Five-membered heteroaryl derivatives and medical use thereof

Abstract

Compounds represented by general formula (I), or stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, and pharmaceutically acceptable salts or eutectic crystals thereof, an intermediate thereof, and the use thereof in diseases related to KRAS inhibition or degradation such as cancers.

Description

A 5-membered heteroaryl derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and uses thereof in KRAS-related diseases such as tumors. Background Art

[0002] RAS proteins, expressed by the RAS gene (Rat Sarcoma viral oncogene), are intracellular guanine nucleotide-binding proteins and GTPases (with weak hydrolytic activity). RAS proteins exist in two distinct states: an inactive GDP-bound state and an active GTP-bound state. Activated RAS proteins interact with various downstream effectors to transmit signals, influencing cell growth, differentiation, the cytoskeleton, protein trafficking, and secretion. Activation of RAS signaling is regulated by guanine nucleotide exchange factors (GEFs, which induce GDP-GTP exchange) or GTPase-activating proteins (GAPs, which convert RAS proteins from an activated state to an inactive state). Mutant RAS proteins can become resistant to GAPs, resulting in a persistently activated RAS protein state, leading to uncontrolled cell growth and, ultimately, the development of cancerous tissue (Molecular Cancer, 2018, 17:33).

[0003] RAS gene mutations are common in cancer patients (Nat. Rev. Drug Discov. 2014, 13, 828-851). For example, RAS mutations account for 97.7% of pancreatic cancer, 52.2% of colorectal cancer, 42.6% of multiple myeloma, and 32.2% of non-small cell lung cancer (NSLC), respectively. KRAS (Kristen Rat Sarcoma viral oncogene) mutations are the most common RAS mutations, accounting for 86% of all RAS mutations. KRAS gene activation is most commonly achieved through point mutations, with 95% of KRAS mutations occurring at codons 12 and 13 of exon 2. Common mutations include KRAS G12C (39%), KRAS G12V (18-21%), and KRAS G12D (17-18%).

[0004] Since the discovery of KRAS mutants in cancer and the observation that their inhibition can suppress tumor growth, inhibitors of KRAS mutants have garnered widespread attention. KRAS has long been considered an undruggable target: RAS has a very high affinity for GTP / GDP (picomolar levels) and lacks a ligand-binding pocket (Clin. Cancer Res. 2015, 21, 1810-1818). KRAS G12D accounts for 36% of pancreatic cancer, 12% of colon cancer, 4% of NSCLC adenocarcinoma, and 6% of endometrial cancer. By organ and tissue classification, KRAS cancers are most prevalent in colon, pancreatic, and lung adenocarcinomas. By mutation type, G12D is the most common, followed by G12V. G12C, which has been initially investigated, ranks third, G13D fourth, and amplification (AMP) 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] Therefore, it is necessary to develop a compound that can inhibit or degrade KRAS protein for the treatment of diseases caused by KRAS mutations.

[0006] Summary of the Invention

[0007] The purpose 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 mutant or amplified KRAS for the treatment of related diseases such as cancer.

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

[0009] In some embodiments, the compound represented by general formula (I) is selected from (Ib), (Ie)

[0010] In some embodiments, Selected from

[0011] In some embodiments, U, V, and W are each independently selected from N or CR b7 ;

[0012] In some embodiments, any two of U, V, and W are selected from N, and the other is selected from CR b7 ;

[0013] In some embodiments, Z is selected from O, S, or Se;

[0014] In some embodiments, Ring B4 is selected from 5-membered heteroaryl, said Ring B4 being optionally substituted with 1 to 4 R b4 replace;

[0015] In some embodiments, ring B4 is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, said ring B4 is optionally substituted with 1 R b4 replace;

[0016] In some embodiments, R b1 Selected from CN or ethynyl;

[0017] 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;

[0018] 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 1-4 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 1-2Alkylene-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;

[0019] 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 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;

[0020] In some embodiments, R b7 selected from H, deuterium, F, Cl, Br, I, CN, OH, CONH2, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted 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, oxehyl, -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-oxehyl;

[0021] 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, -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;

[0022] Alternatively, Rb3 With any R b4 Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0023] 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 replace;

[0024] In some embodiments, R b3 Selected from H, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R z replace;

[0025] In some embodiments, R b3 is selected from H, methyl, ethyl, propyl or isopropyl;

[0026] In some embodiments, R b3 With any R b4 Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0027] In some embodiments, R b3 With R b4 Direct connection to form C 5-6 Carbocyclic group, the carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0028] In some embodiments, R b5 is selected from H, deuterium, halogen, CN 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 Carbocyclyl, 4- to 12-membered heterocyclyl, -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;

[0029] In some embodiments, R b5 is selected from H, deuterium, halogen, OH, CN or one of the following optionally substituted groups: 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 Spirocycloalkyl, -OC 5-12 Bridged 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-C 4-7 Monocyclic cycloalkenyl, -OC1-4 Alkylene-C 4-12 Cycloalkyl, -OC 1-4 Alkylene-C 5-12 Spirocycloalkyl, -OC 1-4 Alkylene-C 5-12 Bridged 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 groups selected from R b5e substituted by a substituent;

[0030] In some embodiments, R b5 is selected from H, deuterium, halogen, OH, CN or one of the following optionally substituted groups: 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 heterocycloalkyl, -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;

[0031] In some embodiments, R b5is selected from H, deuterium, F, Cl, Br, I, OH, CN or one of the following groups that 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-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-oxetanyl, -O-azetidinyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl , -NH-oxetanyl, -NH-azetidinyl, -NH-pyrrolidinyl, -NH-piperidinyl, -NH-piperazinyl, -NH-morpholinyl, -NH-pyridinyl, -NH-pyrimidinyl, -NH-pyrazinyl, -NH-pyridazinyl, -OCH2-oxetanyl, -OCH2-tetrahydrofuranyl, -OCH2-oxetanyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, alkyl, -OCH2-piperidinyl, -OCH2-piperazinyl, -OCH2-morpholinyl, -NHCH2-oxetanyl, -NHCH2-tetrahydrofuranyl, -NHCH2-oxacyclohexyl, -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,

[0032] 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 groups selected from or R b5e substituted by a substituent;

[0033] 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 y1C(=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 replace;

[0034] 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-;

[0035] 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, -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, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0036] Alternatively, R b5a 、R b5b Direct connection to form C 4-8 Carbocyclic group or 4 to 8 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0037] In some embodiments, Rb5a 、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;

[0038] Alternatively, R b5a 、R b5b Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0039] In some embodiments, R b5a 、R b5b 、R b5c 、R b5d Each 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 zsubstituted 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;

[0040] 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;

[0041] In some embodiments, R y1 Selected from H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, wherein the alkyl, alkylene or carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0042] In some embodiments, R y1 Selected from H, C 1-4 alkyl;

[0043] In some embodiments, R y1 Selected from H or methyl;

[0044] In some embodiments, R b6 Selected from H, C 3-12 Carbocyclyl, 4- to 12-membered heterocyclyl, -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, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0045] In some embodiments, R b6 Selected from H, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -OC 1-4 Alkylene-C 3-6 Carbocyclic group, -OC 1-4Alkylene-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, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0046] 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, wherein the alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0047] In some embodiments, R b6 Selected from 1 to 4 R 6a One of the following substituted groups: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -OCH2-cyclopentyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl,

[0048] 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(C1-6 alkyl) 2, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0049] In some embodiments, R b5e 、R b6a Each independently selected from deuterium, halogen, CN, OH, ═O, COOH, CONH2, NH2, NHC 1-4 Alkyl, 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;

[0050] 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-oxetanyl, -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, oxetanyl, 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 -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-phenyl, -CH2-thienyl, -CH2-furyl, -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, oxetanyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, phenyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl 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;

[0051] 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, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and oxolanyl groups, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and oxolanyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CF3, CD3, methyl, or ethyl groups;

[0052] 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 Carbocyclic group, the alkyl or carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0053] 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, said alkyl or cycloalkyl is optionally substituted by 1 to 4 R z replace;

[0054] In some embodiments, R b8 is selected from NH2, NHCH3, -NH-cyclopropyl or -NHCH2-cyclopropyl;

[0055] R b5 、R b6 Not at the same time H;

[0056] In some embodiments, R b5 Selected from

[0057] In some embodiments, when the compound is selected from (Ib), Selected from

[0058] In some embodiments, R b5is 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, 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 groups selected from or R b5e substituted by a substituent;

[0059] In some embodiments, R b5e Each independently selected from deuterium, F, Cl, Br, I, CN, OH, ═O, COOH, CONH2, NH2, NHCH3, N(CH3)2, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2OCH3, -COOCH3, -COOCH2CH3, CF3, methyl, ethyl, methoxy, ethoxy, -CH2CN, ethynyl, Phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl,

[0060] In some embodiments, R b5 is selected from H or pyrazolyl, said pyrazolyl being optionally replaced by R b5e replace;

[0061] In some embodiments, R b5 Selected from

[0062] In some embodiments, Selected from

[0063] In some embodiments, Selected from

[0064] In some embodiments, R b6 Selected from

[0065] In some embodiments, Rb6 Selected from

[0066] In some embodiments, R b7 Selected from H, F, CF3, methyl, methoxy;

[0067] In some embodiments, Selected from

[0068] In some embodiments, Selected from

[0069] In some embodiments, Selected from

[0070] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0071] U, V, and W are each independently selected from N or CR b7 ;

[0072] Z is selected from O or Se;

[0073] Ring B4 is selected from 5-membered heteroaryl, said ring B4 is optionally substituted by 1 to 4 R b4 replace;

[0074] R b1 Selected from CN or ethynyl;

[0075] 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;

[0076] R b3 Selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, the alkyl, alkylene optionally 1 to 4 R z replace;

[0077] Alternatively, R b3 With any R b4 Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0078] R b5 is selected from H, deuterium, halogen, CN or one of the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocyclyl, 4 to 12 membered heterocyclyl, when substituted, is optionally substituted by 1 to 4 members selected from R b5e replace;

[0079] R b6 Selected from H, C 3-12 Carbocyclyl, 4- to 12-membered heterocyclyl, -OC 1-4 Alkylene-C 3-12 Carbocyclic group, -OC 1-4 Alkylene-4 to 12 membered heterocyclic group, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0080] 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 1-2Alkylene-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;

[0081] Y1 is selected from 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)-;

[0082] R y1 Selected from H, C 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, wherein the alkyl, alkylene or carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0083] 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 Carbocyclic group, the alkyl or carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0084] R b5 、R b6 Not at the same time H;

[0085] 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, -C0-4 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;

[0086] b1 is selected from 0, 1 or 2;

[0087] b2 is selected from 0, 1, 2, 3, 4 or 5.

[0088] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0089] R b2 、R b4 、R b7 Each independently selected from H, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, the alkyl, alkoxy, alkylthio, cycloalkyl is optionally substituted by 1 to 4 R z replace;

[0090] R b3 Selected from H;

[0091] Alternatively, R b3 With any R b4 Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0092] R b5 is selected from H, deuterium, halogen, OH, CN or one of the following optionally substituted groups: C 6-10 Aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl, when substituted, optionally substituted by 1 to 4 R b5e replace;

[0093] R b6 Selected from H, C 3-6 Carbocyclic group, 4 to 7 membered heterocyclic group, -OC 1-4 Alkylene-C 3-6 Carbocyclic group, -OC 1-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0094] R b5e 、R b6a Each independently selected from deuterium, halogen, CN, OH, ═O, COOH, CONH2, NH2, NHC 1-4 Alkyl, 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 1-4 Alkoxy, C 1-4 Alkylthio, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0095] R b8 Selected from NH2;

[0096] The remaining definitions are the same as those of the first embodiment of the present invention.

[0097] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0098] R b5 selected from H, one of the following groups optionally substituted: phenyl, 5 to 6 membered heteroaryl, 4-7 membered monocyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered spirocyclic heterocycloalkyl, 6-12 membered bridged heterocycloalkyl, when substituted, optionally substituted by 1 to 4 R b5e replace;

[0099] 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, wherein the alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace;

[0100] 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;

[0101] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0102] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0103] The compound represented by general formula (I) is selected from (Ib)

[0104] Any two of U, V, and W are selected from N, and the other one is selected from CR b7 ;

[0105] 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 one R b4 replace;

[0106] R b3 Selected from H;

[0107] 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 one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0108] Alternatively, R b3 With R b4 Direct connection to form C 5-6 Carbocyclic group, the carbocyclic group is optionally substituted by 1 to 4 R z replace;

[0109] R b5is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 groups selected from R b5e replace;

[0110] R b5e each independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, COOH, CONH2, -Y1-CH3, -Y1-CH2CH3, -Y1-oxetanyl, -Y1-tetrahydrofuranyl, -Y1-oxetanyl, -Y1-azetidinyl, -Y1-pyrrolidinyl, -Y1-piperidinyl, -Y1-piperazinyl, -Y1-morpholinyl, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl 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;

[0111] Y1 is selected from -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-;

[0112] R b6 Selected from 1 to 4 R 6a substituted one of the following groups: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, oxetanyl, tetrahydrofuranyl, oxhexyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -OCH2-cyclopentyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl;

[0113] R 6a Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, CONH2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CF3, CD3, methyl or ethyl;

[0114] R b7selected from H, deuterium, F, Cl, Br, I, CN, OH, CONH2, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z One of the following substituted groups: methyl, ethyl, propyl, isopropyl;

[0115] Preferably, Selected from

[0116] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0117] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (Ib) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0118] Selected from

[0119] R b5 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 R b5e replace;

[0120] R b5e Each independently selected from deuterium, F, Cl, Br, I, CN, OH, ═O, COOH, CONH2, NH2, NHCH3, N(CH3)2, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2OCH3, CF3, methyl, ethyl, methoxy, ethoxy, -CH2CN, ethynyl, Phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl,

[0121] R b6 Selected from

[0122] R b7 Selected from H, F, CF3, methyl, methoxy;

[0123] Preferably, Selected from

[0124] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0125] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-2 below:

[0126] Table E-2

[0127] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0128] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to KRAS activity or expression.

[0129] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating, inhibiting or degrading KRAS-related diseases.

[0130] In some embodiments, the disease associated with inhibition or degradation of KRAS is cancer (eg, gastric cancer, esophageal cancer, or pancreatic cancer).

[0131] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "drug strength").

[0132] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0133] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the 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;.

[0134] 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.

[0135] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably an autoimmune disease, an inflammatory disease, or cancer.

[0136] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein the daily dose can 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.

[0137] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0138] 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.

[0139] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0140] 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 isotopes of carbon 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, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0141] "CN" refers to cyano.

[0142] "Halogen" refers to F, Cl, Br or I.

[0143] "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.

[0144] "Alkylene" refers to substituted or unsubstituted straight-chain and 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.

[0145] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0146] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon radical containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 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 ring. Heterocycloalkyl can be connected to a heteroatom or carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0147] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon group having at least one, typically one or two, or 3 carbon-carbon double bonds, the backbone includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl 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, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl and the like; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0148] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three, carbon-carbon triple bonds, with a backbone comprising from 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0149] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0150] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. 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, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0151] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which may 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 ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The C, N, S optionally substituted in the heterocyclyl ring may be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached 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-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0152] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle 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 atoms selected from N, O or S (=O) n (n is 0, 1 or 2).

[0153] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0154] "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 N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0155] "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 zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 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 "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0156] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0157] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0158] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0159] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0160] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0161] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0162] "Heterobridged ring," "heterobridged cyclic group," "bridged ring heterocyclic group," or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0163] "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.

[0164] "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). 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 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, 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. Non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0165] "Substituted" or "substituted" refers to substitution 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 d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c 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 ring, spiro ring or paracyclic group.

[0166] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a 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.

[0167] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0168] 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" refers to C3, C4, C5 or C6 cycloalkyl;

[0169] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a 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

[0170] 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 the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0171] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0172] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0173] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0174] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0175] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0176] Synthesis method 1:

[0177] Referring to the route and method of WO2023099624, compound D-1-6 of the general formula was obtained;

[0178] The general formula compound D-1-6 reacts with selenium powder and malondicyanide under alkaline conditions to obtain the general formula compound D-1-7;

[0179] Compound D-1-7 and compound D-1-8 of the general formula are reacted through nucleophilic substitution reaction, coupling reaction, etc. to obtain compound (D-1-9);

[0180] R D-1-1 is selected from leaving groups, preferably halogen, OMs, OTs or OTf;

[0181] R D-1-4 Selected from H or a hydroxyl protecting group;

[0182] L1 is selected from a bond or a 5-12 membered nitrogen-containing heterocyclic ring;

[0183] The definitions of the remaining groups are consistent with the description. DETAILED DESCRIPTION

[0184] The following examples 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.

[0185] The compounds used in the reactions described herein were prepared using 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" were obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0186] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0187] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0188] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0189] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0190] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0191] Example 1: Synthesis of Compound 1

[0192] Step 1: Synthesis of compound 1B

[0193] 1A (referenced in Nature, 2023, 619, 160-166) (580 mg, 1.83 mmol) and (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (1.1 g, 5.49 mmol) were dissolved in 12 mL of dry acetonitrile. DIPEA (708 mg, 5.49 mmol) was added dropwise at room temperature. The mixture was reacted at 110°C overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to afford 1B (720 mg, 82%).

[0194] LCMS m / z=482.3[M+1] +

[0195] Step 2: Synthesis of 1C

[0196] At room temperature, 1B (360 mg, 0.75 mmol) and selenium powder (89 mg, 1.12 mmol) were placed in a pressure tube. After three replacements with nitrogen, a solution of malononitrile (74 mg, 1.12 mmol) in ethanol (4 mL) and triethylamine (4 mL) were added. The mixture was allowed to react at 110°C for 40 hours. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography to afford 1C (55 mg, 12%).

[0197] LCMS m / z=610.2[M+1] +

[0198] Step 3: Synthesis of Compound 1

[0199] 1C (65 mg, 0.10 mmol) was dissolved in 2 mL of dichloromethane, and a solution of hydrochloric acid in dioxane (4 N, 2 mL) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative HPLC (preparative conditions: instrument: SHIMADZU LC-20AP; column: C18 column; mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution, B: acetonitrile; elution conditions: B from 30% to 60% in 10 minutes; flow rate: 25 mL / min; column temperature: room temperature; detection wavelength: 220 nm) to obtain compound 1 (26 mg, 51%).

[0200] Compound 1 was prepared by chiral SFC to give compound 1-1 (8.2 mg, chiral HPLC retention time: 1.374 min) and compound 1-2 (5.1 mg, chiral HPLC retention time: 1.909 min). One of compound 1-1 or compound 1-2 has structure 1-A, and the other has structure 1-B.

[0201] (SFC separation conditions: Instrument: Waters 150Prep-SFC; Column: Chiral Whelk column; Mobile phase: A: CO2; B: 0.1% ammonia in methanol; Elution: 55% B in A; Flow rate: 100 mL / min; Pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm; Chiral HPLC detection: Instrument: SHIMADZU LC-30AD sf; Column: Chiral Whelk column; Mobile phase: A: CO2; B: 0.05% diethylamine in methanol; Mobile phase: 40% B; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0202] Compound 1-1: LCMS m / z=510.1[M+1] +

[0203] 1 H NMR(400MHz,DMSO-d6)δ8.46(d,1H),7.18-7.11(m,2H),7.08(d,1H),4.76-4.63(m,1H),4.38-4.29(m,1H), 3.11-2.94(m,3H),2.86-2.75(m,2H),2.66-2.55(m,4H),2.09-1.89(m,4H),1.88-1.73(m,4H),1.20(d,3H).

[0204] Compound 1-2: LCMS m / z=510.1[M+1]+

[0205] 1 H NMR(400MHz,DMSO-d6)δ8.46(d,1H),7.19-7.11(m,2H),7.09(d,1H),4.76-4.67(m,1H),4.39-4.31(m,1H), 3.09-2.95(m,3H),2.88-2.78(m,2H),2.66-2.56(m,4H),2.11-1.90(m,4H),1.89-1.74(m,4H),1.22(d,3H).

[0206] Example 2: Preparation of Compound 2

[0207] Step 1: Synthesis of 2B

[0208] Under nitrogen, 2A (reference: WO2023099624) (300 mg, 0.68 mmol), methyl 3-pyrazolecarboxylate (170 mg, 1.36 mmol), and cesium carbonate (550 mg, 1.7 mmol) were placed in a sealed tube. Dry THF (10 mL) was added and stirred at 65°C for 16 h. The reaction mixture was diluted with water (10 mL), and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford 2B (334 mg, yield: 92%).

[0209] LC-Ms m / z(ESI):535.2[M+H] +

[0210] Step 2: Synthesis of 2C

[0211] 2B (334 mg, 0.63 mmol) was dissolved in 8 mL of tetrahydrofuran and 1 mL of water. Lithium hydroxide monohydrate (131 mg, 3.13 mmol) was added and the mixture was allowed to react at room temperature for 3 h. The pH was adjusted to 4 with 1N hydrochloric acid. The organic phase was extracted with dichloromethane (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford 2C (291 mg, yield: 87%).

[0212] LC-Ms m / z(ESI):521.2[M+H] +

[0213] Step 3: 2D synthesis

[0214] Under nitrogen, 2C (291 mg, 0.56 mmol) and (R)-tetrahydrofuran-3-amine (73 mg, 0.84 mmol) were dissolved in dry DMF (10 mL), followed by the addition of DIPEA (290 mg, 2.24 mmol) and HATU (426 mg, 1.12 mmol). The mixture was stirred at room temperature overnight, and ethyl acetate (80 mL) was added. The mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford 2D (250 mg, yield: 76%).

[0215] LC-Ms m / z(ESI):590.2[M+H] +

[0216] Step 4: Synthesis of compound 2

[0217] Under a nitrogen atmosphere, 2D (200 mg, 0.34 mmol), malononitrile (23 mg, 0.51 mmol), and selenium powder (40 mg, 0.51 mmol) were placed in a sealed tube. Extra dry ethanol (0.5 mL) and triethylamine (0.5 mL) were added and reacted at 110°C overnight. After removing the solvent under reduced pressure, the residue was purified by preparative HPLC to afford compound 2 (10 mg, 4% yield). Preparation conditions: Primary preparation: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18 column; Mobile phase: A: 0.1% TFA in water, B: acetonitrile; Elution: B from 20% to 50% in 15 min; Flow rate: 75 mL / min; Column temperature: Room temperature; Detection wavelength: 210 nm & 254 nm; Secondary preparation: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18 column; Mobile phase: A: 10 mmol / L NH4HCO3 in water, B: acetonitrile; Elution: B from 45% to 66% in 15 min; Flow rate: 75 mL / min; Column temperature: Room temperature; Detection wavelength: 210 nm & 254 nm)

[0218] LC-Ms m / z(ESI):718.2[M+H] +

[0219] 1H NMR(400MHz,DMSO-d6)δ8.65-8.54(m,2H),7.51(s,1H),7.20-7.12(m,2H),6.97(d ,1H),5.53-5.43(m,1H),4.56-4.45(m,1H),3.93-3.83(m,2H),3.77-3.69(m,1H), 3.67-3.60(m,1H),3.18-3.09(m,1H),3.02-2.93(m,1H),2.78-2.60(m,4H),2.42- 2.36(m,3H),2.26-2.13(m,2H),2.10-1.92(m,5H),1.91-1.61(m,8H),1.31(d,3H).

[0220] Compound 2 was prepared by chiral SFC to give compound 2-1 (3.1 mg, chiral HPLC retention time: 0.805 min) and compound 2-2 (2.7 mg, chiral HPLC retention time: 1.713 min). (SFC separation conditions: Instrument: Waters 150Prep-SFC; Column: Chiral AS column; Mobile phase: A is CO2; B is a solution of 0.1% ammonia in isopropanol and acetonitrile; Elution: 65% B in A; Flow rate: 100 mL / min; Pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm. HPLC purification method: Instrument: SHIMADZU LC-20AP; Column: C18 column; Mobile phase: A is water containing 10 mmol / L NH4HCO3; B is acetonitrile; Elution: Gradient elution, B 40% to 70% in 12 min; Flow rate: 30 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm. Chiral HPLC analysis method: Instrument: SHIMADZU LC-30AD sf; Column: Chiral IK Column; mobile phase: A: CO2; B: 0.05% diethanolamine in isopropanol / acetonitrile; mobile phase: 50% B; flow rate: 3 mL / min; pressure: 100 bar; column temperature: 35°C; detection wavelength: 220 nm).

[0221] One of compound 2-1 or compound 2-2 has structure 2-A, and the other has structure 2-B.

[0222] Compound 2-1:

[0223] 1H NMR (400MHz, CD3OD) δ8.84(d,1H),7.47(s,1H),6.98(d,1H),5.52-5.43(m,1H),4.67-4. 59(m,1H),4.56-4.49(m,1H),4.06-3.94(m,2H),3.88-3.81(m,1H),3.79-3.74(m,1H),3 .30-3.21(m,1H),3.15-3.07(m,1H),2.92-2.64(m,4H),2.56(s,3H),2.49-2.39(m,1H), 2.37-2.27(m,1H),2.20-2.03(m,6H),2.00-1.90(m,3H),1.88-1.72(m,3H),1.42(d,3H).

[0224] Compound 2-2:

[0225] 1 H NMR(400MHz,CD3OD)δ8.84(d,1H),7.47(s,1H),6.98(d,1H),5.55-5.47(m,1H),4.6 7-4.59(m,1H),4.56-4.49(m,1H),4.06-3.94(m,2H),3.90-3.82(m,1H),3.80-3.72 (m,1H),3.25-3.17(m,1H),3.14-3.06(m,1H),2.92-2.64(m,4H),2.55(s,3H),2.48 -2.27(m,2H),2.20-2.03(m,6H),2.01-1.90(m,3H),1.86-1.73(m,3H),1.42(d,3H).

[0226] Example 6: Preparation of Compound 6

[0227] Step 1: Synthesis of 6A

[0228] Under nitrogen, 2C (1.1 g, 2.11 mmol) and 3-methylaminooxetane (280 mg, 3.17 mmol) were dissolved in dry DMF (12 mL). DIPEA (0.7 mL, 4.22 mmol) and HATU (1.2 g, 3.17 mmol) were added sequentially. The mixture was stirred at room temperature overnight, and ethyl acetate (80 mL) was added. The mixture was washed sequentially with water (20 mL × 2) and saturated brine (20 mL × 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to afford 6A (650 mg, yield: 52.17%).

[0229] LC-Ms m / z(ESI):590.5[M+H] +

[0230] Step 2: Synthesis of compound 6

[0231] To a sealed tube, 6A (650 mg, 1.10 mmol), malononitrile (110 mg, 1.65 mmol), and selenium powder (870 mg, 11 mmol) were added. Ultra-dry ethanol (6 mL) and triethylamine (6 mL) were also added. The atmosphere was replaced with nitrogen and the reaction was carried out at 90°C for 20 hours. After removing the solvent under reduced pressure, the residue was purified by preparative HPLC to afford compound 6 (22 mg, yield: 2.79%). (First preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 40% to 58% B in A over 20 minutes; Flow rate: 90 mL / min; Column temperature: Room temperature; Detection wavelengths: 210 and 254 nm; Second preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 55% to 85% B in A over 20 minutes; Flow rate: 25 mL / min; Column temperature: Room temperature; Detection wavelengths: 210 and 254 nm;)

[0232] LC-Ms m / z(ESI):718.2[M+H] +

[0233] 1 H NMR (400MHz, CD3OD) δ8.90-8.81(m,1H),7.27(d,1H),6.88(d,1H),5.80-5.29(m,2H),4.95-4.83(m,4H),3.48-3.31(m,3H),3.27-3.18(m,1H),3 .14-3.04(m,1H),2.96-2.63(m,4H),2.58-2.49(m,3H),2.47-2.36(m,1H ),2.21-2.13(m,2H),2.13-1.89(m,7H),1.88-1.72(m,3H),1.42(d,3H).

[0234] Compound 6 was prepared by chiral SFC to give compound 6-1 (6.9 mg; chiral SFC retention time: 1.007 min) and compound 6-2 (5.7 mg, 1.718 min); (SFC separation conditions: instrument: Waters 150Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO2; B is a solution of 0.1% ammonia in methanol and acetonitrile; elution conditions: 55% B in A solution; flow rate: 100 mL / min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK Column; Mobile phase: A: CO2; B: 0.05% diethanolamine in methanol and acetonitrile; Mobile phase: 50% B elution; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0235] One of compound 6-1 and compound 6-2 has structure 6-A, and the other has structure 6-B.

[0236] Compound 6-1:

[0237] 1 H NMR(400MHz,CD3OD)δ8.87(d,1H),7.26(d,1H),6.88(d,1H),5.80-5.30(m,2H),4.95-4.83(m,4H),3.50-3.31(m,3H),3.30-3.05 (m,2H),2.94-2.62(m,4H),2.55(s,3H),2.47-2.36(m,1H),2.23-2.02(m,6H),2.02-1.89(m,3H),1.88-1.73(m,3H),1.42(d,3H).

[0238] Compound 6-2:

[0239] 1 H NMR(400MHz,CD3OD)δ8.86(d,1H),7.26(d,1H),6.88(d,1H),5.80-5.31(m,2H),4.93-4.82(m,4H),3.50-3.31(m,3H),3.26-3.07 (m,2H),2.97-2.63(m,4H),2.55(s,3H),2.50-2.40(m,1H),2.21-2.02(m,6H),2.01-1.90(m,3H),1.89-1.74(m,3H),1.42(d,3H).

[0240] Example 7: Preparation of Compound 7

[0241] Compound 7 (53 mg) was prepared by referring to the synthesis of compound 6. (Preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH₄HCO₃ aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 45% to 62% B in A over 20 minutes; Flow rate: 90 mL / min; Column temperature: room temperature; Detection wavelengths: 210 & 254 nm.)

[0242] LC-Ms m / z(ESI):706.2[M+H] +

[0243] 1 H NMR (400MHz, CD3OD) δ8.88-8.83(m,1H),7.46(s,1H),7.03-6.99(m,1H),5.55-5.44(m,1H),4.69-4.63(m,1H),3.25-3.14(m,2H),2.97-2.81 (m,3H),2.78-2.64(m,2H),2.62-2.55(m,3H),2.54-2.43(m,1H),2.21 -1.91(m,9H),1.89-1.75(m,3H),1.47-1.39(m,3H),1.26-1.14(m,2H).

[0244] Compound 7 was prepared by chiral SFC to give compound 7-1 (17.2 mg; chiral SFC retention time: 0.702 min) and compound 7-2 (18.4 mg; chiral SFC retention time: 1.098 min); (SFC separation conditions: instrument: Waters 150 Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO2; B is a solution of 0.1% ammonia in methanol and acetonitrile; elution conditions: 55% B solution in A; flow rate: 100 mL / min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK Column; Mobile phase: A: CO2; B: 0.05% diethanolamine in methanol and acetonitrile; Mobile phase: 50% B elution; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0245] One of compound 7-1 or compound 7-2 has structure 7-A, and the other has structure 7-B.

[0246] Compound 7-1

[0247] 1 H NMR(400MHz,CD3OD)δ8.86(d,1H),7.45(s,1H),7.00(d,1H),5.51-5.42(m,1H),4.82-4.63(m,1H),3.30-3.21(m,1H),3.15-3.06(m,1H),2 .93-2.63(m,5H),2.56(s,3H),2.49-2.37(m,1H),2.21-2.03(m,6H), 2.01-1.90(m,3H),1.88-1.72(m,3H),1.42(d,3H),1.27-1.14(m,2H).

[0248] Compound 7-2

[0249] 1 H NMR (400MHz, CD3OD) δ8.84(d,1H),7.44(s,1H),7.00(d,1H),5.55-5.45(m,1H),4.85-4.62(m,1H),3.25-3.07(m,2H),2.96-2.65 (m,5H),2.56(s,3H),2.51-2.41(m,1H),2.20-2.01(m,6H),2.01-1.90(m,3H),1.88-1.74(m,3H),1.43(d,3H),1.27-1.14(m,2H).

[0250] Example 8: Preparation of Compound 8

[0251] Compound 8 (75 mg) was prepared by referring to the synthesis of compound 6. (First preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 35% to 65% of solution A over 25 minutes; Flow rate: 80 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm; Second preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 63% to 93% of solution A over 20 minutes; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm)

[0252] LC-Ms m / z(ESI):753.2[M+H] +

[0253] 1 H NMR (400MHz, CD3OD) δ8.88-8.81(m,1H),8.54(d,1H),7.85-7.77(m,1H),7.52-7.46(m,2H ),7.34-7.28(m,1H),6.99(d,1H),5.57-5.45(m,1H),5.36-5.26(m,1H),3.26-3.18(m,1H) ,3.13-3.03(m,1H),2.98-2.83(m,1H),2.81-2.63(m,3H),2.59-2.50(m,3H),2.45-2.34( m,1H),2.21-2.13(m,2H),2.13-2.88(m,7H),1.87-1.73(m,3H),1.62(d,3H),1.43(d,3H).

[0254] Compound 8 was prepared by chiral SFC to give compound 8-1 (26.8 mg; chiral SFC retention time: 0.850 min) and compound 8-2 (34.2 mg; chiral SFC retention time: 1.382 min); (SFC separation conditions: instrument: Waters 150Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO2; B is a solution of 0.1% ammonia in methanol and acetonitrile; elution conditions: 50% B in A solution; flow rate: 100 mL / min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK Column; Mobile phase: A: CO2; B: 0.05% diethanolamine in methanol and acetonitrile; Mobile phase: 50% B elution; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0255] One of compound 8-1 and compound 8-2 has structure 8-A, and the other has structure 8-B.

[0256] Compound 8-1:

[0257] 1H NMR(400MHz,CD3OD)δ8.86(d,1H),8.56-8.52(m,1H),7.84-7.78(m,1H),7.52-7.47 (m,2H),7.34-7.28(m,1H),6.99(d,1H),5.53-5.44(m,1H),5.35-5.27(m,1H),3.30-3.21(m,1H),3.14-3.07(m,1H),2.93-2. 63(m,4H),2.55(d,3H),2.47-2.38(m,1H),2.20-2.03(m,6H),2.01-1.90(m,3H),1.87-1.72(m,3H),1.62(d,3H),1.43(d,3H).

[0258] Compound 8-2:

[0259] 1 H NMR(400MHz,CD3OD)δ8.85(d,1H),8.56-8.51(m,1H),7.85-7.77(m,1H),7.53- 7.46(m,2H),7.34-7.27(m,1H),6.99(d,1H),5.57-5.48(m,1H),5.35-5.27(m, 1H),3.26-3.07(m,2H),2.97-2.63(m,4H),2.55(d,3H),2.48-2.38(m,1H),2.2 1-2.02(m,6H),2.01-1.90(m,3H),1.89-1.74(m,3H),1.62(d,3H),1.43(d,3H).

[0260] Example 9: Preparation of Compound 9

[0261] Compound 9 (70 mg) was prepared by referring to the synthesis of compound 6. (First preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 35% to 65% of solution A over 25 minutes; Flow rate: 80 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm; Second preparation conditions: Instrument: Shimadzu LC-20AP; Preparative column: C18; Mobile phase: A: 10 mmol / L NH4HCO3 aqueous solution; B: acetonitrile; Elution conditions: Gradient elution from 63% to 93% of solution A over 20 minutes; Flow rate: 25 mL / min; Column temperature: room temperature; Detection wavelength: 210 & 254 nm)

[0262] LC-Ms m / z(ESI):706.2[M+H] +

[0263] 1 H NMR(400MHz,CD3OD)δ8.87-8.83(m,1H),7.47-7.41(m,1H),7.02-6.97(m,1H),5 .54-5.42(m,1H),4.85-4.62(m,1H),3.30-3.16(m,1H),3.12-3.02(m,1H),2.96 -2.81(m,2H),2.80-2.63(m,3H),2.56-2.49(m,3H),2.45-2.34(m,1H),2.21-2. 12(m,2H),2.12-1.89(m,7H),1.86-1.70(m,3H),1.42(d,3H),1.26-1.13(m,2H).

[0264] Compound 9 was prepared by chiral SFC to give compound 9-1 (25.8 mg; chiral SFC retention time: 0.682 min) and compound 9-2 (25.7 mg; chiral SFC retention time: 1.054 min); (SFC separation conditions: instrument: Waters 150Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO2; B is a solution of 0.1% ammonia in methanol and acetonitrile; elution conditions: 55% B in A solution; flow rate: 100 mL / min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK Column; Mobile phase: A: CO2; B: 0.05% diethanolamine in methanol and acetonitrile; Mobile phase: 50% B elution; Flow rate: 3 mL / min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

[0265] One of compound 9-1 and compound 9-2 has structure 9-A, and the other has structure 9-B.

[0266] Compound 9-1:

[0267] 1H NMR(400MHz,CD3OD)δ8.86(d,1H),7.44(s,1H),7.00(d,1H),5.51-5.43(m,1H),4.85-4.63(m,1H),3.30-3.05(m,2H),2.93-2.63 (m,6H),2.55(s,3H),2.46-2.36(m,1H),2.19-2.03(m,6H),2.02-1.91(m,3H),1.87-1.71(m,3H),1.42(d,3H),1.26-1.14(m,2H).

[0268] Compound 9-2:

[0269] 1 H NMR(400MHz,CD3OD)δ8.84(d,1H),7.44(s,1H),7.00(d,1H),5.54-5.46(m,1H),4.85-4.63(m,1H),3.24-3.06(m,2H),2.96-2.63 (m,6H),2.54(s,3H),2.47-2.36(m,1H),2.21-2.03(m,6H),2.01-1.89(m,3H),1.87-1.72(m,3H),1.42(d,3H),1.26-1.13(m,2H).

[0270] Biological test 1: In vitro KRAS G12D binding assay

[0271] Add 2 μL of dilution buffer to a 384-well white plate at varying concentrations of compound. Dilute 250X Tag2-KRAS-G12D protein and 10 mM GTP 50-fold and 200-fold, respectively, in dilution buffer, and add 4 μL of the mixture to the assay plate. Dilute 500X Tag1-RAF 100-fold in dilution buffer and add 4 μL to the assay plate; incubate the plate at 25°C for 15 minutes. After incubation, dilute anti-Tag1-Eu and anti-Tag2-XL665 100-fold and 50-fold, respectively, in detection buffer, and add 10 μL of the mixture to the assay plate. Incubate at 4°C for 2 hours. After the reaction, read the signal using a multi-label analyzer (excitation: 320 nm, emission: 615 nm, 665 nm).

[0272] Use the formula Ratio = [Signal 665] / [Signal 615] × 10 4 Calculate the signal ratio and use Equation 2 to calculate the inhibition rate, where R sample is the compound pore signal ratio, Rmin 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.

[0273] Inhibition%=(1-(R sample -R min ) / (R max -R min ))×100%(Formula 1)

[0274] 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.

[0275] Biological test 2: cell proliferation inhibition experiment

[0276] 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 harvested and plated on a 96-well plate at a density of 1000 cells / well, with 80 μL per well plated. The cells were cultured overnight at 37°C, 5% CO2 incubator, and the T0 well was plated at the same time. On the second day, 20 μL of compound at various concentrations was added to each well, resulting in a final DMSO concentration of 0.5% in each well. The cells were cultured at 37°C, 5% CO2 incubator for 6 days. On the second day, the T0 plate was assayed using the CellTiter-Glo kit and recorded as RLU0. After the incubation period, 25 μL of detection solution (Cell 4 Viability Assay, Promega) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and chemiluminescence readings were measured using a Nivo Multilabel 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-treated groups, RLU control The values ​​are the average values ​​of the solvent control group.

[0277] Inhibition % = (1-(RLU compound -RLU0) / (RLU control - RLU0))×100% Formula (2)

[0278] Conclusion: The compounds of the present invention, such as the example compounds, have good proliferation inhibitory activity against ASPC-1 cells (Kras G12D). Specifically, compound 1-1 has an inhibitory activity against ASPC cell proliferation with IC50 = 345.3 nM, and compound 2-1 has an inhibitory activity against ASPC cell proliferation with IC50 = 58.8 nM.

[0279] Biological test 3: cell proliferation inhibition experiment

[0280] Human non-small cell lung cancer H358 (KRAS G12C) cells were purchased from ATCC and cultured in RPMI-1640 complete medium supplemented with 10% FBS and 1% antibiotic-antimycotic combination therapy at 37°C in a 5% CO2 incubator. On the first day, cells were harvested from the exponential growth phase and plated with complete medium at the appropriate concentrations, with 1000 cells per well in a 90 μL volume per well. The following day, 10 μL of compound at various concentrations was added and the cells were incubated in a CO2 incubator for an additional 6 days. Following the completion of the incubation period, 50 μL of pre-thawed and room temperature CTG solution was added to each well according to the instructions of the CellTiter-Glo kit (Promega, G7573). The cells were mixed using a microplate shaker for 2 minutes and then incubated at room temperature for 10 minutes before measuring the fluorescence intensity (RLU) using a microplate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) * 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 .

[0281] Human colon cancer cells SW620 (KRAS G12V) were cultured in RPMI-1640 complete medium supplemented with 10% FBS and 1% antibiotic-antimycotic dual antibody at 37°C in a 5% CO2 incubator. On the first day, cells in the exponential growth phase were harvested and the cell suspension was adjusted to the appropriate concentration in complete medium for plating, with 500 cells per well in a volume of 90 μL per well. The next day, 10 μL of compound at various concentrations was added, and the cells were incubated in a CO2 incubator for an additional 6 days. Following the incubation period, 50 μL of pre-thawed and room temperature CTG solution was added to each well according to the instructions of the CellTiter-Glo kit (Promega, G7573). The cells were mixed using a microplate shaker for 2 minutes and then incubated at room temperature for 10 minutes before measuring the fluorescence signal (RLU) using a microplate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) * 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 .

[0282] Human epidermal carcinoma cells A431 (KRAS WT) were purchased from ATCC and cultured in RPMI-1640 complete medium supplemented with 10% FBS and 1% antibiotic-antimycotic combination therapy at 37°C in a 5% CO2 incubator. On the first day, cells in the exponential growth phase were harvested and the cell suspension was adjusted to the appropriate concentration in complete medium for plating, with 1000 cells per well in a volume of 90 μL per well. The next day, 10 μL of compound at various concentrations was added, and the cells were incubated in a CO2 incubator for an additional 6 days. Following the completion of the incubation period, 50 μL of pre-thawed and room temperature CTG solution was added to each well according to the instructions of the CellTiter-Glo kit (Promega, G7573). The cells were mixed using a microplate shaker for 2 minutes and then incubated at room temperature for 10 minutes before measuring the fluorescence signal (RLU) using a microplate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control) / (RLU vehicle control-RLU blank control)) * 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 .

[0283] Test results:

[0284] 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.

[0285] MRC-5 cell proliferation assay

[0286] Human embryonic lung MRC-5 cells were purchased from ATCC and cultured in EMEM + 10% FBS at 37°C in a 5% CO2 incubator. When the cell density reached 60% to 80%, the culture medium was discarded, the cells were washed once with PBS, and trypsin-EDTA (0.25%) was added to digest the cells. Fresh culture medium was used to terminate the digestion, and the cells were analyzed using Countess. TM II fully automatic cell counter was used to count live cells, and the cell suspension was adjusted to an appropriate concentration with cell culture medium. 195 μL of cell suspension was added to each well of a 96-well cell culture plate to make 300 cells / well. Different concentrations of compounds were added the next day and the cells were placed in an incubator for further culture for 6 days. After the culture was completed, the CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) and the culture plate were taken out and returned to room temperature. 100 μL of cell culture medium was discarded, 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 a microplate reader (PHERAstar FSX). The culture medium wells were set as negative controls, the DMSO wells 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:

[0287] 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%

[0288] Analyze data and calculate IC using 4-parameter curve fitting or Excel 50 value (half inhibitory concentration).

[0289] Conclusion: The compounds of the present invention have weak inhibitory activity against MRC-5 cells. Combined with their proliferation inhibitory activity against H358, ASPC-1 and SW620 cells, the compounds of the present invention have good selectivity.

[0290] Biological test 4: Rat pharmacokinetic test

[0291] Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0292] Experimental Design: On the day of the experiment, 6 SD rats / compound were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0293] Dosing Information

[0294] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0295] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0296] Before and after drug administration, 0.10 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0297] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in rats.

[0298] Mouse pharmacokinetic test

[0299] Experimental animals: Male BALB / c mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0300] Experimental Design: On the day of the experiment, six BALB / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0301] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0302] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0303] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

[0304] Beagle dog pharmacokinetic testing

[0305] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 5-6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0306] Test method: On the test day, 5-6 beagle dogs were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0307] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0308] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm at 4°C for 10 minutes. Blood was collected from both the intravenous and oral gavage groups in the G1 and G2 groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0309] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

[0310] Monkey pharmacokinetic testing

[0311] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0312] Test method: On the day of the test, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0313] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0314] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0315] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in monkeys.

[0316] Caco2 permeability test

[0317] The experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (5μM) was added to the dosing port hole on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port hole. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS / MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficient for transport from the apical side to the basolateral side and from the basolateral side to the apical side of the monolayer cells, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

[0318] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Caco2 permeability.

[0319] Liver microsome stability test

[0320] In this study, liver microsomes from five species, including humans, dogs, rats, and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0321] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver).

[0322] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good metabolic stability in liver microsomes.

[0323] CYP450 enzyme inhibition testing

[0324] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (with midazolam as substrate) was evaluated.

[0325] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on any subtype of CYP enzymes.

[0326] hERG potassium channel function test

[0327] Experimental platform: electrophysiology manual patch clamp system

[0328] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0329] Experimental Methods: hERG potassium channel currents were recorded using the whole-cell patch-clamp technique at room temperature in CHO (Chinese Hamster Ovary) cells stably expressing the hERG potassium channel. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. After perfusion with electrode solution, the tip resistance was approximately 2-5 MΩ. The microelectrodes were connected to the patch-clamp amplifier by inserting them into the amplifier headstage. Clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After whole-cell recordings were obtained, cells were clamped at -80 mV. To elicit hERG potassium currents (I hERG ), a 2-second depolarization step from -80 mV to +20 mV was applied, followed by repolarization to -50 mV, which was maintained for 1 second before returning to -80 mV. This voltage stimulus was applied every 10 seconds, and drug administration was initiated after confirming the stability of the hERG potassium current (at least 1 minute). Compounds were administered for at least 1 minute at each tested concentration, and at least two cells were tested at each concentration (n≥2).

[0330] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0331] Inhibition%=[1-(I / Io)]×100%

[0332] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current before and after drug addition, respectively.

[0333] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation:

[0334] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope))

[0335] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0336] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no obvious hERG inhibitory activity or weak inhibitory activity.

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 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, wherein the alkyl or alkylene 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 or one of the following groups which are optionally substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 Carbocyclyl, 4 to 12 membered heterocyclyl, when substituted, is optionally substituted by 1 to 4 members selected from R b5e replace; 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, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace; 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; Y1 is selected from 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)-; 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 replace; 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; R b5 , R b6 Not at the same time H; 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; b1 is selected from 0, 1 or 2; b2 is 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 are each independently selected from H, deuterium, halogen, CN, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 Cycloalkyl, the alkyl, alkoxy, alkylthio, cycloalkyl is optionally substituted by 1 to 4 R z replace; R b3 Selected from H; 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, OH, CN or one of the following optionally substituted groups: C 6-10 Aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl, when substituted, is optionally replaced by 1 to 4 R b5e replace; R b6 Selected from H, C 3-6 Carbocyclic group, 4- to 7-membered heterocyclic group, -OC 1-4 Alkylene-C 3-6 Carbocyclic group, -OC 1-4 Alkylene-4 to 7 membered heterocyclic group, wherein the alkylene, heteroaryl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace; R b5e , R b6a Each independently selected from deuterium, halogen, CN, OH, =O, COOH, CONH2, NH2, NHC 1-4 Alkyl, 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 1-4 Alkoxy, C 1-4 Alkylthio, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace; R b8 Selected from NH2.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R b5 selected from H, one of the following groups optionally substituted: phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered monocyclic heterocycloalkyl, 6- to 12-membered cyclic heterocycloalkyl, 6- to 12-membered spirocyclic heterocycloalkyl, 6- to 12-membered bridged heterocycloalkyl, when substituted, optionally substituted by 1 to 4 R b5e replace; 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, wherein the alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R b6a replace; 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 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 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 (Ib) Any two of U, V, W are selected from N, and the other one is selected from CR b7 ; 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 b3 Selected from H; 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 one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; 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 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 groups selected from R b5e replace; R b5e each 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, methyl, ethyl, propyl, isopropyl, methyl Oxy, ethoxy, propoxy, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl 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; Y1 is selected from -C(=O)NH-, -C(=O)N(CH3)-, -NHC(=O)-, -N(CH3)C(=O)-; R b6 Selected from 1 to 4 R 6a substituted with one of the following groups: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, oxetanyl, tetrahydrofuranyl, oxhexyl, -OCH2-cyclopropyl, -OCH2-cyclobutyl, -OCH2-cyclopentyl, -OCH2-azetidinyl, -OCH2-pyrrolidinyl, -OCH2-piperidinyl, -OCH2-piperazinyl; R 6a Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, CONH2, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CF3, CD3, methyl or ethyl; 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 one of the following groups: methyl, ethyl, propyl, isopropyl; Preferably, Selected from 5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Selected from R b5 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, thienyl, when substituted, optionally with 1 to 4 R b5e replace; R b5e Each independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, COOH, CONH2, NH2, NHCH3, N(CH3)2, -CONHCH3, -CONHCH2CH3, -CONHCH2CH2OCH3, CF3, methyl, ethyl, methoxy, ethoxy, -CH2CN, ethynyl, Phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, R b6 Selected from R b7 Selected from H, F, CF3, methyl, methoxy; Preferably, Selected from 6. A compound or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures shown in Table E-2.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 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 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating a disease associated with KRAS activity or expression.

9. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 7 for preparing a medicament for treating and inhibiting or degrading KRAS-related diseases, preferably cancer (e.g., gastric cancer, esophageal cancer or pancreatic cancer).

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 7, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being selected from cancer (e.g., gastric cancer, esophageal cancer or pancreatic cancer).

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