),2.38(s,3H),2.09(t,J=7.6Hz,1H),1.99-1.87(m,1H),0.80(t,J=6.4Hz,3H).

[0302] Example 5: Synthesis of Compound 5

[0303] [ka]

[0304] Step 1: Synthesis of Compound 5-2 Compound 5-1 (1.0 g, 8.84 mmol) in THF (30 mL) was added dropwise to a solution of NaH (1.06 g, 26.54 mmol, 60% purity) in THF (30 mL) at 0°C, stirred for 0.5 hours at 0°C, and 2-(trimethylsilyl)ethoxymethyl chloride (1.77 g, 10.62 mmol, 1.88 mL) was added dropwise, and the reaction was continued at 0°C for 1.5 hours. The mixture was slowly added to a saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-2 (2.1 g, 8.63 mmol) with a yield of 97.58%.

[0305] Step 2: Synthesis of Compound 5-3 Compound 5-2 (1.0 g, 4.11 mmol) was dissolved in MeOH (10 mL), Pd / C (200 mg, 10% purity) was added, and the mixture was reacted under a hydrogen atmosphere at 25°C for 4 hours until the starting material was completely consumed. After filtering the reaction mixture, it was concentrated under reduced pressure to obtain compound 5-3 (870 mg, 4.08 mmol) in 99.2% yield. LC-MS (ESI) [M+H] + :214.2.

[0306] Step 3: Synthesis of Compounds 5-4 Compound 5-3 (1.0 g, 4.69 mmol) and compound 4-(1-methoxy-1,3-dioxolan-2-yl)piperazine-1-carboxylate tert-butyl (1.47 g, 4.69 mmol) were dissolved in toluene (10 mL), and p-toluenesulfonic acid (80.71 mg, 468.71 μmol) was added. The mixture was reacted at 120 °C for 16 hours, heating until the starting materials were completely reacted. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution (30 mL), extracted with ethyl acetate (30 mL x 2 times), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-4 (1.28 g). The yield was 53.58%. LC-MS(ESI)[M+H] + :510.4.

[0307] Step 4: Synthesis of Compound 5-5 Diphenyl ether (8 mL) was heated to 280°C, and compound 5-4 (680 mg, 1.33 mmol) was added under reflux. The mixture was reacted for 5 minutes to obtain the product. After cooling the mixture to room temperature, it was added to cyclohexane, stirred, filtered, and the filtrate was concentrated. The filtrate and the cake were purified separately by column chromatography (PE / EA = 10 / 1) to obtain compound 5-5 (100 mg) in a yield of 15.69%. LC-MS (ESI) [M+H] + :478.4.

[0308] Step 5: Synthesis of Compounds 5-6 Compound 5-5 (160 mg, 334.96 μmol) was dissolved in ACN (3 mL), cesium carbonate (327.41 mg, 1.00 mmol) and ethyl bromide (83.91 mg, 502.44 μmol) were added, and the mixture was reacted at 25°C for 1 hour, stirring until the reaction was complete. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2 times). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 1 / 1) to obtain compound 5-6 (83 mg) in a yield of 43.9%. LC-MS (ESI) [M+H] + :564.4.

[0309] Step 6: Synthesis of Compounds 5-7 Compound 5-6 (30 mg, 53.21 μmol) was dissolved in MeOH (3 mL), and HCl (4 M, 4.00 mmol, 1 mL) was added. The mixture was reacted at 25°C for 4 hours to confirm completion of the reaction of the starting materials. The mixture was poured into saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain compound 5-7 (24 mg). The yield was 97.3%. LC-MS (ESI) [M+H] + :464.3. Step 7: Synthesis of Compounds 5-8 Compound 5-7 (177.00 mg, 724.69 μmol) was dissolved in DMF (5 mL), and HATU (455.67 mg, 1.21 mmol), DIEA (234.15 mg, 1.81 mmol, 315.57 μL), and compound 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (280 mg, 603.91 μmol) were added. The resulting mixture was reacted at 25°C for 2 hours to complete the reaction. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-8 (360 mg) with a yield of 86.4%. LC-MS (ESI) [M+H] + :690.2.

[0310] Step 8: Synthesis of Compounds 5-9 Compound 5-8 (350 mg, 507.34 μmol) was dissolved in HCl (4 M, 24.00 mmol, 6 mL) in dioxane (6 mL), and the mixture was reacted at 25°C for 4 hours to confirm completion of the reaction of the starting materials. The reaction mixture was poured into a saturated sodium bicarbonate solution (15 mL), extracted with ethyl acetate (15 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 5-9 (200 mg), with a yield of 70.4%. LC-MS (ESI) [M+H] + :690.2.

[0311] Step 9: Synthesis of Compounds 5-10 Compound 5-9 (300 mg, 536.08 μmol) was dissolved in DMSO (1 mL), and compounds (3,6-dihydro-2H-pyran-4-yl)boronic acid (102.87 mg, 804.12 μmol) and PhenCuPPh (30.45 mg, 53.61 μmol) were added. The resulting reaction system was stirred in the presence of air. After the reaction was complete, water was added to the reaction mixture to quench it, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (MeOH / DCM = 3%) to obtain compound 5-10 (135 mg, 204.06 μmol), with a yield of 38.1%. LC-MS (ESI) [M+H] + :642.2.

[0312] Step 10: Synthesis of Compounds 5-11 Compound 5-10 (130.00 mg, 202.58 μmol) was dissolved in MeOH (0.5 mL), THF (1.5 mL), and water (0.5 mL). LiOH (16.98 mg, 709.04 μmol) was added, and the resulting mixture was reacted at 25°C for 1 hour. After the starting materials had completely reacted, the pH was adjusted to less than 4 with hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-11 (120 mg, 195.55 μmol) with a yield of 96.53%. LC-MS(ESI)[M+H] + :612.2.

[0313] Step 11: Synthesis of Compounds 5-12 Compound 5-11 (110.00 mg, 179.25 μmol), 2-chloro-4-trifluoromethylaniline (52.58 mg, 268.88 μmol), and pyridine (70.89 mg, 896.26 μmol, 72.20 μL) were dissolved in DCM (1.93 mL), phosphoryl chloride (41.23 mg, 268.88 μmol) was added, and the resulting reaction mixture was stirred at 25°C for 1 hour until the starting materials were completely reacted. Water (5 mL) was added to quench the reaction, the product was extracted with ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 5-12 (130 mg, 164.30 μmol) in a yield of 91.66%. LC-MS (ESI) [M+H] + :791.2.

[0314] Step 12: Synthesis of Compound 5 Compound 5-12 (60 mg, 75.83 μmol) was dissolved in DCM (2 mL), boron trichloride (88.85 mg, 758.33 μmol) was added, and the mixture was reacted at 25°C for 0.5 hours, stirring until the starting materials were completely reacted. The reaction mixture was separated by preparative HPLC to obtain compound 5 (5 mg, 7.13 μmol) in yield of 9.40%. LC-MS(ESI)[M+H] + :701.2. 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),10.20(s,1H),8.65(s,1H),8.58(s,1H),8.15(d,J=8.5Hz,1H),7.9 8(d,J=2.0Hz,1H),7.72(d,J=8.6Hz,1H),6.41(d,J=2.4Hz,1H),5.16(s,2H),4.49(d,J=12.2Hz,1H),4.28 (d,J=3.0Hz,2H),3.89(t,J=5.5Hz,2H),3.73(q,J=13.1Hz,2H),3.46(d,J=12.5Hz,1H),3.19(t,J=12.3Hz ,1H),2.93(t,J=12.2Hz,3H),2.71(s,3H),2.44(s,3H),2.00(q,J=6.9,6.3Hz,1H),1.17(t,J=7.4Hz,3H).

[0315] Example 6: Synthesis of Compound 6

[0316] [ka]

[0317] Step 1: Preparation of Compound 6-1 Intermediate 5-7 (160 mg, 345.83 μmol) and 3-(benzyloxy)pyridinecarboxylic acid (87.20 mg, 380.41 μmol) were dissolved in N,N-dimethylformamide (1 mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (157.79 mg, 414.99 μmol) and N,N-diisopropylethylamine (134.09 mg, 1.04 mmol, 180.71 μL) were added sequentially. After addition, the resulting reaction system was stirred at 25°C for 1 hour, and completion of the reaction was confirmed by LC-MS. The reaction solution was directly concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH=5%) to obtain compound 6-1 (210 mg) in yield 90.11%. LC-MS(ESI)[M+H] + :675.2.

[0318] Step 2: Preparation of Compound 6-2 Compound 6-1 (210.31 mg, 311.63 μmol) was dissolved in a HCl dioxane solution (4 M, 4.00 mmol, 1 mL). The resulting reaction system was stirred at 25°C for 1 hour, and the completion of the reaction was confirmed by LC-MS. After cooling the reaction solution to 25°C, the pH was adjusted to neutral with saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (5 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 6-2 (150 mg). The yield was 75.13%. LC-MS(ESI)[M+H] + :545.2.

[0319] Step 3: Preparation of Compound 6-3 Compound 6-2 (67 mg, 123.03 μmol) was dissolved in dimethyl sulfoxide (0.5 mL), and 3,6-dihydro-2H-pyran-4-boronic acid (23.61 mg, 184.54 μmol) and PhenCuPPhBr2 (3.49 mg, 6.15 μmol) were added. The resulting reaction mixture was stirred under air exposure for approximately 12 hours to confirm the complete reaction of the starting materials. After quenching with water (5 mL) to the reaction mixture, it was extracted with ethyl acetate (5 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column (MeOH / DCM = 3%) to obtain compound 6-3 (43 mg), with a yield of 52.98%. LC-MS(ESI)[M+H] + :627.2.

[0320] Step 4: Preparation of Compound 6-4 Compound 6-3 (41 mg, 62.15 μmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). An aqueous solution of lithium hydroxide (4.47 mg, 186.45 μmol) (0.2 mL) was added. After the addition, the resulting reaction system was stirred at room temperature for 5 hours to confirm the complete reaction of the starting materials. The reaction solution was concentrated under reduced pressure to remove the organic solvent. The remaining aqueous phase was adjusted to pH neutral with 1 M hydrochloric acid, extracted with ethyl acetate (5 mL x 2), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 6-4 (35 mg), which was directly usable in the next reaction. The yield of the crude product was 83.72%. LC-MS(ESI)[M+H] + :599.2.

[0321] Step 5: Preparation of Compounds 6-5 Intermediate 6-4 (25 mg, 37.17 μmol), 3-chloro-4-aminotrifluorotoluene (10.90 mg, 55.75 μmol), and pyridine (14.70 mg, 185.84 μmol, 14.97 μL) were dissolved in dichloromethane (0.5 mL). Phosphoryl chloride (17.10 mg, 111.50 μmol) was added, and the resulting reaction system was stirred at 25°C for 2 hours until the reaction was complete. After concentrating the reaction solution under reduced pressure, the resulting residue was purified by silica gel column (DCM / MeOH = 50:1) to obtain compound 6-5 (23 mg) with a yield of 70.64%. LC-MS (ESI) [M+H] + :776.4.

[0322] Step 6: Preparation of Compound 6 Intermediate 6-5 (25 mg, 28.54 μmol) was dissolved in dichloromethane (0.5 mL), and boron trichloride (16.72 mg, 142.68 μmol) was added. After addition, the resulting reaction system was stirred at 25°C for 1 hour, and the completion of the reaction was confirmed by LC-MS. After concentrating the reaction solution under reduced pressure, the resulting residue was purified by preparative HPLC to obtain compound 6 (2.16 mg), with a yield of 11.03%. LC-MS(ESI)[M+H] + : 686.2.

[0323] 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.63(s,1H),8.15(d,J=8.8Hz,1H),8.07-8.04(m,1H),7. 97(d,J=1.9Hz,1H),7.72(d,J=9.0Hz,1H),7.28(d,J=3.8Hz,2H),6.41(s,1H),5.16(s,2H),4.52 (d,J=12.3Hz,1H),4.28(d,J=2.9Hz,2H),3.89(t,J=5.4Hz,2H),3.73(t,J=14.6Hz,2H),3.18(q ,J=12.7Hz,3H),2.91(q,J=12.0,9.3Hz,3H),2.71(tt,J=6.6,2.9Hz,4H),1.17(t,J=7.4Hz,3H).

[0324] Example 7: Synthesis of Compound 7

[0325] [ka]

[0326] Step 1: Preparation of Compound 7-2 At room temperature, compound 7-1 (23 g, 150 mmol) was dissolved in dimethyl sulfoxide (200 mL), sodium methoxide (135 g, 750 mmol) was added, and the mixture was stirred at 120°C for 16 hours under a nitrogen atmosphere. After adding water and extracting several times with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was slurryed with pure ethyl acetate to obtain the target compound 7-2 (11.9 g), with a yield of 43.28%. LC-MS(ESI)[M+H] + :150.1.

[0327] Step 2: Preparation of Compound 7-3 At room temperature, intermediate 7-2 (11.9 g, 80 mmol) was dissolved in N-methylpyrrolidone (240 mL), and m-chloroperbenzoic acid (32 g, 184 mmol) was added. After reacting at room temperature for 16 hours, methyl-tert-butyl ether solution (60 mL) was added, and after stirring for 10 minutes, the liquid was filtered, washed with ethyl acetate, and the cake was recovered. The cake was dissolved in methyl-tert-butyl ether solution (200 mL), stirred for 30 minutes, the liquid was filtered, washed with ethyl acetate, and the resulting solid was dried to obtain compound 7-3 (11.9 g) in 100% yield. LC-MS(ESI)[M+H] + :166.1.

[0328] Step 3: Preparation of Compound 7-4 At room temperature, intermediate 7-3 (10.9 g, 66 mmol) was dissolved in phosphoryl chloride (100 mL) and reacted at 50°C for 16 hours to complete the reaction. After spin-drying the solvent, the solution was made basic using sodium hydroxide under an ice bath, extracted several times with ethyl acetate and water, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was separated and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-4 (11.0 g) with a yield of 90.78%. LC-MS(ESI)[M+H] + :183.9.

[0329] Step 4: Preparation of Compounds 7-5 At room temperature, intermediate 7-4 (11 g, 60 mmol) was dissolved in tetrahydrofuran (110 mL), and 3,4-dihydro-2H-pyran (7.6 g, 90 mmol) and p-toluenesulfonic acid monohydrate (1.1 g, 6 mmol) were added. The resulting reaction mixture was allowed to react at room temperature for 16 hours. After the reaction was complete, it was diluted with water (100 mL), extracted with ethyl acetate (200 mL x 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-5 (14.8 g) with a yield of 92.27%. LC-MS(ESI)[M+H] +:267.9.

[0330] Step 5: Preparation of Compounds 7-6 At room temperature, intermediate 7-5 (14 g, 52 mmol) and vinylboronic acid pinacol ester (12 g, 78 mmol) were dissolved in a mixed solution of 1,4-dioxane (70 mL) and water (35 mL). Methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (1.3 g, 1.56 mmol) and cesium fluoride (20 g, 130 mmol) were added, and after nitrogen purging, the reaction mixture was stirred at 110 °C for 16 hours, and the completion of the reaction was confirmed by LC-MS. The solution was diluted with water (50 mL), extracted with ethyl acetate (200 mL x 2), washed with saturated brine after combining the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (silica gel, petroleum ether / ethyl acetate = 5 / 1) to obtain compound 7-6 (13.2 g) in yield of 98%. LC-MS(ESI)[M+H] + :260.0.

[0331] Step 6: Preparation of Compound 7-7 At room temperature, intermediate 7-6 (13.2 g, 51 mmol) was dissolved in methanol (130 mL), and 10% palladium-carbon catalyst (5 g) was added. The reaction was stirred under a hydrogen atmosphere at room temperature for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (silica gel, petroleum ether / ethyl acetate = 2 / 1) to obtain compound 7-7 (10.9 g), with a yield of 81.9%. LC-MS(ESI)[M+H] + :262.1.

[0332] Step 7: Preparation of Compounds 7-8 At room temperature, compound 7-7 (3 g, 11 mmol) was dissolved in acetonitrile (30 mL), ethyl bromide (19 g, 15 mmol) was added, and the reaction was carried out at 70°C for 16 hours under a nitrogen atmosphere. After the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified and separated by reverse-phase column chromatography (A: formic acid / water, B: acetonitrile) to obtain the target compound 7-8 (1.2 g), with a yield of 31.20%. LC-MS(ESI)[M+H] + :333.9.

[0333] Step 8: Preparation of Compounds 7-9 At room temperature, intermediate 7-8 (1.2 g, 3.6 mmol) was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (0.6 g, 3.6 mmol) was added. The reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, the solution was diluted with water (50 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified and separated by silica gel column chromatography (dichloromethane / (methanol:dichloromethane=1:1)=10 / 1) to obtain target compound 7-9 (0.4 g), with a yield of 31.56%. LC-MS(ESI)[M+H] + :411.8.

[0334] Step 9: Preparation of Compounds 7-10 At room temperature, intermediate 7-9 (0.4 g, 1.1 mmol) and N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.7 g, 2.2 mmol) were dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (2 mL). Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (0.089 g, 0.1 mmol), potassium phosphate (0.7 g, 3.4 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (0.1 g, 0.3 mmol) were added. After nitrogen purging, the reaction mixture was stirred at 100 °C for 16 hours to complete the reaction. The solution was diluted with water (20 mL), extracted with ethyl acetate (100 mL x 3), washed with saturated brine after combining the organic phases, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to obtain target compound 7-10 (0.3 g), with a yield of 57.8%. LC-MS(ESI)[M+H] + :515.0.

[0335] Step 10: Preparation of Compounds 7-11 At room temperature, compound 7-10 (0.3 g, 0.6 mmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and ethanol (2 mL). Raney nickel catalyst (0.5 g) was added, and after hydrogen gas purging, the mixture was reacted at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified and separated by C18 column chromatography (A: formic acid / water, B: acetonitrile) to obtain compound 7-11 (0.15 g). The yield was 49.80%. LC-MS(ESI)[M+H] + :417.9.

[0336] Step 11: Preparation of Compounds 7-12 At room temperature, intermediate 7-11 (0.15 g, 0.29 mmol) was dissolved in tetrahydrofuran (6 mL), and dioxane hydrochloride solution (2 mL, 1 mol / L) was added. The reaction was carried out at room temperature for 16 hours. After the reaction was complete, compound 7-12 (0.15 g) was obtained by concentrated drying under reduced pressure, with a yield of 100%. LC-MS(ESI)[M+H] + :333.1. Step 12: Preparation of Compounds 7-13 At room temperature, intermediate 7-12 (0.13 g, 0.25 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (0.067 g, 0.27 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.14 g, 0.37 mmol), and N,N-diisopropylethylamine (0.16 g, 1.26 mmol) were added sequentially. The reaction was carried out at room temperature for 16 hours until the starting materials were completely consumed. Afterward, the mixture was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified and separated by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 7-13 (0.10 g), with a yield of 47.14%. LC-MS(ESI)[M+H] + :559.2.

[0337] Step 13: Preparation of Compounds 7-14 At room temperature, intermediate 7-13 (0.083 g, 0.15 mmol) was dissolved in dichloromethane (5 mL), and 3,6-dihydro-2H-pyran-4-boronic acid (0.019 g, 0.15 mmol), copper(II) acetate monohydrate (0.045 g, 0.22 mmol), and pyridine (0.047 g, 0.59 mmol) were added. The reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with dichloromethane (20 mL x 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by C18 column chromatography (A: formic acid / water, B: acetonitrile) to obtain compound 7-14 (0.076 g) with a yield of 79.83%. LC-MS(ESI)[M+H] + :641.1.

[0338] Step 14: Preparation of Compounds 7-15 At room temperature, intermediate 7-14 (0.076 g, 0.12 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (1 mL), lithium hydroxide (0.02 g, 0.47 mmol) was added, and the reaction was allowed to proceed at room temperature for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the solution was diluted with water (10 mL). The pH of the solution was adjusted to less than 6 with dilute hydrochloric acid, and then extracted with ethyl acetate (20 mL x 2). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and freeze-dried to obtain compound 7-15 (0.076 g). The yield was 100%. LC-MS(ESI)[M+H] + :613.3.

[0339] Step 15: Preparation of Compounds 7-16 At room temperature, intermediate 7-15 (0.056 g, 0.09 mmol), chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (0.030 g, 0.108 mmol), 1-methylimidazole (0.011 g, 0.135 mmol), and 3-chloro-4-aminotrifluorotoluene (0.017 g, 0.09 mmol) were dissolved in acetonitrile (3 mL). After reacting at room temperature for 1 hour, the completion of the reaction was confirmed by LC-MS. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified and separated by C18 column chromatography (A: formic acid / water, B: acetonitrile) to obtain compound 7-16 (0.092 g) in 100% yield. LC-MS(ESI)[M+H] + :789.9.

[0340] Step 16: Preparation of Compound 7 At room temperature, compound 7-16 (0.09 g, 0.11 mmol) was dissolved in dichloromethane (5 mL), boron trichloride (0.1 mL) was added, and after nitrogen purging, the reaction was carried out at room temperature for 16 hours until the reaction was complete. Methanol (5 mL) was then added to the reaction mixture to quench it, and the solvent was removed by reducing the pressure. The residue was purified by HPLC to obtain compound 7 (24.75 mg), with a yield of 30.1%. LC-MS(ESI)[M+H] + :700.2.

[0341] 1HNMR(400 MHz,MeOH-d4)δ8.60-8.54(m,1H),8.42-8.33(m,1H),8.21-8.15(m,1H) ,7.82-7.76(m,1H),7.66-7.58(m,1H),6.59-6.48(m,1H),5.38-5.31(m ,2H),4.85-4.78(m,1H),4.36-4.31(m,2H),4.20-4.09(m,1H),4.00-3. 94(m,2H),3.31-3.22(m,1H),3.11-2.79(m,6H),2.77-2.72(m,2H),2.55 -2.50(m,3H),1.74-1.50(m,2H),1.37-1.31(m,3H).

[0342] Example 8: Synthesis of Compound 8

[0343] [ka]

[0344] Step 1: Preparation of Compound 8-1 Compound 4-11 (21 mg, 34.17 μmol), 2-methyl-4-trifluoromethylaniline (17.95 mg, 102.50 μmol), and pyridine (27.03 mg, 341.66 μmol, 27.52 μL) were dissolved in DCM (1.5 mL). Phosphoryl chloride (26.19 mg, 170.83 μmol) was added at room temperature. After addition, the reaction system was stirred at room temperature for 1 hour to complete the reaction. Water (5 mL) was added to the reaction mixture to quench it, and the product was extracted with ethyl acetate (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (DCM:MeOH = 19:1) to obtain compound 8-1 (26 mg), with a yield of 65.0%. LC-MS(ESI)[M+H] + :772.3.

[0345] Step 2: Preparation of Compound 8 Compound 8-1 (20 mg, 25.91 μmol) was dissolved in DCM (2 mL), and a hexane solution of boron trichloride (0.2 mL, 1 M) was added at room temperature. The mixture was stirred at room temperature for 1 hour to complete the reaction. Methanol (5 mL) was then added to the reaction mixture to quench it, and the solvent was removed by rotary evaporation under reduced pressure. The resulting residue was purified by preparative HPLC to obtain the crude product of compound 8 (12 mg, including isomers). This crude product was further purified by SFC (column: ChiralPak AD, 250 × 30 mm ID, 10 μm, mobile phase: A: CO2; B: isopropanol (0.1% NH3H2O), composition: B 40%, flow rate: 150 mL / min, back pressure: 100 bar, column temperature: 38 °C, wavelength: 220 nm, cycle time: approximately 5 min) to obtain compound 8 (4.33 mg, yield 24.5%). The analytical conditions for the target product are as follows: Column: ChiralPak AD, 50 × 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: Isopropanol (0.05% DEA); Composition: B 40%, Flow rate: 3 mL / min; Back pressure: 100 bar; Column temperature: 35 °C; Wavelength: 220 nm; LC-MS (ESI) [M+H] + :682.3.

[0346] 1 H NMR(400MHz,MeOD-d4)δ8.41(s,1H),7.65(d,J=8.4Hz,1H),7.51(s,1H),7.42(d,J=8.6 Hz,1H),6.81(s,1H),5.28(s,2H),4.33(s,2H),4.00-3.74(m,4H),3.15-3.02(m,4H),2.86(s,3H) ,2.76-2.65(m,1H),2.44(s,3H),2.33(s,3H),2.19-2.09(m,1H),2.03-1.93(m,1H),0.84(t,J=6.8 Hz,3H).

[0347] Example 9: Synthesis of Compound 9

[0348] [ka]

[0349] Step 1: Preparation of Compound 9-1 Compound 4-11 (30 mg, 48.81 μmol), 2-fluoro-4-trifluoroaniline (34.97 mg, 195.23 μmol), and pyridine (38.61 mg, 488.08 μmol, 39.32 μL) were dissolved in dichloromethane (1 mL). At room temperature, phosphoryl chloride (37.42 mg, 244.04 μmol) was added, and the mixture was stirred at room temperature for 1 hour to complete the reaction. The reaction mixture was poured into water (5 mL) to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (DCM:MeOH = 19:1) to obtain compound 9-1 (27.7 mg) in 73.28% yield. LC-MS (ESI) [M+H] + :776.2.

[0350] Step 2: Preparation of Compound 9 Compound 9-1 (30 mg, 38.67 μmol) was dissolved in DCM (3 mL), and boron trichloride in hexane solution (0.3 mL, 1 M) was added at room temperature. The reaction was stirred at room temperature for 0.6 hours to complete the reaction. Next, methanol (5 mL) was added to quench the reaction, and the solvent was removed by distillation. The residue was purified by HPLC to obtain the crude product of compound 9 (15 mg, including isomers). This crude product was further purified by SFC (ChiralPak AD column, 250 × 30 mm ID, 10 μm; mobile phase [A: carbon dioxide, B: ethanol (containing 0.1% aqueous ammonia)]; component B%: 30%, flow rate: 150 mL / min, column temperature: 38°C, wavelength: 220 nm, cycle time: ~9 min) to obtain compound 9 (5.08 mg) in yield of 33.8%. (Product peak retention time: 0.637 mins; SFC analysis method measurement conditions: Column: ChiralPak AD, 50 × 4.6 mm ID, 3 μm; Mobile phase [A: carbon dioxide, B: ethanol (containing 0.05% DEA)], 5-40% B; Flow rate: 3 mL / min; Column temperature: 35 °C). LC-MS (ESI) [M+H] + :686.2.

[0351] 1H NMR(400MHz,Methanol-d4)δ8.42-8.20(m,2H),7.57(d,J=12.0Hz,1H),7.47(d,J=8.4Hz,1H),6.88-6.79(m,1H),5.34(s,2H),4.36(s,2H),4.09-3.8 1(m,4H),3.60-3.40(m,1H),3.22-3.06(m,3H),2.89(s,3H),2.84-2.68(m, 1H), 2.47 (s, 3H), 2.24-2.14 (m, 1H), 2.10-1.98 (m, 1H), 1.33-1.28 (m, 3H).

[0352] Example 10: Synthesis of Compound 10

[0353] [ka]

[0354] Step 1: Preparation of Compound 10-1 At room temperature, intermediate 7-10 (200 mg, 0.39 mmol) was dissolved in tetrahydrofuran (6 mL), and dioxane hydrochloride solution (2 mL, 1 M) was added. After reacting at room temperature for 2 hours, the completion of the reaction was confirmed by LC-MS. The solvent was removed under reduced pressure, and compound 10-1 (200 mg) was obtained in 100% yield. LC-MS(ESI)[M+H] + :331.1.

[0355] Step 2: Preparation of Compound 10-2 At room temperature, intermediate 10-1 (200 mg, 0.39 mmol) was dissolved in N,N-dimethylformamide (1.5 mL), and 5-(benzyloxy)-6-methylpyrimidine-4-carboxylic acid (95.2 mg, 0.39 mmol)O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (222.2 mg, 0.585 mmol) and N,N-diisopropylethylamine (251.6 mg, 1.95 mmol) were added. After reacting at room temperature for 1 hour, the completion of the reaction was confirmed by LC-MS. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (silica gel, dichloromethane / methanol = 10 / 1) to obtain compound 10-2 (129 mg) in 59.4% yield. LC-MS(ESI)[M+H] + :557.1.

[0356] Step 3: Preparation of Compound 10-3 At room temperature, intermediate 10-2 (69 mg, 0.124 mmol) was dissolved in dichloromethane (5 mL), and 3,6-dihydro-2H-pyran-4-boronic acid (23.8 mg, 0.186 mmol), copper(II) acetate monohydrate (49.9 mg, 0.25 mmol), and triethylamine (37.6 mg, 0.372 mmol) were added. After reacting at room temperature for 16 hours, the completion of the reaction was confirmed by LC-MS. The mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile / water = 45%, formic acid system), and compound 10-3 (50 mg) was isolated. The yield was 63.1%. LC-MS(ESI)[M+H] + :639.1.

[0357] Step 4: Preparation of Compound 10-4 At room temperature, intermediate 10-3 (50 mg, 0.078 mmol) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and water (1 mL), and lithium hydroxide monohydrate (13.1 mg, 0.31 mmol) was added. After reacting at room temperature for 0.5 hours, the completion of the reaction was confirmed by LC-MS. The pH of the solution was adjusted to 3 with dilute hydrochloric acid (1 M), and the solution was extracted with ethyl acetate (10 mL x 2). The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and freeze-dried under vacuum to obtain compound 10-4 (46 mg) in a yield of 96.6%. LC-MS(ESI)[M+H] + :611.2.

[0358] Step 5: Preparation of Compound 10-5 At room temperature, intermediate 10-4 (40 mg, 0.0655 mmol) and 3-chloro-4-aminotrifluorotoluene (38.4 mg, 0.196 mmol) were dissolved in pyridine (1 mL), and then 4 drops of phosphoryl chloride were added. The reaction was allowed to proceed at room temperature for 0.5 hours. After the reaction was complete, the solution was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by C18 column chromatography (acetonitrile / water = 68%, formic acid system), and the target compound 10-5 (20 mg) was isolated. The yield was 38.7%. LC-MS(ESI)[M+H] + :788.2. Step 6: Preparation of Compound 10 At room temperature, compound 10-5 (20 mg, 0.025 mmol) was dissolved in dichloromethane (5 mL). A solution of boron trichloride (0.1 mL, 1 M) in dichloromethane was added, and after nitrogen purging, the mixture was reacted at room temperature for 2 hours. Reaction completion was confirmed by LC-MS. Methanol (2 mL) was added to quench the reaction, and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to obtain compound 10 (5.02 mg), with a yield of 28.8%. LC-MS(ESI)[M+H] + :698.2.

[0359] 1H NMR(400MHz,DMSO-d6)δ10.28(s,2H),8.61(d,J=5.8Hz,1H),8.53(s,1H),8.07(d, J=8.6Hz,1H),7.95(s,1H),7.71(d,J=8.8Hz,1H),6.46(s,1H),5.52(d,J=66.2Hz, 1H),5.31-5.08(m,2H),4.40-3.94(m,4H),3.85(t,J=5.4Hz,2H),3.72-3.39(m,1H ),2.82-2.60(m,3H),2.45-2.35(m,5H),2.16-1.94(m,2H),1.17(t,J=7.5Hz,3H).

[0360] Example 11: Synthesis of Compound 11

[0361] [ka]

[0362] Step 1: Preparation of Compound 11-1 Compound 5-8 (700 mg, 1.01 mmol) was dissolved in a mixed solvent of MeOH (3 mL), THF (9 mL), and water (3 mL). LiOH (85.05 mg, 3.55 mmol) was added, and the resulting mixture was reacted at 25°C for approximately 1 hour. After the reaction was complete, the pH of the solution was adjusted to less than 4 with dilute hydrochloric acid, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated brine (60 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 11-1 (650 mg). The yield was 96.8%. LC-MS(ESI)[M+H] + :662.4.

[0363] Step 2: Preparation of Compound 11-2 Compound 11-1 (350 mg, 528.84 μmol), 2-chloro-4-trifluoromethylaniline (155.14 mg, 793.27 μmol), and pyridine (209.16 mg, 2.64 mmol, 213.01 μL) were dissolved in DCM (5 mL). Phosphoryl chloride (121.63 mg, 793.27 μmol, 73.94 μL) was added. After the addition was complete, the resulting reaction mixture was stirred at 25°C for 1 hour until the starting materials were completely reacted. The solvent was removed under reduced pressure, and the resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-2 (310 mg) with a yield of 69.8%. LC-MS(ESI)[M+H] + :839.2.

[0364] Step 3: Synthesis of Compound 11-3 Compound 11-2 (310 mg, 369.32 μmol) was dissolved in methanol solution of HCl (4 M, 40.00 mmol, 10 mL). This mixture was reacted at 25°C for 1 hour until the starting materials were completely reacted. The reaction mixture was slowly added to saturated sodium bicarbonate solution (40 mL), extracted with ethyl acetate (40 mL x 2), the organic phases were combined, washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-3 (183 mg), with a yield of 69.9%. LC-MS(ESI)[M+H] + :709.2.

[0365] Step 4: Synthesis of Compound 11-4 Compound 11-3 (183 mg, 258.07 μmol) was dissolved in DMSO (4 mL), and (1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl)boronic acid (117.20 mg, 516.14 μmol) and PhenCuPPhBr2 (87.95 mg, 154.84 μmol) were added. The resulting reaction mixture was reacted at 90°C under an air atmosphere for 16 hours, stirring until the starting materials were completely reacted. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-4 (200 mg) in yield of 87.04%. LC-MS(ESI)[M+H] + :890.4.

[0366] Step 12: Synthesis of Compound 11-5 Compound 11-4 (200 mg, 146.01 μmol) was dissolved in DCM (3 mL), and TFA (1.49 g, 13.06 mmol, 1 mL) was added. The resulting mixture was reacted at 25°C for approximately 2 hours until the starting materials were completely reacted. The reaction solution was slowly poured into saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (DCM / MeOH = 5 / 1) to obtain compound 11-5 (110 mg) with a yield of 95.34%. LC-MS(ESI)[M+H] + :790.2.

[0367] Step 13: Synthesis of Compounds 11-6 Compound 11-5 (100 mg, 126.55 μmol) was dissolved in DCM (4 mL), TEA (76.83 mg, 759.27 μmol, 105.90 μL) was added, and cyclopropylsulfonyl chloride (88.95 mg, 632.73 μmol) was slowly added dropwise at 25°C. The mixture was reacted at room temperature for approximately 2 hours, stirring until the starting materials were completely reacted. The mixture was then poured into saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 2), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 11-6 (100 mg) with a yield of 88.4%. LC-MS(ESI)[M+H] + :894.2.

[0368] Step 14: Synthesis of Compound 11 Compound 11-6 (100 mg, 111.81 μmol) was dissolved in DCM (4 mL), and a dichloromethane solution of boron trichloride (1 M, 1 mL) was added. The resulting mixture was reacted at 25°C for 1 hour, stirring until the starting materials were completely reacted. The mixture was then concentrated under reduced pressure to remove the solvent, and the residue was purified and separated by preparative HPLC to obtain compound 11 (5.05 mg), with a yield of 5.62%. LC-MS(ESI)[M+H] + :804.2.

[0369] 1 H NMR (400MHz, DMSO-d6) δ10.19(s, 1H), 8.65(s, 1H), 8.56(s, 1H), 8.16(s, 1H) , 7.97(s, 1H), 7.72(s, 1H), 6.41(s, 1H), 5.16(s, 2H), 4.49(d, J=12.5Hz, 1H), 4.02(s, 2H), 3.73(d, J=12.0Hz, 2H), 3.55(s, 2H), 3.46(d, J=6.5Hz, 3H), 3.19 (s, 4H), 2.98-2.81(m, 5H), 2.71(d, J=10.8Hz, 2H), 2.44(s, 3H), 1.17(s, 3H).

[0370] Example 12: Synthesis of Compound 12

[0371] [ka]

[0372] Step 1: Synthesis of Compound 12-1 Compound 5-11 (100 mg, 162.96 μmol), 4-pentafluorothioaniline (42.86 mg, 195.55 μmol), and pyridine (64.45 mg, 814.78 μmol, 65.64 μL) were dissolved in dichloromethane (3 mL). Phosphoryl chloride (37.48 mg, 244.43 μmol) was added, and the reaction system was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was separated by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 12-1 (116 mg, 142.36 μmol). The yield was 87.36%. LC-MS(ESI)[M+H] + :815.2. Step 2: Synthesis of Compound 12 Compound 12-1 (106 mg, 130.09 μmol) was dissolved in DCM (3 mL), and a dichloromethane solution of boron trichloride (1 M, 2 mL) was added. The mixture was reacted at 25°C for approximately 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was purified and separated by preparative HPLC to obtain compound 12 (4.5 mg, 6.21 μmol) with a yield of 4.77%. LCMS(ESI)[M+H] + :725.2.

[0373] 1 H NMR (400MHz, DMSO-d6) δ10.90(s, 1H), 8.63(s, 1H), 8.55(s, 1H), 7.88(d, J=9.3Hz, 2H), 7.78(d, J=9.0Hz, 2H), 6.41(s, 1H), 4.99(s, 2H), 4.49(d, J=11.3Hz, 1H), 4.27(s, 2H), 3.89(s, 2H), 3.75(d, J=30.6Hz, 2H), 3.51( s, 1H), 3.19(s, 2H), 2.90(s, 3H), 2.71(s, 3H), 2.43(s, 3H), 1.15(s, 3H).

[0374] Example 13: Synthesis of Compound 13

[0375] [ka]

[0376] Step 1: Synthesis of Compound 13-1 Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), 3-chloro-5-(trifluoromethyl)pyridine-2-amine (64 mg, 325.4 μmol), and pyridine (64.4 mg, 813.5 μmol) were dissolved in dichloromethane (5 mL). Phosphoryl chloride (49.9 mg, 325.4 μmol) was added, and the resulting mixture was stirred at 25°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (DCM / MeOH = 10 / 1) to obtain compound 13-1 (40 mg), with a yield of 31%. LC-MS(ESI)[M+H] + :793.2.

[0377] Step 2: Synthesis of Compound 13 Under a nitrogen atmosphere, compound 13-1 (16 mg, 20.2 μmol) was added to trifluoroacetic acid (1 mL) and heated at 90°C for 0.5 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified and separated by HPLC to obtain compound 13 (3.0 mg), with a yield of 21%. LC-MS(ESI)[M+H] + :703.2.

[0378] 1 H NMR(400 MHz,Methanol-d4)δ 8.70(s,1H),8.56(s,1H),8.35(s,1H),6.89(s,1H),5.54(s,2H),4.39(s,2H),4.12(s,1H),4.00( s, 2H), 3.92 (s, 2H), 3.50 (s, 3H), 3.15 (s, 2H), 2.93 (s, 3H), 2.74 (s, 1H), 2.54 (s, 3H), 1.34 (s, 3H).

[0379] Example 14: Synthesis of Compound 14

[0380] [ka]

[0381] Step 1: Synthesis of Compound 14-1 Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), 5-chloro-2-methyl-4-(trifluoromethyl)aniline (37.1 mg, 177.2 μmol), and pyridine (63.7 mg, 805.3 μmol) were dissolved in dichloromethane (6 mL). A solution of phosphoryl chloride (27.2 mg, 177.2 μmol) in dichloromethane (0.2 mL) was added, and the resulting mixture was stirred at 25°C for 0.5 hours until the reaction was complete. The reaction mixture was poured into water and extracted with dichloromethane (2 × 5 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain compound 14-1 (110 mg), with a yield of 84%. LC-MS(ESI)[M+H] + :806.4.

[0382] Step 2: Synthesis of Compound 14 Under a nitrogen atmosphere, compound 14-1 (150 mg, 184.2 μmol) was added to trifluoroacetic acid (5 mL) and reacted at 90°C for 30 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was separated by HPLC purification to obtain compound 14 (99.7 mg), with a yield of 76%. LC-MS(ESI)[M+H] + :716.3.

[0383] 1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),10.11(s,1H),8.58(s,1H),7.99(s,1H),7.76(s,1H), 6.79-6.72(m,1H),5.27(s,2H),4.51(d,J=12.4Hz,1H),4.33(q,J=2.9Hz,2H),3.91(t,J=5.5 Hz,2H),3.70(d,J=11.4Hz,2H),3.49(d,J=12.6Hz,1H),3.23(s,1H),3.08-2.91(m,3H),2.7 8(d,J=23.3Hz,3H),2.59(d,J=11.4Hz,1H),2.45(s,3H),2.37(s,3H),1.20(t,J=7.4Hz,3H).

[0384] Example 15: Synthesis of Compound 15

[0385] [ka]

[0386] Step 1: Synthesis of Compound 15-1 Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), 2-chloro-5-fluoro-4-(trifluoromethyl)aniline (37.8 mg, 177.2 μmol), and pyridine (63.7 mg, 805.3 μmol) were dissolved in dichloromethane (6 mL). Phosphoryl chloride (27.2 mg, 177.2 μmol) was added, and the resulting mixture was stirred at 25°C for 30 minutes. After the reaction was complete, the reaction solution was poured into water and extracted with dichloromethane (2 × 5 mL). The organic phase was dried over anhydrous sodium sulfate and then evaporated under reduced pressure using spin evaporation. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain compound 15-1 (120 mg) with a yield of 87%. LC-MS(ESI)[M+H] + :810.3.

[0387] Step 2: Synthesis of Compound 15 Under a nitrogen atmosphere, compound 15-1 (100 mg, 117.3 μmol) was added to trifluoroacetic acid (5 mL), heated to 90°C, and reacted for 30 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was separated by preparative HPLC to obtain compound 15 (70.2 mg), with a yield of 83%. LC-MS(ESI)[M+H] + = 720.2.

[0388] 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.24(s,1H),8.58(s,1H),8.12(d,J=12.8Hz,1H),8.02(d,J =7.3Hz,1H),6.74(t,J=1.5Hz,1H),5.35(s,2H),4.51(d,J=12.5Hz,1H),4.31(d,J=3.0Hz,2H),3.9 0(t,J=5.5Hz,2H),3.77-3.62(m,2H),3.49(d,J=12.6Hz,1H),3.22(t,J=12.0Hz,1H),2.97(dd,J=1 1.3,5.0Hz,3H),2.77(d,J=22.1Hz,3H),2.58(d,J=11.5Hz,1H),2.44(s,3H),1.18(t,J=7.4Hz,3H).

[0389] Example 16: Synthesis of Compound 16

[0390] [ka]

[0391] Step 1: Synthesis of Compound 16-1 Under a nitrogen atmosphere, compound 4-11 (100 mg, 162.7 μmol), bicyclo[4.2.0]octa-1(6),2,4-triene-3-amine (28.7 mg, 241.1 μmol) (see WO2023284837 for synthesis), and pyridine (63.6 mg, 803.7 μmol, 64.75 μL) were dissolved in dichloromethane (5 mL), phosphoryl chloride (29.6 mg, 192.89 μmol) was added, and the resulting mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (3 mL), extracted with dichloromethane (2 × 5 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 16-1 (75 mg) in a yield of 61%. LC-MS(ESI)[M+H] + :716.4.

[0392] Step 2: Synthesis of Compound 16 Under a nitrogen atmosphere, compound 16-1 (75 mg, 98.2 μmol) was added to trifluoroacetic acid (1.5 mL), and the reaction was completed by heating to 90°C for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and the resulting residue was purified and separated by preparative HPLC to obtain compound 16 (29.5 mg) in 4 units, with a yield of 48%. LC-MS(ESI)[M+H] + :626.4.

[0393] 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),10.23(s,1H),8.57(s,1H),7.37(s,1H),7.28(dd,J=8.1,1.5Hz, 1H),7.02(d,J=8.0Hz,1H),6.73(s,1H),5.10(s,2H),4.50(d,J=12.5Hz,1H),4.31(d,J=3.0Hz,2H),3. 89(t,J=5.5Hz,2H),3.74-3.65(m,2H),3.48(d,J=12.8Hz,1H),3.23(d,J=12.0Hz,1H),3.08(s,4H),2. 97(d,J=8.8Hz,3H),2.76(d,J=21.6Hz,3H),2.57(d,J=11.5Hz,1H),2.44(s,3H),1.17(t,J=7.4Hz,3H).

[0394] Example 17: Synthesis of Compound 17

[0395] [ka]

[0396] Step 1: Synthesis of Compound 17-1 Under nitrogen gas protection, compound 4-11 (120 mg, 195.2 μmol), 2,3-dihydro-1H-inden-5-amine (38.5 mg, 289.3 μmol), and pyridine (76.3 mg, 964.5 μmol) were dissolved in dichloromethane (5 mL), and phosphoryl chloride (35.5 mg, 231.5 μmol) was added. The resulting mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction solution was poured into saturated sodium bicarbonate aqueous solution (3 mL) and quenched. After extraction with dichloromethane (2 × 5 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound 17-1 (120 mg) in 81% yield. LC-MS(ESI)[M+H] + :730.2.

[0397] Step 2: Synthesis of Compound 17 Under nitrogen gas protection, compound 17-1 (120 mg, 155.9 μmol) was added to trifluoroacetic acid (1.0 mL), and the reaction was stirred at 90°C for 1 hour until the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified and separated by preparative HPLC to obtain compound 17 (67.6 mg), with a yield of 68%. LC-MS(ESI)[M+H] + :640.4.

[0398] 1 H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.53(s,1H),7.49(d,J=1.6Hz,1H),7.25(dd,J=8.1,2.0Hz,1H),7 .15(d,J=8.1Hz,1H),6.75-6.71(m,1H),5.10(s,2H),4.50(d,J=12.8Hz,1H),4.31(q,J=2.9Hz,2H),3.89 (t,J=5.5Hz,2H),3.76-3.65(m,2H),3.50(d,J=12.8Hz,1H),3.22(t,J=12.3Hz,2H),2.97(d,J=8.9Hz,3 H),2.80(q,J=7.0Hz,7H),2.57(d,J=10.9Hz,1H),2.43(s,3H),2.02-1.95(m,2H),1.17(t,J=7.4Hz,3H).

[0399] Example 18: Synthesis of Compound 18

[0400] [ka]

[0401] Step 1: Synthesis of Compound 18-1 Compound 4-6 (9g, 15.4 mmol) was dissolved in ethanol (400 mL), and palladium carbon (5%, 1.6 g) and palladium carbon hydroxide (5%, 2.2 g) were added. The mixture was then heated under a hydrogen atmosphere and refluxed for 16 hours until the reaction was complete. After filtering the reaction solution, it was concentrated under reduced pressure, and the resulting crude product was purified by slurrying in a mixed solvent (petroleum ether:ethyl acetate = 5:1) to obtain compound 18-1 (6 g) in a yield of 85%. LC-MS(ESI)[M+H]+ :435.4.

[0402] Step 2: Synthesis of Compound 18-2 Compound 18-1 (6.75 g, 14.43 mmol), (3,6-dihydro-2H-pyran-4-yl)boronic acid (3.69 g, 28.86 mmol), and pyridine (11.41 g, 144.28 mmol, 11.62 mL) were dissolved in dichloromethane (140 mL) and completely dissolved by sonication. Then copper(II) acetate (7.86 g, 43.28 mmol) was added, and the mixture was reacted at room temperature under an oxygen atmosphere for 2 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was sequentially washed with water (3 × 30 mL) and saturated saline solution (50 mL). After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the resulting crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 18-2 (7.43 g), with a yield of 92%. LC-MS(ESI)[M+H] + :517.3.

[0403] Step 3: Synthesis of Compound 18-3 Under a nitrogen atmosphere, compound 18-2 (7.43 g, 13.31 mmol) was dissolved in dioxane hydrochloride solution (4 mol / L, 75 mL), and the reaction was stirred at 25°C for 30 minutes until the reaction was complete. The solvent was removed from the reaction mixture by vacuum concentration, water (100 mL) was added, and the pH was adjusted to 8 with saturated sodium carbonate aqueous solution. After extraction with dichloromethane (3 × 50 mL), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain compound 18-3 (5.4 g). The yield was 93%. LC-MS(ESI)[M+H] + :417.4.

[0404] Step 4: Synthesis of Compound 18-4 Under a nitrogen atmosphere, compound 18-3 (1.72 g, 4.13 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL), and 5-methoxypyrimidine-4-carboxylic acid (0.76 g, 4.96 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (3.14 g, 8.26 mmol), and N,N-diisopropylethylamine (0.53 mmol) were added. (g, 4.13 mmol) was added, and the reaction was stirred at 25°C for 16 hours until the reaction was complete. The mixture was then diluted with water (40 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined and washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol:dichloromethane = 1:9) to obtain compound 18-4 (2.0 g) in 88% yield. LC-MS(ESI)[M+H] + :553.4.

[0405] Step 5: Synthesis of Compound 18-5 Under a nitrogen atmosphere, compound 18-4 (2.5 g, 4.5 mmol) was dissolved in tetrahydrofuran / water (16 mL / 4 mL), lithium hydroxide monohydrate (0.76 g, 18.1 mmol) was added, and the mixture was stirred at 25°C for 1 hour until the reaction was complete. Dilute hydrochloric acid (2 mol / L) was added dropwise to adjust the pH to 2, 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 (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 18-5 (2.0 g) in 84% yield. LC-MS(ESI)[M+H] + :525.2.

[0406] Step 6: Synthesis of Compound 18-6 Under a nitrogen atmosphere, compound 18-5 (0.2 g, 0.38 mmol) was dissolved in dichloromethane (10 mL), and 2-chloro-4-trifluoromethylaniline (0.089 g, 0.42 mmol) and pyridine (0.30 g, 3.8 mmol) were added. Further, a solution of phosphoryl chloride (0.07 g, 0.46 mmol) in dichloromethane (3 mL) was added, and the reaction was carried out at 25°C for 15 minutes until complete. After the reaction, the mixture was diluted with water (10 mL), extracted with a solution of dichloromethane (10 mL x 3), the organic layers were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to obtain compound 18-6 (0.1 g) in a yield of 37%. LC-MS(ESI)[M+H] + :702.2.

[0407] Step 7: Synthesis of Compound 18 Under a nitrogen atmosphere, compound 18-6 (0.15 g, 0.21 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL), and aluminum chloride (0.28 g, 2.1 mmol) was added. The reaction was carried out in a microwave reactor at 150°C for 1 hour. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by preparative HPLC to obtain compound 18 (20 mg) in a yield of 14%. LC-MS(ESI)[M+H] + :688.4.

[0408] 1H NMR(400MHz,MeOD-d4)δ8.65(s,1H),8.41(s,1H),8.16(d,J=8.5Hz,1H),7.83(d,J=1.6Hz, 1H),7.62(dd,J=8.6,1.5Hz,1H),6.88(s,1H),5.44-5.36(m,2H),4.69(d,J=12.6Hz,1H),4 .39(d,J=2.8Hz,2H),4.01-3.95(m,2H),3.95-3.83(m,2H),3.64-3.54(m,1H),3.51-3.39( m,1H),3.19-3.10(m,3H),2.97-2.85(m,3H),2.75(d,J=11.3Hz,1H),1.33(t,J=5.0Hz,3H) Example 19: Synthesis of Compound 19

[0409] [ka]

[0410] Step 1: Synthesis of Compound 19-1 Under a nitrogen atmosphere, compound 18-3 (0.26 g, 0.62 mmol) was dissolved in N,N-dimethylformamide (3 mL), and 3-(benzyloxy)pyridinecarboxylic acid (0.17 g, 0.74 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.28 g, 0.74 mmol), and N,N-diisopropylethylamine (0.4 g, 3.1 mmol) were added. The mixture was stirred at 25°C for 1 hour until the reaction was complete, diluted with water (6 mL), extracted with ethyl acetate (5 mL x 3), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (methanol / dichloromethane = 6%) to obtain compound 19-1 (0.35 g) in 89% yield. LC-MS(ESI)[M+H] + :628.3.

[0411] Step 2: Synthesis of Compound 19-2 Under a nitrogen atmosphere, compound 19-1 (0.28 g, 0.45 mmol) was dissolved in tetrahydrofuran / water (5 mL / 1 mL), lithium hydroxide monohydrate (57 mg, 1.35 mmol) was added, and the reaction was stirred at 25°C for 1 hour until complete. The reaction mixture was adjusted to pH=2 with dilute hydrochloric acid (2 mol / L), diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), combined with the organic phase, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 19-2 (0.24 g) in 90% yield. LC-MS(ESI)[M+H] + :600.3. Step 3: Synthesis of Compound 19-3 Under a nitrogen atmosphere, compound 19-2 (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL), and the intermediates 2-chloro-5-fluoro-4-(trifluoromethyl)aniline (44 mg, 0.20 mmol) and pyridine (130 mg, 1.70 mmol) were added. Further, a solution of phosphoryl chloride (31 mg, 0.20 mmol) in dichloromethane (3 mL) was added, and the reaction was stirred at room temperature for 15 minutes until complete. After dilution with water (6 mL), the mixture was extracted with dichloromethane (5 mL x 3), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 5%) to obtain compound 19-3 (66 mg) in a yield of 50%. LC-MS(ESI)[M+H] + :795.3.

[0412] Step 4: Synthesis of Compound 19 Under a nitrogen atmosphere, compound 19-3 (56 mg, 0.70 mmol) was dissolved in trifluoroacetic acid (3 mL), heated to 90°C, and stirred for 3 hours until the reaction was complete. After the reaction was complete, the mixture was concentrated and dried under reduced pressure. The residue was diluted with water (6 mL), extracted with dichloromethane (5 mL x 3), combined with the organic phase, washed with water (5 mL x 6) and saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by HPLC to obtain compound 19 (7.0 mg). The yield was 14%. LC-MS(ESI)[M+H]+ :705.3.

[0413] 1 H NMR(400MHz,MeOD-d4)δ8.17(d,J=12.6Hz,1H),8.09(s,1H),7.85(d,J=7.1Hz,1H), 7.36(d,J=2.8Hz,2H),6.87(s,1H),5.43(s,2H),4.77-4.66(m,1H),4.42-4.33(m,2 H),3.99(t,J=5.4Hz,2H),3.95-3.83(m,2H),3.76-3.60(m,1H),3.38(d,J=22.3Hz, 1H),3.18-3.09(m,3H),2.96-2.84(m,3H),2.79-2.68(m,1H),1.32(t,J=7.4Hz,3H).

[0414] Example 20: Synthesis of Compound 20

[0415] [ka]

[0416] Step 1: Synthesis of Compound 20-1 Under a nitrogen atmosphere, compound 19-2 (100 mg, 0.17 mmol), 2-chloro-4-trifluoromethylaniline (48.92 mg, 0.25 mmol), and phosphoryl chloride (76.71 mg, 500.3 μmol) were dissolved in DCM (6 mL). Pyridine (79.15 mg, 1.0 mmol) was then added, and the resulting mixture was stirred and reacted at 25°C for 30 minutes until the reaction was complete. After dilution with water (6 mL), the mixture was extracted with dichloromethane (5 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 10 / 1) to obtain compound 20-1 (122 mg) in a yield of 94%. LC-MS(ESI)[M+H] + :777.2.

[0417] Step 2: Synthesis of Compound 20 Under a nitrogen atmosphere, compound 20-1 (122 mg, 0.16 mmol) was dissolved in trifluoroacetic acid (1 mL), heated to 90°C, and stirred for 30 minutes until the reaction was complete. The mixture was then concentrated under reduced pressure and dried, and the residue was purified by HPLC to obtain compound 20 (7.2 mg). The yield was 6.7%. LC-MS(ESI)[M+H] + :687.2. 1 H NMR(400MHz,MeOD-d4)δ8.15(s,1H),8.07(s,1H),7.81(s,1H),7.60(d,J=10.1Hz,1H),7.34(s,2H),6.86(s,1H),5.38(s ,2H),4.36(s,2H),3.94(d,J=36.8Hz,4H),3.64(s,1H),3.45(s,2H),3.15(s,3H),2.90(s,3H),2.69(s,1H),1.33(s,3H) Example 21: Synthesis of Compound 21

[0418] [ka]

[0419] Step 1: Synthesis of Compound 21-1 Under a nitrogen atmosphere, compound 4-11 (33.6 mg, 54.7 μmol), 4-(pentafluorothio)aniline (11.98 mg, 54.7 μmol), and pyridine (21.6 mg, 273.3 μmol) were dissolved in dichloromethane (5 mL). A solution of phosphoryl chloride (25.2 mg, 164.0 μmol) in dichloromethane (0.5 mL) was added, and the resulting mixture was stirred at 25°C for 1 hour until the reaction was complete. The reaction solution was then quenched with saturated sodium bicarbonate aqueous solution (3 mL), extracted with dichloromethane (2 × 5 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (dichloromethane:methanol = 9:1) to obtain compound 21-1 (42 mg) with a yield of 94%. LC-MS(ESI)[M+H] + :816.2.

[0420] Step 2: Synthesis of Compound 21 Under a nitrogen atmosphere, compound 21-1 (42 mg, 51.5 μmol) was dissolved in dichloromethane (5 mL), boron trichloride (25.13 mg, 214.51 μmol, 0.2 mL) was added, and the reaction was stirred at 25°C for 1 hour until the reaction was complete. Then methanol (1 mL) was added to quench the reaction, and after concentration under reduced pressure, the resulting crude product was purified by preparative HPLC to obtain compound 21 (12 mg) in a yield of 39%. LC-MS(ESI)[M+H] + = 726.2.

[0421] 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),10.10(s,1H),8.56(s,1H),7.88(d,J=9.3Hz,2H),7.77(d, J=8.9Hz,2H),6.70-6.52(m,1H),5.36(s,2H),4.50(d,J=12.4Hz,1H),4.33(q,J=2.8Hz,2H),3.9 3(t,J=5.4Hz,2H),3.70(t,J=12.0Hz,2H),3.47(d,J=12.7Hz,1H),3.20(d,J=11.1Hz,2H),3.09- 2.91(m,3H),2.76(d,J=24.2Hz,3H),2.57(d,J=11.4Hz,1H),2.44(s,3H),1.17(t,J=7.4Hz,3H).

[0422] Example 22: Synthesis of Compound 22

[0423] [ka]

[0424] Step 1: Synthesis of Compound 22-1 Under a nitrogen atmosphere, compound 4-11 (120 mg, 195.2 μmol), 2,4-dichloro-5-fluoroaniline (52.7 mg, 292.9 μmol), and pyridine (77.2 mg, 976.2 μmol) were dissolved in dichloromethane (3 mL). Phosphoryl chloride (44.9 mg, 292.9 μmol) was added, and the resulting mixture was stirred at 25°C for 1 hour until the reaction was complete. Water (3 mL) was added to the reaction mixture to quench it, and the mixture was extracted with dichloromethane (2 × 5 mL). The organic phase was dried over anhydrous sodium sulfate and then spin-dried under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 19:1) to obtain compound 22-1 (117 mg) in a yield of 87%. LC-MS(ESI)[M+H] + :776.4.

[0425] Step 2: Synthesis of Compound 22 Under a nitrogen atmosphere, compound 22-1 (117 mg, 150.7 μmol) was dissolved in trifluoroacetic acid (2.5 mL), stirred at 90°C for 0.5 hours until the reaction was complete, concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (20 mL). After washing and extraction with water (5 mL), the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was slurryed with petroleum ether / ethyl acetate (4:1) and purified to obtain compound 22 (51.7 mg) in a yield of 50%. LC-MS(ESI)[M+H] + :686.2.

[0426] 1 H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.58(s,1H),8.00-7.90(m,2H),6.82-6. 70(m,1H),5.28(s,2H),4.51(d,J=12.0Hz,1H),4.39-4.29(m,2H),3.95-3.86( m,2H),3.80-3.64(m,2H),3.54-3.45(m,1H),3.28-3.16(m,1H),3.09-2.88(m, 3H), 2.86-2.73 (m, 3H), 2.66-2.55 (m, 1H), 2.44 (s, 3H), 1.19 (t, J=8.0Hz, 3H).

[0427] Example 23: Synthesis of Compound 23

[0428] [ka]

[0429] Step 1: Synthesis of Compound 23-1 Under nitrogen gas protection, compound 4-11 (100 mg, 161.1 μmol), 4-amino-2,5-difluorotrifluorotoluene (34.9 mg, 177.2 μmol), and pyridine (63.7 mg, 805.3 μmol) were dissolved in dichloromethane (6 mL). A solution of phosphoryl chloride (27.2 mg, 177.2 μmol) in dichloromethane (0.2 mL) was then added. The resulting mixture was stirred at 25°C for 0.5 hours until the reaction was complete. Water (3 mL) was added to the reaction mixture to quench it, and the mixture was extracted with dichloromethane (2 × 5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was separated by silica gel column chromatography (dichloromethane:methanol = 93:7) to obtain compound 23-1 (120 mg) in 89% yield. LC-MS(ESI)[M+H]+:794.4.

[0430] Step 2: Synthesis of Compound 23 Under nitrogen gas protection, compound 23-1 (110 mg, 119.7 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction was stirred at 90°C for 0.5 hours until complete. The mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 90:10) to obtain compound 23 (63.8 mg) in a yield of 75%. LC-MS(ESI)[M+H] + :704.3.

[0431] 1H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.23(s,1H),8.57(s,1H),8.20(dd,J=12.6,6.1Hz,1H),7.88 (dd,J=10.6,6.6Hz,1H),6.73(p,J=1.7Hz,1H),5.30(s,2H),4.51(d,J=12.4Hz,1H),4.31(q,J=2.9Hz ,2H),3.89(t,J=5.5Hz,2H),3.76-3.64(m,2H),3.49(d,J=12.6Hz,1H),3.22(t,J=11.8Hz,1H),2.97 (d,J=9.6Hz,3H),2.76(d,J=19.9Hz,3H),2.58(d,J=11.2Hz,1H),2.44(s,3H),1.17(t,J=7.5Hz,3H).

[0432] Comparative Example Example 42 in WO2022249060A1 was used as the control compound HRO761, and the compound was prepared by referring to the method of this patent.

[0433] Experimental Example 1: WRN Helicase Activity Test Experiment 1. Laboratory equipment The equipment used in this experiment is shown in Table 1.

[0434] [Table 1]

[0435] 2. Experimental materials The WRN enzyme used in the experiment had a His-TEV tag at its N-terminus and was expressed in eukaryotic cells with a purity of 90%. The two single-stranded DNA samples used for detection were labeled with BHQ2 and Cy5, respectively. When the two fluorescent molecules came into close proximity (when the DNA was in a double-stranded state), the fluorescence signal was not detected due to the quenching effect. WRN has helicase activity, dissociating double-stranded DNA into single strands, thereby generating a fluorescence signal. Information on other reagents and consumables required for the experiment is shown in Table 2.

[0436] [Table 2]

[0437] 3. Experimental Method Two labeled single-stranded DNA molecules were annealed to form double-stranded DNA. Annealing buffer: 12 mM Tris (pH 8.0), 300 mM NaCl, 12 mM MgCl2, 2 mM DTT. Annealing program: 95°C, 5 minutes. 2× WRN enzyme (2nM) and 2× substrate (100nM double-stranded DNA, 1000nM captured DNA, 100μM ATP) were prepared using a buffer solution (20mM Bicine, 10mM KCl, 1mM mgCl2, 0.005% BSG, 1 mM TCEP, 0.1% F-127, pH 7.5). The test compounds were dissolved in DMSO to 10mM and gradient diluted in a 96-well V-bottom plate. 0.5μL of the compound was added to 25μL of 2× WRN enzyme and incubated at room temperature for 30 minutes. 25μL of the 2× substrate was added and reacted at room temperature for 30 minutes. Detection was performed using a microplate reader with excitation light at 620nm and emission light at 685nm.

[0438] 4. Data Analysis Using GraphPad Prism 8 software, the concentration-effect curve was fitted to determine the compound concentration IC that shows a 50% inhibitory effect. 50 The IC was calculated. After calculating the percentage inhibition rate corresponding to each compound concentration, the concentration-effect curve was fitted using the "log(inhibitor) vs. normalized response--Variable slope" equation in GraphPad Prism 8 software. 50 I obtained it.

[0439] Inhibition rate (%) = (Average fluorescence intensity of positive control well - Fluorescence intensity of compound well) / (Average fluorescence intensity of positive control well - Average fluorescence intensity of negative control well) × 100 Positive control: 25 μL 2× WRN enzyme + 0.5 μL DMSO + 25 μL 2× substrate Negative control: 25μL 2X buffer + 0.5μL DMSO + 25μL 2X substrate The experimental results are shown in Table 3.

[0440] [Table 3]

[0441] Based on the above test results, the compound of the present invention exhibits excellent WRN helicase activity, confirming its potential for development as a WRN helicase inhibitor. Experimental Example 2: WRN Hydrolyzate Activity Detection Test 1. Laboratory equipment The equipment used in this experiment is shown in Table 4.

[0442] [Table 4]

[0443] 2. Experimental materials The WRN enzyme used in the experiment had a His-TEV tag at its N-terminus, was expressed in eukaryotic cells, and had a purity of 90%. Detection kit (ADP-Glo TM The Kinase Assay was purchased from Promega (product number V9101), stored at -40°C after dispensing, and this kit was capable of quantitatively detecting the amount of ADP produced during the reaction. WRN hydrolyzed ATP to produce ADP, and when the ADP-Glo ​​reagent was added, the excess ATP in the reaction system was consumed. Subsequently, when the Kinase Detection Reagent was added, the ADP produced in the reaction was converted back to ATP, resulting in chemiluminescence. The enzyme activity of WRN could be reflected by detecting the chemiluminescence signal with a microplate reader. Information on other reagents and consumables required for the experiment is shown in Table 5.

[0444] [Table 5]

[0445] 3. Experimental Method Single-stranded DNA was annealed to form double-stranded DNA. 5x annealing buffer: 50mM Tris pH 8.0, 100mM NaCl. Annealing program: 95°C, 5 minutes.

[0446] Using a buffer solution (20 mM Bicine (pH 7.5), 10 mM KCl, 10 mM mgCl2, 0.005% BSG, 0.002% Tween 20, 1 mM TCEP), a 2× WRN enzyme (1 nM) and a 2× substrate (1 nM double-stranded DNA, 100 μM ATP) were prepared. The test compounds were dissolved in DMSO to 10 mM and gradient diluted in a 96-well V-bottom plate. 25 μL of 2× WRN enzyme and 0.5 μL of the compound were added to a 96-well plate and incubated at room temperature for 30 minutes. Subsequently, 25 μL of the 2× substrate was added and reacted at room temperature for 60 minutes. 5 μL of the reaction mixture was dispensed into a 384-well plate, 5 μL of ADP-Glo ​​reagent was added and incubated at room temperature for 60 minutes, followed by 10 μL of Kinase Detection Reagent and incubated at room temperature for 40 minutes. The chemiluminescence signal was measured using a plate reader.

[0447] 4. Data Analysis Using GraphPad Prism 8 software, the concentration-effect curve was fitted to determine the compound concentration IC that shows a 50% inhibitory effect. 50 The IC was calculated. After calculating the percentage inhibition rate corresponding to each compound concentration, the concentration-effect curve was fitted using the "log(inhibitor)vs. normalized response -- Variable slope" equation in GraphPad Prism 8 software. 50 I obtained it.

[0448] Inhibition rate (%) = (Average emission intensity of positive control well - Emission intensity of compound well) / (Average emission intensity of positive control well - Average emission intensity of negative control well) × 100 Positive control: 25 μL 2× WRN enzyme + 0.5 μL DMSO + 25 μL 2× substrate Negative control: 25μL 2X buffer + 0.5μL DMSO + 25μL 2X substrate The experimental results are shown in Table 6.

[0449] [Table 6]

[0450] The above test results demonstrate that the compound of the present invention possesses excellent WRN hydrolase activity. Experimental Example 3: Cell Proliferation Test 1. Laboratory equipment The equipment used in this experiment is shown in Table 7.

[0451] [Table 7]

[0452] 2. Experimental materials Table 8 shows information on other reagents and consumables required for the experiment.

[0453] [Table 8]

[0454] 3. Experimental Method SW48 cells were seeded at a density of 1,500 cells / well, and LoVo·HCT116·SW620 cells at a density of 800 cells / well in 96-well cell culture plates and cultured overnight in a 37°C incubator. After adding test compounds serially diluted with DMSO, the cells were incubated for 5 days, and cell viability was measured using the CellTiter-Glo kit. After equilibrating the CellTiter-Glo reagent to room temperature, an appropriate amount was added to the cell plate and shaken at room temperature for 12 minutes. The luminescence signal was detected using a microplate reader.

[0455] 4. Data Analysis The luminescence signal values ​​of DMSO-treated wells and cell-free wells were used as negative and positive controls, respectively, and the cell proliferation inhibition rate by the compound was calculated. The concentration-inhibition rate curve was fitted using the "log(inhibitor)vs. normalized response--Variable slope" formula in GraphPad Prism 8 software, and IC50 was calculated. 50 The value was calculated. Suppression rate (%) = [1 - (Emission intensity of compound well - Average emission intensity of positive control well) / (Average emission intensity of negative control well - Average emission intensity of positive control well)] × 100 The experimental results are shown in Table 9.

[0456] [Table 9]

[0457] The above test results revealed that the compound of the present invention shows an inhibitory effect on the cell proliferation of MSI-H colorectal cancer cell lines SW48 and HCT116, but does not show an inhibitory effect on MSS SW620 cells.

[0458] Experimental Example 4: γH2AX Induction Test 1. Laboratory equipment The equipment used in this experiment is shown in Table 10.

[0459] [Table 10]

[0460] 2. Experimental materials Table 11 shows information on other reagents and consumables required for the experiment.

[0461] [Table 11]

[0462] 3. Experimental method: SW48, HCT116, and SW620 cells were seeded at a density of 15,000–25,000 cells / well in 96-well cell culture plates and cultured overnight in a 37°C incubator. Test compounds serially diluted with DMSO were added, and after incubation for 2–3 days, γ-H2AX levels were detected using an HTRF Phospho-H2AX (SER139) detection kit. 4×Lysis buffer and Detection buffer were prepared by equilibrating them to room temperature. 4×Lysis buffer was converted to 1×Lysis buffer with ddH2O, and after aspirating and removing the culture medium, 50 μL of 1×Lysis buffer was added to each well, and the cells were lysed by shaking at room temperature for 30 minutes. 16 μL of lysis solution was dispensed into a 384-well plate, and 4 μL of diluted mixed antibody (Phospho-H2AX d2 antibody and Phospho-H2AX Eu Cryptate antibody were each diluted 20-fold in detection buffer and mixed in a 1:1 volume ratio) was added. After incubation at room temperature for 2 to 24 hours, fluorescence signals at 655 nm and 615 nm were measured using a plate reader. In parallel, parallel processing plates for cell viability measurement using the CellTiter-Glo kit were prepared. After equilibrating the CellTiter-Glo reagent to room temperature, an appropriate amount was added to the cell plate and shaken at room temperature for 12 minutes. The luminescence signal was detected using a microplate reader.

[0463] The fluorescence signal values ​​of DMSO-treated wells and positive drug-treated wells were used as negative and positive controls, respectively, and the γ-H2AX production levels induced by the compound were calculated. The concentration-induction rate curve was fitted using the "log(agonist)vs. response--Variable slope(four parameters)" equation of GraphPad Prism 8 software, and the EC2 was calculated. 50 The value was obtained.

[0464] Cell viability (%) = Compound well luminescence intensity / Mean value of negative control well luminescence intensity × 100 HTRF ratio = 665nm fluorescence signal value / 615nm fluorescence signal value × 10 4 The experimental results are shown in Table 12.

[0465] [Table 12]

[0466] The above test results showed that treatment with the compound of the present invention significantly induces DNA damage accumulation (increased γ-H2AX levels) in MSI-H colorectal cancer cell lines SW48 and HCT116, but does not have an inducing effect on SW620 cells of MSS.

[0467] Experimental Example 5: Mouse Pharmacokinetic Study 1. Experimental Objectives CD-1 mice were used as test animals, and Examples 4, 22, and Comparative Example HRO761 were orally administered. Drug concentrations in mouse plasma at each time point were measured by LC-MS / MS to investigate the pharmacokinetic characteristics of the compounds of the present invention in mice.

[0468] 2. Experimental Protocol 2.1 Laboratory chemicals and animals Experimental chemicals: Example 4, Example 22, and Comparative Example HRO761; Animal: CD-1 mouse, male, 24-25g, purchased from Shanghai Jihui Laboratory Animals Co., Ltd.

[0469] 2.2 Preparation of drugs Appropriate amounts of Example 4, Example 22, and Comparative Example HRO761 were weighed, and appropriate amounts of dimethyl sulfoxide, solutol, and physiological saline (final solvent 5% DMSO + 10% solutol + 85% saline) were added sequentially. A 1.0 mg / mL dosage solution was prepared by vortice shaking and sonication.

[0470] 2.3 Administration Three mice in Example 4, Example 22, and Comparative Example HRO761 (oral administration group) were given oral administration (dosage 10 mg / kg, administration volume 10 mL / kg) after an overnight fast, and fed 4 hours after administration.

[0471] 3. Experimental Procedure Blood samples of 0.04 mL were collected from animals before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and treated with heparin sodium for anticoagulation. Blood samples were stored on ice after collection, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 5 minutes). The recovered plasma was stored at -80°C until analysis.

[0472] The content of the target compound in mouse plasma after oral administration was measured by LC-MS / MS. 4. Pharmacokinetic parameter results Based on the calculated plasma compound concentrations at each time point, the pharmacokinetic parameters of Example 4, Example 22, and Comparative Example HRO761 were calculated using Winnonlin software. The pharmacokinetic parameters of Example 4, Example 22, and Comparative Example HRO761 of the present invention are shown in Table 13.

[0473] [Table 13]

[0474] The above test results demonstrate that the compound of the present invention has good mouse pharmacokinetic properties. Experimental Example 6: Pharmacokinetic study in rats: 1. Experimental Objective SD rats were used as experimental animals, and Examples 4, 15, and Comparative Example HRO761 were orally administered. Drug concentrations in rat plasma at different time points were measured using LC-MS / MS, and the pharmacokinetic properties of Examples 4, 15, and Comparative Example HRO761 in rats were studied.

[0475] 2. Experimental Protocol 2.1 Laboratory chemicals and animals Experimental chemicals: Example 4, Example 15, and Comparative Example HRO761; Animal: SD rat, male, 240-260g, purchased from Shanghai Jhihui Laboratory Animals Co., Ltd.

[0476] 2.2 Preparation of drugs Appropriate amounts of Example 4, Example 15, and Comparative Example HRO761 were weighed, and appropriate amounts of dimethyl sulfoxide, solutol, and physiological saline (final solvent 5% DMSO + 10% solutol + 85% physiological saline) were added. A 1.0 mg / mL administration solution was prepared by vortex shaking and sonication.

[0477] 2.3 Administration In Examples 4, 15, and Comparative Example HRO761, the oral administration group (3 rats per group) was fasted overnight, then administered orally (dosage 10 mg / kg, volume 10 mL / kg), and fed 4 hours after administration.

[0478] 3. Experimental Procedure From animals, 0.2 mL of blood was collected before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration, and treated with heparin sodium anticoagulation. After blood collection, the blood samples were stored on ice, and plasma was separated by centrifugation (centrifugation conditions: 8000 rpm, 5 minutes). The recovered plasma was stored at -80°C until analysis.

[0479] The concentrations of Examples 4, 15, and Comparative Example HRO761 in rat plasma after oral administration were measured using LC-MS / MS. 4. Pharmacokinetic parameter results Based on the plasma compound concentrations at each time point, the pharmacokinetic parameters of Example 4, Example 15, and Comparative Example HRO761 in rats were calculated using Winnonlin software. The pharmacokinetic parameters of Example 4, Example 15, and Comparative Example HRO761 of the present invention are shown in Table 14.

[0480] [Table 14]

[0481] The above test results demonstrate that the compound of the present invention possesses excellent rat pharmacokinetic properties. 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 all be included in the scope of protection of this application.

Claims

1. A compound represented by formula (I), its optical isomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 (Here, Ring A is selected from phenyl or a 5-10 membered heteroaryl, wherein the phenyl and 5-10 membered heteroaryl have 1, 2, or 3 R ａ It is arbitrarily replaced by; Ring B is C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ４－２０ Cycloalkenyl, 4-20 member heterocycloalkenyl, C ６－２０ Selected from aryl or 5- to 20-membered heteroaryl; Ring C is C ６－２０ Selected from aryl or 5- to 20-membered heteroaryl; Ring D is C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, 4-20 member heterocycloalkenyl, C ６－２０ Selected from aryl or 5- to 20-membered heteroaryl; Ring E is C ３－２０ selected from cycloalkyl, 5- to 20-membered heterocycloalkyl, C ６－２０ aryl or 5- to 20-membered heteroaryl; L １ is a single bond, -N(R ｂ１ )-,-N(R ｂ１ )C(=O)-, -O-, -S-, -(CR ｂ２ R ｂ３ ) ｔ -, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ２ -or 【Chemistry 2】 Selected from; L ２ is a single bond, -N(R ｂ１ )-,-N(R ｂ１ )C(=O)-, -O-, -S-, -(CR ｂ２ R ｂ３ ) ｔ -, -C(=O)-, -C(=S)-, -S(=O)-, -S(=O) ２ -or 【Transformation 3】 Selected from; R １ These are H, F, Cl, Br, OH, N(R) respectively, independently. ｂ４ ) ２ , CN, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; Alternatively, two R's １ They combine with each other to form one C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Forming aryl or 5-20 member heteroaryl groups; 【Chemistry 4】 teeth 【Transformation 5】 Selected from, 【Transformation 6】 teeth 【Transformation 7】 Selected from; or, 【Transformation 8】 teeth 【Chemistry 9】 Selected from, 【Chemistry 10】 teeth 【Chemistry 11】 Selected from; 【Chemistry 12】 but 【Chemistry 13】 If selected from, T is selected from C; 【Chemistry 14】 but 【Chemistry 15】 If selected from, T is selected from N or CH; 【Chemistry 16】 but 【Chemistry 17】 If selected from, R ２ H, F, Cl, Br, OH, N(R) ｂ４ ) ２ CN, SF ５ ,CHO,COOH,C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, C ２－２０ Alkenil, C ２－２０ Alkynyl, 3-20 member heterocycloalkyl, C ４－２０ Cycloalkenyl, 4-20 member heterocycloalkenyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, C ２－２０ Alkenil, C ２－２０ Alkynyl, 3-20 member heterocycloalkyl, C ４－２０ Cycloalkenyl, 4-20 member heterocycloalkenyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; [Chemistry 18] but 【Chemistry 19】 If selected from, R ２ It is selected from O or S; R ３ , R ４ These are H, F, Cl, Br, OH, N(R) respectively, independently. ｂ４ ) ２ , CN, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Selected from cycloalkyl or 3-20 member heterocycloalkyl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyls and 3- to 20-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R groups; Alternatively, R ３ and R ４ They combine with each other to form one C ３－２０ Forming a cycloalkyl or a 3-20 member heterocycloalkyl, the C ３－２０ Cycloalkyl or 3- to 20-membered heterocycloalkyl groups are optionally substituted with 1, 2, or 3 R groups; R ５ These are H, F, Cl, Br, OH, N(R) respectively, independently. ｂ４ ) ２ SF ５ , CN, CHO, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; Alternatively, two R's ５ They combine with each other to form one C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ４－２０ Cycloalkenyl, 4-20 member heterocycloalkenyl, C ６－２０ Forming an aryl or 5-20 member heteroaryl, the C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ４－２０ Cycloalkenyl, 4-20 member heterocycloalkenyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; R ６ is independently selected from H, F, Cl, Br, OH, N(R ｂ４ ), ２ CN, C １－２０ alkyl, C １－２０ heteroalkyl, C ３－２０ cycloalkyl, 3- to 20-membered heterocycloalkyl, C ６－２０ aryl or 5- to 20-membered heteroaryl, and the C １－２０ alkyl, C １－２０ heteroalkyl, C ３－２０ cycloalkyl, 3- to 20-membered heterocycloalkyl, C ６－２０ aryl and 5- to 20-membered heteroaryl are optionally substituted with 1, 2 or 3 R; Alternatively, two R's ６ They combine with each other to form one C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Forming an aryl or 5-20 member heteroaryl, the C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; R ７ These are H, F, Cl, Br, OH, N(R) respectively, independently. ｂ４ ) ２ , CN, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; R ８ H, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Selected from cycloalkyl or 3-20 member heterocycloalkyl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyls and 3- to 20-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; R ａ Each of these is independently H, F, Cl, Br, OH, NH ２ , CN, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Selected from cycloalkyl or 3-20 member heterocycloalkyl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyls and 3- to 20-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; R ｂ１ H, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryls and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; R ｂ２ , R ｂ３ These are H, F, Cl, Br, OH, and NH, respectively, independently. ２ , CN, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Selected from cycloalkyl or 3-20 member heterocycloalkyl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyls and 3- to 20-membered heterocycloalkyls are optionally substituted with 1, 2, or 3 R atoms; Alternatively, R ｂ２ and R ｂ３ They combine with each other to form one C ３－２０ Forming cycloalkyl or 3-20 member heterocycloalkyl groups; R ｂ４ These are H and C, respectively, independently. １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryls and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 Rs; m, n, p, q, and t are each independently selected from 0, 1, 2, or 3; R is independently H, F, Cl, Br, I, OH, NH ２ CN, SF ５ , CHO, COOH, 【Chemistry 20】 , C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Selected from aryl or 5-20 member heteroaryl, the C １－２０ Alkyl, C １－２０ Heteroalkyl, C ３－２０ Cycloalkyl, 3-20 member heterocycloalkyl, C ６－２０ Aryl and 5- to 20-membered heteroaryls are optionally substituted with 1, 2, or 3 R'; R' is H, F, Cl, Br, I, OH, NH ２ ,CH ３ CF ３ , C ２ H ５ CN, SF ５ , CHO, COOH or 【Chemistry 21】 Selected from; Said C １－６ Heteroalkyl, C １－２０ Heteroalkyls, 3-20 member heterocycloalkyls, 4-20 member heterocycloalkenyls, 5-20 member heteroaryls, or 5-10 member heteroaryls are -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) ２ (—and includes one, two, or three heteroatoms or heteroatomic groups independently selected from N.)

2. R is independently H, F, Cl, Br, I, OH, NH ２ CN, SF ５ , CHO, COOH, 【Chemistry 22】 , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-C １－６ Alkylthio, -C １－６ Alkyl-C １－６ Alkylamino, C １－６ Alkyl-OH, C １－６ Alkyl-NH ２ , -C (=O) -C １－６ Alkyl, C １－６ Alkyl-C(=O)-C １－６ Alkyl, -NH-C(=O)-C １－６ Alkyl, C １－６ Alkyl-NH-C(=O)-C １－６ Alkyl, -NH-S (=O) ２ -C １－６ Alkyl, C １－６ Alkyl-NH-S (=O) ２ -C １－６ Alkyl, C ３－６ Selected from cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, or thiopyranil, Said C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-C １－６ Alkylthio, -C １－６ Alkyl-C １－６ Alkylamino, C １－６ Alkyl-OH, C １－６ Alkyl-NH ２ , -C (=O) -C １－６ Alkyl, C １－６ Alkyl-C(=O)-C １－６ Alkyl, -NH-C(=O)-C １－６ Alkyl, C １－６ Alkyl-NH-C(=O)-C １－６ Alkyl, -NH-S (=O) ２ -C １－６ Alkyl, C １－６ Alkyl-NH-S (=O) ２ -C １－６ Alkyl, C ３－６ Cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl, and thiopyranil are optionally substituted with 1, 2, or 3 R' groups, the compound according to claim 1, its optical isomer, or a pharmaceutically acceptable salt thereof.

3. R is independently H, F, Cl, Br, I, OH, NH ２ CN, SF ５ , CHO, COOH, 【Chemistry 23】 、CH ３ 、CF ３ 、CHF ２ 、CH ２ F、CF ２ Cl、CF ２ Br、CF ２ I、 【Chemistry 24】 A compound according to claim 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

4. Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl, or 1H-pyrrolyl, wherein phenyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, 1H-imidazolyl, 1H-pyrazolyl, and 1H-pyrrolyl have 1, 2, or 3 R ａ A compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted by.

5. Ring A is, 【Chemistry 25】 A compound according to claim 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

6. R ａ These are H, F, Cl, Br, OH, and NH, respectively, independently. ２ , CN, Me, 【Chemistry 26】 Selected from, the Me, 【Chemistry 27】 The compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three R atoms.

7. R ａ These are H, F, Cl, Br, OH, and NH, respectively, independently. ２ , CN, Me, CF ３ , 【Chemistry 28】 A compound according to claim 6, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

8. Ring A is, 【Chemistry 29】 A compound according to claim 5 or 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from among. 【Request Item 9】 【Chemistry 30】 but 【Chemistry 31】 If selected from, R ２ H, F, Cl, Br, OH, NH ２ CN, SF ５ ,CHO,COOH,C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, 3-6 member heterocycloalkyl, C ４－６ Cycloalkenyl, 4-6 member heterocycloalkenyl, C ６－１０ Selected from aryl or 5-10 member heteroaryl, the C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－６ Cycloalkyl, 3-6 member heterocycloalkyl, C ４－６ Cycloalkenyl, 4-6 member heterocycloalkenyl, C ６－１０ The aryl and 5- to 10-membered heteroaryl are optionally substituted with 1, 2, or 3 R members, the compounds according to any one of claims 1 to 3, their optical isomers, or pharmaceutically acceptable salts thereof. 【Request Item 10】 【Chemistry 32】 but 【Transformation 33】 If selected from, R ２ H, F, Cl, Br, OH, NH ２ , CN, Me, 【Transformation 34】 Selected from, the Me, 【Chemistry 35】 The compound according to claim 9, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted with one, two, or three Rs.

11. R ２ がH、F、Cl、Br、OH、NH ２ 、CN、Me、CF ３ 、 【Transformation 36】 A compound according to claim 10, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

12. Structural unit 【Chemistry 37】 but 【Transformation 38】 A compound according to claim 1 or 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from among.

13. Structural unit 【Chemistry 39】 but 【Chemistry 40】 A compound according to claim 12, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

14. R １ However, each is independently H, F, Cl, Br, OH, NH ２ , CN, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-C １－６ Alkylthio, -C １－６ Alkyl-C １－６ Alkylamino, C １－６ Alkyl-OH, C １－６ Alkyl-NH ２ , C １－６ Alkyl-C(=O)-, C １－６ Alkyl-C(=O)-C １－６ Alkyl, C １－６ Alkyl-O-C(=O)-, C １－６ Alkyl-O-C(=O)-C １－６ Alkyl, -NH-C(=O)-C １－６ Alkyl, C １－６ Alkyl-NH-C(=O)-C １－６ Alkyl, C １－６ Alkyl-S (=O) ２ -, C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, -NH-S (=O) ２ -C １－６ Alkyl, C １－６ Alkyl-NH-S (=O) ２ -C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-S (=O) ２ - Or selected from 3- to 6-membered heterocycloalkyl groups, Said C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, -C １－６ Alkyl-C １－６ Alkoxy, -C １－６ Alkyl-C １－６ Alkylthio, -C １－６ Alkyl-C １－６ Alkylamino, C １－６ Alkyl-OH, C １－６ Alkyl-NH ２ , C １－６ Alkyl-C(=O)-, C １－６ Alkyl-C(=O)-C １－６ Alkyl, C １－６ Alkyl-O-C(=O)-, C １－６ Alkyl-O-C(=O)-C １－６ Alkyl, -NH-C(=O)-C １－６ Alkyl, C １－６ Alkyl-NH-C(=O)-C １－６ Alkyl, C １－６ Alkyl-S (=O) ２ -, C １－６ Alkyl-S (=O) ２ -C １－６ Alkyl, -NH-S (=O) ２ -C １－６ Alkyl, C １－６ Alkyl-NH-S (=O) ２ -C １－６ Alkyl, C ３－６ Cycloalkyl, C ３－６ Cycloalkyl-S (=O) ２ - and the 3- to 6-membered heterocycloalkyl are optionally substituted with 1, 2, or 3 R atoms, the compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

15. R １ However, each is independently H, F, Cl, Br, OH, NH ２ , CN, Me, 【Chemistry 41】 A compound according to claim 14, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

16. Ring B consists of cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxynyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridyl, 1,2,3,6-tetrahydropyridyl, tetrahydro-2H-pyranyl, and 5,6-dihydro-2H-pyranyl. A compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from n-2-keto, phenyl, pyridyl, pyrrolidinyl, 2-oxa-6-azaspiro[3,3]heptanyl, 1,1-dioxo-3,6-dihydro-2H-thiopyranil, oxepinyl, azetidinyl, 2-oxa-7-azaspiro[4.4]nonanyl, or hexahydro-1H-flo[3,4-c]pyrrolyl.

17. Structural unit 【Chemistry 42】 but, 【Chemistry 43】 A compound according to claim 15 or 16, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

18. R ５ However, each is independently H, F, Cl, Br, OH, NH ２ CN, SF ５ , CHO, C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, C ３－６ Cycloalkyl or C ３－６ Selected from heterocycloalkyl, the C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylthio, C １－６ Alkylamino, C ３－６ Cycloalkyl and C ３－６ The heterocycloalkyl group is optionally substituted with one, two, or three R atoms; Alternatively, two R's ５ They combine with each other to form one C ３－６ Cycloalkyl, 3-6 member heterocycloalkyl, C ４－１０ Cycloalkenyl, 4-10 member heterocycloalkenyl, C ６－１０ Forming an aryl or 5-10 member heteroaryl, the C ３－６ Cycloalkyl, 3-6 member heterocycloalkyl, C ４－１０ Cycloalkenyl, 4-10 member heterocycloalkenyl, C ６－１０ The aryl and 5- to 10-membered heteroaryl are optionally substituted with 1, 2, or 3 R members, the compounds according to any one of claims 1 to 3, their optical isomers, or pharmaceutically acceptable salts thereof.

19. R ５ However, each is independently H, F, Cl, Br, OH, NH ２ CN, SF ５ Me, CHO, 【Chemistry 44】 Selected from, the Me, 【Chemistry 45】 is arbitrarily replaced by 1, 2, or 3 Rs, Alternatively, two R's ５ They combine with each other, 【Chemistry 46】 Forms the above 【Chemistry 47】 The compound according to claim 18, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted with one, two, or three Rs.

20. R ５ However, each is independently H, F, Cl, Br, OH, NH ２ SF ５ , CN, Me, CF ３ , CHO, 【Chemistry 48】 Selected from, Alternatively, two R's ５ They combine with each other, 【Chemistry 49】 A compound according to claim 19, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which forms a compound according to claim 19.

21. The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from phenyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, or thienyl.

22. Structural unit [Transformation 50] but, 【Chemistry 51】 A compound according to claim 20 or 21, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

23. R ６ However, each is independently H, F, Cl, Br, OH, NH ２ , CN, Me, 【Chemistry 52】 Selected from, the Me, 【Chemistry 53】 A compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted with one, two, or three Rs.

24. R ６ However, each is independently H, F, Cl, Br, OH, NH ２ , CN, Me, CF ３ , 【Chemistry 54】 A compound according to claim 23, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

25. Ring D is 【Transformation 55】 Selected from, T １ , T ２ , T ３ , T ４ Each is independently selected from N or CH; X １ , X ２ , X ３ , X ４ Each of these is independently a single bond or CH ２ Selected from; X ５ , X ６ Each is independently a single bond, CH ２ or CH ２ CH ２ Selected from and X ５ , X ６ Not both are selected from single bonds at the same time; X ７ , X ８ , X ９ , X １０ Each of these is independently a single bond, NH, O, S, CH ２ or 【Transformation 56】 Selected from and X ７ , X ８ , X ９ , X １０ Up to three of these are selected simultaneously from the single bonds; L ａ C １－６ Alkyl, C ２－６ Alkenyl or C １－６ Selected from heteroalkyl groups, the C １－６ Alkyl and C １－６ The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the heteroalkyl group is optionally substituted with one, two, or three R groups.

26. Ring D is 【Chemistry 57】 A compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

27. Structural unit 【Transformation 58】 but, 【Chemistry 59】 A compound according to claim 25 or 26, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

28. R ７ However, each is independently H, F, Cl, Br, OH, NH ２ , CN, Me, 【Transformation 60】 Selected from, the Me, 【Chemistry 61】 A compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted with one, two, or three Rs.

29. R ７ However, each is independently H, F, Cl, Br, OH, NH ２ , CN, Me, CF ３ , 【Transformation 62】 A compound according to claim 28, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

30. The compound according to claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein ring E is selected from phenyl, pyridyl, pyrimidinyl, pyridadinyl, pyrazinyl, or thienyl.

31. Structural unit 【Transformation 63】 but, 【Chemistry 64】 A compound according to claim 29 or 30, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

32. R ３ , R ４ These are H, F, Cl, Br, OH, and NH, respectively, independently. ２ , CN, Me, 【Transformation 65】 Selected from, the Me, 【Chemical 66】 The compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three R atoms.

33. R ３ , R ４ These are H, F, Cl, Br, OH, and NH, respectively, independently. ２ , CN, Me, CF ３ , 【Transformation 67】 A compound according to claim 32, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

34. R ８ H, Me, 【Transformation 68】 Selected from, the Me, 【Transformation 69】 The compound according to any one of claims 1 to 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, which is optionally substituted with one, two, or three R atoms.

35. R ８ H, Me, CF ３ , 【Transformation 70】 A compound according to claim 34, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

36. The compound of the following formula, its optical isomer, or a pharmaceutically acceptable salt thereof. 【Chemistry 71】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

38. Use of a compound according to any one of claims 1 to 36, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 37, in the manufacture of a pharmaceutical for treating tumor-related diseases.

39. The aforementioned tumors are high-frequency microsatellite instability malignancies, mismatch repair deficiency malignancies, or massive (TA) ｎ The use according to claim 38, wherein a malignant tumor is detected in which a repetitive sequence is present.

40. The use according to claim 38, wherein the tumor-related disease is one or more types of real tumor-related diseases.

41. The use according to claim 38, wherein the tumor-related disease includes one or more selected from colorectal cancer, gastric cancer, endometrial cancer, and ovarian cancer.

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