CB1 antagonist and application thereof

Abstract

The invention relates to a CB1 antagonist and application thereof. Particularly, the invention relates to a compound as shown in a general formula (IA), a preparation method thereof, a pharmaceutical composition thereof and application of the compound as shown in the general formula (IA) or the pharmaceutical composition thereof in preparation of drugs for preventing and / or treating CB1-mediated diseases, and substituents in the general formula (IA) are as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a cannabinoid receptor 1 (CB1) antagonist, its stereoisomers, pharmaceutically acceptable salts, and use thereof in preparing medicines for treating CB1-mediated related diseases. Background Art

[0002] CB1 is expressed not only in the brain, but also in peripheral cells and tissues, and is a component of the endocannabinoid system. CB1 activates intracellular signals through stimulation or binding of cannabinoids and their derivatives, and exerts a wide range of biological effects. Activation of this system can increase appetite, promote the synthesis and storage of lipids, etc. CB1 antagonists can reduce weight by inhibiting the endocannabinoid system, reducing appetite, and reducing food intake. Currently, CB1 antagonists have been shown to have weight loss effects, such as rimonabant, and have the effects of sensitizing insulin and improving lipid metabolism disorders. However, it was withdrawn from the market because of its central side effects. There is still a demand to develop drugs that can be used for diseases such as metabolic syndrome, obesity, diabetic nephropathy, insulin-dependent diabetes or non-insulin-dependent diabetes. Summary of the invention

[0003] The present invention provides a compound represented by general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, which have an inhibitory effect on CB1 and have good physicochemical properties, such as higher solubility, physical and / or chemical stability, improved pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, low toxic and side effects, and have the advantages of oral administration, rapid absorption, high clearance rate, etc.

[0004] The present invention relates to a compound represented by general formula (IA), general formula (I), general formula (II), general formula (III), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof:

[0005]

[0006] in,

[0007] Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 aryl or 5-14 membered heteroaryl; in some embodiments, ring A is C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl; in some embodiments, ring A is ring A is C 3-6 Cycloalkyl, C 3-6 Cycloalkylphenyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl and phenyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl; in some embodiments, ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolanyl, azopentyl, oxetanyl, azacyclohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl , oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl, benzotetrahydrofuranyl; in some embodiments, ring A is cyclopropyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, benzocyclobutyl or benzocyclopentyl; in some embodiments, ring A is phenyl; in some embodiments, ring A is

[0008] Each R1 is independently -L1-R 1a ;

[0009] L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 In some embodiments, L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3In some embodiments, L1 is a bond; In some embodiments, L1 is C 1-6 Alkylene, wherein any methylene in the alkylene is optionally replaced by C(O), S(O)2, NH or O; in some embodiments, L1 is a bond, -O-, -(CH2) m -、-O(CH2) m -、-NH(CH2) m -、-CO(CH2) m -, -CONH(CH2) m -or-NHCO(CH2) m -; In some embodiments, L1 is -O-, -(CH2) m -、-O(CH2) m -、-NH(CH2) m -、-CO(CH2) m -, -CONH(CH2) m -or-NHCO(CH2) m -; In some embodiments, L1 is -O-; In some embodiments, L1 is a bond or -O-;

[0010] R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 deuterium, halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-6 Alkyl, -C(O)(CH2)m C 3-8 Cycloalkyl or -C(O)(CH2) m (3-8 membered heterocycloalkyl) group substitution;

[0011] In some embodiments, R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-6 Alkyl, -C(O)(CH2) m C 3-8 Cycloalkyl or -C(O)(CH2) m (3-8 membered heterocycloalkyl) group; in some embodiments, R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-3 Alkyl, -C(O)(CH2) m C 3-6 Cycloalkyl or -C(O)(CH2) m (3-6 membered heterocycloalkyl) group; in some embodiments, R 1a For hydrogen, halogen, SF5, SCF3, C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl may be further substituted with 1-3 halogens, SF5, SCF3, C 1-3 Alkyl, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy substituted; in some embodiments, R 1a For hydrogen, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally further substituted with 1-3 halogen or C 1-3 Alkyl substituted; in some embodiments, R 1a For hydrogen, halogen, C 1-3 The cyclopropyl, azetidinyl or oxetanyl groups are optionally further substituted with 1 to 3 halogen or C 1-3 Alkyl substitution;

[0012] In some embodiments, R 1a For hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-3 selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-3 Alkyl, -C(O)(CH2) m C 3-6 Cycloalkyl or -C(O)(CH2) m (3-6 membered heterocycloalkyl) group; in some embodiments, R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxetanyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cyclopropyl, cyclopentyl, cyclohexyl, oxetan ... butyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubanyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxhexyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl is optionally further substituted by 1-3 selected from halogen, hydroxy, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy or deuterated C 1-3 In some embodiments, R 1aIt is hydrogen, deuterium, F, Cl, hydroxyl, cyano, amino, methylamino, dimethylamino, SF5, SCF3, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -OCHF2, -OCH2F, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3 , -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxetanyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl , pyridyl, pyrimidinyl, pyridone, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxhexyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridone, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl is optionally further substituted by 1-3 selected from F, Cl, hydroxyl, cyano, SF5, SCF3, methyl, ethyl , propyl, isopropyl, tert-butyl, methoxy, ethoxy, -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -OCHF2, -OCH2F, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2 or -OCF2CF3; in some embodiments, R 1ais cyclopropyl, azetidinyl or oxetanyl, optionally further substituted by 1-3 groups selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy or deuterated C 1-3 In some embodiments, R 1a is cyclopropyl, azetidinyl or oxetanyl, optionally further substituted by 1-3 halogen or C 1-3 Alkyl substituted; in some embodiments, R 1a is hydrogen, halogen or C 1-6 alkyl; in some embodiments, R 1a is hydrogen, halogen or C 1-3 alkyl;

[0013] n is 0, 1, 2, 3; in some embodiments, n is 0; in some embodiments, n is 1; in some embodiments, n is 2; in some embodiments, n is 3;

[0014] m is 0, 1, 2, 3; in some embodiments, m is 0; in some embodiments, m is 1; in some embodiments, m is 2; in some embodiments, m is 3;

[0015] R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, -SF5, -SCF3, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3-8 Cycloalkyl or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 R b replace;

[0016] R b for deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or deuterated C 1-6 substituted with an alkoxy group;

[0017] In some embodiments, R2 and R3 are each independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, -SF5, -SCF3, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -OC 3-6 Cycloalkyl or -O-(3-6 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl group is optionally further substituted by 1-5 R b replace;

[0018] In some embodiments, R2 and R3 are each independently hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, -SF5 or -SCF3, wherein the alkyl, alkenyl, alkynyl group is optionally further substituted with 1-5 R b replace;

[0019] In some embodiments, R b for deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl; in some embodiments, R b for deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-3 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-3 Deuterated alkyl or C 1-3 Haloalkyl;

[0020] p is 0, 1, 2, 3; in some embodiments, p is 0; in some embodiments, p is 1; in some embodiments, p is 2; in some embodiments, p is 3;

[0021] q is 0, 1, 2, 3; in some embodiments, q is 0; in some embodiments, q is 1; in some embodiments, q is 2; in some embodiments, q is 3;

[0022] The condition is that any one of the following conditions is satisfied: (1) when R3 is halogen, -CH(CH3)2, -C(CH3)3, -CF3, -OCF3, and p is 0 and q is 1, Not for When R3 is -CF3, p is 0, and q is 1, Not for (2) When ring A is phenyl, R1 is not halogen.

[0023] The first specific embodiment relates to a compound represented by the general formula (IA), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof:

[0024]

[0025] in:

[0026] Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-14 membered heteroaryl;

[0027] Each R1 is independently -L1-R 1a ;

[0028] L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy group substitution;

[0029] R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 deuterium, halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-6 Alkyl, -C(O)(CH2) m C 3-8 Cycloalkyl or -C(O)(CH2) m (3-8 membered heterocycloalkyl) group substitution;

[0030] R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, -SF5, -SCF3, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3-8 Cycloalkyl or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 R b replace;

[0031] R b for deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, hydroxy, cyano, amino, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or deuterated C 1-6 substituted with an alkoxy group;

[0032] n is 0, 1, 2, or 3;

[0033] m is 0, 1, 2, or 3;

[0034] p is 0, 1, 2, or 3;

[0035] q is 0, 1, 2, 3;

[0036] Provided that, when R3 is halogen, -CH(CH3)2, -C(CH3)3, -CF3, -OCF3, and p is 0, q is 1, Not for When R3 is -CF3, p is 0, and q is 1, Not for In other embodiments, the conditions are: (1) when ring A is phenyl, R1 is not halogen; (2) when R3 is -CF3, and p is 0, q is 1, Not for

[0037] The second specific embodiment relates to a compound represented by general formula (I), its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof:

[0038]

[0039] in:

[0040] Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-14 membered heteroaryl;

[0041] Each R1 is independently -L1-R 1a ;

[0042] L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 In some embodiments, L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy group substitution;

[0043] R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-6 Alkyl, -C(O)(CH2) m C 3-8 Cycloalkyl, -C(O)(CH2) m (3-8 membered heterocycloalkyl) group substitution;

[0044] n is 0, 1, 2, or 3;

[0045] m is 0, 1, 2, or 3;

[0046] Provided that, when Ring A is phenyl, R1 is not halogen.

[0047] The third specific embodiment relates to a compound represented by general formula (I), its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof, which satisfies one or more of the following conditions:

[0048] (1) Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6 Cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl, preferably C 3-8 Cycloalkyl, C 3-6 Cycloalkylphenyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl and phenyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6 Cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl, preferably C 3-6 Cycloalkyl, C 3-6 Cycloalkylphenyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl and phenyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolanyl, azopentyl, oxetanyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Thiphenyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl or benzotetrahydrofuranyl, more preferably cyclopropyl, bicyclo[1.1.1]pentane, cubanyl, azetidinyl, oxetanyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, benzocyclobutyl or benzocyclopentyl;

[0049] (2) L1 is a bond;

[0050] (3) L1 is -O-, -(CH2) m -、-O(CH2) m -、-NH(CH2) m -、-CO(CH2) m -, -CONH(CH2) m -or-NHCO(CH2) m -, preferably -O-, -CH2-, -OCH2-, -COCH2-, -CONH- or -NHCO-, more preferably -O-;

[0051] (4)R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-3 Alkyl, -C(O)(CH2) m C 3-6 Cycloalkyl, -C(O)(CH2) m (3-6 membered heterocycloalkyl) group, preferably R 1a For hydrogen, halogen, SF5, SCF3, C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl may be further substituted with 1-3 halogens, SF5, SCF3, C 1-3 Alkyl, halogenated C1-3 Alkyl or halogenated C 1-3 Alkoxy substituted, more preferably R 1a For hydrogen, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally further substituted with 1-3 halogen or C 1-3 Alkyl substituted, more preferably R 1a For hydrogen, halogen, C 1-3 The cyclopropyl, azetidinyl or oxetanyl groups are optionally further substituted with 1 to 3 halogen or C 1-3 Alkyl substitution.

[0052] The fourth specific embodiment relates to a compound represented by general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, wherein general formula (I) is further represented by general formula (II):

[0053]

[0054] Where: L1 and R 1a As mentioned above.

[0055] A specific fifth embodiment relates to a compound represented by general formula (I), its tautomers, stereoisomers or pharmaceutically acceptable salts thereof, wherein general formula (I) is further represented by general formula (III):

[0056]

[0057] in:

[0058] L1 is a bond or C 1-6 Alkylene, any methylene in the alkylene is optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy groups are preferably substituted with a bond, -O-, -(CH2) m -、-O(CH2) m -、-NH(CH2) m -、-CO(CH2) m -, -CONH(CH2) m -or-NHCO(CH2) m -, more preferably a bond or -O-;

[0059] R 1aFor hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-3 selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-3 Alkyl, -C(O)(CH2) m C 3-6 Cycloalkyl or -C(O)(CH2) m (3-6 membered heterocycloalkyl) is substituted with hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxetanyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cyclopropyl, cyclopentyl, cyclohexyl, oxetan ... butyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubanyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxhexyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl is optionally further substituted by 1-3 selected from halogen, hydroxy, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 The alkyl group is substituted, more preferably cyclopropyl, azetidinyl or oxetanyl, optionally further substituted by 1-3 groups selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 The alkyl group is substituted, preferably cyclopropyl, azetidinyl or oxetanyl, optionally further substituted with 1-3 halogen or C 1-3 Alkyl substitution.

[0060] In a specific sixth embodiment, the compound represented by the general formula (I), its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures in Table 1 or Table 2:

[0061] Table 1

[0062]

[0063] Table 2

[0064]

[0065]

[0066] In a specific seventh embodiment, the present invention further provides a pharmaceutical composition comprising a therapeutically effective dose of the compound described in the first to sixth embodiments above, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients.

[0067] In a specific eighth embodiment, the pharmaceutical composition as described above comprises 1-1500 mg of the compound described in the first to sixth embodiments, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

[0068] Specifically, in the ninth embodiment, the present invention further provides a use of the compound described in the first to sixth embodiments, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in the seventh embodiment in the preparation of a drug, preferably the drug is a drug for preventing and / or treating CB1-mediated diseases.

[0069] In a specific tenth embodiment, the CB1-mediated disease is obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.

[0070] In a specific eleventh embodiment, the present invention further provides a method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound described in the first to sixth embodiments, its stereoisomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the seventh embodiment, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.

[0071] The "effective amount" or "therapeutically effective amount" described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a peptide compound, conjugate, or a pharmaceutically acceptable salt thereof disclosed in this application that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1- 20mg, 5-1500mg, 5-1000mg, 5-900mg, 5-800mg, 5-700mg, 5-600mg, 5-500mg, 5-400mg, 5-300mg, 5-250mg, 5-200mg, 5 -150mg, 5-125mg, 5-100mg, 5-90mg, 5-70mg, 5-80mg, 5-60mg, 5-50mg, 5-40mg, 5-30mg, 5-25mg, 5-20mg, 10-1500mg, 10-1000mg, 10-900mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-20 0mg, 10-150mg, 10-125mg, 10-100mg, 10-90mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 2 0-1500mg, 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 20-400mg, 20-350mg, 20-300mg, 20-25 0mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40mg, 20-30mg;50-1500mg, 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-125mg, 5 0-100mg; 100-1500mg, 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;

[0072] In some embodiments, the pharmaceutical composition or preparation of the present invention contains the above-mentioned therapeutically effective amount of any one of the above-mentioned compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0073] The present invention further relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of any of the above compounds, stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification"). In some embodiments, the pharmaceutical composition includes but is not limited to 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg 0mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 525mg, 550mg, 575mg, 600mg, 625mg, 650mg, 675mg, 700mg, 725mg, 750mg, 775mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1200mg, 1300mg, 1400mg, 1500mg of the compound represented by any of the above, its stereoisomers or pharmaceutically acceptable salts thereof.

[0074] The present invention further relates to a method for treating a disease in a mammal, the method comprising administering a compound as described in any one of the above-mentioned embodiments of the present invention, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients, to a subject at a daily dose of 1-1500 mg / day, wherein the daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-100 0 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day. In some embodiments, the daily dose includes but is not limited to 1 mg / day. g / day, 5mg / day, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 75mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 300mg / day, 400mg / day, 600mg / day, 800mg / day, 1000mg / day, 1200mg / day, 1400mg / day, 1500mg / day.

[0075] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains the compound shown in any one of the above items of the present invention, its stereoisomer or a pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer or pharmaceutically acceptable salt is the same as its amount in the above-mentioned pharmaceutical composition.

[0076] The amount of the compound according to the invention or its stereoisomer or pharmaceutically acceptable salt in the present invention is in each case calculated as the free base.

[0077] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0078] Synthetic route

[0079] Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, and the starting materials are commercially available chemicals and / or compounds described in chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec and Bailingwei Technology.

[0080] Specific and similar reactants can be selectively identified through indexes of known chemical substances prepared by the Chemical Abstracts Service of the American Chemical Society, which are available in most public and university libraries and online. Chemicals that are known but not commercially available in the catalog are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services.

[0081] the term

[0082] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0083] The term "alkyl" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms. 1-20 The alkyl group is preferably an alkyl group having 1 to 12 carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), further preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6 Alkyl), most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment. When the alkyl group is substituted with a substituent, the substituent may not be further substituted.

[0084] The term "alkylene" refers to a divalent straight chain or branched saturated alkyl group. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), and the like.

[0085] The term "alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond (C=C), typically containing 2 to 18 carbon atoms, such as 2 to 8 carbon atoms, further such as 2 to 6 carbon atoms, and further such as 2 to 4 carbon atoms, examples of which include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; alkenyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment. When the alkenyl is substituted with a substituent, the substituent is no longer substituted further.

[0086] The term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), generally containing 2 to 18 carbon atoms, further containing 2 to 8 carbon atoms, further containing 2 to 6 carbon atoms, and further containing 2 to 4 carbon atoms, examples of which include but are not limited to ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl and 4-decynyl, etc.; alkynyl can be substituted or unsubstituted, and when substituted, the substituent can be substituted at any available point of attachment. When the alkynyl is substituted by a substituent, the substituent is no longer further substituted.

[0087] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic hydrocarbon substituent (i.e., monocyclic cycloalkyl) or polycyclic hydrocarbon substituent (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms, i.e., C 3-20 The cycloalkyl group is preferably a cycloalkyl group having 3 to 12 carbon atoms (i.e., C 3-12 cycloalkyl), more preferably a cycloalkyl having 3 to 8 carbon atoms (i.e., C 3-8 cycloalkyl), further preferably a cycloalkyl having 3 to 6 carbon atoms (i.e., C 3-6 cycloalkyl), most preferably a cycloalkyl having 3 to 5 carbon atoms (i.e., C3-5 The non-limiting examples of the monocyclic cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl. The non-limiting examples of the polycyclic cycloalkyl include: spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl.

[0088] The term "spirocycloalkyl" refers to a polycyclic group in which the single rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has a completely conjugated π electron system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 The spirocycloalkyl group is preferably a spirocycloalkyl group having 6 to 14 ring atoms (i.e., C 6-14 Spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (i.e., C 7-10 The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of spiro atoms shared between rings, preferably a monospirocycloalkyl group or a bispirocycloalkyl group, more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospirocycloalkyl group.

[0089] The term "fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 The fused cycloalkyl group may contain one or more double bonds, but none of the rings has a completely conjugated π electron system. The fused cycloalkyl group preferably has 6 to 14 ring atoms (i.e., C 6-14 fused cycloalkyl), more preferably a fused cycloalkyl having 7 to 10 ring atoms (i.e., C 7-10 The condensed cycloalkyl group is classified into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl group according to the number of constituent rings, preferably a bicyclic condensed cycloalkyl group or a tricyclic condensed cycloalkyl group, and more preferably a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic condensed cycloalkyl group.

[0090] The term "bridged cycloalkyl" refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., C 5-20 The bridged cycloalkyl group preferably has a bridged cycloalkyl group with 6 to 14 ring atoms (i.e., C 6-14 More preferably, the cycloalkyl group has 7 to 10 ring atoms (i.e., C 7-10 According to the number of constituent rings, the cycloalkyl group may be classified into bicyclic, tricyclic, tetracyclic or polycyclic cycloalkyl groups, and is preferably a bicyclic or tricyclic cycloalkyl group.

[0091] The cycloalkyl may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the cycloalkyl is substituted with a substituent, the substituent is no longer substituted further.

[0092] The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic heterocyclic hydrocarbon substituent (i.e., monocyclic heterocycloalkyl) or polycyclic heterocyclic hydrocarbon substituent (i.e., polycyclic heterocycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3-20 membered heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n(wherein m and n are integers of 0-2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heterocycloalkyl group preferably has 3 to 12 ring atoms (i.e., 3-12 membered heterocycloalkyl), wherein 1-4 heteroatoms are selected from N, O and S atoms, more preferably has 3 to 8 ring atoms (i.e., 3-8 membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, further preferably has 3 to 6 ring atoms (i.e., 3-6 membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms, and most preferably has 5 to 6 ring atoms (i.e., 5-6 membered heterocycloalkyl), wherein 1-4, 1-3 or 1-2 heteroatoms are selected from N, O and S atoms. Non-limiting examples of the monocyclic heterocycloalkyl include: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, 1,3-dioxolane, 2,2-difluoro-1,3-dioxolane, cyclopentanone, 2,2-difluorocyclopentanone, azepanyl, oxolanyl or azacyclopentanyl, etc. Non-limiting examples of the polycyclic heterocycloalkyl include: spiroheterocycloalkyl, fused heterocycloalkyl and bridged heterocycloalkyl.

[0093] The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which the monocyclic rings share one atom (called a spiro atom), which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered spiroheterocycloalkyl group), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding the ring parts of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The spiroheterocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6-14-membered spiroheterocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7-10-membered spiroheterocycloalkyl). The spiro heterocycloalkyl group is divided into monospiro heterocycloalkyl group, bispiro heterocycloalkyl group or polyspiro heterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiro heterocycloalkyl group or bispiro heterocycloalkyl group, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered monospiro heterocycloalkyl group.

[0094] The term "fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered fused heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding the ring parts of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The fused heterocycloalkyl preferably has 6 to 14 ring atoms (i.e., 6-14 membered fused heterocycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7-10 membered fused heterocycloalkyl). According to the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, preferably bicyclic fused heterocycloalkyl groups or tricyclic fused heterocycloalkyl groups, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocycloalkyl groups.

[0095] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, having 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5-20 membered bridged heterocycloalkyl), wherein one or more (e.g., 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n (wherein m and n are integers of 0-2) heteroatoms, but excluding the ring parts of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. The bridged heterocycloalkyl preferably has a bridged heterocycloalkyl having 6 to 14 ring atoms (i.e., a 6-14-membered bridged heterocycloalkyl), and more preferably has a bridged heterocycloalkyl having 7 to 10 ring atoms (i.e., a 7-10-membered bridged heterocycloalkyl). According to the number of constituent rings, it is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl, preferably a bicyclic bridged heterocycloalkyl or a tricyclic bridged heterocycloalkyl.

[0096] The heterocycloalkyl may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is the heterocycloalkyl. The heterocycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment). When the heterocycloalkyl is substituted by a substituent, the substituent is no longer substituted further.

[0097] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aromatic group) or a fused polycyclic group (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms (i.e., C 6-14 The aryl group is preferably an aryl group having 6 to 12 carbon atoms (i.e., C 6-12 aryl), more preferably an aryl having 6 to 10 carbon atoms (i.e., C 6-10 The monocyclic aromatic group is, for example, phenyl. Non-limiting examples of the polycyclic aromatic group include: naphthyl, anthracenyl, phenanthryl, etc.

[0098] The aryl group may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, preferably benzoC 3-8 Cycloalkyl, benzo 3-8 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, more preferably benzo C 4-6 Cycloalkyl, benzo 4-6 yuan heterocycloalkyl, benzo 5-6 yuan heteroaryl, further preferably benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzazetidinyl, benzoxetidinyl, benzoxetidinyl, benzoxetidinyl, benzazetidinyl, benzoxetidinyl, benzoxetidinyl, benzoxazolyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridyl, benzopyrimidinyl, benzopyridone, benzopyrazinyl, benzopyridazinyl. The aryl can be optionally substituted or unsubstituted, and when substituted, the substituent can be substituted at any usable point of attachment. When the aryl is substituted by a substituent, the substituent is no longer further substituted.

[0099] The term "heteroaryl" refers to a monocyclic heteroaromatic group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaromatic group (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., a 5-14 membered heteroaryl), wherein one or more (e.g., 1, 2, 3 or 4) of the ring atoms are selected from nitrogen, oxygen, P(O), m and S(O) n(wherein m, n are integers of 0-2) heteroatoms, preferably heteroatoms selected from nitrogen, oxygen, or sulfur, but excluding -OO-, -OS- or -SS- ring parts, and the remaining ring atoms are carbon. The heteroaryl group preferably has a heteroaryl group of 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl group). The monocyclic heteroaryl group preferably has a heteroaryl group of 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl group), and non-limiting examples include: furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidyl, pyridone, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl group preferably has a 5-6 membered heteroaryl group and a 5-6 membered heteroaryl group, a 5-10 membered heteroaryl group and C 6-10 Aryl or C 6-10 Aryl and 5-10 membered heteroaryl, further preferably 5-6 membered heteroaryl and 5-6 membered heteroaryl, 5-6 membered heteroaryl and phenyl or phenyl and 5-6 membered heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothienyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridinyl, pyridothiphenyl, pyridopyrrolyl and the like.

[0100] The heteroaryl group may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, preferably a 5-6 membered heteroaryl ring and C 3-8 cycloalkyl, 5-6 membered heteroaryl and 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, more preferably 5-6 membered heteroaryl and C 4-6 Cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl. The heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the heteroaryl is substituted with a substituent, the substituent is no longer substituted further.

[0101] The term "alkoxy" refers to -O-(alkyl) or -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 The alkoxy group is preferably an alkoxy group having 1 to 8 carbon atoms (i.e., C 1-8 Alkoxy), more preferably an alkoxy having 1 to 6 carbon atoms (i.e., C 1-6 Alkoxy), most preferably alkoxy having 1 to 3 carbon atoms (i.e. C 1-3Alkoxy). Non-limiting examples include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. The alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the alkoxy is substituted with a substituent, the substituent may not be further substituted.

[0102] The term "alkylthio" refers to -S-(alkyl) or -S-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above, and have 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms (i.e., C 1-10 The alkylthio group is preferably an alkylthio group having 1 to 8 carbon atoms (i.e., C 1-8 alkylthio), more preferably alkylthio having 1 to 6 carbon atoms (i.e., C 1-6 alkylthio), preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3 The alkylthio group may be optionally substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment. When the alkylthio group is substituted with a substituent, the substituent may not be further substituted.

[0103] The term "halo" or "halogen" or "halo" is understood to mean a fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atom, preferably a fluorine, chlorine or bromine atom.

[0104] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, chlorofluoromethyl, dichloromethyl, bromofluoromethyl, trifluoromethyl, chlorodifluoromethyl, dichlorofluoromethyl, trichloromethyl, bromodifluoromethyl, bromochlorofluoromethyl, dibromofluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl, 2-chloro-2-fluoroethyl, 2,2-dichloroethyl, 2-bromo-2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2, 2,2-trichloroethyl, 2-bromo-2,2-difluoroethyl, 2-bromo-2-chloro-2-fluoroethyl, 2-bromo-2,2-dichloroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1-chloro-1,2,2,2-tetrafluoroethyl, 2-chloro-1,1,2,2-tetrafluoroethyl, 1,2-dichloro-1,2,2-trifluoroethyl, 2-bromo-1,1,2,2-tetrafluoroethyl and the like, preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl and 2,2-difluoroethyl.

[0105] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples include: fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, difluoromethoxy, chlorofluoromethoxy, dichloromethoxy, bromofluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, dichlorofluoromethoxy, trichloromethoxy, bromodifluoromethoxy, bromochlorofluoromethoxy, dibromofluoromethoxy, and the like; preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy, 2-chloro-2-fluoroethoxy, 2,2-dichloroethoxy, 2-bromo-2-fluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2 , 2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, 2-bromo-2,2-difluoroethoxy, 2-bromo-2-chloro-2-fluoroethoxy, 2-bromo-2,2-dichloroethoxy, 1,1,2,2-tetrafluoroethoxy, pentafluoroethoxy, 1-chloro-1,2,2,2-tetrafluoroethoxy, 2-chloro-1,1,2,2-tetrafluoroethoxy, 1,2-dichloro-1,2,2-trifluoroethoxy, 2-bromo-1,1,2,2-tetrafluoroethoxy, preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2,2-difluoroethoxy.

[0106] The term "mercapto" refers to -SH. The term "hydroxy" refers to -OH. The term "nitro" refers to -NO2. The term "amino" refers to -NH2. The term "cyano" refers to -CN. The term "carboxy" refers to -C(O)OH. The term "oxo" or "oxo" refers to =O. The term "carbonyl" refers to C=O. The term "aminoacyl" refers to -C(O)NH2. The term "sulfonyl" refers to -S(O)2. The term "deuterated alkyl" refers to an alkyl substituted with one or more deuterium, wherein alkyl is as defined above. The term "deuterated alkoxy" refers to an alkoxy substituted with one or more deuterium, wherein alkoxy is as defined above. The term "haloalkoxy" refers to an alkoxy substituted with one or more halogens, wherein alkoxy is as defined above. The term "hydroxyalkyl" refers to an alkyl substituted with one or more hydroxyl groups, wherein alkyl is as defined above. The term "alkylamino" refers to an alkyl-NH-, wherein alkyl is as defined above.

[0107] The terms "include", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps. Those skilled in the art will appreciate that the above terms such as "comprising" encompass the meaning of "consisting of".

[0108] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0109] When the lower and upper limits of a numerical range are disclosed, any value and any included range falling within the range is specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0110] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0111] The expression mn used herein refers to a range from m to n and a subrange consisting of individual point values ​​therein and individual point values. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C 10 " or "C 3-10 " should also be understood in a similar manner, for example, any sub-ranges and point values ​​contained therein may be included, such as C3-C9, C6-C9, C6-C8, C6-C7, C7-C 10 , C7-C9, C7-C8, C8-C9, etc. and C3, C4, C5, C6, C7, C8, C9, C 10 For example, the expression "C1-C6" or "C 1-6 " covers a range of 1-6 carbon atoms, and should be understood to also cover any sub-ranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., as well as C1, C2, C3, C4, C5, C6, etc. For another example, the expression "three-membered to ten-membered" should be understood to cover any sub-ranges and each point value therein, such as three-membered to five-membered, three-membered to six-membered, three-membered to seven-membered, three-membered to eight-membered, four-membered to five-membered, four-membered to six-membered, four-membered to seven-membered, four-membered to eight-membered, five-membered to seven-membered, five-membered to eight-membered, six-membered to seven-membered, six-membered to eight-membered, nine-membered to ten-membered, etc., as well as three, four, five, six, seven, eight, nine, ten-membered, etc. Other similar expressions in this article should also be understood in a similar manner.

[0112] Different expressions used herein such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0113] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl can but does not have to be present, and the description includes the situation that cycloalkyl is substituted with alkyl and the situation that cycloalkyl is not substituted with alkyl.

[0114] The terms "substituted" and "substituted" refer to one or more (e.g., one, two, three, or four) hydrogens on the designated atom being replaced by a selection from the indicated group, provided that the normal valence of the designated atom in the current situation is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds. When describing a substituent as absent, it should be understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When describing that each carbon atom in a group can be optionally replaced by a heteroatom, the condition is that the normal valence of all atoms in the group in the current situation is not exceeded and a stable compound is formed. Exemplary substituents include, but are not limited to: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Heteroalkyl, C 5-12 Aryl, 5-12 membered heteroaryl, hydroxyl, C 1-6 Alkoxy, C 5-12 Aryloxy, thiol, C 1-6 Alkylthio, cyano, halogen, C 1-6 Alkylthiocarbonyl, C 1-6 Alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, amino, phosphonic acid, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2,-OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2,-HC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2,-SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, etc.

[0115] If a substituent is described as "optionally substituted with...", the substituent may be unsubstituted or substituted. If an atom or group is described as optionally substituted with one or more of the substituent list, one or more hydrogens on the atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced. When the substituent is hydrogen, this may also mean that the corresponding group is "non-substituted" or "unsubstituted". Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0116] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0117] When any variable (e.g., R), as well as variables with labels (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in the composition or structure of a compound, its definition at each occurrence is independent. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may be optionally substituted with up to four R substituents, and the options for each R substituent in each case are independent of each other.

[0118] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds of the present invention, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in the substituents of the compounds of the present invention. All of these isomers and their mixtures are included within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that show better biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures are also included within the scope of the present invention. The purification and separation of such substances can be achieved by standard techniques known in the art.

[0119] The compounds of the present invention also include their tautomers, and the tautomers of the compounds disclosed herein that exist may be "NH2" tautomers, or "NH" tautomers, or a combination of the two. For example:

[0120]

[0121] Therefore, the tautomers of the compounds represented by the general formula (IA), general formula (I), general formula (III), and general formula (III) herein include the following general formulas:

[0122]

[0123] The hydrogen atoms described in the present invention can be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0124] The compounds of the present invention include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example, respectively. 2 H (deuterium, D), 3 H (tritium, T), 11 C. 13 C. 14 C. 15 N. 17 O. 18 O. 32 P. 33 P. 33 S. 34 S. 35S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I, etc., preferably deuterium.

[0125] Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending drug biological half-life. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

[0126] In the compounds of the invention, when a position is specifically designated as deuterium D, the position is understood to have an abundance of deuterium at least 1000 times greater than the natural abundance (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

[0127] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for contact with the tissues of patients without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit-risk ratio, and effective for its intended use.

[0128] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention which are safe and effective when used in mammals and have the desired biological activity.

[0129] The term "pharmaceutical composition" refers to a composition containing one or more compounds of the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs, as well as other components such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredients, and thus exert biological activity.

[0130] The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0131] The term "administration" or "administering" refers to a method that enables a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral or parenteral (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, etc. In particular, injection or oral administration.

[0132] As used herein, the term "treat" includes alleviating, reducing or ameliorating a disease or symptom, preventing other symptoms, ameliorating or preventing the underlying metabolic factors of a symptom, inhibiting a disease or symptom, for example, preventing the disease or symptom from developing, alleviating a disease or symptom, promoting remission of a disease or symptom, or stopping the symptoms of a disease or symptom, and extends to include prevention. "Treatment" also includes achieving a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit refers to the eradication or improvement of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or improving one or more physiological signs associated with the underlying disease, and although the patient may still suffer from the underlying disease, an improvement in the patient's disease can be observed. A prophylactic benefit refers to the use of the composition by a patient to prevent the risk of a certain disease, or when a patient takes it when one or more physiological symptoms of a disease occur, although the disease has not yet been diagnosed.

[0133] The term "active ingredient", "therapeutic agent", "active substance" or "active agent" refers to a chemical entity that is effective in treating or preventing a target disorder, disease or condition. The term "neuropsychiatric disease" refers to a general term for neurological diseases and psychiatric diseases, including neurological diseases and / or psychiatric diseases.

[0134] With respect to a drug, drug unit or active ingredient, the term "effective amount", "therapeutically effective amount" or "prophylactically effective amount" refers to a sufficient amount of the drug or pharmaceutical agent that can achieve the desired effect with acceptable side effects. The determination of the effective amount varies from person to person, depending on the age and general condition of the individual and on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0135] As used herein, "individual" includes humans or non-human animals. Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0136] The term "room temperature" refers to a temperature from 10°C to 40°C. In some embodiments, "room temperature" refers to a temperature from 15°C to 30°C; in other embodiments, "room temperature" refers to a temperature from 18°C ​​to 25°C.

[0137] "Equivalent" or its abbreviation "eq" refers to the equivalent amount of other raw materials required based on the equivalent relationship of chemical reactions, with the basic raw material used in each step as the benchmark (1 equivalent).

[0138] In the context of the present invention, when or whether the words "about" or "approximately" are used, they mean within 10%, suitably within 5%, and especially within 1% of a given value or range. Alternatively, for a person of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error range of the mean. Whenever a number having a value of N is disclosed, any number having a value within N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8% or N+ / -10% will be explicitly disclosed, where "+ / -" means plus or minus.

[0139] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0140] Beneficial Effects

[0141] The compounds shown in this invention have an inhibitory effect on CB1, can inhibit cell proliferation, have good pharmacokinetic characteristics, high bioavailability, good safety, high selectivity, small toxic and side effects, and have the advantages of oral administration, rapid absorption, high clearance rate, etc. At the same time, the compounds of the present invention have good brain penetration and can be used to prevent and / or treat obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout. DETAILED DESCRIPTION

[0142] The content of the present invention will be described in detail below through examples. If no specific conditions are specified in the examples, the experimental method according to conventional conditions is carried out. The examples are given to better illustrate the content of the present invention, but it should not be understood that the content of the present invention is limited to the examples. Those skilled in the art can make non-essential improvements and adjustments to the implementation scheme according to the above invention content, which still belongs to the protection scope of the present invention.

[0143] Unless otherwise specified, raw materials were purchased from Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec and J&K Technology.

[0144] Instrument information and methods

[0145] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

[0146] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0147] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0148] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0149] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0150] Example

[0151] The embodiments of the present invention will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. If no specific conditions are specified in the examples, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be obtained commercially. If not otherwise specified, the ratios or percentages used herein are by weight.

[0152] Example 1 and Example 2

[0153]

[0154] Step 1: Compound 1A (2.00 g, 7.27 mmol), aqueous formaldehyde solution (0.87 g, 29.08 mmol, 37% content), piperidine (62 mg, 0.73 mmol) and glacial acetic acid (87 mg, 1.45 mmol) were added to anhydrous methanol (50 mL) successively, and then heated to 80°C and stirred for 4 hours. After cooling, the mixture was directly concentrated, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 20: 1) to obtain compound 1B (1.9 g, yield: 91%).

[0155] LC-MS (ESI): m / z = 287.0 [M+H] + .

[0156] Step 2: Compound 1B (1.9 g, 6.62 mmol) and hydrazine hydrate (3.31 g, 52.96 mmol, 80% content) were added to anhydrous ethanol (50 mL), and heated to 80°C with nitrogen protection and stirred for 4 hours. After cooling, the mixture was directly filtered, and the filter cake was washed with anhydrous ethanol. The filter cake was collected and dried to obtain compound 1C (1.5 g, yield: 76%).

[0157] LC-MS (ESI): m / z = 301.0 [M+H] + .

[0158] Step 3: Compound 1C (1.5 g, 4.98 mmol) and intermediate 1D (1.41 g, 4.98 mmol, synthesized according to patent WO2022245627A1) were added to toluene (30 mL), heated to 100 ° C and stirred for 2 hours. After cooling, the mixture was directly concentrated, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 1: 1) to obtain compound 1E (2.4 g, yield: 87%).

[0159] LC-MS (ESI): m / z = 552.1 [M+H]+ .

[0160] Step 4: Compound 1E (0.4 g, 0.72 mmol), azetidine (0.12 g, 2.16 mmol), BrettPhos-G3-Pd (33 mg, 0.05 mmol) and cesium carbonate (0.7 g, 2.16 mmol) were added to 1,4-dioxane (20 mL), nitrogen was replaced three times, and the mixture was heated to 95 ° C for 12 h. The mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated. The residue was purified by column chromatography (PE: EA (v: v) = 2: 1) to obtain compound 1F (0.2 g, yield: 52%).

[0161] LC-MS (ESI): m / z = 529.1 [M+H] + .

[0162] Step 5: Add toluene (20 mL) to a 50 mL single-mouth bottle, then add compound 1F (0.15 g, 0.28 mmol) and N,N-diisopropylethylamine (0.18 g, 1.39 mmol), and then slowly dropwise add phosphorus oxychloride (0.11 g, 0.7 mmol). After the addition is complete, the system is protected by nitrogen and stirred at 100 ° C for 1 h. After cooling, the reaction solution is concentrated under reduced pressure to obtain compound 1G (0.1 g crude product), which is directly used in the next step reaction.

[0163] LC-MS (ESI): m / z = 547.1 [M+H] + .

[0164] Step 6: Add compound 1G (100 mg, 0.18 mmol) to a 50 mL single-mouth bottle, dissolve in dichloromethane (10 mL), add acetylguanidine (36 mg, 0.36 mmol), and then add triethylamine (55 mg, 0.54 mmol). After the addition is complete, stir at room temperature for 6 h. Directly concentrate under reduced pressure, add water (20 mL) to the residue, stir for 5 min, extract with dichloromethane 3 times, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography (PE: EA (v: v) = 1: 2) to obtain compound 1H (50 mg, yield: 45%).

[0165] LC-MS (ESI): m / z = 612.2 [M+H] + .

[0166] Step 7: Compound 1H was further subjected to chiral separation to obtain compound 1 (SFC analysis retention time: 1.016 min, 15 mg) and compound 2 (SFC analysis retention time: 1.350 min, 16 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral Whelk Column; mobile phase: A: CO2, B: 0.05% DEA in MeOH; gradient: 5-40% B in A; flow rate: 3 mL / min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters150Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ETOH; Gradient: 40% B gradient elution flow rate: 100mL / min, column temperature: 25°C Wavelength: 220nm Cycle time: 5.5min Sample preparation: Sample concentration 10mg / mL, methanol solution injection: 2.0mL each time. After separation, the fractions were dried by rotary evaporator at a bath temperature of 35°C to obtain compound 1 (15mg) and compound 2 (16mg).

[0167] Compound 1: (SFC analysis retention time: 1.016min) 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.01-7.99(m,2H),7.82-7.80(m,2H),7.33-7.22(m,7H),6.27-6.26(m,2H),4. 89-4.83(m,1H),4.41-4.37(m,1H),3.81-3.77(m,5H),2.29-2.24(m,2H),2.07(s,3H); LC-MS(ESI):m / z=612.2[M+H] + .

[0168] Compound 2: (SFC analysis retention time: 1.350min) 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.01-7.99(m,2H),7.82-7.80(m,2H),7.33-7.22(m,7H),6.27-6.26(m,2H),4. 89-4.83(m,1H),4.41-4.37(m,1H),3.81-3.77(m,5H),2.29-2.24(m,2H),2.07(s,3H); LC-MS(ESI):m / z=612.2[M+H] + .

[0169] Example 3 and Example 4

[0170]

[0171] Step 1: Dissolve compound 3A (10.00 g, 58.77 mmol) and oxalyl chloride (11.19 g, 88.16 mmol) in dichloromethane (100 mL), add DMF (0.43 g, 5.88 mmol) at 0°C, slowly warm to room temperature and stir for 4 hours. Directly concentrate to obtain compound 3B (15 g crude product), which is directly used in the next step reaction.

[0172] Step 2: Sodium pyrithione (8.30 g, 55.67 mmol) was added to carbon tetrachloride (100 mL), DMAP (68 mg, 0.56 mmol) and AIBN (370 mg, 0.23 mmol) were added, heated to 80°C and stirred for 0.5 hours, and a solution of compound 3B (15.00 g, 55.67 mmol) in carbon tetrachloride (20 mL) was slowly added dropwise, and stirred at 80°C for 4 hours. After cooling, water (300 mL) was added to the system, and extracted with ethyl acetate (100 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EA (v:v) = 10:1) to obtain compound 3C (2.8 g, yield: 31.3%).

[0173] 1 H NMR (400MHz, CDCl3) δ3.69 (s, 3H), 2.42 (s, 6H).

[0174] Step 3: Compound 3C (2.80 g, 17.43 mmol) was dissolved in methanol (20 mL), and lithium hydroxide monohydrate (2.19 g, 52.29 mmol) and water (20 mL) were added, and stirred at room temperature for 16 hours. The reaction solution was adjusted to a pH of about 2 with 2N hydrochloric acid, extracted with ethyl acetate (20 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 3D (2.5 g crude product), which was directly used in the next step.

[0175] Step 4: Compound 3D (2.5 g, 17.06 mmol) was dissolved in dichloromethane (50 mL), and HATU (7.78 g, 20.47 mmol), dimethylhydroxylamine hydrochloride (2.35 g, 25.59 mmol) and N,N-diisopropylethylamine (5.18 g, 51.18 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction, 100 mL of water was added to the system, and the mixture was extracted with dichloromethane (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain compound 3E (1.5 g, yield: 46.4%).

[0176] 1 H NMR (400MHz, CDCl3) δ3.66 (s, 3H), 3.18 (s, 3H), 2.47 (s, 6H).

[0177] Step 5: Compound 3E (1.5 g, 7.91 mmol) was dissolved in tetrahydrofuran (20 mL), and benzylmagnesium chloride (1.79 g, 11.87 mmol) was added under ice bath, and the temperature was slowly raised to room temperature for reaction for 4 h. After the reaction, 100 mL of saturated ammonium chloride solution was added to the system, and ethyl acetate (50 mL) was extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain compound 3F (1.2 g, yield: 68.7%).

[0178] 1 H NMR (400MHz, CDCl3) δ7.35-7.27(m,3H),7.17-7.14(m,2H),3.73(s,2H),2.32(s,6H).

[0179] Step 6: Compound 3F (1.20 g, 5.44 mmol), formaldehyde aqueous solution (2.05 g, 27.20 mmol, 40% content), piperidine (69 mg, 0.82 mmol) and glacial acetic acid (72 mg, 1.20 mmol) were added to anhydrous methanol (50 mL) in sequence, and then heated to 80 ° C. and stirred for 4 hours, cooled, concentrated, and directly purified by silica gel column chromatography (PE: EA (v: v) = 20: 1) to obtain compound 3G (1.2 g, yield: 94.8%).

[0180] LC-MS (ESI): m / z = 233.2 [M+H] + .

[0181] Step 7: Compound 3G (1.2 g, 5.16 mmol) and hydrazine hydrate (1.61 g, 25.80 mmol, 80% content) were added to anhydrous ethanol (50 mL), and heated to 80°C with nitrogen protection and stirred for 16 hours. After cooling, the mixture was directly filtered, and the filter cake was washed with anhydrous ethanol and dried to obtain compound 3H (1.5 g crude product), which was directly used in the next step reaction.

[0182] LC-MS (ESI): m / z = 247.1 [M+H] + .

[0183] Step 8: Compound 3H (1.5 g, 6.08 mmol) and intermediate 1D were added to toluene (30 mL), heated to 100° C. and stirred for 16 hours. After cooling, the mixture was directly concentrated, and the residue was separated by silica gel column chromatography (PE:EA (v:v)=1:1) to obtain compound 3I (1.2 g, yield: 39.6%).

[0184] LC-MS (ESI): m / z = 498.2 [M+H] + .

[0185] Step 9: Toluene (20 mL) was added to a 50 mL single-mouth bottle, followed by compound 3I (0.60 g, 1.21 mmol) and N,N-diisopropylethylamine (0.39 g, 3.02 mmol), and then phosphorus oxychloride (0.28 g, 1.81 mmol) was slowly added dropwise. After the addition was completed, the system was protected by nitrogen and stirred at 100° C. for 1 h. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE:EA (v:v) = 2:1) to obtain compound 3J (0.30 g, yield: 48.2%).

[0186] LC-MS (ESI): m / z = 518.1 [M+H] + .

[0187] Step 10: Add compound 3J (300 mg, 0.58 mmol) to a 50 mL single-mouth bottle, add dichloromethane (10 mL) to dissolve, add acetylguanidine (120 mg, 1.16 mmol), then add N,N-diisopropylethylamine (220 mg, 1.74 mmol), and stir at room temperature for 16 h after the addition is complete. Concentrate under reduced pressure, add water (20 mL) to the residue, stir for 5 min, extract with dichloromethane 3 times, separate the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The residue is purified by column chromatography (PE:EA (v:v) = 1:2) to obtain compound 3K (250 mg, yield: 74.3%).

[0188] LC-MS (ESI): m / z = 581.2 [M+H] + .

[0189] Step 11: Compound 3K was further subjected to chiral separation to obtain compound 3 (SFC analysis retention time: 1.548min, 35mg) and compound 4 (SFC analysis retention time: 1.898min, 32mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, Column: Chiral OD Column; Mobile phase: A: CO2, B: 0.05% DEA inisopropanol; Gradient: 5-40% B in A; Flow rate: 3mL / min Column temperature: 35℃ Wavelength: 220nm. SFC preparation method: Instrument: Waters 150Prep-SFC, Column: Chiral OD Column; Mobile phase: A: CO2, B: isopropanol; Gradient: 40% B Gradient elution flow rate: 100mL / min, Column temperature: 25℃ Wavelength: 220nm Cycle time: 5min Sample preparation: Sample concentration 10mg / mL, methanol solution injection: 3.0mL each time. After separation, the fraction was dried by rotary evaporation at a bath temperature of 35°C to obtain Compound 3 (35 mg) and Compound 4 (32 mg).

[0190] Compound 3: (SFC analysis retention time: 1.548min) 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),7.99(d,2H),7.82(d,2H),7.39–7.28(m,5H),4.44-4.33 (m,2H),3.83-3.72(m,1H),2.09-2.05(m,6H),1.92-1.89(m,3H); LC-MS(ESI):m / z=581.2[M+H] + .

[0191] Compound 4: (SFC analysis retention time: 1.898min) 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),7.99(d,2H),7.82(d,2H),7.40–7.28(m,5H),4.45-4.31 (m,2H),3.84-3.77(m,1H),2.09-2.05(m,6H),1.92-1.89(m,3H); LC-MS(ESI):m / z=581.2[M+H] + .

[0192] Example 5 and Example 6

[0193]

[0194] Step 1: Dissolve compound 5A (3.1 g, 10.9 mmol) in dichloromethane (40 mL), then add triethylamine (1.66 g, 16.41 mmol), slowly add ethyl chloroformate (3.56 g, 32.82 mmol) in batches under an ice-water bath, and then react at room temperature overnight. After the reaction is completed, add saturated sodium bicarbonate solution, then adjust the system to be weakly acidic with 2M dilute hydrochloric acid solution, then extract with DCM 3 times, combine the organic phases, concentrate the residue, and purify it by silica gel column chromatography (PE: EA (v: v) = 4: 1) to obtain compound 5B (2 g, yield: 51%).

[0195] LC-MS (ESI): m / z = 356.20 [M+H] + .

[0196] Step 2: Compound 5C (6 g, 40.50 mmol) was dissolved in dichloromethane (50 mL) and DMF (1 mL), and oxalyl chloride (12.85 g, 101.25 mmol) was slowly added in an ice-water bath, stirred for 1 h, and concentrated directly to obtain the acyl chloride intermediate. Then N, O-dimethylhydroxylamine hydrochloride (7.11 g, 72.9 mmol) and triethylamine (12.29 g, 121.5 mmol) were dissolved in dichloromethane (30 mL), and the acyl chloride intermediate obtained above was dissolved in dichloromethane and slowly added, and reacted at room temperature for 2 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by column chromatography (PE: EA (v: v) = 9: 1) to obtain compound 5D (5.5 g, yield: 71%).

[0197] LC-MS (ESI): m / z = 192.10 [M+H] + .

[0198] Step 3: Compound 5D (5.4 g, 28.24 mmol) was dissolved in tetrahydrofuran (60 mL), replaced with nitrogen three times, and then benzylmagnesium bromide (16.55 g, 84.72 mmol) was slowly added in batches under an ice bath, and reacted at room temperature overnight. After the reaction was completed, it was diluted with water, extracted with ethyl acetate three times, and the organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain compound 5E (4.2 g, yield: 67%).

[0199] LC-MS (ESI): m / z = 223.10 [M+H] + .

[0200] Step 4: Compound 5E (4 g, 18.00 mmol), aqueous formaldehyde solution (2.16 g, 72 mmol), acetic acid (0.22 g, 3.6 mmol) and piperidine (0.15 g, 1.8 mmol) were dissolved in methanol (60 mL) and then reacted at 80° C. for 5 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain compound 5F (3.8 g, yield: 90%).

[0201] LC-MS (ESI): m / z = 235.20 [M+H] + .

[0202] Step 5: Compound 5F (3.6 g, 15.37 mmol) was dissolved in ethanol (35 mL) and then hydrazine hydrate (6.16 g, 122.96 mmol) was added and reacted at 80° C. for 4 hours. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with ethanol. The filter cake was collected and dried to obtain compound 5G (2.8 g, yield: 73%).

[0203] LC-MS (ESI): m / z = 249.20 [M+H] + .

[0204] Step 6: Compound 5G (1.2 g, 4.83 mmol) and compound 5B (1.89 g, 5.31 mmol) were dissolved in toluene (40 mL) and reacted at 120° C. for 3 hours. After the reaction was completed, it was directly concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v:v)=4:1) to obtain compound 5H (1.8 g, yield: 67%).

[0205] LC-MS (ESI): m / z = 558.20 [M+H] + .

[0206] Step 7: 5H (1.7 g, 3.05 mmol) was dissolved in toluene (30 mL), and then N,N-diisopropylethylamine (0.99 g, 7.63 mmol) and phosphorus oxychloride (0.70 g, 4.57 mmol) were added, and the mixture was reacted at 100° C. for 3 hours. After the reaction was completed, the mixture was directly concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v:v)=5:1) to obtain compound 5I (0.5 g, yield: 28%).

[0207] LC-MS (ESI): m / z = 576.20 [M+H] + .

[0208] Step 8: 5I (0.2 g, 0.35 mmol), acetylguanidine (0.071 g, 0.70 mmol) and N,N-diisopropylethylamine (0.14 g, 1.05 mmol) were dissolved in N,N-dimethylformamide (8 mL), and then reacted at room temperature for 2 hours. After the reaction was completed, it was diluted with water, extracted with ethyl acetate three times, and the organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (PE: EA (v: v) = 1: 2) to obtain compound 5J (0.1 g, yield: 45%).

[0209] LC-MS (ESI): m / z = 641.1 [M+H] + .

[0210] Step 9: 5J (0.1 g, 0.16 mmol) was further separated by chiral SFC to obtain compound 5 (SFC analysis retention time: 1.816 min, 39 mg) and compound 6 (SFC analysis retention time: 2.139 min, 39 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO2, B: 0.05% DEA in MeOH; gradient: 5-40% B in A; flow rate: 3 mL / min column temperature: 35°C wavelength: 220 nm. SFC preparation method: instrument: Waters150Prep-SFC, column: Chiral IK Column; mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; gradient: 35% B gradient elution. Flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 5.8 min, sample preparation: sample concentration 6.7 mg / mL, methanol solution injection: 3.0 mL each time. After separation, the fractions were dried by rotary evaporator at a bath temperature of 35°C to obtain compound 5 (39 mg) and compound 6 (39 mg).

[0211] Compound 5 (SFC analysis retention time: 1.816 min): 1 H NMR(400MHz, CDCl3)δ8.10(d,2H),7.84(d,2H),7.35-7.28(m,3H),7.18(d,4H),6.87(d,1H ),4.71–4.44(m,2H),4.10(d,1H),3.08(s,4H),2.07(s,3H); LC-MS(ESI):m / z=641.1[M+H] + .

[0212] Compound 6 (SFC analysis retention time: 2.139 min): 1H NMR(400MHz, CDCl3)δ8.10(d,2H),7.83(d,2H),7.34-7.27(m,3H),7.18(d,4H),6.86(d,1H ),4.89–4.43(m,2H),4.09(d,1H),3.08(s,4H),2.06(s,3H); LC-MS(ESI):m / z=641.1[M+H] + .

[0213] Example 7 and Example 8

[0214]

[0215] Step 1: Compound 7A (1.60 g, 8.76 mmol, synthesized according to Angew Chem Int Edit (2016), 55 (11), 3580-3585) was dissolved in DMF (20 mL), and HATU (3.50 g, 9.20 mmol), dimethylhydroxylamine hydrochloride (1.30 g, 13.14 mmol) and N,N-diisopropylethylamine (2.66 g, 26.29 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction, 100 mL of water was added to the system, and the mixture was extracted three times with dichloromethane (50 mL). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was separated by silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain compound 7B (1.4 g, yield: 70.80%).

[0216] LC-MS (ESI): m / z = 226.3 [M+H] + .

[0217] Step 2: Compound 7B (1.40 g, 6.20 mmol) was dissolved in tetrahydrofuran (40 mL), and benzylmagnesium chloride (1.82 g, 9.31 mmol) was slowly added under an ice-salt bath. After the addition was completed, the reaction solution was naturally warmed to room temperature and reacted for 2 h. After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to the system, and extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was separated by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain compound 7C (1.25 g, yield: 78.48%).

[0218] 1 H NMR (400MHz, CDCl3) δ7.34-7.21(m,5H), 4.13-4.09(m,3H), 4.05-4.02(m,3H), 3.74(s,2H).

[0219] Step 3: Compound 7C (1.25 g, 4.87 mmol) and formaldehyde aqueous solution (1.95 g, 19.48 mmol, 30% content) were dissolved in DMF (30 mL), potassium carbonate (1.68 g, 12.17 mmol) was added, and then heated to 90 ° C and stirred for 6 hours. After the reaction was completed, 100 mL of saturated ammonium chloride solution was added to the system, and ethyl acetate (50 mL) was used for extraction four times. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a residue, which was purified by silica gel column chromatography (PE: EA (v: v) = 20: 1) to obtain compound 7D (300 mg, yield: 22.93%).

[0220] 1 H NMR (400MHz, CDCl3) δ7.36-7.34(m,3H),7.31-7.26(m,2H),5.94-5.92(m,2H),4.29-4.26(m,3H),4.12-4.10(m,3H).

[0221] Step 4: Compound 7D (300 mg, 1.12 mmol) and hydrazine hydrate (450 mg, 8.94 mmol, 80% content) were added to anhydrous ethanol (20 mL), heated to 80°C and stirred for 16 hours under nitrogen protection. After cooling and concentration, the mixture was directly filtered, and the filter cake was washed with anhydrous ethanol and dried to obtain compound 7E (300 mg, yield: 95.04%), which was directly used in the next step reaction.

[0222] LC-MS (ESI): m / z = 283.1 [M+H] + .

[0223] Step 5: Compound 7E (300 mg, 1.06 mmol) and intermediate 1D (400 mg, 1.28 mmol) were added to toluene (30 mL), heated to 100° C. and stirred for 16 hours. After cooling, the mixture was directly concentrated, and the residue was separated by silica gel column chromatography (PE:EA (v:v)=1:1) to obtain compound 7F (420 mg, yield: 74.14%).

[0224] LC-MS (ESI): m / z = 533.9 [M+H] + .

[0225] Step 6: Compound 7F (120 mg, 0.22 mmol) and N,N-diisopropylethylamine (60 mg, 0.45 mmol) were dissolved in toluene (20 mL), and then phosphorus oxychloride (70 mg, 0.45 mmol) was slowly added dropwise. After the addition was completed, the system was protected by nitrogen and stirred at 100°C for 2 h. After cooling, the reaction solution was concentrated under reduced pressure to obtain compound 7G (130 mg crude product), which was directly used in the next step.

[0226] LC-MS (ESI): m / z = 552.2 [M+H] + .

[0227] Step 7: Compound 7G (130 mg, 0.22 mmol) was dissolved in dichloromethane (10 mL), acetylguanidine (25 mg, 0.26 mmol) was added, and then N,N-diisopropylethylamine (70 mg, 0.54 mmol) was added, and stirred at room temperature for 16 h after the addition was completed. The reaction solution was concentrated under reduced pressure to obtain a residue, and the obtained residue was purified by column chromatography (PE: EA (v: v) = 1: 5) to obtain compound 7H (110 mg, yield: 82.36%).

[0228] LC-MS (ESI): m / z = 617.0 [M+H] + .

[0229] Step 8: Compound 7H was further separated by chiral SFC to obtain compound 7 (SFC analysis retention time: 2.071 min, 13.20 mg) and compound 8 (SFC analysis retention time: 2.318 min, 11.40 mg). SFC analysis method: instrument: SHIMADZU LC-30AD sf, column: Chiral WHEIK Column; mobile phase: A: CO2, B: 0.05% DEA inisopropanol; gradient: 5-40% B in A; flow rate: 3 mL / min column temperature: 35°C; wavelength: 220 nm. SFC preparation method: Instrument: Waters 150Prep-SFC, Column: Chiral WHEIK Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O inisopropanol; Gradient: 35% B gradient; Elution flow rate: 100mL / min, Column temperature: 25°C; Wavelength: 220nm Cycle time: 6.0min; Sample preparation: Sample concentration 2.5mg / mL, acetonitrile solution injection: 2.0mL each time. After separation, the fraction was dried by rotary evaporator at a bath temperature of 35°C to obtain compound 7 (13.20mg) and compound 8 (11.40mg).

[0230] Compound 7 (SFC analysis retention time: 2.071 min): 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.99-7.97(m,2H),7.82-7.80(m,2H),7.36–7.32(m,2H),7.29-7.24(m,1H),7.19-7.17(m,2H),6. 07-5.91(m,4H),5.86-5.71(m,2H),4.80-4.72(m,1H),4.37-4.34(m,1H),3.74-3.72(m,1H),2.06(s,3H); LC-MS(ESI):m / z=617.1[M+H] + .

[0231] Compound 8 (SFC analysis retention time: 2.318 min): 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.99-7.97(m,2H),7.82-7.80(m,2H),7.36–7.32(m,2H),7.29-7.24(m,1H),7.19-7.17(m,2H),6. 10-5.91(m,4H),5.86-5.66(m,2H),4.80-4.72(m,1H),4.37-4.31(m,1H),3.74-3.72(m,1H),2.06(s,3H); LC-MS(ESI):m / z=617.1[M+H] + .

[0232] Example 9 and Example 10

[0233]

[0234] Step 1: Compound 9A (1.0 g, 4.03 mmol) was dissolved in dichloromethane (20 mL), and HATU (1.84 g, 4.84 mmol), dimethylhydroxylamine hydrochloride (0.47 g, 4.84 mmol) and triethylamine (1.22 g, 12.09 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 h. After the reaction, 50 mL of water was added to the system, and the mixture was extracted with dichloromethane (20 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (PE: EA (v: v) = 3: 1) to obtain compound 9B (1.1 g, yield: 93.7%).

[0235] LC-MS (ESI): m / z = 292.2 [M+H] + .

[0236] Step 2: Compound 9B (1.1 g, 3.78 mmol) was dissolved in tetrahydrofuran (20 mL), and benzylmagnesium chloride (0.86 g, 5.67 mmol) was added under ice bath, and the temperature was slowly raised to room temperature for reaction for 4 h. After the reaction, 100 mL of saturated ammonium chloride solution was added to the system, and ethyl acetate (50 mL) was extracted, and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (PE: EA (v: v) = 10: 1) to obtain compound 9C (0.80 g, yield: 65.7%).

[0237] LC-MS (ESI): m / z = 323.1 [M+H] + .

[0238] Step 3: Compound 9C (0.70 g, 2.17 mmol), formaldehyde aqueous solution (0.81 g, 10.85 mmol, 40% content), piperidine (28 mg, 0.33 mmol) and glacial acetic acid (29 mg, 0.48 mmol) were added to anhydrous methanol (20 mL) in sequence, and then heated to 80°C with stirring for 4 hours, cooled, concentrated, and the residue was purified by silica gel column chromatography (PE:EA (v:v) = 20:1) to obtain compound 9D (0.72 g, yield: 99.1%).

[0239] LC-MS (ESI): m / z = 335.2 [M+H] + .

[0240] Step 4: Compound 9D (0.72 g, 2.15 mmol) and hydrazine hydrate (0.67 g, 10.75 mmol, 80% content) were added to anhydrous ethanol (20 mL), and heated to 80°C with nitrogen protection and stirred for 16 hours. After cooling, the mixture was directly filtered, and the filter cake was washed with anhydrous ethanol and dried to obtain compound 9E (0.80 g crude product), which was directly used in the next step reaction.

[0241] LC-MS (ESI): m / z = 349.1 [M+H] + .

[0242] Step 5: Compound 9E (0.80 g, 2.30 mmol) and intermediate 1D (0.65 g, 2.30 mmol) were added to toluene (20 mL), heated to 100° C. and stirred for 16 hours. After cooling, the mixture was directly concentrated, and the residue was separated by silica gel column chromatography (PE:EA (v:v)=1:1) to obtain compound 9F (0.60 g, yield: 43.58%).

[0243] LC-MS (ESI): m / z = 600.2 [M+H] + .

[0244] Step 6: Toluene (20 mL) was added to a 50 mL single-mouth bottle, followed by compound 9F (0.50 g, 0.83 mmol) and N,N-diisopropylethylamine (0.27 g, 2.07 mmol), and then phosphorus oxychloride (0.19 g, 1.24 mmol) was slowly added dropwise. After the addition was completed, the system was protected by nitrogen and stirred at 100° C. for 1 h. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EA (v: v) = 2: 1) to obtain compound 9G (0.30 g, yield: 58.2%).

[0245] LC-MS (ESI): m / z = 618.1 [M+H] + .

[0246] Step 7: Add compound 9G (300 mg, 0.48 mmol) to a 50 mL single-mouth bottle, add dichloromethane (10 mL) to dissolve, add acetylguanidine (97 mg, 0.96 mmol), then add N,N-diisopropylethylamine (190 mg, 1.44 mmol), stir at room temperature for 16 h after the addition is complete. Concentrate under reduced pressure, add water (20 mL) to the residue, stir for 5 min, extract with dichloromethane 3 times, separate the organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography (PE:EA (v:v) = 1:2) to obtain compound 9H (200 mg, yield: 60.6%).

[0247] LC-MS (ESI): m / z = 683.1 [M+H] + .

[0248] Step 8: Compound 9H was further separated by chiral SFC to obtain compound 9 (SFC analysis retention time: 1.740 min, 82 mg) and compound 10 (SFC analysis retention time: 2.342 min, 94 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, column: Chiral IK Column; mobile phase: A: CO2, B: 0.05% DEA inisopropanol; gradient: 5-40% B in A; flow rate: 3 mL / min column temperature: 35°C wavelength: 220 nm. SFC preparation method: Instrument: Waters 150Prep-SFC, column: Chiral IK Column; mobile phase: A: CO2, B: isopropanol; gradient: 55% B gradient elution flow rate: 100 mL / min, column temperature: 25°C wavelength: 220 nm cycle time: 4.5 min sample preparation: sample concentration 10 mg / mL, methanol solution injection: 4.0 mL each time. After separation and freeze-drying, compound 9 (82 mg) and compound 10 (94 mg) were obtained.

[0249] Compound 9 (SFC analysis retention time: 1.740 min): 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.02(d,2H),7.88–7.83(m,4H),7.68(d,2H),7.35–7.23(m,5H) ,5.10-5.06(m,1H),4.56-4.50(m,1H),3.92-3.88(m,1H),2.09(s,3H); LC-MS(ESI):m / z=683.1[M+H] + .

[0250] Compound 10 (SFC analysis retention time: 2.342 min): 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.02(d,2H),7.88–7.83(m,4H),7.69(d,2H),7.35–7.23(m,5H) ,5.10-5.06(m,1H),4.56-4.50(m,1H),3.92-3.88(m,1H),2.09(s,3H); LC-MS(ESI):m / z=683.0[M+H] + .

[0251] The synthetic routes of the compounds in other embodiments, such as Tables 1 and 2, refer to the synthetic routes of Examples 1-10.

[0252] Biological test evaluation

[0253] The present invention is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present invention.

[0254] 1. TR-FRET cAMP method to determine the effect of compounds on CB1 receptors

[0255] Prepare 1×Stimulation Buffer according to the instructions of the LANCE Ultra cAMP kit for use. Prepare 10× working solution of the test substance. Treat the cells with trypsin, resuspend them in 1×Stimulation Buffer after centrifugation, and inoculate them in a 384-well plate after counting. Add the diluted compounds to the corresponding experimental wells and incubate at 37°C for 10 minutes. Then add Forskolin solution and incubate at 37°C for 30 minutes to induce cAMP production. Dilute Eu-cAMP to 4× working concentration with detection buffer and add it to the corresponding experimental wells. Dilute ULight-anti-cAMP to 4× working concentration with detection buffer and add it to the corresponding experimental wells. Centrifuge and incubate at room temperature. After incubation, use a multi-function microplate reader to detect the readings at 665nm and 620nm. Calculate IC using GraphPad Prism software 50 value.

[0256] The compounds of the present invention, such as the compounds in the examples, have an IC of less than 1000 nM for the cAMP signaling pathway downstream of the CB1 receptor. 50 Values, IC values ​​of some preferred compounds 50 <100 nM, IC of some more preferred compounds 50 <50 nM, IC of some more preferred compounds 50 <10 nM, IC of some more preferred compounds 50 <1nM. IC of some specific compounds 50 The values ​​are shown in Table 1, where AA represents IC 50 <1nM, A represents 1nM≤IC 50 <10nM, B represents 10nM≤IC 50 <50nM, C represents 50nM≤IC 50 <100nM, D represents 100nM≤IC 50 <1000nM.

[0257] Table 1 IC values ​​of compounds on cAMP signaling pathway downstream of CB1 receptor 50 value

[0258]

[0259] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a strong antagonistic effect on the cAMP signaling pathway downstream of the CB1 receptor. The IC 50 Less than 1 nM, for example, the IC of compound 6 50 The IC of compound 10 was 0.3765 nM. 50 It is 0.3893nM.

[0260] 2. NanoBiT method to determine the effect of compounds on CB1 recruitment of arrestin2

[0261] On the first day, HEK293T cells were cultured to 80% confluence, and the cells were collected by trypsin digestion and counted and inoculated into 6-well plates. On the second day, the cell density reached about 70%, and the receptor and βarrestin2 plasmid were co-transfected by Lipo3000. On the third day, 24 hours after transfection, the cells were digested and re-plated into 96-well plates overnight. On the fourth day, 10× working solution of the test substance was prepared, and the detection substrate and the prepared compound were added. Incubate in a 96-well plate, and read the luminescence signal value with an enzyme reader. IC was calculated using GraphPad Prism software. 50 value.

[0262] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a strong antagonistic effect on the β-arrestin signaling pathway downstream of the CB1 receptor. 3. TR-FRET cAMP method to determine the effect of compounds on CB2 receptors

[0263] A Chinese hamster ovary (CHO) cell line that stably expresses CB2 receptors was used. In the TR-FRET cAMP experiment, the positive compound and the test substance were first diluted in a gradient manner, and then the treated cells were counted and inoculated into a 384-well plate. Next, the diluted compound was added to the corresponding experimental wells and incubated at 37°C for 10 minutes. After the incubation, 4 μL of agonist solution was added to the corresponding experimental wells and incubated for 30 minutes to induce cAMP production. After the incubation, Eu-cAMP and ULight prepared in advance were added. TM -anti-cAMP was added to all experimental wells, centrifuged and incubated at room temperature for 1 hour, and the values ​​were read at 665nm and 620nm under excitation at a wavelength of 330nm using an ELISA reader. IC was calculated using GraphPad Prism software 50 value.

[0264] Conclusion: The compounds of the present invention, such as the compounds in the examples, have weak antagonistic effects on the cAMP signaling pathway downstream of the CB2 receptor.

[0265] 4. Pharmacokinetics test in mice

[0266] 1. Experimental animals: Male C57 mice, 18-25 g, purchased from Beijing Huafukang Biotechnology Co., Ltd.

[0267] 2. Experimental design: On the day of the experiment, C57 mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration. The administration was performed according to Table 2.

[0268] Table 2 Dosage information

[0269]

[0270] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC

[0271] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0272] Before and after drug administration, 0.06 mL of blood was collected from the eye sockets under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7 and 24 h. In addition, brain tissue and abdominal adipose tissue were collected from the gavage group at 1, 4, and 24 h after drug administration to observe the distribution of drugs in the brain and adipose tissue of mice. The brain tissue was rinsed with cold saline to remove residual blood on the surface, and after absorbing the water, it was weighed and homogenized; the adipose tissue was rinsed with cold saline to remove residual blood and hair on the surface, and after absorbing the water, it was weighed and homogenized. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC-MS / MS.

[0273] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic characteristics in mice. Moreover, the example compounds have low exposure in the brain tissue of mice, with a lower brain / plasma ratio, and high exposure in the adipose tissue, with a higher fat / plasma ratio.

[0274] 5. Pharmacokinetics test in rats

[0275] 1. Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0276] 2. Experimental design: 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 one day before administration and fed 4 hours after administration.

[0277] Before and after drug administration, 0.15 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0278] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in rats.

[0279] 6. Beagle dog pharmacokinetic test

[0280] 1. Experimental animals: Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0281] 2. Test method: On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.

[0282] Before and after administration, 1 mL of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0283] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in beagle dogs.

[0284] 7. Monkey Pharmacokinetics Test

[0285] 1. Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0286] 2. Experimental method: On the day of the experiment, monkeys were randomly divided into groups according to their body weight. They were fasted but not watered for 14-18 hours one day before administration and fed 4 hours after administration.

[0287] Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS.

[0288] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic characteristics in monkeys.

[0289] 8. hERG potassium channel action test

[0290] 1. Experimental platform: electrophysiological manual patch clamp system

[0291] 2. Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0292] 3. Experimental methods: CHO (Chinese Hamster Ovary) cells that stably express hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (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 applied with a step voltage from -80mV to +20mV for 2s, then repolarized to -50mV, and returned to -80mV after 1s. This voltage stimulation was applied every 10s, and the administration process was started after the hERG potassium current was confirmed to be stable (at least 1 minute). Each test concentration of the compound was applied for at least 1 minute, and at least 2 cells (n≥2) were tested for each concentration.

[0293] 4. Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis. The degree of inhibition of hERG potassium current (peak value of hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0294] Inhibition%=[1–(I / Io)]×100%

[0295] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.

[0296] Compound IC 50 The results were calculated using GraphPad Prism 5 software by fitting the following equation:

[0297] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0298] Among them, X is the Log value of the test sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0299] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on hERG potassium channel current.

[0300] 9. CYP450 enzyme inhibition test

[0301] The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS), the changes in CYP enzyme activity were determined, and the IC 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0302] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory activity on the five isozymes of human liver microsomal cytochrome P450 (CYP).

[0303] 10. Liver microsome stability test

[0304] In this study, liver microsomes from five species, including humans, dogs, rats and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0305] At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS / MS. The ln value of the drug residual rate in the incubation system and the incubation time were used to calculate T. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and liver intrinsic clearance CL int(Liver) .

[0306] Conclusion: The compounds of the present invention, such as the compounds in the examples, showed good metabolic stability in the liver microsome stability test.

[0307] 11. Caco-2 permeability test

[0308] The experiment used a monolayer of Caco-2 cells and three parallel incubations were used in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (2μM) or the control compound digoxin (10μM), nadolol (2μM) and metoprolol (2μM) was added to the dosing port hole on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port hole. After incubation for 2 hours at 37±1°C, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS / MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficient of transport from the apical side of the monolayer cells to the basolateral side and from the basolateral side to the apical side, thereby calculating the efflux rate. The leakage of fluorescent yellow was used to evaluate the integrity of the monolayer cells after 2 hours of incubation.

[0309] Conclusion: The compounds of the present invention, such as the compounds of the examples, showed good permeability in the Caco-2 permeability test.

[0310] 12. Weight loss efficacy test of compounds in diet-induced obesity model

[0311] The diet-induced obesity model was performed using male C57BL / 6J mice aged 8-10 weeks. During the model induction period, mice were fed a high-fat diet purchased from Research Diets, item number D12492, with 60% of calories being fat. After 14 weeks of continuous induction, obese mice were induced, weighing about 50 grams. After the induction was completed, compound administration began, 3 mg / kg QD for 20 consecutive days, and body weight was measured once a day.

[0312] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good weight loss effect in a diet-induced obese mouse model.

Claims

1. A compound represented by general formula (IA), its tautomer, stereoisomer or a pharmaceutically acceptable salt thereof: in: Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-14 membered heteroaryl; Each R1 is independently -L1-R 1a ; L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy group substitution; R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 deuterium, halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-6 Alkyl, -C(O)(CH2) m C 3-8 Cycloalkyl or -C(O)(CH2) m (3-8 membered heterocycloalkyl) group substitution; R2 and R3 are each independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, -SF5, -SCF3, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -OC 3-8 Cycloalkyl or -O-(3-8 membered heterocycloalkyl), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 R b replace; R b for deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-6 Alkyl, halogenated C 1-6 Alkyl, deuterated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy or deuterated C 1-6 substituted with an alkoxy group; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, 2, 3; The conditions are: (1) when ring A is phenyl, R1 is not halogen; (2) when R3 is -CF3, and p is 0 and q is 1, Not for 2. The compound according to claim 1, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, wherein the general formula (IA) is further represented by the general formula (I): in: Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-14 membered heteroaryl; Each R1 is independently -L1-R 1a ; L1 is a bond or C 1-6 Alkylene, any one or more methylene groups in the alkylene are optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy group substitution; R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 Alkylamino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, deuterated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-6 Alkyl, -C(O)(CH2) m C 3-8 Cycloalkyl or -C(O)(CH2) m (3-8 membered heterocycloalkyl) group substitution; n is 0, 1, 2, or 3; m is 0, 1, 2, or 3.

3. The compound according to claim 1 or 2, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) Ring A is C 3-10 Cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6 Cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl, preferably C 3-8 Cycloalkyl, C 3-6 Cycloalkylphenyl, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl and phenyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, phenyl, naphthyl, benzoC 4-6 Cycloalkyl, benzo 4-6 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, 5-6 membered heteroaryl, 5-6 membered heteroaryl and C 4-6 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl or 5-6 membered heteroaryl and 5-6 membered heteroaryl, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolanyl, azopentyl, oxetanyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, Thiphenyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl, benzocyclopentyl or benzotetrahydrofuranyl, more preferably cyclopropyl, bicyclo[1.1.1]pentane, cubanyl, azetidinyl, oxetanyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, benzocyclobutyl or benzocyclopentyl; (2) L1 is a bond; (3) L1 is -O-, -(CH2) m -、-O(CH2) m -、-NH(CH2) m -、-CO(CH2) m -, -CONH(CH2) m -or-NHCO(CH2) m -, preferably -O-, -CH2-, -OCH2-, -COCH2-, -CONH- or -NHCO-, more preferably -O-; (4)R 1a Hydrogen, deuterium, halogen, hydroxyl, thiol, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-3 Alkyl, -C(O)(CH2) m C 3-6 Cycloalkyl or -C(O)(CH2) m (3-6 membered heterocycloalkyl) group, preferably R 1a For hydrogen, halogen, SF5, SCF3, C 1-3 Alkyl, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl may be further substituted with 1-3 halogens, SF5, SCF3, C 1-3 Alkyl, halogenated C 1-3 Alkyl or halogenated C 1-3 Alkoxy substituted, more preferably R 1a For hydrogen, halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C 3-6 The cycloalkyl or 3-6 membered heterocycloalkyl is optionally further substituted with 1-3 halogen or C 1-3 Alkyl substituted, more preferably R 1a For hydrogen, halogen, C 1-3 The cyclopropyl, azetidinyl or oxetanyl groups are optionally further substituted with 1 to 3 halogen or C 1-3 Alkyl substitution.

4. The compound according to claim 2 or 3, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in the general formula (II): Among them: Ring A, L1 and R 1a As claimed in claim 2 or 3.

5. The compound according to claim 2, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in the general formula (III): in: L1 is a bond or C 1-6 Alkylene, any methylene in the alkylene is optionally replaced by C(O), S(O)2, NH or O, and the alkylene is optionally further replaced by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy groups are preferably substituted with a bond, -O-, -(CH2) m -、-O(CH2) m -、-NH(CH2) m -、-CO(CH2) m -, -CONH(CH2) m -or-NHCO(CH2) m -, more preferably a bond or -O-; R 1a For hydrogen, deuterium, halogen, hydroxyl, cyano, amino, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl or 5-10 membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-3 selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)(CH2) m C 1-3 Alkyl, -C(O)(CH2) m C 3-6 Cycloalkyl or -C(O)(CH2) m (3-6 membered heterocycloalkyl) is substituted with hydrogen, deuterium, halogen, hydroxyl, mercapto, cyano, amino, carboxyl, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Alkylamino, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy, deuterated C 1-3 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubic alkyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxetanyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl, wherein the alkyl, alkoxy, alkylthio, alkylamino, cyclopropyl, cyclopentyl, cyclohexyl, oxetan ... butyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, cubanyl, azetidinyl, oxetanyl, oxolyl, azopentyl, oxhexyl, azohexyl, piperidinyl, piperazinyl, morpholinyl, phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, pyridinyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, benzocyclobutyl or benzocyclopentyl is optionally further substituted by 1-3 selected from halogen, hydroxy, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy or deuterated C 1-3 The alkyl group is substituted, more preferably cyclopropyl, azetidinyl or oxetanyl, optionally further substituted by 1-3 groups selected from halogen, hydroxyl, cyano, oxo, SF5, SCF3, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated C 1-3 Alkyl, halogenated C 1-3 Alkoxy or deuterated C 1-3 The alkyl group is substituted, preferably cyclopropyl, azetidinyl or oxetanyl, optionally further substituted with 1-3 halogen or C 1-3 Alkyl substitution.

6. The compound according to any one of claims 1 to 5, its tautomer, stereoisomer or pharmaceutically acceptable salt thereof, characterized in that: Select one of the structures in Table 1 or Table 2.

7. A pharmaceutical composition comprising a therapeutically effective dose of the compound as claimed in any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

8. The pharmaceutical composition according to claim 7, comprising 1-1500 mg of the compound shown in any one of claims 1-6, its stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.

9. Use of the compound according to any one of claims 1 to 6, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 7 or 8 in the preparation of a medicament, preferably a medicament for preventing and / or treating CB1-mediated diseases.

10. The use according to claim 9, wherein the CB1-mediated disease is obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.

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