Imidazol-2-one derivative and use thereof in medicine

Abstract

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

Description

Imidazol-2-one 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 racemate, stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods, as well as use of the compound in the preparation of drugs related to the treatment of diabetes. 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 object of the present invention is to provide a compound that can stimulate the GLP-1 receptor or its racemate, stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, as well as its intermediates and preparation method, and its use 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 racemate, 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 (Ia), (Ib), (Ic), and (Id).

[0010] In some embodiments, the general formula (Id) is selected from the compounds represented by the general formula (Id-1),

[0011] In some embodiments, T is selected from a bond, O, S, CH2, NH, N(R d3 );

[0012] In some embodiments, T is selected from a bond, O, S, CH2, NH;

[0013] In some embodiments, p1 is selected from 0, 1, 2, 3, or 4;

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

[0015] In some embodiments, Y is selected from C, N, Z is selected from CH or N, J is selected from N or C, and at least one of Y, Z, and J is selected from N;

[0016] In some embodiments, 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 Substitution, the nitrogen atom on the heteroaryl or heterocyclic group is optionally oxidized to form a nitrogen oxide;

[0017] In some embodiments, ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic group, 4 to 8 membered heterocyclic group, benzo C 7-8 Carbocyclic group, wherein the ring A is optionally substituted by 1 to 4 R a Substitution, the nitrogen atom on the heteroaryl or heterocyclic group is optionally oxidized to form a nitrogen oxide;

[0018] In some embodiments, Ring A is selected from the group consisting of a substituted by 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,

[0019] In some embodiments, ring A is selected from phenyl, pyridyl, The ring A is optionally substituted with 1 to 4 R a replace;

[0020] In some embodiments, Ring A is selected from In some embodiments, Ring A is selected from In some embodiments, Selected from

[0021] 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;

[0022] 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;

[0023] 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, thienopyridinyl, thienophenyl, furopyridinyl, furophenyl, and said ring B is optionally substituted with 1 to 4 R b replace;

[0024] In some embodiments, Ring B is selected from the group consisting of b One of the following groups substituted: Its right side is connected to Q;

[0025] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q;

[0026] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q;

[0027] In some embodiments, Ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q;

[0028] In some embodiments, ring D is selected from 13 to 16 membered tricyclic or tetracyclic heterocyclyl, 17 to 30 membered tricyclic or tetracyclic heterocyclyl, said ring D being optionally substituted with 1 to 4 R d replace;

[0029] In some embodiments, ring D is selected from the following partially saturated rings: 13-15 membered tricyclic heterocyclyl, 10 membered tricyclic heterocyclyl, 4-6 Carbocyclic, 9-membered spirocarbon ring 4-6 Carbocyclic, 11-membered carbocyclic spiro C 3-5 Carbocyclic, 10-membered heterocyclic spiro C 4-6 Carbocyclic, 11-membered heterocyclic spiro C 3-5carbocycle, 10-membered carbocyclic spiro 4- to 6-membered heterocycle, 11-membered carbocyclic spiro 4- to 5-membered heterocycle, 9-membered heterocyclic spiro 4- to 6-membered heterocycle, 9-membered heterocyclic spiro 8- to 10-membered heterocycle, 9-membered heterocyclic spiro C 3-6 Carbocyclic ring, 10-membered heterocyclic spiro 4 to 6-membered heterocyclic ring, 11-membered heterocyclic spiro 4 to 5-membered heterocyclic ring, 11-membered heterotricyclic spiro C 3-4 Carbocyclic ring, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0030] In some embodiments, Ring D is selected from The ring D is optionally substituted with 1 to 4 R d replace;

[0031] In some embodiments, Ring D is selected from The ring D is optionally substituted with 1 to 4 R d replace;

[0032] In some embodiments, Ring D is selected from In some embodiments, Ring D is selected from R d1 Selected from H or R d , R d2 Selected from H or R d ; In some embodiments, ring D is selected from R d1 Selected from H or R d , R d2 Selected from H or R d , R d3 Selected from H or R d ;

[0033] In some embodiments, Q is selected from a bond, O, S, NH, C 1-4 Alkylene, The alkylene group is optionally substituted by 1 to 4 R k replace;

[0034] In some embodiments, Q is selected from a bond, O, S, NH, CH2, CH(CH3),

[0035] In some embodiments, R 6 Selected from C 1-6 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, said R 6Optional 1 to 4 R 6a replace;

[0036] In some embodiments, R 6 Selected from C 1-4 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Monocarbocyclic group, C 6-10 Carbocyclic group, C 6-10 Spirocarbocyclyl, C 5-10 bridged carbocyclic group, 4 to 8 membered monoheterocyclic group, 7 to 10 membered heterocyclic group, 7 to 10 membered spiro heterocyclic group, 6 to 10 membered bridged heterocyclic group, wherein R 6 Optional 1 to 4 R 6a replace;

[0037] In some embodiments, R 6 is selected from methyl, ethyl, propyl, isopropyl, -CH2O-CH3, -CH2O-CH2CH3, -CH2O-CH(CH3)2, -CH2O-C(CH3)3, -CH2CH2O-CH3, -CH2CH2O-CH2CH3, -CH2CH2O-CH(CH3)2, -CH2CH2O-C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]cyclopentyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or The R 6 Optional 1 to 4 R 6a replace;

[0038] In some embodiments, -QR 6 One of the following groups is selected from the group consisting of ethyl, propyl, isopropyl, -CH2CH2CH2O-CH2CH3, -CH2CH2CH2O-CH(CH3)2, -CH2CH2CH2O-C(CH3)3, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

[0039] In some embodiments, R 6aSelected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl,

[0040] In some embodiments, R 6a Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,

[0041] In some embodiments, -QR 6 is selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

[0042] In some embodiments, -QR 6 is selected from one of the following optionally substituted groups:

[0043] In some embodiments, -QR 6 Selected from optionally substituted When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

[0044] In some embodiments, L1 is selected from -S(=O)2-, -C(=O)-, -C(=S)-; In some embodiments, L1 is selected from -C(=O)-;

[0045] In some embodiments, L2 is selected from -(CR L1 R L2 ) m -; In some embodiments, L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0046] In some embodiments, L2 is selected from -CR L1 R L2 - or optionally 1 to 3 Rk One of the following groups substituted: In some embodiments, L2 is selected from

[0047] In some embodiments, X is selected from S or O, preferably O;

[0048] In some embodiments, m is selected from 1, 2, 3, or 4;

[0049] In some embodiments, R 4 Selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、 In some embodiments, R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2, In some embodiments, R 4 Selected from

[0050] 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;

[0051] 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 Substitution; in some embodiments, R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl;

[0052] In some embodiments, R a 、R b 、R d、R 6a 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, -P(=O)R 5a R 5b 、-S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c 、-C(=O)-MR 5c 、-C(=O)-C 1-4 Alkylene-OC 0-4 Alkylene-R 5c 、C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0053] In some embodiments, R a 、R b 、R d 、R 6a 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, -SC1-4 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, -P(=O)R 5a R 5b 、-S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-C(=O)-MR 5c 、-C(=O)-MR 5c 、-C(=O)-C 1-2 Alkylene-OC 0-2 Alkylene-R 5c 、-CH2-MC(=O)-R 5c 、C 3-11 Carbocyclic group, 3 to 11 membered heterocyclic group, The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0054] In some embodiments, R a 、R b 、R d 、R 6a 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 、 -C(=O)CH3, -C(=O)CH2CH3 or optionally 1 to 3 R k substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirobutyl, cyclopentylspirobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-piperidinyl, -CH2-piperazinyl, -C(=O)R 5c 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c 、-C(=O)-MR 5c 、-C(=O)-CH2-OR 5c 、-C(=O)-CH2-OCH2-R 5c 、-C(=O)-MR 5c 、

[0055] In some embodiments, R d Optional 1 to 3 R k Replacement, R k Selected from R k1 ;

[0056] In some embodiments, M is selected from C 3-6 Carbocyclic or 4 to 7 membered heterocyclic, wherein M is optionally substituted by 1 to 4 R k replace;

[0057] In some embodiments, M is selected from C 3-6 Cycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl or 5 to 6 membered heteroaryl, wherein M is optionally substituted by 1 to 4 R k replace;

[0058] In some embodiments, M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, said M being optionally substituted with 1 to 4 R k replace;

[0059] In some embodiments, M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, said M being optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl;

[0060] In some embodiments, R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl, Preferably, R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl,

[0061] In some embodiments, R b Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0062] In some embodiments, R d Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CD3, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, or optionally 1 to 4 R k1substituted by one of the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-oxetanyl, -CH2-azetidinyl, -S(=O)2CH3, -S(=O)2cyclopropyl, -C(=O)NH-cyclopropyl, -C(=O)CH3, -C(=O)-vinyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O) -cyclopentyl, -C(=O)-bicyclo[2.2.1]heptanyl, -C(=O)-bicyclo[1.1.1]pentanyl, -C(=O)-cyclobutylspirobutyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxahexyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-pyrazolyl, -C(=O)-phenyl, -C(=O)-azetidinyl-CH2-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclobutyl, -C(=O)-pyrazolyl-CH2-cyclopentyl, -C(=O)-pyrrolidinyl-CH2-cyclopropyl, -C(=O)-piperidinyl-CH2-cyclopropyl, -C(=O)-piperazinyl-CH2-cyclopropyl, -C(=O)-azetidinyl-C(=O)-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclobutyl, -C(=O)-pyrazolyl-CH2-cyclopentyl, -C(=O)-pyrrolidinyl-CH2-cyclopropyl, -C(=O)-piperidinyl-CH2-cyclopropyl, -C(=O)-piperazinyl-CH2-cyclopropyl, -C(=O)-azetidinyl-C(=O)-cyclopropyl, -C(=O)-pyrazolyl Pyrrolidyl-C(=O)-cyclopropyl, -C(=O)-piperidinyl-C(=O)-cyclopropyl, -C(=O)-piperazinyl-C(=O)-cyclopropyl, -CH2-azetidinyl-C(=O)-cyclopropyl, -CH2-pyrrolidinyl-C(=O)-cyclopropyl, -CH2-azetidinyl-CH2-cyclopropyl, -CH2-pyrrolidinyl-CH2-cyclopropyl, -CH2-piperidinyl-CH2-cyclopropyl, -CH2-piperazinyl-CH2-cyclopropyl, -C(=O)-cyclopropyl-phenyl, -C(=O)-cyclopropyl-pyridyl, -C(=O)-cyclopropyl-thienyl, -C(=O)-cyclopropyl-furyl, -C(=O)-CH2-O-cyclopropyl, -C(=O)-CH2-OCH2-cyclopropyl;

[0063] R k1 is selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, CH2CN, methyl, ethyl, methoxy, or ethoxy;

[0064] In some embodiments, R d Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, -C(=O)CH3, -C(=O)NHCH3, -C(=O)NH-cyclopropyl,

[0065] In some embodiments, R d1 Selected from H, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl;

[0066] In some embodiments, R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl;

[0067] In some embodiments, R d3 is selected from H or methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c 、-C(=O)-MR 5c 、-C(=O)-M-CH2-OR 5c 、 The methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl are optionally substituted by 1 to 4 R k Replacement (R k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, ), M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, said M being optionally substituted by 1 to 4 R k Replacement (R k Preferably, each independently selected from deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl substituents), R 5c is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl and cyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl, wherein R 5c Optional 1 to 4 R k Replacement (R k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, propenyl, );

[0068] In some embodiments, R 5a 、R 5b 、R 5cEach independently selected from C 1-6 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, the alkyl, alkoxy, alkenyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0069] In some embodiments, R 5a 、R 5b 、R 5c Each independently selected from C 1-4 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 5-8 Bridged ring cycloalkyl, C 5-11 Spirocyclic cycloalkyl, C 5-11 cycloalkyl, 4 to 7 membered monocyclic heterocycloalkyl, 6 to 10 membered bridged heterocycloalkyl, 6 to 11 membered spirocyclic heterocycloalkyl, 6 to 11 membered cycloheterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace;

[0070] In some embodiments, R 5c Selected from 1 to 4 R k substituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylcyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl;

[0071] In some embodiments, R 5cis selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl and cyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl, wherein R 5c Optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, propenyl, substituted by a substituent;

[0072] In some embodiments, R 5d 、R 5e Each independently selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0073] In some embodiments, R 5d 、R 5e Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace;

[0074] In some embodiments, R 5d 、R 5e Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, and ethyl;

[0075] In some embodiments, R 5a 、R 5bEach independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 3 R k replace;

[0076] In some embodiments, R 5f 、R 5g Each independently selected from H, halogen, C 1-6 Alkyl, C 3-10 Carbocyclic group, the alkyl group, the carbocyclic group is optionally substituted by 1 to 4 R k Replacement; or R 5f 、R 5g Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0077] In some embodiments, R 5f 、R 5g Each independently selected from H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k Replacement; or R 5f 、R 5g Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0078] In some embodiments, R 5f 、R 5g Each is independently selected from H, F, Cl, Br, methyl, ethyl; or R 5f 、R 5g Directly connected to form a cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, SH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, and cyclobutyl;

[0079] In some embodiments, R 5f 、R 5g Each is independently selected from H, F, Cl, Br, methyl, ethyl; or R 5f 、R 5g Directly linked to form a cyclobutyl, cyclopentyl, or cyclohexyl group;

[0080] In some embodiments, R 5h Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Carbocyclic group or 4 to 7 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0081] In some embodiments, R 5i Selected from CN, NO2, -S(=O) 1-2 -C 1-6 Alkyl, -S(=O) 1-2 -C 3-6 Carbocyclic group, the alkyl group, the carbocyclic group is optionally substituted by 1 to 4 R k replace;

[0082] In some embodiments, R 5h Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k Substitution; in some embodiments, R 5h Selected from NH2, NHCH3, methyl, ethyl, cyclopropyl;

[0083] In some embodiments, R 5i Selected from CN, NO2, -S(=O) 1-2 -C 1-4 Alkyl, -S(=O) 1-2 -C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k Substitution; in some embodiments, R 5i is selected from CN, NO2, -S(=O)2-methyl, -S(=O)2-cyclopropyl; 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 1-6Alkyl, -SC 1-6 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace;

[0084] In some embodiments, R 1 、R 2 、R 3 、R L1 、R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace;

[0085] 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;

[0086] 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, preferably, R 1 Selected from H; preferably, R 2 Selected from H, methyl or CD3; preferably, R 3 Selected from H, methyl or CD3;

[0087] In some embodiments, R L1 、R L2Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylthio;

[0088] 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 Substitution; in some embodiments, R L1 、R L2 Together with the connected carbon atoms, they form C 3-6 Carbocyclic or 4- to 6-membered heterocyclic ring, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 R k Substitution; 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;

[0089] 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 Substitution; 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 Substitution; in some embodiments, R 5a 、R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted groups:

[0090] 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 3-6Carbocyclic 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, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0091] 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, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0092] 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, 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 deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0093] 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, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, and morpholinyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy;

[0094] In some embodiments, R k Selected from R k1 ;

[0095] In some embodiments, R k1 Selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, CH2CN, methyl, ethyl, methoxy, or ethoxy;

[0096] In some embodiments, Ring A is selected from the group consisting of a Substituted phenyl, ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substituted, its right side is connected to Q; -QR 6 Selected from optionally substituted When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; Ring D is selected from The ring D is optionally substituted with 1 to 4 R d Substituted; X is selected from O or S;

[0097] L1 is selected from -C(=O)-;

[0098] L2 is selected from R 4 Selected from

[0099] R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0100] R b Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0101] R d Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, -C(=O)CH3, -C(=O)-cyclopropyl.

[0102] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0103] Indicates a single bond or a double bond;

[0104] Y is selected from C and N, Z is selected from CH or N, J is selected from N or C, and at least one of Y, Z, and J is selected from N;

[0105] 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 Substitution, the nitrogen atom on the heteroaryl or heterocyclic group is optionally oxidized to form a nitrogen oxide;

[0106] 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;

[0107] Ring D is selected from 13 to 16 membered tricyclic or tetracyclic heterocyclic groups, 17 to 30 membered tricyclic or tetracyclic heterocyclic groups, and said ring D is optionally substituted by 1 to 4 R d replace;

[0108] L1 is selected from -S(=O)2-, -C(=O)-, -C(=S)-;

[0109] L2 is selected from -(CR L1 R L2 ) m -;

[0110] X is selected from S or O;

[0111] Q is selected from a bond, O, S, NH, C 1-4 Alkylene, The alkylene group is optionally substituted by 1 to 4 R k replace;

[0112] m is selected from 1, 2, 3 or 4;

[0113] R 4 Selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、

[0114] 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;

[0115] R 6 Selected from C 1-6 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, said R 6 Optional 1 to 4 R 6a replace;

[0116] R a 、R b 、R d 、R 6a 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, -P(=O)R 5a R 5b 、-S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c 、-C(=O)-MR 5c 、-C(=O)-C 1-4 Alkylene-OC 0-4 Alkylene-R 5c 、-C(=O)-MC 1-4 Alkylene-OR5c 、C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0117] M is selected from C 3-6 Carbocyclic or 4 to 7 membered heterocyclic, wherein M is optionally substituted by 1 to 4 R k replace;

[0118] R 5a 、R 5b 、R 5c Each independently selected from C 1-6 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-12 Carbocyclic group, 4 to 12 membered heterocyclic group, the alkyl, alkenyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0119] R 5d 、R 5e Each independently selected from H, C 1-6 Alkyl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0120] R 5f 、R 5g Each independently selected from H, halogen, C 1-6 Alkyl, C 3-10 Carbocyclic group, the alkyl group, the carbocyclic group is optionally substituted by 1 to 4 R k replace;

[0121] or R 5f 、R 5g Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0122] R 5h Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 Carbocyclic group or 4 to 7 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0123] R 5i Selected from CN, NO2, -S(=O) 1-2 -C 1-6 Alkyl, -S(=O) 1-2 -C 3-6 Carbocyclic group, the alkyl group, the carbocyclic group is optionally substituted by 1 to 4 R k replace;

[0124] 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;

[0125] 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;

[0126] 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;

[0127] 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 3-6Carbocyclic group, -C 1-4 Alkylene-3 to 7 membered heterocyclic group, C 3-6 Carbocyclic group, 3 to 7 membered heterocyclic group, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0128] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0129] 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;

[0130] Ring D is selected from the following partially saturated rings: 13-15 membered tricyclic heterocyclic rings, 10 membered tricyclic heterocyclic rings, 4-6 Carbocyclic, 9-membered spirocarbon ring 4-6 Carbocyclic, 11-membered carbocyclic spiro C 3-5 Carbocyclic, 10-membered heterocyclic spiro C 4-6 Carbocyclic, 11-membered heterocyclic spiro C 3-5 carbocycle, 10-membered carbocyclic spiro 4- to 6-membered heterocycle, 11-membered carbocyclic spiro 4- to 5-membered heterocycle, 9-membered heterocyclic spiro 4- to 6-membered heterocycle, 9-membered heterocyclic spiro C 3-6 Carbocyclic ring, 9-membered heterocyclic spiro 8-10-membered heterocyclic ring, 10-membered heterocyclic spiro 4-6-membered heterocyclic ring, 11-membered heterocyclic spiro 4-5-membered heterocyclic ring, 11-membered heterotricyclic spiro C 3-4 Carbocyclic ring, wherein the ring D is optionally substituted by 1 to 4 R d replace;

[0131] Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic group, 4 to 8 membered heterocyclic group, benzo C 7-8 Carbocyclic group, wherein the ring A is optionally substituted by 1 to 4 R a Substitution, the nitrogen atom on the heteroaryl or heterocyclic group is optionally oxidized to form a nitrogen oxide;

[0132] R 6 Selected from C 1-4 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Monocarbocyclic group, C 6-10 Carbocyclic group, C 6-10 Spirocarbocyclyl, C 5-10bridged carbocyclic group, 4 to 8 membered monoheterocyclic group, 7 to 10 membered heterocyclic group, 7 to 10 membered spiro heterocyclic group, 6 to 10 membered bridged heterocyclic group, wherein R 6 Optional 1 to 4 R 6a replace;

[0133] 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

[0134] R a 、R b 、R d 、R 6a 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, -P(=O)R 5a R 5b 、-S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-MR 5c 、-C(=O)-MR 5c 、-C(=O)-C 1-2 Alkylene-OC 0-2 Alkylene-R 5c 、-C(=O)-MC 1-2 Alkylene-OR 5c 、C3-11 Carbocyclic group, 3 to 11 membered heterocyclic group, The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0135] M is selected from C 3-6 Cycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl or 5 to 6 membered heteroaryl, wherein M is optionally substituted by 1 to 4 R k replace;

[0136] R 5a 、R 5b 、R 5c Each independently selected from C 1-4 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 5-8 Bridged ring cycloalkyl, C 5-11 Spirocyclic cycloalkyl, C 5-11 cycloalkyl, 4 to 7 membered monocyclic heterocycloalkyl, 6 to 10 membered bridged heterocycloalkyl, 6 to 11 membered spirocyclic heterocycloalkyl, 6 to 11 membered cycloheterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace;

[0137] R 5d 、R 5e Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 7 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace;

[0138] R 5f 、R 5g Each independently selected from H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0139] or R 5f 、R 5g Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0140] R5h Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, said alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace;

[0141] R 5i Selected from CN, NO2, -S(=O) 1-2 -C 1-4 Alkyl, -S(=O) 1-2 -C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0142] 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;

[0143] 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;

[0144] 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 Substituted; the remaining definitions are the same as those of the first embodiment of the present invention.

[0145] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0146] 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, thienopyridinyl, thienophenyl, furopyridinyl, furophenyl, and said ring B is optionally substituted with 1 to 4 R b replace;

[0147] L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-;

[0148] 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, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0149] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0150] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0151] Ring B is selected from the group consisting of b One of the following groups substituted: Its right side is connected to Q;

[0152] Ring D is selected from The ring D is optionally substituted with 1 to 4 R d replace;

[0153] Q is selected from a bond, O, S, NH, CH2, CH(CH3),

[0154] Preferably, ring D is selected from The ring D is optionally substituted with 1 to 4 R d replace;

[0155] R 6 is selected from methyl, ethyl, isopropyl, propyl, -CH2O-CH3, -CH2O-CH2CH3, -CH2O-CH(CH3)2, -CH2O-C(CH3)3, -CH2CH2O-CH3, -CH2CH2O-CH2CH3, -CH2CH2O-CH(CH3)2, -CH2CH2O-C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]cyclopentyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, thienyl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or The R 6 Optional 1 to 4 R 6a replace;

[0156] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f Each independently selected from H, deuterium, methyl, ethyl, propyl, isopropyl;

[0157] R a 、R b 、R d 、R 6a 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 、 -C(=O)CH3, -C(=O)CH2CH3 or optionally 1 to 3 R ksubstituted by one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropyloxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirobutyl, cyclopentylspirobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxahexyl, -C(=O)R 5c 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c 、-C(=O)-MR 5c 、-C(=O)-CH2-OR 5c 、-C(=O)-CH2-OCH2-R 5c 、-C(=O)-M-CH2-O-R5c、

[0158] M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, said M being optionally substituted by 1 to 4 R k replace;

[0159] R 5c Selected from 1 to 4 R ksubstituted one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylcyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl;

[0160] R 5f 、R 5g Each is independently selected from H, F, Cl, Br, methyl, and ethyl;

[0161] or R 5f 、R 5g Directly connected to form a cyclobutyl, cyclopentyl or cyclohexyl group, wherein the cyclobutyl, cyclopentyl or cyclohexyl group is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, SH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, and cyclobutyl;

[0162] R 5a 、R 5b Each independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 3 R k replace;

[0163] 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;

[0164] Alternatively, R L1 、R L2 and the carbon atom to which it is attached together form a kSubstituted groups such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;

[0165] Alternatively, R 5a 、R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted groups:

[0166] 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, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are 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;

[0167] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0168] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0169] R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2,

[0170] Ring A is selected from the group consisting of asubstituted by 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,

[0171] L2 is selected from -CR L1 R L2 - or optionally 1 to 3 R k One of the following groups substituted:

[0172] 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;

[0173] 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, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, and morpholinyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy;

[0174] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0175] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0176] X is selected from O or S;

[0177] L1 is selected from -C(=O)-;

[0178] L2 is selected from

[0179] R 4 Selected from

[0180] Ring A is selected from phenyl, pyridyl, The ring A is optionally substituted with 1 to 4 R a replace;

[0181] Ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q;

[0182] Preferably, ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q;

[0183] -QR 6 One of the following groups is selected from the group consisting of ethyl, propyl, isopropyl, -CH2CH2CH2O-CH2CH3, -CH2CH2CH2O-CH(CH3)2, -CH2CH2CH2O-C(CH3)3, When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

[0184] Preferably, -QR 6 Selected from optionally substituted When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

[0185] R 6a Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,

[0186] Preferably, -QR 6 is selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy;

[0187] 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;

[0188] Preferably, R 1 Selected from H;

[0189] Preferably, R 2 Selected from H, methyl or CD3;

[0190] Preferably, R 3 Selected from H, methyl or CD3;

[0191] R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0192] Preferably, R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl,

[0193] R b Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0194] R dEach independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CD3, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, or optionally 1 to 4 R k1 substituted by one of the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-oxetanyl, -CH2-azetidinyl, -S(=O)2CH3, -S(=O)2cyclopropyl, -C(=O)NH-cyclopropyl, -C(=O)CH3, -C(=O)-vinyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O) -cyclopentyl, -C(=O)-bicyclo[2.2.1]heptanyl, -C(=O)-bicyclo[1.1.1]pentanyl, -C(=O)-cyclobutylspirobutyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxahexyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-pyrazolyl, -C(=O)-phenyl, -C(=O)-azetidinyl-CH2-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclobutyl, -C(=O)-pyrazolyl-CH2-cyclopentyl, -C(=O)-pyrrolidinyl-CH2-cyclopropyl, -C(=O)-piperidinyl-CH2-cyclopropyl, -C(=O)-piperazinyl-CH2-cyclopropyl, -C(=O)-azetidinyl-C(=O)-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclobutyl, -C(=O)-pyrazolyl-CH2-cyclopentyl, -C(=O)-pyrrolidinyl-CH2-cyclopropyl, -C(=O)-piperidinyl-CH2-cyclopropyl, -C(=O)-piperazinyl-CH2-cyclopropyl, -C(=O)-azetidinyl-C(=O)-cyclopropyl, -C(=O)-pyrazolyl Pyrrolidyl-C(=O)-cyclopropyl, -C(=O)-piperidinyl-C(=O)-cyclopropyl, -C(=O)-piperazinyl-C(=O)-cyclopropyl, -CH2-azetidinyl-C(=O)-cyclopropyl, -CH2-pyrrolidinyl-C(=O)-cyclopropyl, -CH2-azetidinyl-CH2-cyclopropyl, -CH2-pyrrolidinyl-CH2-cyclopropyl, -CH2-piperidinyl-CH2-cyclopropyl, -CH2-piperazinyl-CH2-cyclopropyl, -C(=O)-cyclopropyl-phenyl, -C(=O)-cyclopropyl-pyridyl, -C(=O)-cyclopropyl-thienyl, -C(=O)-cyclopropyl-furyl, -C(=O)-CH2-O-cyclopropyl, -C(=O)-CH2-OCH2-cyclopropyl;

[0195] R k1 Selected from methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, CH2CN, methyl, ethyl, methoxy, or ethoxy;

[0196] R 5f 、R 5g Each is independently selected from H, F, Cl, Br, methyl, ethyl; or R 5f 、R 5g Directly linked to form a cyclobutyl, cyclopentyl, or cyclohexyl group;

[0197] Preferably, R d Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, -C(=O)CH3, -C(=O)-cyclopropyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl,

[0198] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0199] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0200] The compound represented by general formula (I) is selected from the compound represented by (Id),

[0201] T is selected from a bond, O, S, CH2, NH, N(R d3 );

[0202] p1 is selected from 0, 1, 2, 3 or 4;

[0203] R d1Selected from H, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl;

[0204] R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl;

[0205] R d3 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c 、-C(=O)-MR 5c 、-C(=O)-M-CH2-OR 5c 、 The methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl are optionally substituted by 1 to 4 R k Replacement (R k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, );

[0206] M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, said M being optionally substituted by 1 to 4 R k Replacement (R k Preferably, each independently selected from deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl substituents);

[0207] R 5c is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl and cyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl, wherein R 5c Optional 1 to 4 R k Replacement (R k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, propenyl, );

[0208] R 5d 、R 5e Each is independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, and ethyl;

[0209] R bEach independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0210] R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl,

[0211] Preferably, Selected from

[0212] The present invention relates to the following compound or its racemate, 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:

[0213] Table E-1

[0214] The present invention relates to a pharmaceutical composition comprising the above compound or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0215] The present invention relates to the use of the above-mentioned compound or its racemate, stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition for preparing a drug for treating diseases related to GLP-1R activity or expression.

[0216] The present invention relates to the use of the above-mentioned compound or its racemate, stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in preparing a drug for treating diabetes or obesity.

[0217] 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 racemate, 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").

[0218] 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 racemate, 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.

[0219] 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;.

[0220] 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, 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 racemate, stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0221] 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 racemate, 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).

[0222] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a racemate, stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-8 In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0223] 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 its racemate, stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and the amount of the compound of the present invention or its racemate, stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

[0224] The amount of the compound of the invention or its racemate, stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0225] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0226] Synthesis method 1:

[0227] The general formula (Z1) and the general formula (Z2) undergo a coupling reaction under the catalysis of a heavy metal catalyst to obtain the corresponding general formula (Z3). The general formula (Z3) is deprotected under acidic conditions to obtain the corresponding general formula (Z4). The general formula (Z4) and the general formula (Z5) are reacted with a condensation agent (such as HATU) to obtain the corresponding general formula (I).

[0228] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0229] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79Br and 81 Br.

[0230] "CN" refers to cyano.

[0231] "Halogen" refers to F, Cl, Br or I.

[0232] "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".

[0233] "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.

[0234] "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.

[0235] "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.

[0236] " 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, P or Se, and the C, N, S, P on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic ring. Heterocycloalkyl can be connected to a heteroatom or carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0237] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three, carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, and the like; an alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0238] "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, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0239] "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.

[0240] "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.

[0241] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S, P or Se. The C, N, S, P 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.

[0242] "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). Non-limiting examples include: "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0243] "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.

[0244] "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.

[0245] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0246] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0247] "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.

[0248] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0249] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0250] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0251] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0252] "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.

[0253] "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.

[0254] "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-Ra , 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.

[0255] "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.

[0256] 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, heterocyclic 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 heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic group.

[0257] 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.

[0258] 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

[0259] 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.

[0260] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0261] "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.

[0262] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0263] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0264] "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. DETAILED DESCRIPTION

[0265] 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.

[0266] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6The 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).

[0267] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0268] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0269] 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;

[0270] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0271] In the structural formula, *abs1 or *abs2 represents that the chiral center is in a single unknown configuration.

[0272] HATU: CAS 148893-10-1; LiHMDS: lithium bis(trimethylsilyl)amide; NMP: N-methylpyrrolidone; DIPEA: N,N-diisopropylethylamine;

[0273] Example 1: Preparation of Compound 1

[0274] Step 1: Preparation of 1b

[0275] 1a (220 mg, 0.50 mmol) and 1a-1 (155 mg, 0.55 mmol) were dissolved in NMP (4 mL). CuI (50 mg, 0.26 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (50 mg, 0.35 mmol), and anhydrous potassium carbonate (250 mg, 1.81 mmol) were added. The mixture was reacted at 130°C under a nitrogen atmosphere for 2 h. After cooling to room temperature, 10 mL of water was added and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated aqueous sodium chloride (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 3:1) to obtain 1b (300 mg, 93.67% yield). (1a was synthesized with reference to US2019225604A1).

[0276] LCMS m / z=643.5[M+H] +

[0277] Step 2: Preparation of 1c

[0278] 1b (300 mg, 0.47 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (2 mL) was added. The reaction was carried out at room temperature for 16 h. The system was concentrated to dryness, and 2 mL of saturated aqueous potassium carbonate solution was added. The combined organic layers were extracted with ethyl acetate (2 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 10:1) to give 1c (170 mg, yield 67.12%).

[0279] LCMS m / z=543.4[M+H] +

[0280] Step 3: Preparation of compound 1

[0281] 1c (70 mg, 0.13 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (55 mg, 0.14 mmol), triethylamine (0.1 mL, 0.54 mmol), and 1c-1 (53 mg, 0.13 mmol) were added. The mixture was reacted at room temperature under a nitrogen atmosphere for 2 h. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA)). The product was then lyophilized to afford compound 1 (60 mg, 49.69%). (1c-1 was synthesized according to US2019225604A1).

[0282] LCMS m / z=936.5[M+H] +

[0283] Example 2: Preparation of Compound 2

[0284] Step 1: Preparation of 2a

[0285] 1a-1 (280 mg, 0.99 mmol) was dissolved in ultra-dry THF (5 mL), and iodomethane (156 mg, 1.10 mmol) and anhydrous potassium carbonate (200 mg, 1.45 mmol) were added. The reaction was carried out at 45°C under a nitrogen atmosphere for 16 h. The reaction mixture was cooled to room temperature, and the reaction solution was filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to give 2a (175 mg, 59.54% yield).

[0286] LCMS m / z=296.0[M+H] +

[0287] 1 H NMR (400MHz, DMSO-d6) δ7.49(d,1H),7.27(d,1H),7.24-7.19(m,1H),4.13-3.95(m,2H),3.88-3.74(m,2H),3.12(s,3H)),1.80-1.64(m,4H).

[0288] Step 2: Preparation of 2b

[0289] 2a (175 mg, 0.59 mmol) and 1a (218 mg, 0.49 mmol) were dissolved in NMP (5 mL), and CuI (142.5 mg, 0.75 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (107 mg, 0.75 mmol), and anhydrous potassium carbonate (138 mg, 1 mmol) were added. The reaction was carried out at 130°C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature, and 10 mL of water was added. The mixture was extracted with ethyl acetate (10 mL × 3) and washed with saturated aqueous sodium chloride solution (10 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent petroleum ether:ethyl acetate (v / v) = 1 / 1) to give 2b (288 mg, yield 88.81%).

[0290] LCMS m / z=657.4[M+H] +

[0291] Step 3: Preparation of 2c

[0292] 2b (200 mg, 0.3 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (2 mL) was added. The reaction was carried out at room temperature for 16 h. 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 (eluent: dichloromethane:methanol (v / v) = 10 / 1) to give 2c (105 mg, yield 61.94%).

[0293] LCMS m / z=557.8[M+H] +

[0294] 1 H NMR(400MHz,DMSO-d6)δ7.64(d,1H),7.39-7.21(m,3H),7.11(d,2H),6.91(s,1H),4.12-3.97(m,2H),3.92-3.73(m,3H),3 .24-3.09(m,4H),2.91-2.76(m,1H),2.70-2.54(m,2H),2.44-2.25(m,1H),2.19(s,6H),1.82-1.65(m,4H)),1.08(d,3H).

[0295] Step 4: Preparation of compound 2

[0296] 2c (85 mg, 0.15 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (87 mg, 0.23 mmol), triethylamine (60 mg, 0.46 mmol), and 1c-1 (63 mg, 0.15 mmol) were added. The mixture was reacted at room temperature under a nitrogen atmosphere for 2 h. The mixture 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)) and lyophilized to afford compound 2 (25 mg, 17.19%).

[0297] LCMS m / z=950.4[M+H] +

[0298] 1H NMR(400MHz,CF3COOD)δ7.70-7.58(m,3H),7.39(d,1H),7.35-7.25(m,3H),7.23-7.18(m,1H),7.10-6.80(m,3H),6.15-6.0 5(m,1H),4.95-4.79(m,1H),4.60-4.51(m,2H),4.30-4.07(m,4H),3.97-3.83(m,1H),3.63-3.42(m,2H),3.39(s,3H),3.28 -3.17(m,1H),2.38(s,6H),2.19-2.01(m,5H),2.00-1.70(m,9H),1.55(s,3H)),1.49(s,3H),1.34(d,3H).

[0299] Example 3: Preparation of Compound 3

[0300] Step 1: Preparation of 3a

[0301] 1a-1 (200 mg, 0.71 mmol) was dissolved in ultra-dry DMF (5 mL). Sodium hydride (57 mg, 1.43 mmol, 60% wt) was added under ice-cooling. After stirring for 5 min, deuterated iodomethane (114 mg, 0.79 mmol) was added and the mixture was reacted at room temperature under a nitrogen atmosphere for 2 h. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride solution (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to afford 3a (191 mg, 90.06% yield).

[0302] Step 2: Preparation of 3b

[0303] 3a (175 mg, 0.58 mmol) and 1a (218 mg, 0.49 mmol) were dissolved in NMP (5 mL), and CuI (143 mg, 0.75 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (110 mg, 0.77 mmol), and anhydrous potassium carbonate (140 mg, 1.01 mmol) were added. The reaction was carried out at 130°C under nitrogen atmosphere for 2 h. After cooling to room temperature, 10 mL of water was added, and the product was extracted with ethyl acetate (10 mL × 3), washed with saturated aqueous sodium chloride solution (10 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The product was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent petroleum ether:ethyl acetate (v / v) = 1:1) to give 3b (285 mg, yield 87.48%).

[0304] LCMS m / z=660.5[M+H] +

[0305] Step 3: Preparation of 3c

[0306] 3b (200 mg, 0.3 mmol) was dissolved in dichloromethane (3 mL), and 4 M HCl-dioxane solution (4 mL) was added. The mixture was reacted at room temperature for 16 h, and the system was concentrated to dryness to obtain 3c.

[0307] Step 4: Preparation of compound 3

[0308] 3c (180 mg, 0.3 mmol) was dissolved in ultra-dry DMF (5 mL), and HATU (171 mg, 0.45 mmol), triethylamine (0.2 mL, 1.21 mmol), and 1c-1 (124 mg, 0.3 mmol) were added. The mixture was reacted at room temperature for 2 h under a nitrogen atmosphere. The mixture 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)) and lyophilized to afford compound 3 (30 mg, 10.42%).

[0309] LCMS m / z=953.4[M+H] +

[0310] 1 H NMR(400MHz,CF3COOD)δ7.69-7.58(m,3H),7.39(d,1H),7.35-7.25(m,3H),7.23-7.17(m,1H),7.11-6.80(m,3H),6. 16-6.04(m,1H),4.93-4.79(m,1H),4.60-4.51(m,2H),4.30-4.07(m,4H),3.98-3.83(m,1H),3.59-3.38(m,2H),3.28 -3.17(m,1H),2.38(s,6H),2.19-1.72(m,14H),1.55(s,3H)),1.49(s,3H),1.34(d,3H).

[0311] Example 4: Preparation of Compound 4

[0312] Step 1: Preparation of 4a

[0313] 1a-1 (200 mg, 0.71 mmol) was dissolved in ultra-dry DMF (5 mL). Sodium hydride (58 mg, 1.45 mmol, 60% wt) was added under ice-cooling. After stirring for 5 min, iodoethane (122 mg, 0.78 mmol) was added and the mixture was reacted at room temperature under a nitrogen atmosphere for 2 h. 10 mL of water was added to the reaction solution, which was then extracted with ethyl acetate (10 mL × 3) and washed with saturated sodium chloride solution (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to afford 4a (215 mg, 97.78% yield).

[0314] LCMS m / z=310.1,312.1[M+H] +

[0315] Using 4a as substrate, compound 4 (15 mg) was obtained by referring to the synthesis method of step 2 to step 4 of Example 2.

[0316] LCMS m / z=964.6[M+H] +

[0317] 1 H NMR(400MHz,CF3COOD)δ7.70-7.57(m,3H),7.39(d,1H),7.35-7.23(m,3H),7.19(s,1 H),7.06-7.00(m,1H),6.95-6.88(m,1H),6.15-6.04(m,1H),4.92-4.80(m,1H),4.59 -4.51(m,2H),4.30-4.07(m,4H),4.00-3.84(m,3H),3.59-3.36(m,2H),3.28-3.15(m ,1H),2.38(s,6H),2.19-1.70(m,14H),1.55(s,3H)),1.49(s,3H),1.41-1.27(m,6H).

[0318] Example 5: Preparation of Compound 5

[0319] Step 1: Preparation of 5b

[0320] 5a (120 mg, 0.45 mmol) was dissolved in ultra-dry DMF (5 mL), and sodium hydride (40 mg, 1.0 mmol, 60% wt) was added under a nitrogen atmosphere at 0°C. The mixture was stirred for 1 h, and iodomethane (130 mg, 0.92 mmol) was added. The temperature was warmed to room temperature and reacted for 2 h. 5 mL of saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (5 mL × 3) and washed with saturated aqueous sodium chloride (5 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 (eluent petroleum ether:ethyl acetate (v / v) = 10:1) to give 5b (120 mg, yield 94.99%).

[0321] LCMS m / z=280.0, 282.0 [M+H] +

[0322] Step 2: Preparation of 5c

[0323] 1a (160 mg, 0.36 mmol) and 5b (120 mg, 0.43 mmol) were dissolved in NMP (3 mL), and CuI (40 mg, 0.21 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.28 mmol), and anhydrous potassium carbonate (200 mg, 1.45 mmol) were added. The reaction was allowed to react at 130°C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature, and 10 mL of water was added. The mixture was extracted with ethyl acetate (10 mL × 3) and washed with saturated aqueous sodium chloride solution (10 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent petroleum ether:ethyl acetate (v / v) = 3:1) to give 5c (220 mg, yield 94.74%).

[0324] LCMS m / z=641.3[M+H] +

[0325] Step 3: Preparation of 5d

[0326] 5c (220 mg, 0.34 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (2 mL) was added. The reaction was carried out at room temperature for 3 h. The system was concentrated to dryness, and 5 mL of saturated aqueous potassium carbonate solution was added. The combined organic layers were extracted with ethyl acetate (5 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 (eluent: dichloromethane:methanol (v / v) = 10:1) to give 5d (160 mg, yield 86.20%).

[0327] LCMS m / z=541.4[M+H] +

[0328] Step 4: Preparation of compound 5

[0329] 5d (160 mg, 0.30 mmol) was dissolved in ultra-dry DMF (4 mL), and HATU (150 mg, 0.39 mmol), triethylamine (0.4 mL, 2.88 mmol), and 1c-1 (160 mg, 0.39 mmol) were added. The mixture was reacted at room temperature for 2 h under a nitrogen atmosphere. The mixture 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)) and lyophilized to afford compound 5 (80 mg, 28.94%).

[0330] LCMS m / z=934.4[M+H] +

[0331] 1 H NMR(400MHz,CF3COOD)δ7.67-7.56(m,2H),7.51-7.45(m,1H),7.43-7.37(m,1H),7.36- 7.28(m,2H),7.27-7.21(m,1H),7.17-7.08(m,1H),7.05-6.97(m,1H),6.93-6.87(m,1H) ,6.19-6.00(m,1H),4.96-4.78(m,1H),4.26-4.03(m,2H),3.96-3.83(m,1H),3.60-3.1 4(m,6H),2.38(s,6H),2.34-1.68(m,18H),1.55(s,3H),1.49(s,3H),1.42-1.26(m,3H).

[0332] Example 6: Preparation of Compound 6

[0333] Step 1: Preparation of 6b

[0334] Methyltriphenylphosphonium bromide (20.0 g, 55.99 mmol) was dissolved in ultra-dry THF (100 mL) under ice-bath conditions. 1 M potassium tert-butoxide-tetrahydrofuran solution (60.0 mL, 60.0 mmol) was added, and the mixture was reacted under nitrogen for 0.5 h. 6a (8.0 g, 39.41 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (eluent: petroleum ether) to give 6b (3.46 g, 43.67% yield).

[0335] Step 2: Preparation of 6c

[0336] 6b (2.0 g, 9.95 mmol) was dissolved in dichloromethane (20 mL), and bromosuccinimide (4.4 g, 24.72 mmol) and triethylamine trihydrofluoride (4.8 g, 29.77 mmol) were added under ice bath. The reaction was carried out at room temperature for 16 h. 50 mL of water was added, 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 (eluent petroleum ether) to give 6c (600 mg, yield 20.11%).

[0337] Step 3: Preparation of 6d

[0338] 6c (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 reaction was carried out at room temperature for 16 h, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent petroleum ether) to give 6d (400 mg, yield 99.59%).

[0339] Step 4: Preparation of 6e

[0340] Under ice bath conditions, 1 M diethylzinc n-hexane solution (4 mL, 4 mmol) was dissolved in ultra-dry dichloromethane (4 mL), and trifluoroacetic acid (0.3 mL, 4.04 mmol) was slowly added dropwise. The reaction was carried out under nitrogen atmosphere for 0.5 h. Diiodomethane (0.35 mL, 4.34 mmol) was added, and after stirring for 20 minutes, 6d (400 mg, 1.83 mmol) was added. The reaction was carried out at room temperature for 16 h. 10 mL of saturated aqueous ammonium chloride was added, and the mixture 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 (eluent petroleum ether) to give 6e (370 mg, yield 86.94%).

[0341] Step 5: Preparation of 6f

[0342] 6e (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 h. Di-tert-butyl azodicarboxylate (400 mg, 1.74 mmol) was added and reacted at room temperature for 2 h. 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 (eluent petroleum ether:ethyl acetate (v / v) = 10:1) to give 6f (239 mg, yield 39.16%).

[0343] Step 6: Preparation of 6g

[0344] 6f (230 mg, 0.60 mmol) was dissolved in NMP (2 mL), and methanesulfonic acid (0.3 mL, 4.62 mmol) was added. The mixture was reacted at 80°C for 16 h. 5 mL of water was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The mixture was washed with saturated aqueous sodium chloride solution (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 6g (100 mg).

[0345] Step 7: Preparation of 6h

[0346] 6g (100 mg, 0.54 mmol) was dissolved in toluene (2 mL), 6g-1 (145 mg, 0.61 mmol) and pyridine hydrochloride (10 mg, 0.087 mmol) were added, and the reaction was carried out at 90°C for 1 h. 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 (eluent petroleum ether: ethyl acetate (v / v) = 5:1) to obtain 6h (54 mg, yield 24.59%).

[0347] LCMS m / z=405.3[M+H] +

[0348] Step 8: Preparation of 6i

[0349] 6h (50 mg, 0.12 mmol) was dissolved in pyridine (1 mL), and 6h-1 (40 mg, 0.31 mmol) and diethylamine (20 mg, 0.27 mmol) were added. The mixture was reacted at room temperature for 0.5 h. 5 mL of water was added to the system, and the mixture was extracted with ethyl acetate (5 mL × 3), washed with saturated aqueous sodium chloride solution (5 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain 6i (60 mg).

[0350] Step 9: Preparation of 6j

[0351] 6i (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 obtain 6j (50 mg, yield 94.66%).

[0352] LCMS m / z=472.2[M+H] +

[0353] Step 10: Preparation of 6k

[0354] 6j (80 mg, 0.17 mmol) and 2a (55 mg, 0.19 mmol) were dissolved in NMP (2 mL), and CuI (30 mg, 0.16 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (30 mg, 0.21 mmol), and anhydrous potassium carbonate (120 mg, 0.87 mmol) were added. The reaction was carried out at 130 °C under nitrogen atmosphere for 2 h. After cooling to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL×3), washed with saturated aqueous sodium chloride solution (10 mL×3), and the organic layers were combined and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent petroleum ether:ethyl acetate (v / v) = 5:1) to give 6k (100 mg, yield 85.82%).

[0355] LCMS m / z=687.3[M+H] +

[0356] Step 11: Preparation of 6L

[0357] 6k (100 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), and 4 M HCl-dioxane solution (1 mL) was added. The reaction was carried out at room temperature for 3 h. The system was concentrated to dryness, and 2 mL of saturated aqueous potassium carbonate solution was added. The combined organic layers were extracted with ethyl acetate (2 mL × 3) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: dichloromethane: methanol (v / v) = 10:1) to give 6l (80 mg, yield 93.65%).

[0358] LCMS m / z=587.2[M+H] +

[0359] Step 12: Preparation of compound 6

[0360] 6l (80 mg, 0.14 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (70 mg, 0.18 mmol), triethylamine (0.2 mL, 1.44 mmol), and 1c-1 (66 mg, 0.16 mmol) were added. The mixture was reacted at room temperature under a nitrogen atmosphere for 16 h. The reaction 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)) and lyophilized to afford compound 6 (50 mg, 37.41%).

[0361] LCMS m / z=980.6[M+H] +

[0362] 1 H NMR(400MHz,CF3COOD)δ7.90-7.82(m,1H),7.71-7.51(m,4H),7.44-7.26(m,3H),7.24-7.16(m,1H),7.05-6.99(m,1H),6.98-6.91(m,1H ),6.15-6.03(m,1H),4.91-4.79(m,1H),4.61-4.46(m,2H),4.31-4.05(m,4H),3.97-3.82(m,1H),3.60-3.12(m,6H),2.26-1.15(m,27H).

[0363] Example 7: Preparation of Compound 7

[0364] Step 1: Preparation of 7b

[0365] 7a (2.44 g, 10.0 mmol) was dissolved in ultra-dry DMF (10 mL), and iodomethane (2.14 g, 15.0 mmol) and anhydrous potassium carbonate (2.76 g, 20.0 mmol) were added. The reaction was carried out at 60°C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature, and 20 mL of saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 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 (eluent petroleum ether:ethyl acetate (v / v) = 5:1) to give 7b (2.0 g, yield 77.51%).

[0366] LCMS m / z=258.0, 260.0 [M+H] +

[0367] Step 2: Preparation of 7c

[0368] 7b (200 mg, 0.78 mmol) was dissolved in ethanol (2 mL), and hydrazine hydrate (1 mL, 80% wt) was added. The reaction was stirred at 130° C. for 2 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure. The residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to give 7c (100 mg, yield 52.86%).

[0369] Step 3: Preparation of 7d

[0370] 7c (100 mg, 0.41 mmol) was dissolved in ultra-dry DMF (3 mL), and 7c-1 (190 mg, 0.82 mmol), cesium carbonate (270 mg, 0.82 mmol), and sodium iodide (120 mg, 0.82 mmol) were added. The reaction was carried out at 50 ° C. under a nitrogen atmosphere for 16 h. After cooling to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated aqueous sodium chloride solution (10 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent petroleum ether: ethyl acetate (v / v) = 5:1) to give 7d (60 mg, yield 46.61%).

[0371] LCMS m / z=314.0, 316.0 [M+H] +

[0372] Step 4: Preparation of 7e

[0373] 1a (65 mg, 0.15 mmol) and 7d (50 mg, 0.16 mmol) were dissolved in ultra-dry NMP (2 mL), and CuI (15 mg, 0.079 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (15 mg, 0.11 mmol), and anhydrous potassium carbonate (90 mg, 0.65 mmol) were added. The reaction was stirred at 130°C under nitrogen atmosphere for 5 h. After cooling to room temperature, 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated aqueous sodium chloride solution (10 mL × 3), and the organic layers were combined and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 10:1) to give 7e (90 mg, yield 90.60%).

[0374] LCMS m / z=675.4[M+H] +

[0375] Step 5: Preparation of 7f

[0376] 7e (90 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (2 mL) was added. The reaction was carried out at room temperature for 16 h. The system was concentrated to dryness, and 2 mL of saturated aqueous potassium carbonate solution was added. 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 to give 7f (70 mg).

[0377] LCMS m / z=574.9[M+H] +

[0378] Step 6: Preparation of compound 7

[0379] 1c-1 (50 mg, 0.12 mmol) and 7f (70 mg, 0.12 mmol) were dissolved in ultra-dry DMF (2 mL). HATU (55 mg, 0.14 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added and reacted at room temperature under a nitrogen atmosphere for 16 h. The mixture 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)) and lyophilized to afford compound 7 (30 mg, 25.50%).

[0380] LCMS m / z=968.0[M+H] +

[0381] 1 H NMR(400MHz,CF3COOD)δ7.77-7.29(m,7H),7.08-6.94(m,2H),6.25-6.14(m,1H),5.03-4.89(m,1H),4.71-4.57(m,2H),4.40-4.14(m,4H) ,4.08-3.93(m,1H),3.76-3.44(m,5H),3.38-3.24(m,1H),2.49(s,6H),2.39-1.72(m,14H),1.65(s,3H),1.58(s,3H),1.52-1.35(m,3H).

[0382] Example 8: Preparation of Compound 8

[0383] Step 1: Preparation of 8b

[0384] 7a (2.44 g, 10.0 mmol) was dissolved in ultra-dry DMF (10 mL), and deuterated iodomethane (2.17 g, 15.0 mmol) and anhydrous potassium carbonate (2.76 g, 20.0 mmol) were added. The reaction was carried out at 60°C under a nitrogen atmosphere for 1 h. The mixture was cooled to room temperature, and 20 mL of saturated aqueous ammonium chloride solution was added. The mixture was extracted with ethyl acetate (20 mL × 3) and washed with saturated aqueous sodium chloride solution (20 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 (eluent petroleum ether:ethyl acetate (v / v) = 5:1) to give 8b (2.4 g, yield 91.94%).

[0385] Step 2: Preparation of 8c

[0386] 8b (2.4 g, 9.19 mmol) was dissolved in ethanol (15 mL), and hydrazine hydrate (3 mL, 80% wt) was added. The reaction was stirred at 130° C. for 2 h and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 8c (1.75 g, yield 77.04%).

[0387] LCMS m / z=247.0, 249.0 [M+H] +

[0388] Step 3: Preparation of 8d

[0389] 8c (1.7 g, 6.88 mmol) was dissolved in ultra-dry DMF (20 mL), and 7c-1 (3.19 g, 13.76 mmol), cesium carbonate (4.48 g, 13.76 mmol), and sodium iodide (2.06 g, 13.76 mmol) were added. The mixture was reacted at 60 ° C. under a nitrogen atmosphere for 16 h, cooled to room temperature, and 20 mL of water was added. The mixture was extracted with ethyl acetate (20 mL × 3) and washed with saturated sodium chloride aqueous solution (20 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 (eluent petroleum ether: ethyl acetate (v / v) = 5:1) to give 8d (1.5 g, yield 68.74%).

[0390] LCMS m / z=317.0, 319.0 [M+H] +

[0391] Step 4: Preparation of 8e

[0392] 1a (100 mg, 0.23 mmol) and 8d (80 mg, 0.25 mmol) were dissolved in ultra-dry NMP (4 mL), and CuI (40 mg, 0.21 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (40 mg, 0.28 mmol), and anhydrous potassium carbonate (150 mg, 1.09 mmol) were added. The reaction was carried out at 130°C under nitrogen atmosphere for 5 h. The mixture was cooled to room temperature, and 10 mL of water was added. The mixture was extracted with ethyl acetate (10 mL×3) and washed with saturated aqueous sodium chloride solution (10 mL×3). The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 10:1) to give 8e (120 mg, yield 78.17%).

[0393] LCMS m / z=678.5[M+H] +

[0394] Step 5: Preparation of 8f

[0395] 8e (120 mg, 0.18 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (2 mL) was added. The reaction was carried out at room temperature for 16 h. The system was concentrated to dryness, and 2 mL of saturated aqueous potassium carbonate solution was added. The combined organic layers were extracted with ethyl acetate (2 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8f (90 mg).

[0396] LCMS m / z=578.1[M+H] +

[0397] Step 6: Preparation of compound 8

[0398] 1c-1 (60 mg, 0.15 mmol) and 8f (90 mg, 0.16 mmol) were dissolved in ultra-dry DMF (2 mL). HATU (90 mg, 0.24 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added, and the mixture was reacted at room temperature under a nitrogen atmosphere for 16 h. The mixture 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)) and lyophilized to afford compound 8 (90 mg, 63.56%).

[0399] LCMS m / z=971.5[M+H] +

[0400] 1 H NMR(400MHz,CF3COOD)δ7.67-7.57(m,2H),7.48-7.36(m,2H),7.35-7.24(m,3H),6 .95-6.84(m,2H),6.15-6.04(m,1H),4.93-4.79(m,1H),4.62-4.47(m,2H),4.32-4. 04(m,4H),3.97-3.83(m,1H),3.61-3.32(m,2H),3.29-3.13(m,1H),2.39(s,6H),2 .26-2.14(m,2H),2.09-1.71(m,12H),1.55(s,3H),1.49(s,3H),1.39-1.30(m,3H).

[0401] Example 9: Preparation of Compound 9

[0402] Step 1: Preparation of 9b-P2

[0403] At room temperature, zinc powder (15.21 g, 232.58 mmol, 99.999% purity) was dissolved in DMA (120 mL). Trimethylsilyl chloride (6.50 g, 59.85 mmol) and 1,2-dibromoethane (5.65 g, 30.08 mmol) were added dropwise. A solution of 9a-1 (37.22 g, 155.05 mmol) in DMA (30 mL) was slowly added, and the mixture was allowed to react at room temperature under a nitrogen atmosphere for 2 h. 9a (10.00 g, 31 mmol), Pd(dppf)Cl2.CH2Cl2 (3.04 g, 3.72 mmol), and CuI (0.94 g, 4.96 mmol) were added sequentially to the system (under nitrogen protection), and the reaction was continued at 80°C under a nitrogen atmosphere for 2 h. The reaction was cooled to room temperature and quenched by adding saturated aqueous ammonium chloride solution (500 mL). The system was filtered and the filter cake was washed with ethyl acetate (10 mL × 3). The filtrate was extracted with ethyl acetate (100 mL × 3). The organic phases were combined and backwashed with saturated aqueous sodium chloride solution (300 mL × 2). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to give racemate 9b (4.1 g, yield 43.01%).

[0404] LCMS m / z=308.2[M+H] +

[0405] SFC preparation conditions:

[0406] Instrument: SFC Prep 150AP, Preparative Column: AD (19 mm × 250 mm). Preparation: Dissolve the sample in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: carbon dioxide / isopropanol, 52% methanol; Flow rate: 38 mL / min.

[0407] 4.1 g of racemate 9b was prepared by SFC and concentrated to give white solid compound 9b-P1 (1.86 g, retention time: 4.67 min) and compound 9b-P2 (2.08 g, retention time: 6.32 min).

[0408] Step 2: Preparation of 9c

[0409] 9b-P2 (2.08 g, 6.77 mmol) was dissolved in DMF (25 mL). Sodium hydride (0.24 g, 10.15 mmol, Purity 60%) was slowly added portionwise under a nitrogen atmosphere and ice-bath. The mixture was reacted on ice for 30 minutes under nitrogen atmosphere. Chloroacetonitrile (1.02 g, 13.54 mmol) was then added dropwise, and the temperature was slowly raised to room temperature for 18 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride (100 mL) under ice-bath. The mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and backwashed with saturated brine (150 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to afford 9c (2.13 g, 90.87% yield).

[0410] LCMS m / z=347.1[M+H] +

[0411] Step 3: Preparation of 9d

[0412] 9c (2.13 g, 6.15 mmol) and 9c-1 (2.55 g, 18.45 mmol) were dissolved in tetrahydrofuran (25 mL). Lithium bistrimethylsilylamide (4.12 g, 24.6 mmol) was slowly added dropwise under ice-cooling. The reaction was allowed to react at 0°C for 2 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL) under ice-cooling. The reaction was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to afford 9d (1.65 g, 69.43% yield).

[0413] LCMS m / z=387.2[M+H] +

[0414] SFC preparation conditions:

[0415] Instrument: SFC Prep 150AP, Preparative Column: IC (19 mm × 250 mm). Preparation: Dissolve the sample in methanol and filter through a 0.45 μm filter to prepare the sample solution. Mobile phase: carbon dioxide / isopropanol, 33% methanol; Flow rate: 40 mL / min.

[0416] 9d (1.65 g) was chirally separated by SFC to give 9d-P1 (950 mg, retention time: 9.88 min) and 9d-P2 (600 mg, retention time: 11.78 min).

[0417] Step 4: Preparation of 9e

[0418] Substrate 9d-P1 (913 mg, 2.36 mmol) and hydroxylamine hydrochloride (1.64 g, 23.60 mmol) were dissolved in dimethyl sulfoxide (10 mL). Sodium carbonate (2.50 g, 23.60 mmol) was added and the mixture was reacted at 60°C under a nitrogen atmosphere for 18 h. The reaction was cooled to room temperature and quenched with water (30 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride (30 mL). The organic phases were collected, dried over sodium sulfate, filtered, and concentrated to afford 9e (990 mg, 99.90% yield).

[0419] LCMS m / z=420.1[M+H] +

[0420] Step 5: Preparation of 9f

[0421] 9e (990 mg, 2.36 mmol) was dissolved in DMSO (10 mL), and N,N'-carbonyldiimidazole (765.35 mg, 4.72 mmol) and DBU (898.22 mg, 5.90 mmol) were added sequentially. The mixture was allowed to react at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched by the addition of water (50 mL), and 1N hydrochloric acid was added dropwise until the pH reached 6-7. The mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and backwashed with saturated brine (100 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate (v / v) = 5:1) to obtain 9f (624 mg, 59.35% yield).

[0422] LCMS m / z=444.2[MH] -

[0423] Step 6: Preparation of 9g

[0424] Substrate 9f (622 mg, 1.40 mmol) was dissolved in DMSO (7 mL), and a 2M aqueous solution of sodium hydroxide (168.00 mg, 4.20 mmol) was added dropwise to the system. After addition, the reaction was allowed to react at 30°C for 16 h. Water (30 mL) was added to quench the reaction system, and 1N hydrochloric acid was added dropwise to a pH of 1-2. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride (100 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to yield 9g (582 mg, 99.86% yield).

[0425] LCMS m / z=416.2[MH] -

[0426] Step 7: Preparation of compound 9

[0427] 9g (41.75mg, 0.1mmol) was dissolved in DMF (3mL), and 2c (67mg, 0.12mmol), HATU (57mg, 0.15mmol), and DIPEA (130mg, 1mmol) were added sequentially. The mixture was reacted at 60°C under a nitrogen atmosphere for 24h. The reaction was quenched by the addition of water (30mL) under an ice bath, and extracted with ethyl acetate (10mL x 3). The organic phases were combined and backwashed with saturated sodium chloride (30mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative liquid chromatography (Waters 2767 preparative liquid chromatography; SunFire@Prep C18 column (19mm x 150mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA)), and lyophilized to obtain compound 9 (21mg, 21.96% yield).

[0428] LCMS m / z=956.3[M+H] +

[0429] 1 H NMR(400MHz,CF3COOD)δ7.65(d,1H),7.38-7.22(m,3H),7.21-7.13(m,1H),7.06-6 .97(m,1H),6.95-6.78(m,3H),6.10-5.97(m,1H),5.03-4.86(m,1H),4.62-4.48(m, 2H),4.33-4.20(m,2H),4.19-4.01(m,2H),3.96-3.77(m,1H),3.53-3.28(m,6H),2. 38(s,6H),2.24-1.77(m,11H),1.72(d,3H),1.51(s,3H),1.48(s,3H),1.33(d,3H).

[0430] Example 10: Preparation of Compound 10

[0431] Compound 10 (15 mg, yield 15.69%) was obtained by referring to the synthesis method of compound 9.

[0432] LCMS m / z=956.3[M+H] +

[0433] 1H NMR(400MHz,CF3COOD)δ7.65(d,1H),7.37-7.22(m,3H),7.20-7.12(m,1H),7.05- 6.79(m,4H),6.40-5.97(m,1H),5.34-4.93(m,1H),4.59-4.49(m,2H),4.30-4.21( m,2H),4.19-4.02(m,2H),4.01-3.82(m,1H),3.53-3.06(m,7H),2.37(s,6H),2.3 1-1.72(m,11H),1.71-1.59(m,3H),1.51(s,3H)),1.48(s,3H),1.30-1.14(m,3H).

[0434] Example 11: Preparation of Compound 11

[0435] Step 1: Preparation of 11b

[0436] 11a (10.6 g, 50 mmol) was dissolved in ultra-dry DMSO (60 mL). Potassium tert-butoxide (5 mL, 1 M in THF) was added at room temperature and allowed to react for 30 minutes. A mixture of ethyl acrylate (13.6 mL, 125 mmol) and DMSO (10 mL) was added, and the reaction was continued at 45°C for 3 hours. Potassium tert-butoxide (5 mL, 1 M in THF) was added dropwise, and the reaction was continued at 60°C for 3 hours. Water (200 mL) was added, and the reaction was continued at 80°C for 18 hours. The reaction was cooled to room temperature and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and washed with saturated brine. The organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 11b (6.18 g, 42.2% yield).

[0437] LCMS m / z=294.0, 296.0 [M+H] +

[0438] Step 2: Preparation of 11c

[0439] 11b (6.18 g, 21.12 mmol), iodomethane (6.0 g, 42.24 mmol) and cesium carbonate (13.77 g, 42.24 mmol) were dissolved in acetonitrile (200 mL) and reacted at 70°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to give 11c (5.9 g, yield 91%).

[0440] LCMS m / z=308.0, 310.0 [M+H] +

[0441] Step 3: Preparation of 11e

[0442] 11c (3.07 g, 10 mmol) and 11d (960 mg, 5.0 mmol) were dissolved in DMF (40 mL). Hexamethylphosphoric triamide (4 mL) was added, and the mixture was replaced with nitrogen. The mixture was stirred at -60°C until uniform. LiHMDS (10 mL, 1 M in THF) was slowly added dropwise to the mixture, and the reaction was continued at this temperature for 1 h. 2 M hydrochloric acid (10 mL) was added to the mixture, and the mixture was returned to room temperature and stirred for 30 minutes. 12 M hydrochloric acid (15 mL) was then added to the mixture, and the temperature was raised to 130°C for 10 h. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 5:1) to afford 11e (610 mg, 17.9% yield).

[0443] LCMS m / z=342.0, 344.0 [M+H] +

[0444] Step 4: Preparation of 11f

[0445] 1a (110 mg, 0.25 mmol) and 11e (102 mg, 0.3 mmol) were dissolved in NMP (6 mL), and CuI (71.6 mg, 0.374 mmol), (1S,2S)-N,N'-dimethyl-1,2-cyclohexanediamine (53.2 mg, 0.374 mmol), and anhydrous potassium carbonate (103 mg, 0.74 mmol) were added. The reaction was carried out at 130 ° C. under nitrogen atmosphere for 4 h, and then cooled to room temperature. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×3), washed with saturated aqueous sodium chloride solution (50 mL), 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 (dichloromethane:ethyl acetate (v / v)=30:1) to give 11f (153 mg, yield 87.1%).

[0446] LCMS m / z=703.3[M+H] +

[0447] Step 5: Preparation of compound 11

[0448] 11f (153 mg, 0.218 mmol) was dissolved in dichloromethane (2 mL), and 4 M HCl-dioxane solution (4 mL) was added. The reaction was carried out at room temperature for 3 h. The system was concentrated to dryness, and the resulting residue was dissolved in DMF (4 mL). 1c-1 (89 mg, 0.218 mmol), HATU (114 mg, 0.3 mmol) and DIPEA (51.6 mg, 0.4 mmol) were added and the reaction was carried out at room temperature for 18 h. Under ice bath, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and washed with saturated aqueous sodium chloride solution (30 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated and purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% TFA) and then lyophilized to obtain compound 11 (57 mg, yield 26.2%).

[0449] LCMS m / z=996.3[M+H] +

[0450] 1 H NMR(400MHz,CF3COOD)δ7.80-7.60(m,3H),7.55-7.29(m,4H),7.26(s,1H),7.11(d,1H),7.00(d,1H),6.30-6. 06(m,1H),5.02-4.84(m,1H),4.33-4.11(m,2H),4.07-3.91(m,1H),3.70-3.55(m,1H),3.54-3.39(m,4H),3.37 -3.22(m,1H),2.88-2.75(m,2H),2.62-2.50(m,2H),2.46(s,6H),2.21-1.70(m,15H),1.63(s,3H)),1.57(s,3H),1.42(d,3H).

[0451] Example 12: Preparation of Compound 12

[0452] Step 1: Preparation of 12b

[0453] 12a (CAS: 1552637-88-3, 80 mg, 0.27 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (154 mg, 0.41 mmol), N,N-diisopropylethylamine (70 mg, 0.54 mmol), and cyclopropylcarboxylic acid (30.22 mg, 0.35 mmol) were added. The mixture was reacted at room temperature under a nitrogen atmosphere for 16 h. 10 mL of water was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The mixture was washed with saturated sodium chloride solution (10 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 3:1) to afford 12b (98 mg, 99.54% yield).

[0454] From the second to the fourth steps, compound 12 (10 mg) was obtained by referring to the synthetic method of compound 1.

[0455] LCMS m / z=509.4[M+2H] 2+

[0456] Example 13: Preparation of Compound 13

[0457] Compound 13 (10 mg) was obtained by referring to the synthetic method of compound 12.

[0458] LCMS m / z=518.3[M+2H] 2+

[0459] Example 14: Preparation of Compound 14

[0460] Step 1: Preparation of 14b

[0461] 14a (CAS: 2212020-29-4, 1.8 g, 2.45 mmol) was dissolved in NMP (20 mL), and 14a-1 (CAS: 2491752-99-7, 1.02 g, 2.57 mmol), CuI (699.90 mg, 3.68 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexanediamine (522.73 mg, 3.68 mmol) and potassium carbonate (1.02 g, 7.35 mmol) were added in sequence. The reaction was carried out at 130 °C under nitrogen atmosphere for 3 h and then cooled to room temperature. Water (100 mL) was added, the mixture was filtered and the filter cake was washed with ethyl acetate (10 mL × 2). The filtrate was collected and extracted with ethyl acetate (40 mL × 3). The organic phases were combined and backwashed with saturated aqueous sodium chloride solution (150 mL). The organic phases were collected, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate (v / v) = 30:1) to obtain 14b (1.27 g, yield 49.68%).

[0462] Step 2: Preparation of compound 14

[0463] Substrate 14b (1.27 g, 1.21 mmol) was dissolved in dichloromethane (10 mL), and a 4M HCl solution in 1,4-dioxane (10 mL) was added dropwise. The reaction was allowed to react at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford the crude hydrochloride. The crude product was dissolved in water (20 mL), and saturated sodium bicarbonate was slowly added under ice to a pH of 7-8. The mixture was extracted with dichloromethane:methanol (10:1) (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford compound 14 (975 mg, 84.87% yield).

[0464] LCMS m / z=949.5[M+H] +

[0465] 1 H NMR(400MHz,CF3COOD)δ7.73-7.17(m,8H),7.04(s,1H),7.92(s,1H),6.13 (s,1H),4.87(s,1H),4.37-4.05(m,4H),4.01-4.85(m,1H),3.74(d,2H),3 .67-3.30(m,5H),3.27-3.11(m,1H),2.63-2.48(m,2H),2.39(s,6H),2.19 (d,2H),2.11-1.65(m,10H),1.55(s,3H),1.54-1.42(m,4H),1.33(m,3H).

[0466] Example 15: Preparation of Compound 15

[0467] Compound 14 (40.81 mg, 0.043 mmol) was dissolved in methanol (3 mL), and methyl N-cyanoethylimidate (cas: 5652-84-6, 6.3 mg, 0.065 mmol) and DBU (7.9 mg, 0.052 mmol) were added. After addition, the mixture was heated to 65°C under a nitrogen atmosphere for 2 h. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane:methanol (v / v) = 30:1) to obtain compound 15 (14.5 mg, 28.90% yield).

[0468] LCMS m / z=508.4[M+2H] 2+

[0469] 1 H NMR(400MHz,CF3COOD)δ7.66-7.57(m,2H),7.56-7.48(m,1H),7.43-7.37(m,1H),7.36-7.25(m,4H),7.07-7.00 (m,1H),6.92-6.87(m,1H),6.15-6.05(m,1H),4.92-4.80(m,1H),4.79-4.57(m,1H),4.52-4.29(m,2H),4.23-4. 05(m,2H),3.97-3.82(m,1H),3.58-3.42(m,2H),3.40(s,3H),3.29-3.17(m,1H),3.06-2.94(m,3H),2.61-2.41 (m,2H),2.38(s,6H),2.33-2.16(m,2H),2.09-1.76(m,8H),1.73(d,3H),1.55(s,3H),1.48(s,3H),1.33(d,3H).

[0470] Example 16: Preparation of Compound 16

[0471] Compound 14 (20 mg, 0.02 mmol) was dissolved in DMF (2 mL), and cyanoacetic acid (cas: 372-09-8, 2.5 mg, 0.03 mmol), DIPEA (4 mg, 0.03 mmol), and HATU (11.4 mg, 0.03 mmol) were added. The mixture was allowed to react at room temperature for 2 h. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate (v / v) = 30:1) to obtain compound 16 (9 mg, 44.33% yield).

[0472] LCMS m / z=1016.6[M+H]+

[0473] 1 H NMR(400MHz,CF3COOD)δ7.70-7.50(m,3H),7.48-7.14(m,5H),7.02(d,1H),6.92 (s,1H),6.12(s,1H),4.95-4.76(m,1H),4.49-4.24(m,2H),4.23-4.04(m,3H),4 .00-3.82(m,2H),3.64-3.33(m,5H),3.28-3.16(m,1H),2.38(s,6H),2.25-1.84 (m,11H),1.83-1.66(m,4H),1.55(s,3H),1.54-1.43(m,4H),1.42-1.27(m,3H).

[0474] Example 17: Preparation of Compound 17

[0475] Step 1: Preparation of compound 17b

[0476] Compound 17a (494 mg, 2.0 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (607 mg, 6.0 mmol) and 17a-1 (483.6 mg, 2.4 mmol) were added at -20°C under a nitrogen atmosphere. The reaction was continued at this temperature for 2 h. The reaction mixture was concentrated to obtain a crude product, which was then purified by silica gel column chromatography (eluent: petroleum ether:ethyl acetate (v / v) = 3:1) to obtain compound 17b (201 mg, 41.8% yield).

[0477] LCMS m / z=241.1[M+H] +

[0478] Step 2: Preparation of compound 17

[0479] Compound 14 (35 mg, 0.037 mmol), 17b (12 mg, 0.05 mmol), and pyridine (3 mL) were added to a sealed tube and reacted at 106°C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate (v / v) = 30:1) to obtain compound 17 (19 mg, 48.95% yield).

[0480] LCMS m / z=1050.4[M+H] +

[0481] 1H NMR(400MHz,CF3COOD)δ7.68-7.49(m,3H),7.19(d,1H),7.35-7.27(m,3H),7.24(s,1H),7.03(d,1H),6. 90(d,1H),6.19-6.03(m,1H),4.97-4.71(m,2H),4.31-3.98(m,6H),3.90(t,1H),3.59-3.47(m,1H),3.4 6-3.32(m,4H),3.29-3.15(m,1H),2.96-2.86(m,1H),2.38(s,6H),2.24-2.09(m,4H),2.03(t,1H),1.99 -1.80(m,6H),1.74(d,3H),1.55(s,3H),1.49(s,3H),1.45-1.36(m,1H),1.33(d,3H),1.32-1.22(m,1H).

[0482] Example 20: Preparation of Compound 20

[0483] Compound 14 (40 mg, 0.042 mmol) was dissolved in dichloromethane (2 mL), and triethylamine (8.5 mg, 0.084 mmol) was added. Cyclopropylsulfonyl chloride (7 mg, 0.05 mmol) was added under ice-cooling and allowed to react for 2 h. The reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluent: dichloromethane:ethyl acetate (v / v) = 30:1) to obtain compound 20 (25 mg, 56.6% yield).

[0484] LCMS m / z=527.3[M+2H] 2+

[0485] 1H NMR(400MHz,CF3COOD)δ7.69-7.50(m,3H),7.40(d,1H),7.36-7.23(m,3H),7.20(s,1H),7.02(d,1H),6.91 (d,1H),6.19-6.02(m,1H),4.96-4.76(m,1H),4.23-4.06(m,2H),3.99(t,2H),3.89-3.80(m,2H),3.62-3.4 0(m,2H),3.38(s,3H),3.28-3.15(m,1H),2.72-2.59(m,1H),2.38(s,6H),2.25-2.15(m,2H),2.12-2.01(m, 3H),1.98-1.84(m,5H),1.78-1.70(m,3H),1.55(s,3H),1.48(s,3H),1.39-1.32(m,7H),1.30-1.25(m,2H).

[0486] Using compound 14 as the starting material, the following compounds were synthesized according to similar synthesis conditions as in the above example:

[0487] Example 42: Preparation of Compound 42

[0488] Step 1: Preparation of 42b

[0489] 42a (2 g, 13.23 mmol) was dissolved in water (30 mL), and concentrated hydrochloric acid (20 mL) was added. The mixture was stirred at room temperature for 5 min, followed by the addition of sodium nitrite (1.2 g, 17.33 mmol). The mixture was stirred at 0°C for 30 min, and then tin chloride (5 g, 26.37 mmol) was slowly added at 0°C. The reaction mixture was allowed to react at room temperature for 2 h. Solid potassium carbonate was added until no bubbles were generated, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated aqueous sodium chloride (30 mL × 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to afford 42b (2 g, 90.91% yield), which was used directly in the next step.

[0490] Step 2: Preparation of compound 42

[0491] Using 42b as substrate, the target compound 42 (59 mg, yield 61.92%) was obtained by referring to the synthesis method of Example 6.

[0492] LCMS m / z=490.9[M+2H] 2+

[0493] 1 H NMR(400MHz,CF3COOD)δ7.66-7.57(m,2H),7.46-7.36(m,3H),7.32-7.23(m,2H),7.22-7.16(m,1H ),6.95-6.86(m,2H),6.14-6.03(m,1H),4.92-4.78(m,1H),4.63-4.48(m,2H),4.31-4.04(m,4H),3 .96-3.82(m,1H),3.66-3.46(m,4H),3.44-3.35(m,1H),3.28-3.15(m,1H),2.28-2.13(m,3H),2.10 -1.71(m,12H),1.55(s,3H),1.49(s,3H),1.39-1.30(m,3H),1.22-1.11(m,2H),0.85-0.69(m,2H).

[0494] Example 43: Preparation of Compound 43

[0495] Using 42e as substrate, the target compound 43 (73 mg, 61.10%) was obtained by referring to the synthesis method of Example 6.

[0496] LCMS m / z=492.2[M+2H] 2+

[0497] 1 H NMR(400MHz,CF3COOD)δ7.66-7.55(m,2H),7.47-7.36(m,3H),7.32-7.24(m,2H),7.22-7 .15(m,1H),6.96-6.85(m,2H),6.15-6.02(m,1H),4.91-4.78(m,1H),4.62-4.48(m,2H),4 .30-4.04(m,4H),3.95-3.83(m,1H),3.58-3.34(m,2H),3.28-3.14(m,1H),2.29-1.71(m, 15H),1.55(s,3H),1.49(s,3H),1.40-1.29(m,3H),1.22-1.12(m,2H),0.85-0.69(m,2H).

[0498] Example 44: Preparation of Compound 44

[0499] Using 6j as substrate, the target compound 44 (60 mg, 41.85%) was obtained by referring to the synthesis method of Example 6.

[0500] LCMS m / z=983.5[M+H] +

[0501] 1 H NMR(400MHz,CF3COOD)δ7.93-7.81(m,1H),7.75-7.47(m,4H),7.45-7.25(m,3H),7.23- 7.13(m,1H),7.07-6.97(m,1H),6.96-6.86(m,1H),6.14-6.03(m,1H),4.91-4.78(m,1H ),4.62-4.46(m,2H),4.32-4.05(m,4H),3.96-3.81(m,1H),3.60-3.45(m,1H),3.44-3. 32(m,1H),3.30-3.14(m,1H),2.21-1.67(m,15H),1.61-1.43(m,8H),1.42-1.28(m,4H).

[0502] Example 45: Preparation of Compound 45

[0503] Using 6j as substrate, the target compound 45 (56 mg, 38.36%) was obtained by referring to the synthesis method of Example 6.

[0504] LCMS m / z=1001.5[M+H] +

[0505] 1 H NMR(400MHz,CF3COOD)δ7.90-7.80(m,1H),7.73-7.19(m,7H),7.01-6.84(m,2H),6.16-6.00(m,1H),4.92-4.76(m,1H),4.63-4.47(m,2H ),4.30-4.05(m,4H),3.96-3.81(m,1H),3.58-3.30(m,2H),3.29-3.13(m,1H),2.26-1.67(m,15H),1.61-1.44(m,8H),1.42-1.29(m,4H).

[0506] Example 46: Preparation of Compound 46

[0507] Using 6j as substrate, the target compound 46 (66 mg, 45.35%) was obtained by referring to the synthesis method of Example 6.

[0508] LCMS m / z=998.4[M+H] +

[0509] 1 H NMR(400MHz,CF3COOD)δ7.90-7.79(m,1H),7.76-7.19(m,7H),7.02-6.85(m,2H),6.16-6.01(m,1H),4.92-4.77(m,1H),4.63-4.45(m,2H) ),4.33-4.03(m,4H),3.99-3.81(m,1H),3.65-3.31(m,5H),3.28-3.15(m,1H),2.26-1.68(m,15H),1.62-1.44(m,8H),1.44-1.28(m,4H).

[0510] Example 47: Preparation of Compound 47

[0511] Step 1: Preparation of compound 47

[0512] 47a (76.68 mg, 0.2 mmol, reference: WO2023016546) was dissolved in DMF (3 mL), and 2c (110 mg, 0.2 mmol), HATU (114.07 mg, 0.3 mmol), and DIPEA (258.48 mg, 2.0 mmol) were added sequentially. The mixture was reacted at room temperature under a nitrogen atmosphere for 18 h. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and backwashed with saturated sodium chloride solution (20 mL × 2). The organic phases were collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol (v / v) = 30:1) to obtain compound 47 (76 mg, 41.21% yield).

[0513] LCMS m / z=922.4[M+H] +

[0514] 1H NMR(400MHz,CF3COOD)δ7.71-7.56(m,3H),7.40(d,1H),7.36-7.25(m,3H),7.20(s ,1H),7.03(s,1H),6.95-6.87(m,1H),6.17-6.06(m,1H),4.92-4.79(m,1H),4.61-4 .47(m,2H),4.45-4.33(m,2H),4.31-4.18(m,2H),3.96-3.78(m,3H),3.60-3.41(m, 2H),3.39(s,3H),3.08-2.95(m,1H),2.38(s,6H),2.23-1.64(m,14H),1.34(d,3H).

[0515] Example 48: Preparation of Compound 48

[0516] To a reaction flask, 6k (41 mg, 0.06 mmol) and a 4 mol / L HCl 1,4-dioxane solution (5 mL) were added and allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to yield a crude product (45 mg). The crude product (45 mg) was dissolved in 2.5 mL of DMF, and 47a (25 mg, 0.065 mmol) (synthesis method reference WO2021155841), HATU (33 mg, 0.087 mmol), and DIPEA (38 mg, 0.29 mmol) were added and allowed to react at room temperature for 16 h. The system was concentrated under reduced pressure, and the resulting crude product was subjected to pre-HPLC (instrument and preparative column: Shimadzu LC-20AP preparative HPLC, preparative column model C18, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMF solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: aqueous solution of ammonium bicarbonate (10 mmol / L) / acetonitrile. Gradient elution method: acetonitrile from 30% to 60% (elution time 16 min). Lyophilization gave compound 48 (17 mg, yield: 30%).

[0517] LCMS m / z=952.3[M+1] +

[0518] 1H NMR(400MHz,CF3COOD)δ7.93-7.77(m,1H),7.73-7.10(m,8H),7.07-6.85(m,2H),6.18-5.99(m,1H),4.94-4.76(m,1H),4.63-4.47(m,2H),4.46-4 .33(m,2H),4.32-4.17(m,2H),4.00-3.77(m,3H),3.61-3.31(m,5H),3.1 2-2.92(m,1H),2.21-1.64(m,15H),1.63-1.47(m,2H),1.45-1.24(m,4H).

[0519] Example 49: Preparation of Compound 49

[0520] Compound 49 was prepared using compounds 46a and 47a as raw materials by referring to the synthetic method of Example 48.

[0521] LCMS m / z=970.4[M+1] +

[0522] 1 H NMR(400MHz,CF3COOD)δ7.94-7.76(m,1H),7.74-7.17(m,7H),7.04-6.82(m,2H),6.17-6.01(m,1H),4.94-4.77(m,1H),4.63-4.47(m,2H),4.46-4 .33(m,2H),4.31-4.15(m,2H),3.98-3.78(m,3H),3.64-3.30(m,5H),3.0 9-2.93(m,1H),2.25-1.67(m,15H),1.63-1.47(m,2H),1.44-1.29(m,4H).

[0523] Example 50: Preparation of Compound 50

[0524] Compound 50 was obtained using compounds 44a and 47a as raw materials, referring to the synthetic method of Example 48.

[0525] LCMS m / z=955.3[M+1] +

[0526] Example 51: Preparation of Compound 51

[0527] Compound 51 was obtained using compounds 45a and 47a as raw materials, referring to the synthetic method of Example 48.

[0528] LCMS m / z=973.3[M+1] +

[0529] Example 52: Preparation of Compound 52

[0530] Step 1: Preparation of 52a

[0531] 6d (22 g, 0.1 mol) was dissolved in 300 mL of THF and cooled to -78°C. 40 mL of 2.5 mol / L n-butyllithium solution was added dropwise. After reacting at -78°C for 1 h, di-tert-butyl diazene-1,2-dicarboxylate (34.5 g, 0.15 mol) was slowly added and allowed to react at room temperature for 2 h. 100 mL of saturated aqueous ammonium chloride and 500 mL of ethyl acetate were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 4:1) to afford 52a (11 g, 30% yield).

[0532] Step 2: Preparation of 52b

[0533] 52a (3.7 g, 9.99 mmol) was dissolved in 30 mL of dichloromethane, and a 4 mol / L 1,4-dioxane solution (30 mL) of HCl was added. The reaction was allowed to react at 25°C for 3 h. The reaction solution was concentrated under reduced pressure, and 52A (2.4 g, 10.07 mmol), pyridine hydrochloride (0.12 g, 1 mmol), and 100 mL of toluene were added, followed by reaction at 90°C for 1 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to afford 52b (1.5 g, 38% yield).

[0534] LCMS m / z=391.3[M+1] +

[0535] Step 3: Preparation of 52c

[0536] 52b (1.5 g, 3.8 mmol) was dissolved in 20 mL of pyridine, and 2-isocyanato-1,1-dimethoxyethane (1.3 g, 9.9 mmol) was added. The reaction was allowed to react at room temperature for 8 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain 52c (1.4 g, yield: 71%).

[0537] LCMS m / z=522.4[M+1] +

[0538] Step 4: Preparation of 52d

[0539] 52c (1.4 g, 2.69 mmol) was dissolved in 20 mL of tetrahydrofuran, and methanesulfonic acid (0.58 g, 6.03 mmol) was added. The reaction was allowed to proceed at 60°C for 2 h. The mixture was cooled to room temperature, the pH was adjusted to 9.0 with saturated potassium carbonate solution, and di-tert-butyl dicarbonate (0.59 g, 2.7 mmol) was added. The reaction was allowed to proceed at room temperature for 1 h. 30 mL of purified water and 50 mL of ethyl acetate were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to afford 52d (0.6 g, 49% yield).

[0540] LCMS m / z=458.4[M+1] +

[0541] Step 5: Preparation of 52e

[0542] 52d (0.14 g, 0.31 mmol) was dissolved in 6 mL of NMP, and 52B (0.15 g, 0.51 mmol), CuI (0.086 g, 0.45 mmol), and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (0.064 g, 0.45 mmol) were added, respectively, and the mixture was reacted at 130°C for 3 h. The reaction solution was cooled to room temperature, and 30 mL of purified water and 30 mL of ethyl acetate were added. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:1) to obtain 52e (0.1 g, yield: 48%).

[0543] Step 6: Preparation of compound 52

[0544] 52e (0.1 g, 0.15 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of a 4 mol / L HCl-1,4-dioxane solution was added. The mixture was reacted at 25°C for 3 h. The reaction mixture was concentrated under reduced pressure, and 1c-1 (0.066 g, 0.16 mmol), HATU (0.068 g, 0.18 mmol), and 5 mL of DMF were added. The reaction mixture was allowed to react at room temperature for 8 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2). The crude product was then subjected to pre-HPLC (Shimadzu LC-20AP preparative HPLC, C18 column, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product solution in acetonitrile was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was an aqueous solution of ammonium bicarbonate (10 mmol / L) in acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 30% to 50% (elution time: 14 min), and the compound 52 (80 mg, yield: 55%) was obtained by lyophilization.

[0545] LCMS m / z=966.4[M+1] +

[0546] 1 H NMR(400MHz,CF3COOD)δ7.91-7.80(m,1H),7.78-7.49(m,4H),7.48-7.35(m,2H),7.34-7.25(m,1H ),7.24-7.17(m,1H),7.05-6.98(m,1H),6.97-6.87(m,1H),6.14-6.01(m,1H),5.64-5.43(m,1H),5 .42-5.30(m,1H),4.90-4.76(m,1H),4.62-4.44(m,2H),4.33-4.05(m,4H),3.97-3.81(m,1H),3.59 -3.44(m,1H),3.44-3.32(m,4H),3.27-3.15(m,1H),2.19-1.66(m,14H),1.52(d,6H),1.34(d,3H).

[0547] Using compound 52d as the starting material, the following compounds were synthesized according to similar synthesis conditions as in the above example:

[0548] Using compound 47a as the starting material, the following compounds were synthesized according to similar synthesis conditions as in the above example:

[0549] Example 59: Preparation of Compound 59

[0550] Compound 14 (114 mg, 0.12 mmol), 59a (21 mg, 0.2 mmol), HATU (76 mg, 0.2 mmol), and DIPEA (65 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (5 mL) and allowed to react at room temperature overnight. 15 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The mixture was washed with saturated aqueous sodium chloride (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by column chromatography (eluent: dichloromethane:methanol (v / v) = 30:1) to obtain compound 59 (60 mg, 48.35% yield).

[0551] LCMS m / z=518.3[M+2H] +

[0552] 1H NMR(400MHz,CF3COOD)δ7.69-7.46(m,3H),7.39(d,1H),7.36-7.27(m,3H),7.25(s,1H),7.03(d,1H) ,6.91(d,1H),6.21-6.00(m,1H),5.27-5.00(m,1H),4.93-4.79(m,1H),4.75-4.25(m,4H),4.23-4.05 (m,2H),3.90(t,1H),3.59-3.47(m,1H),3.46-3.35(m,4H),3.27-3.17(m,1H),2.44-2.13(m,11H),2. 08(t,1H),2.00-1.79(m,7H),1.74(d,3H),1.67-1.58(m,1H),1.55(s,3H),1.49(s,3H),1.33(d,3H).

[0553] Biological test example 1: in vitro activity detection

[0554] 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-well 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-well microplate and incubated at room temperature in the dark 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 perform a four-parameter fit with the logarithm as the horizontal axis and the ratio of 665nm / 620nm (Ratio) as the vertical axis to obtain the EC50 value of the curve.

[0555] Table 1: Effects of Compounds on GLP-1EC 50

[0556] A<1nM

[0557] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good agonist effect on the GLP-1 receptor.

[0558] Biological test example 2:

[0559] Oral glucose tolerance test (OGTT)

[0560] 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 screened for oral administration. The control group was given the vehicle. 15 minutes after administration, each group of animals was gavage-administered 25% glucose solution. Blood glucose levels were measured 15 minutes, 30 minutes, 45 minutes, 1 hour, and 2 hours after administration, and the 0-2 hour blood glucose AUC was calculated using Graphpad Prism software. 0-2h The inhibition rate was calculated.

[0561] Calculation formula: Blood glucose inhibition rate = (AUC 0-2h -AUC of the drug-treated group 0-2h ) / AUC of vehicle group 0-2h ×100%

[0562] Conclusion: Compounds of the present invention, such as the examples, exhibited promising oral hypoglycemic effects at the GLP-1 receptor. For example, Compounds 2 and 3 exhibited excellent glucose-lowering properties at a dose of 3 mg / kg: Compound 2 exhibited a blood glucose suppression rate of -25.5% at 3 mg / kg, Compound 3 exhibited a blood glucose suppression rate of -37.1% at 3 mg / kg, and the control compound, Orforglipron, exhibited a blood glucose suppression rate of -9.8% at 3 mg / kg.

[0563] Biological test example 3: mouse pharmacokinetic test

[0564] Test animals: Male C57 mice, 22-25 g, 6 mice per compound.

[0565] 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.

[0566] Table 2. Dosing Information

[0567] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-β-CD);

[0568] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl beta-cyclodextrin)

[0569] 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.

[0570] Table 2-1 Pharmacokinetic results of test compounds in mice

[0571] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral efficacy in mice.

[0572] Biological Test Example 4: Monkey Pharmacokinetic Test

[0573] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 5 per compound, purchased from Hainan Xinzhengyuan Biotechnology Co., Ltd.

[0574] 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.

[0575] Table 3. Dosing Information

[0576] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% Solutol + 90% (0.5% MC);

[0577] 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.

[0578] Table 3-1. Pharmacokinetic parameters of test compounds in monkey plasma

[0579] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral performance in monkeys.

[0580] Biological Test Example 5: CYP450 Enzyme Inhibition Test

[0581] 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.

[0582] Table 4

[0583] Conclusion: The compounds of the present invention, such as the example compounds, have lower CYP inhibitory potential than the control compound Orforglipron.

[0584] Biological Test Example 6: SLC Transporter Inhibition

[0585] The purpose of this study was to evaluate the inhibitory effect of the test substances on the activity of transporters OATP1B1 and OATP1B3.

[0586] 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 ).

[0587] Conclusion: The compounds of the present invention, such as the example compounds, have weak inhibitory effects on OATP1B1 and OATP1B3. For example, the IC value of compound 6 on OATP1B1 is 50 Greater than 2 μM, IC for OATP1B3 50 Greater than 1μM.

Claims

1. A compound or its racemate, stereoisomer, tautomer, deuterated form, 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; Y is selected from C and N, Z is selected from CH or N, J is selected from N or C, and at least one of Y, Z and J is selected from N; 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 heterocyclyl, 11 to 15 membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a Substitution, the nitrogen atom on the heteroaryl or heterocyclic group is optionally oxidized to form a nitrogen oxide; Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 6- and 6-membered heteroaryl, C 3-10 carbocyclic group, 4 to 10 membered heterocyclic group, wherein the ring B is optionally substituted by 1 to 4 R b replace; Ring D is selected from 13 to 16-membered tricyclic or tetracyclic heterocyclic groups, 17 to 30-membered tricyclic or tetracyclic heterocyclic groups, and the ring D is optionally substituted by 1 to 4 R d replace; L1 is selected from -S(=O)2-, -C(=O)-, -C(=S)-; L2 is selected from -(CR L1 R L2 ) m -; X is selected from S or O; Q is selected from a bond, O, S, NH, C 1-4 Alkylene, The alkylene group is optionally substituted by 1 to 4 R k replace; m is selected from 1, 2, 3 or 4; R 4 selected from -C(=O)R 4a 、-C(=O)OR 4a 、-C(=O)NR 4a R 4b 、 R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 6 Selected from C 1-6 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-10 Carbocyclic group, 4 to 10 membered heterocyclic group, said R 6 Optional 1 to 4 R 6a replace; R a , R b , R d , R 6a 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 carbocyclyl, -O-3 to 7 membered heterocyclyl, -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, -P(=O)R 5a R 5b 、-S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c , -C(=O)-MR 5c , -C(=O)-C 1-4 Alkylene-OC 0-4 Alkylene-R 5c 、-C(=O)-MC 1-4 Alkylene-OR 5c , C 3-12 Carbocyclic group, 3 to 12 membered heterocyclic group, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; M is selected from C 3-6 carbocyclic group or 4 to 7 membered heterocyclic group, wherein M is optionally substituted by 1 to 4 R k replace; R 5a , R 5b , R 5c Each independently selected from C 1-6 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 3-12 A carbocyclic group, a 4- to 12-membered heterocyclic group, wherein the alkyl, alkenyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 5d , R 5e Each independently selected from H, C 1-6 Alkyl, C 3-10 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 5f , R 5g Each independently selected from H, halogen, C 1-6 Alkyl, C 3-10 The alkyl group or carbocyclic group is optionally substituted by 1 to 4 R k replace; or R 5f , R 5g Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; R 5h Selected from NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 5i Selected from CN, NO2, -S(=O) 1-2 -C 1-6 Alkyl, -S(=O) 1-2 -C 3-6 The alkyl group or carbocyclic group is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace; Alternatively, R L1 , R L2 Together with the atoms connected to it, they form C 3-8 A carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 5a , R 5b Together with the phosphorus atom to which it is connected, it forms a 5- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 carbocyclyl, -O-3 to 7 membered heterocyclyl, -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, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

2. The compound according to claim 1 or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Ring B is selected from 5-membered heteroaryl or 5-membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b replace; Ring D is selected from the following partially saturated rings: 13-15-membered tricyclic heterocyclic group, 10-membered carbocyclic spiro ring C 4-6 Carbocyclic, 9-membered spirocarbon ring 4-6 Carbocyclic, 11-membered carbocyclic spiro C 3-5 Carbocyclic, 10-membered heterocyclic spiro C 4-6 Carbocyclic, 11-membered heterocyclic spiro C 3-5 carbocyclic ring, 10-membered carbocyclic ring spiro 4 to 6-membered heterocyclic ring, 11-membered carbocyclic ring spiro 4 to 5-membered heterocyclic ring, 9-membered heterocyclic ring spiro 4 to 6-membered heterocyclic ring, 9-membered heterocyclic ring spiro C 3-6 Carbocyclic ring, 9-membered heterocyclic spiro 8- to 10-membered heterocyclic ring, 10-membered heterocyclic spiro 4- to 6-membered heterocyclic ring, 11-membered heterocyclic spiro 4- to 5-membered heterocyclic ring, 11-membered heterotricyclic spiro C 3-4 carbon ring, the ring D is optionally substituted by 1 to 4 R d replace; Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 Monocarbocyclic group, 4- to 8-membered monoheterocyclic group, benzo C 7-8 A carbocyclic group, wherein the ring A is optionally substituted by 1 to 4 R a Substitution, the nitrogen atom on the heteroaryl or heterocyclic group is optionally oxidized to form a nitrogen oxide; R 6 Selected from C 1-4 Alkyl, -C 1-2 Alkylene-OC 1-4 Alkyl, C 3-6 Monocarbocyclic group, C 6-10 Carbocyclic group, C 6-10 Spirocarbocyclyl, C 5-10 bridged carbocyclic group, 4- to 8-membered monoheterocyclic group, 7- to 10-membered heterocyclic group, 7- to 10-membered spiroheterocyclic group, 6- to 10-membered bridged heterocyclic group, wherein R 6 Optional 1 to 4 R 6a replace; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f Each independently selected from H, deuterium, C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace R a , R b , R d , R 6a 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 carbocyclyl, -O-3 to 7 membered heterocyclyl, -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, -P(=O)R 5a R 5b 、-S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c , -C(=O)-MR 5c , -C(=O)-C 1-2 Alkylene-OC 0-2 Alkylene-R 5c 、-C(=O)-MC 1-2 Alkylene-OR 5c , C 3-11 Carbocyclic group, 3 to 11 membered heterocyclic group, The alkyl, alkenyl, alkynyl, alkylene, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; M is selected from C 3-6 cycloalkyl, phenyl, 4 to 7 membered heterocycloalkyl or 5 to 6 membered heteroaryl, wherein M is optionally substituted by 1 to 4 R k replace; R 5a , R 5b , R 5c Each independently selected from C 1-4 Alkyl, -C 1-4 Alkyl-OC 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 3-6 Cycloalkyl, C 5-8 Bridged ring cycloalkyl, C 5-11 Spirocyclic cycloalkyl, C 5-11 cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-10 membered bridged heterocycloalkyl, 6-11 membered spirocyclic heterocycloalkyl, 6-11 membered cycloheterocycloalkyl, phenyl or 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace; R 5d , R 5e Each independently selected from H, C 1-4 Alkyl, C 3-6 cycloalkyl, 4 to 7 membered heterocycloalkyl, phenyl or 5 to 6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, phenyl or heteroaryl is optionally substituted by 1 to 4 R k replace; R 5f , R 5g Each independently selected from H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace; or R 5f , R 5g Direct connection to form C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; R 5h Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered heterocycloalkyl, the alkyl, cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R k replace; R 5i Selected from CN, NO2, -S(=O) 1-2 -C 1-4 Alkyl, -S(=O) 1-2 -C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, halogen, CN, OH, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl group is optionally substituted by 1 to 4 R k replace; Alternatively, R L1 , R L2 Together with the connected carbon atoms, they form C 3-6 A carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 5a , R 5b Together with the phosphorus atom to which it is connected, it forms a 5- to 8-membered monocyclic heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace.

3. The compound according to claim 2, or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, 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, thienopyridinyl, thienophenyl, furopyridinyl, furanophenyl, and said ring B is optionally substituted by 1 to 4 R b replace; L2 is selected from -(CR L1 R L2 )-、-(CR L1 R L2 )2-; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 carbocyclic 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, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CH2CN, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3, or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring B is selected from b One of the following groups substituted: Its right side is connected to Q; Ring D is selected from The ring D is optionally substituted with 1 to 4 R d replace; Preferably, ring D is selected from The ring D is optionally substituted with 1 to 4 R d replace; Q is selected from a bond, O, S, NH, CH2, CH(CH3), R 6 is selected from methyl, ethyl, isopropyl, propyl, -CH2O-CH3, -CH2O-CH2CH3, -CH2O-CH(CH3)2, -CH2O-C(CH3)3, -CH2CH2O-CH3, -CH2CH2O-CH2CH3, -CH2CH2O-CH(CH3)2, -CH2CH2O-C(CH3)3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]cyclopentyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, pyrrolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or The R 6 Optional 1 to 4 R 6a replace; 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 d , R 6a 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 , -C(=O)CH3, -C(=O)CH2CH3 or optionally 1 to 3 R k substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxahexyl, -C(=O)R 5c 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c , -C(=O)-MR 5c 、-C(=O)-CH2-OR 5c 、-C(=O)-CH2-OCH2-R 5c 、-C(=O)-M-CH2-OR 5c , M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, and M is optionally replaced by 1 to 4 R k replace; R 5c Selected from 1 to 4 R k substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl and cyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl; R 5f , R 5g Each is independently selected from H, F, Cl, Br, methyl, ethyl; or R 5f , R 5g Directly connected to form cyclobutyl, cyclopentyl or cyclohexyl, wherein the cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, SH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl; R 5a , R 5b Each independently selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted by 1 to 3 R k replace; R 1 , R 2 , R 3 , R L1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2 or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio; Alternatively, R L1 , R L2 and the carbon atom to which it is attached together form a k Substituted groups as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl; Alternatively, R 5a , R 5b and the connected phosphorus atom together form an optionally 1 to 3 R k Substituted with the following groups: R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

5. The compound according to claim 4, or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein R 4 Selected from -C(=O)OH, -C(=O)OCH3, -C(=O)N(CH3)2, Ring A is selected from a substituted by one of the following groups: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, L2 Selected from -CR L1 R L2 - or optionally 1 to 3 R k One of the following groups substituted: R L1 , R L2 Each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2, NH2, NH(CH3), N(CH3)2, methyl, ethyl, methoxy, ethoxy, isopropoxy, methylthio; R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, The methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, and morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, CH2CN, methyl, ethyl, methoxy, and ethoxy.

6. The compound according to claim 1 or its racemate, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, X is selected from O or S; L1 is selected from -C(=O)-; L2 is selected from R 4 Selected from Ring A is selected from phenyl, pyridyl, The ring A is optionally substituted with 1 to 4 R a replace; Ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q; Preferably, ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q; -QR 6 is selected from one of the following groups which are optionally substituted: ethyl, propyl, isopropyl, -CH2CH2CH2O-CH2CH3、-CH2CH2CH2O-CH(CH3)2、-CH2CH2CH2O-C(CH3)3、 When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; R 6a is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, Preferably, -QR 6 is selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; Preferably, -QR 6 Selected from optionally substituted When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CF3, CHF2, CH2F, CD3, CHD2, CH2D, OCD3, OCF3, methyl, ethyl, propyl, isopropyl, methoxy or ethoxy; 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; Preferably, R 1 Selected from H; Preferably, R 2 Selected from H, methyl or CD3; Preferably, R 3 Selected from H, methyl or CD3; R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl, Preferably, R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, methoxy, cyclopropyl, R b Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R d Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CD3, -CH2CH2OCH3, -CF3, -CH2F, -CHF2, -CH2CH2F, -CH2CH2CH2F, -OCH2CH2OH, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, or optionally 1 to 4 R k1 substituted by one of the following groups: methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-oxetanyl, -CH2-azetidinyl, -S(=O)2CH3, -S(=O)2cyclopropyl, -C(=O)NH-cyclopropyl, -C(=O)CH3, -C(=O)-vinyl, -C(=O)-cyclopropyl, -C(=O)-cyclobutyl, -C(=O) -cyclopentyl, -C(=O)-bicyclo[2.2.1]heptyl, -C(=O)-bicyclo[1.1.1]pentyl, -C(=O)-cyclobutylspirobutyl, -C(=O)-oxetanyl, -C(=O)-tetrahydrofuranyl, -C(=O)-oxacyclohexyl, -C(=O)-azetidinyl, -C(=O)-pyrrolidinyl, -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)-pyrazolyl, -C(=O)-phenyl, -C(=O)-azetidinyl-CH2-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclobutyl, -C(=O)-pyrazolyl-CH2-cyclopentyl, -C(=O)-pyrrolidinyl-CH2-cyclopropyl, -C(=O)-piperidinyl-CH2-cyclopropyl, -C(=O)-piperazinyl-CH2-cyclopropyl, -C(=O)-azetidinyl-C(=O)-cyclopropyl, -C(=O)-pyrazolyl-CH2-cyclobutyl, -C(=O)-pyrazolyl-CH2-cyclopentyl, -C(=O)-pyrrolidinyl-CH2-cyclopropyl, -C(=O)-piperidinyl-CH2-cyclopropyl, -C(=O)-piperazinyl-CH2-cyclopropyl, -C(=O)-azetidinyl-C(=O)-cyclopropyl, -C(=O)-pyrazolyl pyrrolidinyl-C(=O)-cyclopropyl, -C(=O)-piperidinyl-C(=O)-cyclopropyl, -C(=O)-piperazinyl-C(=O)-cyclopropyl, -CH2-azetidinyl-C(=O)-cyclopropyl, -CH2-pyrrolidinyl-C(=O)-cyclopropyl, -CH2-azetidinyl-CH2-cyclopropyl, -CH2-pyrrolidinyl-CH2-cyclopropyl, -CH2-piperidinyl-CH2-cyclopropyl, -CH2-piperazinyl-CH2-cyclopropyl, -C(=O)-cyclopropyl-phenyl, -C(=O)-cyclopropyl-pyridyl, -C(=O)-cyclopropyl-thienyl, -C(=O)-cyclopropyl-furanyl, -C(=O)-CH2-O-cyclopropyl, -C(=O)-CH2-OCH2-cyclopropyl; R k1 is selected from deuterium, F, Cl, Br, OH, CN, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, The methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, -CH2-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, OH, CN, CH2CN, methyl, ethyl, methoxy or ethoxy; R 5f , R 5g Each is independently selected from H, F, Cl, Br, methyl, ethyl; or R 5f , R 5g Directly linked to form cyclobutyl, cyclopentyl or cyclohexyl; Preferably, R d Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CHF2, CH2F, CF3, CD3, methyl, ethyl, methoxy, ethoxy, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, -C(=O)CH3, -C(=O)-cyclopropyl, -C(=O)NHCH3, -C(=O)NH-cyclopropyl, 7. The compound according to claim 1 or its racemate, stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compound represented by (Id), T is selected from a bond, O, S, CH2, NH, N(R d3 ); p1 is selected from 0, 1, 2, 3 or 4; R d1 Selected from H, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl; R d2 Selected from H, deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl; R d3 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -S(=O) 1-2 -R 5c 、-C(=O)R 5c 、-C(=O)NR 5d R 5e 、-NR 5d C(=O)R 5e 、-C(=O)-MC(=O)-R 5c 、-CH2-MC(=O)-R 5c 、-C(=O)-M-CH2-R 5c , -C(=O)-MR 5c 、-C(=O)-M-CH2-OR 5c , The methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl are optionally substituted by 1 to 4 R k Replacement (R k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, )； M is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, 3-oxabicyclo[3.1.0]hexanyl, and M is optionally replaced by 1 to 4 R k Replacement (R k Preferably, each of them is independently selected from deuterium, F, Cl, Br, CHF2, CD3, methyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl). R 5c is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, vinyl, propenyl, allyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, phenyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrazinyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl, cyclopropylspirobutyl, cyclobutylspirobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl and cyclopentyl, 3-oxabicyclo[3.1.0]hexanyl, thienyl, furanyl, thiazolyl, oxazolyl, methoxymethyl, ethoxymethyl, wherein R 5c Optional 1 to 4 R k Replacement (R k Preferably, each is independently selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl, propyl, isopropyl, cyclopropyl, oxetanyl, -CH2-cyclopropyl, -CH2-oxetanyl, methoxy, methoxymethyl, methoxyethyl, CH2CN, vinyl, propenyl, )； R 5d , R 5e Each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, OH, CHF2, CD3, methyl, ethyl; Ring B is selected from The ring B is optionally substituted with 1 to 4 R b Substitution, its right side is connected to Q; R b Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R a Each independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NH(CH3), N(CH3)2, CF3, CD3, -OCF3, -OCD3, methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, isopropoxy, cyclopropyl, -CH2OH, -CH2CH2OH, -CH2CN, -CH2N(CH3)2, -CH2-cyclopropyl, Preferably, Selected from 8. The compound according to claim 1, or its racemate, 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.

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

10. Use of the compound according to any one of claims 1 to 8 or its racemate, stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 9 for preparing a medicament for treating a disease associated with GLP-1R activity or expression, preferably, 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 a compound according to any one of claims 1 to 8 or a racemate, stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease associated with GLP-1R activity or expression.

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