Tetrahydropyridinopyrazole derivative and use thereof in medicine

Abstract

A tetrahydropyridinopyrazole derivative and the use thereof in medicine. Specifically disclosed are a compound as shown in general formula (I) or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating diabetes or obesity.

Description

A tetrahydropyridopyrazole derivative and its application in medicine 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 products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compound in the preparation of drugs for treating diabetes or obesity. Background Art

[0002] Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defects in insulin secretion, impaired insulin action, or both. Long-term high blood sugar levels in diabetes lead to chronic damage and dysfunction of various tissues, particularly the eyes, kidneys, heart, blood vessels, and nerves. Diabetes is primarily divided into two types. Type 1 diabetes: Destruction of pancreatic B cells leads to absolute insulin deficiency. Type 2 diabetes: 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 secreted by L cells in the intestine. GLP-1 stimulates insulin secretion in a physiological, glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation. In nonclinical studies, GLP-1 has been shown to promote β-cell sustainability by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting β-cell neogenesis. In healthy individuals, GLP-1 plays a key role in regulating postprandial blood glucose by stimulating glucose-dependent insulin secretion from the pancreas, leading to increased peripheral glucose absorption. GLP-1 also inhibits glucagon secretion, resulting in reduced hepatic glucose output. Furthermore, 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 damage. Another GLP-1 analog, exenatide, has also shown promising results against neurodegenerative diseases in preclinical studies. Summary of the Invention

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

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

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

[0009] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (II-a) or (II-b),

[0010] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (II-b-1),

[0011] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (III),

[0012] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (III-1),

[0013] In some embodiments, Indicates a single bond or a double bond;

[0014] In some embodiments, Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10Carbocyclic group, 4 to 10 membered heterocyclic group, C 11-15 aryl, 11 to 15 membered heterocyclic group, 11 to 15 membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0015] In some embodiments, ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic group, 4 to 8 membered heteromonocyclic group, benzo C 7-8 Carbocyclic group, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0016] In some embodiments, Ring A is selected from the group consisting of a substituted one of the following groups: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,

[0017] In some embodiments, Ring A is selected from Ring A1 or Ring A2;

[0018] In some embodiments, Ring A1 is selected from the group consisting of a Replaced C 11-15 aryl, 11- to 15-membered heterocyclyl, 11- to 15-membered heteroaryl;

[0019] In some embodiments, Ring A1 is selected from the group consisting of a Substituted benzo C 7-8 Carbocyclic group,

[0020] In some embodiments, Ring A1 is selected from the group consisting of a Replaced

[0021] In some embodiments, Ring A2 is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, and ring A2 is not selected from

[0022] In some embodiments, Ring A2 is selected from the group consisting of a substituted phenyl, pyridyl;

[0023] In some embodiments, Ring A2 is selected from the group consisting of asubstituted phenyl;

[0024] In some embodiments, Ring B is selected from C 6-10 Aryl, 5- to 6-membered heteroaryl, 5- to 5-membered heteroaryl, 5- to 6-membered heteroaryl, 6- to 6-membered heteroaryl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, wherein the ring B is optionally substituted by 1 to 4 R b replace;

[0025] In some embodiments, ring B is selected from 5-membered heteroaryl or 5-membered heteroaryl, and the ring B is optionally substituted with 1 to 4 R b replace;

[0026] 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 said ring B is optionally substituted with 1 to 4 R b replace;

[0027] In some embodiments, Ring B is selected from the group consisting of b Substituted groups: Its right side is connected to ring C;

[0028] In some embodiments, Ring B is selected from the group consisting of b Substituted groups: Its right side is connected to ring C;

[0029] In some embodiments, ring D is selected from C 6-12 Carbocyclic group, 5 to 12 membered heterocyclic group, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0030] In some embodiments, ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0031] In some embodiments, Ring D is selected from the group consisting of dsubstituted one of the following groups: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl,

[0032] In some embodiments, Ring D is selected from the group consisting of d Substituted structures: phenyl,

[0033] In some embodiments, ring C is selected from C 3-12 Carbocyclic group, 4 to 12 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 3-6 Monocyclic alkyl, 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;

[0035] In some embodiments, Ring C is selected from the group consisting of c substituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxanyl, piperazinyl, morpholinyl;

[0036] In some embodiments, Ring C is selected from the group consisting of c substituted oxacyclopentyl or oxacyclohexyl;

[0037] In some embodiments, L1 is selected from -S(=O)2-, -C(=O)-;

[0038] In some embodiments, L1 is selected from -C(=O)-;

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

[0040] In some embodiments, L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0041] In some embodiments, L2 is selected from -CR L1 RL2 - or optionally 1 to 3 R k One of the following groups substituted:

[0042] In some embodiments, L2 is selected from

[0043] In some embodiments, X is selected from S or O;

[0044] In some embodiments, m is selected from 1, 2, 3, or 4;

[0045] In some embodiments, R 4 Selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、

[0046] In some embodiments, R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2,

[0047] In some embodiments, R 4 Selected from

[0048] In some embodiments, R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f Each independently selected from H, deuterium, C 1-6 Alkyl, said alkyl being 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, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace;

[0050] In some embodiments, R 4a 、R 4b 、R 4c 、R4d 、R 4e 、R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl;

[0051] 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 group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-3 to 7 membered heterocyclic group, -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 Carbocyclyl, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbocyclic group, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -P(=O)R 5a R 5b 、 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are 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, 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 1-4Alkyl, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-3 to 7-membered heterocyclic group, -S(=O) 1-2 -C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocyclyl, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbocyclic group, C 3-11 Carbocyclyl, 4- to 11-membered heterocyclyl, -P(=O)R 5a R 5b 、 The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 R k replace;

[0053] 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 k substituted one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl;

[0054] In some embodiments, R a 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, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0055] In some embodiments, R a Each is independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, CD3, OCD3, OCF3, OCHF2, OCH2F, CH2F, CHF2, CF3, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl;

[0056] In some embodiments, 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;

[0057] In some embodiments, R b Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, OCF3, OCHF2, OCH2F, CH2F, CHF2, CF3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0058] In some embodiments, R d 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,

[0059] In some embodiments, R d Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, OCF3, OCHF2, OCH2F, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH,

[0060] In some embodiments, R d1Each independently selected from H, deuterium, CD3, methyl, ethyl, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH,

[0061] In some embodiments, R d1 Each independently selected from H, deuterium, CD3, methyl, ethyl, cyclopropyl;

[0062] In some embodiments, R A Selected from R a ;

[0063] In some embodiments, R A Selected from R A1 ;

[0064] In some embodiments, R A1 Selected from 1 to 3 R A11 Substituted C 1-6 Alkyl, 1 to 3 R k Substituted C 3-6 Carbocyclic group, optionally substituted by 1 to 3 R k Substituted C 7-12 Carbocyclic group, optionally substituted by 1 to 3 R k substituted 4- to 12-membered heterocyclic group, -P(=O)(C 1-6 alkyl)2, -S(=O) 1-2 -C 1-6 alkyl;

[0065] In some embodiments, R A1 Selected from 1 to 3 R A11 Substituted C 1-4 Alkyl, 1 to 3 R k Substituted C 3-6 Carbocyclic group, optionally substituted by 1 to 3 R k Substituted C 7-11 Carbocyclic group, optionally substituted by 1 to 3 R k substituted 4- to 10-membered heterocyclic group, -P(=O)(C 1-4 alkyl)2, -S(=O) 1-2 -C 1-4 alkyl;

[0066] In some embodiments, R A1 Selected from 1 to 3 R A11 Substituted methyl, ethyl, propyl, isopropyl, substituted by 1 to 3 R k Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 3 R kSubstituted cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, optionally substituted by 1 to 3 R k Substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -P(=O)(C 1-2 alkyl)2,-S(=O)-C 1-2 alkyl;

[0067] In some embodiments, R A1 Selected from 1 to 2 R A11 Substituted methyl, ethyl, propyl, isopropyl, 1 to 2 R k Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 2 R k Substituted cyclobutylspirocyclobutyl, optionally substituted by 1 to 3 R k Substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -P(=O)(C 1-2 alkyl)2,-S(=O)2-C 1-2 Alkyl; in some embodiments, R A1 Selected from -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0068] In some embodiments, R A1 Selected from -CH2-cyclopropyl, In some embodiments, R A11 Selected from deuterium, OH, CN, NH2, C 1-6 Alkoxy, -NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, C 3-12 Carbocyclyl, 4- to 12-membered heterocyclyl;

[0069] In some embodiments, R A11 Selected from deuterium, OH, CN, NH2, C 1-4 Alkoxy, -NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 3-10 Carbocyclyl, 4- to 10-membered heterocyclyl;

[0070] In some embodiments, R A11 Selected from deuterium, OH, CN, NH2, methoxy, ethoxy, -NH(C 1-2 alkyl), N(C 1-2Alkyl)2, C 3-7 Carbocyclyl, 4- to 8-membered heterocyclyl;

[0071] In some embodiments, R A11 is selected from deuterium, OH, CN, NH2, methoxy, ethoxy, NH(CH3), N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl;

[0072] In some embodiments, R 5a 、R 5b Each independently selected from C 1-6 Alkyl, C 3-6 Carbocyclic ring, the alkyl group, the carbocyclic ring is optionally 1 to 4 R k replace;

[0073] 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;

[0074] 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;

[0075] 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 1-6 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;

[0076] In some embodiments, R 1 、R 2 、R 3 、R L1 、RL2 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 is optionally substituted by 1 to 4 R k replace;

[0077] 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;

[0078] 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;

[0079] In some embodiments, 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;

[0080] In some embodiments, R L1 、R L2 Together with the connected atoms, they form C 3-8 Carbocyclic or 4- to 8-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0081] In some embodiments, R L1 、R L2 Together with the connected carbon atoms, they form C 3-6Carbocyclic or 4- to 6-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0082] In some embodiments, R L1 、R L2 and the carbon atom to which it is attached together form a k Substituted groups such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;

[0083] 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;

[0084] 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;

[0085] In some embodiments, R 5a 、R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted groups:

[0086] 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 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-3 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6substituted by an alkoxy substituent;

[0087] 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 group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-3 to 6 membered heterocyclic group, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0088] 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, 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 groups selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0089] 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, 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;

[0090] In some embodiments, a or b are each independently selected from 0, 1, 2, or 3;

[0091] Optionally,

[0092] When ring A is selected from C 11-15 When aryl, 11- to 15-membered heterocyclic group, or 11- to 15-membered heteroaryl, R A Selected from R a , the ring A is optionally substituted with 1 to 4 R a replace;

[0093] Or when ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 In the case of a carbocyclic group or a 4- to 10-membered heterocyclic group, R A Selected from R A1 , R A1 Selected from 1 to 3 R A11 Substituted C 1-6 Alkyl, 1 to 3 R k Substituted C 3-6 Carbocyclic group, optionally substituted by 1 to 3 R k Substituted C 7-12 Carbocyclic group, optionally substituted by 1 to 3 R k substituted 4- to 12-membered heterocyclic group, -P(=O)(C 1-6 alkyl)2, -S(=O) 1-2 -C 1-6 Alkyl, the R A11 Selected from deuterium, OH, CN, NH2, C 1-6 Alkoxy, -NH(C 1-6 alkyl), N(C 1-6 alkyl) 2, wherein the ring A is optionally substituted by 1 to 4 R areplace.

[0094] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0095] represents a single bond or a double bond;

[0096] Ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, C 11-15 aryl, 11 to 15 membered heterocyclic group, 11 to 15 membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0097] Ring B is selected from C 6-10 Aryl, 5- to 6-membered heteroaryl, 5- to 5-membered heteroaryl, 5- to 6-membered heteroaryl, 6- to 6-membered heteroaryl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, wherein the ring B is optionally substituted by 1 to 4 R b replace;

[0098] Ring D is selected from C 6-12 Carbocyclic group, 5 to 12 membered heterocyclic group, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0099] Ring C is selected from C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, wherein the ring C is optionally substituted by 1 to 4 R c replace;

[0100] L1 is selected from -S(=O)2-, -C(=O)-;

[0101] L2 is selected from -(CR L1 R L2 ) m -;

[0102] X is selected from S or O;

[0103] m is selected from 1, 2, 3 or 4;

[0104] R 4 Selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、

[0105] R 4a 、R 4b 、R 4c 、R4d 、R 4e 、R 4f Each independently selected from H, deuterium, C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0106] R a 、R b 、R c 、R d 、R A 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 group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-3 to 7 membered heterocyclic group, -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 Carbocyclyl, -NHC(=O)-C 1-6 Alkyl, -NHC(=O)-C 3-6 Carbocyclic group, C 3-12 Carbocyclyl, 3- to 12-membered heterocyclyl, -P(=O)R 5a R 5b 、 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0107] R 5a 、R 5b Each independently selected from C 1-6 Alkyl, C 3-6 Carbocyclic group, the alkyl group, the carbocyclic group is optionally substituted by 1 to 4 R k replace;

[0108] R 1 、R 2 、R 3 、RL1 、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 is optionally substituted by 1 to 4 R k replace;

[0109] Alternatively, R L1 、R L2 Together with the connected atoms, they form C 3-8 A carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0110] Alternatively, R 5a 、R 5b Together with the phosphorus atom to which it is attached, it forms a 5- to 8-membered heterocyclic group, which is optionally substituted by 1 to 4 R k replace;

[0111] 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 group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 1-4 Alkylene-C 3-6 Carbocyclic group, -C 1-4 Alkylene-3 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0112] The condition is,

[0113] When ring A is selected from C11-15 When aryl, 11- to 15-membered heterocyclic group, or 11- to 15-membered heteroaryl, R A Selected from R a , the ring A is optionally substituted with 1 to 4 R a replace;

[0114] Or when ring A is selected from C 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 In the case of a carbocyclic group or a 4- to 10-membered heterocyclic group, R A Selected from R A1 , R A1 Selected from 1 to 3 R A11 Substituted C 1-6 Alkyl, 1 to 3 R k Substituted C 3-6 Carbocyclic group, optionally substituted by 1 to 3 R k Substituted C 7-12 Carbocyclic group, optionally substituted by 1 to 3 R k substituted 4- to 12-membered heterocyclic group, -P(=O)(C 1-6 alkyl)2, -S(=O) 1-2 -C 1-6 Alkyl, the R A11 Selected from deuterium, OH, CN, NH2, C 1-6 Alkoxy, -NH(C 1-6 alkyl), N(C 1-6 Alkyl)2, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, wherein the ring A is optionally substituted by 1 to 4 R a replace.

[0115] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0116] 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;

[0117] Ring C is selected from C 3-6 Monocyclic alkyl, 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;

[0118] Ring D is selected from phenyl, naphthyl, benzo 4-6 carbocyclyl, benzo 4 to 7 membered heterocyclyl, 5 to 6 membered heteroaryl or 8-10 membered heteroaryl, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0119] Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic group, 4 to 8 membered heteromonocyclic group, benzo C 7-8 Carbocyclic group, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0120] 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;

[0121] 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;

[0122] 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;

[0123] Alternatively, R L1 、R L2 Together with the connected carbon atoms, they form C 3-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0124] Alternatively, R 5a 、R 5b Together with the phosphorus atom to which it is connected, it forms a 5- to 8-membered monocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0125] 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 group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-3 to 7-membered heterocyclic group, -S(=O) 1-2 -C 1-4 Alkyl, -C(=O)NH-C 1-4 Alkyl, -C(=O)NH-C 3-6 Carbocyclyl, -NHC(=O)-C 1-4 Alkyl, -NHC(=O)-C 3-6 Carbocyclic group, C 3-11 Carbocyclyl, 3- to 11-membered heterocyclyl, -P(=O)R 5a R 5b 、 The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0126] R A1 Selected from 1 to 3 R A11 Substituted C 1-4 Alkyl, 1 to 3 R k Substituted C 3-6 Carbocyclic group, optionally substituted by 1 to 3 R k Substituted C 7-11 Carbocyclic group, optionally substituted by 1 to 3 R k substituted 4- to 10-membered heterocyclic group, -P(=O)(C 1-4 alkyl)2, -S(=O) 1-2 -C 1-4 alkyl;

[0127] R A11 Selected from deuterium, OH, CN, NH2, C 1-4 Alkoxy, -NH(C 1-4 alkyl), N(C 1-4 Alkyl)2, C 3-10 Carbocyclyl, 4- to 10-membered heterocyclyl;

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

[0129] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0130] 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 said ring B is optionally substituted by 1 to 4 R b replace;

[0131] L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0132] 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 group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 1-2 Alkylene-C 3-6 Carbocyclic group, -C 1-2 Alkylene-3 to 6 membered heterocyclic group, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0133] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0134] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0135] Ring B is selected from the group consisting of b Substituted groups: Its right side is connected to ring C;

[0136] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl;

[0137] R a 、R b 、R c 、R d 、R A 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, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl;

[0138] R A1 Selected from 1 to 3 R A11 Substituted methyl, ethyl, propyl, isopropyl, substituted by 1 to 3 R k Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 3 R k Substituted cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, optionally substituted by 1 to 3 R k Substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -P(=O)(C 1-2 alkyl)2,-S(=O)-C 1-2alkyl;

[0139] R A11 Selected from deuterium, OH, CN, NH2, methoxy, ethoxy, -NH(C 1-2 alkyl), N(C 1-2 Alkyl)2, C 3-7 Carbocyclyl, 4- to 8-membered heterocyclyl;

[0140] 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;

[0141] 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;

[0142] Alternatively, R L1 、R L2 and the carbon atom to which it is attached together form a k Substituted groups such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;

[0143] Alternatively, R 5a 、R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted groups:

[0144] 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 groups selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0145] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0146] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0147] R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2,

[0148] Ring A is selected from the group consisting of a substituted one of the following groups: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,

[0149] R A1 Selected from 1 to 2 R A11 Substituted methyl, ethyl, propyl, isopropyl, 1 to 2 R k Substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, optionally substituted by 1 to 2 R k Substituted cyclobutylspirocyclobutyl, optionally substituted by 1 to 3 R k Substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -P(=O)(C 1-2alkyl)2,-S(=O)2-C 1-2 alkyl;

[0150] R A11 is selected from deuterium, OH, CN, NH2, methoxy, ethoxy, NH(CH3), N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl;

[0151] Ring C is selected from optionally 1 to 4 R c substituted one of the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxanyl, piperazinyl, morpholinyl;

[0152] Ring D is selected from the group consisting of d substituted one of the following groups: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl,

[0153] L2 is selected from -CR L1 R L2 - or optionally 1 to 3 R k One of the following groups substituted:

[0154] 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;

[0155] 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;

[0156] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0157] As a sixth 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,

[0158] X is selected from O or S;

[0159] L1 is selected from -C(=O)-;

[0160] L2 is selected from

[0161] R 4 Selected from

[0162] Ring A1 is selected from the group consisting of a Replaced

[0163] Ring A2 is selected from the group consisting of a substituted phenyl, pyridyl;

[0164] Ring B is selected from the group consisting of b Substituted groups: Its right side is connected to ring C;

[0165] Ring C is selected from optionally 1 to 4 R c substituted oxacyclopentyl or oxacyclohexyl;

[0166] Ring D is selected from the group consisting of dSubstituted structures: phenyl,

[0167] 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;

[0168] R a 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, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0169] R b or R c Each is 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, and cyclopropyl;

[0170] R A1 Selected from -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0171] R d 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,

[0172] As a seventh embodiment of the present invention, the compound represented by the following general formula (II-b-1) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0173] R A1 Selected from -CH2-cyclopropyl,

[0174] R a Each is independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, CD3, OCD3, OCF3, OCHF2, OCH2F, CH2F, CHF2, CF3, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl;

[0175] R d Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, OCF3, OCHF2, OCH2F, methyl, ethyl, methoxy, ethoxy, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH,

[0176] R d1 Each independently selected from H, deuterium, CD3, methyl, ethyl, cyclopropyl, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH,

[0177] R b Each independently selected from H, deuterium, F, Cl, Br, I, =O, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, CD3, OCD3, OCF3, OCHF2, OCH2F, CH2F, CHF2, CF3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0178] 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, cyclopropyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;

[0179] a or b are each independently selected from 0, 1, 2 or 3.

[0180] As an eighth embodiment of the present invention, the compound represented by the following general formula (III) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0181] R d1 Each independently selected from H, deuterium, CD3, methyl, ethyl, cyclopropyl;

[0182] The remaining definitions are the same as those of the seventh embodiment of the present invention.

[0183] As a ninth embodiment of the present invention, the compound represented by the following general formula (III-1) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0184] R d1 Each independently selected from H, deuterium, CD3, methyl, ethyl, cyclopropyl;

[0185] The remaining definitions are the same as those of the seventh embodiment of the present invention.

[0186] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below:

[0187] Table E-1

[0188] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0189] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions for preparing drugs for treating diseases related to GLP-1R activity or expression.

[0190] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in preparing drugs for treating diabetes or obesity.

[0191] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0192] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0193] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., diabetes or obesity). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-800 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;.

[0194] 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, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg g, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0195] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably a disease related to GLP-1R activity or expression (such as diabetes or obesity).

[0196] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein 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, 100-400 mg / day, 200-400 mg / day, and 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, and 800 mg / day.

[0197] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, 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 the amount in the above-mentioned pharmaceutical composition.

[0198] 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.

[0199] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0200] Synthesis method 1:

[0201] 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).

[0202] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0203] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0204] "CN" refers to cyano.

[0205] "Halogen" refers to F, Cl, Br or I.

[0206] "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".

[0207] "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.

[0208] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0209] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0210] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0211] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups 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-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -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.

[0212] "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, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 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-pentyn Alkynyl, 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; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0213] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0214] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0215] "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 ring, and contains one 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 optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0216] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2).

[0217] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0218] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0219] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0220] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0221] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0222] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0223] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0224] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0225] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0226] "Heterobridged ring," "heterobridged cyclic group," "bridged ring heterocyclic group," or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0227] "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.

[0228] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, 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 of which include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0229] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0230] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0231] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic groups, carbocyclic groups, aromatic groups, aryls, heteroaryls, cycloalkyl groups, heteromonocyclic groups, heteroparallel groups, heterospirocyclic groups, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heteroparallel ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroparallel ring.

[0232] C x-y Carbocyclic groups (including aryl, cycloalkyl, monocyclic carbocyclic, spirocyclic carbocyclic, fused carbocyclic or bridged carbocyclic) 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 a C3, C4, C5 or C6 cycloalkyl group.

[0233] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0234] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0235] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0236] "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, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0237] "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.

[0238] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0239] "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.

[0240] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0241] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0242] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0243] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0244] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0245] “IC 50"It 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

[0246] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0247] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0248] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0249] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0250] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0251] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0252] Example 1: Preparation of Compound 1

[0253] Step 1: Preparation of 1b

[0254] Methyltriphenylphosphonium bromide (20.0 g, 55.99 mmol) was dissolved in ultra-dry THF (100 mL) in an ice bath. 1 M potassium tert-butoxide-tetrahydrofuran solution (60.0 mL, 60.0 mmol) was added to the system, and the reaction was carried out under a nitrogen atmosphere for 0.5 h. Then, 1a (8.0 g, 39.41 mmol) was added, and the system was warmed to room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to give 1b (3.46 g, 43.67% yield).

[0255] Step 2: Preparation of 1c

[0256] 1b (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-cooling 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 give 1c (600 mg, yield 20.11%).

[0257] Step 3: Preparation of 1d

[0258] 1c (550 mg, 1.83 mmol) was dissolved in petroleum ether (10 mL), and potassium tert-butoxide (1.2 g, 10.69 mmol) was added. The mixture was reacted at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to give 1d (400 mg, yield 99.59%).

[0259] Step 4: Preparation of 1e

[0260] A 1 M 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 reacted under nitrogen atmosphere for 0.5 h. Diiodomethane (0.35 mL, 4.34 mmol) was then added and stirred for 20 min. 1d (400 mg, 1.83 mmol) was then added and the system was allowed to warm to room temperature for 16 h. 10 mL of saturated aqueous ammonium chloride was added to the reaction solution, which 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 give 1e (370 mg, 86.94% yield).

[0261] Step 5: Preparation of 1f

[0262] 1e (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 for 1 hour. Di-tert-butyl azodicarboxylate (400 mg, 1.74 mmol) was added and the temperature was raised to room temperature and reacted for 2 hours. 10 mL of water was added and 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 1f (239 mg, yield 39.16%).

[0263] Step 6: Preparation of 1g

[0264] 1f (230 mg, 0.60 mmol) was dissolved in N-methylpyrrolidone (2 mL), and methanesulfonic acid (0.3 mL, 4.62 mmol) was added and reacted at 80°C for 16 hours. 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 1g (100 mg, yield 90.74%).

[0265] Step 7: 1h preparation

[0266] 1g (230mg, 0.60mmol) was dissolved in toluene (2mL), 1g-1 (145mg, 0.61mmol) and pyridine hydrochloride (10mg, 0.087mmol) were added, and the reaction was carried out at 90°C for 1 hour. The system was concentrated under reduced pressure, and the reaction solution was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 1h (54mg, yield 24.59%).

[0267] LCMS m / z=405.3[M+H] +

[0268] Step 8: Preparation of 1i

[0269] 1h (50 mg, 0.12 mmol) was dissolved in pyridine (1 mL), and 1h-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 hour. 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 1i (60 mg, yield 90.62%).

[0270] Step 9: Preparation of 1j

[0271] 1i (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 reaction was carried out at 60°C for 0.5 h. 5 mL of saturated aqueous sodium bicarbonate 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. The filtrate was concentrated under reduced pressure to give 1j (50 mg, yield 94.66%).

[0272] LCMS m / z=472.2[M+H] +

[0273] Step 10: Preparation of 1k

[0274] 1j (50 mg, 0.11 mmol) and 1j-1 (25 mg, 0.11 mmol) were dissolved in N-methylpyrrolidone (2 mL), and cuprous iodide (20 mg, 0.11 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (20 mg, 0.14 mmol), and anhydrous potassium carbonate (80 mg, 0.58 mmol) were added to the system. The reaction was carried out at 130 ° C. under a nitrogen atmosphere for 2 hours 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), and 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 1k (30 mg, yield 45.66%).

[0275] LCMS m / z=620.3[M+H] +

[0276] Step 11: Preparation of 1L

[0277] 1k (30 mg, 0.048 mmol) was dissolved in dichloromethane (1 mL), and 4 M hydrochloric acid-dioxane solution (1 mL) was added. The reaction was carried out at room temperature for 3 hours. The system was concentrated to dryness, and 2 mL of saturated aqueous potassium carbonate solution was added to the reaction solution. The combined organic layers were extracted with ethyl acetate (2 mL × 3) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 1l (20 mg, yield 79.51%).

[0278] LCMS m / z=520.4[M+H] +

[0279] Step 12: Preparation of Compound 1

[0280] 11 (20 mg, 0.038 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (21 mg, 0.055 mmol), triethylamine (0.1 mL, 0.72 mmol), and 11-1 (20 mg, 0.049 mmol) were added. The mixture was reacted at room temperature under a nitrogen atmosphere for 16 hours. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; 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 title compound 1 (8 mg, 22.76%).

[0281] LCMS m / z=913.3[M+H] +

[0282] 1H NMR(400MHz,CF3COOD)δ8.88(s,1H),7.99–7.81(m,2H),7.75–7.51(m,4H),7 .44–7.31(m,2H),6.97(s,2H),6.22–5.98(m,1H),4.93–4.77(m,1H),4.44(s ,3H),4.23–4.05(m,2H),3.99–3.83(m,1H),3.61–3.32(m,2H),3.30-3.15(m ,1H),2.09–1.71(m,10H),1.62-1.51(m,5H),1.49(s,3H),1.44–1.30(m,5H).

[0283] Example 2: Preparation of Compound 2

[0284] Step 1: Preparation of 2b

[0285] 2a (15 g, 81.94 mmol) was dissolved in dichloromethane (400 mL), and bromosuccinimide (36 g, 202.27 mmol) and triethylamine trihydrofluoride (39 g, 241.92 mmol) were added under ice bath and reacted at room temperature for 16 hours. 500 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (100 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 2b (13 g, yield 56.27%).

[0286] Step 2: Preparation of 2c

[0287] 2b (12 g, 42.56 mmol) was dissolved in petroleum ether (150 mL), and potassium tert-butoxide (28.65 g, 255.32 mmol) was added. The mixture was reacted at room temperature for 16 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain 2c (6 g, yield 70.12%).

[0288] Step 3: 2D preparation

[0289] Under ice bath conditions, a 1 M diethylzinc n-hexane solution (60 mL, 60 mmol) was dissolved in ultra-dry dichloromethane (200 mL). Trifluoroacetic acid (4.6 mL, 61.93 mmol) was slowly added dropwise to the system under nitrogen atmosphere and reacted for 0.5 h. Diiodomethane (4.9 mL, 60.83 mmol) was then added and stirred for 20 min. 2c (6 g, 29.84 mmol) was then added and the system was warmed to room temperature for 16 h. 200 mL of saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with dichloromethane (100 mL × 3). The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to give 2d (5 g, 77.9% yield).

[0290] Step 4: Preparation of compound 2

[0291] Using 2d as a substrate, compound 2 was obtained by referring to the synthesis method from step 5 to step 12 of Example 1.

[0292] LCMS m / z=895.6[M+H] +

[0293] 1 H NMR(400MHz,CF3COOD)δ8.95(s,1H),8.04-7.95(m,1H),7.81-7.67(m,5H),7.67-7.60(m,1H),7.58-7.5 2(m,1H),7.52-7.46(m,1H),7.05(s,2H),6.26-6.16(m,1H),5.02-4.89(m,1H),4.52(s,3H),4.32-4.15 (m,2H),4.09-3.93(m,1H),3.70-3.44(m,2H),3.40-3.21(m,1H),2.18-2.10(m,1H),2.10-1.94(m,5H), 1.93-1.82(m,4H),1.82-1.70(m,2H),1.64(s,3H)),1.58(s,3H),1.50-1.39(m,3H),1.37-1.20(m,2H).

[0294] Example 3: Preparation of Compound 3

[0295] Step 1: Preparation of 3b

[0296] Triethylamine (75 mL) and formic acid (50 mL) were mixed and stirred in an ice bath for 10 min, and then 3a (10 g, 46.07 mmol) and McLaughlin's acid (6.64 g, 46.07 mmol) were added in sequence. The mixture was then reacted at 100°C for 5 h. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 3b (11.2 g, 93.10% yield).

[0297] Step 2: Preparation of 3c

[0298] 3b (11.2 g, 42.90 mmol) was added to 30 mL of chlorosulfonic acid and allowed to react at room temperature for 2 h. After completion of the reaction as determined by TLC, the reaction solution was poured into cold water with stirring, and then extracted with ethyl acetate (3 × 200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by column chromatography to obtain 3c (9.5 g, 91.11% yield).

[0299] Step 3: 3D preparation

[0300] Methyltriphenylphosphonium bromide (27.92 g, 78.16 mmol) and potassium carbonate (10.96 g, 97.70 mmol) were added to THF under ice-bath and stirred for 15 min. 3c (9.5 g, 39.08 mmol) was then added and reacted for 30 min. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 3d (5.8 g, 61.55% yield).

[0301] Step 4: Preparation of 3e

[0302] 1M diethylzinc n-hexane solution (16 mL) was added to ultra-dry dichloromethane (30 mL) under an ice bath and nitrogen protection. The solution was stirred at 0°C for 5 minutes, and then a solution of diiodomethane (1.34 mL, 16.6 mmol) in ultra-dry dichloromethane was added. The resulting mixture was stirred at 0°C for another 20 minutes, and then 3d (2 g, 8.30 mmol) was added. The mixture was warmed to room temperature and stirred for 1 hour. Then a 1M aqueous solution of hydrochloric acid (10 mL) was added. The mixture was stirred at room temperature for 3 minutes, and the two phases were separated. The organic layer was dried, concentrated and purified by column chromatography to obtain 3e (1.4 g, 66.15% yield).

[0303] Step 5: Preparation of 3f

[0304] Using 3e as the starting material, compound 3 was synthesized according to the preparation method of steps 5 to 12 of Example 1.

[0305] LCMS m / z=935.6[M+H] +

[0306] Biological test example 1:

[0307] In vitro activity assay

[0308] HEK293-CRE-luc-GLP-1R cells were added to a 384-well cell culture plate (Greiner #781946) at a certain cell density (5 μL / well); 5 μl / well of 2× working solution was added to the 384 microplate and the microplate was sealed with sealing film. Place in a 37°C 5% CO2 incubator (Incubator, Thermo) and incubate for 1 hour. Subsequently, cAMP-GS HIRANGE KIT (PerkinElmer, 62AM6PEB) was used for detection, and the detection reagent was prepared according to the kit instructions. After incubation, the detection reagent was added to the 384 microplate and incubated in the dark at room temperature for 1 hour. The HTRF signals at 665nm and 620nm were then detected using a multifunctional microplate reader, and the data in Excel format were exported from the microplate reader. Open Prism GraphPad, calculate the logarithm of the sample concentration, and use the logarithm as the horizontal axis and the 665nm / 620nm ratio (Ratio) as the vertical axis to perform a four-parameter fit to obtain the EC of the curve. 50 value.

[0309] Biological test results:

[0310] Table 1 EC of compounds 50 value

[0311] A<1nM, 1nM≤B<10nM, C≥10nM

[0312] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good agonist effect on the GLP-1 receptor, and their EC 50 The value is less than 10 nM, for example, the EC of compound 1 50 The value was less than 1 nM.

[0313] Biological test example 2:

[0314] Oral glucose tolerance test (OGTT)

[0315] An OGTT experiment was performed in male C57BL / 6-G1p1rem2 (hGLP1R) Smoc mice to evaluate the hypoglycemic effect of GLP-1 receptor agonists. The animals were fasted for more than 16 hours and randomly divided into groups for tail tip blood sampling. Basal fasting blood glucose (FBG) was measured using a blood glucose meter. Mice with FBG within the range of 3.5 to 6.5 mmol / L were orally administered, and the control group was given the vehicle. 15 minutes after administration, each group of animals was gavaged with 25% glucose solution. Blood glucose levels were measured 15 minutes, 30 minutes, 45 minutes, 1 hour, and 2 hours after administration, and 0-2 hour blood glucose AUC was calculated using Graphpad Prism software. 0-2h The inhibition rate was calculated.

[0316] Calculation formula: Blood glucose inhibition rate = (AUC 0-2h -AUC of the drug-treated group 0-2h ) / AUC of vehicle group 0-2h ×100%

[0317] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good oral hypoglycemic effect on the GLP-1 receptor.

[0318] Biological test example 3: mouse pharmacokinetic test

[0319] Test animals: Male C57 mice, 22-25 g, 6 mice per compound.

[0320] Experimental Design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0321] Table 2. Dosing Information

[0322] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-β-CD);

[0323] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl beta-cyclodextrin)

[0324] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 7, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0325] Table 2-1 Pharmacokinetic results of test compounds in mice

[0326] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral efficacy in mice.

[0327] Biological Test Example 4: Monkey Pharmacokinetic Test

[0328] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 5 per compound, purchased from Hainan Xinzhengyuan Biotechnology Co., Ltd.

[0329] Experimental method: On the day of the experiment, 5 monkeys were randomly divided into two groups according to their body weight, with two monkeys in the intravenous administration group and three monkeys in the oral administration group. They were fasted but not watered for 14-18 hours before administration and were fed 4 hours after administration.

[0330] Table 3. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 90% (0.5% MC);

[0331] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral gavage groups at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0332] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance in monkeys.

[0333] Biological Test Example 5: CYP450 Enzyme Inhibition Test

[0334] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0335] Table 4

[0336] Conclusion: The compounds of the present invention, such as the example compounds, have lower CYP inhibitory potential than the control compound Orforglipron.

[0337] Biological Test Example 6: SLC Transporter Inhibition

[0338] The purpose of this study was to evaluate the inhibitory effect of the test substances on the activity of transporters OATP1B1 and OATP1B3.

[0339] HEK293-OATP1B1 and OATP1B3 cells were incubated with or without the analyte (0-30 μM) for the corresponding time, and samples were collected. The substrate content in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The transport activity of the transporter in the presence and absence of the analyte was calculated to obtain the percentage of transporter activity of the transporter cells under the action of different concentrations of the analyte (% VC (Vehicle Control, solvent control), the percentage of transporter activity in the presence and absence of the analyte), and the half-maximal inhibitory concentration (IC50) was calculated from this. 50 ).

[0340] Conclusion: The compounds of the present invention, such as the compounds in the examples, have weak inhibitory effects on OATP1B1 and OATP1B3.

Claims

1. A compound or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, 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 group, 4- to 10-membered heterocyclic group, C 11-15 aryl, 11- to 15-membered heterocyclic group, 11- to 15-membered heteroaryl, and said ring A is optionally substituted by 1 to 4 R a substituents; Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5-fused-5-membered heteroaryl, 5-fused-6-membered heteroaryl, 6-fused-6-membered heteroaryl, C 3-10 carbocyclic group, 4- to 10-membered heterocyclic group, and said Ring B is optionally substituted with 1 to 4 R b substituents; Ring D is selected from C 6-12 a carbocyclic group or a 5- to 12-membered heterocyclic group, and said Ring D is optionally substituted with 1 to 4 Rs d ; Ring C is selected from C 3-12 a carbocyclic group, or a 4- to 12-membered heterocyclic group, and said Ring C is optionally substituted with 1 to 4 R c substituents; 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, said alkyl optionally being substituted by 1 to 4 R k substituents; 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, -O-C 3-6 carbocyclic group, -O-3- to 7-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-3- to 7-membered heterocyclic group, -C 1-4 alkylene-C 3-6 carbocyclic group, -C 1-4 alkylene-3- to 7-membered heterocyclic group, -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 group, -NHC(═O)-C 1-6 alkyl, -NHC(═O)-C 3-6 carbocyclic group, C 3-12 carbocyclic group, 3- to 12-membered heterocyclic group, -P(═O)R 5a R 5b 、 The alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 Rs k substituted; R 5a and R 5b are each independently selected from C 1-6 alkyl, C 3-6 carbocyclic group, and the alkyl and carbocyclic group are optionally substituted by 1 to 4 R k substituents; R 1 、R 2 、R 3 、R L1 、R L2 are 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, and the alkyl, alkenyl, and alkynyl are optionally substituted by 1 to 4 R k substituents; Alternatively, R L1 , R L2 together with the atoms to which they are attached form a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, said carbocyclic group or heterocyclic group being optionally substituted with 1 to 4 R k substituents; Alternatively, R 5a , R 5b together with the phosphorus atom to which they are attached form a 5- to 8-membered heterocyclic group, which heterocyclic group is optionally substituted by 1 to 4 R k substituents; 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, -O-C 3-6 carbocyclic group, -O-3- to 7-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-3- to 7-membered heterocyclic group, -C 1-4 alkylene-C 3-6 carbocyclic group, -C 1-4 alkylene-3- to 7-membered heterocyclic group, C 3-6 carbocyclic group, 3- to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy; provided that When ring A is selected from C 11-15 When it is aryl, 11- to 15-membered heterocyclic group, 11- to 15-membered heteroaryl, R A is selected from R a , and the ring A is optionally substituted with 1 to 4 R a substituents; Or when ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 carbocyclic group, 4- to 10-membered heterocyclic group, R A is selected from R A1 , R A1 is selected from C A11 alkyl substituted with 1 to 3 R 1-6 , C k carbocyclic group substituted with 1 to 3 R 3-6 , optionally C k carbocyclic group substituted with 1 to 3 R 7-12 , optionally 4- to 12-membered heterocyclic group substituted with 1 to 3 R k , -P(=O)(C 1-6 alkyl)2, -S(=O) 1-2 -C 1-6 alkyl, and the R A11 is selected from deuterium, OH, CN, NH2, C 1-6 alkoxy, -NH(C 1-6 alkyl), N(C 1-6 alkyl)2, C 3-12 carbocyclic group, 4- to 12-membered heterocyclic group, and the ring A is optionally substituted with 1 to 4 R a .

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Ring B is selected from 5-fused 5-membered heteroaryl or 5-fused 6-membered heteroaryl, and said Ring B is optionally substituted with 1 to 4 Rs b substituted; Ring C is selected from C 3-6 monocyclic alkyl, 4- to 7-membered monocyclic heterocyclic group, 6- to 11-membered spiro heterocyclic group, 5- to 11-membered bridged heterocyclic group, 7- to 10-membered fused heterocyclic group, and said ring C is optionally substituted by 1 to 4 R c substituents; Ring D is selected from phenyl, naphthyl, benzo C 4-6 carbocyclic group, benzo 4- to 7-membered heterocyclic group, 5- to 6-membered heteroaryl group or 8- to 10-membered fused heterocyclic aryl group, and said ring D is optionally substituted with 1 to 4 R d substituents; Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 monocyclic carbocyclic group, 4- to 8-membered heteromonocyclic group, benzo-C 7-8 carbocyclic group, and the Ring A is optionally substituted with 1 to 4 R a substituents; R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f each independently selected from H, deuterium, C 1-4 alkyl, said alkyl optionally being substituted by 1 to 4 R k substituents; R 5a and R 5b are each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with 1 to 4 R k substituents; R 1 、R 2 、R 3 、R L1 、R L2 are 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, and the alkyl, alkenyl, and alkynyl are optionally substituted by 1 to 4 R k substituents; Alternatively, R L1 , R L2 and the adjacent carbon atom together form a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, said carbocyclic group or heterocyclic group being optionally substituted by 1 to 4 R k substituents; Alternatively, R 5a , R 5b and the adjacent phosphorus atom together form a 5- to 8-membered monocyclic heterocyclic group which is optionally substituted with 1 to 4 R k substituents; R a 、R b 、R c 、R d are 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, -O-C 3-6 carbocyclic group, -O-3- to 7-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-3- to 7-membered heterocyclic group, -C 1-2 alkylene-C 3-6 carbocyclic group, -C 1-2 alkylene-3- to 7-membered heterocyclic group, -S(=O) 1-2 -C 1-4 alkyl, -C(=O)NH-C 1-4 alkyl, -C(=O)NH-C 3-6 carbocyclic group, -NHC(=O)-C 1-4 alkyl, -NHC(=O)-C 3-6 carbocyclic group, C 3-11 carbocyclic group, 3- to 11-membered heterocyclic group, -P(=O)R 5a R 5b 、 The alkyl, alkenyl, alkynyl, alkylene, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 Rs k substituted; R A1 selected from C alkyl substituted with 1 to 3 R A11 alkyl, C carbocyclic group substituted with 1 to 3 R 1-4 alkyl, optionally substituted 4- to 10-membered heterocyclic group substituted with 1 to 3 R k alkyl, -P(=O)(C alkyl)2, -S(=O) 3-6 -C k alkyl; 7-11 selected from C carbocyclic group substituted with 1 to 3 R k alkyl, optionally substituted 4- to 10-membered heterocyclic group substituted with 1 to 3 R 1-4 alkyl, -P(=O)(C alkyl)2, -S(=O) 1-2 -C 1-4 alkyl; R A11 selected from deuterium, OH, CN, NH2, C 1-4 alkoxy, -NH(C 1-4 alkyl), N(C 1-4 alkyl)2, C 3-10 carbocyclic group, 4- to 10-membered heterocyclic group.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, Ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrrolimidazolyl, pyrazolothienyl, imidazolothienyl, imidazimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridyl, pyrazolopyrimidinyl, imidazolophenyl, imidazolopyridyl, imidazolopyrimidinyl, and ring B is optionally substituted with 1 to 4 Rs b substituted; 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, -O-C 3-6 carbocyclic group, -O-3- to 6-membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-3- to 6-membered heterocyclic group, -C 1-2 alkylene-C 3-6 carbocyclic group, -C 1-2 alkylene-3- to 6-membered heterocyclic group, C 3- 6-carbocyclic group, 3- to 6-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein, Ring B is selected from the following groups optionally substituted by 1 to 4 Rs b as follows: 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 one of the following groups substituted by 1 to 3 Rs k : methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutyl spiro cyclobutyl, cyclopentyl spiro cyclobutyl, cyclopentyl spiro cyclopentyl, cyclohexyl spiro cyclobutyl, cyclohexyl spiro cyclopentyl, cyclohexyl spiro cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinyl spiro cyclohexyl; R A1 selected from methyl, ethyl, propyl, isopropyl substituted with 1 to 3 R A11 substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl substituted with 1 to 3 R k substituted cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, optionally substituted with 1 to 3 R k substituted azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -P(=O)(C k alkyl)2, -S(=O)-C 1-2 alkyl; 1-2 alkyl; R A11 selected from deuterium, OH, CN, NH2, methoxy, ethoxy, -NH(C 1-2 alkyl), N(C 1-2 alkyl)2, C 3-7 carbocyclic group, 4- to 8-membered heterocyclic group; R 5a and R 5b are each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 3 R k substituents; 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 one of the following groups optionally substituted by 1 to 3 R k substituents: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio; Alternatively, R L1 , R L2 and the adjacent carbon atom together form a group optionally substituted with 1 to 3 R k groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl; Alternatively, R 5a , R 5b and the linked phosphorus atom together form an optionally 1 to 3 R k substituted group as follows: 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 are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 alkyl, C 1-4 alkoxy.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein R 4 selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2, Ring A is selected from one of the following groups optionally substituted by 1 to 4 Rs a : phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxanyl, 1,3-dioxolanyl, 1,4-dioxanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, R A1 Selected from methyl, ethyl, propyl, isopropyl substituted by 1 to 2 R A11 groups, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl substituted by 1 to 2 R k groups, cyclobutylspirocyclobutyl optionally substituted by 1 to 2 R k groups, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl optionally substituted by 1 to 3 R k groups, -P(=O)(C 1-2 alkyl)2, -S(=O)2-C 1-2 alkyl; R A11 selected from deuterium, OH, CN, NH2, methoxy, ethoxy, NH(CH3), N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl; Ring C is selected from one of the following groups optionally substituted by 1 to 4 Rs c : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxanyl, 1,3-dioxolanyl, 1,4-dioxanyl, piperazinyl, morpholinyl; Ring D is selected from among the following groups optionally substituted with 1 to 4 Rs d one of the following: phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl, L2 is selected from -CR L1 R L2 - or optionally one of the following groups substituted with 1 to 3 Rs k : R L1 and R L2 are 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, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 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 compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by the general formula (I) is selected from the compounds represented by the general formula (II-a) or (II-b), X is selected from O or S; L1 is selected from -C(=O)-; L2 is selected from R 4 selected from Ring A1 is selected from optionally being substituted by 1 to 4 Rs a substituted Ring A2 is selected from phenyl and pyridyl optionally substituted with 1 to 3 R a substituents; Ring B is selected from the following groups optionally substituted by 1 to 4 Rs b as follows: its right side is connected to ring C; Ring C is selected from an optionally 1 to 4 R c substituted oxolanyl or oxanyl; Ring D is selected from the following structures optionally substituted by 1 to 4 Rs d : 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 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, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl, 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; R A1 selected from -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl, R d 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 its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E-1.

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

9. Use of the compound according to any one of claims 1-7 or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal in the preparation of a drug for treating a disease related to GLP-1R activity or expression level.

10. The application according to claim 9, wherein The disease is selected from diabetes or obesity.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound according to any one of claims 1-7 or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to GLP-1R activity or expression level, more preferably diabetes or obesity.

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