Tetrahydropyridinopyrazole derivative and application thereof in medicine

Abstract

The invention provides a tetrahydropyridinopyrazole derivative and application thereof in medicine, and particularly relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or eutectic of the compound, and an intermediate and a preparation method of the tetrahydropyridinopyrazole derivative. The invention also relates to application in preparation of related medicines for treating diabetes mellitus. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a compound described by general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as applications in the preparation of drugs for treating diabetes. Background Art

[0002] Diabetes is a group of metabolic diseases characterized by high blood sugar. High blood sugar is caused by defects in insulin secretion or impaired biological action, or both. Long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. It is mainly divided into two types. Type 1 diabetes: destruction of pancreatic B cells leads to absolute insulin deficiency. Type 2 diabetes: mainly insulin resistance with relative insulin deficiency or impaired insulin secretion with insulin resistance.

[0003] Drugs for type 2 diabetes can be divided into six major categories (insulin, insulin secretagogues, biguanides, glucosidase inhibitors, thiazolidinediones, and SGLT2 inhibitors), each of which works through a different primary mechanism.

[0004] GLP-1 is a 30-amino acid incretin hormone that is secreted by L cells in the intestine. GLP-1 stimulates insulin secretion in a physiological and glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates beta-cell proliferation. In nonclinical experiments, GLP-1 promotes the sustained capacity of beta cells by stimulating the transcription of important genes for glucose-dependent insulin secretion and promoting beta-cell neogenesis. In healthy people, GLP-1 plays an important role in regulating postprandial blood glucose by stimulating glucose-dependent insulin secretion from the pancreas, which leads to increased peripheral glucose absorption. GLP-1 also inhibits the secretion of glucagon, resulting in a decrease in hepatic glucose output. In addition, GLP-1 delays gastric emptying, slows small intestinal motility, and delays food absorption.

[0005] In addition to its potential application in diabetes, studies have also found that GLP-1 receptor agonists have antagonistic effects on neurodegeneration and AD progression. In AD transgenic mice, systemic administration of liraglutide for 8 weeks prevented memory impairment, neuronal loss, and deterioration of hippocampal synaptic plasticity. In addition, based on the number of activated microglia, liraglutide can significantly reduce the deposition and inflammation of amyloid plaques. Similarly, in rats injected with monoclonal antibodies (mAbs) into the hippocampus, liraglutide pretreatment significantly protected mAb-induced spatial memory and long-term potentiation impairments. Another GLP-1 analog, exenatide, has also shown promising results against neurodegenerative diseases in preclinical studies. Summary of the invention

[0006] The object of the present invention is to provide a compound that can stimulate the GLP-1 receptor or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use thereof in the preparation of drugs for the treatment of diabetes.

[0007] The compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.

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

[0009]

[0010] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (II-a) or (II-b),

[0011]

[0012] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (III-a), (III-b), (III-c), and (III-d).

[0013]

[0014] In some embodiments, represents a single or double bond;

[0015] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0016] In some embodiments, ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 monocarbocyclic ring, 4 to 8 membered heteromonocyclic ring, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0017] In some embodiments, Ring A is selected from asubstituted by one of the following groups: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl;

[0018] In some embodiments, Ring A is selected from a substituted phenyl or pyridyl;

[0019] In some embodiments, Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 6- and 6-membered heteroaryl, C 3-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B is optionally substituted by 1 to 4 R b replace;

[0020] In some embodiments, ring B is selected from 5-membered heteroaryl or 5-membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b replace;

[0021] In some embodiments, ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, imidazopyrimidinyl, and the ring B is optionally substituted by 1 to 4 R b replace;

[0022] In some embodiments, Ring B is selected from b One of the following groups substituted:

[0023] Its right side is connected to ring C;

[0024] In some embodiments, Ring B1 is selected from 5-membered heteroaryl, wherein Ring B1 is optionally substituted with 1 to 4 R b replace;

[0025] In some embodiments, ring B1 is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, and the ring B1 is optionally substituted by 1 to 4 Rb replace;

[0026] In some embodiments, Ring B1 is selected from b One of the following groups substituted:

[0027] Its right side is connected to ring C;

[0028] In some embodiments, ring D is selected from C 6-12 carbocyclic ring, 5 to 12 membered heterocyclic ring, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0029] In some embodiments, ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclic ring, benzo 4 to 7 membered heterocyclic ring, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl ring, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0030] In some embodiments, Ring D is selected from d substituted by one of the following groups: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl,

[0031] In some embodiments, Ring D is selected from d Substituted structures: phenyl,

[0032] In some embodiments, ring C is selected from C 3-12 Carbocyclic ring, 4 to 12 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 4 R c replace;

[0033] In some embodiments, ring C is selected from C 3-6 monocycloalkyl, 4-7 membered monoheterocyclic group, 6-11 membered spiro heterocyclic group, 5-11 membered bridged heterocyclic group, 7-10 membered heterocyclic group, wherein the ring C is optionally substituted by 1 to 4 R c replace;

[0034] In some embodiments, Ring C is selected from c Substituted with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl;

[0035] In some embodiments, Ring C is selected from c Substituted oxacyclopentyl or oxacyclohexyl;

[0036] In some embodiments, L1 is selected from -S(=O)2-, -C(=O)-;

[0037] In some embodiments, L1 is selected from -C(=O)-;

[0038] In some embodiments, L2 is selected from -(CR L1 R L2 ) m -;

[0039] In some embodiments, L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0040] In some embodiments, L2 is selected from -CR L1 R L2 - or optionally 1 to 3 R k One of the following groups substituted:

[0041] In some embodiments, L2 is selected from

[0042] In some embodiments, X is selected from S or O;

[0043] In some embodiments, m is selected from 1, 2, 3 or 4;

[0044] In some embodiments, R 4 Selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b ,

[0045] In some embodiments, R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2,

[0046] In some embodiments, R 4 Selected from

[0047] In some embodiments, R4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0048] In some embodiments, R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0049] In some embodiments, R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl;

[0050] In some embodiments, R a , R b , R c , R d Each independently selected from H, deuterium, halogen, =O, CN, OH, NO2, 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, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, -C(=O)NH-C 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -S(=O) 1-2 -C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbocyclic ring, -NHC(=O)-C 1-6Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3- to 7-membered heterocyclic ring, -P(=O)R 5a R 5b , The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring may be optionally substituted with 1 to 4 R k replace;

[0051] In some embodiments, R a , R b , R c , R d Each independently selected from H, deuterium, halogen, =O, 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, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -S(=O) 1-2 -C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocyclic ring, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3- to 7-membered heterocyclic ring, -P(=O)R 5a R 5b , The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0052] In some embodiments, R a , R b , R c , R d Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, -P(=O)R 5a R 5b , or optionally 1 to 3 R kSubstituted one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0053] In some embodiments, R a , R b or R c Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl,

[0054] In some embodiments, R d is selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH,

[0055]

[0056] In some embodiments, R 5a , R 5b Each independently selected from C 1-6 Alkyl, C 3-6 The alkyl group or the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0057] In some embodiments, R 5a , R 5b Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0058] In some embodiments, R 5a , R 5b Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 3 R k replace;

[0059] In some embodiments, R 1 , R 2 , R 3 , R L1 , R L2Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace;

[0060] In some embodiments, R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace;

[0061] In some embodiments, R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2 or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0062] In some embodiments, R 1 , R 2 , R 3 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0063] In some embodiments, R L1 , R L2Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylthio;

[0064] In some embodiments, R L1 , R L2 Together with the atoms connected to it, they form C 3-8 A carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0065] In some embodiments, R L1 , R L2 Together with the connected carbon atoms, they form C 3-6 A carbocyclic ring or a 4- to 6-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0066] In some embodiments, R L1 , R L2 and the carbon atom to which it is attached together form a k Substituted groups as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;

[0067] In some embodiments, R 5a , R 5b Together with the phosphorus atom to which it is attached, it forms a 5- to 8-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0068] In some embodiments, R 5a , R 5b Together with the phosphorus atom to which it is connected, it forms a 5- to 8-membered monocyclic heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0069] In some embodiments, R 5a , R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted with the following groups:

[0070] In some embodiments, R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0071] In some embodiments, R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0072] In some embodiments, R keach independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0073] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0074] Optionally, when X is selected from O, Ring B is not selected from optionally 1 to 4 R b Substituted 5- and 6-membered heteroaryl.

[0075] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0076] represents a single or double bond;

[0077] Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring A is optionally substituted by 1 to 4 Ra replace;

[0078] Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 6- and 6-membered heteroaryl, C 3-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B is optionally substituted by 1 to 4 R b replace;

[0079] Ring D is selected from C 6-12 carbocyclic ring, 5 to 12 membered heterocyclic ring, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0080] Ring C is selected from C 3-12 Carbocyclic ring, 4 to 12 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 4 R c replace;

[0081] L1 is selected from -S(=O)2-, -C(=O)-;

[0082] L2 is selected from -(CR L1 R L2 ) m -;

[0083] X is selected from S or O;

[0084] m is selected from 1, 2, 3 or 4;

[0085] R 4 Selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b ,

[0086] R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0087] R a , R b , R c , R d Each independently selected from H, deuterium, halogen, =O, CN, OH, NO2, COOH, CONH2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, -C(=O)NH-C 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -S(=O) 1-2 -C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbocyclic ring, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3- to 7-membered heterocyclic ring, -P(=O)R 5a R 5b , The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring may be optionally substituted with 1 to 4 R k replace;

[0088] R 5a , R 5b Each independently selected from C 1-6 Alkyl, C 3-6 The alkyl group or the carbocyclic ring is optionally substituted by 1 to 4 R k replace;

[0089] R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace;

[0090] Alternatively, R L1 , R L2 Together with the atoms connected to it, they form C 3-8A carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0091] Alternatively, R 5a , R 5b Together with the phosphorus atom to which it is attached, it forms a 5- to 8-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0092] R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0093] The condition is,

[0094] When X is selected from O, Ring B is not selected from optionally 1 to 4 R b Substituted 5- and 6-membered heteroaryl.

[0095] As a second embodiment of the present invention, the compound represented by the following general formula (II-a) or (II-b) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0096]

[0097] Ring B1 is selected from 5-membered heteroaryl, and the ring B1 is optionally substituted by 1 to 4 R b replace;

[0098] Ring B is selected from 5-membered heteroaryl or 5-membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b replace;

[0099] Ring C is selected from C 3-6 monocycloalkyl, 4-7 membered monoheterocyclic group, 6-11 membered spiro heterocyclic group, 5-11 membered bridged heterocyclic group, 7-10 membered heterocyclic group, wherein the ring C is optionally substituted by 1 to 4 R c replace;

[0100] Ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclic ring, benzo 4 to 7 membered heterocyclic ring, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl ring, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0101] Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 monocarbocyclic ring, 4 to 8 membered heteromonocyclic ring, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0102] R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0103] R 5a , R 5b Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0104] R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace;

[0105] Alternatively, R L1 , R L2 Together with the connected carbon atoms, they form C 3-6A carbocyclic ring or a 4- to 6-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0106] Alternatively, R 5a , R 5b Together with the phosphorus atom to which it is connected, it forms a 5- to 8-membered monocyclic heterocyclic ring, which is optionally substituted by 1 to 4 R k replace;

[0107] R a , R b , R c , R d Each independently selected from H, deuterium, halogen, =O, 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, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -S(=O) 1-2 -C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocyclic ring, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3- to 7-membered heterocyclic ring, -P(=O)R 5a R 5b , The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0108] The remaining definitions are the same as those of the first embodiment of the present invention.

[0109] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (II-a) or (II-b) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0110] Ring B1 is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, and the ring B1 is optionally substituted by 1 to 4 R b replace;

[0111] Ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, imidazopyrimidinyl, and the ring B is optionally substituted by 1 to 4 R b replace;

[0112] L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0113] R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0114] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0115] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (II-a) or (II-b) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0116] Ring B1 is selected from b One of the following groups substituted:

[0117] Its right side is connected to ring C;

[0118] Ring B is selected from b One of the following groups substituted:

[0119]

[0120] Its right side is connected to ring C;

[0121] R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl;

[0122] R a , R b , R c , R d Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, -P(=O)R 5a R 5b , or optionally 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0123] R 5a , R 5b Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 3 R k replace;

[0124] R 1 , R 2 , R 3 , RL1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2 or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0125] Alternatively, R L1 , R L2 and the carbon atom to which it is attached together form a k Substituted groups as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;

[0126] Alternatively, R 5a , R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted with the following groups:

[0127] R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0128] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0129] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (II-a) or (II-b) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0130] R 4Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2,

[0131] Ring A is selected from a substituted by one of the following groups: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl;

[0132] Ring C is selected from optionally 1 to 4 R c Substituted with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl;

[0133] Ring D is selected from d substituted by one of the following groups: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl,

[0134] L2 Selected from -CR L1 R L2 - or optionally 1 to 3 R k One of the following groups substituted:

[0135] R L1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylthio;

[0136] R kEach independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0137] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0138] As a sixth embodiment of the present invention, the compounds represented by the following general formula (III-a), (III-b), (III-c), (III-d) or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0139]

[0140] X is selected from O or S;

[0141] L1 is selected from -C(=O)-;

[0142] L2 is selected from

[0143] R 4 Selected from

[0144] Ring A is selected from a substituted phenyl or pyridyl;

[0145] Ring C is selected from optionally 1 to 4 R c Substituted oxacyclopentyl or oxacyclohexyl;

[0146] Ring D is selected from d Substituted structures: phenyl,

[0147] R 1 , R 2 , R 3Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0148] R a , R b or R c Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl,

[0149] R d is selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH,

[0150] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below:

[0151] Table E-1

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161] The present invention relates to a pharmaceutical composition, comprising the above compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0162] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases related to GLP-1R activity or expression.

[0163] The present invention relates to the use of the above-mentioned compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in preparing a drug for treating diabetes.

[0164] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

[0165] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

[0166] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., diabetes) being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising 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, 1-800 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, 3-500 mg g, 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, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 25 0-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 7 5-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200 mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0167] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 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,

[0168] 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg,

[0169] 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 of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0170] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to GLP-1R activity or expression (such as diabetes).

[0171] A method for treating a disease in a mammal, the method comprising administering to a subject a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0172] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

[0173] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0174] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0175] Synthesis method 1:

[0176]

[0177] The general formula (Z1) and the general formula (Z2) are cyclized to obtain the corresponding general formula (Z3), and the general formula (Z3) is then cyclized with the general formula (Z4) to obtain the corresponding general formula (Z5). The general formula (Z5) and the general formula (Z6) undergo a coupling reaction under the catalysis of a heavy metal catalyst to obtain the corresponding general formula (Z7). The general formula (Z7) is deprotected under strong acid conditions (such as TFA) to obtain the corresponding general formula (Z8). The general formula (Z8) and the general formula (Z9) are combined with a condensation agent (such as HATU) to obtain the corresponding general formula (I).

[0178] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0179] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0180] "CN" refers to cyano.

[0181] "Halogen" refers to F, Cl, Br or I.

[0182] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0183] "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.

[0184] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0185] "Alkylene" refers to substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0186] "Heteroalkylene" refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0187] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0188] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0189] "Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-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, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0190] "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 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 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, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentynyl 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

[0191] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0192] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0193] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, 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]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl,

[0194] "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0195] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O or S (=O) n (n is 0, 1 or 2).

[0196] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0197] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0198] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0199] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0200] "Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

[0201] "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.

[0202] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0203] "Heterocyclic ring", "heterocyclic group", "cyclic heterocyclic group" or "cyclic heterocyclic group" refers to a "cyclic ring" containing a heteroatom.

[0204] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0205] "Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

[0206] "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.

[0207] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 selected heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0208] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -Alkenyl-Ra , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0209] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0210] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0211] 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.

[0212] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0213] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0214] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0215] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0216] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0217] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0218] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0219] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0220] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0221] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0222] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0223] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0224] “IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0225] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0226] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0227] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0228] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0229] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plate: The silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification of products is 0.4mm-0.5mm;

[0230] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier. Boc: tert-butoxycarbonyl;

[0231] Ts: p-toluenesulfonyl;

[0232] Cbz: benzyloxycarbonyl;

[0233] TMS: trimethylsilyl.

[0234] DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DBU: CAS6674-22-2; DMSO: dimethyl sulfoxide; DCM: dichloromethane; HATU: CAS148893-10-1.

[0235] abs1 / abs2 represents a single configuration where the chiral center is unknown.

[0236] Example 1: Preparation of Compound 1

[0237]

[0238] Step 1: Preparation of compound 1b

[0239] Substrate 1a (5.08 g, 26.0 mmol) was dissolved in chloroform (55 mL), precooled in an ice bath for 5 minutes, and N-bromosuccinimide (4.63 g, 26.0 mmol) was added in batches. After the addition was completed, the reaction was continued in an ice bath for 2 hours. Water (60 mL) was added to the reaction system to quench the reaction, and dichloromethane (100 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 1b (6.2 g, yield 86.99%).

[0240] LCMS m / z=274.1[M+H] +

[0241] Step 2: Preparation of compound 1c

[0242] The substrate 1b (5.43 g, 16.84 mmol) was dissolved in 1,4-dioxane (60 mL), and then 1b-1 (5.49 g, 18.52 mmol), bistriphenylphosphine palladium dichloride (0.59 g, 0.84 mmol) and lithium tert-butoxide (2.97 g, 37.05 mmol) were added in sequence. After the addition was completed, the temperature was raised to 100 ° C under a nitrogen atmosphere and reacted for 18 hours. The reaction was cooled to room temperature, and water (100 mL) was added to the reaction system to quench the reaction, and ethyl acetate (50 mL × 3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 1c (1.68 g, yield 32.67%).

[0243] LCMS m / z=306.0[M+H] +

[0244] Step 3: Preparation of compound 1d

[0245] Substrate 1c (1.55 g, 5.08 mmol) was dissolved in a mixed solvent of methanol (30 mL), and then platinum dichloride (0.27 g, 1.02 mmol) was added, and the temperature was raised to 40°C under a hydrogen atmosphere for 36 hours. The reaction was cooled to room temperature, the reaction system was filtered and the filter cake was washed with ethyl acetate (5 mL × 2), and the filtrate was collected and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain the target product 1d (0.493 g, yield 31.59%).

[0246] LCMS m / z=308.1[M+H] +

[0247] Step 4: Preparation of compound 1e

[0248] The substrate 1d (0.49 g, 1.59 mmol) was dissolved in DMF (10 mL). Sodium hydride (0.038 g, 1.59 mmol) was slowly added to the system in batches under nitrogen atmosphere and ice bath. After the addition, the reaction was continued under nitrogen atmosphere and ice bath for 30 minutes. Finally, chloroacetonitrile (0.24 g, 3.18 mmol) was added dropwise to the system. After the addition, the temperature was slowly raised to room temperature and the reaction was continued for 18 hours. Under ice bath, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction. The reaction was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, and the organic phases were backwashed with saturated brine (80 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 1e (0.486 g, yield 88.23%).

[0249] LCMS m / z=347.2[M+H] +

[0250] Step 5: Preparation of Compound 1f

[0251] The substrate 1e (0.423 g, 1.22 mmol) and 1e-1 (0.45 g, 3.62 mmol) were dissolved in tetrahydrofuran (5 mL), precooled under nitrogen atmosphere and ice bath for 5 minutes, 1M lithium bistrimethylsilylamide (0.82 mL, 4.88 mmol) was added dropwise to the reaction system, and the reaction was continued under nitrogen atmosphere and ice bath for 2 hours. Under ice bath, saturated aqueous ammonium chloride solution (20 mL) was added to the reaction system to quench the reaction, and ethyl acetate (20 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 1f (0.258 g, yield 56.77%).

[0252] LCMS m / z=373.2[M+H] +

[0253] Step 6: Preparation of compound 1g

[0254] The substrate 1f (0.222 g, 0.60 mmol) was dissolved in DMSO (5 mL), and then an aqueous solution of hydroxylamine (0.40 g, 6.0 mmol, 50% wt) was added. The reaction was carried out at room temperature for 18 hours. The raw material was completely converted under the monitoring of TLC and LCMS. Water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined, and the organic phases were backwashed with saturated brine (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was dissolved in DMSO (5 mL), and then N,N'-carbonyldiimidazole (0.19 g, 1.2 mmol) and DBU (0.23 g, 1.5 mmol) were added in sequence. After the addition was completed, the reaction was carried out at room temperature for 1 hour under a nitrogen atmosphere. Water (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined and backwashed with saturated brine (60 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1 g (0.258 g, yield 99.65%) of a crude product, which was directly used in the next step without any purification.

[0255] LCMS m / z=432.2[M+H] +

[0256] Step 7: Preparation of compound 1h

[0257] The substrate 1g (0.258g, 0.6mmol) was dissolved in DMSO (5mL), and then sodium hydroxide (0.060g, 1.5mmol) was prepared into a 2M sodium hydroxide aqueous solution and added dropwise to the system. After the addition, the reaction was allowed to proceed at 30°C for 18 hours. Water (50mL) was added to the reaction system to quench the reaction, and the pH was adjusted to 2-3 with a 1N hydrochloric acid aqueous solution. The filter cake was filtered and washed with water (5mL×2). The filter cake was dissolved with ethyl acetate (30mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1h (0.176g, yield 72.71%).

[0258] LCMS m / z=404.2[M+H] +

[0259] 1 H NMR(400MHz,DMSO-d6)δ12.29(s,1H),7.03(s,1H),6.85(d,1H),3.71–3.63(m,2H), 3.27–3.17(m,1H),1.97–1.62(m,6H),1.57–1.39(m,2H),1.23(s,3H),1.17(s,3H).

[0260] Step 8: Preparation of Compound 1

[0261] The substrate 1h (0.04 g, 0.1 mmol) was dissolved in DCM (3 mL), precooled in an ice bath and nitrogen atmosphere for 5 minutes, and then DMF (0.00073 g, 0.01 mmol) and oxalyl chloride (0.025 g, 0.20 mmol) were added dropwise. After the addition was completed, the temperature was naturally raised to room temperature for reaction for 1 hour; the reaction solution and excess oxalyl chloride were removed by vacuum concentration to obtain a crude acyl chloride. Under an ice bath, 1h-1 (0.051 g, 0.11 mmol) was dissolved in DCM (2 mL), and then triethylamine (0.10 g, 1.0 mmol) was added. Finally, the crude acyl chloride was dissolved in DCM (1 mL), slowly added dropwise to the system, and reacted at room temperature for 18 hours under a nitrogen atmosphere. Water (10 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 1 (0.03 g, yield 34.29%).

[0262] LCMS m / z=875.3[M+H] +

[0263] Example 2: Preparation of Compound 2

[0264]

[0265] Step 1: Preparation of compound 2b

[0266] Substrate 2a (10.18 g, 53.0 mmol) was dissolved in methanol (30 mL), and then methyl azidoacetate (15.25 g, 132.53 mmol) was added. The mixture was precooled at -20 °C for 10 minutes, and then sodium methoxide (23.86 g, 132.53 mmol, 30% wt in MeOH) was slowly added dropwise. After the addition was completed, the mixture was heated to 0 °C and reacted for 24 hours. Saturated aqueous ammonium chloride solution (100 mL) was slowly added to the reaction system, and a large amount of solid precipitated. The solid was filtered and the filter cake was washed with water (10 mL × 2). The filter cake was collected and dissolved with ethyl acetate (200 mL). The organic phase was backwashed with saturated aqueous sodium chloride solution (200 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain product 2b (9.18 g, yield 59.90%).

[0267] Step 2: Preparation of compound 2c

[0268] Substrate 2b (11.06 g, 38.26 mmol) was dissolved in toluene (100 mL), and then heated to 100 °C for 1 hour under nitrogen atmosphere. The reaction was cooled to room temperature, the reaction system was filtered and the filter cake was washed with toluene (5 mL × 2), and the filter cake was collected and dried to obtain the target product 2c (7.55 g, yield 75.59%).

[0269] Step 3: Preparation of compound 2d

[0270] At room temperature, zinc powder (14.19 g, 216.9 mmol, Purity>99.99%) was dissolved in DMA (90 mL), and then trimethylsilyl chloride (6.07 g, 55.88 mmol) and 1,2-dibromoethane (5.28 g, 28.08 mmol) were added dropwise. After the addition was completed, 2c-1 (34.72 g, 144.60 mmol) was dissolved in DMF (25 mL) and slowly added dropwise to the system. After the addition was completed, the reaction was carried out at room temperature for 2 hours under a nitrogen atmosphere. Substrate 2c (7.55 g, 28.92 mmol), Pd(dppf)Cl2.CH2Cl2 (2.72 g, 3.33 mmol) and cuprous iodide (906.0 mg, 4.76 mmol) were added to the system in sequence. After the addition was completed, the temperature was raised to 80°C under a nitrogen atmosphere and the reaction was carried out for 2 hours. The reaction was cooled to room temperature, saturated aqueous ammonium chloride solution (150 mL) was added to quench the reaction, the system was filtered and the filter cake was washed with ethyl acetate (10 mL × 3), the filtrate was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and the organic phases were backwashed with saturated aqueous sodium chloride solution (150 mL × 2), the organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain the target product racemate 2d (1.1 g, yield: 12.90%).

[0271] LCMS m / z=295.0[M+H] +

[0272] 1.1 g of the racemate was prepared by SFC and freeze-dried to obtain white solid compound 2d-P1 (486.4 mg, retention time: 1.449 min) and compound 2d-P2 (433.4 mg, retention time: 1.592 min).

[0273] SFC preparation conditions:

[0274] Instrument: Waters 150Prep-SFC, preparation column: Chiral Cellulose-2column. Preparation method: The crude product was dissolved in acetonitrile and methanol to prepare a sample solution with a concentration of 20 mg / mL. Mobile phase system: carbon dioxide / 0.1% NH3.H2O in methanol, 0.1% NH3.H2O in methanol with a content of 35%; flow rate: 100 mL / min, elution time: 3.8 min.

[0275] Chirality test method:

[0276] Instrument: SHIMADZU LC-30AD sf, preparation column: Chiral Cellulose-2 column. Preparation method: The crude product is dissolved in acetonitrile and methanol to prepare the sample solution. Mobile phase system: carbon dioxide / 0.05% DEA methanol solution. Elution gradient: 5%-40%; elution time: 3min).

[0277] Step 4: Preparation of compound 2e-P1

[0278] Under ice bath, the substrate 2d-P1 (182.51 mg, 0.62 mmol) was dissolved in DMF (10 mL), and then sodium hydride (49.60 mg, 1.24 mmol, 60% wt in mineral oil) was added in batches, stirred under ice bath for 30 minutes, and finally chloroacetonitrile (140.43 mg, 1.86 mmol) was added. After addition, the reaction was carried out at 25 ° C for 18 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with saturated aqueous sodium chloride solution (50 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 2e-P1 (195 mg, yield 94.33%).

[0279] LCMS m / z=334.1[M+H] +

[0280] Step 5: Preparation of compound 2f-P1

[0281] The substrate 2e-P1 (193.38 mg, 0.58 mmol) and 1e-1 (287.96 mg, 2.32 mmol) were dissolved in tetrahydrofuran (5 mL), precooled under nitrogen atmosphere and ice bath for 5 minutes, and LiHMDS (291.15 mg, 1.74 mmol) was added dropwise to the reaction system. After the addition, the reaction was continued under nitrogen atmosphere and ice bath for 2 hours. Under ice bath, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction system to quench the reaction, and ethyl acetate (10 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 2f-P1 (118 mg, yield 56.60%).

[0282] LCMS m / z=360.2[M+H] +

[0283] Step 6: Preparation of compound 2g-P1

[0284] The substrate 2f-P1 (100 mg, 0.28 mmol) was dissolved in DMSO (5 mL), and then an aqueous solution of hydroxylamine (184.97 mg, 2.80 mmol, 50% wt in H2O) was added. After the addition was completed, the reaction was carried out at 25°C for 18 hours. The raw material was completely converted under TLC and LCMS monitoring. Water (25 mL) was added to quench the reaction, and ethyl acetate (10 mL×3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with a saturated aqueous sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product (109.89 mg, 0.28 mmol) was dissolved in DMSO (5 mL), and then N,N'-carbonyldiimidazole (90.80 mg, 0.56 mmol) and DBU (106.57 mg, 0.70 mmol) were added in sequence. After the addition was completed, the reaction was carried out at 25°C for 2 hours under a nitrogen atmosphere. Water (50 mL) was added to the reaction system to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL×3). The organic phases were combined and backwashed with saturated brine (50 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the target product 2g-P1 (76 mg, yield 65.39%).

[0285] LCMS m / z=419.2[M+H] +

[0286] Step 7: Preparation of compound 2h-P1

[0287] The substrate 2g-P1 (75.32 mg, 0.18 mmol) was dissolved in DMSO (3 mL), and then sodium hydroxide (18 mg, 0.45 mmol) was prepared into a 2M sodium hydroxide aqueous solution and added dropwise to the system. After addition, the reaction was allowed to proceed at 30°C for 18 hours. Water (30 mL) was added to the reaction system to quench the reaction, and the pH was adjusted to 2-3 with a 1N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (10 mL × 2), the organic phases were combined, and the organic phases were backwashed with a saturated sodium chloride aqueous solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude target product 2h-P1 (61 mg, yield 83.80%), which was used directly in the next step without any purification.

[0288] LCMS m / z=405.1[M+H] +

[0289] Step 8: Preparation of Compound 2

[0290] The crude product 2h-P1 (61 mg, 0.15 mmol) was dissolved in DMF (3 mL), and then 1h-1 (73.43 mg, 0.15 mmol), HATU (62.74 mg, 0.17 mmol) and N, N-diisopropylethylamine (96.93 mg, 0.75 mmol) were added in sequence. After the addition, the temperature was raised to 40 ° C under a nitrogen atmosphere for 24 hours. Under an ice bath, water (30 mL) was added to the reaction system to quench the reaction, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with a saturated sodium chloride aqueous solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 2 (26 mg, yield 19.72%).

[0291] LCMS m / z=876.2[M+H] +

[0292] Example 3: Preparation of Compound 3

[0293]

[0294] Step 1: Preparation of compound 3a-P2

[0295] Under ice bath, the substrate 2d-P2 (135.41 mg, 0.46 mmol) was dissolved in DMF (5 mL), and then sodium hydride (36.80 mg, 0.92 mmol, 60% wt in mineral oil) was added in batches, stirred under ice bath for 30 minutes, and finally chloroacetonitrile (104.19 mg, 1.38 mmol) was added. After addition, the reaction was carried out at 25 ° C for 18 hours under nitrogen atmosphere. Saturated aqueous ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with saturated aqueous sodium chloride solution (50 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 3a-P2 (142 mg, yield 92.59%).

[0296] LCMS m / z=334.1[M+H] +

[0297] Step 2: Preparation of compound 3b-P2

[0298] The substrate 3a-P2 (143.37 mg, 0.43 mmol) and 1e-1 (213.49 mg, 1.72 mmol) were dissolved in tetrahydrofuran (5 mL), precooled under nitrogen atmosphere and ice bath for 5 minutes, and LiHMDS (215.86 mg, 1.29 mmol) was added dropwise to the reaction system. After the addition, the reaction was continued under nitrogen atmosphere and ice bath for 2 hours. Under ice bath, saturated aqueous ammonium chloride solution (10 mL) was added to the reaction system to quench the reaction, and ethyl acetate (10 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 3b-P2 (84 mg, yield 54.35%).

[0299] LCMS m / z=360.2[M+H] +

[0300] Step 6: Preparation of compound 3c-P2

[0301] The substrate 3b-P2 (82.67 mg, 0.23 mmol) was dissolved in DMSO (5 mL), and then hydroxylamine aqueous solution (151.94 mg, 2.30 mmol, 50% wt in H2O) was added. After addition, the reaction was allowed to react at 25°C for 18 hours. Water (25 mL) was added to the reaction system to quench the reaction, and ethyl acetate (10 mL×3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with saturated sodium chloride aqueous solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product; the crude product (90.27 mg, 0.23 mmol) was dissolved in DMSO (5 mL), and then N,N'-carbonyldiimidazole (74.59 mg, 0.46 mmol) and DBU (87.54 mg, 0.58 mmol) were added in sequence. After addition, the reaction was allowed to react at room temperature under nitrogen atmosphere for 2 hours. Water (50 mL) was added to the reaction system to quench the reaction, and the reaction was extracted with ethyl acetate (15 mL×3). The organic phases were combined and backwashed with saturated sodium chloride aqueous solution (50 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the target product 3c-P2 (50 mg, yield 51.95%).

[0302] LCMS m / z=419.2[M+H] +

[0303] Step 7: Preparation of compound 3d-P2

[0304] The substrate 3c-P2 (50 mg, 0.12 mmol) was dissolved in DMSO (3 mL), and then sodium hydroxide (12 mg, 0.30 mmol) was added dropwise to the system in a 2M sodium hydroxide aqueous solution. After addition, the reaction was allowed to proceed at 30°C for 18 hours. Water (30 mL) was added to the reaction system to quench the reaction, and the pH was adjusted to 2-3 with 1N hydrochloric acid aqueous solution. The mixture was extracted with ethyl acetate (10 mL × 2), the organic phases were combined, and the organic phases were backwashed with a saturated sodium chloride aqueous solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude target product 3d-P2 (34 mg, yield 70.36%), which was used directly in the next step without any purification.

[0305] LCMS m / z=405.2[M+H] +

[0306] Step 8: Preparation of compound 3

[0307] The crude product 3d-P2 (34 mg, 0.084 mmol) was dissolved in DMF (3 mL), and then 1h-1 (41.12 mg, 0.084 mmol), HATU (35.13 mg, 0.092 mmol) and N,N-diisopropylethylamine (54.28 mg, 0.42 mmol) were added in sequence. After the addition, the temperature was raised to 40 ° C under a nitrogen atmosphere for 24 hours. Under an ice bath, water (30 mL) was added to the reaction system to quench the reaction, and ethyl acetate (10 mL × 3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with a saturated sodium chloride aqueous solution (30 mL × 2). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain compound 3 (16 mg, yield 21.78%).

[0308] LCMS m / z=876.3[M+H] +

[0309] Example 4: Preparation of Compound 4

[0310]

[0311] Step 1: Preparation of compound 1d

[0312] At room temperature, zinc powder (12.93 g, 197.7 mmol, Purity>99.99%) was dissolved in DMA (100 mL), and then trimethylsilyl chloride (5.53 g, 50.87 mmol) and 1,2-dibromoethane (4.80 g, 25.57 mmol) were added dropwise. After the addition, 2c-1 (31.64 g, 131.8 mmol) was dissolved in DMF (30 mL) and slowly added dropwise to the system. After the addition, the reaction was carried out at room temperature for 2 hours under nitrogen atmosphere. Substrate 1b (8.5 g, 26.36 mmol), Pd(dppf)Cl2.CH2Cl2 (2.58 g, 3.16 mmol) and cuprous iodide (0.80 g, 4.22 mmol) were added to the system in sequence (under nitrogen atmosphere protection). After the addition, the temperature was raised to 80°C under nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature, saturated aqueous ammonium chloride solution (500 mL) was added to quench the reaction, the system was filtered and the filter cake was washed with ethyl acetate (10 mL x 3), the filtrate was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, and the organic phases were backwashed with saturated aqueous sodium chloride solution (300 mL x 2), the organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by silica gel column chromatography to obtain the target product racemate 1d (3.6 g, yield 44.43%).

[0313] LCMS m / z=308.2[M+H] +

[0314] SFC preparation conditions:

[0315] Instrument: Waters 150Prep-SFC C, preparation column: Chiralcel OX Column. Preparation method: Dissolve the crude product in acetonitrile and prepare a 10 mg / ml sample solution. Mobile phase system: carbon dioxide / methanol, methanol content 30%; elution time: 8 min.

[0316] Two batches of racemate (5.98 g) were prepared by SFC and concentrated to give a white solid compound 1d-P1 (2.8 g, retention time:

[0317] 1.137 min) and compound 1d-P2 (3.0 g, retention time: 1.526 min).

[0318] Step 2: Preparation of compound 4a

[0319] 4a (370.0 mg, yield 99.81%) was obtained from substrate 1d-P1 (330 mg, 1.07 mmol) according to the synthetic method of 1e.

[0320] LCMS m / z=347.2[M+H] +

[0321] Step 3: Preparation of compound 4b

[0322] 4b (70.0 mg, yield 65.11%) was obtained from substrate 4a (100.00 mg, 0.29 mmol) according to the synthetic method of 1f.

[0323] LCMS m / z=373.2[M+H] +

[0324] Step 4: Preparation of compound 4c

[0325] 4c (81.0 mg, yield 99.88%) was obtained from substrate 4b (70 mg, 0.19 mmol) according to the synthetic method of 1g.

[0326] LCMS m / z=432.2[M+H] +

[0327] Step 5: Preparation of compound 4d

[0328] 4d (75 mg, yield 97.84%) was obtained from substrate 4c (81.99 mg, 0.19 mmol) according to the synthetic method of 1h.

[0329] LCMS m / z=404.2[M+H] +

[0330] Step 6: Preparation of compound 4

[0331] Substrate 4c (0.075 g, 0.19 mmol) was dissolved in DMF (3 mL), and then 1h-1 (0.098 g, 0.20 mmol), HATU (0.079 g, 0.21 mmol) and N,N-diisopropylethylamine (0.12 g, 0.95 mmol) were added in sequence. After the addition, the temperature was raised to 50 ° C under a nitrogen atmosphere for 18 hours. The reaction was cooled to room temperature, water (30 mL) was added to the system to quench the reaction, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, and the organic phases were backwashed with saturated brine (50 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography and freeze-dried to obtain the target product, compound 4 (0.069 g, yield 41.51%).

[0332] LCMS m / z=875.5[M+H] +

[0333] Example 5: Preparation of Compound 5

[0334]

[0335] Step 1: Preparation of compound 5a

[0336] 5a (330.0 mg, yield 98.59%) was obtained from substrate 1d-P2 (297 mg, 0.97 mmol) according to the synthetic method of 1e.

[0337] LCMS m / z=347.2[M+H] +

[0338] Step 2: Preparation of compound 5b

[0339] 5b (78.0 mg, yield 72.55%) was obtained from substrate 5a (100.00 mg, 0.29 mmol) according to the synthetic method of 1f.

[0340] LCMS m / z=373.2[M+H] +

[0341] Step 3: Preparation of compound 5c

[0342] 5c (83.0 mg, yield 91.85%) was obtained from substrate 5b (78 mg, 0.21 mmol) according to the synthetic method of 1g.

[0343] LCMS m / z=432.2[M+H] +

[0344] Step 4: Preparation of compound 5d

[0345] 5d (77 mg, yield 99.22%) was obtained from substrate 5c (83.0 mg, 0.19 mmol) according to the synthetic method of 1h.

[0346] LCMS m / z=404.2[M+H] +

[0347] Step 5: Preparation of compound 5

[0348] Compound 5 (72.0 mg, yield 43.12%) was obtained from substrate 5d (77.0 mg, 0.19 mmol) according to the synthesis method of compound 4.

[0349] LCMS m / z=875.5[M+H] +

[0350] Example 6: Preparation of Compound 6

[0351]

[0352] Step 1: Preparation of compounds 6a-P1 and 6a-P2

[0353] 6a-P1 (157.0 mg, yield 12.79%) and 6a-P2 (88.0 mg, yield 7.17%) were obtained from substrate 4a (1.10 g, 3.18 mmol) according to the synthetic method of 1f.

[0354] LCMS m / z=387.1[M+H] +

[0355] Step 2: Preparation of compound 6b

[0356] 6b (140.0 mg, yield 76.64%) was obtained from substrate 6a-P1 (157.00 mg, 0.41 mmol) according to the synthetic method of 1g.

[0357] LCMS m / z=446.2[M+H] +

[0358] Step 4: Preparation of compound 6c

[0359] 6c (41.0 mg, yield 98.21%) was obtained from substrate 4b (44.55 mg, 0.1 mmol) according to the synthetic method of 1h.

[0360] LCMS m / z=418.1[M+H] +

[0361] Step 5: Preparation of compound 6

[0362] Compound 6 (20.0 mg, yield 22.91%) was obtained from substrate 4b (41.0 mg, 0.1 mmol) according to the synthesis method of compound 4.

[0363] LCMS m / z=889.2[M+H] +

[0364] Example 7: Preparation of Compound 7

[0365]

[0366] Step 2: Preparation of compound 7a

[0367] 6b (53.0 mg, yield 51.72%) was obtained from substrate 6a-P2 (88.90 mg, 0.23 mmol) according to the synthetic method of 1g.

[0368] LCMS m / z=446.2[M+H] +

[0369] Step 4: Preparation of compound 7b

[0370] 6c (49.5 mg, yield 98.81%) was obtained from substrate 7a (53.0 mg, 0.12 mmol) according to the synthetic method of 1h.

[0371] LCMS m / z=418.1[M+H] +

[0372] Step 5: Preparation of compound 7

[0373] Compound 6 (18.0 mg, yield 17.25%) was obtained from substrate 7b (49.0 mg, 0.12 mmol) according to the synthesis method of compound 4.

[0374] LCMS m / z=889.2[M+H] +

[0375] Example 8: Preparation of Compound 8

[0376]

[0377] Step 1: Preparation of 8a-P1 and 8a-P2

[0378] Substrate 5a (2.13 g, 6.15 mmol) and 4a-1 (2.55 g, 18.45 mmol) were dissolved in tetrahydrofuran (25 mL), and lithium bis(trimethylsilyl)amide (4.12 g, 24.6 mmol) was slowly added dropwise under ice bath, and the reaction was continued at 0°C for 2 hours. Under ice bath, saturated aqueous ammonium chloride solution (50 mL) was added to the reaction system to quench the reaction, and ethyl acetate (30 mL×3) was used for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain chiral mixture 8a (1.65 g, yield 69.43%).

[0379] LCMS m / z=387.2[M+H] +

[0380] SFC preparation conditions:

[0381] Instrument: SFC Prep 150AP, preparation column: IC (19mm×250mm). Preparation method: The sample is dissolved in methanol and filtered with a 0.45μm filter to prepare the sample solution. Mobile phase system: carbon dioxide / isopropanol, isopropanol content 33%; flow rate: 40mL / min.

[0382] The chiral mixture 8a (1.65 g) was subjected to SFC chiral separation to obtain 8a-P1 (950 mg, retention time: 9.88 min) and 8a-P2 (600 mg, retention time: 11.78 min).

[0383] Step 2: Preparation of 8b

[0384] Substrate 8a-P1 (913 mg, 2.36 mmol) and hydroxylamine hydrochloride (1.64 g, 23.60 mmol) were dissolved in dimethyl sulfoxide (10 mL), and then sodium carbonate (2.50 g, 23.60 mmol) was added. After addition, the temperature was raised to 60 ° C under nitrogen atmosphere for 18 hours. The reaction was cooled to room temperature, quenched by adding water (30 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, backwashed with saturated sodium chloride (30 mL), the organic phases were collected, dried over sodium sulfate, filtered and concentrated to obtain a crude product; the crude product was dissolved in DMSO (10 mL), and then N, N'-carbonyldiimidazole (765.35 mg, 4.72 mmol) and DBU (898.22 mg, 5.90 mmol) were added in sequence. After addition, the reaction was reacted at room temperature under nitrogen atmosphere for 2 hours. Water (50 mL) was added to the reaction system to quench the reaction, and 1N hydrochloric acid was added dropwise to pH = 6-7. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and backwashed with saturated brine (100 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain 8b (624 mg, yield 59.35%).

[0385] LCMS m / z=444.2[MH] -

[0386] Step 3: Preparation of 8c

[0387] Substrate 8b (622 mg, 1.40 mmol) was dissolved in DMSO (7 mL), and then a 2M aqueous solution of sodium hydroxide (168.00 mg, 4.20 mmol) was added dropwise to the system. After addition, the mixture was reacted at 30°C for 16 hours. Water (30 mL) was added to the reaction system to quench the reaction, and 1N hydrochloric acid was added dropwise to pH = 1-2. The aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined, and the organic phases were backwashed with saturated sodium chloride (100 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 8c (582 mg, yield 99.86%), which was directly used in the next step without any purification.

[0388] LCMS m / z=416.2[MH] -

[0389] Step 4: Preparation of compound 8

[0390] Compound 8 (20.0 mg, yield 31.31%) was obtained from substrate 8c (30.0 mg, 0.072 mmol) according to the synthesis method of compound 4.

[0391] LCMS m / z=889.3[M+H] +

[0392] Example 9: Preparation of Compound 9

[0393]

[0394] Step 1: Preparation of 9a

[0395] 9a (383 mg, yield 63.27%) was obtained from substrate 8a-P2 (566 mg, 1.46 mmol) according to the synthetic method of 8b.

[0396] LCMS m / z=444.2[MH] -

[0397] Step 2: Preparation of 9b

[0398] Substrate 9a (378 mg, 0.85 mmol) was used to obtain 9b (336 mg, yield 94.86%) by referring to the synthetic method of 8c.

[0399] LCMS m / z=416.3[MH] -

[0400] Step 3: Preparation of compound 9

[0401] Compound 9 (15.0 mg, yield 18.54%) was obtained from substrate 9b (38.0 mg, 0.091 mmol) according to the synthesis method of compound 4.

[0402] LCMS m / z=887.2[MH] -

[0403] Example 10: Preparation of Compound 10

[0404]

[0405] Step 1: Preparation of 10b

[0406] Methyltriphenylphosphonium bromide (20.0 g, 55.99 mmol) was dissolved in ultra-dry THF (100 mL) under ice bath conditions, and 1 M potassium tert-butoxide-tetrahydrofuran solution (60.0 mL, 60.0 mmol) was added to the system. The reaction was carried out under nitrogen atmosphere under the same conditions for 0.5 hour, and then 10a (8.0 g, 39.41 mmol) was added. The system was warmed to room temperature and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 10b (3.46 g, yield 43.67%).

[0407] Step 2: Preparation of 10c

[0408] 10b (2.0 g, 9.95 mmol) was dissolved in dichloromethane (20 mL), and bromosuccinimide (4.4 g, 24.72 mmol) and triethylamine trihydrofluoride (4.8 g, 29.77 mmol) were added under ice bath and reacted at room temperature for 16 hours. 50 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 10c (600 mg, yield 20.11%).

[0409] Step 3: Preparation of 10d

[0410] 10c (550 mg, 1.83 mmol) was dissolved in petroleum ether (10 mL), potassium tert-butoxide (1.2 g, 10.69 mmol) was added, and the mixture was reacted at room temperature for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 10d (400 mg, yield 99.59%).

[0411] Step 4: Preparation of 10e

[0412] 1M diethylzinc n-hexane solution (4 mL, 4 mmol) was dissolved in ultra-dry dichloromethane (4 mL) under ice bath conditions, trifluoroacetic acid (0.3 mL, 4.04 mmol) was slowly added dropwise to the system, and the reaction was carried out under the same conditions of nitrogen atmosphere for 0.5 hour, and then diiodomethane (0.35 mL, 4.34 mmol) was added. After stirring for 20 minutes, 10d (400 mg, 1.83 mmol) was added, and the system was warmed to room temperature for 16 hours. 10 mL of saturated aqueous ammonium chloride solution was added to the reaction solution, and the solution was extracted with dichloromethane (10 mL×3). The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 10e (370 mg, yield 86.94%).

[0413] Step 5: Preparation of 10f

[0414] 10e (370 mg, 1.59 mmol) was dissolved in ultra-dry THF (5 mL), and 2.5 M n-butyllithium tetrahydrofuran solution (0.7 mL, 1.75 mmol) was added at -78°C and reacted under the same conditions for 1 hour. Di-tert-butyl azodicarboxylate (400 mg, 1.74 mmol) was added to the system and the temperature was raised to room temperature for 2 hours. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 10f (239 mg, yield 39.16%).

[0415] Step 6: Preparation of 10g

[0416] 10f (230 mg, 0.60 mmol) was dissolved in N-methylpyrrolidone (2 mL), and methanesulfonic acid (0.3 mL, 4.62 mmol) was added. The mixture was reacted at 80 °C for 16 h. 5 mL of water was added to the system, and the mixture was extracted with ethyl acetate (5 mL × 3), washed with saturated aqueous sodium chloride solution (5 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 10 g (100 mg, yield 90.74%), which was used directly in the next step without further purification.

[0417] Step 7: 10h preparation

[0418] Dissolve 10g (100mg, 0.54mmol) in toluene (2mL), add 10g-1 (145mg, 0.61mmol) and pyridine hydrochloride (10mg, 0.087mmol), react at 90℃ for 1 hour, concentrate the reaction solution under reduced pressure, and separate and purify the residue by column chromatography to obtain 10h (54mg, yield 24.59%).

[0419] LCMS m / z=405.3[M+H] +

[0420] Step 8: Preparation of 10i

[0421] 10h (50 mg, 0.12 mmol) was dissolved in pyridine (1 mL), and 10h-1 (40 mg, 0.31 mmol) and diethylamine (20 mg, 0.27 mmol) were added. The mixture was reacted at room temperature for 0.5 h. 5 mL of water was added to the system, and the mixture was extracted with ethyl acetate (5 mL×3), washed with saturated aqueous sodium chloride solution (5 mL×3), and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 10i (60 mg, yield 90.62%), which was used directly in the next step without further purification.

[0422] Step 9: Preparation of 10j

[0423] 10i (60 mg, 0.11 mmol) was dissolved in ultra-dry THF (2 mL), and methanesulfonic acid (0.1 mL, 1.54 mmol) was added. The mixture was reacted at 60 °C for 0.5 h. 5 mL of saturated sodium bicarbonate aqueous solution was added to the system, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 10j (50 mg, yield 94.66%).

[0424] LCMS m / z=472.2[M+H] +

[0425] Step 10: Preparation of 10k

[0426] 10j (150 mg, 0.32 mmol) and 10j-1 (88 mg, 0.38 mmol) were dissolved in N-methylpyrrolidone (3 mL), and cuprous iodide (61 mg, 0.32 mmol), (1S, 2S)-N, N'-dimethyl-1,2-cyclohexanediamine (68 mg, 0.48 mmol) and anhydrous potassium carbonate (89 mg, 0.64 mmol) were added to the system. The reaction was carried out at 130 ° C for 2 hours under a nitrogen atmosphere and then cooled to room temperature. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL×3), washed with saturated sodium chloride aqueous solution (10 mL×3), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 10k (132 mg, yield 66.96%).

[0427] LCMS m / z=620.4[M+H] +

[0428] Step 11: Preparation of 10L

[0429] 10k (132 mg, 0.21 mmol) was dissolved in dichloromethane (2 mL), 4 M hydrochloric acid-dioxane solution (1 mL) was added, and the reaction was carried out at room temperature for 3 hours. The system was concentrated to dryness to obtain a crude product 10l (118 mg, yield 99.63%), which was directly used in the next step reaction.

[0430] LCMS m / z=520.3[M+H] +

[0431] Step 12: Preparation of compound 10

[0432] The crude product 101 (60 mg, 0.11 mmol) was dissolved in ultra-dry DMF (1 mL), and HATU (41 mg, 0.11 mmol), triethylamine (0.15 mL, 0.91 mmol), and 8c (30 mg, 0.072 mmol) were added and reacted at 60°C in a nitrogen atmosphere for 48 hours. The reaction solution was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 0.1% TFA)) to obtain the target compound 10 (10 mg, 15.14%).

[0433] LCMS m / z=919.5[M+H] +

[0434] Example 11: Preparation of Compound 11

[0435]

[0436] Step 1: Preparation of 11b

[0437] 11a (2 g, 13.23 mmol) was dissolved in water (30 mL), concentrated hydrochloric acid (20 mL) was added, sodium nitrite (1.2 g, 17.33 mmol) was added after stirring at room temperature for 5 min, and the mixture was stirred at 0°C for 30 min. Tin chloride (5 g, 26.37 mmol) was slowly added at 0°C and reacted at room temperature for 2 hours. Potassium carbonate solid was added to the system until no bubbles were generated, and then extracted with ethyl acetate (30 mL×3), washed with saturated sodium chloride aqueous solution (30 mL×3), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 11b (2 g, yield 90.91%), which was directly used in the next step.

[0438] Step 2: Preparation of compound 11

[0439] Using 11b as substrate, the target compound 11 (10 mg, 15.45%) was obtained by referring to the synthesis method from step 7 to step 12 of Example 10.

[0440] LCMS m / z=901.5[M+H] +

[0441] Biological test cases

[0442] Cells: HEK293 / CRE-luc / GLP-1R

[0443] Cell culture medium: DMEM + 10% FBS + 400 μg / ml G418 + 100 μg / ml Hygromycin B

[0444] Cryopreservation medium: 90% FBS, 10% (V / V) DMSO

[0445] Assay buffer: DMEM + 1% FBS

[0446] Experimental procedures

[0447] The cells were cultured in DMEM medium + 10% FBS + 400 μg / ml G418 + 100 μg / ml Hygromycin B in a 37°C CO2 incubator and passaged every 3-4 days.

[0448] Cell plating: adjust the cell density to 1.67×105 cells / mL by trypsin digestion; inoculate 60 μL of cells per well in a 384-well plate (10,000 cells / well); set up NC wells (negative control) and background wells (no cells). Incubate in an incubator for about 18±2 hours.

[0449] The compound was diluted in a gradient manner with detection buffer, and the detection concentration ranged from 0.01 nM to 1000 nM.

[0450] Remove the cell culture plate and then aspirate all the supernatant from the cells. Wash twice with 1X PBS.

[0451] Add the diluted compounds to a 384-well plate (10 μL / well), set up 3 replicate wells for each concentration, add 10 μL of detection buffer to the NC wells, seal and incubate at 37°C for 6 hours.

[0452] The plate was removed and the cells were allowed to equilibrate to room temperature (at least 15 min), and then all supernatant was aspirated from the cells.

[0453] Add 10 μL / well Steady- Reagent and incubate at room temperature for 5 min to lyse the cells.

[0454] The test results were read using a BMG microplate reader.

[0455] Data processing

[0456] Calculate the average background value.

[0457] The fold of induction (FI) was calculated as (value of the induced well - background value) / (value of the negative control well - background value).

[0458] The EC of the samples was calculated using Graphpad Prim 8.0 software using a four-parameter fitting analysis. 50 Numeric value.

[0459] Statistical analysis

[0460] All results were statistically analyzed using Graphpad Prism software with mean ± SEM. Specific data are presented in graphs. P < 0.05 was considered statistically significant.

[0461] Biological test results:

[0462] Compound <![CDATA[EC 50 (nM)]]> Compound 1 A Compound 8 A

[0463] A<10nM, 10nM≤B<50nM, 50nM≤C<100nM

[0464] Conclusion: The compounds of the present invention have a good agonist effect on GLP-1 receptors. 50 The values ​​were less than 100 nM, for example, the EC values ​​of compound 1 and compound 8 50 The value is less than 10nM.

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein: represents a single bond or a double bond; Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring A is optionally substituted by 1 to 4 R a replace; Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 6- and 6-membered heteroaryl, C 3-10 carbocyclic ring, 4 to 10 membered heterocyclic ring, wherein the ring B is optionally substituted by 1 to 4 R b replace; Ring D is selected from C 6-12 carbocyclic ring, 5 to 12 membered heterocyclic ring, wherein the ring D is optionally substituted by 1 to 4 R d replace; Ring C is selected from C 3-12 Carbocyclic ring, 4 to 12 membered heterocyclic ring, wherein the ring C is optionally substituted by 1 to 4 R c replace; L1 is selected from -S(=O)2-, -C(=O)-; L2 is selected from -(CR L1 R L2 ) m -; X is selected from S or O; m is selected from 1, 2, 3 or 4; R 4 selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、 R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R a , R b , R c , R d Each independently selected from H, deuterium, halogen, =O, CN, OH, NO2, 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, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, -C(=O)NH-C 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -S(=O) 1-2 -C 1-6 Alkyl, -C(=O)NH-C 3-6 Carbocyclic ring, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3- to 7-membered heterocyclic ring, -P(=O)R 5a R 5b , The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring may be optionally substituted with 1 to 4 R k replace; R 5a , R 5b Each independently selected from C 1-6 Alkyl, C 3-6 The alkyl group or the carbocyclic ring is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace; Alternatively, R L1 , R L2 Together with the atoms connected to it, they form C 3-8 A carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R 5a , R 5b Together with the phosphorus atom to which it is attached, it forms a 5- to 8-membered heterocyclic ring, which is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; The condition is, When X is selected from O, Ring B is not selected from optionally 1 to 4 R b Substituted 5- and 6-membered heteroaryl.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (II-a) or (II-b), Ring B1 is selected from 5-membered heteroaryl, and the ring B1 is optionally substituted by 1 to 4 R b replace; Ring B is selected from 5-membered heteroaryl or 5-membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b replace; Ring C is selected from C 3-6 monocycloalkyl, 4-7 membered monoheterocyclic group, 6-11 membered spiro heterocyclic group, 5-11 membered bridged heterocyclic group, 7-10 membered heterocyclic group, wherein the ring C is optionally substituted by 1 to 4 R c replace; Ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclic ring, benzo 4 to 7 membered heterocyclic ring, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl ring, wherein the ring D is optionally substituted by 1 to 4 R d replace; Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 monocarbocyclic ring, 4 to 8 membered heteromonocyclic ring, wherein the ring A is optionally substituted by 1 to 4 R a replace; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 5a , R 5b Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace; Alternatively, R L1 , R L2 Together with the connected carbon atoms, they form C 3-6 A carbocyclic ring or a 4- to 6-membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally substituted by 1 to 4 R k replace; Alternatively, R 5a , R 5b Together with the phosphorus atom to which it is connected, it forms a 5- to 8-membered monocyclic heterocyclic ring, which is optionally substituted by 1 to 4 R k replace; R a , R b , R c , R d Each independently selected from H, deuterium, halogen, =O, 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, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 7 membered heterocyclic ring, -S(=O) 1-2 -C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocyclic ring, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbon ring, C 3-6 Carbocyclic ring, 3- to 7-membered heterocyclic ring, -P(=O)R 5a R 5b , The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace.

3. The compound according to claim 2, or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, Ring B1 is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, and the ring B1 is optionally substituted by 1 to 4 R b replace; Ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, imidazopyrimidinyl, and the ring B is optionally substituted by 1 to 4 R b replace; L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, 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: Ring B1 is selected from b One of the following groups substituted: Its right side is connected to ring C; Ring B is selected from b One of the following groups substituted: Its right side is connected to ring C; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl; R a , R b , R c , R d Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, -P(=O)R 5a R 5b , or optionally 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R 5a , R 5b Each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 3 R k replace; R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2 or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio; Alternatively, R L1 , R L2 and the carbon atom to which it is attached together form a k Substituted groups as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl; Alternatively, R 5a , R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted with the following groups: R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2, Ring A is selected from a substituted by one of the following groups: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl; Ring C is selected from optionally 1 to 4 R c Substituted with one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl; Ring D is selected from d substituted by one of the following groups: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl, L2 Selected from -CR L1 R L2 - or optionally 1 to 3 R k One of the following groups substituted: R L1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylthio; R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy.

6. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (III-a), (III-b), (III-c) and (III-d), X is selected from O or S; L1 is selected from -C(=O)-; L2 is selected from R 4 Selected from Ring A is selected from a substituted phenyl or pyridyl; Ring C is selected from optionally 1 to 4 R c Substituted oxacyclopentyl or oxacyclohexyl; Ring D is selected from d Substituted structures: phenyl, R 1 , R 2 , R 3 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio; R a , R b or R c Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, R d is selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH, 7. The compound according to claim 1, 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 in Table E-1.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomers, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for preparing a medicament for treating a disease associated with GLP-1R activity or expression.

10. The use according to claim 9, characterized in that: The disease is selected from diabetes.

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