KOR antagonist and use thereof in medicine

Abstract

The present invention relates to a KOR antagonist and a use thereof in medicine, and in particular to a compound of general formula (I) or (II) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate thereof and a preparation method therefor, and a use in preparation of a drug for treatment of a κ-opioid receptor-related disease.

Description

A KOR antagonist and its medical application Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, tautomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compound in preparing drugs for treating diseases associated with antagonizing KOR. Background Art

[0002] Opioid receptors are a collective term for a group of G protein-coupled receptors. The kappa-opioid receptor (KOR) is a member of the opioid receptor family. It binds to the opioid peptide dynorphin, its primary endogenous ligand. Kappa-opioid receptors are widely distributed in the brain, spinal cord, and pain-sensing neurons, participating in important physiological processes such as pain perception, neuronal secretion, emotional behavior, and cognition. When receiving sustained neural signals, dynorphin acts on kappa-opioid receptors, and agonizing them can cause negative emotions such as anxiety and depression.

[0003] Research indicates that blocking the effects of dynorphin with κ-opioid receptor antagonists has therapeutic benefits for patients with mood disorders, anxiety disorders, and substance use disorders. Currently available κ-opioid receptor antagonists suffer from delayed onset of action, lasting several hours to days, and persistent antagonism at the minimum effective dose for several weeks. Furthermore, they have low blood-brain barrier penetration. While progress has been made in the development of highly selective and potent κ-opioid receptor antagonists, the discovery of safer, shorter-acting κ-opioid receptor antagonists with improved pharmacokinetics remains clinically valuable.

[0004] Summary of the Invention

[0005] The object of the present invention is to provide a compound having KOR antagonistic activity or its stereoisomers, tautomers, racemates, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use thereof in the preparation of drugs for treating diseases related to KOR antagonism.

[0006] The compound of the present invention has good KOR antagonistic activity, bioavailability and safety.

[0007] The compound of the present invention has good Kappa opioid receptor inhibitory activity and good Kappa opioid receptor selectivity, as well as good pharmacokinetic properties, good brain entry effect, good metabolic stability in human liver microsomes, and poor hERG inhibitory activity.

[0008] The present invention provides a compound of general formula (I) or its stereoisomers, tautomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0009] The present invention also provides a compound of general formula (II) or its stereoisomers, tautomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0010] In some embodiments, the compound of formula (I) is selected from formula (Ia), (Ib) or (Ic),

[0011] In some embodiments, Formula (II) is selected from Formula (IIa), (IIb) or (IIc),

[0012] In some embodiments, the compound of formula (I) is selected from formula (Id),

[0013] In some embodiments, the compound of formula (II) is selected from formula (IId),

[0014] In some embodiments, the compound of formula (I) is selected from formula (Ie),

[0015] In some embodiments, the compounds represented by formula (I), (Ia), (Ib), (Ic), and (Id) are optionally substituted with 1 to 12 deuteriums;

[0016] In some embodiments, in the general formula (I), (Ia), (Ib), (Ic), and (Id), Optionally substituted with 1 to 9 deuteriums;

[0017] In some embodiments, Selected from

[0018] In some embodiments, R 6 Selected from C 1-6 Alkyl, 5 to 10 membered heteroaryl or 4 to 12 membered heterocyclic group, wherein the alkyl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R 6a replace;

[0019] In some embodiments, R 6 Selected from C 1-4alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group, 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl and 4- to 6-membered carbocyclic group, wherein the alkyl, heteroaryl, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R 6a replace;

[0020] In some embodiments, R 6 Selected from C 1-4 alkylene, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 6-membered cycloalkyl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 6-membered heteroaryl and 6-membered cycloalkyl, 5-membered heteroaryl and 4-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heterocycloalkyl, 6-membered heteroaryl and 4-membered heterocycloalkyl, 6-membered heteroaryl and 5-membered heterocycloalkyl, 6-membered heteroaryl and 6-membered heterocycloalkyl, wherein R 6 Optional 1 to 4 R 6a replace;

[0021] In some embodiments, R 6 Selected from or optionally 1 to 4 R 6a substituted methyl and ethyl groups;

[0022] In some embodiments, R 6 Selected from

[0023] In some embodiments, R 6a Each independently selected from H, deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-9 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, -OC 3-6 Cycloalkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -NHC(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6Alkyl, -C(=O)-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0024] In some embodiments, R 6a Each independently selected from H, deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkoxy, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -NHC(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0025] In some embodiments, R 6a Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH 2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxahexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k replace;

[0026] In some embodiments, X is selected from O, NH, N(C 1-4 alkyl), N(C 3-6 cycloalkyl), CH2, CH(C 1-4 alkyl), CH(C 3-6 cycloalkyl), wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CF3, C 1-4 substituted by an alkyl substituent;

[0027] In some embodiments, X is selected from O, NH, N(CH3), N(cyclopropyl), CH2, CH(CH3), CH(cyclopropyl), wherein the methyl or cyclopropyl group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CF3, C 1-4 substituted by an alkyl substituent;

[0028] In some embodiments, X is selected from O, NH, N(CH3), CH2, CH(CH3);

[0029] In some embodiments, Q is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-12 Carbocyclic ring, -C 0-4 Alkylene-4 to 12 membered heterocyclic ring, wherein Q is optionally replaced by 1 to 4 R q replace;

[0030] In some embodiments, Q is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-7 Monocyclic carbocycle, -C 0-2 Alkylene-C 6-12 cyclic carbon ring, -C 0-2 Alkylene-C 6-12 Spirocyclic carbocycle, -C 0-2 Alkylene-C 4-12 Bridged carbon ring, -C 0-2 Alkylene-4-7 membered monocyclic heterocycle, -C 0-2 Alkylene-6-12 membered heterocyclic ring, -C 0-2 Alkylene-6-12 membered spiro heterocycle, -C 0-2 Alkylene-6-12 membered bridged heterocyclic ring, wherein Q is optionally replaced by 1 to 4 R q replace;

[0031] In some embodiments, Q is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxetan ... cyclohexyl, oxadiazole, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-cycloheptyl, -CH2-cyclohexenyl, -CH2-bicyclo[1.1.1]pentyl, -CH2-bicyclo[2.2.1]heptyl, -CH2-bicyclo[2.2.2]octyl, -CH2-bicyclo[3.2.1]octyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH 2-morpholinyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-oxacyclohexenyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-cycloheptyl, -CH2CH2-cyclohexenyl, -CH2CH2-bicyclo[1.1.1]pentyl, -CH2CH2-bicyclo[2.2.1]heptyl, -CH2CH2-bicyclo[2.2.2]octyl, -CH2CH2-bicyclo[3.2.1]octyl, -CH2CH2-azetidinyl, -CH2CH2-pyrrolidinyl, -CH2CH2-piperidinyl, -CH2CH2-piperazinyl, -CH2CH2-morpholinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-tetrahydrofuranyl, -CH2CH2-oxahexyl, -CH2CH2-oxahexyl, Q A 、-CH2-Q A 、-CH2CH2-Q A , said Q is optionally replaced by 1 to 4 R q replace;

[0032] Q A Selected from In some embodiments, Q is selected from The Q is optionally replaced by 1 to 4 R q replace;

[0033] In some embodiments, R qEach independently selected from deuterium, halogen, CN, OH, =O, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 alkyl)2, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)C 3-6 Cycloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0034] In some embodiments, R q Each independently selected from deuterium, halogen, CN, OH, =O, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 alkyl)2, -C(=O)C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0035] In some embodiments, R qEach independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NHCH3, N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)CH3, -C(=O)-cyclopropyl, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 R k replace;

[0036] In some embodiments, R q Each is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3 or cyclopropyl;

[0037] In some embodiments, R q is selected from F, methoxy, methyl;

[0038] In some embodiments, R 7 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0039] In some embodiments, R 7 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R kreplace;

[0040] In some embodiments, R 7 is selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace;

[0041] In some embodiments, R 7 is selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy, OCD3 or cyclopropyl;

[0042] In some embodiments, m is selected from 0, 1, 2, 3, 4, 5, 6, 7, or 8;

[0043] In some embodiments, m is selected from 0, 1, 2;

[0044] In some embodiments, R 5 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0045] In some embodiments, R 5 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0046] In some embodiments, R 5 is selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace;

[0047] In some embodiments, R 5 is selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy or cyclopropyl;

[0048] In some embodiments, R 5 Selected from methyl, ethyl, CF3, CHF2, CH2F, CD3;

[0049] In some embodiments, R 5 Selected from the following groups optionally substituted by 1 to 5 deuteriums or F: methyl, ethyl;

[0050] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0051] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0052] In some embodiments, R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl, said CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 4 R k replace;

[0053] In some embodiments, R 3 Selected from the following groups optionally substituted by 1 to 5 deuteriums or F: methyl, ethyl;

[0054] In some embodiments, R 1 is selected from H, deuterium, F, Cl, Br, CN, methyl, CD3, CF3, CHF2, CH2F or cyclopropyl;

[0055] In some embodiments, R 1 Selected from F, Cl, Br;

[0056] In some embodiments, R 2 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, methoxy or cyclopropyl;

[0057] In some embodiments, R 2 Selected from H, deuterium;

[0058] In some embodiments, R 3 Selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, ethynyl, propynyl, -CH2-ethynyl, -CH2OCH3, methoxy, -OCF3, -OCD3, cyclopropyl, -O-cyclopropyl;

[0059] In some embodiments, R 3Selected from methyl, ethyl, CF3, CD3, CH2CF3, CH2CHF2, CH2CH2F;

[0060] In some embodiments, R 4 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, methoxy or cyclopropyl;

[0061] In some embodiments, R 4 Selected from H, deuterium;

[0062] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0063] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, 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 Carbocycle, -O-4 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-4 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbocyclic ring, -C 0-2Alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0064] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0065] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, -OCF3, -OCD3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0066] In some embodiments, R1, R3, and R5 are each independently selected from 0, 1, or 2;

[0067] In some embodiments, r2, r4, and r6 are each independently selected from 0 or 1;

[0068] In some embodiments, r7 is selected from 1, 2, or 3;

[0069] In some embodiments, n is selected from 0, 1 or 2;

[0070] In some embodiments, Q is selected from Q1 or Q2;

[0071] In some embodiments, Q1 is selected from

[0072] In some embodiments, Q1 is selected from

[0073] In some embodiments, Q2 is selected from 1 to 4 R q Substituted with the following groups: Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0074] In some embodiments, Q2 is selected from 1 to 2 R q Substituted from the following groups: tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclohexyl, Preferably

[0075] In some embodiments, Q2 is selected from Preferably More preferably

[0076] In some embodiments, one of X1 and X2 is N and the other is O;

[0077] In some embodiments, s1, s2 are selected from 1 or 2;

[0078] In some embodiments, R 6b is selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, - CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, or 1 to 3 R kSubstituted methyl, said CH2, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 R k replace;

[0079] In some embodiments, R 6b Selected from H, CF3, CD3, CHF2, CH2F, -CH2-cyclopropyl, -CH2-ethynyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl;

[0080] In some embodiments, R 6A Selected from or optionally 1 to 4 R 6a substituted methyl and ethyl groups;

[0081] In some embodiments, R 6A Selected from

[0082] In some embodiments, R 6c Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2- cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxahexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k replace;

[0083] In some embodiments, R 6cSelected from H, CF3, CD3, CHF2, CH2F, -CH2-cyclopropyl, -CH2-ethynyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl,

[0084] In some embodiments, R 6c Selected from CF3, CD3, CHF2, CH2F, methyl, ethyl, cyclopropyl, cyclobutyl,

[0085] Optionally, when R 6 for Q is selected from Q1, and R 6a When selected from methyl, the methyl group is 1 to 3 R k replace;

[0086] Q1 is selected from s1 and s2 are selected from 1 or 2.

[0087] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0088] R 6 Selected from C 1-6 Alkyl, 5 to 10 membered heteroaryl or 4 to 12 membered heterocyclic group, wherein the alkyl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R 6a replace;

[0089] R 6a Each independently selected from H, deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-9 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, -OC 3-6 Cycloalkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -NHC(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 Rk replace;

[0090] X is selected from O, NH, N(C 1-4 alkyl), N(C 3-6 cycloalkyl), CH2, CH(C 1-4 alkyl), CH(C 3-6 cycloalkyl), wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CF3, C 1-4 substituted by an alkyl substituent;

[0091] Q is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-12 Carbocyclic ring, -C 0-4 Alkylene-4 to 12 membered heterocyclic ring, wherein Q is optionally replaced by 1 to 4 R q replace;

[0092] R q Each independently selected from deuterium, halogen, CN, OH, =O, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 alkyl)2, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)C 3-6 Cycloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0093] R 7 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0094] m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0095] R 5 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0096] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0097] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0098] The condition is that when R 6 for Q is selected from Q1, R 6a When selected from methyl, the methyl group is 1 to 3 R k replace;

[0099] Q1 is selected from s1 and s2 are selected from 1 or 2.

[0100] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0101] R 6 Selected from C 1-4 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclic group, 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl and 4- to 6-membered carbocyclic group, wherein the alkyl, heteroaryl, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R 6a replace;

[0102] X is selected from O, NH, N(CH3), N(cyclopropyl), CH2, CH(CH3), CH(cyclopropyl), wherein the methyl or cyclopropyl group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CF3, C 1-4 substituted by an alkyl substituent;

[0103] Q is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-7 Monocyclic carbocycle, -C 0-2 Alkylene-C 6-12 cyclic carbon ring, -C 0-2 Alkylene-C 6-12 Spirocyclic carbocycle, -C 0-2 Alkylene-C 4-12 Bridged carbon ring, -C 0-2 Alkylene-4-7 membered monocyclic heterocycle, -C 0-2 Alkylene-6-12 membered heterocyclic ring, -C 0-2 Alkylene-6-12 membered spiro heterocycle, -C 0-2Alkylene-6-12 membered bridged heterocyclic ring, wherein Q is optionally replaced by 1 to 4 R q replace;

[0104] R 5 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0105] R 7 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0106] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 R k replace;

[0107] R q Each independently selected from deuterium, halogen, CN, OH, =O, NH2, NHC 1-4 Alkyl, N(C1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 alkyl)2, -C(=O)C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0108] R 6a Each independently selected from H, deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkoxy, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -NHC(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace;

[0109] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, 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 Carbocycle, -O-4 to 7 membered heterocycle, -NH-C 3-6Carbocyclic ring, -NH-4 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbocyclic ring, -C 0-2 Alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0110] The definitions of the remaining substituents are consistent with those described in Scheme 1 of the present invention.

[0111] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0112] R 6 Selected from C 1-4 alkylene, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 6-membered cycloalkyl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 6-membered heteroaryl and 6-membered cycloalkyl, 5-membered heteroaryl and 4-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heterocycloalkyl, 6-membered heteroaryl and 4-membered heterocycloalkyl, 6-membered heteroaryl and 5-membered heterocycloalkyl, 6-membered heteroaryl and 6-membered heterocycloalkyl, wherein R 6 Optional 1 to 4 R 6a replace;

[0113] Q is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxahexyl, oxadiazol ... hexenyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-cycloheptyl, -CH2-cyclohexenyl, -CH2-bicyclo[1.1.1]pentyl, -CH2-bicyclo[2.2.1]heptyl, -CH2-bicyclo[2.2.2]octyl, -CH2-bicyclo[3.2.1]octyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl , -CH2-azetidinyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxetanyl, -CH2-oxetanyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-cycloheptyl, -CH2CH2-cyclohexenyl, -CH2CH2-bicyclo[1.1.1]pentyl, -CH2CH2-bicyclo[2.2.1]heptyl, -C H2CH2-bicyclo[2.2.2]octyl, -CH2CH2-bicyclo[3.2.1]octyl, -CH2CH2-azetidinyl, -CH2CH2-pyrrolidinyl, -CH2CH2-piperidinyl, -CH2CH2-piperazinyl, -CH2CH2-morpholinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-tetrahydrofuranyl, -CH2CH2-oxahexyl, -CH2CH2-oxahexyl, Q A 、-CH2-Q A 、-CH2CH2-Q A , said Q is optionally replaced by 1 to 4 R q replace;

[0114] Preferably, Q is selected from Q2, and Q2 is selected from 1 to 4 R q Substituted with the following groups: Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0115] Q A Selected from

[0116] r1, r3, r5 are each independently selected from 0, 1 or 2;

[0117] r2, r4, and r6 are each independently selected from 0 or 1;

[0118] r7 is selected from 1, 2 or 3;

[0119] The definitions of the remaining substituents are consistent with those described in Schemes 1 and 2 of the present invention.

[0120] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0121] R 6 Selected from or optionally 1 to 4 R 6a substituted methyl and ethyl groups;

[0122] Preferably, R 6 Selected from

[0123] n is selected from 0, 1 or 2;

[0124] R 6a Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH 2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxahexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k replace;

[0125] R5 is selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace;

[0126] R 7 is selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace;

[0127] R 1 、R 2 、R 3 、R 4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl, said CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 4 R k replace;

[0128] R q Each independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NHCH3, N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)CH3, -C(=O)-cyclopropyl, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 R k replace;

[0129] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2 or 3 of the present invention.

[0130] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0131] R 6 Selected from

[0132] X is selected from O, NH, N(CH3), CH2, CH(CH3);

[0133] R 1 is selected from H, deuterium, F, Cl, Br, CN, methyl, CD3, CF3, CHF2, CH2F or cyclopropyl;

[0134] R 2 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, methoxy or cyclopropyl;

[0135] R 3 Selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, ethynyl, propynyl, -CH2-ethynyl, -CH2OCH3, methoxy, -OCF3, -OCD3, cyclopropyl, -O-cyclopropyl;

[0136] R 4 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, methoxy or cyclopropyl;

[0137] R 5 is selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy or cyclopropyl;

[0138] R 7 is selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy, OCD3 or cyclopropyl;

[0139] Q is selected from The Q is optionally replaced by 1 to 4 R q replace;

[0140] R qEach is independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3 or cyclopropyl;

[0141] R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0142] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3 or 4 of the present invention.

[0143] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or (II), or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the general formula (I) is selected from (Ia), (Ib) or (Ic), and the general formula (II) is selected from (IIa), (IIb) or (IIc),

[0144] Q1 is selected from

[0145] Q2 is selected from 1 to 4 R q Substituted with the following groups: Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0146] Q is selected from Q1 or Q2; preferably, Q is selected from Q2;

[0147] X1 and X2, one is N and the other is O;

[0148] s1 and s2 are selected from 1 or 2;

[0149] R 6b is selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, - CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, or 1 to 3 R k Substituted methyl, said CH2, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 R k replace;

[0150] R 6c is selected from the group consisting of H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxhexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O- Butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k replace;

[0151] R 6A Selected from or optionally 1 to 4 R 6a substituted methyl and ethyl groups;

[0152] Preferably, R 6A Selected from

[0153] Preferably, R 6A Selected from

[0154] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4 or 5 of the present invention.

[0155] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb) or (IIc), or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0156] R 5 Selected from methyl, ethyl, CF3, CHF2, CH2F, CD3;

[0157] R 4 Selected from H, deuterium;

[0158] R 3 Selected from methyl, ethyl, CF3, CD3, CH2CF3, CH2CHF2, CH2CH2F;

[0159] R 2 Selected from H, deuterium;

[0160] R 1 Selected from F, Cl, Br;

[0161] R 6b Selected from H, CF3, CD3, CHF2, CH2F, -CH2-cyclopropyl, -CH2-ethynyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl;

[0162] R 6c Selected from H, CF3, CD3, CHF2, CH2F, -CH2-cyclopropyl, -CH2-ethynyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl,

[0163] Q2 is selected from 1 to 2 R q Substituted from the following groups: tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclohexyl, Preferably

[0164] R q is selected from F, methoxy, methyl;

[0165] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4, 5 or 6 of the present invention.

[0166] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the general formula (I) is selected from (Id),

[0167] R 6c Selected from CF3, CD3, CHF2, CH2F, methyl, ethyl, cyclopropyl, cyclobutyl,

[0168] Q2 is selected from Preferably More preferably

[0169] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4, 5, 6 or 7 of the present invention.

[0170] As a ninth embodiment of the present invention, the compound represented by the following general formula (IId) or its stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0171] R 6c Selected from CF3, CD3, CHF2, CH2F, methyl, ethyl, cyclopropyl, cyclobutyl,

[0172] R 5 is selected from the following groups optionally substituted by 1 to 5 deuteriums, F: methyl, ethyl; preferably, R 5 is selected from methyl, ethyl, CF3, CHF2, CH2F, CD3; R 3 is selected from the following groups optionally substituted by 1 to 5 deuteriums, F: methyl, ethyl; preferably, R 3 Selected from methyl, ethyl, CF3, CD3, CH2CF3, CH2CHF2, CH2CH2F;

[0173] R 7is selected from deuterium, F, Cl, Br, CN or the following groups optionally substituted by 1 to 5 deuterium or F: methyl, ethyl, isopropyl, methoxy;

[0174] m is selected from 0, 1, 2; preferably, m is selected from 0;

[0175] Q2 is selected from Preferably More preferably

[0176] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4, 5, 6 or 7 of the present invention.

[0177] As a tenth embodiment of the present invention, the compound represented by the aforementioned general formula (Ie) or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0178] R 3 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, ethynyl, propynyl, -CH2-ethynyl, -CH2OCH3, methoxy, -OCF3, -OCD3, cyclopropyl, -O-cyclopropyl; preferably, R 3 Selected from methyl, ethyl, CF3, CD3, CH2CF3, CH2CHF2, CH2CH2F;

[0179] R 5 is selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy or cyclopropyl; preferably, R 5 Selected from methyl, ethyl, CF3, CHF2, CH2F, CD3;

[0180] R 6aSelected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2- cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxahexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k substituted; preferably, R 6a Selected from H, CF3, CD3, CHF2, CH2F, methyl, ethyl, isopropyl, cyclopropyl;

[0181] Q2 is selected from 1 to 4 R q Substituted with the following groups: s1, s2 are selected from 1 or 2; preferably, Q2 is selected from More preferably

[0182] The definitions of the remaining substituents are consistent with those described in Scheme 1, 2, 3, 4, 5, 6 or 7 of the present invention.

[0183] The present invention relates to the following compound or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A below:

[0184] Table A

[0185] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1-1500 mg of the compound of the present invention or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

[0186] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomers, tautomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0187] The present invention relates to use of the compound of the present invention or its stereoisomers, tautomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in preparing drugs for treating diseases related to antagonizing KOR activity, preferably in preparing drugs for depression or anxiety.

[0188] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0189] As used herein, an "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a compound disclosed herein to provide a degree of relief of one or more symptoms of the disease or condition being treated (e.g., a disease associated with antagonistic KOR activity, such as depression or anxiety). 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, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 80-800 mg, 90-900 mg, 100-1100 mg, 110-12 ... mg, 75-600mg, 80-600mg, 90-600mg, 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6 -500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-5 00mg, 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, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300m g, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-20 0mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0190] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg g, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0191] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, preferably 1-1500 mg. The disease is preferably a KOR-related disease (such as depression or anxiety).

[0192] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1000 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 100-1500 mg / day, 100-10 ... In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0193] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0194] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases related to antagonizing KOR.

[0195] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases related to antagonizing KOR. Preferably, the diseases are selected from depression or anxiety.

[0196] The amount of the compound of the invention or its stereoisomers, tautomers, racemates, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is in each case calculated as the free base.

[0197] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0198] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. 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 11 C. 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 15 O. 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S. 35 S and 36 S, nitrogen isotopes include 13 N.14 N and 15 N, fluorine isotopes include 17 F. 18 F and 19 F, chlorine isotopes include 35 Cl, 36 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br, Iodine isotopes include 123 I. 125 I, phosphorus isotopes include 31 P. 32 P.

[0199] "CN" refers to cyano.

[0200] "Halogen" refers to F, Cl, Br or I.

[0201] "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".

[0202] "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.

[0203] "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.

[0204] "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.

[0205] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0206] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0207] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three, carbon-carbon triple bonds, with a backbone comprising from 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2- methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0208] "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.

[0209] "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.

[0210] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0211] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which the substituted or unsubstituted rings share an 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:

[0212] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0213] "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:

[0214] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0215] "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 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:

[0216] "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0217] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0218] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0219] "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.

[0220] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0221] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0222] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0223] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0224] "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.

[0225] "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 connecting 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.

[0226] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2)m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0227] "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.

[0228] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0229] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C yA 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.

[0230] 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 For example, the general formula fragment is When X is selected from CH2 or NH, it means that the R group on the general fragment can be located on C or X. When X is selected from CH2, the general fragment can be When X is selected from NH, the general fragment can be

[0231] 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.

[0232] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0233] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0234] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, racemates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0235] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0236] "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.

[0237] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0238] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0239] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0240] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0241] "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

[0242] 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.

[0243] 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).

[0244] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0245] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0246] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0247] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0248] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0249] Reagent and Solvent Abbreviations:

[0250] DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DCM: dichloromethane;

[0251] Synthesis method:

[0252] GP is independently selected from amino protecting groups, preferably Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl);

[0253] X is selected from a leaving group, preferably halogen, OMs, OTs or Otf;

[0254] The definitions of the remaining groups are consistent with those of the aforementioned compound of formula (I);

[0255] The compound of general formula (A-1) and the compound of general formula (A-2) undergo a ring-closure reaction to obtain the compound of general formula (A-3);

[0256] The compound of the general formula (A-4) and the compound of the general formula (A-5) are reacted by reductive amination to obtain the compound of the general formula (A-6);

[0257] The compound of formula (A-6) is subjected to a deamino protecting group reaction to obtain a compound of formula (A-7);

[0258] The compound of general formula (A-7) reacts with the compound of general formula (A-3) in the presence of an alkaline reagent (such as TEA, DIEA, K2CO3) through a nucleophilic substitution reaction to obtain the compound of general formula A.

[0259] Example 1: Synthesis of Compound 1

[0260] Step 1: Preparation of 1c

[0261] 1a (2 g, 13.28 mmol) and 1b (1.33 g, 13.28 mmol) were dissolved in 1,4-dioxane (100 mL). N,N-Diisopropylethylamine (2.58 g, 19.93 mmol) was added at 0°C. The mixture was allowed to react at room temperature for 30 minutes, followed by 3 hours at 100°C. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 85:15) to obtain 1c (1.92 g, 74% yield).

[0262] LCMS m / z=197.1[M+1] + .

[0263] Step 2: Preparation of 1d

[0264] 1c (0.5 g, 2.55 mmol) was dissolved in tetrahydrofuran (10 mL), and 2N aqueous sodium hydroxide solution (10 mL) was added. The mixture was reacted at room temperature for 1 h. The pH was adjusted to 3-4 with 1N aqueous hydrochloric acid, and the mixture was concentrated under reduced pressure to obtain 1d (0.43 g, crude product).

[0265] LCMS m / z=169.2[M+1] + .

[0266] Step 3: Preparation of 1e

[0267] 1-(2-Amino-5-ethyl-3-fluorophenyl)ethan-1-one (0.4 g, 2.21 mmol, obtained by reference to WO2018170492 A1) 1d (0.43 g, crude) was dissolved in phosphorus oxychloride (10 mL) and reacted at 110°C for 1 h. After cooling to room temperature, the mixture was poured into 50 mL of water and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 85:15) to afford 1e (0.54 g, 74% yield).

[0268] LCMS m / z=332.0[M+1] + .

[0269] Step 4: Preparation of 1f

[0270] 1e (300 mg, 0.90 mmol) and 4-piperidone ethylene glycol acetal (259 mg, 1.81 mmol) were dissolved in ethanol (10 mL), and N,N-diisopropylethylamine (234 mg, 1.81 mmol) was added. The mixture was microwaved at 130°C for 3 h. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 80:20) to afford 1f (363 mg, 92% yield).

[0271] LCMS m / z=439.3[M+1] + .

[0272] Step 5: Preparation of 1g

[0273] Dissolve 1f (100 mg, 0.23 mmol) in tetrahydrofuran (5 mL), add 10% aqueous sulfuric acid (25 mL), and react at 45°C for 2 h. Cool to room temperature, adjust the pH to 8-9 with saturated aqueous sodium carbonate, and extract with ethyl acetate (30 mL x 2). The organic phases are combined, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate concentrated under reduced pressure to yield 1g (76 mg, 84% yield).

[0274] LCMS m / z=395.3[M+1] + .

[0275] Step 6: Synthesis of Compound 1

[0276] Under nitrogen, 1g (76mg, 0.19mmol), 4-aminotetrahydropyran (29mg, 0.29mmol), sodium triacetoxyborohydride (82mg, 0.39mmol), and acetic acid (29mg, 0.48mmol) were dissolved in 1,2-dichloroethane (10mL) and allowed to react overnight at room temperature. The product was concentrated under reduced pressure to obtain a residue, which was then purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18, i.d. x length = 19mm x 250mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45μm filter to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL / min; elution time 15 min) to obtain the trifluoroacetic acid salt of compound 1 (20 mg, yield: 22%).

[0277] LCMS m / z=480.3[M+1] + .

[0278] 1 H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.76(d,1H),4.49-4.33(m,2H),4.10-3.70(m,6H),3.69-3.53(m,2H),2.98(q ,2H),2.89(s,3H),2.51-2.32(m,3H),2.31-2.22(m,2H),2.20-2.02(m,4H),1.53-1.37(m,5H),1.36-1.27(m,2H).

[0279] Example 2: Synthesis of Compound 2

[0280] Synthesis of compound 2

[0281] Under nitrogen, 1 g (50 mg, 0.13 mmol), (3R,4R)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride (24 mg, 0.15 mmol), and sodium triacetoxyborohydride (55 mg, 0.26 mmol) were dissolved in 1,2-dichloroethane (5 mL) and allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by Pre-HPLC (apparatus and preparative column: Waters 2767 Preparative HPLC System, XBridge@Prep C18, ID x L = 19 mm x 250 mm). Preparation Method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL / min; elution time 15 min), and the trifluoroacetic acid salt of compound 2 (5 mg) was obtained after lyophilization.

[0282] LCMS m / z=498.3[M+1] + .

[0283] 1 H NMR(400MHz, CDCl3)δ7.46(s,1H),7.28-7.22(m,1H),5.02-4.77(m,1H),4. 31-4.17(m,1H),4.15-4.05(m,1H),3.80-3.61(m,2H),3.60-3.38(m,3H),3. 35-3.22(m,1H),2.97-2.83(m,2H),2.78(q,2H),2.46(s,3H),2.34-2.10(m ,3H),2.05-1.94(m,1H),1.93-1.73(m,3H),1.31(t,3H),1.18-1.06(m,4H).

[0284] Example 3: Synthesis of Compound 3

[0285] The trifluoroacetate of compound 3 was obtained using 1 g of (3S,4R)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as a raw material, referring to the synthesis method of Example 2.

[0286] LCMS m / z=498.3[M+1] + .

[0287] 1H NMR(400MHz, CDCl3)δ7.47(s,1H),7.29-7.24(m,1H),5.02-4.79(m,1H),4.26-4.18(m, 1H),4.06-3.97(m,1H),3.80-3.71(m,1H),3.67-3.58(m,1H),3.53-3.31(m,3H),3.30-3.20(m,1H),2.99-2.84(m,2H ),2.79(q,2H),2.48(s,3H),2.25-2.04(m,4H),2.04-1.89(m,1H),1.87-1.69(m,2H),1.31(t,3H),1.18-1.07(m,4H).

[0288] Example 4: Synthesis of Compound 4

[0289] The trifluoroacetate of compound 4 was obtained using 1 g of (3S,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as a raw material, referring to the synthesis method of Example 2.

[0290] LCMS m / z=498.3[M+1] + .

[0291] 1 H NMR(400MHz,DMSO-d6)δ8.97-8.71(m,2H),7.70(s,1H),7.54(d,1H),5.05-4.86(m, 1H),4.11-3.99(m,1H),3.97-3.87(m,1H),3.87-3.68(m,1H),3.66-3.31(m,5H),2.9 5-2.82(m,2H),2.79(q,2H),2.49(s,3H),2.36-2.23(m,1H),2.14-1.97(m,2H),1.93 -1.77(m,2H),1.58-1.36(m,2H),1.27(t,3H),1.22-1.13(m,2H),1.07-0.97(m,2H).

[0292] Example 5: Synthesis of Compound 5

[0293] The trifluoroacetate of compound 5 was obtained using 1 g of (3R,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as a raw material, referring to the synthesis method of Example 2.

[0294] LCMS m / z=498.3[M+1] + .

[0295] 1 H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.76(d,1H),5.18-4.87(m,1H),4.61-4.44(m,1H),4.41-4.26(m,1H),4.16-3.90(m,4H),3.83-3.70(m,1H ),3.69-3.52(m,3H),2.98(q,2H),2.88(s,3H),2.59-2.42(m,3H),2.41 -2.32(m,1H),2.28-2.02(m,3H),1.50-1.37(m,5H),1.35-1.27(m,2H).

[0296] Example 6: Synthesis of trifluoroacetate salt of compound 6

[0297] Step 1: Preparation of 6c

[0298] 6a (1 g, 11.89 mmol), 6b (1.58 g, 11.89 mmol), sodium ascorbate (0.47 g, 2.38 mmol), and copper acetate (0.24 g, 1.19 mmol) were added to tert-butanol (10 mL) and water (10 mL) and allowed to react overnight at room temperature. Water (20 mL) was added to precipitate a solid, which was filtered. The filter cake was slurried with ethyl acetate (20 mL) overnight, filtered, and concentrated under reduced pressure to afford 6c (1 g, 38% yield).

[0299] LCMS m / z=218.3[M+1] + .

[0300] Step 2: Preparation of 6e

[0301] Compounds 6c (0.9 g, 4.14 mmol) and 6d (0.75 g, 4.14 mmol) were dissolved in phosphorus oxychloride (10 mL) and reacted at 110°C for 2 h. The mixture was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The residue was dissolved in ethyl acetate (10 mL), the pH was adjusted to approximately 7-8 with saturated aqueous sodium carbonate solution, and extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 75:25) to obtain 6e (1 g, 63% yield).

[0302] LCMS m / z=381.2[M+1] + .

[0303] Step 3: Preparation of 6g

[0304] 6e (900 mg, 2.36 mmol), 4-piperidone ethylene glycol acetal (675.81 mg, 4.72 mmol), and potassium carbonate (978.53 mg, 7.08 mmol) were added to N,N-dimethylformamide (5 mL) and reacted at 90°C for 2 h. The mixture was cooled to room temperature, and water (10 mL) was added, followed by extraction with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 80:20) to afford 6g (915 mg, 79% yield).

[0305] LCMS m / z=488.2[M+1] + .

[0306] Step 4: 6h preparation

[0307] Dissolve 6g (800mg, 1.64mmol) in methanol (10mL) and add palladium on carbon (872.64mg, 0.82mmol, 10%) under nitrogen. Reaction is carried out at 60°C under a hydrogen atmosphere for 18h. Cool to room temperature, filter through a pad of celite, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product is purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 60:40) to obtain 6h (500mg, 76% yield).

[0308] LCMS m / z=398.3[M+1] + .

[0309] Step 5: Preparation of 6i

[0310] 6h (450 mg, 1.13 mmol) and potassium carbonate (780.89 mg, 5.65 mmol) were added to N,N-dimethylformamide (5 mL), followed by iodomethane (561.37 mg, 3.95 mmol). The reaction was allowed to proceed at room temperature under a nitrogen atmosphere for 1 h. The reaction solution was added to water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 90:10) to afford 6i (170 mg, 36% yield).

[0311] LCMS m / z=412.4[M+1] + .

[0312] Step 6: Preparation of 6j

[0313] 6i (55 mg, 0.13 mmol) was dissolved in 10% aqueous sulfuric acid (5 mL) and tetrahydrofuran (1 mL) and reacted at 45°C for 2 h. The mixture was cooled to room temperature, adjusted to pH 8-9 with saturated aqueous sodium carbonate, and extracted with ethyl acetate (10 mL x 2). The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford 6j (45 mg, 91% yield).

[0314] LCMS m / z=368.2[M+1] + .

[0315] Step 7: Synthesis of trifluoroacetate salt of compound 6

[0316] 6j (45 mg, 0.12 mmol), 6k (18.21 mg, 0.18 mmol), and acetic acid (14.41 mg, 0.24 mmol) were added to 1,2-dichloroethane (2 mL) and reacted at 40°C for 2 h. Sodium triacetoxyborohydride (50.87 mg, 0.24 mmol) was then added and reacted at 40°C for 18 h. The crude product was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL / min; elution time 15 min), and the trifluoroacetic acid salt of compound 6 (40 mg, yield: 58%) was obtained after lyophilization.

[0317] LCMS m / z=453.4[M+1] + .

[0318] 1 H NMR(400MHz,D2O)δ7.94(s,1H),7.77(s,1H),7.58(d,1H),4.31(s,3H),4.08-3.98(m,2H),3.78-3.66(m,2H),3.58-3.40( m,4H),3.19-3.04(m,2H),2.80(q,2H),2.47(s,3H),2.08-1.94(m,4H),1.74-1.56(m,2H),1.47-1.32(m,2H),1.25(t,3H).

[0319] Example 7: Synthesis of Compound 7

[0320] 6j (100 mg, 0.27 mmol) and 7a (63.01 mg, 0.41 mmol) were added to 1,2-dichloroethane (2 mL) and reacted at 45°C for 18 h. Sodium triacetoxyborohydride (171.67 mg, 0.81 mmol) was added and reacted at 45°C for 2 h. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by Pre-HPLC (Instrument and Preparative Column: Waters 2767 Preparative HPLC System, XBridge@Prep C18, ID x L = 19 mm x 250 mm). Preparation Method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. The mobile phase system was acetonitrile / water (containing 0.05% ammonia). Gradient elution method: acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min), and compound 7 (45 mg, yield: 39%) was obtained after lyophilization.

[0321] LCMS m / z=471.3[M+1] + .

[0322] 1 H NMR (400MHz, CDCl3) δ7.71(s,1H),7.46(s,1H),7.21(dd,1H),4.73-4.50(m,1H),4.30(s,3H),4.22-4.08(m,1H ),4.05-3.94(m,1H),3.58-3.32(m,4H),2.96-2.64(m,6H),2.48(s,3H),1.81-1.64(m,4H),1.36-1.21(m,6H).

[0323] Example 8: Synthesis of Compound 8

[0324] Under nitrogen, 8a (200 mg, 0.54 mmol) and 7a (130 mg, 0.84 mmol) were dissolved in 1,2-dichloroethane (10 mL) and allowed to react at room temperature for 1 h. Sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added and allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC System, XBridge@Prep C18, ID x L = 19 mm x 250 mm). Preparation Method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min). After lyophilization, compound 8 (100 mg, yield: 39%) was obtained.

[0325] LCMS m / z=472.3[M+1] + .

[0326] 1 H NMR(400MHz,CF3COOD)δ8.01(s,1H),7.84(d,1H),5.31-5.06(m,1H),4.70-4.51(m,1H),4.53-4.44(m,1H),4.27-3.82 (m,6H),3.77-3.60(m,2H),3.06(q,2H),2.95(s,3H),2.82(s,3H),2.67-2.48(m,3H),2.35-2.14(m,3H),1.50(t,3H).

[0327] Example 9: Synthesis of Compound 9

[0328] The trifluoroacetate of compound 9 was obtained using 8a and (3R,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as raw materials, referring to the synthesis method of Example 8.

[0329] LCMS m / z=472.2[M+1] + .

[0330] 1H NMR(400MHz,CF3COOD)δ7.95(s,1H),7.77(d,1H),5.19-4.89(m,1H),4.59-4.43(m,1H),4.42-4.27(m,1H),4.15-3.90(m,4H),3 .81-3.69(m,1H),3.68-3.51(m,3H),2.98(q,2H),2.88(s,3H),2.75(s,3H),2.60-2.39(m,3H),2.29-2.03(m,3H),1.42(t,3H).

[0331] Example 10: Synthesis of Compound 10

[0332] Compound 10 was obtained using 6j and (3R,4S)-3-fluorotetrahydro-2H-pyran-4-amine hydrochloride as raw materials, referring to the synthetic method of Example 7.

[0333] LCMS m / z=471.3[M+1] + .

[0334] 1 H NMR(400MHz, CDCl3)δ7.71(s,1H),7.46(s,1H),7.21(dd,1H),4.44-4.17(m ,4H),4.10-3.98(m,1H),3.92-3.79(m,1H),3.57-3.45(m,2H),3.44-3.36(m ,1H),3.35-3.26(m,1H),3.05-2.91(m,1H),2.87-2.64(m,5H),2.48(s,3H), 2.06-1.92(m,1H),1.91-1.76(m,2H),1.54-1.38(m,1H),1.36-1.12(m,5H).

[0335] Example 11: Preparation of Compound 11

[0336] The trifluoroacetate of compound 11 was obtained using 1 g of (R)-3-aminotetrahydrofuran as a substrate according to the synthetic method of Example 1.

[0337] LCMS m / z=466.3[M+1] + .

[0338] 1H NMR(400MHz,D2O)δ7.57(s,1H),7.44(d,1H),4.23-4.10(m,2H),4.09-3.96(m,2H),3.92-3.82(m,1H),3.57-3.35(m,3H),3.01-2.86(m,2 H),2.85-2.75(m,2H),2.60-2.41(m,4H),2.40-2.31(m,1H),2.25-2.07(m,3H),1.65-1.45(m,2H),1.40-1.23(m,5H),1.21-1.05(m,2H).

[0339] Example 12: Preparation of Compound 12

[0340] Compound 12 was obtained using 12b (12b was obtained using 6h and deuterated iodomethane as substrates, and the synthesis method of Example 6) and 7a as substrates, and the synthesis method of Example 7.

[0341] LCMS m / z=474.2[M+1] + .

[0342] 1 H NMR(400MHz, CDCl3)δ7.70(s,1H),7.46(s,1H),7.20(dd,1H),4.71-4.51(m,1H),4.22-4.08(m,1H),4.0 7-3.94(m,1H),3.58-3.33(m,4H),2.96-2.69(m,6H),2.47(s,3H),1.81-1.64(m,4H),1.36-1.22(m,5H).

[0343] Example 13: Preparation of Compound 13

[0344] The trifluoroacetate salt of compound 13 was obtained using 8a and 13a as substrates according to the synthetic method of Example 2.

[0345] LCMS m / z=458.3[M+1] + .

[0346] 1H NMR(400MHz, CDCl3)δ7.48(s,1H),7.30-7.25(m,1H),5.68-5.30(m,1H),4.29-4.17(m,1H),4.14-3.94(m,2H),3.92-3.63(m,4H) ,3.33-3.19(m,1H),3.00-2.85(m,2H),2.79(q,2H),2.53(s,3H),2.50(s,3H),2.15-2.02(m,2H),1.89-1.68(m,2H),1.31(t,3H).

[0347] Example 14: Synthesis of Compound 14

[0348] Compound 14 was prepared using 6h as the starting material according to the synthesis method of Example 1.

[0349] LCMS m / z=457.3[M+1] + .

[0350] 1 H NMR(400MHz, CDCl3)δ7.89(s,1H),7.45(s,1H),7.24-7.08(m,1H),5.09-4.57(m,1H),4.29-3.87 (m,2H),3.65-3.23(m,4H),3.22-2.60(m,6H),2.49(s,3H),2.10-1.69(m,4H),1.68-1.20(m,6H).

[0351] Example 15: Synthesis of Compound 15

[0352] Step 1: Preparation of 15a

[0353] 6h (200 mg, 0.50 mmol) was dissolved in 1,2-dichloroethane (10 mL), and cyclopropylboronic acid (430 mg, 5.01 mmol), 2,2'-bipyridine (120 mg, 0.77 mmol), copper acetate (91 mg, 0.50 mmol), and potassium carbonate (210 mg, 1.52 mmol) were added. The mixture was reacted at 70°C for 4 h. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 80:20) to afford 15a (100 mg, 45% yield).

[0354] LCMS m / z=438.3[M+H] + .

[0355] Compound 15 was prepared using 15a as the starting material according to the synthesis method of Example 7.

[0356] LCMS m / z=497.2[M+1] +

[0357] 1 H NMR (400MHz, CDCl3) δ7.68(s,1H),7.46(s,1H),7.20(dd,1H),4.94-4.49(m,1H),4.27-3.93(m,3H),3.6 5-3.28(m,4H),3.10-2.62(m,6H),2.45(s,3H),2.02-1.65(m,4H),1.50-1.24(m,7H),1.21-1.12(m,2H).

[0358] Example 16: Synthesis of Compound 16

[0359] Compound 16 was obtained using 15b as the starting material according to the synthetic method of Example 15.

[0360] LCMS m / z=497.4[M+1] + .

[0361] 1 H NMR(400MHz, CDCl3)δ7.67(s,1H),7.46(s,1H),7.20(dd,1H),4.42-4.17(m,1H),4.16-3.98(m,2H),3.92-3.79(m,1H),3.56-3.23(m,4H),3 .05-2.91(m,1H),2.87-2.59(m,5H),2.46(s,3H),2.05-1.90(m,1H), 1.89-1.73(m,2H),1.54-1.37(m,3H),1.31(t,3H),1.25-1.09(m,4H).

[0362] Example 17: Synthesis of Compound 17

[0363] Compound 17 was obtained using 17b (17a as the starting material, obtained by referring to the synthesis method of patent WO2010 / 102218) as a substrate and referring to the synthesis method of Example 1.

[0364] LCMS m / z=475.4[M+1] + .

[0365] 1H NMR(400MHz,CF3COOD)δ7.95(s,1H),7.77(d,1H),5.24-4.97(m,1H),4.66-4.47(m,1H),4.46-4.35(m,1H),4.2 1-3.73(m,6H),3.70-3.51(m,2H),2.98(q,2H),2.88(s,3H),2.62-2.39(m,3H),2.30-2.05(m,3H),1.42(t,3H).

[0366] Example 18: Preparation of Compound 18

[0367] Compound 18 was obtained using 18b (18b was obtained using 6h and difluoroiodomethane as substrates, according to the synthesis method of Example 6) and 7a as substrates, according to the synthesis method of Example 7.

[0368] LCMS m / z=507.3[M+1] + .

[0369] 1 H NMR(400MHz, CDCl3)δ7.98(s,1H),7.61-7.28(m,2H),7.26-7.22(m,1H),4.70-4.49(m,1H),4.22-4.08(m,1H) ,4.05-3.94(m,1H),3.54-3.34(m,4H),2.90-2.73(m,6H),2.51(s,3H),1.78-1.65(m,4H),1.38-1.19(m,6H).

[0370] Example 19: Synthesis of Compound 19

[0371] Step 1: Preparation of 19b

[0372] 19a (4 g, 38.43 mmol) was dissolved in dichloromethane (40 mL). N,N-dimethylformamide (0.28 g, 3.83 mmol) and oxalyl chloride (7.32 g, 57.67 mmol) were added at 0°C and reacted for 2 h at room temperature. The mixture was added dropwise to a cold solution of ammonia in methanol (40 mL, 7 N) and reacted for 16 h at room temperature. The mixture was then concentrated under reduced pressure to afford 19b (3.4 g, 86% yield).

[0373] LCMS m / z=104.1[M+1] + .

[0374] Step 2: Preparation of 19c

[0375] 19b (3.3 g, 32.01 mmol) was dissolved in tetrahydrofuran (100 mL), and phosphorus pentasulfide (14.19 g, 63.84 mmol) was added. The mixture was reacted at 50°C for 16 h. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 90:10) to afford 19c (1.9 g, 50% yield).

[0376] LCMS m / z=120.1[M+1] + .

[0377] Step 3: Preparation of 19d

[0378] 19c (1.9 g, 15.94 mmol) was dissolved in ethanol (20 mL) and water (10 mL). Hydroxylamine hydrochloride (2.22 g, 31.95 mmol) and triethylamine (4.84 g, 47.83 mmol) were added and reacted at 80°C for 16 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. Water (10 mL) and ethyl acetate (30 mL) were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 19d (1.5 g, 80% yield).

[0379] LCMS m / z=119.2[M+1] + .

[0380] Preparation of 19g

[0381] 19g was obtained using 19d as the starting material according to the synthetic method of Example 1.

[0382] LCMS m / z=350.1[M+1] + .

[0383] Preparation of 19i

[0384] Compound 19h (2.7 g, 17.35 mmol) was dissolved in dichloromethane (100 mL), and N,N-diisopropylethylamine (2.24 g, 17.33 mol) was added. The mixture was allowed to react at room temperature for 30 min. Tert-butyloxycarbonyl-4-piperidone (3.8 g, 19.07 mmol) was added, and the reaction was allowed to react at room temperature for 6 h. Sodium triacetoxyborohydride (7.35 g, 34.68 mmol) was added, and the reaction was allowed to react at room temperature overnight. Water (100 mL) was added, and the mixture was stirred at room temperature for 1 h. The layers were separated, and the aqueous phase was adjusted to a pH of 9-10 with saturated sodium bicarbonate aqueous solution. The mixture was extracted four times with ethyl acetate, dried, and concentrated under reduced pressure to afford 19i (5 g, 95% yield).

[0385] LCMS m / z=303.3[M+H] + .

[0386] Preparation of 19j

[0387] Compound 19i (0.1 g, 0.33 mmol) was dissolved in methanol (2 mL), and dioxane hydrochloride (2 mL, 4 N) was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of 19j (0.091 g, crude product).

[0388] LCMS m / z=203.1[M+1] + .

[0389] Synthesis of compound 19

[0390] Compound 19j (0.091 g, crude) and compound 11g (0.12 g, 0.34 mmol) were dissolved in dimethyl sulfoxide (5 mL), potassium carbonate (0.19 g, 1.37 mmol) was added, and the mixture was reacted at 90°C for 16 h. After cooling to room temperature, water (10 mL) and ethyl acetate (30 mL) were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column model, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% ammonium bicarbonate). Gradient elution method: acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL / min; elution time: 15 min). After lyophilization, compound 19 (50 mg, yield: 28%) was obtained.

[0391] LCMS m / z=516.2[M+1] + .

[0392] 1 H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.76(d,1H),5.24-5.11(m,1H),5.09-4.95(m, 1H),4.63-4.47(m,1H),4.46-4.35(m,1H),4.20-3.74(m,6H),3.70-3.51(m,2H),2.98(q,2H),2.88(s,3H), 2.85-2.70(m,1H),2.60-2.40(m,3H),2.29-2.07(m,3H),2.05-1.90(m,1H),1.71-1.56(m,1H),1.42(t,3H).

[0393] Example 20: Synthesis of Compound 20

[0394] Compound 20 was obtained using 20a as the starting material by referring to the synthetic method of Example 19.

[0395] LCMS m / z=516.2[M+1] + .

[0396] 1 H NMR(400MHz,CF3COOD)δ8.05(s,1H),7.87(d,1H),5.36-5.05(m,1H),4.74-4.57(m,1H),4.56-4.43(m,1H),4.32-3.84(m,6H),3.8 3-3.63(m,2H),3.08(q,2H),3.01(s,3H),2.73-2.49(m,3H),2.39-2.17(m,3H),2.07-1.88(m,2H),1.82-1.64(m,2H),1.52(t,3H).

[0397] Example 21: Synthesis of Compound 21

[0398] Compound 21 was obtained using 21a as the starting material by referring to the synthetic method of Example 19.

[0399] LCMS m / z=538.3[M+1] + .

[0400] 1 H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.76(d,1H),6.06-5.83(m,1H),5.31 -5.01(m,3H),4.65-4.48(m,1H),4.47-4.35(m,1H),4.21-3.75(m,6H),3.7 1-3.50(m,2H),2.98(q,2H),2.89(s,3H),2.80-2.68(m,2H),2.59-2.39(m, 3H),2.28-2.05(m,3H),1.56-1.48(m,2H),1.42(t,3H),1.36-1.30(m,2H).

[0401] Example 22: Synthesis of Compound 22

[0402] Compound 22 was obtained using 22a as the starting material by referring to the synthetic method of Example 19.

[0403] LCMS m / z=540.2[M+1] + .

[0404] 1 H NMR(400MHz,CF3COOD)δ7.95(s,1H),7.77(d,1H),5.26-4.98(m,1H),4.65-4.48(m,1H),4.47-4.32(m,3H),4.24-3.75(m ,8H),3.71-3.50(m,2H),2.98(q,2H),2.92(s,3H),2.70-2.59(m,2H),2.58-2.40(m,4H),2.28-2.09(m,3H),1.42(t,3H).

[0405] Example 23: Synthesis of Compound 23

[0406] Compound 23 was obtained using 23a as the starting material by referring to the synthetic method of Example 19.

[0407] LCMS m / z=512.3[M+1] + .

[0408] 1 H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.76(d,1H),5.27-4.98(m,1H),4.65-4.48(m,1H),4.47-4.35(m,1H),4.21-3.76(m,6H),3.70-3.55 (m,2H),2.98(q,2H),2.90(s,3H),2.59-2.42(m,3H),2.27-2.09(m,3H),1.68(s,3H),1.57-1.50(m,2H),1.42(t,3H),1.30-1.23(m,2H).

[0409] Example 24: Synthesis of Compound 24

[0410] Compound 24 was obtained using 24a as the starting material by referring to the synthetic method of Example 19.

[0411] LCMS m / z=516.2[M+1] + .

[0412] 1H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.77(d,1H),5.27-5.11(m,1H),5.09-4.95(m,1H),4.63-4.47(m,1H),4.46-4.35(m,1H),4.17-3.75(m ,6H),3.70-3.52(m,2H),2.99(q,2H),2.87(s,3H),2.63-2.36(m,4H), 2.25-2.16(m,1H),2.15-1.97(m,3H),1.76-1.61(m,1H),1.43(t,3H).

[0413] Example 25: Synthesis of Compound 25

[0414] Compound 25 was obtained using 25a as the starting material by referring to the synthetic method of Example 19.

[0415] LCMS m / z=566.2[M+1] + .

[0416] Example 26: Synthesis of Compound 26

[0417] Compound 26 was obtained using 26a as the starting material by referring to the synthetic method of Example 19.

[0418] LCMS m / z=538.2[M+1] + .

[0419] 1 H NMR(400MHz,CF3COOD)δ7.94(s,1H),7.77(d,1H),5.23-5.00(m,1H),4.61-4.47(m,1H),4.46-4.36(m,1H),4.21 -3.74(m,6H),3.71-3.52(m,2H),2.98(q,2H),2.90(s,3H),2.62-2.05(m,13H),1.64-1.54(m,2H),1.42(t,3H).

[0420] Example 27: Synthesis of Compound 27

[0421] Compound 27 was obtained using 27a as the starting material by referring to the synthetic method of Example 19.

[0422] LCMS m / z=516.2[M+1] + .

[0423] 1 H NMR(400MHz,CF3COOD)δ8.04(s,1H),7.88(d,1H),5.38-5.23(m,1H),5.22-5.09(m,1H),4.73-4.57(m,1H),4.56-4.44(m,1H),4.3 0-3.84(m,6H),3.81-3.59(m,2H),3.09(q,2H),2.97(s,3H),2.76-2.46(m,4H),2.38-2.07(m,4H),1.86-1.72(m,1H),1.53(t,3H).

[0424] Example 28: Synthesis of Compound 28

[0425] Compound 28 was obtained using 28a as the starting material by referring to the synthesis method of Example 19.

[0426] LCMS m / z=516.3[M+1] + .

[0427] 1 H NMR(400MHz,CF3COOD)δ8.02(s,1H),7.85(d,1H),5.34-5.20(m,1H),5.19 -5.03(m,1H),4.71-4.56(m,1H),4.55-4.44(m,1H),4.30-3.84(m,6H),3.8 3-3.59(m,2H),3.07(q,2H),2.97(s,3H),2.94-2.82(m,1H),2.70-2.48(m, 3H),2.39-2.15(m,3H),2.14-1.99(m,1H),1.81-1.65(m,1H),1.51(t,3H).

[0428] 1. Determination of Human Opioid Receptor Inhibitory Activity

[0429] 1.1 Determination of human kappa opioid receptor inhibitory activity

[0430] KOR-CHO cells were cultured in F-12 medium supplemented with 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% CO2. When the cell density reached approximately 80%, the old medium was removed and the cells were rinsed with PBS. After incubation for approximately 1 minute with 0.25% Trypsin-EDTA solution, the cells were then added to complete F-12 medium prewarmed at 37°C and harvested by centrifugation. After centrifugation, the cells were resuspended in 1× stimulation buffer, counted, and plated in 5 μL volumes in 384-well plates. Then, 1 μL of 10× compound solution was added, the cells were centrifuged, and the plates were incubated at 37°C for 10 minutes. Then, 4 μL of a mixed solution of dynorphin (3.75 nM) and forskolin (2.5 μM) was added, the plates were centrifuged, and the plates were incubated at 37°C for 30 minutes. Finally, add 5 μL of 4×Eu-cAMP solution and 5 μL of 4×ULight-anti-cAMP solution prepared with detection buffer, centrifuge, and incubate at room temperature for 1 hour. Read the values ​​at 665 nm and 620 nm using a BMG microplate reader (PHERAstar FSX) under 330 nm excitation. Calculate the inhibition rate (%) according to the following formula: (R 化合物 -R 阴性对照 ) / (R 阳性对照 -R 阴性对照 )*100, where R is the ratio of the readings at 665 nm to 620 nm, the positive control is 10 μM LY2795050, and the negative control is 0.1% DMSO. The IC values ​​were obtained by fitting the curve using a four-parameter model using GraphPad Prime software. 50 value.

[0431] 1.2 Determination of human mu opioid receptor inhibitory activity

[0432] MOR-CHO cells were cultured in F-12 medium supplemented with 10% fetal bovine serum and 0.2 mg / mL Hygromycin B at 37°C and 5% CO2. When the cell density reached approximately 80%, the medium was removed and the cells were rinsed with PBS. After incubation with 0.25% Trypsin-EDTA solution for approximately 1 minute, the cells were then incubated with complete F-12 medium prewarmed at 37°C and harvested by centrifugation. After centrifugation, the cells were resuspended in 1× Stimulation buffer, counted, and plated in 5 μL volumes in 384-well plates. Then, 1 μL of 10× compound solution was added, the cells were centrifuged, and the plates were incubated at 37°C for 10 minutes. Then, 4 μL of a mixture of endomorphin 1 (25 nM) and forskolin (7.5 μM) was added, the plates were centrifuged, and the plates were incubated at 37°C for 30 minutes. Finally, add 5 μL of 4×Eu-cAMP solution and 5 μL of 4×ULight-anti-cAMP solution prepared with detection buffer, centrifuge, and incubate at room temperature for 1 hour. Read the values ​​at 665 nm and 620 nm using a BMG microplate reader (PHERAstar FSX) under 330 nm excitation. Calculate the inhibition rate (%) according to the following formula: (R 化合物 -R 阴性对照 ) / (R 阳性对照 -R 阴性对照 )*100, where R is the ratio of the readings at 665 nm to 620 nm, the positive control is 5 μM naloxone, and the negative control is 0.1% DMSO. The IC was obtained by fitting the curve using a four-parameter model using GraphPad Prime software. 50 value.

[0433] Table 1. Inhibitory activity of compounds on hKOR cAMP and hMOR cAMP

[0434] Conclusion: The compounds of the present invention, such as the example compounds, have good Kappa opioid receptor inhibitory activity and good Kappa opioid receptor selectivity. Among them, compound 2, compound 5, compound 7, compound 8, compound 10, compound 11, and compound 27 have good Kappa opioid receptor inhibitory activity, and the mu opioid receptor / Kappa opioid receptor inhibitory activity is greater than 100 times. Among them, compound 19 and compound 20 have a mu opioid receptor / Kappa opioid receptor inhibitory activity greater than 400 times.

[0435] 2. Mouse Brain-to-Blood Ratio Test

[0436] 2.1 Experimental Animals: Male ICR mice, 20-25 g, 9 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0437] 2.2 Experimental Protocol 1: On the day of the experiment, ICR 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.

[0438] Table 2. Dosing Information

[0439] Note: Oral administration solvent: 0.5% MC (MC: methylcellulose solution)

[0440] Whole blood and brain tissue were collected at 0.25, 4, and 24 hours after oral administration. Whole blood was centrifuged to separate plasma. Brain tissue was rinsed with cold saline to remove residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and testing. Quantitative analysis was performed using LC-MS / MS. The results are shown in Table 3.1.

[0441] Table 3.1 Pharmacokinetic parameters of test compounds in mouse brain tissue

[0442] / :not applicable;

[0443] 2.3 Experimental Plan 2: On the day of the experiment, ICR 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.

[0444] After oral administration (dosing information is provided in Table 2), whole blood and brain tissue were collected at 0.25, 2.5, and 24 hours. The whole blood was centrifuged to separate the plasma. The brain tissue was rinsed with cold saline to remove any residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and testing. Quantitative analysis of the samples was performed using LC-MS / MS. The results are shown in Table 3.2.

[0445] Table 3.2 Pharmacokinetic parameters of test compounds in mouse brain tissue

[0446] / :not applicable;

[0447] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties, among which Compound 1, Compound 2, Compound 7, Compound 8, Compound 10, Compound 11, Compound 12, Compound 17, and Compound 20 have good brain penetration effects.

[0448] 3. Rat Brain-to-Blood Ratio Test

[0449] 3.1 Experimental Animals: Male SD rats, 160-180 g, 9 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0450] 3.2 Experimental Plan 1: On the day of the experiment, SD rats 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.

[0451] Table 4. Dosing Information

[0452] Note: Oral administration solvent: 0.5% MC (MC: methylcellulose solution)

[0453] Whole blood and brain tissue were collected at 0.25, 4, and 24 hours after oral administration. Whole blood was centrifuged to separate plasma. Brain tissue was rinsed with cold saline to remove residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and testing. Quantitative analysis was performed using LC-MS / MS. The results are shown in Table 5.1.

[0454] Table 5.1 Pharmacokinetic parameters of test compounds in rat brain tissue

[0455] / :not applicable.

[0456] 3.3 Experimental Plan 2: On the day of the experiment, SD rats 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.

[0457] After oral administration (dosing information is provided in Table 4), whole blood and brain tissue were collected at 0.25, 2.5, and 24 hours. The whole blood was centrifuged to separate the plasma. The brain tissue was rinsed with cold saline to remove any residual blood, blotted dry, and homogenized. All samples were stored at -80°C prior to analysis and testing. Quantitative analysis of the samples was performed using LC-MS / MS. The results are shown in Table 5.2.

[0458] Table 5.2 Pharmacokinetic parameters of test compounds in rat brain tissue

[0459] / :not applicable.

[0460] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties, among which compound 7, compound 8, compound 10 and compound 19 have good brain penetration effect.

[0461] 4.CYP450 enzyme inhibition test

[0462] The purpose of this study was to evaluate the effects of test substances on the activities of five cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test substances. The reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the samples were processed and metabolites generated from the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the inhibitory potential of the test substances against each CYP enzyme isoform.

[0463] Conclusion: The inhibitory activities of the compounds of the present invention, such as compound 7, compound 8, and compound 10, against CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 are all greater than 20 μM.

[0464] 5. hERG potassium channel effect test

[0465] Experimental platform: electrophysiology manual patch clamp system

[0466] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0467] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0468] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0469] Inhibition%=[1-(I / Io)]×100%

[0470] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0471] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation:

[0472] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0473] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0474] Conclusion: The compounds of the present invention have poor inhibitory activity on hERG.

[0475] 6. Liver Microsome Stability Test

[0476] In this study, human liver microsomes were used as an in vitro model to evaluate the metabolic stability of the test substances.

[0477] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(Liver) .

[0478] Table 6. Human liver microsome stability results

[0479] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good metabolic stability in human liver microsomes.

[0480] 7. Beagle Dog Pharmacokinetic Test

[0481] 7.1 Test Animals: Male beagle dogs, weighing approximately 8-13 kg, 6 per compound.

[0482] 7.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14–18 hours prior to dosing. Food was resumed 4 hours after dosing. Dosing was performed according to Table 7.

[0483] Table 7. Dosing Information

[0484] *Dosage is based on the free base.

[0485] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC (MC: methylcellulose solution)

[0486] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 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.

[0487] Conclusion: The compounds of the present invention, such as the example compounds, have good bioavailability in beagle dogs.

[0488] 8. Mouse forced swimming test

[0489] Male C57BL / 6J mice, 6-8 weeks old and weighing approximately 20-25 g, were purchased from Zhejiang Weitonglihua Laboratory Animal Technology Co., Ltd. After acclimation for 7 days, their weights were recorded and the mice were randomly divided into groups. A cylindrical swimming tub was filled with water (23 ± 1°C) at a height of two-thirds of the tub's volume. The mice were placed in the tub and allowed to swim for approximately 10 minutes. The mice were then removed, dried, and returned to their cages for formal testing the following day. The next day, the tub was filled with water (23 ± 1°C). The forced swimming apparatus (Cyons, model ABOS-01) and a camera (Cyons, model ABOS-01) were positioned and connected to a computer with Vistrack software (Shanghai Xinruan Information Technology Co., Ltd.). The mice were removed from their home cages and administered the test substance (or test substance) or intraperitoneally (or ketamine, the positive control). The mice were tested for swimming at designated time points after drug administration. Before the mouse swimming test, the experimenter soothed the animal for about 1 minute, then put the animal into the water, and the operator immediately left the video shooting range. The software recorded the mouse swimming video for 6 minutes. After the test, the mouse was taken out and thoroughly dried and put back into the cage. The above process was repeated until all mice were tested. After the experiment, all animals were euthanized. Finally, the data analyst evaluated the mouse's immobility behavior through the video (the immobility state is defined as passive floating, with no other movement except the movements necessary to keep the head above water), and analyzed the length of time the mouse was immobile from the 2nd minute to the 6th minute of the test phase. The longer the mouse was immobile, the more severe the depression. All raw data were entered into Excel, and statistical analysis was performed using GraphPad Prism 10.0.

[0490] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good antidepressant effects.

[0491] 9. Repeated 14-day DRF test in rats

[0492] The experimental animals were SD rats, 6-8 weeks old, weighing approximately 180-200 g, with individual body weights within ±20% of the mean body weight. They were purchased from Beijing Weitonglihua Laboratory Animal Technology Co., Ltd. After at least 5 days of acclimatization, the rats were randomly divided into a vehicle control group, low-, medium-, and high-dose test substance groups. The rats were divided into a main experimental group (5 rats / sex / group) and a TK satellite group (3 rats / sex / group, excluding the vehicle control group). All groups were administered the vehicle control or the corresponding concentration of the drug formulation by oral gavage at a volume of 10 mL / kg once daily for 14 consecutive days, followed by a 7-day recovery period.

[0493] Clinical observations were conducted at least twice daily during the trial. Body weights were measured twice weekly during the dosing period and once during the recovery period. Food intake was also measured weekly. Blood samples were collected from 3 animals / sex / group in the main experimental group at the end of dosing and 2 animals / group at the end of the recovery period for hematological and biochemical analysis. Animals were anesthetized and euthanized via exsanguination via the abdominal aorta. Gross autopsy and organ weighing were performed. Major organs and tissues, including the brain, heart, liver, spleen, lungs, and kidneys, as well as those found to be abnormal by naked eye, were fixed, stained, and histopathologically examined.

[0494] Blood samples were collected from the animals in the TK satellite group through the jugular vein before the first and last administration, and 15 minutes, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration, and 48 hours, 72 hours, and 96 hours after the last administration. The plasma was separated and the content of the test substance in the plasma was detected, and the C max 、T max , AUC last Toxicokinetic parameters.

[0495] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good safety.

[0496] The structure of Navacaprant (positive) is as follows:

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, racemate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I) or (II), wherein: R 6 Selected from C 1-6 alkyl, 5- to 10-membered heteroaryl or 4- to 12-membered heterocyclic group, wherein the alkyl, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R 6a replace; R 6a Each independently selected from H, deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-9 Carbocyclic group, -C 0-4 Alkylene-4 to 10-membered heterocyclic group, -OC 3-6 Cycloalkyl, C 1-6 Alkoxy, SC 1-6 Alkyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -NHC(=O)-C 1-6 Alkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; X is selected from O, NH, N(C 1-4 Alkyl), N(C 3-6 cycloalkyl), CH2, CH(C 1-4 alkyl), CH(C 3-6 cycloalkyl), wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CF3, C 1-4 substituted by an alkyl substituent; Q is selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-4 Alkylene-C 3-12 Carbon ring, -C 0-4 Alkylene-4 to 12 membered heterocyclic ring, wherein Q is optionally substituted by 1 to 4 R q replace; R q Each independently selected from deuterium, halogen, CN, OH, =O, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-6 Alkyl, -C(=O)N(C 1-6 Alkyl)2, -C(=O)C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -C(=O)C 3-6 Cycloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 5 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; R 7 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; m is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R 1 , R 2 , R 3 , R 4 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; The condition is that when R 6 for Q is selected from Q1, and R 6a When selected from methyl, the methyl group is substituted by 1 to 3 R k replace; Q1 is selected from s1, s2 are selected from 1 or 2.

2. The compound according to claim 1 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 6 Selected from C 1-4 alkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl and 4- to 6-membered carbocyclyl, wherein the alkyl, heteroaryl, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R 6a replace; X is selected from O, NH, N(CH3), N(cyclopropyl), CH2, CH(CH3), CH(cyclopropyl), wherein the methyl or cyclopropyl group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, CN, OH, NH2, CF3, C 1-4 substituted by an alkyl substituent; Q is selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-7 Monocyclic carbocyclic ring, -C 0-2 Alkylene-C 6-12 Ring carbon ring, -C 0-2 Alkylene-C 6-12 Spirocarbon ring, -C 0-2 Alkylene-C 4-12 Bridged carbon ring, -C 0-2 Alkylene-4-7 membered monocyclic heterocyclic ring, -C 0-2 Alkylene-6-12 membered heterocyclic ring, -C 0-2 Alkylene-6-12 membered spiro heterocyclic ring, -C 0-2 Alkylene-6-12 membered bridged heterocyclic ring, wherein Q is optionally replaced by 1 to 4 R q replace; R 5 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 7 Selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 , R 4 Each independently selected from H, deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R k replace; R q Each independently selected from deuterium, halogen, CN, OH, =O, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, -C(=O)NH2, -C(=O)NHC 1-4 Alkyl, -C(=O)N(C 1-4 Alkyl)2, -C(=O)C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 6a Each independently selected from H, deuterium, halogen, CN, OH, NH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 7 membered heterocycloalkyl, -OC 3-6 Cycloalkyl, C 1-4 Alkoxy, SC 1-4 Alkyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -NHC(=O)-C 1-4 Alkyl, -C(=O)-C 1-4 Alkyl, -C(=O)OC 1-4 Alkyl, -C(=O)-4 to 7 membered heterocycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl or heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-4 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-4 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-4 to 7 membered heterocyclic ring, The alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; The remaining groups are defined in accordance with those described in claim 1.

3. The compound according to claim 2 or its stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 6 Selected from C 1-4 alkylene, 5- to 6-membered monocyclic heteroaryl, 4- to 6-membered monocyclic heterocyclyl, 5-membered heteroaryl and 5-membered heteroaryl, 5-membered heteroaryl and 6-membered heteroaryl, benzo 5-membered heteroaryl, benzo 6-membered heteroaryl, 5-membered heteroaryl and 4-membered cycloalkyl, 5-membered heteroaryl and 5-membered cycloalkyl, 5-membered heteroaryl and 6-membered cycloalkyl, 6-membered heteroaryl and 4-membered cycloalkyl, 6-membered heteroaryl and 5-membered cycloalkyl, 6-membered heteroaryl and 6-membered cycloalkyl, 5-membered heteroaryl and 4-membered heterocycloalkyl, 5-membered heteroaryl and 5-membered heterocycloalkyl, 5-membered heteroaryl and 6-membered heterocycloalkyl, 6-membered heteroaryl and 4-membered heterocycloalkyl, 6-membered heteroaryl and 5-membered heterocycloalkyl, 6-membered heteroaryl and 6-membered heterocycloalkyl, wherein R 6 Optional 1 to 4 R 6a replace; Q is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, oxahexyl, oxadienyl, hexenyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-cycloheptyl, -CH2-cyclohexenyl, -CH2-bicyclo[1.1.1]pentyl, -CH2-bicyclo[2.2.1]heptyl, -CH2-bicyclo[2.2.2]octyl, -CH2-bicyclo[3.2.1]octyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl , -CH2-azacyclohexenyl, -CH2-oxetanyl, -CH2-tetrahydrofuranyl, -CH2-oxacyclohexyl, -CH2-oxacyclohexenyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-cycloheptyl, -CH2CH2-cyclohexenyl, -CH2CH2-bicyclo[1.1.1]pentyl, -CH2CH2-bicyclo[2.2.1]heptyl, -C H2CH2-bicyclo[2.2.2]octyl, -CH2CH2-bicyclo[3.2.1]octyl, -CH2CH2-azetidinyl, -CH2CH2-pyrrolidinyl, -CH2CH2-piperidinyl, -CH2CH2-piperazinyl, -CH2CH2-morpholinyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, -CH2CH2-tetrahydrofuranyl, -CH2CH2-oxetanyl, -CH2CH2-oxetanyl, Q A 、-CH2-Q A 、-CH2CH2-Q A , the Q is optionally replaced by 1 to 4 R q replace; Q A Selected from r1, r3, r5 are each independently selected from 0, 1 or 2; r2, r4, r6 are each independently selected from 0 or 1; r7 is selected from 1, 2 or 3.

4. The compound according to claim 3 or its stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 6 Selected from or optionally 1 to 4 R 6a Substituted methyl and ethyl groups; n is selected from 0, 1 or 2; R 6a Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH 2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxahexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane yl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k replace; R 5 is selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace; R 7 is selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 , R 4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl are optionally substituted by 1 to 4 R k replace; R q each independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NHCH3, N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)CH3, -C(=O)-cyclopropyl, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -O-cyclopropyl, wherein the CH2, methyl, ethyl, isopropyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 R k replace.

5. The compound according to claim 4 or its stereoisomer, tautomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 6 Selected from X is selected from O, NH, N(CH3), CH2, CH(CH3); R 1 is selected from H, deuterium, F, Cl, Br, CN, methyl, CD3, CF3, CHF2, CH2F or cyclopropyl; R 2 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, methoxy or cyclopropyl; R 3 Selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, ethynyl, propynyl, -CH2-ethynyl, -CH2OCH3, methoxy, -OCF3, -OCD3, cyclopropyl, -O-cyclopropyl; R 4 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, methoxy or cyclopropyl; R 5 Selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy or cyclopropyl; R 7 Selected from deuterium, F, Cl, Br, CN, methyl, ethyl, CD3, CF3, CHF2, CH2F, -CH2CH2F, -CH2CHF2, -CH2CF3, propyl, isopropyl, -CH2OCH3, methoxy, OCD3 or cyclopropyl; Q is selected from The Q is optionally replaced by 1 to 4 R q replace; R q Each independently selected from deuterium, F, Cl, Br, CN, OH, methyl, ethyl, isopropyl, CD3, CF3, CHF2, CH2F, -CH2OCH3, -CH2OH, -CH2CN, methoxy, -OCF3, -OCD3 or cyclopropyl; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, propenyl, allyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

6. The compound according to claim 1 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the general formula (I) is selected from the general formula (Ia), (Ib) or (Ic), the general formula (II) is selected from the general formula (IIa), (IIb) or (IIc), Q1 is selected from Q2 is selected from 1 to 4 R q Substituted with the following groups: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, -CH2-vinyl, -CH2-ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, X1 and X2, one is N and the other is O; s1, s2 are selected from 1 or 2; R 6b is selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, - CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, or 1 to 3 R k substituted methyl, the CH2, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 R k replace; R 6c is selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, methyl, ethyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2- cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxhexyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-isobutyl, -O-cyclopropyl, The CH2, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, Optional 1 to 4 R k replace; R 6A Selected from The remaining groups are defined the same as in any one of claims 2 to 5.

7. The compound according to claim 6 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R 5 Selected from methyl, ethyl, CF3, CHF2, CH2F, CD3; R 4 Selected from H, deuterium; R 3 Selected from methyl, ethyl, CF3, CD3, CH2CF3, CH2CHF2, CH2CH2F; R 2 Selected from H, deuterium; R 1 Selected from F, Cl, Br; R 6b is selected from H, CF3, CD3, CHF2, CH2F, -CH2-cyclopropyl, -CH2-ethynyl, ethyl, propyl, isopropyl, Cyclopropyl, cyclobutyl, oxetanyl, azetidinyl; R 6c is selected from H, CF3, CD3, CHF2, CH2F, -CH2-cyclopropyl, -CH2-ethynyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, Q2 is selected from 1 to 2 R q Substituted with the following groups: tetrahydrofuranyl, tetrahydropyranyl, cyclobutyl, cyclohexyl, Preferably R q Selected from F, methoxy, methyl.

8. The compound according to claim 1 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the general formula (Id) or (IId), R 6c Selected from CF3, CD3, CHF2, CH2F, methyl, ethyl, cyclopropyl, cyclobutyl, R 5 Selected from the following groups optionally substituted by 1 to 5 deuteriums, F: methyl, ethyl; R 3 Selected from the following groups optionally substituted by 1 to 5 deuteriums, F: methyl, ethyl; R 7 is selected from deuterium, F, Cl, Br, CN or the following groups optionally substituted by 1 to 5 deuterium or F: methyl, ethyl, isopropyl, methoxy; m is selected from 0, 1, 2; Q2 is selected from Preferably More preferably 9. The compound according to claim 1 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound is selected from one of the structures shown in Table A.

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

11. Use of the compound according to any one of claims 1 to 9 or its stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating a disease associated with antagonizing KOR.

12. The use according to claim 11, wherein: The disease is selected from depression or anxiety.

13. 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 9 or a stereoisomer, tautomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 10, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a KOR-antagonistic disease.

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