Triazole ring compound as WRN helicase inhibitor

Abstract

The invention discloses a triazole ring compound used as a WRN helicase inhibitor and a preparation method of the triazole ring compound. Specifically, the invention discloses a compound as shown in a formula (I), an optical isomer or a pharmacologically acceptable salt thereof. # imgabs0 #

Description

[0001] The present invention claims the following priority:

[0002] Application number CN2023115290186, application date: November 15, 2023. Technical Field

[0003] The present invention relates to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof. Specifically, the present invention relates to a class of triazolocyclic compounds serving as WRN helicase inhibitors. Background Art

[0004] There are many short tandem repeat regions in the entire genome of the human body. These repetitive DNA regions are called "microsatellites". They are prone to slippage and errors during replication, so they are very dependent on the MMR (mismatch repair) system for repair. When the MMR (mismatch repair) system is abnormal, it causes dMMR (mismatch repair deficiency), which cannot recognize and repair microsatellite replication errors and cause MSI, which may lead to frameshift mutations, thereby causing abnormalities in tumor-related genes, and then inducing the occurrence and development of cancer. In 2017, immune checkpoint inhibitors (ICI) were approved for the treatment of highly microsatellite unstable / mismatch repair deficient (MSI-H / dMMR) tumors, and MSI-H / dMMR also became the first "pan-tumor" tumor marker. Microsatellite high instability (MSI-H) cancer cells rely on WRN (Werner syndrome RecQ helicase) helicase activity. Inhibition of WRN can induce DNA double-strand breaks, activate DNA damage response, and induce apoptosis and cell cycle arrest. Common treatments for dMMR (mismatch repair deficiency) / MSI-H cancer patients include targeted therapy, chemotherapy, and immunotherapy. The clinical effectiveness of targeted therapy and chemotherapy is limited by drug resistance and drug toxicity, and about half of immunotherapy patients do not respond positively to immune checkpoint inhibitors. 45-60% of MSI-H cancer patients do not respond to immunotherapy, and the primary and secondary resistance problems of targeted therapy, chemotherapy, and immunotherapy need to be solved urgently. In 2019, the Broad Institute of Harvard and MIT in the United States analyzed the Achilles and drive databases to evaluate the degree of dependence of each cell line on different targets. They found that the activity of the RecQ DNA helicase WRN is essential in dMMR / MSI-H cell lines both in vivo and in vitro, while MSS cells do not rely on WRN for survival. In the MSI-H model, knocking out WRN induces double-strand DNA breaks and selectively promotes apoptosis and cell cycle arrest. This tumor suppression mechanism is different from targeted drugs (inhibiting cancer cell-specific oncogenic changes) and immunotherapy (inhibiting immune evasion and tolerance). In 2021, the research group of Dr. Mathew J Garnett from the Wellcome Sanger Institute used PDX models to demonstrate that WRN inhibitors can be used as second-line or third-line monotherapy for dMMR patients. In dMMR tumors, tumor mutation is negatively correlated with immune checkpoint blockade response, while WRN sensitivity is not related to mutation load. Due to the existence of different modes of action, combined treatment with checkpoint inhibitors, chemotherapy or targeted therapy and WRN inhibitors may inhibit cross-resistance and promote tumor eradication.In addition, because the loss of DNA repair modulates the structure of neoantigens and increases the mutation burden, leading to enhanced immune responses, WRN inhibition may also synergize with immunotherapy. Therefore, WRN may serve as a key target for monotherapy or combination therapy with targeted drugs, chemotherapy, or immunotherapy in dMMR / MSI-H tumors.

[0005] MSI-H tumors can occur in multiple sites, with the highest incidence in endometrial cancer (31%), colon adenocarcinoma (20%), and gastric cancer (19%). There are approximately 325,000 new MSI-H tumor patients in the United States each year, and approximately 300,000 in China. Its drug development has great market value. In tumors with normal mismatch repair (MSS), the loss (or reduction) of WRN expression does not affect the growth of tumor cells. In tumors with mismatch repair deficiency (MSI-H), if accompanied by the loss (or reduction) of WRN expression, it can cause an increase in the accumulation of double-strand breaks in cellular DNA, and the cell cycle is blocked in the G1 or G2 / M phase, leading to tumor cell death. This is the so-called synthetic lethal effect. The development of WRN helicase inhibitors is expected to become one of the effective treatments for MSI-H cancer. Summary of the invention

[0006] In one aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof,

[0007]

[0008] in,

[0009] Ring B is selected from C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl or 5-20 membered heteroaryl;

[0010] Ring D is selected from C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl or 5-20 membered heteroaryl;

[0011] Ring E is selected from C 3-20 Cycloalkyl, 5-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl;

[0012] L1 is selected from 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-

[0013] or

[0014] L2 is selected from 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-

[0015] or

[0016] Z is selected from O, S or Se;

[0017] X is selected from H, Cl, Br, I or F;

[0018] R1 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, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0019] Alternatively, two R1s are connected together to form a C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl;

[0020] Selected from Selected from

[0021] or, Selected from Selected from

[0022] when Selected from When , T is selected from C;

[0023] when Selected from When , T is selected from N or CH;

[0024] when Selected from When R2 is selected from 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 Alkenyl, C 2-20 Alkynyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0025] when Selected from When, R2 is selected from O or S;

[0026] R3 and R4 are 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 or 3-20 membered heterocycloalkyl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

[0027] Alternatively, R3 and R4 are connected together to form a C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, the C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R;

[0028] R5 is independently selected from H, F, Cl, Br, I, OH, NH2, CF3, CN, SF5, CHO, COOH, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl;

[0029] R6 are 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, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0030] Alternatively, two R6s are connected together to form a C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0031] R7 are 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, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0032] R b1 Selected from H, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0033] R b2 , R b3 are independently selected from H, F, Cl, Br, OH, NH2, CN, C 1-20 Alkyl, C1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R;

[0034] Or, R b2 With R b3 Connect together to form a C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl;

[0035] R b4 are independently selected from H, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R;

[0036] m, n, p, q, t are independently selected from 0, 1, 2 or 3;

[0037] R is independently selected from H, F, Cl, Br, OH, NH2, CN, SF5, CHO, COOH, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R';

[0038] R' is selected from H, F, Cl, Br, I, OH, NH2, CH3, CF3, C2H5, CN, SF5, CHO, COOH or

[0039] C 1-20The heteroalkyl, 3-20 membered heterocycloalkyl, 4-20 membered heterocycloalkenyl or 5-20 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N, and the other variables are as defined herein.

[0040] In some embodiments of the present invention, R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, 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, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl or thiopyranyl,

[0041] 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(=O)-C 1-6 Alkyl, C1-6 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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl and thiopyranyl are optionally substituted with 1, 2 or 3 R's, and the other variables are as defined herein.

[0042] In some embodiments of the present invention, R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, CH3, CF3, CHF2, CH2F, CF2Cl, CF2Br, CF2I, Other variables are as defined herein.

[0043] In some embodiments of the present invention, R5 is independently selected from H, F, Cl, Br, I, OH, NH2, CF3, CN, SF5, CHO, COOH, C 1-12 Alkyl, C 1-12 Alkoxy, C 1-12 Alkylthio, C 1-12 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 3-12 Cycloalkyl or 3-12 membered heterocycloalkyl, and other variables are as defined in the present invention.

[0044] In some embodiments of the present invention, R5 is independently selected from H, F, Cl, Br, I, OH, NH2, CF3, CN, SF5, CHO, COOH, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, -C 1-3 Alkyl-C 1-3 Alkoxy, -C 1-3 Alkyl-C 1-3Alkylthio, -C 1-3 Alkyl-C 1-3 Alkylamino, Other variables are as defined herein.

[0045] In some embodiments of the present invention, R5 is independently selected from H, F, Cl or C 1-6 Alkyl, and other variables are as defined herein.

[0046] In some embodiments of the present invention, X is selected from H, Cl, Br or I.

[0047] In some embodiments of the present invention, X is selected from Cl.

[0048] In some embodiments of the present invention, the structural unit Selected from

[0049] Other variables are as defined herein.

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

[0051] Other variables are as defined herein.

[0052] In some embodiments of the present invention, the structural unit Selected from Other variables are as defined herein.

[0053] In some embodiments of the present invention, R6 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0054] In some embodiments of the present invention, R6 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, CF3, Other variables are as defined herein.

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

[0056] T1, T2, T3, T4 are each independently selected from N or CH;

[0057] X1, X2, X3, and X4 are each independently selected from a single bond or CH2;

[0058] X5 and X6 are each independently selected from a single bond, CH2 or CH2CH2, and X5 and X6 are not simultaneously selected from a single bond;

[0059] X7, X8, X9, X 10 are independently selected from a single bond, NH, O, S, CH2 or And X7, X8, X9, X 10 At most 3 of them are simultaneously selected from single bonds;

[0060] L a Selected from C 1-6 Alkyl, C 2-6 Alkenyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl and C 1-6 The heteroalkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0061] In some embodiments of the present invention, ring D is selected from

[0062] Other variables are as defined herein.

[0063] In some embodiments of the present invention, the structural unit Selected from

[0064] Other variables are as defined herein.

[0065] In some embodiments of the present invention, R1 is independently selected from 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, C 1-6 Alkyl-C(=O)-, C 1-6 Alkyl-C(=O)-C 1-6 Alkyl, C 1-6 Alkyl-OC(=O)-, C 1-6Alkyl-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 Cycloalkyl-S(=O)2- or 3-6-membered heterocycloalkyl,

[0066] 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-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 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0067] In some embodiments of the present invention, R1 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, Other variables are as defined herein.

[0068] In some embodiments 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-dioxinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 5, 6-dihydro-2H-pyran-2-onyl, phenyl, pyridinyl, pyrrolidinyl, 2-oxa-6-aza-spiro[3,3]heptanyl, 1,1-dioxo-3,6-dihydro-2H-thiopyranyl, oxepanyl, azetidinyl, 2-oxa-7-azaspiro[4.4]nonanyl or hexahydro-1H-furo[3,4-c]pyrrolyl, and the other variables are as defined herein.

[0069] In some embodiments of the present invention, the structural unit Selected from:

[0070] Other variables are as defined herein.

[0071] In some embodiments of the present invention, R7 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0072] In some embodiments of the present invention, R7 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, CF3, Other variables are as defined herein.

[0073] In some embodiments of the present invention, ring E is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or thienyl, and the other variables are as defined herein.

[0074] In some embodiments of the present invention, the structural unit Selected from

[0075] Other variables are as defined herein.

[0076] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0077] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, OH, NH2, CN, Me, CF3, Other variables are as defined herein.

[0078] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, OH, NH2, CN, Other variables are as defined herein.

[0079] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl, Br, OH, NH2 or CN, and other variables are as defined in the present invention.

[0080] In some embodiments of the present invention, R3 and R4 are independently selected from H, F, Cl or Br, and other variables are as defined in the present invention.

[0081] The present invention also provides the following compounds, their optical isomers or their pharmaceutically acceptable salts, which are selected from

[0082]

[0083]

[0084]

[0085] In yet another aspect of the present invention, the present invention also provides a pharmaceutical composition. In some embodiments of the present invention, the pharmaceutical composition protects the aforementioned compound, its optical isomer or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments of the present invention, the above-mentioned pharmaceutical composition further comprises a pharmaceutical excipient.

[0087] In another aspect of the present invention, the present invention also provides the use of the above-mentioned compound, its optical isomer or its pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in the preparation of a drug for treating tumor-related diseases.

[0088] The purpose of the present invention is to provide a compound as a WRN inhibitor or its stereoisomers, deuterated products, solvent compounds, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods, as well as their use in the preparation of drugs for the treatment of microsatellite highly instability tumor-related diseases.

[0089] In some embodiments of the present invention, the tumor-related disease is one or more diseases associated with solid tumors.

[0090] The compounds of the present invention can be used alone or in combination with other chemotherapeutic drugs, targeted therapeutic drugs or immunotherapeutic drugs to treat a variety of tumors, especially malignant tumors with high microsatellite instability (MSI), or malignant tumors with mismatch repair deficiency (dMMR), or malignant tumors with a large number of (TA) n Malignant tumors with repetitive sequences include but are not limited to colorectal cancer, gastric cancer, endometrial cancer, ovarian cancer, etc.

[0091] Definition and Description

[0092] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0093] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0094] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, prepared from compounds having specific substituents discovered by the present invention and relatively nontoxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, etc.; also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups, and thus can be converted into any base or acid addition salt.

[0095] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in the form of free acid or base are prepared by reacting with a suitable base or acid in a stoichiometric amount.

[0096] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0097] Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0098] The compounds of the invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C). For another example, deuterium can be used to replace hydrogen to form a deuterated drug. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.

[0099] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0100] The term "substituted by..." means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. The term "optionally substituted by..." means that it may be substituted or not substituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of chemical practicability.

[0101] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1, 2, or 3 Rs, the group may be optionally substituted with up to three Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds. For example, Can be selected from wait.

[0102] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected, such as When L2 represents a single bond, it means that the structure is actually A hyphen ("-") not between two letters or symbols indicates the point of attachment of a substituent. 1-6 Alkylcarbonyl - refers to a C- 1-6 However, when the attachment point of the substituent is obvious to those skilled in the art, for example, a halogen substituent, the "-" may be omitted.

[0103] Unless otherwise indicated, when a group bond is indicated by a dash When, for example, In the figure, the dashed line indicates the point of attachment of the group to the rest of the molecule.

[0104] When the substituent is listed without indicating the atom through which it is connected to the substituted group, the substituent can be bonded through any atom thereof. For example, a pyridyl substituent can be bonded to the substituted group through any carbon atom on the pyridine ring.

[0105] When the listed linking group does not indicate its linking direction, its linking direction is arbitrary, for example, The connecting group L is at this time You can connect phenyl and cyclopentyl groups in the same direction as reading from left to right to form It is also possible to connect phenyl and cyclopentyl groups in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0106] Unless otherwise specified, the number of atoms on the ring refers to the number of atoms that make up the ring itself in a compound (such as a monocyclic compound, a paracyclic compound, a spirocyclic compound, a bridged ring compound, a cross-linked compound, a carbocyclic compound, a heterocyclic compound) in which atoms are bonded to form a ring. The number of atoms on the ring is usually defined as the number of members of the ring. For example, a "4-6 membered ring" refers to a "ring" with 4-6 atoms arranged around it. When a ring is substituted with a substituent, the atoms contained in the substituent are not included in the ring atoms. Unless otherwise specified, benzene is a 6-membered ring, naphthalene is a 10-membered ring, and thiophene is a 5-membered ring.

[0107] Unless otherwise specified, the term "alkyl" refers to a saturated hydrocarbon group containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof, which may represent a straight chain and / or branched alkyl group, which may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). Unless otherwise specifically stated in the specification, an alkyl group may be optionally substituted.

[0108] Unless otherwise specified, the term “C 1-20 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 20 carbon atoms. 1-20 Alkyl groups include C 1-19 , C 1-15 , C 1-10 , C 1-5 , C 1-4 , C 2-20 , C 2-12 , C 2-6 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 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, 1,20-eicosylene, and the like.

[0109] Unless otherwise specified, the term “C 1-6 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 , C 1-4 , C 2-6 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl ("Me"), ethyl ("Et"), propyl such as n-propyl ("n-Pr") or isopropyl ("i-Pr"), butyl such as n-butyl ("n-Bu"), isobutyl ("i-Bu"), sec-butyl ("s-Bu") or tert-butyl ("t-Bu"), pentyl, hexyl, methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylidene, 1,6-hexylidene, and the like.

[0110] Unless otherwise specified, the term “C 1-3 "Alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl, etc.; it may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), methylene, 1,2-ethylene, 1,3-propylene, and the like.

[0111] Unless otherwise specified, the term "alkenyl" refers to a group containing a carbon-carbon sp 2 A double bonded hydrocarbon group may represent a straight chain and / or branched alkenyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight chain alkenyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkenyl group may be optionally substituted.

[0112] Unless otherwise specified, “C 2-20 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 20 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-20 Alkenyl includes C 2-19 , C 2-15 , C 2-10 , C 2-5 , C 2-4 , C 3-20 , C 4-12 , C 5-6 It may be monovalent, divalent or polyvalent. 2-20 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, pentenyl, hexenyl, butadienyl, pentyladienyl, hexadienyl, octenyl, decenyl, n-undecenyl, ethenylene, propenylene, sec-butenylene, 2-methylbutenylene, and the like.

[0113] Unless otherwise specified, “C 2-6 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-6 Alkenyl includes C 2-4 , C 2-3 , C4, C3 and C2 alkenyl, etc.; which may be monovalent, divalent or polyvalent. 2-6Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylenyl, hexadienyl, ethenylene, propenylene, sec-butenylene, and the like.

[0114] Unless otherwise specified, “C 2-3 "Alkenyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position of the group. 2-3 Alkenyl includes C3 and C2 alkenyl; the C 2-3 The alkenyl group may be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, ethenylene, propenylene, and the like.

[0115] Unless otherwise specified, the term "alkynyl" refers to a hydrocarbon group containing at least one unsaturated site, i.e., a carbon-carbon sp triple bond, which may represent a straight and / or branched alkynyl group, wherein a branched chain refers to one or more alkyl groups such as methyl, ethyl or propyl groups connected to a straight alkynyl chain. It may be monovalent, divalent or polyvalent. Unless otherwise specifically stated in the specification, an alkynyl group may be optionally substituted.

[0116] Unless otherwise specified, the term “C 2-20 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 20 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. 2-20 Alkynyl groups include C 2-19 , C 2-15 , C 2-10 , C 2-5 , C 2-4 , C 3-20 , C 4-12 , C 5-6 Alkynyl, etc.; which may be monovalent, divalent or polyvalent. 2-20 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, pentynyl, pentynylene, 1-butynyl, butadiynyl, cyclopropylethynyl, 3-methyl-2-pentynylene, and the like.

[0117] Unless otherwise specified, the term “C 2-6 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-6 Alkynyl groups include C 2-5 , C 2-4 , C 2-3 , C2, C 2-6 , C6 and C5 alkynyl, etc.2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, pentynyl, pentynylene, and the like.

[0118] Unless otherwise specified, “C 2-3 "Alkynyl" is used to refer to a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which can be located at any position of the group. It can be monovalent, divalent or polyvalent. The C 2-3 Alkynyl groups include C3 and C2 alkynyl groups. 2-3 Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, ethynylene, propynylene, and the like.

[0119] Unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term means a stable straight or branched alkyl radical or combination thereof consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group, wherein the "alkyl" in the "alkyl radical" is defined as above in the present invention. In some embodiments, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-20 In some embodiments, the heteroalkyl group is C 1-6 In other embodiments, the heteroalkyl group is C 1-3Heteroalkyl. A heteroatom or heteroatom group may be located at any internal position of a heteroalkyl group, including the position at which the alkyl group is attached to the rest of the molecule. Examples of heteroalkyl groups include, but are not limited to, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, etc.; up to two heteroatoms thereof may be consecutive, for example, -CH2-NH-OCH3. Unless otherwise specified in the specification, heteroalkyl groups may be optionally substituted. Unless otherwise specified, the term "alkoxy" refers to an alkyl group connected to the rest of the molecule via an oxygen atom, wherein the "alkyl" in the "alkyl group" is as defined above in the present invention. Unless otherwise specified in the specification, alkoxy groups may be optionally substituted.

[0120] Unless otherwise specified, the term “C 1-20 "Alkoxy" refers to those alkyl groups containing 1 to 20 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-20 Alkoxy includes C 1-19 , C 1-10 , C 1-5 , C 2-20 , C 2-8 , C6, C5 and C4 alkoxy, etc. 1-20 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, n-hexyloxy, 1-methylhexyloxy, n-nonyloxy, n-decyloxy, n-undecyloxy, n-dodecyloxy, 2-ethyldodecyloxy, n-eicosyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy, heptyleneoxy, dodecyleneoxy and the like.

[0121] Unless otherwise specified, the term “C 1-6 "Alkoxy" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-6 Alkoxy includes C 1-4 , C 1-3 , C 1-2 , C 2-6, C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexyloxy, methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, pentyleneoxy and the like.

[0122] Unless otherwise specified, the term “C 1-4 "Alkoxy" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-4 Alkoxy includes C 1-3 , C 1-2 , C 2-4 , C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), methyleneoxy, ethyleneoxy, propyleneoxy, butyleneoxy, and the like.

[0123] Unless otherwise specified, the term “C 1-3 "Alkoxy" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via an oxygen atom. 1-3 Alkoxy includes C 1-2 , C 2-3 , C3 and C2 alkoxy, etc. 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), methyleneoxy, ethyleneoxy, propyleneoxy, and the like.

[0124] Unless otherwise specified, the term "amino" may be monovalent - NH2, divalent Or multiple price

[0125] Unless otherwise specified, the term "alkylamino" refers to an alkyl group attached to the rest of the molecule via an amino group as defined above, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, the alkylamino group may be optionally substituted.

[0126] Unless otherwise specified, the term “C 1-20 "Alkylamino" refers to those alkyl groups containing 1 to 20 carbon atoms which are attached to the rest of the molecule through an amino group. 1-20 Alkylamino groups include C 1-19 , C 1-14 , C1-12 , C 2-6 , C 2-4 , C 15 , C 10 , C8, C5 and C 20 Alkylamino, etc. 1-20 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, -NHCH2CH2CH2CH3, -NHCH2CH2CH2CH2CH3, -NHCH2CH2CH2CH2CH3, -N(CH2CH2CH3)(CH2CH2CH2CH3), and the like.

[0127] Unless otherwise specified, the term “C 1-6 "Alkylamino" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule through an amino group. 1-6 Alkylamino groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0128] Unless otherwise specified, the term “C 1-4 "Alkylamino" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule through an amino group. 1-4 Alkylamino groups include C 1-3 , C 1-2 , C 2-4 , C4, C3 and C2 alkylamino, etc. 1-4 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0129] Unless otherwise specified, the term “C 1-3"Alkylamino" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule through an amino group. 1-3 Alkylamino groups include C 1-2 , C3 and C2 alkylamino, etc. 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0130] Unless otherwise specified, the term "alkylthio" refers to an alkyl group connected to the rest of the molecule via a sulfur atom, wherein "alkyl" in "alkyl group" is as defined above in the present invention. Unless otherwise specifically stated in the specification, alkylthio may be optionally substituted.

[0131] Unless otherwise specified, the term “C 1-20 "Alkylthio" refers to those alkyl groups containing 1 to 20 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-20 Alkylthio includes C 1-19 , C 1-14 , C 1-12 , C 2-6 , C 2-4 , C 15 , C 10 , C8, C5 and C 20 Alkylthio, etc. 1-20 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -SCH2CH2CH2CH3, -SCH2CH2(CH3)2, -SCH2CH2CH2CH2CH3, -SCH2CH2CH2CH2CH3, -SCH2(CH2CH2CH3)(CH2CH2CH2CH3), and the like.

[0132] Unless otherwise specified, the term “C 1-6 "Alkylthio" refers to those alkyl groups containing 1 to 6 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-6 Alkylthio includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0133] Unless otherwise specified, the term “C 1-4 "Alkylthio" refers to those alkyl groups containing 1 to 4 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-4 Alkylthio includes C 1-3 , C 1-2 , C 2-4 , C4, C3 and C2 alkylthio, etc. 1-4 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0134] Unless otherwise specified, the term “C 1-3 "Alkylthio" refers to those alkyl groups containing 1 to 3 carbon atoms which are attached to the rest of the molecule via a sulfur atom. 1-3 Alkylthio includes C 1-3 , C 1-2 and C3 alkylthio, etc. 1-3 Examples of alkylthio groups include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0135] Unless otherwise specified, the term "cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic saturated hydrocarbon group composed of carbon and hydrogen atoms, which may include cyclo, spiro and / or bridged ring systems. Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic cycloalkyls include, but are not limited to, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, and the like. "C 4-6 "Cycloalkyl" means a cycloalkyl group having 4 to 6 ring carbon atoms. Similarly, "C 3-4 "Cycloalkyl" means a cycloalkyl group having 3-4 ring carbon atoms. Unless stated otherwise specifically in the specification, a cycloalkyl group may be optionally substituted.

[0136] Unless otherwise specified, “C 3-20 "Cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group having 3 to 20 ring carbon atoms, such as 3 to 15 ring carbon atoms, such as 3 to 6 ring carbon atoms; it may be monovalent, divalent or polyvalent. 3-20 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0137] Unless otherwise specified, “C 3-6 "Cycloalkyl" refers to a saturated monocyclic or bicyclic hydrocarbon group having 3-6 ring carbon atoms, such as 3-5 ring carbon atoms, such as 3-4 ring carbon atoms; it can be monovalent, divalent or polyvalent. 3-6Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0138] Unless otherwise specified, “C 4-6 "Cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, which is a monocyclic or bicyclic system. 4-6 Cycloalkyl includes C 4-5 , C 5-6 , C4, C5 and C6 cycloalkyl, etc.; which may be monovalent, divalent or polyvalent. 4-6 Examples of cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0139] Unless otherwise specified, the term "heterocycloalkyl" refers to a non-aromatic saturated cyclic group that exists in a monocyclic, fused, spirocyclic and / or bridged ring, wherein at least one of the ring atoms is a heteroatom or heteroatom group, and the rest are carbon atoms; in some embodiments, each occurrence of the heteroatom is independently selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), the nitrogen heteroatom is optionally quaternized, and in other embodiments, each occurrence of the heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. The heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl, including the position at which the heterocycloalkyl is attached to the rest of the molecule. In some embodiments, the heterocycloalkyl is a 3-20 membered heterocycloalkyl; in some embodiments, the heterocycloalkyl is a 3-10 membered heterocycloalkyl; in other embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. Unless otherwise specifically stated in the specification, the heterocycloalkyl may be optionally substituted. Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from B, O, S and N or heteroatoms as described above, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-6 membered heterocycloalkyl", the heteroatom or heteroatom group may be located at any interior position of the heterocycloalkyl, including the position that may occupy the connection position of the heterocycloalkyl with the rest of the molecule. The 3-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl, etc. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.

[0140] Unless otherwise specified, the term "cycloalkenyl" herein refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical composed of carbon and hydrogen atoms having one or more carbon-carbon sp 2 Double bonds, which may include cyclopentenyl, spirocyclic and / or bridged ring systems. Monocyclic cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyls include, but are not limited to, bicyclo[2.2.1]hept-2-enyl, etc. Unless otherwise specifically stated in the specification, cycloalkenyls may be optionally substituted. "C 3-7 "Cycloalkenyl" includes C3, C4, C5, C6 and C7 cycloalkenyl. Examples of cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl and cyclohexenyl.

[0141] Unless otherwise specified, the term "heterocycloalkenyl" herein refers to a cyclic alkenyl group containing several heteroatoms or heteroatoms. In some embodiments, each occurrence of the heteroatoms is independently selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized (i.e., NO and S(O) p, p is 1 or 2), the nitrogen heteroatom is optionally quaternized, in other embodiments, each occurrence of the heteroatom group is independently selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- and -S(=O)N(H)-. "5-6 membered heterocycloalkenyl" by itself or in combination with other terms refers to an unsaturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from B, O, S and N or heteroatoms as described above, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). Examples of heterocycloalkenyl groups include, but are not limited to Etc. Unless stated otherwise specifically in the specification, a heterocycloalkenyl group may be optionally substituted.

[0142] Unless otherwise specified, when a substituent connected to ring A can be connected to ring A to form a ring, it means that the substituent can be connected to any position of ring A to form a new ring together with ring A, including a cyclic, spiro or bridged ring; wherein ring A can be selected from cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl, etc. as described above. For example, when The R in connected to form a 6-membered ring, examples of which include but are not limited to wait.

[0143] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12Etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring, 6-8-membered ring, and 6-10-membered ring, etc.

[0144] Unless otherwise specified, the term "aryl" refers to a hydrocarbon ring system group containing at least one aromatic ring. In the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a paracyclic, spirocyclic and / or bridged ring system. The aryl group includes, but is not limited to, benzene, naphthalene, anthracene, fluoranthene, phenanthrene, triphenylene, perylene, tetracene, pyrene, benzopyrene, acenaphthene, fluorene and derivative groups thereof. Unless otherwise specifically stated in the specification, the aryl group can be optionally substituted.

[0145] Unless otherwise specified, the term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 yuan, containing 1 to 3 heteroatoms; more preferably 5 yuan or 6 yuan, containing 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc. Heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include: etc. Non-limiting examples of heteroaryl groups also include triazine, pyridine, pyrimidine, imidazole, furan, thiophene, benzofuran, benzothiophene, indole, carbazole, pyrroloimidazole, pyrrolopyrrole, thienopyrrole, thienothiophene, furopyrrole, furanofuran, thienofuran, benzisoxazole, benzisothiazole, benzimidazole, quinoline, isoquinoline, o-naphthyridine, quinoxaline, phenanthridine, primary dine, quinazoline, quinazolinone, dibenzothiophene, dibenzofuran, carbazole, and derivatives thereof. Unless otherwise specifically stated in the specification, the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio or heterocycloalkylthio.

[0146] The term "substituted" as used in the present invention means that in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl), at least one hydrogen atom is replaced by a bond with a non-hydrogen atom, wherein the non-hydrogen atom includes but is not limited to halogen atoms (e.g., F, Cl, Br, I), oxygen atom-containing groups (e.g., hydroxyl, alkoxy, ester groups), sulfur atom-containing groups (e.g., thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, sulfoxide groups), nitrogen atom-containing groups (e.g., amine groups, amide groups, alkylamino groups, dialkylamine groups, arylamine groups, aryl-alkyl-amine groups, diarylamine groups, N-oxide groups, imide groups, enamine groups), silicon atom-containing groups (e.g., trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, triarylsilyl groups) and other heteroatoms in various other groups.

[0147] The term "substituted" as used herein also means that one or more hydrogen atoms in any of the above groups (i.e., alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl, heteroaryl) are replaced by a higher order bond (such as a double bond or a triple bond) of a heteroatom, such as oxygen in carbonyl, carboxyl and ester groups, and nitrogen in imines, oximes, hydrazones and nitriles. For example, "substituted" means that one or more hydrogen atoms in any of the above groups are replaced by -NR g R h 、-NR g C(=O)R h 、-NR g C(=O)NR g R h 、-NR g C(=O)OR h 、-NR g S02R h 、-OC(=O)NR g R h 、-OR g 、-SR g 、-SOR g 、SO2R g 、-OSO2R g 、-SO2OR g ,

[0148] =NSO2R g With -SO2NR g R h Substituted. "Substituted" may also mean that one or more hydrogen atoms in any of the above groups are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h 、-CH2SO2Rg 、-CH2SO2NR g R h The R g With R h Identical or different, independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl."substituted" can also mean that one or more hydrogen atoms in any of the above-mentioned groups are replaced by amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, alkylthio, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl-alkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic radical, N-heterocyclic radical, heterocycloalkyl-alkyl, heteroaryl, N-heteroaryl, heteroaryl-alkyl. In addition, each of the above-mentioned substituents can also be optionally replaced by one or more of the above-mentioned substituents.

[0149] It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and therefore may exist as two or more stereoisomers. Therefore, the compounds of the present invention may exist as single stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, such as racemates, and, where appropriate, as tautomers and geometric isomers.

[0150] The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers, and the like.

[0151] As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

[0152] The term "diastereomer" as used herein refers to stereoisomers having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography such as HPLC.

[0153] Stereochemical definitions and conventions may be followed in SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule about its chiral center. The prefixes d and l or (+) and (-) are used to indicate the sign of the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are optically inactive.

[0154] The racemic mixture can be used in its own form or split into individual isomers. Stereochemically pure compounds or mixtures enriched in one or more isomers can be obtained by splitting. Methods for separating isomers are well known (see Allinger NL and Eliel EL, "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971), including physical methods, such as chromatography using chiral adsorbents. Individual isomers in chiral form can be prepared from chiral precursors. Alternatively, the individual isomers can be chemically separated from the mixture by forming diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α-bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractionally crystallizing the salts, then freeing one or both of the resolved bases, and optionally repeating this process to obtain one or both isomers that are substantially free of the other isomer, i.e., the desired stereoisomers having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight. Alternatively, as is well known to those skilled in the art, the racemates can be covalently linked to chiral compounds (auxiliaries) to obtain diastereomers.

[0155] The term "tautomer" or "tautomeric form" as used herein refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0156] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the embodiments of the present invention.

[0157] Technical and scientific terms used herein without specific definition have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. DETAILED DESCRIPTION

[0158] The present application is described in detail below by way of examples, but it is not intended that there is any adverse limitation to the present application. The present application has been described in detail herein, and its specific embodiments are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0159] Example 1: Synthesis of Compound 1

[0160]

[0161] Step 1: Synthesis of compound 1-2

[0162] Compound 1-1 (17 g) was dissolved in dichloromethane (100 mL), trifluoroacetic acid (20 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was concentrated to obtain a crude product, which was slurried with dichloromethane (~30 mL) for 30 minutes, filtered, and the filter cake was washed with a small amount of dichloromethane and dried to obtain compound 1-2 (21.5 g, crude product). LC-MS (ESI) [M+H] + 327.0.

[0163] Step 2: Synthesis of Compound 1-3

[0164] Compound 1-2 (21.5 g, crude product) and 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid (11.93 g) were dissolved in N, N-dimethylformamide (215 mL), and N, N-diisopropylethylamine (25.3 g, 34 mL) was added. After stirring for 5 minutes, 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (19.35 g) was added and allowed to react at room temperature for 1 hour. The reaction solution was poured into water with stirring, and a sticky solid precipitated. The mixture was allowed to stand and the supernatant was discarded. The solid was slurried with anhydrous ether (100 mL) for 30 minutes, filtered, and the filter cake was washed with a small amount of anhydrous ether and dried to obtain compound 1-3 (15.8 g). LC-MS (ESI) [M+H] + 553.2.

[0165] Step 3: Synthesis of Compound 1-4

[0166] Compound 1-3 (15.8 g), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (18.0 g) were dissolved in 1,4-dioxane (160 mL) / water (40 mL), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (1.11 g), cesium carbonate (27.9 g) were added, and nitrogen was replaced three times and then placed at 100°C to react overnight. The reaction solution was concentrated and extracted with saturated brine / (dichloromethane: methanol = 5:1) system. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was slurried with anhydrous ether (200 mL) to obtain compound 1-4 (7.8 g). LC-MS (ESI) [M+H] + 557.3.

[0167] Step 4: Synthesis of Compound 1-5

[0168] Compound 1-4 (3.4 g) was dissolved in N, N-dimethylformamide (35 mL), and N, N-diisopropylethylamine (2.37 g, 3.19 mL) and ethyl bromoacetate (1.53 g) were added, and the mixture was reacted at 70 ° C for 3 hours. The reaction solution was added dropwise into water (100 mL) under stirring, and solid precipitated. The solid was filtered, and the filter cake was washed with a small amount of water and dried to obtain a crude product. The crude product was slurried with anhydrous ether (50 mL) for 30 minutes to obtain compound 1-5 (2.8 g). LC-MS (ESI) [M+H] + 643.4.

[0169] Step 5: Synthesis of Compound 1-6

[0170] Compound 1-5 (2.8 g) was dissolved in tetrahydrofuran (30 mL), and a solution of lithium hydroxide monohydrate (366 mg) in water (15 mL) was added, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was extracted with an ethyl acetate / water system, the organic phase was discarded, the aqueous phase was adjusted to acidity with 0.5 M dilute hydrochloric acid, and then extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-6 (2.47 g). LC-MS (ESI) [M+H] + 615.4.

[0171] Step 6: Synthesis of Compounds 1-7

[0172] Compound 1-6 (85 mg) and 4-(trifluoromethoxy)aniline (29.4 mg) were dissolved in dichloromethane (1 mL), pyridine (110 mg, 111 μL) and phosphorus oxychloride (84.8 mg) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1-7 (120 mg, crude product), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + 774.4.

[0173] Step 7: Synthesis of compound 1

[0174] Compound 1-7 (160 mg) was dissolved in trifluoroacetic acid (3 mL) and reacted at 100°C for 1 hour. The reaction solution was diluted with dichloromethane and washed with water and saturated brine in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to liquid phase preparation (acid method) to obtain compound 1 (62 mg). LC-MS (ESI) [M+H] + 684.3.

[0175] 1 H NMR (400MHz, DMSO-d6) δ10.64(s,1H),10.14(s,1H),8.51(s,1H),7.61(d,J=9.1Hz,2H ),7.27(d,J=8.6Hz,2H),6.73(s,1H),5.10(s,2H),4.46(d,J=12.5Hz,1H),4.17(d,J=2 .9Hz,2H),3.73(t,J=5.4Hz,2H),3.51–3.39(m,3H),3.24–3.08(m,3H),3.03–2.80(m,3 H), 2.75 (d, J = 11.1Hz, 1H), 2.58 (d, J = 11.3Hz, 1H), 2.38 (s, 3H), 1.10 (t, J = 7.4Hz, 3H).

[0176] Example 2: Synthesis of Compound 2

[0177]

[0178] Step 1: Synthesis of compound 2-1

[0179] Compound 1-6 (130 mg) and 4-(chlorodifluoromethoxy)aniline (49 mg) were dissolved in dichloromethane (1 mL), pyridine (168 mg, 170 μL) and phosphorus oxychloride (130 mg) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain compound 2-1 (200 mg, crude product), which was directly used in the next step without purification. LC-MS (ESI) [M+H] + 790.4.

[0180] Step 2: Synthesis of compound 2

[0181] Compound 2-1 (150 mg) was dissolved in trifluoroacetic acid (2 mL) and reacted at 90°C for 1 hour. The reaction solution was concentrated, diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was subjected to liquid phase preparation (alkaline method) to obtain compound 2 (25 mg). LC-MS (ESI) [M+H] + 700.2.

[0182] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),10.25(s,1H),8.59(s,1H),7.68(d,J=8.7Hz, 2H),7.34(d,J=8.6Hz,2H),6.81(s,1H),5.17(s,2H),4.53(d,J=12.6Hz,1H),4.25(s ,2H),3.80(t,J=5.5Hz,2H),3.57–3.46(m,3H),3.32–3.15(m,3H),3.09–2.93(m,3H) ,2.83(d,J=11.2Hz,1H),2.65(d,J=11.1Hz,1H),2.45(s,3H),1.18(t,J=7.3Hz,3H).

[0183] Example 3: Synthesis of Compound 3

[0184]

[0185] Step 1: Synthesis of compound 3-1

[0186] Compound 1-6 (150 mg) was dissolved in dichloromethane (2 mL), and 4-(chlorodifluoromethoxy)-2-iodoaniline (117 mg), pyridine (193 mg, 197 μL), and phosphorus oxychloride (150 mg) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-1 (223 mg, crude product), which was directly used in the next step without purification. LC-MS (ESI) [M+H] + 916.2.

[0187] Step 2: Synthesis of compound 3

[0188] Compound 3-1 (130 mg) was dissolved in trifluoroacetic acid (1 mL) and reacted at 80°C for 1 hour. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to liquid phase preparation (acid method) to obtain compound 3 (32 mg). LC-MS (ESI) [M+H] + 826.2.

[0189] 1 H NMR (400MHz, DMSO-d6) δ10.49–9.83(m,2H),8.49(s,1H),7.82(d,J=2.7Hz,1H),7.46(d,J=8. 9Hz,1H),7.36(dd,J=8.8,2.7Hz,1H),6.83(s,1H),5.13(s,2H),4.45(d,J=12.4Hz,1H),4.20 (d,J=2.9Hz,2H),3.74(t,J=5.4Hz,2H),3.54–3.38(m,3H),3.18(d,J=123.5Hz,2H),3.07–2. 83(m,3H),2.75(d,J=11.2Hz,1H),2.57(d,J=11.1Hz,1H),2.37(s,3H),1.15(t,J=7.4Hz,3H).

[0190] Example 4: Synthesis of Compound 4

[0191]

[0192] Step 1: Synthesis of compound 4-2

[0193] Compound 4-1 (250 mg) was dissolved in acetonitrile (1 mL), N-chlorosuccinimide (190 mg) was added, and the mixture was reacted at 80°C overnight. The reaction solution was diluted with dichloromethane, and silica gel was added to mix the sample, and purified by silica gel column (0-1% ethyl acetate / petroleum ether) to obtain compound 4-2 (200 mg). LC-MS (ESI) [M+H] + 228.0.

[0194] Step 2: Synthesis of compound 4-3

[0195] Compound 1-6 (80 mg) was dissolved in dichloromethane (1 mL), and compound 4-2 (91.8 mg), pyridine (103 mg, 105 μL), and phosphorus oxychloride (79.8 mg) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was diluted with dichloromethane and washed with water, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4-3 (160 mg, crude product), which was directly used in the next step without purification. LC-MS (ESI) [M+H] + 824.2.

[0196] Step 3: Synthesis of compound 4

[0197] Compound 4-3 (144 mg) was dissolved in trifluoroacetic acid (1 mL) and reacted at 80°C for 1 hour. The reaction solution was diluted with dichloromethane and washed with water, saturated sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to liquid phase preparation (acid method) to obtain compound 4 (38 mg). LC-MS (ESI) [M+H] + 734.2.

[0198] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,2H),8.48(s,1H),7.77(d,J=9.0Hz,1H),7.57(d,J=2.8H z,1H),7.40–7.24(m,1H),6.77(s,1H),5.19(s,2H),4.45(d,J=12.4Hz,1H),4.19(d,J=2.9 Hz,2H),3.74(t,J=5.5Hz,2H),3.53–3.39(m,3H),3.24–3.11(m,3H),2.92(q,J=8.0,6.9H z, 3H), 2.74 (d, J = 11.5Hz, 1H), 2.56 (d, J = 11.0Hz, 1H), 2.37 (s, 3H), 1.13 (t, J = 7.5Hz, 3H).

[0199] Example 5: Synthesis of Compound 5

[0200]

[0201] Step 1: Synthesis of compound 5-1

[0202] Compound 3-1 (160 mg) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (65.8 mg) were dissolved in 1,4-dioxane (2 mL) / water (0.4 mL), anhydrous potassium carbonate (72.4 mg) and [1,1'-bis(di-tert-butylphosphino)ferrocene] palladium dichloride (12.8 mg) were added, and nitrogen was replaced three times and then placed at 100°C for 1 hour. The reaction solution was concentrated, extracted with dichloromethane / water system, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 5-1 (200 mg, crude product), with a small amount of dehalogenated byproducts, which was directly used in the next step. LC-MS (ESI) [M+H] + 804.4.

[0203] Step 2: Synthesis of compound 5

[0204] Compound 5-1 (150 mg) was dissolved in trifluoroacetic acid (1 mL) and reacted at 80°C for 1 hour. The reaction solution was diluted with dichloromethane and washed with water, saturated sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to liquid phase preparation (alkaline method) to obtain 36 mg of the product, and the dehalogenated byproduct could not be separated. The product was subjected to thin layer chromatography to obtain compound 5 (12 mg). LC-MS (ESI) [M+H] + 714.3.

[0205] 1 H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.61(s,1H),7.54(d,J=8.8Hz,1H),7.29(s,1H),7 .21(d,J=8.6Hz,1H),6.88(s,1H),5.24(s,2H),4.56(d,J=12.5Hz,1H),4.31(s,2H),3. 85(t,J=5.5Hz,2H),3.58–3.52(m,3H),3.36–3.22(m,3H),3.10–2.98(m,3H),2.85(d,J =11.2Hz, 1H), 2.68 (d, J = 10.7Hz, 1H), 2.48 (s, 3H), 2.32 (s, 3H), 1.23 (t, J = 7.6Hz, 3H).

[0206] Example 6: Synthesis of Compound 6

[0207]

[0208] Step 1: Synthesis of compound 6-1

[0209] Compound 4-1 (1 g) was dissolved in toluene (10 mL), and cuprous bromide (741 mg) and pyridine (408.62 mg, 416 μL) were added, and the mixture was reacted at 1 atm air pressure and 65° C. overnight. The reaction solution was concentrated and purified by silica gel column (eluted with petroleum ether) to obtain compound 6-1 (0.8 g). 1 H NMR (400MHz, DMSO-d6) δ8.11–8.01 (m, 4H), 7.62 (d, J = 9.1Hz, 4H).

[0210] Step 2: Synthesis of compound 6-2

[0211] Compound 6-1 (0.8 g) was dissolved in ethyl acetate (20 mL), tris(dibenzylideneacetone)dipalladium (382 mg), potassium nitrate (464 mg), N-fluorobisbenzenesulfonamide (4.61 g) were added, and the mixture was placed under 1 atm air pressure and reacted at 80°C for 40 hours. The reaction solution was diluted with ethyl acetate, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified on a silica gel column (eluted with petroleum ether) to obtain compound 6-2 (240 mg). LC-MS (ESI) [M+H] + 401.0.

[0212] Step 3: Synthesis of compound 6-3

[0213] Compound 6-2 (240 mg) was dissolved in anhydrous ethanol (5 mL), and cuprous chloride (355 mg) and sodium borohydride (158 mg) were added, and the mixture was allowed to react at room temperature for 1 hour. After filtering the reaction solution, silica gel was added and the sample was stirred, and column chromatography with petroleum ether / ethyl acetate = 10 / 1 was performed to obtain compound 6-3 (27 mg). LC-MS (ESI) [M+H] + 211.6.

[0214] Step 4: Synthesis of compound 6-4

[0215] Compound 1-6 (45 mg) was dissolved in dichloromethane (1 mL), and compound 6-3 (20 mg), pyridine (57.9 mg, 59 μL), and phosphorus oxychloride (44.9 mg) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain compound 6-4 (80 mg, crude product), which was directly used in the next step without purification. LC-MS (ESI) [M+H] + 808.2.

[0216] Step 5: Synthesis of compound 6

[0217] Compound 6-4 (80 mg) was dissolved in trifluoroacetic acid (0.5 mL) and reacted at 80°C for 1 hour. The reaction solution was diluted with dichloromethane, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was subjected to liquid phase preparation (acid method) to obtain compound 6 (12 mg). LC-MS (ESI) [M+H] + 718.3.

[0218] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.56(s,1H),8.01(t,J=8.9Hz,1H),7.50(dd,J=10.9 ,2.7Hz,1H),7.23(d,J=8.8Hz,1H),6.82(s,1H),5.26(s,2H),4.52(d,J=12.4Hz,1H),4.26 (d,J=2.9Hz,2H),3.80(t,J=5.5Hz,2H),3.53–3.47(m,3H),3.30–3.14(m,3H),3.11–2.89( m, 3H), 2.81 (d, J = 11.1Hz, 1H), 2.64 (d, J = 10.7Hz, 1H), 2.44 (s, 3H), 1.18 (t, J = 7.4Hz, 3H).

[0219] Example 7: Synthesis of Compound 7

[0220]

[0221] Step 1: Synthesis of compound 7-2

[0222] Compound 7-1 (3 g), ethyl bromoacetate (1.16 g) and diisopropylethylamine (2.70 g, 3.63 mL) were dissolved in N, N-dimethylformamide (30 mL) and reacted at 45 ° C for 12 hours. Water was added to quench the reaction, and the organic phases were combined and extracted with ethyl acetate (10 mL × 3), washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound 7-2 (3 g). LC-MS (ESI) [M+H-56] + 461.0.

[0223] Step 2: Synthesis of compound 7-3

[0224] Compound 7-2 (3 g) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (10 mL) was added, and the reaction was allowed to react at room temperature for 2 hours. The reaction solution was concentrated to obtain compound 7-3 (150 mg, crude product), which was used directly in the next step without purification. LC-MS (ESI) [M+H] + 417.2.

[0225] Step 3: Synthesis of compound 7-4

[0226] Compound 7-3 (3 g), 3-(benzyloxy)picolinic acid (1.65 g), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.72 g) and N,N-diisopropylethylamine (2.79 g, 3.76 mL) were dissolved in N,N-dimethylformamide (30 mL) and reacted at 45°C for 12 hours. Water was added to quench the reaction, and the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound 7-4 (3 g). LC-MS (ESI) [M+H] + 628.4.

[0227] Step 4: Synthesis of compound 7-5

[0228] Compound 7-4 (0.4 g) and lithium hydroxide (45.78 mg) were dissolved in tetrahydrofuran (10 mL) / water (2 mL), reacted at room temperature for 12 hours, quenched with water, adjusted to pH 5-6 with 1M hydrochloric acid, extracted with dichloromethane (10 mL×3), combined the organic phases, concentrated to obtain compound 7-5 (0.4 g, crude product), which was directly used for the next step without purification. LC-MS (ESI) [M+H] + 600.4.

[0229] Step 5: Synthesis of compound 7-6

[0230] Compound 7-5 (150 mg) was dissolved in dichloromethane (5 mL), and 4-(chlorodifluoromethoxy)aniline (48.42 mg), pyridine (98.93 mg, 100.76 μL), phosphorus oxychloride (115.07 mg, 155.08 μL) were added, and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated to obtain compound 7-6 (150 mg, crude product), which was directly used in the next step without purification. LC-MS (ESI) [M+H] + 775.4.

[0231] Step 6: Synthesis of compound 7

[0232] Compound 7-6 (70 mg) was added to trifluoroacetic acid (5 mL), and the reaction was carried out at 100°C for 12 hours. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid to obtain a crude product, and compound 7 (18 mg) was prepared by liquid phase. LC-MS (ESI) [M+H] + 685.0.

[0233] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),10.56(s,1H),8.48(s,1H),8.05(s,1H),7.72–7 .65(m,2H),7.37–7.24(m,3H),6.83–6.77(m,1H),5.18(s,2H),4.55(d,J=12.5Hz,1H), 4.29–4.20(m,2H),3.80(t,J=5.4Hz,2H),3.55–3.35(m,6H),3.23(t,J=12.2Hz,1H),3. 01–2.94(m,2H),2.80(d,J=11.0Hz,1H),2.63(d,J=10.9Hz,1H),1.17(t,J=7.3Hz,3H).

[0234] Example 8: Synthesis of Compound 8

[0235]

[0236] Step 1: Synthesis of compound 8-2

[0237] Compound 8-1 (500 mg), ethyl 2-iodopropionate (264.84 mg), and N,N-diisopropylethylamine (450.33 mg) were dissolved in N,N-dimethylformamide (10 mL), and the reaction was stirred at 50°C for 16 hours. The product was detected by LCMS. Compound 8-2 (44 mg) was obtained directly by reverse phase column chromatography with water / acetonitrile = 1 / 9. LC-MS (ESI) [M+H] + 531.5.

[0238] Step 2: Synthesis of compound 8-3

[0239] Compound 8-2 (40 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (25.79 mg) was added at room temperature. The reaction was stirred at room temperature for 30 minutes. The product was generated by LCMS. The reaction solution was concentrated under reduced pressure to obtain crude compound 8-3 (32 mg). The product was directly used for the next step without purification. LC-MS (ESI) [M+H] + 431.2.

[0240] Step 3: Synthesis of compound 8-4

[0241] Compound 8-3 (30 mg), 5-benzyloxy-6-methylpyrimidine-4-carboxylic acid (17.02 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (26.29 mg), N,N-diisopropylethylamine (27.02 mg) were dissolved in dichloromethane (5 mL), and the reaction was stirred at room temperature for 1 h. LCMS detection showed that the product was generated. Water was added to quench, dichloromethane was extracted, and the organic phase was dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure to obtain a crude compound 8-4 (25 mg, crude product). LC-MS (ESI) [M+H] + 657.4.

[0242] Step 4: Synthesis of compound 8-5

[0243] Compound 8-4 (22 mg) was dissolved in methanol / tetrahydrofuran / water (2 / 2 / 2 mL), and lithium hydroxide (4.01 mg) was added at room temperature. The reaction was stirred at room temperature for 2 hours. The product was generated by LCMS detection. Water was added to quench, and ethyl acetate was extracted. The aqueous phase was adjusted to pH 2-3 with hydrochloric acid, and the aqueous phase was back-extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain crude compound 8-5 (20 mg), which was directly used for the next step without purification. LC-MS (ESI) [M+H] + 629.4.

[0244] Step 5: Synthesis of compound 8-6

[0245] Compound 8-5 (18 mg) was dissolved in dichloromethane (2 mL), and 4-(chlorodifluoromethoxy)aniline (5.54 mg), pyridine (13.59 mg), and phosphorus oxychloride (13.17 mg) were added, and the mixture was reacted at room temperature for 0.5 hours. The reaction solution was diluted with dichloromethane and washed with water, saturated brine, and dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography using dichloromethane / methanol = 1 / 1 to obtain compound 8-6 (15 mg). LC-MS (ESI) [M+H] + 804.3.

[0246] Step 6: Synthesis of compound 8

[0247] Compound 8-6 (13 mg) was dissolved in trifluoroacetic acid (5 mL), and the reaction was stirred at 100°C for 30 minutes. LCMS detection showed that the product was generated. The reaction solution was concentrated under reduced pressure to obtain a crude product, and compound 8 (2.04 mg) was prepared by liquid phase. LC-MS (ESI) [M+H] + 714.4.

[0248] 1H NMR (400MHz, DMSO-d6) δ9.61(s,1H),8.47(s,1H),7.50(d,J=9.2Hz,2H),7.25(d,J=8 .4Hz,1H),6.69(s,1H),5.51(brs,1H),4.48–4.43(m,1H),4.16(s,1H),3.73–3.70(m ,2H),3.45–3.40(m,3H),3.18–3.15(m,3H),2.95–2.86(m,3H),2.80–2.75(m,1H),2. 62–2.60(m,1H),2.36(s,3H),2.26–2.25(m,1H),1.74(s,3H),1.12(t,J=6.8Hz,3H).

[0249] Experimental Example 1 WRN hydrolase activity detection experiment

[0250] 1. Experimental instruments

[0251] The instruments used in the experiment are shown in Table 1.

[0252] Table 1

[0253] Instrument Name Instrument Manufacturer model Centrifuge Eppendorf 5810R ELISA reader PerkinElmer EnVision-2015

[0254] 2. Experimental Materials

[0255] The WRN enzyme used in the experiment has a His-TEV tag at the N-terminus and is expressed in eukaryotic cells with a purity of 90%. The detection kit (ADP-Glo TM Kinase Assay was purchased from Promega, item number V9101, and stored in a refrigerator at -40°C after aliquoting. The kit can quantitatively detect the amount of ADP generated in the reaction. WRN hydrolyzes ATP to generate ADP. Adding ADP-Glo ​​reagent will consume the excess ATP in the reaction system, and then adding Kinase Detection Reagent will convert the ADP generated by the reaction into ATP and generate chemiluminescence. Detecting the chemiluminescence signal with an enzyme reader can reflect the enzyme activity of WRN.

[0256] The information of other reagents and consumables required for the experiment is shown in Table 2.

[0257] Table 2

[0258]

[0259]

[0260] 3. Experimental methods

[0261] Annealing of single-stranded DNA to double-stranded DNA. 5× Annealing Buffer: 50 mM Tris pH 8.0, 100 mM NaCl. Annealing Program: 95°C, 5 min.

[0262] 2×WRN enzyme (1nM) and 2× substrate (1nM double-stranded DNA, 100uM ATP) were prepared using a buffer solution (20mM Bicine (pH 7.5), 10mM KCl, 10mM MgCl2, 0.005% BSG, 0.002% Tween 20, 1mM TCEP). The test compound was dissolved to 10mM with DMSO and diluted in a gradient manner using a 96-well V-bottom plate. First, 25uL 2×WRN enzyme and 0.5uL compound were added to the 96-well plate and incubated at room temperature for 30min. Then 25uL 2× substrate was added and reacted at room temperature for 60min. 5uL was taken from the reaction plate and added to a 384-well plate for detection. 5uL ADP-Glo ​​reagent was added and incubated at room temperature for 60min. 10uL KinaseDetection Reagent was added and incubated at room temperature for 40min. The chemiluminescent signal was detected by an enzyme reader.

[0263] 4. Data Analysis

[0264] GraphPad Prism 8 software was used to fit the concentration-effect curves and calculate the compound concentration IC of 50% inhibition. 50 First, the percentage inhibition rate corresponding to each compound concentration was calculated, and then the concentration-effect curve was fitted using the "log (inhibitor) vs. normalized response--Variable slope" equation of GraphPad Prism 8 software to obtain the IC 50 .

[0265] Inhibition rate (%) = (average luminescence intensity of positive control wells - luminescence intensity of compound wells) / (average luminescence intensity of positive control wells - average luminescence intensity of negative control wells) * 100

[0266] Positive control: 25uL 2×WRN enzyme + 0.5uL DMSO + 25uL 2×substrate

[0267] Negative control: 25uL 2× buffer + 0.5uL DMSO + 25uL 2× substrate

[0268] 5. Experimental results and conclusions

[0269] The experimental results are shown in Table 3. 50 The grading is as follows: "++++" represents 0.01 μM <IC 50<0.05μM, "++++" represents 0.05μM <IC 50 <0.15μM, "+++" represents 0.15μM <IC 50 <0.75μM, "++" represents 0.75μM <IC 50 <1.5 μM.

[0270] Table 3 IC values ​​of selected compounds in the WRN hydrolase activity assay 50 value

[0271] Compound No. <![CDATA[WRN ATPase,IC 50 (μM) <!-- 29 -->]]> Example 1 ++++ Example 2 +++++ Example 3 +++ Example 4 ++++ Example 5 ++++ Example 6 ++++ Example 7 ++++ Example 8 ++

[0272] The above tests show that the compounds of the present invention have good WRN hydrolase activity.

[0273] The exemplary embodiments of the present invention are described above. It should be understood that the protection scope of the present application is not limited to the above exemplary embodiments. Any modification, equivalent substitution, improvement, etc. made by those skilled in the art within the spirit and principle of the present invention shall be included in the protection scope of the present application.

Claims

1. A compound represented by formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, in, Ring B is selected from C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl or 5-20 membered heteroaryl; Ring D is selected from C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl or 5-20 membered heteroaryl; Ring E is selected from C 3-20 Cycloalkyl, 5-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl; L1 is selected from 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 L2 is selected from 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 Z is selected from O, S or Se; X is selected from H, Cl, Br, I or F; R1 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, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; Alternatively, two R1s are connected together to form a C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl; Selected from Selected from or, Selected from Selected from when Selected from When , T is selected from C; when Selected from When , T is selected from N or CH; when Selected from When R2 is selected from 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 Alkenyl, C 2-20 Alkynyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, C 2-20 Alkenyl, C 2-20 Alkynyl, 3-20 membered heterocycloalkyl, C 4-20 Cycloalkenyl, 4-20 membered heterocycloalkenyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; when Selected from When, R2 is selected from O or S; R3 and R4 are 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 or 3-20 membered heterocycloalkyl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; Alternatively, R3 and R4 are connected together to form a C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, the C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R; R5 is independently selected from H, F, Cl, Br, I, OH, NH2, CF3, CN, SF5, CHO, COOH, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl; R6 are 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, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; Alternatively, two R6s are connected together to form a C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; R7 are 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, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; R b1 Selected from H, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; R b2 , R b3 are independently selected from H, F, Cl, Br, OH, NH2, CN, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl and 3-20 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R; Or, R b2 With R b3 Connect together to form a C 3-20 Cycloalkyl or 3-20 membered heterocycloalkyl; R b4 are independently selected from H, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R; m, n, p, q, t are independently selected from 0, 1, 2 or 3; R is independently selected from H, F, Cl, Br, OH, NH2, CN, SF5, CHO, COOH, C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl or 5-20 membered heteroaryl, the C 1-20 Alkyl, C 1-20 Heteroalkyl, C 3-20 Cycloalkyl, 3-20 membered heterocycloalkyl, C 6-20 Aryl and 5-20 membered heteroaryl are optionally substituted with 1, 2 or 3 R'; R' is selected from H, F, Cl, Br, I, OH, NH2, CH3, CF3, C2H5, CN, SF5, CHO, COOH or C 1-20 The heteroalkyl, 3-20 membered heterocycloalkyl, 4-20 membered heterocycloalkenyl or 5-20 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O)2- and N.

2. The compound according to claim 1, its optical isomer or its pharmaceutically acceptable salt, wherein: R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, 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, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl or thiopyranyl, 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(=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, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, piperazinyl, pyranyl, furanyl, thiazolyl, oxazolyl and thiopyranyl are optionally substituted with 1, 2 or 3 R's.

3. The compound according to claim 2, its optical isomer or its pharmaceutically acceptable salt, wherein: R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, SF5, CHO, COOH, CH3, CF3, CHF2, CH2F, CF2Cl, CF2Br, CF2I, 4. The compound according to any one of claims 1 to 3, its optical isomer or its pharmaceutically acceptable salt, wherein: Structural unit Selected from 5. The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R6 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R.

6. The compound according to claim 5, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R6 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, CF3, 7. The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Ring D is selected from T1, T2, T3, T4 are each independently selected from N or CH; X1, X2, X3, and X4 are each independently selected from a single bond or CH2; X5 and X6 are each 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 are independently selected from a single bond, NH, O, S, CH2 or And X7, X8, X9, X 10 At most 3 of them are simultaneously selected from single bonds; L a Selected from C 1-6 Alkyl, C 2-6 Alkenyl or C 1-6 Heteroalkyl, the C 1-6 Alkyl and C 1-6 Heteroalkyl is optionally substituted with 1, 2, or 3 R groups.

8. The compound according to claim 7, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Ring D is selected from 9. The compound according to claim 6 or 8, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from 10. The compound according to any one of claims 1 to 3, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R1 is independently selected from 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, 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-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 3-6-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-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 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R groups.

11. The compound according to claim 10, its optical isomers and pharmaceutically acceptable salts thereof, wherein: R1 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, 12. The compound according to claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Ring B is selected from cyclohexyl, 3,6-dihydro-2H-pyranyl, 3,4-dihydro-2H-pyranyl, morpholinyl, cyclohexenyl, piperidinyl, 2,3-dihydro-1,4-dioxinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyran-2-onyl, phenyl, pyridinyl, pyrrolidinyl, 2-oxa-6-aza-spiro[3,3]heptanyl, 1,1-dioxo-3,6-dihydro-2H-thiopyranyl, oxepanyl, azetidinyl, 2-oxa-7-azaspiro[4.4]nonanyl or hexahydro-1H-furo[3,4-c]pyrrolyl.

13. The compound according to claim 11 or 12, its optical isomers and pharmaceutically acceptable salts thereof, wherein: Structural unit Selected from:

14. The compound according to any one of claims 1 to 3, its optical isomer or a pharmaceutically acceptable salt thereof, wherein: R7 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R.

15. The compound according to claim 14, its optical isomer or its pharmaceutically acceptable salt, wherein: R7 is independently selected from H, F, Cl, Br, OH, NH2, CN, Me, CF3, 16. The compound according to claim 1, its optical isomer or its pharmaceutically acceptable salt, wherein: Ring E is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or thienyl.

17. The compound according to claim 15 or 16, its optical isomer or its pharmaceutically acceptable salt, wherein: Structural unit Selected from 18. The compound according to any one of claims 1 to 3, its optical isomer or its pharmaceutically acceptable salt, wherein: R3 and R4 are independently selected from H, F, Cl, Br, OH, NH2, CN, Me, The Me, Optionally substituted with 1, 2 or 3 R.

19. The compound according to claim 18, its optical isomer or its pharmaceutically acceptable salt, wherein: R3 and R4 are independently selected from H, F, Cl, Br, OH, NH2, CN, Me, CF3, 20. A compound of the following formula, an optical isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from 21. A pharmaceutical composition, wherein: The invention comprises the compound according to any one of claims 1 to 20, its optical isomer or a pharmaceutically acceptable salt thereof.

22. Use of the compound according to any one of claims 1 to 20, its optical isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating tumor-related diseases.

23. The use according to claim 22, wherein: The tumor is a malignant tumor with high microsatellite instability, a malignant tumor with mismatch repair deficiency, or a malignant tumor with a large number of (TA) n Repeated sequence malignancies.

24. The use according to claim 22, wherein: The tumor-related diseases are one or more diseases related to solid tumors.

25. The use according to claim 22, wherein: The tumor-related diseases include one or more of colorectal cancer, gastric cancer, endometrial cancer and ovarian cancer.

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