Tricyclic derivatives substituted with a sulfonyl moiety, methods of preparation and use thereof

Abstract

The present disclosure discloses a kind of tricyclic derivatives of sulfonyl fragment substitution, its preparation method and application. In particular, the present disclosure relates to the compound shown in general formula (I) or its isomer, its preparation method and pharmaceutical composition containing the compound, and its application in the preparation of treating disease drugs. The compound has the structure as shown in formula (I).

Description

Technical Field

[0001] This disclosure belongs to the field of medicinal chemistry, specifically relating to a sulfone-substituted tricyclic derivative, its preparation method, and its application. Background Technology

[0002] The RecQ helicase subfamily is a class of enzymes that untangle nucleotide double strands. Within cells, they participate in DNA replication, repair, transcriptional recombination, RNA splicing, ribosome assembly, protein translation, and telomere stabilization. This family was first discovered in prokaryotes, and its members are highly conserved from prokaryotes (RecQ) to yeast (sgs1) and humans (five RecQ helicases: RECQ1, BLM, WRN, RECQ4, and RECQ5). WRN is a member of the DNA helicase RecQ family, including WRN, BLM, and RecQ1, RecQ4, and RecQ5. Mutations in WRN can lead to various chromosomal instability disorders such as Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome. WRN consists of 1432 amino acids and has a molecular weight of 160 kDa. WRN is primarily located in the nucleolus and rapidly migrates to other nuclear regions after DNA damage. WRN is the only member of the human RecQ helicase family with 3'→5' exonuclease activity. Its N-terminal exonuclease region facilitates the processing of complex nucleic acid structures, while the central unwinding domain binds to and hydrolyzes ATP, providing energy to unwind double-stranded DNA. The C-terminal HRDC domain regulates the catalytic activity of WRN in binding to DNA.

[0003] Microsatellites (MS) are DNA sequences in the cellular genome that are tandemly repeated in units of a few nucleotides (usually 1-6), also known as short tandem repeats (STRs). When DNA mismatch repair (NMR) function is impaired, replication errors in microsatellites cannot be corrected and accumulate, leading to changes in microsatellite sequence length or base composition, a condition known as microsatellite instability (MSI), and resulting in a highly mutated phenotype in the genome. In tumors, loss-of-function mutations in key MMR genes (MLH1, MSH2, MSH6, and PMS2) and related genes, or loss of MLH1 expression due to high methylation of the MLH1 promoter region, often lead to MMR dysfunction. Based on the microsatellite stability of tumor cells, tumors can be classified into microsatellite highly unstable (MSI) tumors and microsatellite stable (MSS) tumors. MSI is prevalent in cancers, with high incidence rates in solid tumors including endometrial cancer (approximately 30%), gastric cancer (approximately 20%), and colorectal cancer (approximately 15%).

[0004] There is a synthetic lethal relationship between WRN and MSI-H: In MSI tumor cell lines, knocking out WRN leads to genomic instability, cell cycle arrest, and DNA double-strand breaks in these cancer cells, ultimately resulting in cancer cell death. Therefore, developing small-molecule inhibitors targeting WRN holds promise for selectively killing MSI-H cancer cells, providing personalized anti-tumor therapy for MSI cancer patients. Summary of the Invention

[0005] The purpose of this disclosure is to provide a sulfone-substituted tricyclic derivative, its preparation method, and its application.

[0006] This disclosure provides a compound, isomer, or pharmaceutically acceptable salt thereof of formula (I):

[0007] in, Ring A is selected from C 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl; Ring B is selected from C 5-6 cycloalkyl, C 5-6Cycloalkenyl, 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl; Ring C is selected from C 4-7 cycloalkyl, C 4-7 Cycloalkenyl, 4-7 membered heterocyclic alkyl, 4-7 membered heterocyclic alkenyl; Ring D is selected from C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; x is selected from 0, 1, 2, 3, and 4; y is selected from 0 and 1; z is selected from 0, 1, 2, 3; w is selected from 0, 1, 2, 3, 4.

[0008] In some embodiments of this disclosure, the compound is shown as of formula (II-1) or (II-2):

[0009] in, It can be a single bond or a double bond; M1 is selected from N or CR 1-1 ; M2 is selected from N or CR 1-2 ; M3 is selected from N or CR. 1-3 ; M4 is selected from N or CR. 2-1 ; M5 is selected from O, N, NR 3-1 CR 3-1 or CR 3-1 R 3-2 ; M6 is selected from bond, O, N, NR. 3-3 CR 3-3 CR 3-3 R 3-4 , OCR 3-5 R 3-6 , NCR 3-5 R 3-6 , NR 3-3 CR 3-5 R 3-6 , CR 3-3 CR 3-5 R 3-6 , CR 3-3 R 3-4 CR 3-5 R 3-6 , CR 3-3 O、 CR 3-3 R 3-4 O、 CR 3-3 NR 3-5 , CR 3-3 R 3-4 NR 3-5 , CR 3-3 =CR 3-5 , CR 3-3 =N、 N=CR 3-5 ,in The terminal is connected to M5; R 1-1 R 1-2 R 1-3 R 1-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R 2-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R 3-1 R 3-2 R 3-3 R 3-4 R 3-5 R 3-6 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; Other functional groups are defined as defined in any of the technical solutions described herein.

[0010] In some embodiments of this disclosure, Selected from , , , , , , , , , , , , , , , , , , , , , Other functional groups are defined as defined in any technical solution herein.

[0011] In some embodiments of this disclosure, ring D is phenyl; other groups are defined as defined in any of the technical solutions herein.

[0012] In some embodiments of this disclosure, It is phenyl; other groups are defined as defined in any technical solution herein.

[0013] In some embodiments of this disclosure, R1, R 1-1 R 1-2 R 1-3 R 1-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The group is substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl groups; other groups are defined as defined in any of the technical embodiments herein.

[0014] In some embodiments of this disclosure, R1 is independently selected from hydrogen, Other functional groups are defined as defined in any technical solution herein.

[0015] In some embodiments of this disclosure, R 1-1The group is independently selected from hydrogen; other groups are defined as defined in any of the technical solutions herein.

[0016] In some embodiments of this disclosure, R 1-2 The group is independently selected from hydrogen; other groups are defined as defined in any of the technical solutions herein.

[0017] In some embodiments of this disclosure, R 1-3 The group is independently selected from hydrogen; other groups are defined as defined in any of the technical solutions herein.

[0018] In some embodiments of this disclosure, R 1-4 Selected independently Other functional groups are defined as defined in any technical solution herein.

[0019] In some embodiments of this disclosure, R2, R 2-1 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The group is substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl groups; other groups are defined as defined in any of the technical embodiments herein.

[0020] In some embodiments of this disclosure, R2, R 2-1 Each group is independently selected from hydrogen; other groups are defined as defined in any of the technical solutions herein.

[0021] In some embodiments of this disclosure, R3, R 3-1 R 3-2 R 3-3 R 3-4 R 3-5 R 3-6 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The group is substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl groups; other groups are defined as defined in any of the technical embodiments herein.

[0022] In some embodiments of this disclosure, R3 is independently selected from hydrogen and methyl; other groups are defined as defined in any of the technical solutions herein.

[0023] In some embodiments of this disclosure, R 3-1 Each group is independently selected from hydrogen and methyl; other groups are defined as defined in any technical solution herein.

[0024] In some embodiments of this disclosure, R 3-2 R 3-3 R 3-4 R 3-5 R 3-6 Each group is independently selected from hydrogen; other groups are defined as defined in any of the technical solutions herein.

[0025] In some embodiments of this disclosure, R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The group is substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl groups; other groups are defined as defined in any of the technical embodiments herein.

[0026] In some embodiments of this disclosure, R4 is selected from cyclopropyl; other groups are defined as defined in any of the technical solutions herein.

[0027] In certain embodiments of this disclosure, R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 The group is substituted by one or more substituents of cycloalkyl or 3-6 membered heterocycloalkyl groups; other groups are defined as defined in any of the technical embodiments herein.

[0028] In some embodiments of this disclosure, R5 is independently selected from hydrogen; other groups are defined as defined in any of the technical solutions herein.

[0029] This disclosure also provides a pharmaceutical composition comprising the compound, isomer, or pharmaceutically acceptable salt thereof of the disclosed compound and a pharmaceutically acceptable carrier.

[0030] In some embodiments of this disclosure, the amount of the compound, isomer, or pharmaceutically acceptable salt thereof in the pharmaceutical composition is selected from 0.1 mg to 1000 mg.

[0031] In some embodiments of this disclosure, the pharmaceutically acceptable carrier in the pharmaceutical composition includes one or more of fillers, disintegrants, binders, flow aids, and lubricants.

[0032] This disclosure also provides the use of the above-described compounds, isomers, or pharmaceutically acceptable salts thereof, or the above-described pharmaceutical compositions, in the preparation of a medicament for treating WRN-mediated diseases.

[0033] In some embodiments of this disclosure, the disease is selected from cancer; preferably, the cancer is selected from colorectal cancer, endometrial cancer, or gastric cancer; more preferably, the cancer is a cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

[0034] This disclosure also provides a method for treating WRN-mediated diseases in humans, wherein the method comprises administering to a person in need an effective preventive or therapeutic amount of a compound of the disclosure, an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0035] Technical effect The disclosed compounds exhibit good WRN enzyme and cell inhibitory activity, and are selective for MSS and WRN-KO cells.

[0036] Explanation and Definition Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense.

[0037] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0038] The term "pharmaceutically acceptable salt" refers to derivatives obtained from the compounds of this disclosure prepared with relatively non-toxic acids or bases. These salts can be prepared during the synthesis, isolation, and purification of the compounds, or by reacting the purified free form of the compounds with suitable acids or bases. When the compounds contain relatively acidic functional groups (e.g., -COOH, -OH, -SO3H, etc.), they react with suitable inorganic or organic cations (bases) to give base addition salts, including salts formed with alkali metals or alkaline earth metals, ammonium salts formed with amines or their derivatives, and salts formed with amino acids. When the compounds contain relatively basic functional groups (e.g., -NH2, etc.), they react with suitable inorganic or organic anions (acids) to give acid addition salts, including salts formed with inorganic or organic acids (e.g., carboxylic acids, etc.).

[0039] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering a bioactive pharmaceutical agent to animals, particularly mammals. Depending on the route of administration and dosage form, this includes, for example, adjuvants, excipients, or excipients such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatizers, antibacterial agents, antifungal agents, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated based on a multitude of factors, within the scope of those skilled in the art. These include, but are not limited to, the type and nature of the formulated active pharmaceutical agent, the recipient to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as various solid and semi-solid dosage forms. In addition to the active pharmaceutical agent, such carriers include many different components and additives, and the inclusion of such additional components in the formulation for various reasons (e.g., stabilizing active pharmaceutical agents, binders, etc.) is well known to those skilled in the art.

[0040] The term "effective preventive or therapeutic dose" refers to a sufficient amount of the disclosed compound, its pharmaceutically acceptable salt, or isomer thereof, to provide a reasonable benefit / risk ratio for treating any medical condition and / or preventing the disorder. However, it should be understood that the total daily dose of the disclosed compound, its isomer, or its pharmaceutically acceptable salt and composition must be determined by the attending physician within the bounds of reliable medical judgment. For any given patient, the specific effective therapeutic dose level must be determined based on a number of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; medications used in combination with or concurrently with the specific compound used; and similar factors known in the medical field.

[0041] The compounds and their isomers disclosed herein are all within the scope of this disclosure, including geometric isomers and stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, racemic mixtures and other mixtures, all of which are within the scope of this disclosure.

[0042] The term "stereoisomers" as used in this disclosure includes trans-restricted isomers, cis-trans isomers, enantiomers, diastereomers, racemic mixtures thereof, and other mixtures, all of which fall within the scope of this disclosure. The term "enantiomer" refers to stereoisomers that are mirror images of each other. The term "diastereomer" refers to stereoisomers in which the molecules have two or more chiral centers and are not mirror images of each other. The term "cis-trans isomer" refers to different spatial configurations in which the double bonds or single bonds of cyclic carbon atoms in a molecule cannot rotate freely. The term "trans-restricted isomer" refers to a stereoisomer that can be separated due to impeded or very slow rotation of single bonds. Stereoisomers of the compounds disclosed herein can be prepared by chiral synthesis or by chiral reagents or other conventional techniques. For example, an enantiomer of a compound disclosed herein can be prepared by asymmetric catalysis or chiral derivative derivatization. Alternatively, a single stereoisomer can be obtained from a mixture using chiral resolution techniques. Or, it can be prepared directly from chiral starting materials. The separation of optically pure compounds in this disclosure is typically accomplished using preparative chromatography, employing a chiral chromatographic column to achieve the separation of chiral compounds.

[0043] The absolute stereoconfiguration of a compound can be confirmed using conventional techniques in the art. For example, single-crystal X-ray diffraction (SFC) can be used, or the absolute configuration of the compound can be confirmed by examining the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereoconfiguration can be determined by comparing it with a product whose absolute configuration is known. Compounds marked as "absolute configuration unknown / undetermined" in this article are typically racemic compounds resolved into single isomers via chiral preparative SFC, followed by characterization and testing.

[0044] The phrase “optionally substituted” in this disclosure refers to either the situation where one or more hydrogen atoms of the substituted group can be “substituted” or “not substituted” by one or more substituents.

[0045] When a substituent can be cross-bonded to a ring, it means that the substituent can bond with any atom on that ring. For example, structural units. This indicates that the substituent R3 can be substituted at any position on ring A.

[0046] When a listed substituent does not specify which atom it is attached to a given group or given structural formula, the substituent may be attached by any of its bondable atoms.

[0047] When any variable (e.g., R) d When a compound appears more than once in its composition or structure, its definition is independent in each case. For example, This indicates that ring A is replaced by x R3s, and each R3...d Each has its own independent options.

[0048] Unless otherwise specified, the term "halogen" refers to a fluorine, chlorine, bromine, or iodine atom.

[0049] Unless otherwise specified, the term "alkyl" refers to a branched or straight-chain saturated aliphatic alkane with a specified number of carbon atoms, minus a hydrogen-derived group. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, and C6 alkyl groups. 1-6 Alkyl group, C 1-3 "alkyl"; specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, etc. "COalkyl" refers to hydrogen.

[0050] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms. C is preferred. 1-6 Halogenated alkyl, more preferably C 1-3 Alkyl halogens. Examples of alkyl halogens include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl groups are as defined above.

[0051] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group by replacing one or more hydrogen atoms with a hydroxyl group, and "hydroxyalkyl" as used in this disclosure includes "C 1-6 Hydroxyalkyl, C 1-3 "Hydroxyalkyl"; specific examples include, but are not limited to, -CH2OH, -CH2CH2OH, -CH(OH)CH3, -CH2CH2CH2OH, , , , wait.

[0052] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein, in which an alkyl group is attached to another group by an oxygen atom, i.e., "alkyl-O-". This includes "C". 1-6 Alkoxy (structure is C) 1-6 alkyl-O-), "C 1-3 "Alkoxy" is a suffix, specifically including but not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" in this disclosure is preferably C 1-3 Alkyl group.

[0053] Unless otherwise specified, the term "haloalkoxy" refers to a group obtained by substituting one or more hydrogen atoms in an alkoxy group with a halogen. Preferably, the "haloalkoxy" described in this disclosure is "haloC". 1-6 Alkoxy, halogenated C 1-3 Alkoxy groups. Specific examples described in this disclosure include: fluoromethoxy groups (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH2CF3, -OCHFCH3, etc. Alkoxy groups are as defined above.

[0054] Unless otherwise specified, the term "alkenyl" refers to a group derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing one hydrogen atom, including "C". 2-6 "alkenyl", "C" 2-5 "alkenyl", "C" 2-4 "alkenyl", "C" 2-3 "Alkenyl", specific examples include but are not limited to: -CH=CH2, -CH=CHCH3, -C(CH2)=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, etc.

[0055] Unless otherwise specified, the term "alkynyl" refers to a group derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing one hydrogen atom, including "C". 2-6 "Alkyne", "C" 2-4 "Alkyne", "C" 2-3 "Alkyne group", specific examples include but are not limited to: -C≡CH, -C≡CHCH3, HC≡CHCH2-, HC≡CC≡C-, etc.

[0056] Unless otherwise specified, the term "cycle" refers to a saturated, partially saturated, or unsaturated monocyclic or polycyclic ring, including spirocyclic, fused, or bridged rings. The group derived from a ring by removing a hydrogen atom is called a "cycloyl group," which includes monovalent, divalent (commonly referred to as a subcyclic ring), trivalent, and tetravalent rings, with the specific valence depending on the number of substituents attached to the ring. This disclosure no longer specifically distinguishes the valence of the ring in its description of "cycloyl groups." Representative "cycloyl groups" include substituted or unsubstituted cycloalkyl, heterocyclic alkyl, cycloalkenyl, heterocyclic alkenyl, cycloynyl, heterocyclic alynyl, aryl, or heteroaryl groups.

[0057] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon group refers to a polycyclic group formed by two or more cyclic alkyl structures linked by spiro, bridging, fusion, or other means. The carbon atom in the cycloalkyl group can be further oxidized, i.e., forming C(O). The cycloalkyl group includes "C 3-8 cycloalkyl, C 3-6 cycloalkyl, C3-5 "Cycloalkyl". Preferably, the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0058] Unless otherwise specified, "cycloalkenyl" refers to one or more double bonds in a "cycloalkyl" group, and the cycloalkenyl group is not aromatic. The carbon atom in the cycloalkenyl group may be further oxidized, forming C(O). The cycloalkenyl group includes "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". Specific examples include, but are not limited to, those mentioned above. , , , .

[0059] Unless otherwise specified, the term "heterocyclic alkyl" refers to a saturated cyclic group derived from which one or more cyclic carbon atoms in a cycloalkyl group are replaced by heteroatoms and / or heteroatom groups. The heteroatoms and / or heteroatom groups are generally selected from N, O, S, NO, SO, S(O)₂, P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxidized to form -C(O); preferably, the heteroatoms are independently selected from 1 to 3 N and / or O atoms. The heterocyclic group includes "3-8 membered heterocyclic groups", "3-6 membered heterocyclic groups", "3-5 membered heterocyclic groups", "4-6 membered heterocyclic groups", and "5-6 membered heterocyclic groups". Specific examples include, but are not limited to, nitrogen-containing heterocyclic butyl, oxocyclic butane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, etc.

[0060] Unless otherwise specified, the term "heterocyclic alkenyl" refers to one or more double bonds in a "heterocyclic alkyl" group, wherein the heterocycle is not aromatic. Preferably, the heteroatoms are independently selected from 1-3 N and / or O atoms. The heterocyclic group includes "3-8-membered heterocyclic alkenyl", "3-6-membered heterocyclic alkenyl", "3-5-membered heterocyclic alkenyl", and "5-6-membered heterocyclic alkenyl". Specific examples include, but are not limited to: , , , , wait.

[0061] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic, hydrocarbon group, which may be a monocyclic or fused rings, preferably C12. 6-10 Aryl; examples of aryl include, but are not limited to, phenyl and naphthyl.

[0062] The term "heteroaryl" as used in this disclosure refers to an aromatic monocyclic group having at least one heteroatom and / or heteroatomic group as a heteroatom and / or heteroatomic group. The heteroatom and / or heteroatomic group is generally selected from N, O, S, P, NO, SO, S(O)2, P(O), and NR, where R is H or any possible substituent group. The carbon atom in the heterocycle is optionally oxidized to form -C(O). Preferably, the heteroatom is independently selected from 1-3 N and / or O atoms. The heteroaryl includes "5-6 membered heteroaryl" groups; specific examples include, but are not limited to, pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazoyl, pyrazinyl, pyridazinyl, triazinyl, oxazolyl, isoxazolyl, thiazoyl, isoxazolyl, pyridinyl, pyridinyl, pyrimidinyl, etc. .

[0063] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl," it should be understood that "alkyl" or "aryl" represents a linked alkylene group or an arylene group, respectively.

[0064] The combinations of substituents and / or variables described in this disclosure are permitted only when these combinations produce stable compounds or usable synthetic intermediates. A stable compound or stable structure is a compound that is sufficiently stable to withstand chemical reactions, be isolated with useful purity, and be formulated into an effective therapeutic agent.

[0065] The preparation methods of some compounds in this disclosure reference the preparation methods of the aforementioned similar compounds. Those skilled in the art should understand that when using or referring to the referenced preparation methods, the reactant ratios, reaction solvents, reaction temperatures, etc., can be appropriately adjusted according to the different reactants.

[0066] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein. Detailed Implementation

[0067] The structures of the compounds disclosed herein were determined by nuclear magnetic resonance (NMR) mass spectrometry. NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Ascend 400 NMR instrument, with deuterated dimethyl sulfoxide (DMSO) as the solvent. d 6), deuterated methanol (CD3OD) and deuterated chloroform (CDCl3), with heavy water (D2O) internally labeled as tetramethylsilane (TMS).

[0068] Thin-layer chromatography (TLC) used HSGF254 silica gel plates from Yantai Jiangyou Silica Gel Development Co., Ltd. The TLC plates were 0.20 mm ± 0.03 mm in size and 20 x 20 cm in size for preparative applications. Column chromatography used 200-300 mesh silica gel from Qingdao Hailang Silica Gel Desiccant Co., Ltd. as the carrier.

[0069] The starting materials used in the embodiments of this disclosure are known and commercially available, or can be synthesized using methods known in the art.

[0070] Unless otherwise specified, all reactions in this disclosure are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, using a dry solvent, and the reaction temperature is in degrees Celsius.

[0071] Preparation General Rules Synthesis Route 1:

[0072] The following embodiments are synthesized according to the above synthetic route.

[0073] Biological test cases I. In vitro WRN enzyme activity assay This experiment was used to establish an ATPase assay to measure the DNA-dependent ATP hydrolytic activity of WRN helicases. This assay was also used to evaluate the inhibitory properties of the disclosed compounds on DNA-dependent WRN enzyme activity.

[0074] 1. Experimental materials

[0075] 2. Experimental Methods 1) Use DMSO to perform serial dilutions of the compound in a 384 PP Plate compound dilution plate (ensure that the initial concentration in the final reaction system is 10 μM, 9 concentrations, and a 1:3 dilution ratio).

[0076] 2) Use Echo to transfer 0.1 μL of the compound into a 384 reaction microplate (Greiner 784075) to ensure that the final DMSO content is 1% (double replicate).

[0077] 3) Add 5 μL of WRNase solution to each well of a 384 reaction microplate to ensure a final WRNase concentration of 10 nM. Incubate at 25°C for 2 hours. The reaction buffer consists of 400 μM ATP, 30 mM Tris (pH 7.5), 2 mM MgCl2, 0.02% BSA, 50 mM NaCl, and 0.1% pluronic F-127. .

[0078] 4) Add 5 μL of single-stranded DNA substrate to each well, dilute with the same buffer as above (without ATP), and the final substrate concentration is 10 nM. Incubate at 25°C for 1 hour.

[0079] 5) Add 5 μL of ADP-Glo ​​reagent to the reaction system and incubate at room temperature for 1 hour to remove excess ATP from the reaction.

[0080] 6) Add 10 μL of ATP detection reagent to the reaction system and incubate at room temperature for 1 hour.

[0081] 7) Use an Envision microplate reader (PerkinElmer) to detect the chemiluminescent signal and calculate the WRN enzyme activity inhibition rate for each well.

[0082] 8) Data analysis to calculate the IC50 (nM) of the compounds in this disclosure.

[0083] 3. Experimental Results The disclosed compound has an IC50 response to WRN enzyme. 50 In the range of 1-1000 nM, preferably, the IC50 of some compounds 50 In the range of 1-500 nM, and more preferably, the IC50 of some compounds... 50 In the range of 1-200 nM, and more preferably, the IC50 of some compounds... 50 In the range of 1-100 nM, and more preferably, the IC50 of some compounds... 50 In the range of 1-50 nM, most preferably, the IC50 of some compounds is... 50 Less than 10 nM.

[0084] Conclusion: The compounds of the embodiments disclosed herein exhibit good inhibitory activity against DNA-dependent WRN enzymes.

[0085] II. Cell proliferation inhibition experiment This experiment used chemiluminescence immunoassay (CellTiter-Glo) to measure intracellular ATP content to detect the inhibitory effect of the compound on the proliferation of relevant MSI / MSS cell lines, and determined the IC50 of the compound on the proliferation inhibition of the above cell lines.

[0086] 1. Experimental materials RPMI-1640 medium, DMEM medium, McCoy's 5a medium, Leibovitz's L-15 medium, fetal bovine serum (FBS), 100X Pen / Strep, and GlutaMAX-I supplement were purchased from GIBCO. RKO, SW48, HCT116, LoVo, RL95-2, IM95 (MSI), and SW620 (MSS) cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd. HCT116_WRN-KO cell line was provided by ICE. Cell Titer-Glo luminescence assay reagents were purchased from Promega.

[0087] 2. Experimental Methods 1) Day 0: Seed cells in 384-well culture plates, 50 μl per well, and incubate overnight in an incubator (37 ℃, 5% CO2).

[0088] 2) Day 1: Using D300e (TECAN), add 100 nL of cell culture medium containing serially diluted test compounds (starting concentration of 10 μM, 9 concentrations, 1:3 dilution ratio) to the cells in the culture plate. The final concentration of DMSO is 0.2%. Incubate the culture plate in a cell culture incubator for 120 hours (37 ℃, 5% CO2). Set up a blank control by adding 100 nL of DMSO to each well.

[0089] 3) Day 5: Add 20 μL of Cell Titer-Glo reagent to each well, shake at 500 rpm for 10 minutes, incubate at room temperature in the dark for 10 minutes to stabilize the luminescence signal, and then use an Envision microplate reader (PerkinElmer) to detect the luminescence signal, perform data analysis, and calculate the IC50 (nM) of the compound.

[0090] 3. Experimental Results The disclosed compound has an IC50 response to mesenchymal stem cell (MSI) 50In the range of 1-1000 nM, preferably, the IC50 of some compounds 50 In the range of 1-500 nM, and more preferably, the IC50 of some compounds... 50 In the range of 1-200 nM, and more preferably, the IC50 of some compounds... 50 In the range of 1-100 nM, and more preferably, the IC50 of some compounds... 50 In the range of 1-50 nM, most preferably, the IC50 of some compounds is... 50 Less than 10 nM.

[0091] Conclusion: The compounds of the embodiments disclosed herein exhibit good inhibitory activity against mesenchymal stem cell (MSI) and are selective.

Claims

1. A compound, isomer, or pharmaceutically acceptable salt thereof of formula (I): in, Ring A is selected from C 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl; Ring B is selected from C 5-6 cycloalkyl, C 5-6 Cycloalkenyl, 5-6 membered heterocyclic alkyl, 5-6 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl; Ring C is selected from C 4-7 cycloalkyl, C 4-7 Cycloalkenyl, 4-7 membered heterocyclic alkyl, 4-7 membered heterocyclic alkenyl; Ring D is selected from C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-8 membered heterocyclic alkyl, 3-8 membered heterocyclic alkenyl, phenyl, 5-6 membered heteroaryl; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R2 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups; x is selected from 0, 1, 2, 3, and 4; y is selected from 0 and 1; z is selected from 0, 1, 2, 3; w is selected from 0, 1, 2, 3, 4.

2. The compound, isomer, or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein the compound is shown in formula (II-1) or (II-2): in, It can be a single bond or a double bond; M1 is selected from N or CR 1-1 ; M2 is selected from N or CR 1-2 ; M3 is selected from N or CR. 1-3 ; M4 is selected from N or CR. 2-1 ; M5 is selected from O, N, NR 3-1 CR 3-1 or CR 3-1 R 3-2 ; M6 is selected from bond, O, N, NR. 3-3 CR 3-3 CR 3-3 R 3-4 , OCR 3-5 R 3-6 , NCR 3-5 R 3-6 , NR 3-3 CR 3-5 R 3-6 , CR 3- 3CR 3-5 R 3-6 , CR 3-3 R 3-4 CR 3-5 R 3-6 , CR 3-3 O、 CR 3-3 R 3-4 O、 CR 3-3 NR 3-5 , CR 3-3 R 3-4 NR 3-5 , CR 3-3 =CR 3-5 , CR 3-3 =N、 N=CR 3-5 ,in The terminal is connected to M5; R 1-1 R 1-2 R 1-3 R 1-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 The alkyl group or one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups are substituted. R 2-1 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 The alkyl group or one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups are substituted. R 3-1 R 3-2 R 3-3 R 3-4 R 3-5 R 3-6 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocyclic alkyl, wherein the hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-8 It is substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl groups.

3. The compound, isomer, or pharmaceutically acceptable salt thereof as described in claim 2, wherein, Selected from , , , , , , , , , , , , , , , , , , , , , .

4. The compound, isomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3, wherein, It is a phenyl group.

5. The compound, isomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 4, wherein, R1, R 1-1 R 1-2 R 1-3 R 1-4 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Substituted by one or more substituents in cycloalkyl or 3-6 membered heterocycloalkyl groups; Preferably, R1 is independently selected from hydrogen, . And / or, R 1-1 Independently selected from hydrogen; And / or, R 1-2 Independently selected from hydrogen; And / or, R 1-3 Independently selected from hydrogen; And / or, R 1-4 Selected independently .

6. The compound, isomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 5, wherein, R2, R 2-1 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Substituted by one or more substituents in cycloalkyl or 3-6 membered heterocycloalkyl groups; Preferably, R2, R 2-1 Each is independently selected from hydrogen; or, R3, R 3-1 R 3-2 R 3-3 R 3-4 R 3-5 R 3-6 Each is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Substituted by one or more substituents in cycloalkyl or 3-6 membered heterocycloalkyl groups; Preferably, R3 is independently selected from hydrogen and methyl; And / or, R 3-1 Each is independently selected from hydrogen and methyl; And / or, R 3-2 R 3-3 R 3-4 R 3-5 R 3-6 Each is independently selected from hydrogen.

7. The compound, isomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 6, wherein, R4 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Substituted by one or more substituents in cycloalkyl or 3-6 membered heterocycloalkyl groups; Preferably, R4 is selected from cyclopropyl; or, R5 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, and C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the hydroxyl, amino, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further converted by deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 3-6 Substituted by one or more substituents in cycloalkyl or 3-6 membered heterocycloalkyl groups; Preferably, R5 is independently selected from hydrogen.

8. The compound, isomer, or pharmaceutically acceptable salt thereof as described in any one of claims 1 to 7, characterized in that, The compounds are shown below: 。 9. A pharmaceutical composition comprising the compound, isomer, or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

10. Use of the compound, isomer, or pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 8, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating cancer. Preferably, the cancer is selected from colorectal cancer, endometrial cancer, or gastric cancer; more preferably, the cancer is a cancer with high microsatellite instability or mismatch repair deficiency.

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