Five-membered heteroaryl derivative and application thereof in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal of the compound, an intermediate of the compound, and application of the compound in inhibiting or degrading KRAS related diseases such as cancers. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, as well as intermediates and preparation methods thereof, and use thereof in KRAS-related diseases such as tumors or autoimmune system diseases. Background Art

[0002] RAS protein is expressed by the RAS gene (Rat Sarcoma viral oncogene). It is an intracellular guanine nucleotide binding protein and belongs to GTPase (weak hydrolysis activity). RAS protein exists in two different states: inactive GDP-bound state and active GTP-bound state. Activated RAS protein conducts signal transduction by interacting with different downstream effectors, which has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion. The activation of RAS signal transduction is regulated by guanine nucleotide exchange factor (GEF, which can cause GDP-GTP exchange) or GTPase activating protein (GAP, which can cause RAS protein to change from activated state to inactivated state). Mutant RAS protein can cause resistance to GAP, resulting in RAS protein being in a continuously activated state, causing uncontrolled cell growth and eventually developing into cancerous tissue (Molecular Cancer, 2018, 17: 33).

[0003] RAS gene mutation is a common type of gene mutation in cancer patients (Nat. Rev. Drug Discov. 2014, 13, 828-851). For example, RAS gene mutation accounts for 97.7%, 52.2%, 42.6% and 32.2% in pancreatic cancer, colorectal cancer, multiple myeloma and NSLCL, respectively. KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most influential mutation in RAS mutation, accounting for 86% of all RAS mutations. The most common way for KRAS gene to be activated is point mutation. 95% of KRAS mutations mainly occur in codons 12 and 13 of exon 2. Common mutation forms include KRAS G12C mutation (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%) mutations.

[0004] Since the discovery of KRAS mutant proteins in cancer and the observation that inhibition of these mutant proteins can inhibit tumor proliferation, KRAS mutant protein inhibitors have received widespread attention. KRAS has long been considered an "undruggable target": RAS has a high affinity for GTP / GDP (picomolar level), and the entire protein lacks other "ligand binding pockets" (Clin. Cancer Res. 2015, 21, 1810–1818). KRAS G12D accounts for 36% of pancreatic cancer patients, 12% of colon cancer patients, 4% of NSCLC adenocarcinoma patients, and 6% of endometrial cancer patients. According to organ and tissue classification, KRAS cancer is most concentrated in three types: colon cancer, pancreatic cancer, and lung adenocarcinoma. According to mutation classification, G12D accounts for the highest proportion, followed by G12V, G12C, which has been initially conquered, ranks third, G13D ranks fourth, and amplification (AMP) ranks fifth. G12D and G12V account for a high proportion in colon cancer and pancreatic cancer, and G12C accounts for a high proportion in lung adenocarcinoma.

[0005] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years.

[0006] Therefore, it is necessary to develop a compound that can inhibit or degrade KRAS protein for the treatment of diseases caused by KRAS mutations. Summary of the invention

[0007] The object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade KRAS, for use in treating KRAS-related diseases such as cancer.

[0008] The present invention provides a compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I),

[0009]

[0010] In some embodiments, the compound represented by general formula (I) is selected from (Ia), (Ic), (Id)

[0011]

[0012] In some embodiments, Selected from

[0013] In some embodiments, U, V, and W are each independently selected from N or CR b7 In some embodiments, any two of U, V, and W are selected from N, and the other is selected from CR b7 ; In some embodiments, Z is selected from O, S or Se;

[0014] In some embodiments, Ring B4 is selected from 5-membered heteroaryl, wherein Ring B4 is optionally substituted by 1 to 4 R b4 In some embodiments, ring B4 is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, and the ring B4 is optionally substituted with 1 R b4 replace;

[0015] In some embodiments, R b1 is selected from CN or ethynyl;

[0016] In some embodiments, R b2 , R b4 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0017] In some embodiments, R b2 , R b4 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, -C 1-2 Alkylene-phenyl, -C 1-2 Alkylene-5 to 6 membered heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 R z Substitution; in some embodiments, R b2 , R b4 Each independently selected from deuterium, F, Cl, Br, I, CN, OH or optionally substituted by 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl; in some embodiments, R b7 is selected from H, deuterium, F, Cl, Br, I, CN, OH, CONH2, NH2, NHCH3, N(CH3)2 or optionally 1 to 4 R z substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxhexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-phenyl, -CH2-pyridyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxhexyl;

[0018] In some embodiments, R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z Replace; alternatively, R b3 With any R b4 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z Substitution; in some embodiments, R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl, alkylene, alkenyl, alkynyl is optionally substituted by 1 to 4 R z Substitution; in some embodiments, R b3 is selected from H, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R z Substitution; in some embodiments, R b3 is selected from H, methyl, ethyl, propyl or isopropyl; in some embodiments, R b3 With any R b4 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0019] In some embodiments, R b3 With R b4 Direct connection to form C 5-6 The carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0020] In some embodiments, R b5 is selected from H, deuterium, halogen, CN, -LK or one of the following groups which are optionally substituted: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-12 Carbocyclic group, 4- to 12-membered heterocyclic group, -OC 3-12 carbocyclyl, -O-4 to 12 membered heterocyclyl, -NH-C 3-12 Carbocyclic group, -NH-4 to 12-membered heterocyclic group, -OC 1-4 Alkylene-C 3-12 Carbocyclic group, -OC 1-4Alkylene-4 to 12-membered heterocyclic group, -NHC 1-4 Alkylene-C 3-12 Carbocyclic group, -NHC 1-4 Alkylene-4 to 12 membered heterocyclyl, when substituted, is optionally substituted by 1 to 4 members selected from or R b5e substituted by a substituent;

[0021] In some embodiments, R b5 is selected from H, deuterium, halogen, OH, CN, -LK or one of the following groups which are optionally substituted: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-7 Monocyclic cycloalkyl, C 4-7 Monocyclic cycloalkenyl, C 4-12 Cycloalkyl, C 5-12 Spirocyclic cycloalkyl, C 5-12 Bridged ring cycloalkyl, C 6-10 Aryl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered spirocyclic heterocycloalkyl, 6-12 membered bridged heterocycloalkyl, 5-10 membered heteroaryl, -OC 3-7 Monocyclic cycloalkyl, -OC 4-7 Monocyclic cycloalkenyl, -OC 4-12 Cycloalkyl, -OC 5-12 Spirocyclic cycloalkyl, -OC 5-12 Bridged ring cycloalkyl, -OC 6-10 aryl, -O-4-7 membered monocyclic heterocycloalkyl, -O-4-7 membered monocyclic heterocycloalkenyl, -O-6-12 membered cyclic heterocycloalkyl, -O-6-12 membered spirocyclic heterocycloalkyl, -O-6-12 membered bridged heterocycloalkyl, -O-5-10 membered heteroaryl, -NH-C 3-7 Monocyclic cycloalkyl, -NH-C 4-7 Monocyclic cycloalkenyl, -NH-C 4-12 Cycloalkyl, -NH-C 5-12 Spirocyclic cycloalkyl, -NH-C 5-12 Bridged ring cycloalkyl, -NH-C 6-10 aryl, -NH-4-7 membered monocyclic heterocycloalkyl, -NH-4-7 membered monocyclic heterocycloalkenyl, -NH-6-12 membered cyclic heterocycloalkyl, -NH-6-12 membered spirocyclic heterocycloalkyl, -NH-6-12 membered bridged heterocycloalkyl, -NH-5-10 membered heteroaryl, -OC 1-4 Alkylene-C 3-7 Monocyclic cycloalkyl, -OC 1-4 Alkylene-C4-7 Monocyclic cycloalkenyl, -OC 1-4 Alkylene-C 4-12 Cycloalkyl, -OC 1-4 Alkylene-C 5-12 Spirocyclic cycloalkyl, -OC 1-4 Alkylene-C 5-12 Bridged ring cycloalkyl, -OC 1-4 Alkylene-C 6-10 Aryl, -OC 1-4 Alkylene-4-7 membered monocyclic heterocycloalkyl, -OC 1-4 Alkylene-4-7 membered monocyclic heterocycloalkenyl, -OC 1-4 Alkylene-6-12 membered heterocyclic alkyl, -OC 1-4 Alkylene-6-12 membered spirocyclic heterocycloalkyl, -OC 1-4 Alkylene-6-12 membered bridged heterocyclic alkyl, -OC 1-4 Alkylene-5-10 membered heteroaryl, -NHC 1-4 Alkylene-C 3-7 Monocyclic cycloalkyl, -NHC 1-4 Alkylene-C 4-7 Monocyclic cycloalkenyl, -NHC 1-4 Alkylene-C 4-12 Cycloalkyl, -NHC 1-4 Alkylene-C 5-12 Spirocyclic cycloalkyl, -NHC 1-4 Alkylene-C 5-12 Bridged ring cycloalkyl, -NHC 1-4 Alkylene-C 6-10 Aryl, -NHC 1-4 Alkylene-4-7 membered monocyclic heterocycloalkyl, -NHC 1-4 Alkylene-4-7 membered monocyclic heterocycloalkenyl, -NHC 1-4 Alkylene-6-12 membered heterocyclic alkyl, -NHC 1-4 Alkylene-6-12 membered spirocyclic heterocycloalkyl, -NHC 1-4 Alkylene-6-12 membered bridged heterocycloalkyl, -NHC 1-4 Alkylene-5-10 membered heteroaryl, when substituted, is optionally substituted by 1 to 4 members selected from R b5e substituted by a substituent;

[0022] In some embodiments, R b5 is selected from H, deuterium, halogen, OH, CN, -LK or one of the following groups which are optionally substituted: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4alkynyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered paracyclic heterocycloalkyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, 8-10 membered paracyclic heterocyclyl, -O-4-7 membered monocyclic heterocycloalkyl, -O-5-6 membered heteroaryl, -O-phenyl, -NH-4-7 membered monocyclic heterocycloalkyl, -NH-5-6 membered heteroaryl, -NH-phenyl, -OCH2-4-7 membered monocyclic heterocycloalkyl, -OCH2-5-6 membered heteroaryl, -OCH2-phenyl, -NHCH2-4-7 membered monocyclic heterocycloalkyl, -NHCH2-5-6 membered heteroaryl, -NHCH2-phenyl, when substituted, is optionally substituted by 1 to 4 members selected from or R b5e substituted by a substituent;

[0023] In some embodiments, R b5 is selected from H, deuterium, F, Cl, Br, I, OH, CN or one of the following groups which are optionally substituted: methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, oxetanyl, tetrahydrofuranyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxhexyl, -CH2-azetidinyl, - CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-oxacyclohexyl, -O-azetidinyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl, -NH-oxacyclohexyl, -NH-azetidinyl, -NH-pyrrolidinyl, -NH-piperidinyl, -NH-piperazinyl , -NH-morpholinyl, -NH-pyridinyl, -NH-pyrimidinyl, -NH-pyrazinyl, -NH-pyridazinyl, -OCH2-oxetanyl, -OCH2-tetrahydrofuranyl, -OCH2-oxacyclohexyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl, -OCH2-morpholinyl, -NHCH2-oxetanyl, -NHCH2-tetrahydrofuranyl, -NHCH2-oxacyclohexyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl, -OCH2-morpholinyl, -NHCH2-oxetanyl, -NHCH2-tetrahydrofuranyl, -NHCH2-oxacyclohexyl, Cyclohexyl, -NHCH2-azetidinyl, -NHCH2-pyrrolidinyl, -NHCH2-piperidinyl, -NHCH2-piperazinyl, -NHCH2-morpholinyl, -O-phenyl, -O-pyridinyl, -O-pyrimidinyl, -NH-phenyl, -NH-pyridinyl, -NH-pyrimidinyl, -OCH2-phenyl, -OCH2-pyridinyl, -OCH2-pyrimidinyl, -NHCH2-phenyl, -NHCH2-pyridinyl, -NHCH2-pyrimidinyl,

[0024] Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 selected from or R b5e substituted by a substituent;

[0025] In some embodiments, Y1 is selected from C 1-4 Alkylene, C(=O), S(=O)2, -NR y1 -、-C(=O)NR y1 -、-S(=O)2NR y1 -、-NR y1 C(=O)-、-OC(=O)NR y1 -、-NR y1 C(=O)O-、-NR y1 S(=O)2-, -C(=O)O-, -OC(=O)-, the alkylene group is optionally substituted by 1 to 4 R z Substitution; in some embodiments, Y1 is selected from -CH2-, C(=O), S(=O)2, -C(=O)O-, -OC(=O)-, -NH-, -C(=O)NH-, -C(=O)N(CH3)-, -S(=O)2NH-, -NHC(=O)-, -N(CH3)C(=O)-, -NHS(=O)2-, -OC(=O)NH-, -NHC(=O)O-;

[0026] In some embodiments, R b5a , R b5b , R b5c , R b5d Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 alkyl)2, -COOH, -C(=O)OC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-OC 1-6 Alkyl, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C1-2 Alkylene-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-NHC 1-6 Alkyl, -C 1-2 Alkylene-N(C 1-6 alkyl) 2, wherein the alkyl, alkylene, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z Replace; alternatively, R b5a , R b5b Direct connection to form C 4-8 A carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0027] In some embodiments, R b5a , R b5b , R b5c , R b5d Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 alkyl)2, -COOH, -C(=O)OC 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-OC 1-4 Alkyl, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-NHC 1-4 Alkyl, -C 1-2 Alkylene-N(C 1-4 alkyl) 2, wherein the alkyl, alkylene, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z Replace; alternatively, R b5a , R b5b Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0028] In some embodiments, R b5a , R b5b , R b5c , R b5deach independently selected from H, deuterium, F, Cl, Br, I, CN, NH2, NHCH3, N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -COOH, -C(=O)OCH3, -C(=O)OCH2CH3 or optionally substituted by 1 to 4 R z substituted by one of the following groups: methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, -CH2OCH3, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2N(CH3)2; alternatively, R b5a , R b5b Directly connected to form cyclobutenyl, cyclopentenyl, cyclohexenyl, azacyclohexenyl, the cyclobutenyl, cyclopentenyl, cyclohexenyl, azacyclohexenyl optionally 1 to 4 R z replace;

[0029] In some embodiments, R y1 Selected from H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 The alkyl, alkylene or carbocyclic group is optionally substituted by 1 to 4 R z Substitution; in some embodiments, R y1 Selected from H, C 1-4 alkyl; in some embodiments, R y1 Selected from H or methyl;

[0030] In some embodiments, R b6 Selected from H, C 3-12 Carbocyclic group, 4- to 12-membered heterocyclic group, -OC 1-4 Alkylene-C 3-12 Carbocyclic group, -OC 1-4 Alkylene-4 to 12-membered heterocyclic group, -5 to 6-membered heteroaryl-C(=O)NH-C 3-12 carbocyclic group, -5 to 6 membered heteroaryl-NHC(=O)-4 to 12 membered heterocyclic group or -LK, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0031] In some embodiments, R b6 Selected from H, C 3-6 Carbocyclic group, 4- to 7-membered heterocyclic group, -OC 1-4 Alkylene-C3-6 Carbocyclic group, -OC 1-4 Alkylene-4 to 7 membered heterocyclic group, -5 to 6 membered heteroaryl-C(=O)NH-C 3-6 carbocyclic group, -5 to 6 membered heteroaryl-NHC(=O)-4 to 7 membered heterocyclic group or -LK, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0032] In some embodiments, R b6 Selected from H, C 3-6 Carbocyclic group, 4- to 7-membered heterocyclic group, -OC 1-2 Alkylene-C 3-6 Carbocyclic group, -OC 1-2 Alkylene-4 to 7 membered heterocyclic group, or -LK, wherein the alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0033] In some embodiments, R b5e , R b6a Each independently selected from deuterium, halogen, CN, OH, =O, COOH, CONH2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -Y1-C 1-6 Alkyl, -Y1-C 0-4 Alkylene-C 3-6 Carbocyclic group, -Y1-C 0-4 Alkylene-4 to 7 membered heterocyclic group, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-NHC 1-6 Alkyl, -C 1-2 Alkylene-N(C 1-6 alkyl) 2, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0034] In some embodiments, R b5e , R b6a Each independently selected from deuterium, halogen, CN, OH, =O, COOH, CONH2, NH2, NHC 1-4Alkyl, N(C 1-4 Alkyl)2, -Y1-C 1-4 Alkyl, -Y1-C 0-2 Alkylene-C 3-6 Carbocyclic group, -Y1-C 0-2 Alkylene-4 to 7 membered heterocyclic group, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, -C 1-2 Alkylene-NHC 1-4 Alkyl, -C 1-2 Alkylene-N(C 1-4 alkyl) 2, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0035] In some embodiments, R b5eEach is independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, COOH, CONH2, -Y1-CH3, -Y1-CH2CH3, -Y1-oxetanyl, -Y1-tetrahydrofuranyl, -Y1-oxacyclohexyl, -Y1-azetidinyl, -Y1-pyrrolidinyl, -Y1-piperidinyl, -Y1-piperazinyl, -Y1-morpholinyl, -Y1-CH2-phenyl, -Y1-CH2-pyridinyl, -Y1-C(CH3)4, NH2, NHCH3, N(CH3)2, methyl, ethyl , propyl, isopropyl, vinyl, ethynyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, phenyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl yl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-phenyl, -CH2-thienyl, -CH2-furanyl, -CH2-thiazolyl, -CH2-oxazolyl, -CH2-imidazolyl, -CH2-pyrazolyl, -CH2-pyrrolyl, -CH2-triazolyl, -CH2-pyridyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, phenyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NHCH3, N(CH3)2, methyl, ethyl, methoxy, ethoxy;

[0036] In some embodiments, R 6aEach is independently selected from deuterium, F, Cl, Br, I, CN, OH, CONH2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CF3, CD3, methyl or ethyl; in some embodiments, R b8 Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHC 3-6 Carbocyclic group, N(C 1-6 Alkyl)C 3-6 The alkyl or carbocyclic group is optionally substituted by 1 to 4 R z Substitution; in some embodiments, R b8 Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, NHC 3-6 Cycloalkyl, N(C 1-4 Alkyl)C 3-6 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z replace;

[0037] In some embodiments, R b8 is selected from NH2, NHCH3, -NH-cyclopropyl or -NHCH2-cyclopropyl;

[0038] R b5 , R b6 H; R b5 , R b6 At most 1 of -LK;

[0039] When Z is selected from S, R b6 Selected from -LK;

[0040] In some embodiments, when the compound is selected from (Ia), Selected from The right side is directly connected to L;

[0041] In some embodiments, Ring B4 is selected from

[0042] In some embodiments, R b3 is selected from H, methyl;

[0043] In some embodiments, Rb2 , R b4 Each independently selected from deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl, propyl, isopropyl;

[0044] or R b3 With R b4 Directly connected to form a 6-membered carbon ring;

[0045] In some embodiments, R b5 Selected from H, F, OH, CN;

[0046] In some embodiments, when the compound is selected from (Ib), Selected from

[0047] In some embodiments, R b5 is selected from H, deuterium, F, Cl, Br, I, CN, one of the following groups optionally substituted: oxetanyl, tetrahydrofuranyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl,

[0048] Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 selected from or R b5e substituted by a substituent;

[0049] In some embodiments, R b7 Selected from H, F, CF3, methyl, methoxy;

[0050] In some embodiments, L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-;

[0051] In some embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-;

[0052] In some embodiments, each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2)q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally substituted by 1 to 2 R z replace;

[0053] In some embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0054] In some embodiments, R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0055] In some embodiments, each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0056] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0057] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0058] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4 or Cy5;

[0059] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3 or Cy4;

[0060] In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, 5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak 3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1 -Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy 3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4- Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1- Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, - Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3 -Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2 -Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy 4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy 3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-,-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak 3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-A k5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak 2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak 4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak 3-Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;,

[0061] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0062] In certain embodiments, L is selected from -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-Cy2-CH2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -Cy1-Ak2-, -Ak1-Cy1-Ak2-, -OCH2-Cy1-CH2-Cy2-, -OCH2-Cy1-CH2-Cy2-CH2-;

[0063] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace;

[0064] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0065] In certain embodiments, R LSelect from H or C 1-4 alkyl;

[0066] In certain embodiments, R L is selected from H, methyl or ethyl;

[0067] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 7-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0068] In certain embodiments, Cy5 is defined the same as Cy1;

[0069] In certain embodiments, Cy1, Cy2, Cy3, Cy4, and Cy5 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0070] s1, s3, s5 are each independently selected from 0, 1 or 2, s2, s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2 or 3, s7 is selected from 1, 2 or 3;

[0071] In certain embodiments, Cy1, Cy2, Cy3, Cy4, and Cy5 are each independently selected from a bond or one of the following optionally substituted groups:

[0072] When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH2;

[0073] In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups:

[0074] When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH2

[0075] In certain embodiments, L is selected from the group shown in Table L-1, wherein the left side of the group is connected to B;

[0076] In certain embodiments, L is selected from the group shown in Table L-2, wherein the left side of the group is connected to B;

[0077] In certain embodiments, K is selected from K1 or K2; in certain embodiments, K1 is selected from In certain embodiments, K2 is selected from

[0078]

[0079] In certain embodiments, Selected from

[0080] In certain embodiments, Selected from

[0081] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R z Substitution, Q cannot directly form a nitrogen-nitrogen bond with the ring on the right;

[0082] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q - or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0083] In certain embodiments, Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3), Q cannot directly form a nitrogen-nitrogen bond with the ring on the right;

[0084] In certain embodiments, R q Select from H or C 1-4 alkyl;

[0085] In certain embodiments, A is selected from C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0086] In certain embodiments, A is selected from phenyl or 5-6 membered heteroaryl;

[0087] In certain embodiments, each F is independently selected from C 3-20 Carbocyclic group, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

[0088] In certain embodiments, each F is independently selected from C 3-7 Monocyclic, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclyl, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl, C 6-14 Aryl, 5-10 membered heteroaryl;

[0089] In certain embodiments, F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl,

[0090] In certain embodiments, Fa is selected from N or CR k1 In certain embodiments, Fb is selected from N or CR k1 ;

[0091] In certain embodiments, Fc is selected from O, S, NH, N(CH3) or NR k7a In certain embodiments, Fd is selected from N or CR k1 ;

[0092] In certain embodiments, Ff is selected from a bond, O, CH2, CHF, CF2, NH, N(CH3), N(R k1 )、C(R k1 )2;

[0093] In certain embodiments, Fg is selected from N or C; in certain embodiments, Fh is selected from N or C; in certain embodiments, Faa is selected from a bond, O, CH2; in certain embodiments, Fab is selected from O, CH2; in certain embodiments, ring E is selected from phenyl or 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0094] In certain embodiments, each ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0095] In certain embodiments, Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl, or oxazolyl;

[0096] In certain embodiments, ring F1, ring F2, ring F3, and ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0097] In certain embodiments, ring F1 and ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace;

[0098] In certain embodiments, ring F3 and ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0099] In certain embodiments, R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0100] In certain embodiments, R k1 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace;

[0101] In certain embodiments, R k1 Selected from R k7a ;

[0102] In certain embodiments, R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0103] In certain embodiments, R k1 , R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, C 1-4 Alkyl or C 1-4 Alkoxy, wherein the alkyl or alkoxy is optionally substituted by 1 to 4 substituents selected from F, Cl, Br, I, OH or NH2;

[0104] In certain embodiments, R k1 , R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2;

[0105] In certain embodiments, both R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z In certain embodiments, two R k3 Direct connection to form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 selected from R z In certain embodiments, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from Rz In certain embodiments, two R k1 Direct connection to form C 3-6 Cycloalkyl or 4-7 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 selected from R z Substitution; in certain embodiments, R k4 Each independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R k4 Each independently selected from H, CF3 or C 1-4 alkyl;

[0106] In certain embodiments, R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2, In certain embodiments, R k6 are each independently selected from C(═O), CH, S(═O), S(═O) 2 , CH 2 or N; in certain embodiments, R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ;

[0107] In certain embodiments, R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 selected from F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C 3-6 Substituted by a cycloalkyl substituent;

[0108] In certain embodiments, R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2;

[0109] In certain embodiments, M1 is selected from a bond, -CH2-C(=O)NH-, or -C(=O)CH2NH-;

[0110] In certain embodiments, M2 is selected from -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R z Substitution; In certain embodiments, M3 is selected from -NH- or -O-;

[0111] In certain embodiments, R k10 Selected from C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R z replace;

[0112] In certain embodiments, R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio or -OC(=O)-C 1-4 Alkyl, wherein the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 R z replace;

[0113] In certain embodiments, R k12 , R k13 Each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 R z replace;

[0114] In certain embodiments, G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R z replace;

[0115] In certain embodiments, R L2 Each independently selected from deuterium, F, Cl, Br, I, OH, =O, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0116] In certain embodiments, R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, SF5, CN, NO2, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0117] In certain embodiments, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0118] In certain embodiments, R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4Alkyl, C 1-4 substituted by an alkoxy substituent;

[0119] In certain embodiments, R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, SF5, CH2OH, OCH2OH, CH2OCH3, methyl, ethyl, vinyl, ethynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl;

[0120] In certain embodiments, n1, n2, n3 are each independently selected from 0, 1, 2 or 3; in certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5; in certain embodiments, p2 are each independently selected from 0, 1, 2 or 3; in certain embodiments, b1 is selected from 0, 1 or 2; in certain embodiments, b2 is selected from 0, 1, 2, 3, 4 or 5;

[0121] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1; in certain embodiments, K is selected from one of the structural fragments shown in Table K-2.

[0122] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0123] U, V, W are each independently selected from N or CR b7 ;

[0124] Z is selected from O, S or Se;

[0125] Ring B4 is selected from 5-membered heteroaryl, wherein the ring B4 is optionally substituted by 1 to 4 R b4 replace;

[0126] R b1 is selected from CN or ethynyl;

[0127] R b2 , R b4 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0128] R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0129] Alternatively, R b3 With any R b4 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0130] R b5 is selected from H, deuterium, halogen, CN;

[0131] R b6 Selected from -LK;

[0132] R b8 Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHC 3-6 Carbocyclic group, N(C 1-6 Alkyl)C 3-6 The alkyl or carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0133] L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-;

[0134] Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond,

[0135] The CH, -CH2- are optionally replaced by 1 to 2 R z replace;

[0136] q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0137] R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0138] Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0139] K is selected from K1 or K2;

[0140] K1 is selected from K2 is selected from

[0141] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q - or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R z Substitution, Q cannot directly form a nitrogen-nitrogen bond with the ring on the right;

[0142] R q Select from H or C 1-4 alkyl;

[0143] A is selected from C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

[0144] F are each independently selected from C 3-20 Carbocyclic group, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

[0145] R k1 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace;

[0146] R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0147] R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0148] Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace;

[0149] Alternatively, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace;

[0150] R k4 Each independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z replace;

[0151] M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-;

[0152] M2 is selected from -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0153] M3 is selected from -NH- or -O-;

[0154] R k10 Selected from C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R z replace;

[0155] R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio or -OC(=O)-C 1-4 Alkyl, wherein the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 R z replace;

[0156] R k12 , R k13 Each independently selected from H, C 1-4 Alkyl or C 3-6Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z replace;

[0157] R k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 R z replace;

[0158] G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R z replace;

[0159] R L2 Each independently selected from deuterium, F, Cl, Br, I, OH, =O, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0160] R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, SF5, CN, NO2, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0161] Alternatively, RL2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0162] b1 is selected from 0, 1 or 2; b2 is selected from 0, 1, 2, 3, 4 or 5; n1, n2, n3 are each independently selected from 0, 1, 2 or 3;

[0163] p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0164] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0165] R b2 , R b4 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, -C 1-2 Alkylene-phenyl, -C 1-2 Alkylene-5 to 6 membered heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 R z replace;

[0166] R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl, alkylene, alkenyl, alkynyl is optionally substituted with 1 to 4 R z replace;

[0167] Alternatively, R b3With any R b4 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0168] R b5 is selected from H, deuterium, halogen, OH, CN; R b6 Selected from -LK;R b8 Selected from NH2;

[0169] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0170] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace;

[0171] R L Each independently selected from H or C 1-4 alkyl;

[0172] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0173] A is selected from phenyl or 5-6 membered heteroaryl;

[0174] F are each independently selected from C 3-7 Monocyclic, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclyl, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl, C 6-14 Aryl, 5-10 membered heteroaryl;

[0175] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q - or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0176] R q Select from H or C 1-4 alkyl;

[0177] R k4 Each independently selected from H, CF3 or C 1-4 alkyl;

[0178] The remaining definitions are the same as those of the first embodiment of the present invention.

[0179] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0180] R L is selected from H, methyl or ethyl;

[0181] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0182] s1, s3, s5 are each independently selected from 0, 1 or 2; s2, s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3;

[0183] Selected from

[0184] Selected from

[0185] F is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl,

[0186]

[0187] Fa is selected from N or CR k1 ; Fb is selected from N or CR k1 ; Fc is selected from O, S, NH, N(CH3) or NR k7a ;

[0188] Fd is selected from N or CR k1 ; Ff is selected from a bond, O, CH2, CHF, CF2, NH, N(CH3), N(R k1 )、C(R k1 )2;

[0189] Fg is selected from N or C; Fh is selected from N or C; Faa is selected from a bond, O, CH2; Fab is selected from O, CH2;

[0190] Ring E is selected from phenyl or 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0191] Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;

[0192] Ring F1, ring F2, ring F3, ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0193] Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3),

[0194] Q cannot directly form a nitrogen-nitrogen bond with the ring on the right;

[0195] R k1 , R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2;

[0196] R k4 Each is independently selected from H or methyl;

[0197] R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2,

[0198] R k6 Each is independently selected from CO, CH, S(═O), S(═O)2, CH2 or N;

[0199] R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ;

[0200] R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted by a cycloalkyl substituent;

[0201] R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2;

[0202] R L2 , R zEach independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0203] Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0204] p2 is independently selected from 0, 1, 2 or 3;

[0205] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0206] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0207] Ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0208] Ring F1 and Ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace;

[0209] Ring F3 and Ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0210] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0211] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted:

[0212] When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH2;

[0213] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0214] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by the general formula (I) is selected from (Ia)

[0215]

[0216] Any two of U, V, W are selected from N, and the other one is selected from CR b7 ;

[0217] R b3 is selected from H, methyl, ethyl, propyl or isopropyl;

[0218] Ring B4 is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, and the ring B4 is optionally substituted by 1 R b4 replace;

[0219] R b2 , R b4 Each independently selected from deuterium, F, Cl, Br, I, CN, OH or optionally substituted by 1 to 4 R zsubstituted by one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl;

[0220] Alternatively, R b3 With R b4 Direct connection to form C 5-6 The carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0221] R b5 Selected from H, deuterium, F, Cl, Br, I, OH, CN

[0222] R b7 Selected from H;

[0223] L is selected from -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-Cy2-CH2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-C H2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -Cy1-Ak2-, -Ak1-Cy1-Ak2-, -OCH2-Cy1-CH2-Cy2-, -OCH2-Cy1-CH2-Cy2-CH2-;

[0224] Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups:

[0225] When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH2;

[0226] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0227] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (Ia) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0228] Selected from The right side is directly connected to L;

[0229] Ring B4 is selected from

[0230] R b3 is selected from H, methyl;

[0231] R b2 , R b4 Each independently selected from deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl, propyl, isopropyl;

[0232] or R b3 With R b4 Directly connected to form a 6-membered carbon ring;

[0233] R b5 Selected from H, F, OH, CN;

[0234] L is selected from one of the structures shown in Table L-1 or Table L-2;

[0235] K is selected from one of the structural fragments shown in Table K-1 or Table K-2;

[0236] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0237] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below.

[0238] The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0239] The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating a disease associated with KRAS activity or expression.

[0240] The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating, inhibiting or degrading KRAS-related diseases.

[0241] In some embodiments, the disease associated with inhibiting or degrading KRAS is cancer.

[0242] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

[0243] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

[0244] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3 -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300- 400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 9 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40 -200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;.

[0245] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0246] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being an autoimmune disease, an inflammatory disease or a cancer.

[0247] A method for treating a disease in a mammal, the method comprising administering to a subject a drug compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 2 5-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day, 1500 mg / day.

[0248] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

[0249] The amount of the compound of the invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0250] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0251] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0252] "CN" refers to cyano. "Halogen" refers to F, Cl, Br or I.

[0253] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0254] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0255] "Alkylene" refers to substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0256] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0257] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazole, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0258] The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0259] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like; alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

[0260] "Alkynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms on the main chain and 2 to 4 carbon atoms on the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0261] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0262] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0263] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The C, N, S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholin ... 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl,

[0264] "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0265] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O or S (=O) n (n is 0, 1 or 2).

[0266]

[0267] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0268] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

[0269] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0270] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0271] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0272] "Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

[0273] "Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0274] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0275] "Heterocyclic ring", "heterocyclic group", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0276] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0277] "Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

[0278] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0279] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0280] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -Alkenyl-R a , OR dor -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0281] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0282] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0283] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x , C x+1 , C x+2 , C x+3 , C x+4 …C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" means C3, C4, C5 or C6 cycloalkyl;

[0284] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0285] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0286] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0287] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0288] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0289] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0290] Synthesis method 1:

[0291]

[0292] The compound of the general formula (D-1-1) and the compound of the general formula (D-1-6) undergo nucleophilic substitution reaction, coupling reaction, etc. to obtain the compound of the general formula (D-1-2);

[0293] The compound of the general formula (D-1-2) is obtained by removing the hydroxyl protecting group to obtain the compound of the general formula (D-1-3);

[0294] The hydroxyl group of the compound of general formula (D-1-3) is oxidized to an aldehyde group to obtain a compound of general formula (D-1-4);

[0295] The general formula compound (D-1-4) and the general formula compound (D-1-7) are subjected to reductive amination reaction to obtain the general formula compound (D-1-5). DETAILED DESCRIPTION

[0296] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0297] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0298] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0299] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0300] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0301] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0302] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0303] Preparation of compounds Aa and Ab:

[0304]

[0305] The intermediate A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and Boc2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added, and the reaction was carried out at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain a racemic mixture of Aa and Ab (3.4 g, yield: 82%).

[0306] The racemic mixture of Aa and Ab is subjected to chiral separation, and the chiral separation method is as follows:

[0307] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0308] 2. Dissolve the sample in methanol and filter it with a 0.45 μm filter to prepare a sample solution.

[0309] 3. Preparative chromatographic conditions: a. The mobile phase consists of A and B system: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content is 20%; c. Flow rate is 40 mL / min.

[0310] Peak time: chiral isomer 1 (compound Aa): 5.7 min, chiral isomer 2 (compound Ab): 6.47 min.

[0311] According to the MicroED structure determination of compound Ab-1, compound Aa is of R configuration and compound Ab is of S configuration.

[0312] LCMS m / z=307.3[M+1] + .

[0313] Synthesis of intermediate A-2:

[0314]

[0315] Step 1: Preparation of Ab-1

[0316] Ab (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 mL), and NBS (0.81 g, 4.55 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain Ab-1 (1.6 g, yield: 92%).

[0317] LCMS m / z=385.3[M+1] + .

[0318] The compound Ab-1 was determined to be in S configuration by MicroED structure analysis.

[0319] Step 2: Preparation of Ab-2

[0320] Ab-1 (1.6 g, 4.16 mmol), intermediate Ab-1-1 (3.46 g, 8.29 mmol), Pd(dppf)Cl2·DCM (0.34 g, 0.42 mmol) and cesium carbonate (2.70 g, 8.3 mmol) were added to a reaction bottle, 1,4-dioxane (50 mL) and water (5 mL) were added, and the reaction was carried out at 100°C for 20 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain Ab-2 (1.4 g, yield: 56%).

[0321] Step 3: Preparation of Ab-3

[0322] Ab-2 (1.4 g, 2.35 mmol) was dissolved in THF (50 mL), 10% palladium carbon (1.25 g) was added, and the mixture was reacted at 45°C under a hydrogen atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain Ab-3 (0.85 g, yield: 87%).

[0323] LCMS m / z=418.1[M+1] + .

[0324] Step 4: Preparation of A-2

[0325] Ab-3 (620 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the reaction was concentrated under reduced pressure to obtain a crude product A-2 (460 mg).

[0326] LCMS m / z=318.3[M+1] + .

[0327] Synthesis of intermediate A-1:

[0328]

[0329] Step 1: Preparation of Aa-1

[0330] Aa (1.8 g, 5.88 mmol) was dissolved in acetonitrile (50 mL), and NBS (1.05 g, 5.90 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain Aa-1 (1.6 g, yield: 71%).

[0331] LCMS m / z=385.3[M+1] + .

[0332] Step 2: Preparation of Aa-2

[0333] Aa-1 (0.77 g, 2.0 mmol), intermediate Ab-1-1 (1.67 g, 4.0 mmol) (synthesis method see WO2022235945), Pd (dppf) Cl2·DCM (0.16 g, 0.20 mmol) and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100 ° C for 20 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain Aa-2 (0.70 g, yield: 59%).

[0334] Step 3: Preparation of Aa-3

[0335] Aa-2 (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), 10% palladium carbon (0.63 g) was added, and the mixture was reacted at 45°C under a hydrogen atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain Aa-3 (0.25 g, yield: 51%).

[0336] LCMS m / z=418.1[M+1] + .

[0337] Step 4: Preparation of A-1

[0338] Aa-3 (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the reaction was concentrated under reduced pressure to obtain a crude product A-1 (190 mg).

[0339] LCMS m / z=318.3[M+1] + .

[0340] Example 3: Preparation of Compound 3

[0341]

[0342] 3A (reference Nature ,2023,619,160-166.) (46 mg, 0.1 mmol) and 3B (30 mg, 0.1 mmol) were dissolved in 2 mL of dichloromethane, acetic acid (0.05 mL) was added, the reaction was carried out at room temperature for 1 h, sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added, and the reaction was continued for 48 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 3 (3 mg, 4%).

[0343] LC-Ms m / z(ESI):747.3[M+H] +

[0344] Example 4: Preparation of Compound 4

[0345]

[0346] Step 1: Synthesis of 4A

[0347] A-1 (0.22 g, 0.69 mmol) was dissolved in 5 mL DMAc, tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (0.25 g, 1.03 mmol) was added, and then 2 drops of glacial acetic acid were added, and the reaction was allowed to react at room temperature for 1 h, and then sodium triacetoxyborohydride (0.29 g, 1.38 mmol) was added to the reaction, and the reaction was continued for 2 h. Saturated sodium bicarbonate aqueous solution was added to quench, and the mixture was extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain 4A as a light yellow solid (0.24 g. Yield 64%).

[0348] LCMS m / z=541.3[M+H] +

[0349] Step 2: Synthesis of 4B

[0350] 4A (240 mg, 0.44 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was directly added. The mixture was reacted at room temperature for 0.5 h, and concentrated under reduced pressure. 20 mL of dichloromethane was added to dissolve the residue, and the pH was adjusted to about 8 with saturated aqueous sodium bicarbonate solution. The organic layer was dried and concentrated to obtain 4B (0.18 g, yield: 92%).

[0351] LCMS m / z=441.2[M+H] +

[0352] Step 3: 4D synthesis

[0353] 4C (500 mg, 1.26 mmol) (synthesis method reference Nature, 2023, 619, 160-166.) was dissolved in a mixture of 6 mL DCM and 0.5 mL DMF, and 1,1-cyclopropane dimethanol (190 mg, 1.89 mmol), cesium carbonate (820 mg, 2.52 mmol), triethylenediamine (280 mg, 2.52 mmol) were added, and the mixture was reacted at room temperature for 5 h. 50 mL DCM was added for dilution, the mixture was washed with water twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain the product (100 mg, yield: 17.12%).

[0354] LCMS m / z=464.3[M+H] +

[0355] Step 4: Synthesis of 4E

[0356] Dissolve triphenylphosphine (87 mg, 0.33 mmol), imidazole (45 mg, 0.66 mmol), and iodine (84 mg, 0.33 mmol) in 3 mL of tetrahydrofuran, protect with nitrogen, and react for 20 min in the dark. Then add a tetrahydrofuran solution of 4D (100 mg, 0.22 mmol) (dissolved in 1 mL), and heat to 50°C to react for 2 h. Directly concentrate under reduced pressure, and the residue is subjected to column chromatography to obtain the product (50 mg, yield: 39.63%).

[0357] LCMS m / z=574.1[M+H] +

[0358] Step 5: Synthesis of compound 4

[0359] 4E (100 mg, 0.17 mmol) was dissolved in 3 mL DMF, 4B (82 mg, 0.19 mmol) and potassium carbonate (47 mg, 0.34 mmol) were added, and the mixture was heated to 85°C for 3 h under nitrogen protection. The mixture was cooled to room temperature, diluted with 30 mL ethyl acetate, washed with water twice, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 4 (12 mg, yield: 7.97%).

[0360] LCMS m / z=886.4[M+H] +

[0361] 1 H NMR (400MHz, CD3OD) δ8.70(d,1H),7.69(d,1H),6.90(d,1H),6.69(d,1H),4.52–4.38(m,2H),3.93–3.70(m,4H),3. 63–3.45(m,3H),3.16–2.92(m,6H),2.86–2.50(m,10H),2.33–1.75(m,20H),1.07–0.97(m,2H),0.93–0.83(m,2H).

[0362] Example 5: Preparation of Compound 5

[0363]

[0364] Referring to the preparation method of Example 4, Compound 5 was obtained.

[0365] LCMS m / z=860.4[M+H] +

[0366] 1 H NMR(400MHz,CD3OD)δ8.63(d,1H),7.64(d,1H),6.79(d,1H),6.55(d,1H),4.49–4.3 6(m,2H),3.87–3.79(m,1H),3.66(d,1H),3.21–3.13(m,2H),3.05–2.92(m,3H),2.8 9–2.77(m,4H),2.74–2.58(m,6H),2.27–2.10(m,8H),2.08–1.94(m,7H),1.93–1.80 (m,5H),1.73–1.60(m,2H),1.33–1.26(m,2H),0.84–0.72(m,2H),0.65–0.50(m,2H).

[0367] Biological test cases

[0368] Biological test 1: In vitro KRAS G12D binding assay

[0369] Add 2 μL of dilution buffer to the 384-well white plate with different concentrations of compounds. Dilute 250X Tag2-KRAS-G12D protein and 10mM GTP 50-fold and 200-fold respectively with dilution buffer, and take 4 μL of the mixture to the test plate. Dilute 500X Tag1-RAF 100-fold with dilution buffer and take 4 μL to the test plate; incubate the test plate at 25°C for 15 minutes. After the incubation, dilute anti-Tag1-Eu and anti-Tag2-XL665 100-fold and 50-fold respectively with detection buffer, take 10 μL of the mixture and add it to the test plate, incubate at 4°C for 2 hours. After the reaction, read the signal value using a multi-label analyzer, excitation: 320nm, emission: 615nm, 665nm.

[0370] The formula used is Ratio = [Signal 665] / [Signal 615] × 10 4 Calculate the signal ratio and use formula 2 to calculate the inhibition rate, where R sample is the compound pore signal ratio, R min is the signal ratio of the control well without KRAS G12D protein, R max The IC was calculated by four-parameter curve fitting using GraphPad Prism software. 50 value.

[0371] Inhibition%=(1-(R sample -R min ) / (R max -R min ))×100%(Formula 1)

[0372] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity on the protein interaction between KRAS G12D and RAF1.

[0373] Biological test 2: Cell proliferation inhibition experiment

[0374] ASPC-1 cell culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ° C, 5% CO2 incubator. On the first day, ASPC-1 cells in the exponential growth phase were collected and plated on 96-well culture plates, 80 μL per well, with a plating density of 1000 cells / well, and cultured overnight in a 37 ° C, 5% CO2 incubator. T0 wells were plated at the same time. On the second day, 20 μL of different concentrations of compounds were added to each well, so that the final DMSO concentration in each well was 0.5%, and cultured in a 37 ° C, 5% CO2 incubator for 6 days. On the second day, the CellTiter-Glo kit was used to detect the T0 plate while adding drugs, recorded as RLU0. After the culture was completed, 25 μL of detection solution (Cell4Viability Assay, Promega) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence readings were detected using the Nivo multi-label analyzer (PerkinElmer). The results were processed according to formula (3) to calculate the proliferation inhibition rate of each concentration of the compound, and GraphPad Prism software was used to fit the curve using four parameters to calculate the concentration GI of the compound when the proliferation inhibition rate was 50%. 50 Value. RLU compound The readings for the drug treatment groups, RLU control The values ​​are the average values ​​of the solvent control group.

[0375] Inhibition % = (1-(RLU compound -RLU0) / (RLU control - RLU0))×100% Formula (2)

[0376] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good proliferation inhibitory activity on ASPC-1 cells (Kras G12D).

[0377] Biological test 3: Cell proliferation inhibition experiment

[0378] Human non-small cell lung cancer cells H358 (KRAS G12C) were purchased from ATCC, and the complete cell culture medium was RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, and cultured at 37 ° C, 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating, so that the cells were 1000 / well, and the volume was 90 μL per well. On the next day, 10 μL of compounds of different concentrations were added, and the cells were placed in a CO2 incubator for incubation for 6 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CTG solution that had been pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes, and the fluorescence signal value RLU was measured with an enzyme plate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)) * 100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curve was plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate and IC 50 .

[0379] Human colon cancer cells SW620 (KRAS G12V) were cultured in RPMI-1640+10% FBS+1% antibiotic-antifungal dual antibody in a complete cell culture medium at 37°C, 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating, so that the cells were 500 / well, and the volume was 90μL per well. On the next day, 10μL of compounds of different concentrations were added and placed in a CO2 incubator for 6 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50μL of CTG solution that had been pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before the fluorescence signal value RLU was measured using an enzyme reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1–

[0380] (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control))*100%. The inhibition rate of different concentrations of compounds was calculated in Excel, and then the inhibition curve was plotted and related parameters were calculated using GraphPad Prism software, including minimum inhibition rate, maximum inhibition rate and IC 50 .

[0381] Human epidermal cancer cells A431 (KRAS WT) were purchased from ATCC. The complete cell culture medium was RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, and cultured at 37 ° C, 5% CO2 incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating, so that the cells were 1000 / well, and the volume was 90 μL per well. On the next day, 10 μL of compounds of different concentrations were added, and the cells were placed in a CO2 incubator for 6 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes, and the fluorescence signal value RLU was measured with an enzyme plate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU solvent control – RLU blank control)) * 100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curve was plotted and related parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, maximum inhibition rate and IC 50 .

[0382] Conclusion: The compounds of the present invention, such as the example compounds, have good proliferation inhibitory activity against H358 cells (Kras G12C) and SW620 cells (KRAS G12V). Combined with the proliferation inhibitory activity against A431 cells (Kras WT), the compounds of the present invention have good selectivity.

[0383] MRC-5 cell proliferation assay

[0384] Human embryonic lung cells MRC-5 were purchased from ATCC, and the cell culture medium was EMEM + 10% FBS, and cultured in a 37°C, 5% CO2 incubator. When the cell density was 60% to 80%, the culture medium was discarded, PBS was washed once, and trypsin-EDTA (0.25%) was added to digest the cells. Fresh culture medium was used to terminate the digestion, and Countess TMII fully automatic cell counter for live cell counting, cell suspension adjusted to an appropriate concentration with cell culture medium, 195 μL of cell suspension added to each well of a 96-well cell culture plate to make 300 cells / well, different concentrations of compounds added the next day, and continued to culture in an incubator for 6 days. After the culture was completed, the CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) and the culture plate were taken out and restored to room temperature, 100 μL of cell culture medium was aspirated, and 60 μL of CTG reagent was added, and shaken for 2 minutes to fully lyse the cells. After standing at room temperature for 30 minutes, the fluorescence signal value was read with an enzyme reader (PHERAstar FSX). The culture medium wells were set as negative controls, the DMSO wells were set as positive controls, and the inhibitory activity percentage of the compound was standardized by the readings of the negative and positive controls. The inhibition rate calculation formula is:

[0385] Inhibition rate (%) = (fluorescence value of positive control group - fluorescence value of experimental group) / (fluorescence value of positive control group - fluorescence value of negative control group) * 100%

[0386] Analyze data and calculate IC using 4-parameter curve fitting or Excel 50 value (half inhibitory concentration).

[0387] Conclusion: The compounds of the present invention have weak inhibitory activity on MRC-5 cells. Combined with the proliferation inhibitory activity on H358, ASPC-1 and SW620, the compounds of the present invention have good selectivity.

[0388] Biological test 3: KRAS G12D degradation detection in ASPC-1 cells

[0389] ASPC-1 is a human pancreatic cancer cell line purchased from ATCC. The culture conditions are: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in 12-well plates, 3×10 5 / well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO2 incubator for 24 hours. After the culture was completed, the cells were collected and lysed on ice for 20 minutes with RIPA lysis buffer (beyotime, Cat. P0013B). After centrifugation at 12000 rpm and 4°C for 10 minutes, the supernatant protein samples were collected and quantified with a BCA kit (Beyotime, Cat. P0009). The protein was diluted to 1 mg / mL and the expression of KRAS G12D (CST, Cat. 14429S) and the internal reference β-actin (CST, Cat. 4970S) was detected using a fully automatic protein blot quantitative analyzer (Proteinsimple). The relative peak area of ​​KRAS G12D was calculated using the "Compass for SW" software when the internal reference area was 10000. According to formula (1), the proportion of KRAS G12D relative to the vehicle control group at different drug concentrations was calculated, where KRAS G12D treat is the relative peak area of ​​the drug-treated group, KRAS G12D solvent The data processed according to formula (3) were used to calculate DC using GraphPad Prism 8.3.0 software using a four-parameter nonlinear regression model. 50 value

[0390] KRAS G12D % = KRAS G12D streat / KRAS G12D solvent ×100% Formula 3

[0391] Conclusion: The compounds of the present invention, such as compound 3, have good degradation activity on KRAS G12D protein in ASPC-1 cells.

[0392] Pharmacokinetic test in rats

[0393] Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0394] Experimental design: On the day of the experiment, 6 SD rats / compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.

[0395] Dosing Information

[0396]

[0397] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC.

[0398] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0399] Before and after drug administration, 0.10 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0400] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties in rats. Specifically, compound 3 has better oral absorption performance and / or lower clearance rate in rats.

[0401] Mouse pharmacokinetic test

[0402] Experimental animals: Male BALB / c mice, 20-25 g, 6 mice / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0403] Experimental design: On the day of the experiment, 6 BALB / c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.

[0404]

[0405] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC.

[0406] Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0407] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

[0408] Beagle dog pharmacokinetic testing

[0409] Experimental animals: Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0410] Test method: On the test day, 5-6 beagle dogs / compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.

[0411]

[0412]

[0413] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC.

[0414] Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group in the G1 and G2 groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0415] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

[0416] Monkey pharmacokinetic testing

[0417] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0418] Test method: On the test day, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.

[0419]

[0420] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC.

[0421] Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0422] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in monkeys.

Claims

1. A compound or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by general formula (I), U, V, W are each independently selected from N or CR b7 ; Z is selected from O, S or Se; Ring B4 is selected from 5-membered heteroaryl, wherein the ring B4 is optionally substituted by 1 to 4 R b4 replace; R b1 is selected from CN or ethynyl; R b2 , R b4 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace; R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace; Alternatively, R b3 With any R b4 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace; R b5 is selected from H, deuterium, halogen, CN; R b6 Selected from -LK; R b8 Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, NHC 3-6 Carbocyclic group, N(C 1-6 Alkyl)C 3-6 The alkyl or carbocyclic group is optionally substituted by 1 to 4 R z replace; L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-; Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally substituted by 1 to 2 R z replace; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; K is selected from K1 or K2; K1 is selected from K2 is selected from Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q - or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R z Substitution, Q cannot directly form a nitrogen-nitrogen bond with the ring on the right; R q Select from H or C 1-4 alkyl; A is selected from C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; F are each independently selected from C 3-20 Carbocyclic group, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; R k1 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace; R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R k4 Each independently selected from H, C 1-4 Alkyl, C 3-8 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z replace; M1 is selected from a bond, -CH2-C(=O)NH- or -C(=O)CH2NH-; M2 is selected from -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Cycloalkyl or 4-10 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R z replace; M3 is selected from -NH- or -O-; R k10 Selected from C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R z replace; R k11 Each independently selected from H, F, Cl, Br, I, =O, OH, SH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio or -OC(=O)-C 1-4 Alkyl, wherein the alkyl, alkoxy or alkylthio group is optionally substituted by 1 to 4 R z replace; R k12 , R k13 Each independently selected from H, C 1-4 Alkyl or C 3-6 Cycloalkyl, the alkyl or cycloalkyl group is optionally substituted by 1 to 4 R z replace; R k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted by 1 to 4 R z replace; G is selected from C 6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R z replace; R L2 Each independently selected from deuterium, F, Cl, Br, I, OH, =O, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, SF5, CN, NO2, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace; b1 is selected from 0, 1 or 2; b2 is selected from 0, 1, 2, 3, 4 or 5; n1, n2, n3 are each independently selected from 0, 1, 2 or 3; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R b2 , R b4 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, -C 1-2 Alkylene-C 3-6 Cycloalkyl, -C 1-2 Alkylene-4 to 7 membered heterocycloalkyl, -C 1-2 Alkylene-phenyl, -C 1-2 Alkylene-5 to 6 membered heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 R z replace; R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkyl, alkylene, alkenyl, alkynyl is optionally substituted by 1 to 4 R z replace; Alternatively, R b3 With any R b4 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace; R b5 Selected from H, deuterium, halogen, OH, CN R b6 Selected from -LK; R b8 Selected from NH2; L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; A is selected from phenyl or 5-6 membered heteroaryl; F are each independently selected from C 3-7 Monocyclic group, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclyl, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl, C 6-14 Aryl, 5-10 membered heteroaryl; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q - or a 4-7 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R z replace; R q Select from H or C 1-4 alkyl; R k4 Each independently selected from H, CF3 or C 1-4 alkyl.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R L is selected from H, methyl or ethyl; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, s5 are each independently selected from 0, 1 or 2; s2, s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3; Selected from Selected from F is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, Fa is selected from N or CR k1 ; Fb is selected from N or CR k1 ; Fc is selected from O, S, NH, N(CH3) or NR k7a ; Fd is selected from N or CR k1 ; Ff is selected from a bond, O, CH2, CHF, CF2, NH, N(CH3), N(R k1 )、C(R k1 )2; Fg is selected from N or C; Fh is selected from N or C; Faa is selected from a bond, O, CH2; Fab is selected from O, CH2; Ring E is selected from phenyl or 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 replace; Ring A is selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl; Ring F1, ring F2, ring F3, ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, ring F4 are optionally substituted by 1 to 2 R k1 replace; Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3), Q cannot directly form a nitrogen-nitrogen bond with the ring on the right; R k1 , R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2; R k4 Each is independently selected from H or methyl; R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2, R k6 Each is independently selected from CO, CH, S(═O), S(═O)2, CH2 or N; R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ; R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted by a cycloalkyl substituent; R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2; R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace; p2 is independently selected from 0, 1, 2 or 3.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace; Ring F1 and Ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace; Ring F3 and Ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH2.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound represented by the general formula (I) is selected from (Ia) Any two of U, V, W are selected from N, and the other one is selected from CR b7 ; R b3 is selected from H, methyl, ethyl, propyl or isopropyl; Ring B4 is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, and the ring B4 is optionally substituted by 1 R b4 replace; R b2 , R b4 Each independently selected from deuterium, F, Cl, Br, I, CN, OH or optionally substituted by 1 to 4 R z substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl; Alternatively, R b3 With R b4 Direct connection to form C 5-6 The carbocyclic group is optionally substituted by 1 to 4 R z replace; R b5 Selected from H, deuterium, F, Cl, Br, I, OH, CN; R b7 Selected from H; L is selected from -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-Cy2-CH2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-C H2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -Cy1-Ak2-, -Ak1-Cy1-Ak2-, -OCH2-Cy1-CH2-Cy2-, -OCH2-Cy1-CH2-Cy2-CH2-; Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH2.

6. The compound according to claim 5 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, When the compound is selected from (Ia), Selected from The right side is directly connected to L; Ring B4 is selected from R b3 is selected from H, methyl; R b2 , R b4 Each independently selected from deuterium, F, Cl, Br, I, CN, OH, CF3, methyl, ethyl, propyl, isopropyl; or R b3 With R b4 Directly connected to form a 6-membered carbon ring; R b5 Selected from H, F, OH, CN; L is selected from one of the structures shown in Table L-1 or Table L-2; Table L-1L Group Table L-2 K is selected from one of the structural fragments shown in Table K-1 or Table K-2; Table K-1 Table K-2 7. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1 Table E-1 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating a disease associated with KRAS activity or expression.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and inhibiting or degrading KRAS-related diseases, preferably cancer.

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