Cycloalkenyl sulfone derivative as well as preparation method and application thereof

Abstract

The invention discloses a cycloalkenyl sulfone derivative as well as a preparation method and application thereof. In particular, the present invention relates to a compound represented by general formula (IA) or a stereoisomer thereof, a preparation method thereof, a pharmaceutical composition containing the compound, and an application thereof in preparation of drugs for treating diseases. The compound has a structure as shown in a formula (IA). # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a cyclopentyl sulfone derivative, a preparation method and application thereof. Background Art

[0002] The RecQ helicase subfamily is a class of enzymes that can unwind double-stranded nucleotides. In cells, they participate in DNA replication, repair, transcriptional recombination, RNA splicing, ribosome assembly, protein translation, and telomere stability. The family was first discovered in prokaryotes. RecQ family 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 RecQ family of DNA helicases, including WRN, BLM, RecQ1, RecQ4 and RecQ5. When mutated, it can cause different chromosomal instability diseases such as Werner syndrome, Bloom syndrome and Rothmund-Thomson syndrome. Among them, WRN consists of 1432 amino acids and has a molecular mass of 160KD. WRN is mainly located in the nucleolus. After DNA damage, it will quickly move to other nuclear regions. WRN is the only member of the human RecQ helicase family that has 3'→5' exonuclease activity. Its N-terminal exonuclease region facilitates WRN to process complex nucleic acid structures, and the middle unwinding domain can bind and hydrolyze ATP to provide energy for unwinding double-stranded DNA. The C-terminal HRDC domain can regulate the activity of catalyzing WRN binding to DNA.

[0003] Microsatellite (MS) refers to a DNA sequence in the cell genome that is repeated in tandem with a few nucleotides (mostly 1 to 6) as a unit, also known as short tandem repeat (STR). When the DNA mismatch repair (NMR) function is abnormal, the replication errors of microsatellites cannot be corrected and continue to accumulate, causing changes in the length or base composition of the microsatellite sequence, which is called microsatellite instability (MSI), and at the same time causing the genome to present a high mutation phenotype. In tumors, the loss of MLH1 expression caused by loss-of-function mutations of MMR key genes (MLH1, MSH2, MSH6 and PMS2) and their related genes or hypermethylation of the MLH1 promoter region often leads to DNA mismatch repair (MMR) MMR function defects. According to the microsatellite stability of tumor cells, tumors can be divided into microsatellite high instability (MSI) tumors and microsatellite stable (MSS) tumors. MSI is common in cancers, among which solid tumors with higher incidence include endometrial cancer (about 30%), gastric cancer (about 20%), and colorectal cancer (about 15%).

[0004] There is a synthetic lethal relationship between WRN and MSI-H: in MSI tumor cell lines, knocking out WRN will cause these cancer cells to have characteristics such as genomic instability, cell cycle arrest, DNA double-strand breaks, and ultimately lead to the death of cancer cells. Therefore, by developing small molecule inhibitors targeting WRN, it is expected to achieve selective killing of MSI-H cancer cells and provide personalized anti-tumor treatment for MSI tumor patients. Summary of the invention

[0005] The purpose of the present disclosure is to provide a cyclic alkenyl sulfone derivative, a preparation method and application thereof.

[0006] The present disclosure provides a compound represented by formula (IA), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] Ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl;

[0010] Ring B is selected from C 6-14 Aryl or 5-14 membered heteroaryl; or Ring B is absent;

[0011] Ring C is selected from 3-8 membered heterocycloalkenyl or 5-14 membered heteroaryl;

[0012] L 1 Selected from bond, -CONH-, -SO 2 NH-, -CONH-C 1-6 Alkylene-, the -CONH-, -SO 2 NH-, -CONH-C 1-6 Alkylene - optionally substituted with one or more R 2 replace;

[0013] R 1 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -NHCO-CH 2 =CH 2 、-SO 2 -CH 2 =CH 2 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -NHCO-CH 2 =CH 2 、-SO 2 -CH 2 =CH 2 , optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0014] R 2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0015] R 3 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0016] Or, one of the R 3 and R 2 The 5-7 membered heterocycloalkenyl is connected to form a 5-7 membered heterocycloalkenyl, wherein the 5-7 membered heterocycloalkenyl is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0017] R 4 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, -OR 4-1 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0018] R 4-1 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl, 5-10 membered heteroaryl; the C 6-10 Aryl, 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0019] x is selected from 0, 1, 2 or 3;

[0020] y is selected from 0, 1, 2 or 3;

[0021] z is selected from 0, 1, 2 or 3.

[0022] The present disclosure provides a compound represented by formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof:

[0023]

[0024] in,

[0025] Ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl;

[0026] Ring B is selected from C 6-14 Aryl or 5-14 membered heteroaryl; or Ring B is absent;

[0027] R 1 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0028] R 2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0029] R 3 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0030] Or, one of the R 3 and R 2 The 5-7 membered heterocycloalkenyl is connected to form a 5-7 membered heterocycloalkenyl, wherein the 5-7 membered heterocycloalkenyl is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0031] R 4 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, -OR 4-1, the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0032] R 4-1 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl, 5-10 membered heteroaryl; the C 6-10Aryl, 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0033] x is selected from 0, 1, 2 or 3;

[0034] y is selected from 0, 1, 2 or 3;

[0035] z is selected from 0, 1, 2 or 3.

[0036] In certain embodiments of the present disclosure, ring A is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 5-6 membered heteroaryl, phenyl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl and C 3-6 Cycloalkenyl, phenyl and 3-6 membered heterocycloalkenyl;

[0037] Preferably, ring A is selected from phenyl, The definitions of other groups are as defined in any technical scheme herein.

[0038] In certain embodiments of the present disclosure, the ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and 2-6 membered heterocycloalkenyl; or the ring B is absent;

[0039] Preferably, the ring B is selected from phenyl, or ring B does not exist;

[0040] The definitions of other groups are as defined in any technical scheme herein.

[0041] In certain embodiments of the present disclosure, the ring C is selected from a 5-6 membered heterocycloalkenyl or a 5-6 membered heteroaryl;

[0042] Preferably, the ring C is selected from

[0043] The definitions of other groups are as defined in any technical scheme herein.

[0044] In certain embodiments of the present disclosure, the compound is as shown in formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII),

[0045]

[0046] The definitions of other groups are as defined in any technical scheme herein.

[0047] In certain embodiments of the present disclosure, the compound is as shown in formula (VIII),

[0048]

[0049] R 4 'Selected from amino, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, -OR 4-1 , the amino group, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0050] R 4-1 independently selected from deuterium, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, 3-8 membered heterocycloalkyl, the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Hydroxyalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl, 5-10 membered heteroaryl; the C 6-10 Aryl, 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0051] Preferably,

[0052] R 4 'Selected from amino, cyano, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 8-10 membered heterocycloalkyl, -OR 4-1 , the amino group, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 8-10 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-6 membered heteroaryl;

[0053] R 4-1 independently selected from deuterium, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, 3-6 membered heterocycloalkyl, the C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents in aryl, 5-6 membered heteroaryl; the C 6-10 Aryl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0054] Preferably, R 4 'Selected from ethynyl,

[0055] y is selected from 0, 1 or 2;

[0056] z is selected from 0, 1 or 2;

[0057] The definitions of other groups are as defined in any technical scheme herein.

[0058] In certain embodiments of the present disclosure, the compound is as shown in Formula (VIII-1), Formula (VIII-2) or Formula (VIII-3),

[0059]

[0060] Wherein, ring B is selected from 3-12 membered heterocycloalkyl, preferably 8-10 membered heterocycloalkyl, more preferably

[0061] R 4-2 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl; the C 6-10 Aryl, 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl;

[0062] Preferably, R 4-2 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-6 membered heteroaryl; the C 6-10 Aryl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0063] More preferably, R 4-2 independently selected from hydrogen, cyclopropyl;

[0064] w is selected from 0, 1 or 2;

[0065] The definitions of other groups are as defined in any technical scheme herein.

[0066] In certain embodiments of the present disclosure, the compound is as shown in Formula (IX-1), Formula (IX-2), Formula (IX-3) or Formula (IX-4),

[0067]

[0068] Among them, M 1 N or CH;

[0069] M 2 N or CH;

[0070] The definitions of other groups are as defined in any technical scheme herein.

[0071] In certain embodiments of the present disclosure, the compound is as shown in formula (X),

[0072]

[0073] Among them, R 2 Selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocycloalkyl

[0074] Preferably, R 2 Selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0075] More preferably, R 2 Selected from hydroxyl group;

[0076] The definitions of other groups are as defined in any technical scheme herein.

[0077] In certain embodiments of the present disclosure, the compound is as shown in formula (XI),

[0078]

[0079] R 3 'Selected from hydrogen, deuterium, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0080] Preferably, R 3 'Selected from C 2-6 Alkynyl, the C 2-6 The alkynyl group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl;

[0081] More preferably, R 3 'Selected from

[0082] The definitions of other groups are as defined in any technical scheme herein.

[0083] In certain embodiments of the present disclosure, the compound is as shown in formula (XII),

[0084]

[0085] in,

[0086] M 3 is selected from N or CH;

[0087] R 1a , R 1b and R 1c are each independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl.

[0088] The definitions of other groups are as defined in any technical scheme herein.

[0089] In certain embodiments of the present disclosure, the compound is as shown in formula (XIII),

[0090]

[0091] The definitions of other groups are as defined in any technical scheme herein.

[0092] In certain embodiments of the present disclosure, the compound is as shown in formula (XIII-1),

[0093]

[0094] The definitions of other groups are as defined in any technical scheme herein.

[0095] In certain embodiments of the present disclosure, the compound is as shown in formula (XIV),

[0096]

[0097] in,

[0098] M 4 Select from NH or CH2 ;

[0099] The definitions of other groups are as defined in any technical scheme herein.

[0100] In certain embodiments of the present disclosure, the compound is as shown in formula (XIV-1) or as shown in formula (XIV-2),

[0101]

[0102] The definitions of other groups are as defined in any technical scheme herein.

[0103] In certain embodiments of the present disclosure, R 1 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NHCO-CH 2 =CH 2 、-SO 2 -CH 2 =CH 2 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NHCO-CH 2 =CH 2 、-SO 2 -CH 2 =CH 2 , optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C1-3 Haloalkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0104] The definitions of other groups are as defined in any technical scheme herein.

[0105] In certain embodiments of the present disclosure, R 1 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0106] Preferably, R 1 are independently selected from hydrogen;

[0107] The definitions of other groups are as defined in any technical scheme herein.

[0108] In certain embodiments of the present disclosure, R 2 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0109] Preferably, R 2 is selected from hydrogen or hydroxyl;

[0110] The definitions of other groups are as defined in any technical scheme herein.

[0111] In certain embodiments of the present disclosure, R 3 Selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0112] R 3 Selected from hydrogen, hydroxyl,

[0113] The definitions of other groups are as defined in any technical scheme herein.

[0114] In certain embodiments of the present disclosure, one R 3 and R 2 The 5-7 membered heterocycloalkenyl is connected to form a 5-7 membered heterocycloalkenyl, wherein the 5-7 membered heterocycloalkenyl is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 The cycloalkyl group and the 3-6-membered heterocycloalkyl group are substituted by one or more substituents; the definitions of other groups are as defined in any technical solution of this invention.

[0115] In certain embodiments of the present disclosure, R 4 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6Cycloalkyl, 8-10 membered heterocycloalkyl, -OR 4-1 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-6 membered heteroaryl;

[0116] R 4-1 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents in aryl, 5-6 membered heteroaryl; the C 6-10 Aryl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl;

[0117] Preferably, R 4 are independently selected from hydrogen, methyl, trifluoromethyl, chlorine, ethoxy, methoxy, ethynyl,

[0118] The definitions of other groups are as defined in any technical scheme herein.

[0119] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned compound, stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0120] The present disclosure also provides a use of the above-mentioned compound, stereoisomer or pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition in the preparation of a drug for treating a WRN-mediated disease.

[0121] In certain embodiments of the present 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 microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) cancer.

[0122] Technical Effects

[0123] The compounds of the present invention have good WRN enzyme and cell inhibitory activities.

[0124] Description and Definition

[0125] 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 ambiguous or unclear without a special definition, but should be understood according to the ordinary meaning.

[0126] The term "pharmaceutically acceptable" 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.

[0127] The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound prepared with a relatively nontoxic acid or base. These salts can be prepared during compound synthesis, separation, and purification, or the purified free form of the compound can be used alone to react with a suitable acid or base. When the compound contains a relatively acidic functional group (e.g., -COOH, -OH, -SO3H, etc.), it reacts with a suitable inorganic or organic cation (base) to obtain a base addition salt, 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 compound contains a relatively basic functional group (e.g., -NH2, etc.), it reacts with a suitable inorganic or organic anion (acid) to obtain an acid addition salt, including a salt formed with an inorganic acid or an organic acid (e.g., a carboxylic acid, etc.).

[0128] The term "pharmaceutically acceptable carrier" refers to a medium generally acceptable in the art for delivering biologically active agents to animals, particularly mammals, including, for example, adjuvants, excipients or excipients, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, aromatics, antibacterial agents, antifungal agents, lubricants and dispersants, depending on the nature of the mode of administration and dosage form. Pharmaceutically acceptable carriers are formulated within the scope of ordinary technicians in the field according to a large number of factors. They include, but are not limited to: the type and nature of the active agent to be formulated, the subject to whom the composition containing the 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 and a variety of solid and semi-solid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in the prescription for various reasons (e.g., stabilizing the active agent, adhesives, etc.) are well known to ordinary technicians in the field.

[0129] The term "effective preventive or therapeutic amount" refers to a sufficient amount of the disclosed compound, its pharmaceutically acceptable salt, or its stereoisomer to treat the disorder at a reasonable effect / risk ratio applicable to any medical treatment and / or prevention. However, it should be recognized that the total daily dosage of the disclosed compound, its stereoisomer, or its pharmaceutically acceptable salt and composition must be determined by the attending physician within the scope of sound medical judgment. For any specific patient, the specific therapeutically effective dosage level must be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, route of administration and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used; and similar factors known in the medical field.

[0130] The absolute stereo configuration of the compound can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction can also be used to confirm the absolute configuration of the compound by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis. Or after separation, the stereo configuration is determined by comparing it with the product with determined absolute configuration. The compounds marked as "absolute configuration unknown / undetermined" herein are usually separated into single isomers by chiral preparative SFC from racemic compounds, and then characterized and tested.

[0131] The term "optionally" means that it may be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be any on the basis of chemical practicability. For example, the term "optionally substituted with one or more R 1 "Substituted" means that one or more R 1 Replaced by R 1 replace.

[0132] When any variable (such as R 1 ) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. For example, Indicates that the structure fragment is x R 1 replaced, and each R 1 All have independent options.

[0133] When a substituent has a bond that crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents a substituent R 1 Substitutions can occur at any position on the structural fragment.

[0134] When the substituent is listed without indicating the atom through which it is connected to the compound included in the general chemical formula but not specifically mentioned, the substituent can be bonded through any atom. For example, pyrimidine as a substituent means that any carbon atom or nitrogen atom on the pyrimidine ring is connected to the substituted group; when the structure appears , it indicates that the atom is a bonding atom, for example Indicates that the C atoms on the structural fragment are bonding atoms.

[0135] Unless otherwise specified, the term "alkyl" refers to a group derived from a branched or straight chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen. 1-6 "Alkyl" refers to a group including C 1 , C 2 , C 3 , C 4 , C 5 , C 6 Alkyl, "C 1-6 Alkyl", "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.

[0136] Unless otherwise specified, the term "alkylene" refers to a group derived from an alkyl group by removing one hydrogen atom, and the alkyl group is as defined above.

[0137] Unless otherwise specified, the term "alkenyl" refers to a radical derived from a straight-chain or branched alkene (containing at least one carbon-carbon double bond) by removing a hydrogen atom, including "C 2-6 Alkenyl", "C 2-5 Alkenyl", "C 2-4 Alkenyl", "C 2-3 Examples include, but are not limited to, -CH=CH 2 、-CH=CHCH 3 、-C(CH 2 )=CH 2 、-CH=CHCH 2 CH 3 、-CH 2 CH=CHCH 3 wait.

[0138] Unless otherwise specified, the term "alkynyl" refers to a radical derived from a straight-chain or branched alkyne (containing at least one carbon-carbon triple bond) by removing a hydrogen atom, including "C 2-6 Alkynyl", "C 2-4 Alkynyl", "C 2-3 "Alkynyl", specific examples include but are not limited to: -C≡CH, -C≡CHCH3 、CH≡CHCH 2 -, CH≡CC≡C-, etc.

[0139] Unless otherwise specified, the term "alkoxy" refers to an alkyl group as defined herein attached to another group through an oxygen atom, i.e., "alkyl-O-". 1-6 Alkoxy (structure C 1-6 Alkyl-O-), "C 1-3 "alkoxy", specific examples include but are not limited to methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, etc.; preferably, the "alkoxy" described in the present disclosure is preferably C 1-3 Alkoxy.

[0140] Unless otherwise specified, the term "halogen" means a fluorine, chlorine, bromine or iodine atom.

[0141] Unless otherwise specified, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. 1-6 Haloalkyl, more preferably C 1-3 Haloalkyl. Examples of haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc. Alkyl is as defined above.

[0142] Unless otherwise specified, the term "hydroxyalkyl" refers to a group derived from an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. The "hydroxyalkyl" described in the present disclosure includes "C 1-6 Hydroxyalkyl", "C 1-4 "Hydroxyalkyl"; specific examples include but are not limited to -CH 2 OH, -CH 2 CH 2 OH, -CH(OH)CH 3 、-CH 2 CH 2 CH 2 OH, wait.

[0143] Unless otherwise specified, the term "alkylthio" refers to an -S-alkyl group wherein alkyl is as previously defined.

[0144] Unless otherwise specified, the term "haloalkoxy" refers to a group in which one or more hydrogen atoms in an alkoxy group are replaced by halogen. Preferably, the "haloalkoxy" described in the present disclosure is preferably a "haloC 1-6 Alkoxy", "halogenated C 1-3Alkoxy". Specific examples of the present disclosure include: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH 2 CF 3 、-OCHFCH 3 etc. Alkoxy is as defined above.

[0145] Unless otherwise specified, the term "hetero" refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatomic radicals), wherein the heteroatoms are generally selected from N, O, and S, and the oxidized forms generally include NO, SO, S(O) 2 , P(O), the nitrogen atom may be substituted, i.e. NR (R is H or other substituents defined herein); the number of atoms in the ring is usually defined as the number of ring members, for example, "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around each ring, each ring optionally containing 1 to 3 heteroatoms, i.e. N, O, CO, S, NO, SO, S(O) 2 or NR, each ring being optionally substituted with an R group, wherein R is a group as defined herein.

[0146] Unless otherwise specified, the term "cycloalkyl" refers to a saturated cyclic alkyl 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 connected by spiro, bridge, condensed, etc. The carbon atoms in the cycloalkyl group can be further oxidized, that is, to form C(O). Unless otherwise specified, the "monocyclic cycloalkyl" described herein can be understood as a monocyclic cycloalkyl group. When it is polycyclic, it will be specifically specified as a spiro, condensed or bridged ring group. The cycloalkyl group includes "C 3-12 Cycloalkyl", "C 3-8 Cycloalkyl", "C 3-6 Cycloalkyl", "C 3-5 Preferably, specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0147] Unless otherwise specified, the term "heterocycloalkyl" refers to a saturated cyclic group derived from a cycloalkyl group in which one or more ring carbon atoms are replaced by heteroatoms and / or heteroatoms. The heteroatoms and / or heteroatoms are generally selected from N, O, S, NO, SO, S(O) 2 , P(O), and NR, wherein the carbon atoms in the heterocyclic ring are optionally oxo-substituted, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocycloalkyl group includes "3-12 membered heterocycloalkyl", "3-8 membered heterocycloalkyl", "3-6 membered heterocycloalkyl", "3-5 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl".

[0148] Unless otherwise specified, "cycloalkenyl" means that one or more ring bonds in "cycloalkyl" are double bonds and the cycloalkenyl is not aromatic. The carbon atoms in the cycloalkenyl can be further oxidized, i.e., C(O). The cycloalkenyl can be fused to aryl, heteroaryl, or heterocycloalkenyl, wherein the ring connected to the parent structure is a cycloalkenyl. The cycloalkenyl includes "3-12 membered cycloalkenyl", "3-8 membered cycloalkenyl", "3-6 membered cycloalkenyl", "3-5 membered cycloalkenyl", and "5-6 membered cycloalkenyl". The definition of "cycloalkyl" is the same as described above. Unless otherwise specified, the term "heterocycloalkenyl" means that one or more ring bonds in "heterocycloalkyl" are double bonds and are not aromatic. The "heterocycloalkyl" is the same as described above. Preferably, the heteroatoms are independently selected from 1-3 N and / or O. The heterocycloalkenyl can be fused to aryl or heteroaryl, wherein the ring connected to the parent structure is a heterocycloalkenyl, etc. The heterocycloalkenyl group includes "3-12 membered heterocycloalkenyl group", "3-8 membered heterocycloalkenyl group", "3-6 membered heterocycloalkenyl group", "3-5 membered heterocycloalkenyl group", "5-6 membered heterocycloalkenyl group". Examples of the heterocycloalkenyl group include but are not limited to

[0149] Unless otherwise specified, the term "aryl" refers to an unsaturated, usually aromatic hydrocarbon group, which may be a single ring or multiple rings fused together. A fused ring aryl group refers to a group formed by two or more cyclic structures sharing two adjacent atoms, and the ring directly connected to the parent structure is aromatic (the ring not directly connected to the parent structure is an aromatic ring or a non-aromatic ring). The aryl group may be fused to a heterocycloalkenyl or cycloalkenyl group, wherein the ring connected to the parent structure is an aryl group, etc. Preferably C 6-14 Aryl, preferably C 6-10 Aryl; examples of aryl include, but are not limited to, phenyl, naphthyl.

[0150] The "heteroaryl" described in the present invention refers to a monocyclic or polycyclic group with aromatic properties containing one or more heteroatoms in the ring, and the heteroatoms are generally selected from N, O, and S; preferably, the heteroatoms are independently selected from 1-3 N and / or O, and in addition, the N atom and the S atom may be optionally oxidized and the N atom may be optionally quaternized. The "heteroaryl" includes "monocyclic heteroaryl" and "condensed ring heteroaryl", and the condensed ring heteroaryl refers to a group containing one or more heteroatoms formed by two or more cyclic structures sharing two adjacent atoms, and the ring directly connected to the parent structure has aromatic properties (the ring not directly connected to the parent structure is an aromatic ring or a non-aromatic ring). The heteroaryl group described in the present invention is preferably a "nitrogen-containing heteroaryl group", preferably a "5-6-membered nitrogen-containing aryl group", and the heteroatom in the "nitrogen-containing heteroaryl group" contains at least one nitrogen atom, for example, only 1, 2 or 3 nitrogen atoms, or, one nitrogen atom and 1 or 2 other heteroatoms (such as S and / or O atoms), or, 2 nitrogen atoms and 1 or 2 other heteroatoms. The heteroaryl group may be fused to a heterocycloalkenyl group or a cycloalkenyl group, wherein the ring connected to the parent structure is a heteroaryl group. Specific examples of the heteroaryl group include, but are not limited to, furanyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, wait.

[0151] In various parts of this disclosure, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be a 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 the "alkyl" or "aryl" represents an alkylene group or an arylene group, respectively, that is linked.

[0152] Combinations of substituents and / or variables described herein are permissible only if these combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is one that is sufficiently stable to withstand chemical reactions, to be isolated to a useful degree of purity, and to be formulated into an effective therapeutic agent.

[0153] In the examples of the present invention, the naming of the title compound is converted from the compound structure with the help of Chemdraw. If there is a discrepancy between the compound name and the compound structure, it can be determined by comprehensive relevant information and reaction routes; if it cannot be confirmed by other means, the given compound structure shall prevail.

[0154] The preparation methods of some compounds in the present invention refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should be aware that when using or referring to the preparation methods cited, the feed ratio of reactants, reaction solvent, reaction temperature, etc. can be appropriately adjusted according to the different reactants.

[0155] 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. DETAILED DESCRIPTION

[0156] The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) mass spectroscopy. NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using a Bruker Ascend 400 NMR instrument, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), heavy water (D 2 (O) The internal standard was tetramethylsilane (TMS).

[0157] The thin layer chromatography silica gel plate used was HSGF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd. The specification used by TLC was 0.20 mm ± 0.03 mm, preparative type 20 x 20 cm, and column chromatography used 200-300 mesh silica gel from Qingdao Hailang Silica Gel Desiccant Co., Ltd. as the carrier.

[0158] The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.

[0159] Unless otherwise specified, all reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

[0160] General Preparation 1)

[0162] 2)

[0164] 3)

[0166]

[0167] The following examples were synthesized according to the general preparation method.

[0168]

[0169]

[0170] Example 1

[0171] (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-(4-methoxyphenyl)-1H-benzo[d]imidazole-4-carboxamide

[0172]

[0173] Reaction route:

[0174]

[0175] Steps:

[0176] Step A: Dissolve silica gel (1.8 g) and ammonium chloride (388.93 mg, 7.27 mmol) in ethanol (8 mL) and water (8 mL), add iron powder (898 mg, 11.82 mmol), and add a solution of methyl 3-amino-4-bromo-2-nitrobenzoate (500 mg, 1.82 mmol) in tetrahydrofuran (8 mL) after the internal temperature rises to 60°C. The reaction is carried out at an internal temperature of 70°C for 2 hours.

[0177] After TLC monitoring showed that the raw material disappeared, the iron powder was filtered, water (30 mL) was added to the filtrate and stirred for 10 minutes, ethyl acetate (40 mL) was added and extracted twice, the organic phases were combined, the organic phase was first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain crude methyl 2,3-diamino-4-bromobenzoate (550 mg), which was directly used in the next step.

[0178] Step B: Dissolve methyl 2,3-diamino-4-bromobenzoate (550 mg, 2.24 mmol) and p-toluenesulfonic acid (42.64 mg, 0.22 mmol) in trimethyl orthoformate (5.95 g, 56.1 mmol) and react at 80° C. for 1 hour.

[0179] After LCMS monitoring showed that the starting material disappeared, aqueous sodium bicarbonate solution (20 mL) was added and stirred for 10 minutes. Ethyl acetate (40 mL) was added and extracted twice. The organic phases were combined, washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate. Finally, the residue was concentrated under reduced pressure and purified by silica gel column chromatography to give methyl 7-bromo-1H-benzo[d]imidazole-4-carboxylate (430 mg).

[0180] MS (ESI) M / Z: 255.2 [M+H] + .

[0181] Step C: Dissolve methyl 7-bromo-1H-benzo[d]imidazole-4-carboxylate (430 mg, 1.69 mmol) and p-methoxyphenylboronic acid (384.26 mg, 2.53 mmol) in dioxane (10 mL) and water (2 mL), add sodium carbonate (446.74 mg, 4.22 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (68.7 mg, 0.084 mmol), replace with vacuum nitrogen 2-3 times, and react at 95 °C overnight.

[0182] After TLC monitoring showed that the starting material disappeared, water (30 mL) was added and extracted with ethyl acetate (20 mL×2). The organic phase was first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-(4-methoxyphenyl)-1H-benzo[d]imidazole-4-carboxylate (260 mg).

[0183] MS (ESI) M / Z: 283.3 [M+H] + .

[0184] Step D: Dissolve methyl 7-(4-methoxyphenyl)-1H-benzo[d]imidazole-4-carboxylate (260 mg, 0.92 mmol) in methanol (6 mL) and water (6 mL), add sodium hydroxide (110.52 mg, 2.76 mmol), and react at 60°C for 3 hours.

[0185] After TLC monitoring showed that the starting material disappeared, the methanol was concentrated to dryness, and the pH was adjusted to acidic with dilute hydrochloric acid to precipitate solids, which were filtered and dried to obtain 7-(4-methoxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid (230 mg).

[0186] Step E: Dissolve 7-(4-methoxyphenyl)-1H-benzo[d]imidazole-4-carboxylic acid (100 mg, 0.37 mmol) and (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide hydrobromide (79.38 mg, 0.37 mmol) in DMF (5 mL), add N,N-diisopropylethylamine (144.26 mg, 1.12 mmol). Add HATU (184.26 mg, 0.49 mmol) under ice bath. React at room temperature overnight.

[0187] After TLC monitoring showed that the starting material disappeared, water (30 mL) was added, and ethyl acetate (20 mL*2) was used for extraction. The organic phase was first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-(4-methoxyphenyl)-1H-benzo[d]imidazole-4-carboxamide (80.19 mg)

[0188] MS (ESI) M / Z: 384.0 [M+H] + .

[0189] 1 H NMR (400 MHz, DMSO-d 6 )δ13.23–12.42(m,1H),10.48–9.12(m,1H),8.68–8.07(m,2H),8.01–7.80(m,1H),7.77–7.58(m,1 H),7.57–7.24(m,2H),7.19–6.85(m,3H),5.65–5.34(m,1H),3.94–3.71(m,4H),3.31–3.21(m,1H).

[0190] Example 2

[0191] (R)-6-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-(4-methoxyphenyl)-1,6-naphthyridin-5(6H)-one

[0192]

[0193] Reaction route:

[0194]

[0195] Steps:

[0196] Step A: Dissolve methyl 2,6-dichloronicotinate (1 g, 4.8 mmol) and p-methoxyphenylboronic acid (737.5 mg, 4.8 mmol) in 1,4-dioxane (20 mL), add sodium carbonate (1.28 g, 12.1 mmol), water (2.5 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (197.8 mg, 0.24 mmol), replace nitrogen, and react at 95 °C overnight.

[0197] After LCMS monitoring showed that the starting material disappeared, water (20 mL) was added, and ethyl acetate (40 mL) was added for extraction twice. The organic phases were combined, washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate. Finally, the residue was concentrated under reduced pressure and purified by silica gel column chromatography to give methyl 2-chloro-6-(4-methoxyphenyl)nicotinate (870 mg).

[0198] MS (ESI) M / Z: 278.2 [M+H] + .

[0199] Step B: Dissolve 2-chloro-6-(4-methoxyphenyl)nicotinate (870 mg, 3.14 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (746.5 mg, 3.76 mmol) in 1,4-dioxane (15 mL), add sodium carbonate (1.33 g, 12.5 mmol), water (3 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (128 mg, 0.15 mmol), replace nitrogen, and react at 100°C overnight.

[0200] LCMS monitoring showed that the starting material disappeared. The mixture was cooled, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed with saturated brine (20 mL), and then dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to give (E)-2-(2-ethoxyvinyl)-6-(4-methoxyphenyl)nicotinate (420 mg).

[0201] MS (ESI) M / Z: 313.9 [M+H] + .

[0202] Step C: Dissolve (E)-2-(2-ethoxyvinyl)-6-(4-methoxyphenyl)nicotinate (420 mg, 1.34 mmol) in methanol (6 mL), add sodium hydroxide (95 mg, 1.0 mmol) and water (6 mL), and react at 60° C. for 3 hours.

[0203] After TLC monitoring showed that the starting material disappeared, the reaction solution was concentrated under reduced pressure to remove methanol. 1M hydrochloric acid was added to the reaction solution to adjust the pH to acidic, and solids precipitated, which were filtered and dried to obtain (E)-2-(2-ethoxyvinyl)-6-(4-methoxyphenyl)nicotinic acid (356 mg).

[0204] MS (ESI) M / Z: 300.3 [M+H] + .

[0205] Step D: (E)-2-(2-ethoxyvinyl)-6-(4-methoxyphenyl)nicotinic acid (200 mg, 0.67 mmol) and (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide hydrobromide (142.4 mg, 0.67 mmol) were dissolved in N,N-dimethylformamide (4 mL), and N,N-diisopropylethylamine (259.3 mg, 2.0 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (305.2 mg, 0.8 mmol) were added under ice-water bath and reacted at room temperature for 1 hour.

[0206] After TLC showed the disappearance of the starting material, water (10 mL) was added, extracted with ethyl acetate (20 mL×2), the organic phase was dried, concentrated to dryness to obtain a crude product, and finally concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain (E)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-(2-ethoxyvinyl)-6-(4-methoxyphenyl)nicotinamide (200 mg).

[0207] MS (ESI) M / Z: 415.3 [M+H] + .

[0208] Step E: (E)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-(2-ethoxyvinyl)-6-(4-methoxyphenyl)nicotinamide was dissolved in acetic acid (6 mL) and reacted at 90° C. overnight.

[0209] After LCMS monitoring showed that the raw material disappeared, the pH value was adjusted to neutral with saturated sodium bicarbonate aqueous solution, ethyl acetate was added with methanol (20 mL × 2) for extraction, the organic phase was dried, and concentrated to dryness under reduced pressure. The crude product was slurried and filtered with petroleum ether: ethyl acetate (2: 1, 10 mL) to obtain (R)-6-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-(4-methoxyphenyl)-1,6-naphthyridin-5(6H)-one (39.92 mg).

[0210] MS (ESI) M / Z: 369.2 [M+H] + .

[0211] 1 H NMR (400 MHz, DMSO-d 6)δ8.54(d,J=8.5Hz,1H),8.22(d,J=8.5Hz,2H),8.09(d,J=8.5Hz,1H),7.58–7.38(m,2H),7.20 –7.00(m,3H),6.83(d,J=7.8Hz,1H),6.27–6.06(m,1H),3.98–3.74(m,4H),3.63–3.46(m,1H).

[0212] Example 3

[0213] (R)-6-(Cyclopropylethynyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide

[0214]

[0215] Reaction route:

[0216]

[0217] Steps:

[0218] Step A: Dissolve methyl 6-bromo-2-methoxynicotinate (1.0 g, 4.06 mmol) and cyclopropylacetylene (537.2 mg, 8.31 mmol) in tetrahydrofuran (10 mL) and triethylamine (10 mL), add cuprous iodide (77.4 mg, 0.4 mmol) and bistriphenylphosphine palladium dichloride (213.9 mg, 0.3 mmol), and stir at 85 °C overnight.

[0219] After LCMS monitoring showed that the raw material disappeared, the mixture was filtered with celite pad, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate (20 mL) twice, and the organic phases were combined, washed with saturated brine (10 mL), and then dried over anhydrous sodium sulfate. Finally, the residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain methyl 6-(cyclopropylethynyl)-2-methoxynicotinate (930 mg).

[0220] MS (ESI) M / Z: 232.0 [M+H] + .

[0221] Step B: Dissolve methyl 6-(cyclopropylethynyl)-2-methoxynicotinate (930 mg, 4.02 mmol) in methanol (10 mL) and water (10 mL), add sodium hydroxide (483.1 mg, 12.07 mmol) and react at 60 °C for 3 hours.

[0222] After TLC monitoring showed that the starting material disappeared, the methanol was concentrated to dryness, and 1 mol / L dilute hydrochloric acid was added to make the pH acidic. Solid precipitated and was filtered to obtain 6-(cyclopropylethynyl)-2-methoxynicotinic acid (706 mg).

[0223] MS (ESI) M / Z: 218.4 [M+H] + .

[0224] Step C: Dissolve 6-(cyclopropylethynyl)-2-methoxynicotinic acid (200 mg, 0.6 mmol) in acetonitrile (4 mL), add trimethylsilyl iodide (843.6 mg, 4.2 mmol), and react at 50 degrees Celsius for 5 minutes.

[0225] After TLC monitoring showed that the starting material disappeared, ethyl acetate (20 mL) and water (10 mL) were added for extraction. The organic phase was first washed with saturated brine (10 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain a crude product of 6-(cyclopropylethynyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid, which was directly used for the next step.

[0226] MS (ESI) M / Z: 226.2 [M+Na] + .

[0227] Step D: Dissolve the crude product of 6-(cyclopropylethynyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.6 mmol) and (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide hydrobromide (196.2 mg, 0.92 mmol) in DMF (4 mL), add N,N-diisopropylethylamine (359.4 mg, 1.06 mmol), add HATU (420.5 mg, 1.1 mmol) under ice bath, and react at room temperature for 1 hour.

[0228] After TLC monitoring showed that the starting material disappeared, water (30 mL) was added, and ethyl acetate (20 mL×2) was used for extraction. The organic phase was first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain (R)-6-(cyclopropylethynyl)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (16.06 mg).

[0229] MS (ESI) M / Z: 319.1 [M+H] + .

[0230] 1 H NMR (400 MHz, DMSO-d 6)δ12.88(s,1H),10.08(d,J=7.9Hz,1H),8.22(d,J=7.4Hz,1H),7.25(dd,J=6.7,2.0Hz,1H),6.96(dd,J=6.7,3.0Hz,1H),6.56(d,J=7.4Hz,1 H),5.40–5.23(m,1H),3.71(dd,J=13.7,7.9Hz,1H),3.24(dd,J=13.7,4.1Hz,1H),1.69–1.57(m,1H),1.03–0.95(m,2H),0.89–0.84(m,2H).

[0231] Example 4

[0232] (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-(4-methoxyphenyl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide

[0233]

[0234] Reaction route:

[0235]

[0236] Steps:

[0237] Step A: Dissolve methyl 2,3-diamino-4-bromobenzoate (805 mg, 3.29 mmol) and p-toluenesulfonic acid (56.5 mg, 0.33 mmol) in trimethyl orthoacetate (9.87 g, 82.12 mmol) and react at 80° C. for 1 hour.

[0238] After LCMS monitoring showed that the starting material disappeared, aqueous sodium bicarbonate solution (20 mL) was added and stirred for 10 minutes. Ethyl acetate (40 mL) was added and extracted twice. The organic phases were combined, washed with saturated brine (50 mL), and then dried over anhydrous sodium sulfate. Finally, the residue was concentrated under reduced pressure and purified by silica gel column chromatography to give 7-bromo-2-methyl-1H-benzimidazole-4-carboxylic acid methyl ester (390 mg).

[0239] MS (ESI) M / Z: 269.2 [M+H] + .

[0240] Step B: Dissolve methyl 7-bromo-2-methyl-1H-benzimidazole-4-carboxylate (390 mg, 1.45 mmol) and p-methoxyphenylboronic acid (330.47 mg, 2.18 mmol) in dioxane (10 mL) and water (2 mL), add sodium carbonate (384.2 mg, 3.62 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (59.08 mg, 0.073 mmol), replace with vacuum nitrogen 2-3 times, and react at 95 ° C overnight.

[0241] After TLC monitoring showed that the starting material disappeared, water (30 mL) was added and extracted with ethyl acetate (20 mL×2). The organic phase was first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-(4-methoxyphenyl)-2-methyl-1H-benzimidazole-4-carboxylate (360 mg).

[0242] MS (ESI) M / Z: 297.2 [M+H] + .

[0243] Step C: Dissolve methyl 7-(4-methoxyphenyl)-2-methyl-1H-benzimidazole-4-carboxylate (360 mg, 1.22 mmol) in methanol (6 mL) and water (6 mL), add sodium hydroxide (145.95 mg, 3.65 mmol), and react at 60° C. for 3 hours.

[0244] After TLC monitoring showed that the starting material disappeared, the methanol was concentrated to dryness, and the pH was adjusted to acidic with dilute hydrochloric acid to precipitate solids, which were filtered and air-dried to obtain 7-(4-methoxyphenyl)-2-methyl-1H-benzimidazole-4-carboxylic acid (320 mg).

[0245] Step D: Dissolve 7-(4-methoxyphenyl)-2-methyl-1H-benzimidazole-4-carboxylic acid (100 mg, 0.354 mmol) and (R)-3-amino-2,3-dihydrothiophene 1,1-dioxide hydrobromide (75.43 mg, 0.354 mmol) in DMF (5 mL), add N,N-diisopropylethylamine (137.1 mg, 1.06 mmol). Add HATU (175.1 mg, 0.46 mmol) under ice bath. React at room temperature overnight.

[0246] After TLC monitoring showed that the starting material disappeared, water (30 mL) was added and extracted with ethyl acetate (20 mL×2). The organic phase was first washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure to obtain (R)-N-(1,1-dioxido-2,3-dihydrothiophen-3-yl)-7-(4-methoxyphenyl)-2-methyl-1H-benzo[d]imidazole-4-carboxamide (64.32 mg).

[0247] MS (ESI) M / Z: 398.1 [M+H] + .

[0248] 1 H NMR (400 MHz, DMSO-d 6 )δ12.80–12.20(m,1H),10.49–9.06(m,1H),8.29–8.03(m,1H),7.97–7.55(m,2H),7.51–7.23(m ,2H),7.17–6.82(m,3H),5.58–5.38(m,1H),3.96–3.73(m,4H),3.32–3.23(m,1H),2.57(s,3H).

[0249] Biological test cases

[0250] 1. In vitro WRN enzyme activity assay

[0251] This experiment was used to establish an ATPase assay to measure the DNA-dependent ATP hydrolysis activity of WRN helicase. The assay was also used to evaluate the inhibitory properties of the compounds of the invention on DNA-dependent WRN enzyme activity.

[0252] 1. Experimental Materials

[0253] Reagents factory Part Number WRN protein (AA N517-P1238) ICE ssDNAsubstrate Bioengineering ATP,100mM Solution Bioengineering R0441 ADP-Glo ​​assay kit Promega V9102 Pluronic F-127* Bioengineering A600750

[0254] 2. Experimental methods

[0255] 1) Use DMSO to perform a gradient dilution of the compound in the 384PP Plate compound dilution plate (ensure that the starting concentration in the final reaction system is 10 μM, 9 concentrations, and a 1:3 dilution ratio).

[0256] 2) Use Echo to transfer 0.1 μL of compound to a 384-well reaction microplate (Greiner 784075), ensuring that the final DMSO content is 1% (duplicate).

[0257] 3) Add 2.5 μL of WRN enzyme solution to each well of a 384-well reaction microplate to ensure that the WRN enzyme concentration in the final reaction system is 10 nM. Incubate at 25°C for 3 hours. The reaction buffer is 300 mM ATP, 30 mM Tris pH 7.5, 2 mM MgCl2, 0.02% BSA, 50 mM NaCl, and 0.1% pluronic F-127*.

[0258] 4) Add 2.5 μL of single-stranded DNA substrate to each well, dilute with the same buffer as above, and incubate at 25°C for 30 minutes.

[0259] 5) Add 5 μL ADP-Glo ​​reagent to the reaction system and incubate at room temperature for 1 hour to remove excess ATP.

[0260] 6) Add 10 μL ATP detection reagent to the reaction system and incubate at room temperature for 1 hour.

[0261] 7) The chemiluminescent signal was detected using Envision microplate reader (PerkinElmer), and the WRN enzyme activity inhibition rate of each well was calculated.

[0262] 8) GraphPad Prism 8 software was used for data analysis and calculation of IC50 of the compounds of the present invention.

[0263] 3. Experimental results

[0264] The example compounds of the present invention have good inhibitory activity against DNA-dependent WRN enzyme.

[0265] 2. Cell Proliferation Inhibition Experiment

[0266] In this experiment, chemiluminescence was used to determine the intracellular ATP content (CellTiter-Glo) to detect the inhibitory effect of the compound on the relevant MSI / MSS cell lines, and the IC50 of the compound on the inhibition of proliferation of the above cell lines was obtained.

[0267] 1. Experimental Materials

[0268] 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 (MSI), and SW620 (MSS) cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd.; Cell Titer-Glo luminescent cell viability detection reagent was purchased from Promega.

[0269] 2. Experimental methods

[0270] 1) Day 0: The cells were seeded into a 96-well culture plate, with 100 μl per well, and incubated in an incubator (37° C., 5% CO 2 ) overnight.

[0271] 2) Day 1: Use D300e (TECAN) to add 200 nL of cell culture medium containing gradient dilutions of the test compound (starting concentration is 10 μM, 9 concentrations, 1:3 dilution ratio) to the cells in the culture plate, and the final DMSO concentration is 0.2%. The culture plate is placed in a cell culture incubator and incubated for 120 hours (37°C, 5% CO 2 ), and set up blank control by adding 200 nL DMSO to each well.

[0272] 3) Day 5: Add 50 μL 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 luminescent signal, and then use Envision microplate reader (PerkinElmer) to detect the luminescent signal, and use GraphPad Prism 8 software for data analysis and calculation of the IC50 of the compound.

[0273] 3. Experimental results

[0274]

[0275]

[0276] The structure of control example 1 is as follows:

[0277] (WO2023062575 patent example 61) The structure of control example 2 is as follows:

[0278] (WO2023062575 patent example 117) The example compounds of the present invention have good inhibitory activity on cells.

Claims

1. A compound represented by formula (IA), a stereoisomer or a pharmaceutically acceptable salt thereof: in, Ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl; Ring B is selected from C 6-14 Aryl or 5-14 membered heteroaryl; or Ring B is absent; Ring C is selected from 3-8 membered heterocycloalkenyl or 5-14 membered heteroaryl; L1 is selected from a bond, -CONH-, -SO2NH-, -CONH-C 1-6 Alkylene-, the -CONH-, -SO2NH-, -CONH-C 1-6 Alkylene - optionally substituted with one or more R2; R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -NHCO-CH2=CH2, -SO2-CH2=CH2, the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, -NHCO-CH2=CH2, -SO2-CH2=CH2, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R3 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; Alternatively, one of R3 and R2 is linked to form a 5-7 membered heterocycloalkenyl group, wherein the 5-7 membered heterocycloalkenyl group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, -OR 4-1 , the amino group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, C 3-8 Cycloalkyl, 3-12 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl; R 4-1 independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl, 5-10 membered heteroaryl; the C 6-10 Aryl, 5-10 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 It is substituted by one or more substituents of cycloalkyl or 3-8 membered heterocycloalkyl; x is selected from 0, 1, 2 or 3; y is selected from 0, 1, 2 or 3; z is selected from 0, 1, 2 or 3.

2. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound is as shown in formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (IX-1), formula (IX-2), formula (IX-3) or formula (IX-4), Wherein, M1 is N or CH; M2 is N or CH.

3. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound is as shown in formula (XI), R3' is selected from hydrogen, deuterium, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy, 3-8 membered heterocycloalkyl, the amino, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 haloalkoxy, 3-8 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl; Preferably, R3' is selected from C 2-6 Alkynyl, the C 2-6 The alkynyl group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-10 membered heteroaryl; More preferably, R3' is selected from y is selected from 0, 1 or 2.

4. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: R1 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NHCO-CH2=CH2, -SO2-CH2=CH2, the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, -NHCO-CH2=CH2, -SO2-CH2=CH2, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl; Preferably, R1 is independently selected from hydrogen or -SO2-CH2=CH2.

5. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: R2 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl; Alternatively, one of R3 and R2 is linked to form a 5-7 membered heterocycloalkenyl group, wherein the 5-7 membered heterocycloalkenyl group is optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl; Preferably, R2 is selected from hydrogen or hydroxy.

6. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that: R3 is selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl; R3 is selected from hydrogen, hydroxyl, 7. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, characterized in that: R4 is independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 8-10 membered heterocycloalkyl, -OR 4-1 , the amino group, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents of aryl or 5-6 membered heteroaryl; R 4-1 are independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, the amino, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, 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, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, optionally further substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 is substituted by one or more substituents in aryl, 5-6 membered heteroaryl; the C 6-10 Aryl, 5-6 membered heteroaryl, optionally substituted with deuterium, halogen, amino, hydroxyl, cyano, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 It is substituted by one or more substituents of cycloalkyl or 3-6-membered heterocycloalkyl; Preferably, R4 is independently selected from hydrogen, methyl, trifluoromethyl, chlorine, ethoxy, methoxy, ethynyl, 8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, characterized in that: The compound is shown below:

9. A pharmaceutical composition comprising the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

10. Use of the compound, stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating cancer; 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.

Images