Cannabinoid receptor 1 antagonist and use thereof

Abstract

Disclosed are a cannabinoid receptor 1 antagonist and a use thereof, and in particular, disclosed are a compound represented by formula (I), formula (IV), formula (IV-a), or formula (IV-b), and a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, and a use thereof as a CB1 antagonist in preparation of drugs for treating related diseases, wherein each group in formula (I), formula (IV), formula (IV-a), and formula (IV-b) is as defined in the description.

Description

Cannabinoid receptor 1 antagonist and its application Technical Field

[0001] The present invention relates to a cannabinoid receptor 1 (CB1) antagonist, its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, cocrystals or deuterated substances, and use thereof in preparing drugs 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, exerting 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 appetite and food intake by inhibiting the endocannabinoid system, thereby reducing weight. 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 However, it was withdrawn from the market due to its central nervous system side effects.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 aims to provide a CB1 antagonist with the advantages of novel structure, good efficacy, high bioavailability, few side effects, rapid onset and long-lasting effect.

[0004] The present invention relates to a compound represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), and its stereoisomers and pharmaceutically acceptable salts.

[0005] wherein R1, R2, and R3 are each independently selected from 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 Halogenated alkyl, 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 with 1-5 Ra; in certain embodiments, R1, R2, R3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C2-4 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 are optionally further substituted with 1-5 Ra; in certain embodiments, R1, R2, R3 are each independently selected from 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 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R1, R2, R3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, wherein the alkyl, alkenyl, alkynyl is optionally further substituted with 1-5 Ra; in certain embodiments, R1, R2, R3 are each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, wherein the alkyl is optionally further substituted with 1-5 Ra; in certain embodiments, R1, R3 are each independently selected from deuterium, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, wherein the alkyl group is optionally further substituted with 1-5 Ra;

[0006] In certain embodiments, R2 is selected from hydrogen;

[0007] In certain embodiments, R1 is selected from halogen; R3 is selected from C 1-4 In certain embodiments, R1 is selected from halogen, C 1-4 Alkyl, C 2-4 Alkynyl; in certain embodiments, R1 is selected from F, Cl, Br, methyl, ethyl, acetylene;

[0008] In certain embodiments, R3 is selected from deuterium, halogen, C 1-4 Halogenated alkyl, -SF5, C 2-4 Alkenyl, C2-4 Alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

[0009] In certain embodiments, R1 is selected from F, Cl, Br; R3 is selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F; In certain embodiments, R1 is selected from F, Cl, Br, methyl; R3 is selected from -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, vinyl, ethynyl, 1-fluorovinyl; In certain embodiments, R1 is selected from Cl; R3 is selected from -CF3; In certain embodiments, R1 is selected from halogen, C 1-3 Alkyl; in certain embodiments, R1 is selected from Cl; in certain embodiments, R1 is selected from -CH3; in certain embodiments, R1 is selected from acetylene;

[0010] In certain embodiments, R3 is selected from halogen, SF5, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl; in certain embodiments, R3 is selected from F, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, vinyl, ethynyl, 1-fluorovinyl, SF5;

[0011] R A Selected from -L1-W1-L2-W2-R A1 、-C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 In certain embodiments, R A Selected from -L1-W1-L2-W2-R A1 In certain embodiments, R A Selected from -W1-L2-W2-R A1 In certain embodiments, R A Selected from -W1-W2-R A1 In certain embodiments, R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-NR W1 -R A1 、-N=C(NH2)-NR W1 -NR W1 C(O)-R A1 In certain embodiments, R A1 Selected from C 1-4Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R W1 Selected from H, C 1-2 alkyl;

[0012] In certain embodiments, Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Alkyl, -S(O)2NH2, -C(O)C 3-6 Cycloalkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 1-4 Alkyl, -S(=O)(=NH)-C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 substituted with an alkyl group;

[0013] In certain embodiments, R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0014] L1, L2 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH2;

[0015] In certain embodiments, L1 is selected from a bond;

[0016] In certain embodiments, L2 is selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, 3-6 membered cycloalkyl, the alkyl, cycloalkyl is optionally further substituted by 1-4 substituents selected from halogen; in certain embodiments, L2 is selected from a bond, C 1-2 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each is independently selected from F, Cl, =O, methyl, ethyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl is optionally further substituted with 1-4 substituents selected from F, Cl; in certain embodiments, L2 is selected from a bond;

[0017] W1 and W2 are each independently selected from a bond, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 In certain embodiments, W1 and W2 are each independently selected from a bond, -O-, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 In certain embodiments, W1 and W2 are each independently selected from a bond, -NR W1 -, -(C=O)NR W1 -、-NR W1 (C=O)-、-NR W1 -NR w1(C=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 In certain embodiments, W1 and W2 are each independently selected from a bond, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 In certain embodiments, W1 and W2 are each independently selected from a bond, -NR W1 -、-NR W1 -NR w1 (C=O)-、-NR W1 (C=O)-、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-; In certain embodiments, W1 is selected from -NR W1 -、-NR W1 S(O)2-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-; in certain embodiments, W2 is selected from a bond, -NR W1 -、-NR W1 (C=O)-、-NR W1 -NR w1 (C=O)-;

[0018] In certain embodiments, with the proviso that L1, L2, W1, and W2 are not simultaneously a bond; in certain embodiments, with the proviso that L2, W1, and W2 are not simultaneously a bond; in certain embodiments, with the proviso that W1 and W2 are not simultaneously a bond;

[0019] R A1 Selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, 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 with 1-5 Ra; in certain embodiments, R A1 Selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 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 with 1-5 Ra; in certain embodiments, R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; in certain embodiments, R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

[0020] In certain embodiments, R A1 Selected from cyano, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

[0021] In certain embodiments, R A1is selected from cyano, methyl, ethyl, propyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxhexyl, thihexyl, azetyl, azohexyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxazolyl, Optionally further substituted with 1-5 Ra;

[0022] In certain embodiments, R A1 is selected from cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxhexyl, azetyl, azohexyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Optionally further substituted with 1-5 Ra;

[0023] In certain embodiments, R A1 is selected from cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, azetidinyl, oxetanyl, azetyl, azetyl, phenyl, Optionally further substituted with 1-5 Ra;

[0024] R W1 Selected from H, C 1-4 Alkyl, halogen, cyano;

[0025] In certain embodiments, R W1 Selected from H, C 1-2 Alkyl, halogen, cyano; in certain embodiments, R W1 Selected from H, C 1-2 alkyl, cyano; in certain embodiments, R W1 Selected from H, cyano;

[0026] Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkyl subunit, C 1-6 Haloalkyl subunit, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C 3-8 Cycloalkyl or -S(O)2C 1-4 Alkyl, 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 In certain embodiments, Ra is selected from deuterium, halogen, hydroxy, cyano, oxo, C 1-4 Alkyl, C 1-3 Alkyl subunit, C 1-3 Haloalkyl subunit, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 In certain embodiments, Ra is selected from deuterium, halogen, hydroxy, oxo, C 1-4 Alkyl, C 1-3 Alkyl subunit, C 1-3 Haloalkyl subunit, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 3-6 Cycloalkyl or -S(O)2C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0027] In certain embodiments, Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4Deuterated alkyl, -S(O)2NH2 or -S(O)2NHC 1-4 Alkyl, 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 In certain embodiments, Ra is selected from deuterium, halogen, cyano, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 In certain embodiments, Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2 or -S(O)2NHC 1-4 Alkyl, wherein the alkyl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 In certain embodiments, Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 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 In certain embodiments, Ra is selected from deuterium, halogen, cyano, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 In certain embodiments, Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl; in certain embodiments, Ra is selected from oxo, methyl, ethyl, propyl, -CD3, -CHD2, -CH2D, -CH2CD3, -CH2CHD2, -CH2CH2D, -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, methylidene, ethylidene, 1-methylethylidene;

[0028] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl;

[0029] In certain embodiments, alternatively, two R s on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 In certain embodiments, alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 Alkenyl, C 2-6 In certain embodiments, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 Alkenyl, C 2-6 In certain embodiments, two Ra on the same carbon atom together with the carbon atom to which they are attached form a C 2-6 alkenyl;

[0030] In certain embodiments, R A Selected from

[0031] In certain embodiments, R A Selected from

[0032] In certain embodiments, R A Selected from:

[0033] R A2 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-6 substituted with an alkoxy group;

[0034] In certain embodiments, R A2 Selected from C3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group;

[0035] In certain embodiments, R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl , oxo, methylidene, ethylidene, 1-methylethylidene, fluoromethylidene, difluoromethylidene, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, -CH2F, -CHF2, -CF3, -CH -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -OCD2CH2D, -OCD2CHD2, -OCD2CD3;

[0036] R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group;

[0037] In certain embodiments, R A2 Selected from C 3-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group;

[0038] In certain embodiments, R A2 is selected from cyclopropyl, cyclobutyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl, azopentyl, oxhexyl, azohexyl, morpholinyl, piperazinyl, the cyclopropyl, cyclobutyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl, azopentyl, oxhexyl, azohexyl, morpholinyl, piperazinyl, the cyclopropyl, cyclobutyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, oxetanyl, azetidinyl, oxolanyl , azetidinyl, oxacyclohexyl, azacyclohexyl, morpholinyl, piperazinyl are optionally further substituted by 1-3 groups selected from methyl, ethyl, F, Cl, oxo, methylidene, ethylidene, 1-methylethylidene, fluoromethylidene, difluoromethylidene, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3;

[0039] X1, X2, X3, X4 are selected from CH or N; in some embodiments, X1, X2, X3, X4 are selected from CH or N, and at least one of X1, X2, X3, X4 is selected from N; in certain embodiments, X1, X2 are selected from CH, X3, X4 are selected from N; in certain embodiments, X1, X2 are selected from N, X3, X4 are selected from CH; in certain embodiments, X1 is selected from N, X2, X3, X4 are selected from CH; in certain embodiments, X2 is selected from N, X1, X3, X4 are selected from CH; in certain embodiments, X3 is selected from N, X1, X2, X4 are selected from CH; in certain embodiments, X4 is selected from N, X1, X2, X3 are selected from CH;

[0040] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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;

[0041] In certain embodiments, alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0042] In certain embodiments, alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0043] In certain embodiments, alternatively, two R3 on different carbon atoms together with the carbon atom to which they are attached form C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, C 1-4 substituted with an alkyl group;

[0044] n is selected from 0, 1, 2, 3, 4, or 5; in certain embodiments, n is selected from 0, 1, 2, or 3; in certain embodiments, n is selected from 0 or 1; in certain embodiments, n is selected from 0;

[0045] m is selected from 1, 2, 3, 4, or 5; in certain embodiments, m is selected from 1, 2, or 3; in certain embodiments, m is selected from 1 or 2; in certain embodiments, m is selected from 1;

[0046] k is selected from 1, 2, 3, 4, or 5; in certain embodiments, k is selected from 1, 2, or 3; in certain embodiments, k is selected from 1 or 2; in certain embodiments, k is selected from 1;

[0047] The compound of formula (I) of the present invention satisfies the following conditions:

[0048] (1)R A Not for

[0049] (2)R A Selected from When R3 is not C 2-6 Alkynyl and C 1-6 deuterated alkyl;

[0050] (3) When m and k are both selected from 1, R1 and R3 are not simultaneously selected from halogen;

[0051] In some embodiments, the compounds of the present invention are not selected from the following structures

[0052] Specifically, one embodiment of the present invention relates to a compound represented by formula (I), formula (IV), formula (IV-a), formula (IV-b), and stereoisomers and pharmaceutically acceptable salts thereof.

[0053] wherein R1, R2, and R3 are each independently selected from 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 Halogenated alkyl, C 3-8Cycloalkyl, -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 with 1-5 Ra;

[0054] R A Selected from -L1-W1-L2-W2-R A1 、-C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ;

[0055] L1, L2 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH2;

[0056] W1 and W2 are each independently selected from a bond, -O-, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0057] The condition is that L1, L2, W1, and W2 are not bonds at the same time;

[0058] R A1 Selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C3-8 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 with 1-5 Ra;

[0059] R W1 Selected from H, C 1-4 Alkyl, halogen, cyano;

[0060] Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkyl subunit, C 1-6 Haloalkyl subunit, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C 3-8 Cycloalkyl or -S(O)2C 1-4 Alkyl, 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;

[0061] R A2 Selected from C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-6 substituted with an alkoxy group;

[0062] X1, X2, X3, X4 are selected from CH or N;

[0063] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl;

[0064] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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;

[0065] n is selected from 0, 1, 2, 3, 4 or 5;

[0066] m is selected from 1, 2, 3, 4 or 5;

[0067] k is selected from 1, 2, 3, 4 or 5;

[0068] And the compound of formula (I) satisfies the following conditions:

[0069] (1)R A Not for

[0070] (2)R A Selected from When R3 is not C 2-6 Alkynyl and C 1-6 deuterated alkyl;

[0071] (3) When m and k are both selected from 1, R1 and R3 are not both selected from halogen.

[0072] Specifically, one embodiment of the present invention relates to a compound represented by formula (I) or formula (IV), its stereoisomers, and pharmaceutically acceptable salts.

[0073] wherein R1, R2, and R3 are each independently selected from 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 Halogenated alkyl, 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 with 1-5 Ra;

[0074] R A Selected from -L1-W1-L2-W2-R A1 、-C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ;

[0075] L1, L2 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH2;

[0076] W1 and W2 are each independently selected from a bond, -O-, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0077] The condition is that L1, L2, W1, and W2 are not bonds at the same time;

[0078] R A1 Selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 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 with 1-5 Ra;

[0079] R W1 Selected from H, C 1-4 Alkyl, halogen, cyano;

[0080] Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkyl subunit, C 1-6 Haloalkyl subunit, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C 3-8 Cycloalkyl or -S(O)2C 1-4Alkyl, 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;

[0081] R A2 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-6 substituted with an alkoxy group;

[0082] X1, X2, X3, and X4 are selected from CH or N, and at least one of X1, X2, X3, and X4 is selected from N;

[0083] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl;

[0084] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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;

[0085] n is selected from 0, 1, 2, 3, 4 or 5;

[0086] m is selected from 1, 2, 3, 4 or 5;

[0087] k is selected from 1, 2, 3, 4 or 5;

[0088] And the compound of formula (I) satisfies the following conditions:

[0089] (1)R A Not for

[0090] (2)R A Selected from When R3 is not C 2-6 Alkynyl and C 1-6 deuterated alkyl;

[0091] (3) When m and k are both selected from 1, R1 and R3 are not both selected from halogen.

[0092] Another embodiment of the present invention relates to a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts.

[0093] wherein R1, R2, and R3 are each independently selected from 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 Halogenated alkyl, 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 with 1-5 Ra;

[0094] Provided that: when m and k are both selected from 1, R1 and R3 are not simultaneously selected from halogen;

[0095] R A Selected from -L1-W1-L2-W2-R A1 、-C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ;

[0096] L1, L2 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH2;

[0097] W1 and W2 are each independently selected from a bond, -O-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0098] The condition is that L1, L2, W1, and W2 are not bonds at the same time;

[0099] R A1 Selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 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 with 1-5 Ra;

[0100] R W1 Selected from H, C 1-4 Alkyl, halogen, cyano;

[0101] Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C 3-8 Cycloalkyl or -S(O)2C 1-4 Alkyl, 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;

[0102] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl;

[0103] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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;

[0104] n is selected from 0, 1, 2, 3, 4 or 5;

[0105] m is selected from 1, 2, 3, 4 or 5;

[0106] k is selected from 1, 2, 3, 4 or 5;

[0107] The conditions are:

[0108] (1)R A Not for

[0109] (2)R A Selected from When R3 is not C2-6 Alkynyl and C 1-6 Deuterated alkyl.

[0110] Another embodiment of the present invention relates to a compound represented by formula (IV), its stereoisomers, and pharmaceutically acceptable salts.

[0111] wherein R1, R2, and R3 are each independently selected from 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 Halogenated alkyl, 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 with 1-5 Ra;

[0112] Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkyl subunit, C 1-6 Haloalkyl subunit, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C 3-8 Cycloalkyl or -S(O)2C 1-4Alkyl, 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;

[0113] R A2 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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;

[0114] X1, X2, X3, X4 are selected from CH or N; in some embodiments, X1, X2, X3, X4 are selected from CH or N, and at least one of X1, X2, X3, X4 is selected from N;

[0115] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl;

[0116] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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;

[0117] n is selected from 0, 1, 2, 3, 4 or 5;

[0118] m is selected from 1, 2, 3, 4 or 5;

[0119] k is selected from 1, 2, 3, 4 or 5.

[0120] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0121] R1, R2, R3 are each independently selected from 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 with 1-5 Ra;

[0122] n is selected from 0, 1, 2 or 3;

[0123] m is selected from 1, 2 or 3;

[0124] k is selected from 1, 2 or 3.

[0125] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0126] R A Selected from -W1-L2-W2-R A1、 -C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ;

[0127] L2 is selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen;

[0128] W1 and W2 are each independently selected from a bond, -NR W1 -, -(C=O)NR W1 -、-NR W1 (C=O)-、-NR W1 -NRw1 (C=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0129] The condition is that L2, W1, and W2 are not bonds at the same time;

[0130] R A1 Selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 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 with 1-5 Ra;

[0131] R W1 Selected from H, C 1-2 Alkyl, halogen, cyano;

[0132] Ra is selected from deuterium, halogen, hydroxy, cyano, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-3 Alkyl subunit, C 1-3 Haloalkyl subunit, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C3-8 Cycloalkyl, -S(O)2C 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0133] R A2 Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group;

[0134] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl;

[0135] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

[0136] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0137] R A Selected from -W1-W2-R A1、-C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 , preferably R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-N=C(NH2)-NR W1 R A1 、-N=C(NH2)-R A1 、-NR W1 -R A1 、-N=S(=O)(C 1-6 alkyl)-R A1 、-NR W1 S(O)2-NR W1 C(O)-R A1 、-NR W1 -S(O)(=NH)-R A1 、-N=C(CH3)-NR W1 R A1 、-N=C(NH2)-NR W1 -NR W1 C(O)-R A1 、-C 3-6 Cycloalkyl-R A1 、-3-6 membered heterocycloalkyl-R A1 ;

[0138] W1 and W2 are each independently selected from a bond, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0139] The condition is that W1 and W2 are not bonds at the same time;

[0140] R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8Aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

[0141] R W1 Selected from H, C 1-2 Alkyl, cyano;

[0142] Ra is selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, C 1-3 Alkyl subunit, C 1-3 Haloalkyl subunit, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 3-6 Cycloalkyl or -S(O)2C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0143] R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group;

[0144] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 3-6 Cycloalkyl;

[0145] Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

[0146] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0147] R A Selected from -W1-L2-W2-R A1、 -C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ;

[0148] L2 is selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen;

[0149] W1 and W2 are each independently selected from a bond, -NR W1 -、-CONR W1 -、-NR W1 CO-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0150] The condition is that L2, W1, and W2 are not bonds at the same time;

[0151] RA1 Selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 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 with 1-5 Ra;

[0152] R W1 Selected from H, C 1-2 Alkyl, halogen, cyano;

[0153] Ra is selected from deuterium, halogen, cyano, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0154] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl.

[0155] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0156] R A Selected from -W1-W2-R A1 、-C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 , preferably R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-N=C(NH2)-NR W1 R A1 、-N=C(NH2)-R A1 、-NR W1 -R A1 、-N=S(=O)(C 1-6 alkyl)-R A1 、-NR W1 S(O)2-NR W1 C(O)-R A1 、-NR W1 -S(O)(=NH)-R A1 、-N=C(CH3)-NR W1 R A1 、-C 3-6 Cycloalkyl-R A1 、-3-6 membered heterocycloalkyl-R A1 ;

[0157] W1 and W2 are each independently selected from a bond, -NR W1 -、-CONR W1 -、-NR W1 CO-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0158] The condition is that W1 and W2 are not bonds at the same time;

[0159] R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

[0160] R W1Selected from H, C 1-2 Alkyl, cyano;

[0161] Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2 or -S(O)2NHC 1-4 alkyl;

[0162] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl.

[0163] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0164] R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-N=C(NH2)-NR W1 R A1 、-N=C(NH2)-R A1 、-NR W1 -R A1 、-N=S(=O)(C 1-6 alkyl)-R A1 、-NR W1 S(O)2-NR W1 C(O)-R A1 、-NR W1 -S(O)(=NH)-R A1 、-N=C(CH3)-NR W1 R A1 、、-C 3-6 Cycloalkyl-R A1 、-3-6 membered heterocycloalkyl-R A1 ;

[0165] R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

[0166] R W1 Selected from H, C 1-2 Alkyl, cyano;

[0167] Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2 or -S(O)2NHC 1-4 alkyl.

[0168] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0169] R1 is selected from halogen, C 1-4 Alkyl, C 2-4 Alkynyl;

[0170] R2 is selected from hydrogen;

[0171] R3 is selected from deuterium, halogen, C 1-4 Halogenated alkyl, -SF5, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

[0172] Alternatively, two R3 on different carbon atoms together with the carbon atom to which they are attached form C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, C 1-4 substituted with an alkyl group;

[0173] X1, X2, X3, X4 are selected from CH or N;

[0174] R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-NR W1 -R A1 、-N=C(NH2)-NR W1 -NRW1 C(O)-R A1 ;

[0175] R A1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra;

[0176] R W1 Selected from H, C 1-2 alkyl;

[0177] Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Alkyl, -S(O)2NH2, -C(O)C 3-6 Cycloalkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 1-4 Alkyl, -S(=O)(=NH)-C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 substituted with an alkyl group;

[0178] R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

[0179] In some specific embodiments, the compounds represented by formula (I), (II), (III), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0180] R1 is selected from halogen, C 1-4 Alkyl, C 2-4 Alkynyl;

[0181] R2 is selected from hydrogen;

[0182] R3 is selected from deuterium, halogen, C 1-4Halogenated alkyl, -SF5, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

[0183] Alternatively, two R3 on different carbon atoms together with the carbon atom to which they are attached form C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, C 1-4 substituted with an alkyl group;

[0184] R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-NR W1 -R A1 、-N=C(NH2)-NR W1 -NR W1 C(O)-R A1 ;

[0185] R A1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein said alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra;

[0186] R W1 Selected from H, C 1-2 alkyl;

[0187] Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Alkyl, -S(O)2NH2, -C(O)C 3-6 Cycloalkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 1-4 Alkyl, -S(=O)(=NH)-C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 substituted with an alkyl group.

[0188] In some specific embodiments, the compounds represented by formula (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0189] R1 is selected from halogen, C1-4 Alkyl, C 2-4 Alkynyl;

[0190] R2 is selected from hydrogen;

[0191] R3 is selected from deuterium, halogen, C 1-4 Halogenated alkyl, -SF5, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra;

[0192] Alternatively, two R3 on different carbon atoms together with the carbon atom to which they are attached form C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, C 1-4 substituted with an alkyl group;

[0193] X1, X2, X3, X4 are selected from CH or N;

[0194] R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

[0195] In some specific embodiments, the compounds represented by formula (I), (II), (III), (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0196] R A Selected from:

[0197] R A2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl , oxo, methylidene, ethylidene, 1-methylethylidene, fluoromethylidene, difluoromethylidene, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, -CH2F, -CHF2, -CF3, -CH -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -OCD2CH2D, -OCD2CHD2, -OCD2CD3.

[0198] In some specific embodiments, the compounds represented by formula (I), (II), (III), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0199] R A Selected from:

[0200] In some specific embodiments, the compounds represented by formula (IV), (IV-a), (IV-b), their stereoisomers, and pharmaceutically acceptable salts, wherein

[0201] R A2is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl , oxo, methylidene, ethylidene, 1-methylethylidene, fluoromethylidene, difluoromethylidene, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, -CH2F, -CHF2, -CF3, -CH -OCHF2, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -OCD2CH2D, -OCD2CHD2, -OCD2CD3.

[0202] Another embodiment of the present invention relates to a compound represented by formula (I), its stereoisomers, and pharmaceutically acceptable salts.

[0203] wherein R1, R2, and R3 are each independently selected from 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 Halogenated alkyl, 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 with 1-5 Ra;

[0204] Provided that: when m and k are both selected from 1, R1 and R3 are not simultaneously selected from halogen;

[0205] R A Selected from -L1-W1-L2-W2-R A1 ;

[0206] L1, L2 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen, CN, OH, and NH2;

[0207] W1 and W2 are each independently selected from a bond, -O-, -S-, -NR W1 -、-CONR W1 -、-NR W1 CO-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0208] The condition is that L1, L2, W1, and W2 are not bonds at the same time;

[0209] R A1 Selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, 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 with 1-5 Ra;

[0210] R W1 Selected from H, C 1-4 Alkyl, halogen, cyano;

[0211] Ra is selected from deuterium, halogen, hydroxy, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, 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 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;

[0212] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl;

[0213] n is selected from 0, 1, 2, 3, 4 or 5;

[0214] m is selected from 1, 2, 3, 4 or 5;

[0215] k is selected from 1, 2, 3, 4 or 5;

[0216] Provided that: the compound is not selected from the following structures

[0217] In some embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein

[0218] R1, R2, R3 are each independently selected from 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 with 1-5 Ra;

[0219] n is selected from 0, 1, 2 or 3;

[0220] m is selected from 1, 2 or 3;

[0221] k is selected from 1, 2 or 3;

[0222] Provided that: when m and k are selected from 1, R1 and R3 are not simultaneously selected from halogen.

[0223] In some embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein:

[0224] R A Selected from -W1-L2-W2-R A1 ;

[0225] L2 is selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, the alkylene, alkenylene optionally further 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted with 1-4 substituents selected from halogen;

[0226] W1 and W2 are each independently selected from a bond, -NR W1 -、-CONR W1 -、-NR W1 CO-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0227] The condition is that L2, W1, and W2 are not bonds at the same time;

[0228] R A1 Selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, 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 with 1-5 Ra;

[0229] R W1 Selected from H, C 1-2 Alkyl, halogen, cyano;

[0230] Ra is selected from deuterium, halogen, cyano, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group;

[0231] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl, C 2-6 Alkynyl.

[0232] In some embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein:

[0233] R A Selected from -W1-W2-R A1 ;

[0234] W1 and W2 are each independently selected from a bond, -NR W1 -、-CONR W1 -、-NR W1 CO-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-;

[0235] The condition is that W1 and W2 are not bonds at the same time;

[0236] R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8Aryl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra;

[0237] R W1 Selected from H, C 1-2 Alkyl, cyano;

[0238] Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 alkyl halide;

[0239] Alternatively, two Ra on the same carbon atom together with the carbon atom to which they are attached form C 2-6 Alkenyl.

[0240] In some embodiments, the compound of formula (I), its stereoisomers, and pharmaceutically acceptable salts, wherein,

[0241] R A Selected from:

[0242] In some embodiments, the compound of formula (I), (II), (III), (IV), (IV-a), (IV-b), stereoisomers, and pharmaceutically acceptable salts thereof, wherein the compound is selected from one of the structures in Table 1:

[0243] Table 1

[0244] In some embodiments, the compound of formula (I), (II), (III), (IV), (IV-a), (IV-b), stereoisomers, and pharmaceutically acceptable salts thereof, wherein the compound is selected from one of the structures in Table 2:

[0245] Table 2

[0246] The present invention also relates to a pharmaceutical composition, comprising: the above-mentioned compound, its stereoisomers, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and / or excipients.

[0247] The present invention also relates to the use of the compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts or compositions containing the compound of the present invention in the preparation of drugs for treating diseases mediated by CB1 receptors.

[0248] The present invention relates to the use of a compound represented by general formula (I) and its stereoisomers, pharmaceutically acceptable salts or a composition containing the compound of the present invention in the preparation of a CB1 antagonist.

[0249] In some embodiments of the present invention, the CB1-mediated disease is obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.

[0250] The present invention also relates to a method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of any one of the compounds of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, preferably 1-1000 mg. The disease is preferably obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia, or gout. In some embodiments, the mammal of the present invention includes a human.

[0251] As used herein, an "effective amount" or "therapeutically effective amount" refers to the administration of a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1000 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, 1-20 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-25 0mg, 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, 10-1000mg, 10-900 mg, 10-800mg, 10-700mg, 10-600mg, 10-500mg, 10-450mg, 10-400mg, 10-300mg, 10-250mg, 10-200mg, 10-150mg, 10-125mg, 10-100mg, 10-90 mg, 10-80mg, 10-70mg, 10-60mg, 10-50mg, 10-40mg, 10-30mg, 10-20mg; 20-1000mg, 20-900mg, 20-800mg, 20-700mg, 20-600mg, 20-500mg, 2 0-400mg, 20-350mg, 20-300mg, 20-250mg, 20-200mg, 20-150mg, 20-125mg, 20-100mg, 20-90mg, 20-80mg, 20-70mg, 20-60mg, 20-50mg, 20-40 mg, 20-30mg; 50-1000mg, 50-900mg, 50-800mg, 50-700mg, 50-600mg, 50-500mg, 50-400mg, 50-300mg, 50-250mg, 50-200mg, 50-150mg, 50-1 25mg, 50-100mg; 100-1000mg, 100-900mg, 100-800mg, 100-700mg, 100-600mg, 100-500mg, 100-400mg, 100-300mg, 100-250mg, 100-200mg;.

[0252] In some embodiments, the pharmaceutical composition includes but is not limited to: 1-1000 mg, 5-500 mg, 10-250 mg, 50-250 mg, 100-200 mg, 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, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 120 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg of a compound of the invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

[0253] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, preferably 1-1000 mg. The disease is preferably obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia, or gout.

[0254] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof at a daily dose of 1-1000 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to: 1-1000 mg / day, 1-300 mg / day, 5-500 mg / day, 10-500 mg / day , 10-400 mg / day, 10-300 mg / day, 10-100 mg / day, 20-400 mg / day, 20-200 mg / day, 20-100 mg / day, 50-500 mg / day, 50-250 mg / day, 50-200 mg / day, 50-150 mg / day, 50-100 mg / day, 100-500 mg / day, 100-300 mg / day, 100-200 mg / day;

[0255] In some embodiments, daily doses include but are not limited to: 1 mg / day, 2.5 mg / day, 5 mg / day, 10 mg / day, 12.5 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 120 mg / day, 150 mg / day, 200 mg / day, 250 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 1000 mg / day.

[0256] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, solvate, or pharmaceutically acceptable salt is the same as that in the above-mentioned pharmaceutical composition.

[0257] The amount of the compound of the present invention or its stereoisomers, tautomers, solvates, or pharmaceutically acceptable salts in the present invention is calculated in each case based on the free base form.

[0258] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0259] Synthesis route

[0260] Those skilled in the art can prepare the compounds of the present invention by combining known organic synthesis techniques, using commercially available chemicals and / or compounds described in the chemical literature as starting materials. "Commercially available chemicals" are obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0261] Specific and similar reactants can be selectively identified by indexes of known chemical substances prepared by the American Chemical Society's Chemical Abstracts Service, 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 facilities, many of which standard chemical supply facilities (e.g., those listed above) offer custom synthesis services.

[0262] the term

[0263] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly 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 document, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0264] 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 having 1 to 6 carbon atoms (ie, C 1-6 Alkyl), most preferably an alkyl group having 1 to 3 carbon atoms (i.e., C 1-3 Non-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. Alkyl groups 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 is not further substituted.

[0265] 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.

[0266] The term "alkenyl" refers to a straight or branched chain 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 still 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; alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment. When the alkenyl group is substituted with a substituent, the substituent may not be further substituted.

[0267] The term "alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond (C≡C), typically 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 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. Alkynyl groups may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. When the alkynyl group is substituted with a substituent, the substituent may not be further substituted.

[0268] 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 from 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 3-12cycloalkyl), 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., C 3-5 Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, and cyclooctyl. Non-limiting examples of polycyclic cycloalkyl groups include spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0269] The term "spiroalkyl" refers to a polycyclic group in which the rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring 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 (ie, C 6-14 Spirocycloalkyl), more preferably a spirocycloalkyl having 7 to 10 ring atoms (ie, C 7-10 Spirocycloalkyl). The spirocycloalkyl group is classified 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.

[0270] The term "fused cycloalkyl" refers to an all-carbon polycyclic group 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., C 5-20 The fused cycloalkyl group may contain one or more double bonds, but no ring 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 (ie, C 7-10The 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, 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.

[0271] 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 bridged cycloalkyl), more preferably a bridged cycloalkyl having 7 to 10 ring atoms (ie, 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.

[0272] The cycloalkyl group may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is the cycloalkyl group. The cycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. When the cycloalkyl group is substituted with a substituent, the substituent may not be further substituted.

[0273] 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, excluding the ring portion 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 to 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 to 4, 1 to 3 or 1 to 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 to 4, 1 to 3 or 1 to 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 to 4, 1 to 3 or 1 to 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.

[0274] 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 from 0 to 2) heteroatoms, excluding the ring portion 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 group preferably has 6 to 14 ring atoms (i.e., 6-14 membered spiroheterocycloalkyl), more preferably 7 to 10 ring atoms (i.e., 7-10 membered spiroheterocycloalkyl). The spiroheterocycloalkyl group is divided into monospiroheterocycloalkyl group, bispiroheterocycloalkyl group or polyspiroheterocycloalkyl group according to the number of spiro atoms shared between rings, preferably monospiroheterocycloalkyl group or bispiroheterocycloalkyl 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 monospiroheterocycloalkyl group.

[0275] The term "fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and which has from 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 from 0 to 2) heteroatoms, excluding the ring portion 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 group preferably has 6 to 14 ring atoms (i.e., a 6-14-membered fused heterocycloalkyl group), and more preferably has 7 to 10 ring atoms (i.e., a 7-10-membered fused heterocycloalkyl group). 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.

[0276] The term "bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, having from 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 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 from 0 to 2) heteroatoms, excluding the ring portion 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 group preferably has a bridged heterocycloalkyl group with 6 to 14 ring atoms (i.e., a 6-14-membered bridged heterocycloalkyl group), and more preferably a bridged heterocycloalkyl group with 7 to 10 ring atoms (i.e., a 7-10-membered bridged heterocycloalkyl group). According to the number of constituent rings, it is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups, preferably bicyclic bridged heterocycloalkyl groups or tricyclic bridged heterocycloalkyl groups.

[0277] The heterocycloalkyl group may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heterocycloalkyl group. The heterocycloalkyl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. When the heterocycloalkyl group is substituted with a substituent, the substituent may not be further substituted.

[0278] The term "aryl" refers to an all-carbon monocyclic group (i.e., monocyclic aryl) or a fused polycyclic group (i.e., polycyclic aryl) 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 group having 6 to 10 carbon atoms (i.e., C 6-10 The monocyclic aryl group is, for example, phenyl. Non-limiting examples of the polycyclic aryl group include: naphthyl, anthracenyl, phenanthrenyl, etc.

[0279] 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 membered heterocycloalkyl, benzo 5-6 membered heteroaryl, further preferably benzocyclobutyl, benzocyclopentyl, benzocyclohexyl, benzoazetidinyl, benzoxetanyl, benzoxolyl, benzoazepine, benzooxetanyl, benzoazepine, benzothiophenyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzopyridinyl, benzopyrimidinyl, benzopyridonyl, benzopyrazinyl, benzopyridazinyl. Described aryl can be optionally substituted or unsubstituted, and when substituted, substituent can be substituted on any usable point of attachment. When described aryl is substituted by substituent, described substituent is no longer further substituted.

[0280] The term "heteroaryl" refers to a monocyclic heteroaryl group (i.e., a monocyclic heteroaryl) or a fused polycyclic heteroaryl 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) 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 the ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. The heteroaryl preferably has a heteroaryl of 5 to 10 ring atoms (i.e., a 5-10 membered heteroaryl). The monocyclic heteroaryl preferably has a heteroaryl of 5 to 6 ring atoms (i.e., a 5-6 membered heteroaryl), non-limiting examples of which include furyl, pyranyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyrrolyl, pyridyl, pyrimidinyl, pyridonyl, pyrazinyl, pyridazinyl, etc. The polycyclic heteroaryl, preferably a 5-6 membered heteroaryl, a 5-6 membered heteroaryl, a 5-10 membered heteroaryl, 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, benzothiophenyl, thienophenyl, quinazolinyl, benzothiazolyl, carbazolyl, thienopyridyl, pyridothiphenyl, pyridopyrrolyl and the like.

[0281] 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, 4-6 membered heterocycloalkyl, 5-6 membered heteroarylphenyl. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. When the heteroaryl group is substituted with a substituent, the substituent may not be further substituted.

[0282] 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 (ie, C 1-6 Alkoxy), most preferably alkoxy having 1 to 3 carbon atoms (ie C 1-3Alkoxy groups are substituted with a substituent. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. When the alkoxy group is substituted with a substituent, the substituent may not be further substituted.

[0283] 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 an alkylthio group having 1 to 6 carbon atoms (ie, C 1-6 alkylthio), more preferably alkylthio having 1 to 3 carbon atoms (i.e., C 1-3

[0014] alkylthio). Non-limiting examples include methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like. The alkylthio group may be optionally substituted or unsubstituted. 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.

[0284] 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.

[0285] 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, etc., preferably fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2-difluoroethyl.

[0286] 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.

[0287] The term "mercapto" refers to -SH.

[0288] The term "hydroxy" refers to -OH.

[0289] The term "nitro" refers to -NO2.

[0290] The term "amino" refers to -NH2.

[0291] The term "cyano" refers to -CN.

[0292] The term "carboxy" refers to -C(O)OH.

[0293] The term "oxo" or "oxo" refers to =0.

[0294] The term "carbonyl" refers to C=O; C=O is synonymous with C(O) in this description;

[0295] The term "aminoacyl" refers to -C(O)NH2.

[0296] The term "sulfonyl" refers to -S(O)2; in this description, -S(O)2 is synonymous with -S(=O)2;

[0297] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium groups, wherein alkyl is as defined above.

[0298] The term "deuterated alkoxy" refers to an alkoxy group substituted with one or more deuterium groups, wherein alkoxy is as defined above.

[0299] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0300] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0301] The term "alkylamino" refers to an alkyl-NH- group, wherein alkyl is as defined above.

[0302] The terms "include," "comprising," "having," "containing," or "involving," and their variations herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps. Those skilled in the art will understand that the above terms, such as "comprising," encompass the meaning of "consisting of."

[0303] 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.

[0304] When the lower limit and upper limit of a numerical range are disclosed, any value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to mean each value and range encompassed within the broader range.

[0305] Herein, "Z" and "-Z-" both represent the same specific group and can be used interchangeably.

[0306] The expression mn used herein refers to the range from m to n and the subranges and individual point values ​​therein. 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 encompassed, 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 subranges 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 subranges 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 herein should be understood in a similar manner.

[0307] As used herein, different expressions such as “X is selected from A, B or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all convey the same meaning, that is, X can be any one or more of A, B, and C.

[0308] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both the occurrence of the event or circumstance and the non-occurrence of the event or circumstance. For example, "cycloalkyl optionally substituted with alkyl" means that alkyl may but need not be present, and the description includes both the case where the cycloalkyl is substituted with alkyl and the case where the cycloalkyl is not substituted with alkyl.

[0309] The terms "substituted" and "substituted" refer to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom 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 a substituent is described as not present, it is understood that the substituent can be one or more hydrogen atoms, provided that the structure allows the compound to reach a stable state. When each carbon atom in a group is described as optionally substituted by a heteroatom, the proviso 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 1-6Alkylcarbamoyl, N-carbamoyl, nitro, silyl, sulfinyl, sulfonyl, sulfoxide, halo 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 1-6 Alkyl), -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.

[0310] If a substituent is described as being "optionally substituted with...", the substituent may be unsubstituted or substituted. If an atom or group is described as being optionally substituted with one or more of the substituents listed, one or more hydrogen atoms on the atom or group may be replaced by independently selected, optional substituents. When the substituent is oxo (i.e., =0), this 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.

[0311] 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.

[0312] 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 a compound's composition or structure, 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 at each occurrence are independent of each other.

[0313] 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 enantiomerically or diastereomerically enriched mixtures, 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 within the scope of the present invention. In certain embodiments, preferred compounds are those isomeric compounds that exhibit superior biological activity. Purified or partially purified isomers and stereoisomers of the compounds of the present invention, or racemic mixtures or diastereomeric mixtures, are also within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0314] The compounds of the present invention also include their tautomers. The tautomers of the compounds disclosed herein may be "NH2" tautomers, or "NH" tautomers, or a combination of the two. For example:

[0315] The hydrogen atoms described in the present invention can all 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.

[0316] 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. 35 S. 36 S. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and131 I, etc., preferably deuterium.

[0317] Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed by the present disclosure. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom, where the deuterium replacement can be partial or complete. Partial deuterium replacement refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0318] In the compounds of the present 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).

[0319] The term "pharmaceutically acceptable" refers to a substance that is, within the scope of normal medical judgment, suitable for use in 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.

[0320] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are safe and effective when used in mammals and have the desired biological activity.

[0321] The term "pharmaceutical composition" refers to a composition containing one or more compounds described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, 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, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0322] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0323] 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 intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular injection or infusion), topical, rectal administration, and the like. In particular, injection or oral administration.

[0324] As used herein, the term "treating" includes alleviating, alleviating 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 amelioration of the condition being treated. In addition, a therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and although the patient may still have the underlying disease, an improvement in the patient's disease is observed. A prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a certain disease, or when a patient develops one or more physiological symptoms of a disease, even though the disease has not yet been diagnosed.

[0325] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating or preventing a target disorder, disease, or condition. The term "neuropsychiatric disorder" refers to a general term encompassing neurological and / or psychiatric disorders.

[0326] With respect to a drug, pharmaceutical unit, or active ingredient, the terms "effective amount," "therapeutically effective amount," or "prophylactically effective amount" refer to a sufficient amount of the drug or pharmaceutical agent to achieve the desired effect with acceptable side effects. The determination of an effective amount varies from person to person, depending on the individual's age and general condition, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine testing.

[0327] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein 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.).

[0328] 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.

[0329] "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).

[0330] 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 those of ordinary skill in the art, the term "about" or "approximately" means within an acceptable standard error of the mean. Whenever a number having a value of N is disclosed, any number having a value of N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8% or N + / - 10% is expressly disclosed, where "+ / -" means plus or minus.

[0331] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0332] Figure 1 shows the weight loss efficacy test results of the compound in a diet-induced obesity model. DETAILED DESCRIPTION

[0333] The present invention will be described in detail below through examples. Where specific conditions are not specified in the examples, the experimental methods are carried out according to conventional conditions. The examples are provided to better illustrate the present invention, but it should not be understood that the present invention is limited to the examples. Any non-essential improvements and adjustments made by those skilled in the art to the embodiments based on the above invention are still within the scope of protection of the present invention.

[0334] 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.

[0335] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0336] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0337] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0338] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0339] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0340] Example 1 and Example 2

[0341] Step 1: Dissolve compound 1A (2.00 g, 7.71 mmol) in dichloromethane (20 mL) and add triethylamine (1.17 g, 11.57 mmol). After purging the nitrogen atmosphere three times, slowly add cyclopropanecarbonyl chloride (1.05 g, 10.02 mmol) dropwise in an ice bath. After addition, stir the mixture in an ice bath for 2 h. Quench the reaction with water (30 mL) and extract twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 90:10) to afford compound 1B (2.2 g, yield: 100%). LC-MS (ESI): m / z = 328.2 [M+H] + .

[0342] Step 2: Dissolve compound 1B (400 mg, 1.22 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 6 h. The reaction solution was concentrated under reduced pressure to obtain compound 1C (600 mg), which was used directly in the next reaction. LC-MS (ESI): m / z = 128.1 [M+H] + .

[0343] Step 3: Compound 1D (230 mg, 0.44 mmol, synthesized with reference to patent WO2022245627) was dissolved in dichloromethane (30 mL). Compound 1C (390 mg, 1.1 mmol) and triethylamine (220 mg, 2.17 mmol) were added, respectively, and stirred at room temperature overnight. The reaction was quenched with water (40 mL) and extracted three times with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate = 60:40) to obtain compound 1E (200 mg).

[0344] Step 4: Chiral resolution of compound 1E afforded compounds 1 (SFC retention time: 0.942 min, 70 mg) and 1-2 (SFC retention time: 1.635 min, 80 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 254 nm. SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 35% B; Flow rate: 100 mL / min, Column temperature: 25°C, Wavelength: 254 nm, Cycle time: 6.0 min. Sample preparation: Sample concentration: 10 mg / mL, ethanol solution injection: 1.5 mL per injection.

[0345] Compound 1 (SFC analysis retention time: 0.942 min): 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.03-8.01(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.38(m,2H),7.33-7.22(m, 5H),5.05-5.01(m,1H),4.52-4.46(m,1H),3.89-3.86(m,1H),1.99-1.97(m,1H),0.92-0.84(m,4H); LC-MS(ESI):m / z=617.1[M+H] + .

[0346] Compound 2 (SFC analysis retention time: 1.635 min): 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),8.03-8.01(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.38(m,2H),7.33-7.22(m, 5H),5.05-5.01(m,1H),4.52-4.46(m,1H),3.89-3.86(m,1H),1.99-1.97(m,1H),0.92-0.84(m,4H); LC-MS(ESI):m / z=617.1[M+H] + .

[0347] Example 3

[0348] Step 1: Dissolve compound 3A (99.17 mg, 0.78 mmol, synthesized according to patent WO201711552) in isopropanol (6 mL) and add N,N-diisopropylethylamine (201.61 mg, 1.56 mmol). The mixture is allowed to react at room temperature for 3 h. Then, a solution of compound 1D (207 mg, 0.39 mmol) in dichloromethane (10 mL) is added dropwise at -25°C and allowed to react overnight at room temperature. After completion of the reaction, the reaction solution is concentrated, and the resulting residue is purified by preparative HPLC to yield compound 3 (210 mg, 87% yield).

[0349] 1 H NMR(400MHz,DMSO-d6)δ8.01-7.99(d,2H),7.88-7.86(d,2H),7.54-7.51(d,2H),7.39-7.37(d,2H),7.34-7.28(m,4H),7.26-7.22(m ,1H),5.07-5.02(m,1H),4.53(s,1H),3.88(s,1H),3.43(s,2H),2.62-2.58(t,2H),1.94-1.87(m,2H); LC-MS(ESI):m / z=617.3[M+H] + .

[0350] Example 4 and Example 5

[0351] Step 1: Dissolve compound 4A (5.00 g, 39.65 mmol) in DMF (40 mL) and add potassium carbonate (13.70 g, 99.12 mmol). After purging the nitrogen atmosphere three times, deuterated iodomethane (5.75 g, 39.65 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the reaction was stirred at room temperature for 2 h. Dilute the reaction with water (100 mL) and extract three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 80:20) to afford compound 4B (2.00 g, yield: 35.24%). LC-MS (ESI): m / z = 144.1 [M+H] + .

[0352] Step 2: Compound 4B (2.00 g, 13.97 mmol) was dissolved in tetrahydrofuran (15 mL) and water (5 mL). Lithium hydroxide monohydrate (1.76 g, 41.91 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with water (10 mL) and adjusted to pH 5 with dilute hydrochloric acid. The mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 4C (1.20 g, yield: 66.52%). LC-MS (ESI): m / z = 130.1 [M+H] + .

[0353] Step 3: Compound 4C (1.20 g, 9.29 mmol) was dissolved in DMF (40 mL), and HATU (3.89 g, 10.22 mmol) and triethylamine (2.35 g, 23.23 mmol) were added. The atmosphere was purged with nitrogen and stirred at room temperature for 15 minutes before the addition of 1,3-di(tert-butoxycarbonyl)guanidine (2.89 g, 11.15 mmol). After the addition was complete, the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (100 mL) and extracted three times with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 80:20) to afford compound 4D (1.50 g, yield: 43.58%). LC-MS (ESI): m / z = 371.3 [M+H] + .

[0354] Step 4: Dissolve compound 4D (1.50 g, 4.05 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (5 mL), and stir at room temperature for 4 h. The reaction solution was concentrated under reduced pressure to obtain compound 4E (1.2 g crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 171.1 [M+H] + .

[0355] Step 5: Compound 4E (200 mg, 0.95 mmol) was synthesized according to the third step of Example 1 to obtain compound 4F (450 mg, yield: 71.77%). LC-MS (ESI): m / z = 660.2 [M+H] + .

[0356] Step 6: Chiral resolution of compound 4F afforded compound 4 (SFC retention time: 2.033 min, 169.8 mg) and compound 5 (SFC retention time: 2.235 min, 145.1 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 40% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 2.5 min; Sample preparation: Sample concentration: 10 mg / mL, ethanol solution injection: 3.0 mL per injection.

[0357] Compound 4 (SFC analysis retention time: 2.033 min): 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.48(s,1H),8.14(s,1H),8.04-8.02(m,2H),7.81-7.79(m,2H),7.51-7.49(m,2H),7.38-7.36 (m,2H),7.33-7.30(m,2H),7.26-7.24(m,3H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.93-3.89(m,1H); LC-MS(ESI):m / z=660.6[M+H] + .

[0358] Compound 5 (SFC analysis retention time: 2.235 min): 1 H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.48(s,1H),8.14(s,1H),8.04-8.02(m,2H),7.81-7.79(m,2H),7.51-7.49(m,2H),7.38-7.36 (m,2H),7.33-7.29(m,2H),7.26-7.24(m,3H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.93-3.89(m,1H); LC-MS(ESI):m / z=660.5[M+H] + .

[0359] Example 6 and Example 7

[0360] Step 1: Dissolve compound 4H-1,2,4-triazole-3-carboxylic acid (1.13 g, 10 mmol) in N,N-dimethylformamide (20 mL). HATU (5.7 g, 15 mmol), 1,3-di(tert-butoxycarbonyl)guanidine (2.59 g, 10 mmol), and N,N-diisopropylethylamine (3.9 g, 30 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, 100 mL of ethyl acetate was added to the system, and the mixture was washed with saturated brine (50 mL x 4). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by silica gel column chromatography (dichloromethane:anhydrous methanol (v:v) = 20:1) to obtain compound 6A (443 mg, yield: 12.5%). LC-MS (ESI): m / z = 355.5 [M+H] + .

[0361] Step 2: Dissolve compound 6A (443 mg, 1.25 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 6B (371 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 155.5 [M+H] + .

[0362] Step 3: Compound 6B (371 mg crude product) was synthesized by referring to the third step of Example 1 to obtain compound 6C (224 mg, yield: 61%).

[0363] Step 4: Chiral resolution of compound 6C afforded compound 6 (SFC retention time: 2.323 min, 58.3 mg) and compound 7 (SFC retention time: 2.668 min, 56.5 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; Gradient: 45% B gradient elution flow rate: 100 mL / min, Column temperature: Room temperature, Wavelength: 220 nm, Cycle time: 5.0 min; Sample preparation: Sample concentration: 3 mg / mL, Methanol solution injection: 5 mL per injection.

[0364] Compound 6 (SFC analysis retention time: 2.323 min):1 H NMR(400MHz,DMSO-d6)δ14.92(s,1H),9.67(s,1H),8.78(s,1H),8.08-7.85(m,4H),7.83-7.77(m,2H),7.57-7.50(m,2H),7 .40-7.34(m,2H),7.32-7.20(m,5H),5.09-4.99(m,1H),4.58-4.46(m,1H),3.96-3.83(m,1H); LC-MS(ESI):m / z=644.2[M+H] + .

[0365] Compound 7 (SFC analysis retention time: 2.668 min): 1 H NMR(400MHz,DMSO-d6)δ14.92(s,1H),9.67(s,1H),8.78(s,1H),8.08-7.85(m,4H),7.83-7.77(m,2H),7.57-7.50(m,2H),7 .40-7.34(m,2H),7.32-7.20(m,5H),5.09-4.99(m,1H),4.58-4.46(m,1H),3.96-3.83(m,1H); LC-MS(ESI):m / z=644.2[M+H] + .

[0366] Example 8 and Example 9

[0367] Step 1: Dissolve compound 1A (2.2 g, 8.57 mmol) and 8A (0.8 g, 7.14 mmol) in N,N-dimethylformamide (20 mL). Add diisopropylethylamine (2.76 g, 21.4 mmol) and HATU (3.26 g, 8.57 mmol). Stir overnight at room temperature. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to afford compound 8B (0.8 g, yield: 31.7%). LC-MS (ESI): m / z = 354.2 [M+H] + .

[0368] Step 2: Dissolve compound 8B (400 mg, 1.12 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (3 mL), and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 8C (600 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 154.0 [M+H]+ .

[0369] Step 3: Compound 8C (600 mg, 1.12 mmol) was subjected to the same operation as in Step 3 of Example 1 (solvent: DMF) to obtain compound 8D (170 mg, yield: 63.0%).

[0370] Step 4: Chiral resolution of compound 8D afforded compound 8 (SFC retention time: 2.118 min, 50 mg) and compound 9 (SFC retention time: 2.498 min, 60 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; Gradient: 40% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 6.2 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile-methanol mixture injection: 3.0 mL per injection.

[0371] Compound 8 (SFC analysis retention time: 2.118 min): 1 H NMR(400MHz,DMSO-d6)δ13.01-12.80(m,1H),8.03-7.99(m,4H),7.89(s,1H),7.80-7.76(m,2H),7.52-7.50(m,2H),7.37 -7.35(m,2H),7.30-7.16(m,5H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.92-3.88(m,1H); LC-MS(ESI):m / z=643.1[M+H] + .

[0372] Compound 9 (SFC analysis retention time: 2.498 min): 1H NMR (400MHz, DMSO-d6) δ13.01-12.80(m,1H),8.03-7.99(m,4H),7.89(s,1H),7.80-7.78(m,2H),7.52-7.50(m,2H),7.37 -7.35(m,2H),7.30-7.21(m,5H),5.06-5.02(m,1H),4.54-4.49(m,1H),3.92-3.88(m,1H); LC-MS(ESI):m / z=643.1[M+H] + .

[0373] Example 10 and Example 11

[0374] Step 1: Compounds 1A (2.77 g, 10.7 mmol) and 10A (0.8 g, 7.14 mmol) were dissolved in N,N-dimethylformamide (20 mL). Diisopropylethylamine (2.76 g, 21.4 mmol) and HATU (3.26 g, 8.57 mmol) were added. After completion of the addition, the mixture was stirred at room temperature overnight. Water (100 mL) was added and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to afford compound 10B (1.6 g, yield: 63.4%). 1 H NMR (400MHz, CDCl3) δ4.84-4.83(m,2H),3.37(s,1H),3.09-2.93(m,4H),1.50(s,18H).

[0375] Step 2: Dissolve compound 10B (600 mg, 1.70 mmol) in dichloromethane (12 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 10C (800 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 154.2 [M+H] + .

[0376] Step 3: Compound 1D (250 mg, 0.47 mmol) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 10D (180 mg, yield: 59.6%).

[0377] Step 4: Chiral resolution of compound 10D afforded compound 10 (SFC retention time: 2.305 min, 70 mg) and compound 11 (SFC retention time: 2.547 min, 80 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral Whelk Column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation: Instrument: Waters 150 Prep-SFC, Column: Chiral Whelk Column; Mobile phase: A: CO2, B: isopropanol; Gradient: 40% B; Flow rate: 120 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 4.3 min. Sample preparation: Sample concentration: 10 mg / mL, acetonitrile-methanol mixture injected: 2.0 mL per injection.

[0378] Compound 10 (SFC analysis retention time: 2.305 min): 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.33-7.22(m,5H),5.04 -5.00(m,1H),4.79-4.78(m,2H),4.51-4.45(m,1H),3.89-3.85(m,1H),3.33-3.29(m,1H),2.84-2.82(m,4H); LC-MS(ESI):m / z=643.2[M+H] + .

[0379] Compound 11 (SFC analysis retention time: 2.547 min): 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.01-7.99(m,2H),7.82-7.79(m,2H),7.51-7.49(m,2H),7.39-7.37(m,2H),7.33-7.22(m,5H),5.05 -5.00(m,1H),4.79-4.78(m,2H),4.51-4.45(m,1H),3.89-3.84(m,1H),3.33-3.29(m,1H),2.84-2.82(m,4H); LC-MS(ESI):m / z=643.2[M+H] + .

[0380] Example 12 and Example 13

[0381] Step 1: Dissolve compound 1A (2.78 g, 10.70 mmol) and compound 12A (1.0 g, 8.92 mmol) in N,N-dimethylformamide (20 mL). Add diisopropylethylamine (4.7 mL, 26.76 mmol) and HATU (4.10 g, 10.70 mmol). Stir overnight at room temperature. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried and concentrated under reduced pressure. The resulting residue is purified by column chromatography (dichloromethane:methanol (v:v) = 10:1) to afford compound 12B (0.45 g, 14.27% yield). LC-MS (ESI): m / z = 354.1 [M+H] + .

[0382] Step 2: Dissolve compound 12B (450 mg, 1.27 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 12C (190 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 154.1 [M+H] + .

[0383] Step 3: Compound 12C (190 mg, 1.14 mmol) was subjected to the same operation as in the first step of Example 3 (solvent: DMF) to obtain compound 12D (120 mg, yield: 49.28%).

[0384] Step 4: Chiral resolution of compound 12D afforded compound 12 (SFC retention time: 2.118 min, 50 mg) and compound 13 (SFC retention time: 2.498 min, 60 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 45% B gradient elution flow rate: 100 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 5.0 min; Sample preparation: Sample concentration: 5 mg / mL, acetonitrile and ethanol mixture injection: 2.0 mL per injection.

[0385] Compound 12 (SFC analysis retention time: 2.136 min): 1 H NMR (400MHz, DMSO-d6) δ8.01-7.85(m,2H),7.81-7.77(m,1H),7.54-7.50(m,1H),7.37-7.34(m,1H),7.30-7.20(m,6H),7. 16-7.10(m,3H),7.04-6.97(m,3H),5.08-4.99(m,1H),4.55-4.46(m,1H),3.93-3.86(m,1H); LC-MS(ESI):m / z=643.2[M+H] + .

[0386] Compound 13 (SFC analysis retention time: 2.594 min): 1 H NMR (400MHz, DMSO-d6) δ8.06-7.85(m,2H),7.82-7.78(m,1H),7.55-7.50(m,1H),7.37-7.34(m,1H),7.39-7.21(m,6H),7. 16-7.10(m,3H),7.04-6.97(m,3H),5.08-4.99(m,1H),4.55-4.46(m,1H),3.93-3.86(m,1H); LC-MS(ESI):m / z=643.2[M+H] + .

[0387] Example 14 and Example 15

[0388] Step 1: Dissolve compound 1D (0.5 g, 0.95 mmol) in dichloromethane (10 mL) and add N,N-diisopropylethylamine (0.96 g, 9.5 mmol). Then, add a solution of compound 14A (0.5 g, 4.37 mmol, synthesized according to patent WO2020181952) in tetrahydrofuran (5 mL) at 0°C. After the addition is complete, stir at room temperature for 1 hour. After the reaction is completed, add water (50 mL), extract with dichloromethane (100 mL × 3), combine the organic phases, wash with saturated brine (40 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The resulting residue is purified by column chromatography (dichloromethane:methanol (v / v) = 50:1) to obtain compound 14B (0.52 g, yield: 91%). LC-MS (ESI): m / z = 604.1 [M+H] + .

[0389] Step 2: Compound 14B (0.52 g) was subjected to chiral resolution to afford compound 14 (SFC retention time: 1.744 min, 220 mg) and compound 15 (SFC retention time: 1.948 min, 206 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf; Column: Chiral AS column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B from 5-40%; Flow rate: 3 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC; Column: Chiral AS column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in ethanol; Gradient: B for 35%; Elution flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 6.0 min; Sample preparation: Sample concentration: 15 mg / mL, dissolved in acetonitrile and methanol. Injection: 3.0 mL per injection.

[0390] Compound 14 (SFC analysis retention time: 1.744 min): 1 H NMR(400MHz,DMSO-d6)δ8.60(d,1H),8.00(d,2H),7.85(d,2H),7.76(d,2H ),7.45(d,2H),7.33(t,2H),7.26(d,1H),7.24-7.18(m,2H),5.07(dd,1H) ,4.69-4.60(m,1H),4.49(td,1H),4.29(td,1H),4.16-4.08(m,1H),4.06- 3.99(m,1H),3.98-3.84(m,2H),1.75(d,3H); LC-MS(ESI):m / z=604.1[M+H] + .

[0391] Compound 15 (SFC analysis retention time: 1.948 min): 1H NMR(400MHz,DMSO-d6)δ8.61(d,1H),8.00(d,2H),7.85(d,2H),7.76(d,2H ),7.45(d,2H),7.33(t,2H),7.26(d,1H),7.24-7.19(m,2H),5.07(dd,1H) ,4.70-4.60(m,1H),4.49(dt,1H),4.29(td,1H),4.16-4.07(m,1H),4.06- 3.99(m,1H),3.97-3.84(m,2H),1.75(d,3H); LC-MS(ESI):m / z=604.1[M+H] + .

[0392] Example 16 and Example 17

[0393] Step 1: Dissolve compound 1D (500 mg, 0.95 mmol) in DMF (8 mL) and add N,N-diisopropylethylamine (429.72 mg, 3.32 mmol). Then, add a solution of compound 16A (188 mg, 1.09 mmol) in DMF (2 mL) at -0°C. After complete addition, stir at room temperature for 1 h. After the reaction, add water (50 mL) and extract with ethyl acetate (100 mL x 3). The combined organic phases are washed with saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16B (620 mg crude product), which is used directly in the next reaction. LC-MS (ESI): m / z = 607.2 [M+H-56] + .

[0394] Step 2: Dissolve compound 16B (620 mg, 0.94 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (2 mL), and stir at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain compound 16C (529 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 562.3 [M+H] + .

[0395] Step 3: Compound 16C (530 mg, 0.94 mmol) was dissolved in dichloromethane (5 mL) and tetrahydrofuran (5 mL). Triethylamine (333 mg, 3.29 mmol) was added. After purging the nitrogen atmosphere three times, acetyl chloride (111 mg, 1.41 mmol) was slowly added dropwise in an ice bath. After the addition was complete, the reaction was stirred in the ice bath for 1 hour. The reaction was quenched with water (30 mL) and extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol (v / v) = 50:1) to afford compound 16D (490 mg, yield: 86%). LC-MS (ESI): m / z = 604.3 [M+H] + .

[0396] Step 4: Compound 16D (490 mg) was subjected to chiral resolution to afford compound 16 (SFC retention time: 1.210 min, 153 mg) and compound 17 (SFC retention time: 1.335 min, 151 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf; Column: Chiral OJ column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B from 5-40%; Flow rate: 3 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC; Column: Chiral OJ column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 25%; Elution flow rate: 70 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 7.0 min; Sample preparation: Sample concentration: 10 mg / mL, dissolved in acetonitrile and methanol. Injection: 3.0 mL per injection.

[0397] Compound 16 (SFC analysis retention time: 1.210 min): 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),7.99(d,2H),7.83(d,2H),7.64(d,2H),7.43(d,2H),7.32(t,2H),7.27-7.20(m ,3H),4.95(dd,1H),4.89-4.74(m,2H),4.54-4.32(m,4H),3.84(dd,1H),1.86(s,3H); LC-MS(ESI):m / z=604.3[M+H] + .

[0398] Compound 17 (SFC analysis retention time: 1.335 min): 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),7.99(d,2H),7.82(d,2H),7.64(d,2H),7.43(d,2H),7.32(t,2H),7.27-7.20(m ,3H),4.95(dd,1H),4.89-4.74(m,2H),4.55-4.31(m,4H),3.84(dd,1H),1.86(s,3H); LC-MS(ESI):m / z=604.3[M+H] + .

[0399] Example 18, Example 19, Example 20 and Example 21

[0400] Step 1: Compound 1D (1.05 g, 1.99 mmol) was dissolved in DMF (15 mL), and N,N-diisopropylethylamine (0.90 g, 6.96 mmol) was added. A solution of compound 18A (0.25 g, 2.49 mmol) in DMF (5 mL) was then added dropwise at 0°C. The mixture was stirred at room temperature for 1 h. After the reaction, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane:methanol (v / v) = 50:1) to afford compound 18B (985 mg, yield: 83%). LC-MS (ESI): m / z = 590.1 [M+H] + .

[0401] Step 2: Compound 18B (985 mg) was subjected to chiral resolution to afford compound 18 (SFC retention time: 2.420 min, 226 mg), compound 19 (SFC retention time: 2.769 min, 170 mg), compound 20 (SFC retention time: 3.279 min, 180 mg), and compound 21 (SFC retention time: 3.537 min, 204 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf; Column: Chiral OD column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B from 20-30%; Flow rate: 1.5 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Wavelength: 254 nm. SFC separation method: First separation: Instrument: Waters 150Prep-SFC; Column: Chiral OD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 35%; Elution flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 5.0 min; Sample preparation: Compound concentration: 20 mg / mL, dissolved in acetonitrile and methanol. Injection: 5.0 mL per injection. Fraction A and fraction B were separated. Fraction A was further separated and purified by SFC using the following methods: Instrument: Waters 150 Prep-SFC; Column: Chiral AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in isopropanol and acetonitrile; Gradient: B for 35%; Elution flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 4.0 min; Sample preparation: Compounds were dissolved in acetonitrile and methanol at a concentration of 10 mg / mL. Injection: 5.0 mL per injection. Compounds 18 and 19 were isolated.

[0402] Fraction B was further separated and purified by SFC using the following methods: Instrument: Waters 150 Prep-SFC; Column: Chiral WHEIK column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 40%; Elution flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 3.0 min; Sample preparation: Compound 20 and Compound 21 were isolated at a concentration of 10 mg / mL in acetonitrile and methanol. Injection: 5.0 mL per injection.

[0403] Compound 18 (SFC analysis retention time: 2.420 min): 1 H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.00(d,2H),7.87(s,1H),7.83(d,2H),7.75(d,2H),7.44(d,2H),7.33(t,2H),7.28-7.19(m,3H ),5.11(dd,1H),4.60(t,1H),4.48(d,1H),4.01(dd,1H),3.14-3.02(m,2H),2.23(s,1H),2.04(dd,1H); LC-MS(ESI):m / z=590.1[M+H] + .

[0404] Compound 19 (SFC analysis retention time: 2.769 min): 1 H NMR(400MHz,DMSO-d6)δ8.29(d,1H),8.02(d,2H),7.87(t,3H),7.75(d,2H),7.44(d,2H),7.34(t,2H),7.29-7.20(m,3H ),5.11(dd,1H),4.55(dd,2H),4.17(d,1H),3.10(dq,2H),2.25(s,1H),2.02-1.90(m,1H); LC-MS(ESI):m / z=590.1[M+H] + .

[0405] Compound 20 (SFC analysis retention time: 3.279 min): 1 H NMR(400MHz,DMSO-d6)δ8.29(d,1H),8.02(d,2H),7.87(t,3H),7.75(d,2H),7.44(d,2H),7.34(t,2H),7.29-7.20(m,3H ),5.11(dd,1H),4.54(dd,2H),4.17(d,1H),3.09(dq,2H),2.26(s,1H),2.02-1.89(m,1H); LC-MS(ESI):m / z=590.1[M+H] + .

[0406] Compound 21 (SFC analysis retention time: 3.537 min): 1H NMR(400MHz,DMSO-d6)δ8.34(d,1H),8.00(d,2H),7.87(s,1H),7.83(d,2H),7.75(d,2H),7.44(d,2H),7.33(t,2H),7.28-7.19(m,3H ),5.11(dd,1H),4.60(t,1H),4.48(d,1H),4.01(dd,1H),3.14-3.05(m,2H),2.24(s,1H),2.04(dd,1H); LC-MS(ESI):m / z=590.1[M+H] + .

[0407] Example 22 and Example 23

[0408] Step 1: To compound 22A (0.8 g, 2.64 mmol, preparation reference: ChemMedChem, 2015, vol. 10, #3, pp. 461-469) was added a 0.5 M ammonia solution in 1,4-dioxane (20 mL). The mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to afford compound 22B (0.75 g crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 282.0 [MH] - .

[0409] Step 2: Compound 22B (0.75 g, 2.65 mmol) was added to dichloromethane (20 mL). Triethylamine (0.8 g, 7.95 mmol) and isopropyl chloroformate (0.65 g, 5.30 mmol) were added under ice-cooling. The mixture was stirred at room temperature for 2 hours. After dilution with water, the mixture was extracted twice with DCM. The organic phases were combined, dried, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to afford compound 22C (0.5 g, yield: 51%). LC-MS (ESI): m / z = 368.0 [MH] - .

[0410] Step 3: Compound 22C (0.4 g, 1.08 mmol) and intermediate 22D (0.36 g, 1.40 mmol, synthesized with reference to patent WO2022245627) were added to toluene (20 mL) and heated to 100°C under nitrogen with stirring for 10 hours. The mixture was then cooled and concentrated. The resulting residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 22E (0.3 g, yield: 49%). LC-MS (ESI): m / z = 566.0 [M+H] + .

[0411] Step 4: To a 50 mL single-necked flask, add toluene (15 mL), followed by compound 22E (0.30 g, 0.53 mmol) and N,N-diisopropylethylamine (0.14 g, 1.06 mmol), and then slowly add phosphorus oxychloride (0.16 g, 1.06 mmol) dropwise. After the addition is complete, the system is protected by nitrogen and stirred at 100°C for 1 h. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 2:1) to obtain compound 22F (0.16 g, yield: 52%). LC-MS (ESI): m / z = 584.0 [M+H] + .

[0412] Step 5: Compound 22F (160 mg, 0.27 mmol) and tauramide hydrochloride (87 mg, 0.54 mmol) were treated according to the procedure of Example 1 to obtain compound 22G (150 mg, yield: 82%). LC-MS (ESI): m / z = 672.1 [M+H] + .

[0413] Step 6: Compound 22G was further subjected to chiral resolution to afford compound 22 (SFC retention time: 0.732 min, 73 mg) and compound 23 (SFC retention time: 1.339 min, 71 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral Wheel Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH; Gradient: 40% B gradient elution flow rate: 100 mL / min, column temperature: 25°C, Wavelength: 220 nm, Cycle time: 4.0 min. Sample preparation: Sample concentration: 10 mg / mL, Methanol solution injection: 1.5 mL each time.

[0414] Compound 22 (SFC analysis retention time: 0.732 min): 1H NMR(400MHz,DMSO-d6)δ8.30-8.22(m,1H),8.07-7.99(m,4H),7.73-7.66(m,2H),7.48-7.42(m,2H),7.36-7.30(m,2H),7.28-7.21(m,3 H),7.04(s,2H),5.15-5.07(m,1H),4.55(t,1H),4.12-4.03(m,1H),3.79-3.67(m,2H),3.30-3.26(m,2H); LC-MS(ESI):m / z=672.1[M+H] + .

[0415] Compound 23 (SFC analysis retention time: 1.339 min): 1 H NMR(400MHz,DMSO-d6)δ8.30-8.22(m,1H),8.07-7.99(m,4H),7.73-7.66(m,2H),7.48-7.42(m,2H),7.36-7.30(m,2H),7.28-7.21(m,3 H),7.04(s,2H),5.15-5.07(m,1H),4.55(t,1H),4.12-4.03(m,1H),3.79-3.67(m,2H),3.30-3.26(m,2H); LC-MS(ESI):m / z=672.1[M+H] + .

[0416] Example 24 and Example 25

[0417] Step 1: Dissolve compound 24A (1.20 g, 5.66 mmol) in DMF (20 mL), add triethylamine (1.72 g, 16.98 mmol), then add HATU (2.20 g, 8.49 mmol), and stir at room temperature under nitrogen for 2 h. Quench the reaction with water (30 mL) and extract twice with dichloromethane (30 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated. The resulting residue is purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to afford compound 24B (1.7 g, yield: 66%). LC-MS (ESI): m / z = 454.2 [M+H] + .

[0418] Step 2: Dissolve compound 24B (700 mg, 1.54 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 10 h. The reaction solution is concentrated under vacuum to obtain compound 24C (500 mg crude product), which is used directly in the next reaction. LC-MS (ESI): m / z = 154.1 [M+H] + .

[0419] Step 3: Compound 24C (870 mg, 3.26 mmol) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 24D (200 mg).

[0420] Step 4: Compound 24D was chiral resolved by SFC to yield compounds 24 (SFC retention time: 0.836 min, 70 mg) and 25 (SFC retention time: 1.437 min, 70 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral Cellulose-2 column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 40% B; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral Cellulose-2 column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; Gradient: 45% B; Flow rate: 100 mL / min, Column temperature: 25°C, Wavelength: 254 nm, Cycle time: 4.5 min. Sample preparation: Sample concentration 10 mg / mL, ethanol solution injection: 2.0 mL each time.

[0421] Compound 24 (SFC analysis retention time: 0.836 min): 1 H NMR(400MHz,DMSO-d6)δ13.41(s,1H),10.57(s,1H),8.70-8.40(m,1H),8.23-8.09(m,1H),8.03(d,2H),7.80(d,2H),7.55-7.44 (m,2H),7.39-7.28(m,4H),7.27-7.20(m,3H),5.08-4.99(m,1H),4.51(t,1H),3.95-3.87(m,1H); LC-MS(ESI):m / z=643.1[M+H] + .

[0422] Compound 25 (SFC analysis retention time: 1.437 min): 1H NMR(400MHz,DMSO-d6)δ13.41(s,1H),10.57(s,1H),8.70-8.40(m,1H),8.23-8.09(m,1H),8.03(d,2H),7.80(d,2H),7.55-7.44 (m,2H),7.39-7.28(m,4H),7.27-7.20(m,3H),5.08-4.99(m,1H),4.51(t,1H),3.95-3.87(m,1H); LC-MS(ESI):m / z=643.1[M+H] + .

[0423] Example 26 and Example 27

[0424] Step 1: Dissolve compound 1A (2.38 g, 9.19 mmol) and compound 26A (1.50 g, 7.07 mmol) in N,N-dimethylformamide (30 mL). Add diisopropylethylamine (1.79 g, 17.67 mmol) and HATU (2.96 g, 7.78 mmol). Stir overnight at room temperature. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 26B (1.20 g, yield: 37.43%). LC-MS (ESI): m / z = 454.2 [M+H] + .

[0425] Step 2: Dissolve compound 26B (1.20 g, 2.65 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 26C (1.00 g crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 154.2 [M+H] + .

[0426] Step 3: Compound 26C (1.00 g, 2.65 mmol) was treated according to the procedure of Step 3 of Example 1 to obtain Compound 26D (600 mg, yield: 81.85%). LC-MS (ESI): m / z = 643.3 [M+H] + .

[0427] Step 4: Chiral resolution of compound 26D afforded compound 26 (SFC retention time: 2.004 min, 218.2 mg) and compound 27 (SFC retention time: 2.433 min, 212.1 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in methanol; Gradient: 40% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 5.9 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile and dichloromethane mixed solution injection: 8.0 mL each time.

[0428] Compound 26 (SFC analysis retention time: 2.004 min): 1 H NMR (400MHz, CDCl3) δ12.11(s,1H),9.76(s,1H),9.03(br s,2H),8.14-8.12(m,2H),7.76-7.74(m,2H),7.64(s,1H),7.57-7.55(m,2H),7.21-7.16(m,5H),6.97-6.96(m, 2H),6.88-6.86(m,1H),4.63-4.61(m,1H),4.57-4.51(m,1H),4.31-4.28(m,1H); LC-MS(ESI):m / z=643.1[M+H] + .

[0429] Compound 27 (SFC analysis retention time: 2.433 min): 1 H NMR (400MHz, CDCl3) δ12.11(s,1H),9.76(s,1H),9.03(br s,2H),8.14-8.12(m,2H),7.76-7.74(m,2H),7.64-7.63(m,1H),7.57-7.55(m,2H),7.21-7.14(m,5H),7.00-6.96 (m,2H),6.88-6.85(m,1H),4.63-4.61(m,1H),4.57-4.51(m,1H),4.31-4.28(m,1H); LC-MS(ESI):m / z=643.1[M+H]+ .

[0430] Example 28, Example 29, Example 30 and Example 31

[0431] Step 1: Compound 1A (1.00 g, 3.86 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.17 g, 11.57 mmol) and 3-tetrahydrofurancarboxylic acid (0.45 g, 3.86 mmol) were added. The atmosphere was purged with nitrogen three times, and then HATU (1.76 g, 4.63 mmol) was added under ice-cooling. After completion of the addition, the reaction mixture was stirred at room temperature for 12 h. The reaction was quenched with water (30 mL) and extracted twice with dichloromethane (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 3:1) to afford compound 28A (0.60 g, yield: 43.53%). LC-MS (ESI): m / z = 257.2 [M-101+H] + .

[0432] Step 2: Dissolve compound 28A (600 mg, 1.68 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 6 h. The reaction solution was concentrated under reduced pressure to obtain compound 28B (600 mg), which was used directly in the next reaction. LC-MS (ESI): m / z = 158.1 [M+H] + .

[0433] Step 3: Compound 28B (130 mg, 0.29 mmol) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 28C (160 mg).

[0434] Step 4: Compound 28C was subjected to chiral resolution to afford compound 28 (SFC retention time: 0.680 min, 35 mg), compound 29 (SFC retention time: 0.749 min, 30 mg), compound 30 (SFC retention time: 1.411 min, 32 mg), and compound 31 (SFC retention time: 2.517 min, 36 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral OX Column; Mobile Phase: A: CO2, B: 0.05% DEA in methanol and acetonitrile; Gradient: 5-40% B in A; Flow Rate: 3 mL / min, Column Temperature: 35°C, Wavelength: 254 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol and acetonitrile; Gradient: 35% B gradient elution flow rate: 100 mL / min, column temperature: 25°C, wavelength: 254 nm, cycle time: 10.0 min; Sample preparation: Sample concentration: 10 mg / mL, ethanol solution injection: 5 mL per injection.

[0435] Compound 28 (SFC analysis retention time: 0.680 min): 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.50(d,2H),7.38(d,2H),7.33-7.22(m,5H),5.05-5.02(m, 1H),4.49(t,1H),3.89-3.84(m,2H),3.78-3.65(m,3H),3.27-3.21(m,1H),2.11-1.94(m,2H); LC-MS(ESI):m / z=647.1[M+H] + .

[0436] Compound 29 (SFC analysis retention time: 0.749 min): 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.33-7.23(m,5H),5.06-5.02(m, 1H),4.49(t,1H),3.90-3.85(m,2H),3.77-3.64(m,3H),3.28-3.22(m,1H),2.10-1.95(m,2H); LC-MS(ESI):m / z=647.1[M+H] + .

[0437] Compound 30 (SFC analysis retention time: 1.411 min): 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.34-7.23(m,5H),5.06-5.02(m, 1H),4.49(t,1H),3.90-3.84(m,2H),3.77-3.64(m,3H),3.28-3.23(m,1H),2.09-1.96(m,2H); LC-MS(ESI):m / z=647.1[M+H] + .

[0438] Compound 31 (SFC analysis retention time: 2.517 min): 1 H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.01(d,2H),7.82(d,2H),7.51(d,2H),7.38(d,2H),7.34-7.22(m,5H),5.06-5.02(m, 1H),4.49(t,1H),3.90-3.85(m,2H),3.77-3.65(m,3H),3.28-3.23(m,1H),2.08-1.95(m,2H); LC-MS(ESI):m / z=647.1[M+H] + .

[0439] Example 32 and Example 33

[0440] Step 1: Compound 32A (10.0 g, 77.19 mmol) and DMAP (4.72 g, 38.59 mmol) were added to THF (200 mL), followed by the addition of BOC anhydride (42.12 g, 192.97 mmol). The mixture was stirred at room temperature overnight, diluted with water, and extracted with EA. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v:v) = 5:1) to afford compound 32B (22 g, yield: 86%). LC-MS (ESI): m / z = 330.1 [M+H] + .

[0441] Step 2: Compound 32B (5.0 g, 15.16 mmol), acetamide (1.79 g, 30.32 mmol), palladium acetate (0.68 g, 3.03 mmol), Xantphos (3.51 g, 6.06 mmol), and potassium carbonate (4.19 g, 30.32 mmol) were added sequentially to 1,4-dioxane (80 mL) under nitrogen atmosphere. The mixture was heated to 100°C and stirred overnight. After cooling, the mixture was filtered. The filtrate was diluted with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (PE:EA (v:v) = 2:1) to afford compound 32C (4.7 g, yield: 88%). LC-MS (ESI): m / z = 353.2 [M+H] + .

[0442] Step 3: Compound 32C (1.0 g, 2.84 mmol) was added to dichloromethane (6 mL), followed by 3 mL of trifluoroacetic acid, and stirred at room temperature for 10 hours. After concentration, saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford compound 32D (crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 153.1 [M+H] + .

[0443] Step 4: Compound 32D (0.2 g, 1.31 mmol) and compound 1D (0.52 g, 0.98 mmol) were added to dry THF (15 mL) under nitrogen protection. LiHMDS (3.93 mL, 3.93 mmol) was slowly added under ice-cooling. After complete addition, the mixture was stirred for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution and extracted with EA. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a residue which was purified by silica gel column chromatography (PE:EA (v:v) = 1:1) to afford compound 32E (300 mg).

[0444] Step 5: Compound 32E was further resolved by chiral SFC to afford compounds 32 (SFC retention time: 2.002 min, 120 mg) and 33 (SFC retention time: 2.314 min, 120 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral AD column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 5-40% B; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral AD column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in isopropanol; Gradient: 40% B gradient elution flow rate: 100 mL / min, column temperature: 25°C, Wavelength: 254 nm, Cycle time: 4.5 min. Sample preparation: Sample concentration: 10 mg / mL, ethanol solution injection: 2.0 mL per injection.

[0445] Compound 32 (SFC analysis retention time: 2.002 min): 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.14(s,1H),8.96(s,1H),8.24(s,1H),7.99(d,2H),7.83(d,2H),7.50-7.30(m ,6H),7.30-7.18(m,3H),5.11-5.07(m,1H),4.59(t,1H),3.97-3.93(m,1H),2.08(s,3H); LC-MS(ESI):m / z=642.1[M+H] + .

[0446] Compound 33 (SFC analysis retention time: 2.314 min): 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),10.14(s,1H),8.96(s,1H),8.24(s,1H),7.99(d,2H),7.83(d,2H),7.50-7.30(m ,6H),7.30-7.18(m,3H),5.11-5.07(m,1H),4.59(t,1H),3.97-3.93(m,1H),2.08(s,3H); LC-MS(ESI):m / z=642.1[M+H] + .

[0447] Example 34 and Example 35

[0448] Step 1: Compound 34A (60 mg, 0.40 mmol) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 34B (130 mg, yield: 53.37%). LC-MS (ESI): m / z = 641.1 [M+H] + .

[0449] Step 2: Chiral resolution of compound 34B afforded compound 34 (SFC retention time: 2.392 min, 15.4 mg) and compound 35 (SFC retention time: 2.847 min, 19.2 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral WHEIK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHEIK Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in methanol; Gradient: 45% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 5.1 min; Sample preparation: Sample concentration: 5 mg / mL, acetonitrile and dichloromethane mixed solution injection: 2.0 mL each time.

[0450] Compound 34 (SFC analysis retention time: 2.392 min): 1 H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.98(s,1H),7.97-7.92(m,4H),7.82-7.80(m,2H),7.65-7.63(m,2H),7.43-7.41(m,2H),7.37-7.33(m, 2H),7.29-7.25(m,3H),6.89-6.87(m,1H),5.18-5.14(m,1H),4.75-4.7 0(m,1H),4.11-4.07(m,1H),2.05(s,3H); LC-MS(ESI):m / z=641.1[M+H] + .

[0451] Compound 35 (SFC analysis retention time: 2.847 min): 1H NMR (400MHz, DMSO-d6) δ10.34(s,1H),9.98(s,1H),7.97-7.92(m,4H),7.82-7.80(m,2H),7.65-7.63(m,2H),7.43-7.41(m,2H),7.35-7.33(m, 2H),7.29-7.27(m,3H),6.89-6.87(m,1H),5.18-5.14(m,1H),4.75-4.7 0(m,1H),4.11-4.07(m,1H),2.05(s,3H); LC-MS(ESI):m / z=641.1[M+H] + .

[0452] Example 36 and Example 37

[0453] Step 1: Dissolve compound 1A (2.00 g, 7.71 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 6 hours. The reaction solution was concentrated under reduced pressure to obtain compound 36A (1.00 g crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 60.2 [M+H] + .

[0454] Step 2: Compound 36A (1.00 g crude product) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 36B (350 mg, yield: 33.56%). LC-MS (ESI): m / z = 549.2 [M+H] + .

[0455] Step 3: Compound 36B (350 mg, 0.64 mmol) was dissolved in dichloromethane (50 mL). Compound 36C (100 mg, 0.75 mmol, synthesized according to patent CN107759587) and triethylamine (130 mg, 1.28 mmol) were added, respectively. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with water (40 mL) and extracted twice with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 50:50) to afford compound 36D (400 mg, yield: 97.11%). LC-MS (ESI): m / z = 646.4 [M+H] + .

[0456] Step 4: Chiral resolution of compound 36D afforded compound 36 (SFC retention time: 0.856 min, 56.4 mg) and compound 37 (SFC retention time: 1.160 min, 94.8 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral OX Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 50% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in methanol; Gradient: 55% B gradient; Elution flow rate: 100 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 7.0 min; Sample preparation: Sample concentration: 5 mg / mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

[0457] Compound 36 (SFC analysis retention time: 0.856 min): 1 H NMR(400MHz,DMSO-d6)δ8.01-7.97(m,2H),7.85-7.82(m,2H),7.72-7.69(m,1H),7. 60-7.53(m,1H),7.46-7.44(m,1H),7.41-7.37(m,1H),7.33-7.30(m,2H),7.27-7.2 2(m,3H),5.10-4.99(m,1H),4.55-4.47(m,1H),4.03-3.83(m,1H),3.76-3.67(m,1H ),3.57-3.38(m,2H),3.13-3.11(m,2H),2.92(s,3H); LC-MS(ESI):m / z=646.1[M+H] + .

[0458] Compound 37 (SFC analysis retention time: 1.160 min): 1H NMR(400MHz,DMSO-d6)δ8.01-7.97(m,2H),7.85-7.82(m,2H),7.72-7.69(m,1H),7. 60-7.53(m,1H),7.46-7.44(m,1H),7.41-7.37(m,1H),7.33-7.30(m,2H),7.27-7.2 2(m,3H),5.10-4.99(m,1H),4.55-4.47(m,1H),4.03-3.83(m,1H),3.76-3.67(m,1H ),3.57-3.41(m,2H),3.13-3.11(m,2H),2.92(s,3H); LC-MS(ESI):m / z=646.2[M+H] + .

[0459] Example 38 and Example 39

[0460] Step 1: Compound 38A (1.00 g, 9.08 mmol) was dissolved in dioxane (20 mL), and pyridine (2.15 g, 27.24 mmol) was added. After the reaction mixture was purged with nitrogen, acetyl chloride (750 mg, 9.55 mmol) was slowly added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred at 80°C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (dichloromethane:methanol (v:v) = 90:10) to provide compound 38B (420 mg, yield: 30.40%). 1 H NMR (400MHz, DMSO-d6) δ12.50(br s,2H),8.73-8.72(m,1H),8.47(s,1H),6.15-6.13(s,1H),1.92(s,3H).

[0461] Step 2: Compound 1D (500 mg, 0.95 mmol) was dissolved in tetrahydrofuran (20 mL), and compound 38B (290 mg, 1.90 mmol) and potassium tert-butoxide (320 mg, 2.85 mmol) were added, respectively. The reaction mixture was stirred at 75°C for 2 hours. Water (40 mL) was added to quench the reaction and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate) to afford compound 38C (140 mg, yield: 22.95%). LC-MS (ESI): m / z = 642.1 [M+H] + .

[0462] Step 3: Chiral SFC separation of compound 38C afforded compound 38 (SFC retention time: 2.408 min, 11.20 mg) and compound 39 (SFC retention time: 2.607 min, 14.30 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral WHEIK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHEIK 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: 6.5 min; Sample preparation: Sample concentration: 3.3 mg / mL, acetonitrile and dichloromethane mixed solution injection: 2.0 mL each time.

[0463] Compound 38 (SFC analysis retention time: 2.408 min): 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.24-8.22(m,1H),7.99-7.97(m,2H),7.78-7.76(m,2H),7.49-7.47(m,1H),7. 36-7.24(m,10H),4.99-4.95(m,1H),4.53-4.45(m,1H),3.87-3.83(m,1H),2.10(s,3H); LC-MS(ESI):m / z=642.1[M+H] + .

[0464] Compound 39 (SFC analysis retention time: 2.607 min): 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.24-8.22(m,1H),7.99-7.97(m,2H),7.78-7.76(m,2H),7.49-7.47(m,1H),7. 36-7.24(m,10H),4.99-4.95(m,1H),4.53-4.45(m,1H),3.87-3.83(m,1H),2.10(s,3H); LC-MS(ESI):m / z=642.1[M+H] + .

[0465] Example 40 and Example 41

[0466] Step 1: Dissolve compound 40A (0.5 g, 4.46 mmol) and N-Boc-guanidine (1.06 g, 6.7 mmol) in N,N-dimethylformamide (10 mL). Add diisopropylethylamine (1.72 g, 13.38 mmol) and HATU (2.0 g, 5.35 mmol). Stir overnight at room temperature after addition. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 40B (1.0 g, yield: 88.6%). LC-MS (ESI): m / z = 254.2 [M+H] + .

[0467] Step 2: Dissolve compound 40B (300 mg, 1.18 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 40C (500 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 154.1 [M+H] + .

[0468] Step 3: Compound 1D (200 mg, 0.38 mmol) was dissolved in dichloromethane (10 mL). Crude compound 40C (500 mg, 1.18 mmol) and diisopropylethylamine (765 mg, 5.9 mmol) were added, respectively, and stirred at room temperature overnight. The reaction was quenched with water (40 mL) and extracted twice with dichloromethane (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 40D (230 mg, 94.2% yield).

[0469] Step 4: Chiral SFC separation of compound 40D afforded compound 40 (SFC retention time: 0.913 min, 90 mg) and compound 41 (SFC retention time: 1.370 min, 39 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral OX Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OX Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 30% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 4.0 min; Sample preparation: Sample concentration: 7.0 mg / mL, acetonitrile-ethanol mixture injection: 2.0 mL per injection.

[0470] Compound 40 (SFC analysis retention time: 0.913 min): 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2 H),7.51-7.48(m,2H),7.39-7.37(m,2H),7.32-7.21(m,5H),5.94(s,1H) ,5.04-5.00(m,1H),4.51-4.45(m,1H),3.89-3.84(m,1H),3.10-3.07(m, 2H),2.86-2.83(m,2H),2.08-2.04(m,2H); LC-MS(ESI): m / z=643.1[M+H] + .

[0471] Compound 41 (SFC analysis retention time: 1.370 min): 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.01-7.99(m,2H),7.81-7.79(m,2 H),7.51-7.48(m,2H),7.40-7.36(m,2H),7.32-7.21(m,5H),5.94(s,1H) ,5.04-5.00(m,1H),4.51-4.45(m,1H),3.89-3.85(m,1H),3.10-3.07(m, 2H),2.86-2.83(m,2H),2.10-2.04(m,2H); LC-MS(ESI): m / z=643.1[M+H]+ .

[0472] Example 42 and Example 43

[0473] Step 1: Dissolve compound 42A (2.0 g, 15.37 mmol) and BOC-guanidine (3.67 g, 23.05 mmol) in DMF (50 mL). Add triethylamine (4.67 g, 46.11 mmol) and then HATU (7.60 g, 19.98 mmol). Stir under nitrogen for 2 h at room temperature. Quench the reaction with water (50 mL) and extract twice with ethyl acetate (30 mL). The organic phase is collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by silica gel column chromatography to yield compound 42B (3.5 g, yield: 84%). LC-MS (ESI): m / z = 272.2 [M+H] + .

[0474] Step 2: Dissolve compound 42B (500 mg, 1.84 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (2.5 mL), and stir at room temperature for 10 h. The reaction solution was concentrated to obtain compound 42C (320 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 172.1 [M+H] + .

[0475] Step 3: Compound 42C (320 mg, 1.12 mmol) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 42D (180 mg).

[0476] Step 4: Compound 42D was further resolved by chiral SFC to afford compound 42 (SFC retention time: 0.736 min, 70 mg) and compound 43 (SFC retention time: 1.429 min, 70 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral Cellulose-2 column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 40% B; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral Cellulose-2 column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in isopropanol; Gradient: 45% B gradient elution flow rate: 100 mL / min, column temperature: 25°C, Wavelength: 254 nm, Cycle time: 4.5 min. Sample preparation: Sample concentration: 10 mg / mL, ethanol solution injection: 2.0 mL each time.

[0477] Compound 42 (SFC analysis retention time: 0.736 min): 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.01(d,2H),7.82(d,2H),7.52-7.46(m,2H),7.41-7.36(m,2H),7.34-7.21(m,5H),5.07-4.98(m,1H) ,4.49(t,1H),3.92-3.81(m,3H),3.34-3.31(m,1H),3.28-3.25(m,1H),2.78-2.65(m,1H),1.72-1.48(m,4H); LC-MS(ESI):m / z=661.2[M+H] + .

[0478] Compound 43 (SFC analysis retention time: 1.429 min): 1 H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.01(d,2H),7.82(d,2H),7.46-7.52(m,2H),7.41-7.36(m,2H),7.34-7.21(m,5H),5.07-4.98(m,1H) ,4.49(t,1H),3.92-3.81(m,3H),3.34-3.31(m,1H),3.28-3.25(m,1H),2.78-2.65(m,1H),1.72-1.48(m,4H); LC-MS(ESI):m / z=661.2[M+H] + .

[0479] Example 44, Example 45, Example 46 and Example 47

[0480] Step 1: Add tert-butyl 2-methylmercaptoethylamine carbonate (3.00 g, 15.68 mmol) to a 7 mol / L ammonia methanol solution (50 mL). Cool to 0-10°C in an ice bath. Slowly add iodophenyl diacetic acid (12.63 g, 39.20 mmol), then return to room temperature and stir for 4 hours. After completion of the reaction, ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL) were added for separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 44B (2.54 g, yield: 72.85%). LC-MS (ESI): m / z = 223.1 [M+H] + .

[0481] Step 2: Compound 44B was added to a 4 mol / L 1,4-dioxane hydrochloride solution (30 mL) and allowed to react at room temperature for 4 hours. After completion of the reaction, the filter cake was collected, washed with acetonitrile, and dried to obtain compound 44C (1.6 g, yield: 89.69%). LC-MS (ESI): m / z = 123.1 [M+H] + .

[0482] Step 3: Compound 44C (0.14 g, 0.91 mmol) was treated according to the procedure of Step 3 of Example 1 to obtain compound 44D (331 mg, yield: 71.16%). LC-MS (ESI): m / z = 612.0 [M+H] + .

[0483] Step 4: Compound 44D (331 mg, 0.54 mmol) was subjected to chiral SFC separation to afford compound 44 (SFC retention time: 0.882 min, 63.8 mg), compound 45 (SFC retention time: 1.082 min, 65.7 mg), compound 46 (SFC retention time: 1.385 min, 76.4 mg), and compound 47 (SFC retention time: 1.586 min, 77.6 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf; Column: Chiral OX column; Mobile phase: A for CO2; B for 0.05% DEA in ethanol; Gradient: B 5-40%; Flow rate: 3.0 mL / min; Column pressure: 100 bar; Column temperature: 35°C; Wavelength: 220 nm. SFC chiral separation method: Instrument: Waters 150 Prep-SFC; Column: Chiral OX column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B 40%; Flow rate: 120 mL / min; Column pressure: 100 bar; Column temperature: room temperature; Wavelength: 220 nm; Cycle time: ~3.5 min. Sample preparation: Compounds were dissolved in acetonitrile at a concentration of 3.0 mg / mL; Injection: 2 mL per injection.

[0484] Compound 44 (SFC analysis retention time: 0.882 min): 1H NMR (400MHz, CDCl3) δ8.15-8.09(m,1H),8.05-8.02(m,2H),7.68-7.66(m,2H),7.58-7.51(m,2H),7.35-7.20(m,4H),7.16-7.06(m,2H),4 .72-4.68(m,1H),4.56-4.51(m,1H),4.22-4.18(m,2H),4.09-4.04(m,1H),3.65-3.50(m,2H),3.17(s,3H); LC-MS(ESI):m / z=612.0[M+H] + .

[0485] Compound 45 (SFC analysis retention time: 1.082 min): 1 H NMR (400MHz, CDCl3) δ8.15-8.09(m,1H),8.06-8.01(m,2H),7.70-7.65(m,2H),7.60-7.50(m,2H),7.37-7.20(m,4H),7.16-7.07(m,2H),4 .79-4.63(m,1H),4.59-4.45(m,1H),4.28-4.15(m,2H),4.13-4.04(m,1H),3.67-3.48(m,2H),3.17(s,3H); LC-MS(ESI):m / z=612.0[M+H] + .

[0486] Compound 46 (SFC analysis retention time: 1.385 min): 1 H NMR (400MHz, CDCl3) δ8.14-8.07(m,1H),8.06-8.00(m,2H),7.72-7.63(m,2H),7.58-7.50(m,2H),7.34-7.21(m,4H),7.15-7.08(m,2H),4 .75-4.66(m,1H),4.58-4.49(m,1H),4.25-4.16(m,2H),4.10-4.03(m,1H),3.67-3.50(m,2H),3.18(s,3H); LC-MS(ESI):m / z=612.0[M+H] + .

[0487] Compound 47 (SFC analysis retention time: 1.586 min): 1H NMR (400MHz, CDCl3) δ8.17-8.08(m,1H),8.07-8.00(m,2H),7.72-7.65(m,2H),7.56-7.50(m,2H),7.37-7.19(m,4H),7.17-7.06(m,2H),4 .76-4.63(m,1H),4.57-4.46(m,1H),4.24-4.14(m,2H),4.14-4.04(m,1H),3.60-3.39(m,2H),3.12(s,3H); LC-MS(ESI):m / z=612.0[M+H] + .

[0488] Example 48 and Example 49

[0489] Step 1: Dissolve compound 48A (1.0 g, 5.61 mmol) and N-Boc-guanidine (1.01 g, 6.73 mmol) in N,N-dimethylformamide (10 mL). Add diisopropylethylamine (2.18 g, 16.83 mmol) and HATU (3.20 g, 8.42 mmol). After addition, stir at room temperature overnight. Add water (100 mL) and extract with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to yield compound 48B (0.80 g, yield: 44.6%). LC-MS (ESI): m / z = 320.2 [M+H] + .

[0490] Step 2: Dissolve compound 48B (800 mg, 2.50 mmol) in dichloromethane (9 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 48C (600 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 220.1 [M+H] + .

[0491] Step 3: The crude compound 48C (150 mg, 0.68 mmol) was subjected to the procedure of Step 3 of Example 40 to obtain compound 48D (50 mg).

[0492] Step 4: Chiral SFC separation of compound 48D afforded compound 48 (SFC retention time: 2.228 min, 11 mg) and compound 49 (SFC retention time: 2.661 min, 15 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 254 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 40% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 7.5 min; Sample preparation: Sample concentration: 2 mg / mL, ethanol solution injection: 2 mL per injection.

[0493] Compound 48 (SFC analysis retention time: 2.228 min): 1 H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.01(d,2H),7.82(d,2H),7.50(d,2H),7.39(d,2H),7.34-7.22(m,5H),5.05-4.99(m,1H),4.52-4 .46(m,1H),3.90-3.85(m,1H),3.17-3.11(m,4H),2.82-2.75(m,1H),2.20-2.12(m,2H),2.06-1.94(m,2H); LC-MS(ESI):m / z=709.1[M+H] + .

[0494] Compound 49 (SFC analysis retention time: 2.661 min): 1 H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.01(d,2H),7.82(d,2H),7.50(d,2H),7.39(d,2H),7.34-7.22(m,5H),5.05-5.00(m,1H),4.52-4 .46(m,1H),3.90-3.85(m,1H),3.17-3.10(m,4H),2.83-2.75(m,1H),2.20-2.12(m,2H),2.05-1.94(m,2H); LC-MS(ESI):m / z=709.1[M+H] + .

[0495] Example 50 and Example 51

[0496] Step 1: Dissolve compound 50A (1.0 g, 6.98 mmol) and N-Boc-guanidine (1.67 g, 10.47 mmol) in N,N-dimethylformamide (10 mL). Add diisopropylethylamine (2.71 g, 20.94 mmol) and HATU (3.98 g, 10.47 mmol). After addition, stir at room temperature overnight. Add water (100 mL) and extract with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to yield compound 50B (1.2 g, yield: 60.4%). LC-MS (ESI): m / z = 285.2 [M+H] + .

[0497] Step 2: Dissolve compound 50B (600 mg, 2.11 mmol) in dichloromethane (9 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure to obtain compound 50C (600 mg crude product), which is used directly in the next reaction.

[0498] Step 3: The crude product of compound 50C (100 mg, 0.54 mmol) was subjected to the procedure of step 3 of Example 40 to obtain compound 50D (80 mg).

[0499] Step 4: Chiral SFC separation of compound 50D afforded compound 50 (SFC retention time: 0.855 min, 51 mg) and compound 51 (SFC retention time: 1.642 min, 45 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 50% B; Flow rate: 100 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 2.5 min. Sample preparation: Sample concentration: 5 mg / mL, ethanol solution injection: 5 mL per injection.

[0500] Compound 50 (SFC analysis retention time: 0.855 min): 1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.01(d,2H),7.81(d,2H),7.49(d,2 H),7.38(d,2H),7.33-7.23(m,5H),5.05-5.01(m,1H),4.49(t,1H),3.90-3 .86(m,1H),2.81-2.75(m,2H),2.50-2.38(m,1H),2.16(s,3H),1.87-1.82( m,2H),1.72-1.67(m,2H),1.60-1.50(m,2H); LC-MS(ESI):m / z=674.1[M+H] + .

[0501] Compound 51 (SFC analysis retention time: 1.642 min): 1 H NMR(400MHz,DMSO-d6)δ10.48(s,1H),8.00(d,2H),7.81(d,2H),7.49(d,2 H),7.38(d,2H),7.33-7.23(m,5H),5.05-5.01(m,1H),4.49(t,1H),3.90-3 .86(m,1H),2.79-2.72(m,2H),2.49-2.37(m,1H),2.13(s,3H),1.84-1.78( m,2H),1.71-1.66(m,2H),1.59-1.49(m,2H); LC-MS(ESI):m / z=674.1[M+H] + .

[0502] Example 52 and Example 53

[0503] Step 1: Compound 52A (1.00 g, 7.19 mmol) was dissolved in dichloromethane (20 mL). Triethylamine (1.86 g, 14.38 mmol) was added. After the reaction mixture was purged with nitrogen, acetyl chloride (680 mg, 8.64 mmol) was slowly added dropwise under an ice bath. After complete addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 52B (700 mg, yield: 53.76%).

[0504] 1H NMR (400MHz, CDCl3) δ9.16 (s, 1H), 8.98 (s, 1H), 8.90 (s, 1H), 7.68 (br s, 1H), 2.29 (s, 3H); LC-MS (ESI): m / z=182.1[M+H] + .

[0505] Step 2: Compound 52B (700 mg, 3.86 mmol) was dissolved in methanol (20 mL), and palladium on carbon (690 mg, 0.58 mmol, 10% wt) was added. The reaction mixture was purged with hydrogen and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 52C (400 mg crude product), which was used directly in the next reaction.

[0506] 1 H NMR (400MHz, CDCl3) δ7.83-7.82(m,1H),7.78(s,1H),7.75-7.74(m,1H),7.14(br s,1H),3.74(br s,1H),2.19(s,3H); LC-MS(ESI): m / z=152.2[M+H] + .

[0507] Step 3: Compound 1D (200 mg, 0.38 mmol) was dissolved in tetrahydrofuran (25 mL), and compound 52C (70 mg, 0.46 mmol) and DIPEA (100 mg, 0.76 mmol) were added, respectively. The reaction mixture was stirred at room temperature for 16 hours. Water (40 mL) was added to quench the reaction and the mixture was extracted three times with ethyl acetate (40 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 52D (140 mg, yield: 57.47%). LC-MS (ESI): m / z = 641.2 [M+H] + .

[0508] Step 4: Chiral SFC resolution of compound 52D afforded compound 52 (SFC retention time: 0.848 min, 24.3 mg) and compound 53 (SFC retention time: 1.133 min, 24.0 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral WHEIK Column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHEIK Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in isopropanol; Gradient: 45% B gradient; Elution flow rate: 100 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 5.0 min; Sample preparation: Sample concentration: 5 mg / mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

[0509] Compound 52 (SFC analysis retention time: 0.848 min): 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.89(s,1H),8.34-8.33(m,1H),8.11-8. 10(m,1H),7.99(s,1H),7.87-7.84(m,2H),7.76-7.74(m,2H),7.70-7.68(m,2H) ,7.44-7.42(m,2H),7.37-7.34(m,2H),7.29-7.26(m,3H),5.19-5.15(m,1H),4 .75-4.70(m,1H),4.19-4.15(m,1H),2.04(s,3H); LC-MS(ESI):m / z=641.1[M+H] + .

[0510] Compound 53 (SFC analysis retention time: 1.133 min): 1H NMR(400MHz,DMSO-d6)δ10.07(s,1H),9.89(s,1H),8.34-8.33(m,1H),8.11-8. 10(m,1H),7.99(s,1H),7.87-7.84(m,2H),7.76-7.74(m,2H),7.70-7.68(m,2H) ,7.45-7.42(m,2H),7.37-7.34(m,2H),7.29-7.25(m,3H),5.19-5.14(m,1H),4 .75-4.69(m,1H),4.19-4.15(m,1H),2.04(s,3H); LC-MS(ESI):m / z=641.0[M+H] + .

[0511] Example 54 and Example 55

[0512] Step 1: Dissolve compound 54A (1.00 g, 7.19 mmol) in dichloromethane (20 mL) and add triethylamine (1.86 g, 14.38 mmol). After replacing the reaction mixture with nitrogen, slowly add acetyl chloride (680 mg, 8.64 mmol) dropwise in an ice bath. After complete addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and extracted three times with dichloromethane (15 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 54B (230 mg, yield: 17.66%). LC-MS (ESI): m / z = 182.1 [M+H] + .

[0513] Step 2: Compound 54B (230 mg, 1.27 mmol) was dissolved in methanol (10 mL) and palladium on carbon (130 mg, 0.19 mmol, 10% wt) was added. The reaction mixture was replaced with hydrogen and stirred at room temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain compound 54C (120 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 152.2 [M+H] + .

[0514] Step 3: Compound 54C (120 mg, 0.79 mmol) was treated with the same procedure as in Step 3 of Example 52 to obtain Compound 54D (300 mg, yield: 82.11%). LC-MS (ESI): m / z = 641.2 [M+H] + .

[0515] Step 4: Chiral SFC resolution of compound 54D afforded compound 54 (SFC retention time: 1.951 min, 36.4 mg) and compound 55 (SFC retention time: 2.193 min, 50.1 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral AD Column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral AD Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in isopropanol; Gradient: 35% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 7.5 min; Sample preparation: Sample concentration: 5 mg / mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

[0516] Compound 54 (SFC analysis retention time: 1.951 min): 1 H NMR(400MHz,DMSO-d6)δ10.27(s,1H),9.89(s,1H),7.97-7.95(m,3H),7.77-7.75(m,2H),7.39-7.22(m,10H),7.10 -7.01(m,1H),5.00-4.98(m,1H),4.57-4.51(m,1H),3.92-3.88(m,1H),2.08(s,3H); LC-MS(ESI):m / z=641.0[M+H] + .

[0517] Compound 55 (SFC analysis retention time: 2.193 min): 1 H NMR (400MHz, DMSO-d6) δ10.27(s,1H),9.89(s,1H),7.97-7.95(m,3H),7.77-7.75(m,2H),7.39-7.24(m,10H),7.11 -6.98(m,1H),5.00-4.98(m,1H),4.57-4.51(m,1H),3.92-3.88(m,1H),2.08(s,3H); LC-MS(ESI):m / z=641.1[M+H] + .

[0518] Example 56 and Example 57

[0519] Step 1: Dissolve compound 56A (2.0 g, 19.59 mmol) and BOC-guanidine (3.43 g, 21.55 mmol) in N,N-dimethylformamide (50 mL). Add triethylamine (3.96 g, 39.18 mmol) and HATU (8.94 g, 23.51 mmol). Stir overnight at room temperature. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 56B (1.2 g, yield: 25%). LC-MS (ESI): m / z = 244.1 [M+H] + .

[0520] Step 2: Dissolve compound 56B (600 mg, 1.70 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 56C (800 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 144.1 [M+H] + .

[0521] Step 3: Compound 56C (480 mg, 1.87 mmol) was prepared by referring to the third step of Example 1 to obtain compound 56D (150 mg, yield: 46%).

[0522] Step 4: Chiral SFC separation of compound 56D afforded compound 56 (SFC retention time: 2.305 min, 50 mg) and compound 57 (SFC retention time: 2.547 min, 45 mg). SFC analysis: Instrument: SHIMADZU LC-20AP, Column: C18 column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral Wheel Column; Mobile phase: A: CO2, B: isopropanol; Gradient: 40% B; Flow rate: 120 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 4.3 min. Sample preparation: Sample concentration: 10 mg / mL, acetonitrile-methanol mixture injected: 2.0 mL per injection.

[0523] Compound 56 (SFC analysis retention time: 1.708 min): 1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.01(d,2H),7.84(d,2H),7.55-7.49(m,2H),7.42-7.36(m,2H),7.34-7.21(m,5 H),6.90(s,1H),5.08-5.00(m,1H),4.50(t,1H),3.90-3.83(m,1H),1.22-1.09(m,4H); LC-MS(ESI):m / z=633.2[M+H] + .

[0524] Compound 57 (SFC analysis retention time: 2.087 min): 1 H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.01(d,2H),7.84(d,2H),7.55-7.49(m,2H),7.42-7.36(m,2H),7.34-7.21(m,5 H),6.90(s,1H),5.08-5.00(m,1H),4.50(t,1H),3.90-3.83(m,1H),1.22-1.09(m,4H); LC-MS(ESI):m / z=633.2[M+H] + .

[0525] Example 58 and Example 59

[0526] Step 1: Dissolve compound 58A (2.0 g, 19.61 mmol) and BOC-guanidine (3.74 g, 23.53 mmol) in dichloromethane (50 mL). Add triethylamine (5.94 g, 58.83 mmol) and then HATU (8.94 g, 23.53 mmol). Stir under nitrogen for 2 h at room temperature. Quench the reaction with water (50 mL) and extract twice with ethyl acetate (30 mL). The organic phase is collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by silica gel column chromatography to yield compound 58B (3.5 g, yield: 74%). LC-MS (ESI): m / z = 244.2 [M+H] + .

[0527] Step 2: Dissolve compound 58B (3.5 g, 14.41 mmol) in dichloromethane (35 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 16 h. The reaction solution was concentrated to obtain compound 58C (6.4 g crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 144.1 [M+H] + .

[0528] Step 3: Compound 58C (500 mg, 1.77 mmol) was prepared by following the procedure of Step 3 of Example 1 to obtain compound 58D (200 mg).

[0529] Step 4: Compound 58D was further resolved by chiral SFC to yield compound 58 (SFC retention time: 0.944 min, 73.7 mg) and compound 59 (SFC retention time: 1.781 min, 78.6 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral IK column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 40% B; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO2, B: isopropanol; Gradient: 50% B; Flow rate: 100 mL / min, Column temperature: Room temperature, Wavelength: 220 nm, Cycle time: 7 min. Sample preparation: Sample concentration: 5 mg / mL, ethanol solution injection: 3.0 mL per injection.

[0530] Compound 58 (SFC analysis retention time: 0.944 min): 1 H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.00(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.35-7.20(m,5H),5.05-5.01(m,1H ),4.69-4.65(m,2H),4.62-4.56(m,2H),4.52-4.46(m,1H),4.05-3.99(m,1H),3.89-3.84(m,1H); LC-MS(ESI):m / z=633.1[M+H] + .

[0531] Compound 59 (SFC analysis retention time: 1.781 min): 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.00(d,2H),7.82(d,2H),7.51(d,2H),7.39(d,2H),7.35-7.20(m,5H),5.05-5.01(m,1H ),4.69-4.65(m,2H),4.62-4.56(m,2H),4.52-4.46(m,1H),4.05-3.99(m,1H),3.89-3.84(m,1H); LC-MS(ESI):m / z=633.1[M+H] + .

[0532] Example 60, Example 61, Example 62 and Example 63

[0533] Step 1: Dissolve compound 60A (500 mg, 3.87 mmol) and BOC-guanidine (575 mg, 4.64 mmol) in tetrahydrofuran (10 mL). Add triethylamine (1.5 g, 19.35 mmol) and then 1-n-propylphosphoric anhydride (1.45 g, 5.81 mmol). Stir under nitrogen for 2 h at room temperature. Quench the reaction with water (50 mL) and extract twice with ethyl acetate (30 mL). The organic phase is collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by silica gel column chromatography to yield compound 60B (800 mg, yield: 76%). LC-MS (ESI): m / z = 271.2 [M+H] + .

[0534] Step 2: Dissolve compound 60B (800 mg, 2.96 mmol) in dichloromethane (35 mL), add trifluoroacetic acid (10 mL), and stir at room temperature for 16 h. The reaction solution was concentrated to obtain compound 60C (1 g crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 171.2 [M+H] + .

[0535] Step 3: Compound 60C (1 g) was treated with the same procedure as in Step 3 of Example 1 to give Compound 60D (1 g, yield: 80%). LC-MS (ESI): m / z = 660.1 [M+H] + .

[0536] Step 4: Compound 60D was further resolved by chiral SFC to yield compound 60 (SFC retention time: 0.795 min, 41.6 mg), compound 61 (SFC retention time: 0.826 min, 27.9 mg), compound 62 (SFC retention time: 1.265 min, 64.8 mg), and compound 63 (SFC retention time: 1.312 min, 68.3 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, Column: Chiral OX column; Mobile phase: A: CO2, B: 0.05% DEA in 1% ethanol and acetonitrile; Gradient: 40% B; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm.

[0537] SFC splitting method:

[0538] First resolution: Instrument: Waters 150 Prep-SFC; Column: Chiral OX column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol and acetonitrile; Gradient: B for 50%; Elution flow rate: 100 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 5.0 min; Sample preparation: Compound at 10 mg / mL, dissolved in acetonitrile and methanol. Injection: 5.0 mL per injection. Fraction A and fraction B were separated.

[0539] Fraction A was further separated and purified by SFC using the following methods: Instrument: SHIMADZU LC-20AP; Column: Chiral IA column; Mobile phase: A for n-Hexane; B for 0.1% NH₃·H₂O in isopropanol and acetonitrile; Gradient: B for 17%; Elution flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 14 min; Sample preparation: Compounds were dissolved in acetonitrile and methanol at a concentration of 10 mg / mL. Injection: 5.0 mL per injection. Compounds 60 and 61 were isolated.

[0540] Fraction B was further separated and purified by SFC using the following methods: Instrument: Waters 150 Prep-SFC; Column: Chiral IC column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in isopropanol and acetonitrile; Gradient: B for 40%; Elution flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 7.5 min; Sample preparation: Compound 62 and Compound 63 were isolated at a concentration of 10 mg / mL in acetonitrile and methanol. Injection: 4.0 mL per injection.

[0541] Compound 60 (SFC analysis retention time: 0.795 min): 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2 H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H); LC-MS(ESI):m / z=660.1[M+H] + .

[0542] Compound 61 (SFC analysis retention time: 0.826 min): 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2 H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H); LC-MS(ESI):m / z=660.1[M+H] + .

[0543] Compound 62 (SFC analysis retention time: 1.265 min): 1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2 H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H); LC-MS(ESI):m / z=660.1[M+H] + .

[0544] Compound 63 (SFC analysis retention time: 1.312 min): 1 H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.01-7.99(m,2H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.40-7.37(m,2 H),7.33-7.22(m,5H),5.06-5.02(m,1H),4.52-4.46(m,1H),3.89-3.85(m,1H),3.10-3.06(m,1H),2.70-2.66(m 1H),2.48-2.36(m,3H),2.20(s,3H),1.97-1.86(m,2H); LC-MS(ESI):m / z=660.1[M+H] + .

[0545] Example 64 and Example 65

[0546] Step 1: Compound 64A (1.4 g, 6.19 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.89 g, 18.77 mmol) was added. The atmosphere was replaced with nitrogen three times, and methyl chloroformate (664 mg, 7.06 mmol) was slowly added dropwise in an ice bath. After addition, the mixture was slowly returned to room temperature and stirred for 1 hour. After completion of the reaction as monitored by TLC, water (10 mL) was added and stirred for 5 minutes. The organic phase was washed twice with dilute hydrochloric acid (1 mol / L), and the aqueous phase was extracted three times with dichloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide compound 64B (1.63 g, yield: 93%).

[0547] 1HNMR (400MHz, CDCl3) δ9.01(s,1H),8.60(s,1H),8.37-8.35(m,1H),8.25-8.23(m,1H),3.72(s,3H).

[0548] Step 2: Compound 64B (1.63 g, 5.74 mmol) and compound 22D (1.47 g, 5.74 mmol) were dissolved in toluene (20 mL). After addition, the system was protected with nitrogen and heated to 110°C with stirring for 4 h. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 64D (2.24 g, yield: 77%). LCMS (ESI): m / z = 509.1 [M+H] + .

[0549] Step 3: To a 100 mL single-necked flask, add toluene (20 mL), followed by compound 64D (2.24 g, 4.41 mmol) and N,N-diisopropylethylamine (1.42 g, 11.03 mmol). Then, slowly add phosphorus oxychloride (1.01 g, 6.62 mmol) dropwise. After the addition is complete, the system is protected with nitrogen and heated to 100°C with stirring for 1 h. After completion of the reaction as monitored by TLC, the reaction solution is concentrated under reduced pressure to yield compound 64E (3 g crude product), which is used directly in the next reaction. LCMS (ESI): m / z = 527.2 [M+H] + .

[0550] Step 4: Compound 64E (350 mg, 0.66 mmol) was dissolved in dichloromethane (30 mL), and compound 1C (320 mg, 1.12 mmol) and triethylamine (200 mg, 1.98 mmol) were added. After the addition was complete, the reaction was stirred at room temperature overnight, quenched with water (40 mL), and extracted three times with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to afford compound 64F (180 mg).

[0551] Step 5: Compound 64F was subjected to chiral SFC separation to yield compound 64 (SFC retention time: 5.85 min, 50 mg) and compound 65 (SFC retention time: 7.05 min, 40 mg). SFC analysis method: Instrument: SHIMADZU LC-30AD sf, Column: Chiral Cellulose-2 column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 40% B; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparative method: Instrument: SFC Prep 150AP; Column: AD (19 mm × 250 mm); The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO2, Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content: 40%; c. Flow rate: 40 mL / min.

[0552] Compound 64 (SFC analysis retention time: 5.85 min): 1 H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.01(s,1H),8.38(d,1H),8.14(d,1H),7.60-7.46(m,2H),7.44-7.36(m,2 H),7.36-7.20(m,5H),5.13-4.98(m,1H),4.54(t,1H),4.02-3.88(m,1H),1.97-1.86(m,1H),0.96-0.76(m,4H);

[0553] LC-MS (ESI): m / z = 618.2 [M+H] + .

[0554] Compound 65 (SFC analysis retention time: 7.05 min): 1 H NMR(400MHz,DMSO-d6)δ10.70(s,1H),9.01(s,1H),8.38(d,1H),8.14(d,1H),7.60-7.46(m,2H),7.44-7.36(m,2 H),7.36-7.20(m,5H),5.13-4.98(m,1H),4.54(t,1H),4.02-3.88(m,1H),1.97-1.86(m,1H),0.96-0.76(m,4H);

[0555] LC-MS (ESI): m / z = 618.2 [M+H] + .

[0556] Example 66 and Example 67

[0557] Step 1: Dissolve compound 1D (900 mg, 1.71 mmol) in DMF (20 mL). Add 4,6-diaminopyrimidine (380 mg, 3.42 mmol) and triethylamine (520 mg, 5.13 mmol), respectively, and stir at room temperature overnight. Quench the reaction with water (40 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 66A (1 g, yield: 97%). LC-MS (ESI): m / z = 600.1 [M+H] + .

[0558] Step 2: Compound 66A (1.0 g, 1.67 mmol) and triethylamine (0.42 g, 4.17 mmol) were added to dry dichloromethane (30 mL). Acetyl chloride (0.20 g, 2.50 mmol) was slowly added under an ice bath. After the addition was complete, the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added and the mixture was extracted twice with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 66B (130 mg, yield: 12%). LC-MS (ESI): m / z = 642.2 [M+H] + .

[0559] Step 3: Chiral SFC separation of compound 66B afforded compound 66 (pre-SFC preparative peak, 30 mg) and compound 67 (post-SFC preparative peak, 35 mg). SFC preparative method: Instrument: SFC Prep 150AP; Column: IK (19 mm × 250 mm); The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO2; Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content: 50%; c. Flow rate: 38 mL / min.

[0560] Compound 66 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.38(s,1H),8.33-8.19(m,1H),7.96(d,2H),7.76(d,2H),7.46-7.29(m,9H),7 .27-7.21(m,1H),5.08-4.97(m,1H),4.63-4.46(m,1H),3.94-3.82(m,1H),2.11(s,3H); LC-MS(ESI):m / z=642.2[M+H]+ .

[0561] Compound 67 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),10.38(s,1H),8.33-8.19(m,1H),7.96(d,2H),7.76(d,2H),7.46-7.29(m,9H),7 .27-7.21(m,1H),5.08-4.97(m,1H),4.63-4.46(m,1H),3.94-3.82(m,1H),2.11(s,3H); LC-MS(ESI):m / z=642.2[M+H] + .

[0562] Example 68 and Example 69

[0563] Step 1: Dissolve compound 68A (500 mg, 4.23 mmol) and BOC-guanidine (1.01 g, 6.35 mmol) in N,N-dimethylformamide (20 mL). Add DIPEA (1.64 g, 12.69 mmol) and HATU (2.09 g, 5.55 mmol). After addition, stir at room temperature for 3 hours. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 68B (800 mg) and compound 68C (200 mg). LC-MS (ESI): m / z = 260.1 [M+H] + .

[0564] Step 2: Dissolve compound 68B (800 mg, 3.09 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 68D (800 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 160.1 [M+H] + .

[0565] Step 3: Compound 68D (150 mg, 0.56 mmol) was prepared by referring to the third step of Example 40 to obtain compound 68E (120 mg, yield: 65%).

[0566] Step 4: Chiral SFC separation of compound 68E afforded compound 68 (pre-SFC preparative peak, 35 mg) and compound 69 (post-SFC preparative peak, 40 mg). SFC preparative method: Instrument: SFC Prep 150AP; Column: IK (19 mm × 250 mm); The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO2, Mobile phase B: isopropanol; b. Isocratic elution, mobile phase B content: 50%; c. Flow rate: 38 mL / min.

[0567] Compound 68 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.00(d,2H),7.81(d,2H),7.53-7.46(m,2H),7.42-7.36(m,2H),7.35-7.21(m,5H) ,5.25-5.17(m,0.5H),5.11-4.98(m,1.5H),4.54-4.42(m,1H),3.92-3.83(m,1H),3.38-3.31(m,1H),2.48-2.30(m,4H).

[0568] LC-MS (ESI): m / z = 649.2 [M+H] + .

[0569] Compound 69 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.00(d,2H),7.81(d,2H),7.53-7.46(m,2H),7.42-7.36(m,2H),7.35-7.21(m,5H) ,5.25-5.17(m,0.5H),5.11-4.98(m,1.5H),4.54-4.42(m,1H),3.92-3.83(m,1H),3.38-3.31(m,1H),2.48-2.30(m,4H).

[0570] LC-MS (ESI): m / z = 649.2 [M+H] + .

[0571] Example 70 and Example 71

[0572] Step 1: Compound 70A (1.00 g, 9.99 mmol) and tert-butyloxycarbonylguanidine (1.67 g, 10.49 mmol) were dissolved in N,N-dimethylformamide (20 mL). Diisopropylethylamine (3.03 g, 29.96 mmol) and HATU (4.56 g, 11.99 mmol) were added. After completion of the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 70B (1.10 g, yield: 45.64%). LC-MS (ESI): m / z = 186.1 [M-56+H] + .

[0573] Step 2: Dissolve compound 70B (500 mg, 2.07 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 70C (420 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 142.2 [M+H] + .

[0574] Step 3: Compound 70C (420 mg crude product, 2.07 mmol) was treated according to the procedure of Step 3 of Example 1 to obtain compound 70D (550 mg, yield: 91.75%). LC-MS (ESI): m / z = 631.2 [M+H] + .

[0575] Step 4: Chiral SFC separation of compound 70D afforded compound 70 (SFC retention time: 2.217 min, 203.8 mg) and compound 71 (SFC retention time: 2.485 min, 153.5 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral WHELK Column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHELK Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in isopropanol; Gradient: 35% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 4.5 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.

[0576] Compound 70 (SFC analysis retention time: 2.217 min): 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.02-8.00(m,2H),7.82-7.80(m,2H) ),7.51-7.49(m,2H),7.39-7.37(m,2H),7.34-7.22(m,5H),5.05-5.01(m, 1H),4.52-4.46(m,1H),3.92-3.85(m,1H),3.35-3.27(m,1H),2.22-2.07( m,4H),1.97-1.86(m,1H),1.83-1.75(m,1H); LC-MS(ESI):m / z=643.1[M+H] + .

[0577] Compound 71 (SFC analysis retention time: 2.485 min): 1 H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.02-8.00(m,2H),7.82-7.80(m,2H) ),7.51-7.49(m,2H),7.39-7.37(m,2H),7.34-7.22(m,5H),5.05-5.01(m, 1H),4.52-4.46(m,1H),3.92-3.85(m,1H),3.35-3.27(m,1H),2.19-2.07( m,4H),1.97-1.88(m,1H),1.83-1.75(m,1H); LC-MS(ESI):m / z=643.0[M+H] + .

[0578] Example 72 and Example 73

[0579] Step 1: Compound 72A (1.00 g, 7.93 mmol) and tert-butyloxycarbonylguanidine (1.64 g, 10.31 mmol) were dissolved in N,N-dimethylformamide (20 mL). Diisopropylethylamine (2.41 g, 23.79 mmol) and HATU (3.32 g, 8.72 mmol) were added. After the addition was complete, the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 72B (1.00 g, yield: 47.18%). LC-MS (ESI): m / z = 268.2 [M+H] + .

[0580] Step 2: Dissolve compound 72B (500 mg, 1.87 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 72C (500 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 168.1 [M+H] + .

[0581] Step 3: Compound 72C (500 mg crude product, 1.87 mmol) was treated according to the procedure of Step 3 of Example 1 to obtain compound 72D (600 mg, yield: 96.13%). LC-MS (ESI): m / z = 657.2 [M+H] + .

[0582] Step 4: Chiral SFC separation of compound 72D afforded compound 72 (SFC retention time: 1.884 min, 265.0 mg) and compound 73 (SFC retention time: 2.165 min, 262.2 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral OD Column; Mobile Phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OD Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in ethanol; Gradient: 35% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 4.3 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.

[0583] Compound 72 (SFC analysis retention time: 1.884 min): 1 H NMR(400MHz,DMSO-d6)δ9.26(br s,1H),8.03-7.92(m,5H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.37-7.35(m,2H),7.31-7.22(m,5H),6.89-6. 88(m,1H),5.06-5.02(m,1H),4.54-4.49(m,1H),3.95(s,3H),3.92-3.88(m,1H); LC-MS(ESI):m / z=657.0[M+H] + .

[0584] Compound 73 (SFC analysis retention time: 2.165 min): 1 H NMR(400MHz,DMSO-d6)δ9.26(br s,1H),8.06-7.92(m,5H),7.83-7.81(m,2H),7.52-7.50(m,2H),7.37-7.35(m,2H),7.31-7.24(m,5H),6.89-6. 88(m,1H),5.06-5.02(m,1H),4.54-4.49(m,1H),3.95(s,3H),3.92-3.88(m,1H); LC-MS(ESI):m / z=657.1[M+H] + .

[0585] Example 74 and Example 75

[0586] Step 1: Dissolve compound 68C (200 mg, 0.77 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 74A (200 mg crude product), which was used directly in the next step. LC-MS (ESI): m / z = 160.1 [M+H] + .

[0587] Step 2: Compound 74A (150 mg, 0.56 mmol) was prepared by referring to the third step of Example 40 to obtain compound 74B (120 mg, yield: 65%).

[0588] Step 3: Chiral SFC separation of compound 74B afforded compound 74 (pre-SFC peak, 45 mg) and compound 75 (post-SFC peak, 35 mg). SFC preparative method: Instrument: SFC Prep 150AP; Column: IG (19 mm × 250 mm); The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A, B composition: Mobile phase A: CO2, Mobile phase B: isopropanol (0.01% ammonia solution); b. Isocratic elution, mobile phase B content: 30%; c. Flow rate: 40 mL / min.

[0589] Compound 74 (peak before SFC preparation): 1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.00(d,2H),7.80(d,2H),7.53-7.46(m,2H),7.41-7.36(m,2H),7.35-7.21(m,5H),5.12-4.99(m,1.5H),4 .98-4.90(m,0.5H),4.55-4.43(m,1H),3.91-3.82(m,1H),2.86-2.74(m, 1H),2.59-2.51(m,2H),2.33-2.17(m,2H); LC-MS(ESI): m / z=649.2[M+H] + .

[0590] Compound 75 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.00(d,2H),7.80(d,2H),7.53-7.46(m,2H),7.41-7.36(m,2H),7.35-7.21(m,5H),5.12-4.99(m,1.5H),4 .98-4.90(m,0.5H),4.55-4.43(m,1H),3.91-3.82(m,1H),2.86-2.74(m, 1H),2.59-2.51(m,2H),2.33-2.17(m,2H); LC-MS(ESI): m / z=649.2[M+H] + .

[0591] Example 76 and Example 77

[0592] Step 1: Compound 76A (1.0 g, 4.42 mmol) was dissolved in dichloromethane (20 mL), and triethylamine (1.34 g, 13.26 mmol) was added. The atmosphere was replaced with nitrogen three times. Isopropyl chloroformate (810 mg, 6.63 mmol) was slowly added dropwise in an ice bath. After addition, the mixture was slowly returned to room temperature and stirred for 1 hour. After completion of the reaction, as monitored by TLC, water (10 mL) was added and stirred for 5 minutes. The organic phase was washed twice with dilute hydrochloric acid (1 mol / L) and then extracted three times with chloromethane (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide compound 76B (1.0 g, yield: 72%).

[0593] Step 2: Compound 76B (0.6 g, 1.92 mmol) and compound 22D (0.49 g, 1.92 mmol) were dissolved in toluene (20 mL). After addition, the system was protected with nitrogen and heated to 110°C with stirring for 4 h. After cooling, the mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 76C (0.6 g, yield: 61%). LCMS (ESI): m / z = 509.1 [M+H] + .

[0594] Step 3: To a 100 mL single-necked flask, add toluene (20 mL), followed by compound 76C (0.6 g, 1.18 mmol) and N,N-diisopropylethylamine (0.31 g, 2.36 mmol). Then, slowly add phosphorus oxychloride (0.36 g, 2.36 mmol) dropwise. After the addition is complete, the system is protected by nitrogen and heated to 100°C with stirring for 1 h. After the reaction is complete as monitored by TLC, the reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to obtain compound 76D (0.39 g, yield: 63%). LCMS (ESI): m / z = 527.2 [M+H] + .

[0595] Step 4: Compound 76D (220 mg, 0.42 mmol) was dissolved in dichloromethane (20 mL), and compound 1C (200 mg, 0.84 mmol) and triethylamine (130 mg, 1.26 mmol) were added. After the addition was complete, the reaction was stirred at room temperature overnight. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 76E (150 mg).

[0596] Step 5: Compound 76E obtained in the previous step was further resolved by chiral SFC to yield compounds 76 (pre-SFC preparative peak, 55 mg) and 77 (post-SFC preparative peak, 50 mg). SFC preparative method: 1. Apparatus: SFC Prep 150AP; Column: IK (19 mm × 250 mm); The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: CO2, Mobile phase B: isopropanol (0.01% ammonia solution); b. Isocratic elution, mobile phase B content: 52%.

[0597] Compound 76 (peak before SFC preparation): 1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.15-9.06(m,1H),8.45-8.39(m,1H),8.00(d,1H),7.55-7.47(m,2H),7.43-7.36(m,2H),7.35 -7.20(m,5H),5.09-4.98(m,1H),4.51(t,1H),3.95-3.83(m,1H),2.02-1.90(m,1H),0.94-0.78(m,4H); LC-MS(ESI):m / z=618.1[M+H] + .

[0598] Compound 77 (eluted after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.86(s,1H),9.15-9.06(m,1H),8.45-8.39(m,1H),8.00(d,1H),7.55-7.47(m,2H),7.43-7.36(m,2H),7.35 -7.20(m,5H),5.09-4.98(m,1H),4.51(t,1H),3.95-3.83(m,1H),2.02-1.90(m,1H),0.94-0.78(m,4H); LC-MS(ESI):m / z=618.1[M+H] + .

[0599] Example 78 and Example 79

[0600] Step 1: Compound 78A (1.00 g, 6.53 mmol) and tert-butyloxycarbonylguanidine (1.35 g, 8.49 mmol) were dissolved in N,N-dimethylformamide (20 mL). Diisopropylethylamine (1.98 g, 19.59 mmol) and HATU (2.98 g, 7.84 mmol) were added. After completion of the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 78B (1.00 g, yield: 52.03%). LC-MS (ESI): m / z = 295.2 [M+H] + .

[0601] Step 2: Dissolve compound 78B (500 mg, 1.70 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain compound 78C (400 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 195.1 [M+H] + .

[0602] Step 3: Compound 78C (200 mg crude product, 0.85 mmol) was treated according to the procedure of Step 3 of Example 1 to obtain Compound 78D (250 mg, yield: 96.18%). LC-MS (ESI): m / z = 684.2 [M+H] + .

[0603] Step 4: Chiral SFC separation of compound 78D afforded compound 78 (SFC retention time: 2.135 min, 62.6 mg) and compound 79 (SFC retention time: 2.366 min, 62.1 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral OD Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral OD Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in ethanol; Gradient: 35% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 3.5 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

[0604] Compound 78 (SFC analysis retention time: 2.135 min): 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.05-8.03(m,2H),7.95(br s,2H),7.84-7.79(m,3H),7.54-7.52(m,2H),7.39-7.37(m,2H),7.30-7.24(m,5H),6.87-6.86(m,1H),6.49-6. 47(m,1H),5.06-5.02(m,1H),4.53-4.47(m,1H),3.91-3.87(m,1H),3.47(s,3H); LC-MS(ESI):m / z=684.1[M+H] + .

[0605] Compound 79 (SFC analysis retention time: 2.366 min): 1 H NMR(400MHz,DMSO-d6)δ11.04(s,1H),8.05-8.03(m,2H),7.95(br s,2H),7.84-7.79(m,3H),7.54-7.52(m,2H),7.39-7.37(m,2H),7.32-7.22(m,5H),6.87-6.86(m,1H),6.49-6. 47(m,1H),5.06-5.02(m,1H),4.53-4.47(m,1H),3.91-3.87(m,1H),3.47(s,3H); LC-MS(ESI):m / z=684.0[M+H] + .

[0606] Example 80 and Example 81

[0607] Step 1: Compound 80A (1.00 g, 9.99 mmol) and tert-butyloxycarbonylguanidine (2.07 g, 12.98 mmol) were dissolved in N,N-dimethylformamide (25 mL). Diisopropylethylamine (3.03 g, 29.96 mmol) and HATU (4.56 g, 11.99 mmol) were added. After completion of the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water (100 mL) and extracted twice with ethyl acetate (50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 80B (2.00 g, yield: 82.98%). LC-MS (ESI): m / z = 186.1 [M-56+H] + .

[0608] Step 2: Dissolve compound 80B (500 mg, 2.07 mmol) in dichloromethane (24 mL), add trifluoroacetic acid (6 mL), and stir at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 80C (500 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 142.1 [M+H] + .

[0609] Step 3: Compound 80C (250 mg crude product, 1.03 mmol) was subjected to the same procedure as in Step 3 of Example 1 to obtain compound 80D (230 mg, yield: 95.92%). LC-MS (ESI): m / z = 631.2 [M+H] + .

[0610] Step 4: Chiral SFC separation of compound 80D afforded compound 80 (SFC retention time: 0.525 min, 84.2 mg) and compound 81 (SFC retention time: 0.797 min, 62.3 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3.H2O in isopropanol; Gradient: 40% B gradient; Elution flow rate: 120 mL / min; Column temperature: 25°C; Wavelength: 220 nm; Cycle time: 2.5 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile and dichloromethane mixed solution injection: 5.0 mL each time.

[0611] Compound 80 (SFC analysis retention time: 0.525 min): 1 H NMR(400MHz,DMSO-d6)δ8.03-8.01(m,2H),7.837.81(m,2H),7.46-7.44(m,2H),7.38-7.36(m,2H),7.33-7.29(m,2H),7.25-7.22(m,3H), 5.03-4.99(m,1H),4.52-4.46(m,1H),3.92-3.88(m,1H),1.35(s,3H),1.15-1.14(m,2H),0.76-0.73(m,2H); LC-MS(ESI):m / z=631.1[M+H] + .

[0612] Compound 81 (SFC analysis retention time: 0.797 min): 1 H NMR(400MHz,DMSO-d6)δ8.03-8.01(m,2H),7.837.81(m,2H),7.47-7.44(m,2H),7.38-7.36(m,2H),7.33-7.29(m,2H),7.25-7.22(m,3H), 5.03-4.99(m,1H),4.52-4.46(m,1H),3.92-3.88(m,1H),1.35(s,3H),1.15-1.14(m,2H),0.76-0.73(m,2H); LC-MS(ESI):m / z=631.2[M+H] + .

[0613] Example 82 and Example 83

[0614] Step 1: Dissolve compound 82A (2.0 g, 16.12 mmol) and N-Boc-guanidine (3.85 g, 24.18 mmol) in N,N-dimethylformamide (30 mL). Add diisopropylethylamine (6.25 g, 48.36 mmol) and HATU (9.19 g, 24.18 mmol). After addition, stir at room temperature overnight. Add water (100 mL) and extract with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to yield compound 82B (1.50 g, yield: 35.1%). LC-MS (ESI): m / z = 266.1 [M+H] + .

[0615] Step 2: Dissolve compound 82B (500 mg, 1.88 mmol) in dichloromethane (9 mL), add trifluoroacetic acid (3 mL), and stir at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure to obtain compound 82C (500 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 166.1 [M+H] + .

[0616] Step 3: The crude compound 82C (200 mg, 1.22 mmol) was subjected to the procedure of Step 3 of Example 40 to obtain compound 82D (80 mg).

[0617] Step 4: Chiral SFC separation of compound 82D afforded compound 82 (pre-SFC elution, 20 mg) and compound 83 (post-SFC elution, 25 mg). SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phases: A: CO2, B: 0.1% NH3·H2O in methanol; Gradient: 50% B gradient elution, flow rate: 40 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 20 min; Sample preparation: Sample concentration: 2 mg / mL, methanol solution injection: 2 mL per injection.

[0618] Compound 82 (peak before SFC preparation): 1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.28(s,1H),9.02(s,1H),8.78(s,1H),8.02(d,4H),7.80(d,2H),7.53(d,2H) ,7.36(d,2H),7.30-7.22(m,5H),5.07-5.03(m,1H),4.53(t,1H),3.93-3.88(m,1H); LC-MS(ESI):m / z=655.3[M+H] + .

[0619] Compound 83 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ9.90(s,1H),9.28(s,1H),9.02(s,1H),8.78(s,1H),8.02(d,4H),7.80(d,2H),7.53(d,2H) ,7.36(d,2H),7.30-7.21(m,5H),5.07-5.03(m,1H),4.53(t,1H),3.93-3.88(m,1H); LC-MS(ESI):m / z=655.3[M+H] + .

[0620] Example 84 and Example 85

[0621] Step 1: Compound 84A (358 mg, 2.55 mmol) was subjected to the same procedure as in Step 1 of Example 18 to obtain compound 84B (0.48 g, yield: 80%). LC-MS (ESI): m / z = 630.3 [M+H] + .

[0622] Step 2: Compound 84B (0.48 g) was subjected to chiral SFC separation to yield compound 84 (pre-SFC preparative peak, 160 mg) and compound 85 (post-SFC preparative peak, 156 mg). SFC preparative method: 1. Apparatus: SFC Prep 150AP; Column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: CO2; Mobile phase B: Isopropanol (0.01% ammonia solution); b. Isocratic elution, mobile phase B content: 45%; c. Flow rate: 38 mL / min.

[0623] Compound 84 (peak before SFC preparation): 1H NMR(400MHz,DMSO-d6)δ8.67(d,1H),8.01(d,2H),7.86(d,2H),7.76(d,2H), 7.45(d,2H),7.33(t,2H),7.26(t,1H),7.22(d,2H),5.07(dd,1H),4.76-4.6 6(m,1H),4.53-4.41(m,2H),4.32-4.20(m,1H),4.12-4.00(m,1H),3.97-3.8 6(m,2H),1.56-1.47(m,1H),0.76-0.65(m,4H); LC-MS(ESI):m / z=630.3[M+H] + .

[0624] Compound 85 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.67(d,1H),8.01(d,2H),7.86(d,2H),7.76(d,2H), 7.45(t,2H),7.33(t,2H),7.26(t,1H),7.22(d,2H),5.08(dd,1H),4.76-4.6 5(m,1H),4.54-4.40(m,2H),4.31-4.20(m,1H),4.10-4.01(m,1H),3.98-3.8 5(m,2H),1.56-1.47(m,1H),0.80-0.63(m,4H); LC-MS(ESI):m / z=630.3[M+H] + .

[0625] Example 86 and Example 87

[0626] Step 1: Dissolve compound 86A (5.0 g, 29.03 mmol) in dichloromethane (100 mL). Add triethylamine (8.8 g, 87.09 mmol). After purging the nitrogen atmosphere three times, slowly add a solution of methylaminocarbonyl chloride (4.07 g, 43.55 mmol) in dichloromethane (10 mL) dropwise in an ice bath. After the addition is complete, stir the reaction mixture in an ice bath for 30 min. Quench the reaction with water (100 mL) and extract twice with dichloromethane (100 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 86B (4.2 g, yield: 63%). LC-MS (ESI): m / z = 174.2 [M+H-56] + .

[0627] Step 2: Dissolve compound 86B (1.0 g, 4.36 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain compound 86C (1.15 g, crude product), which was used directly in the next reaction.

[0628] Step 3: Compound 86C (1.15 g, 4.36 mmol) was treated according to the first step of Example 18 to obtain compound 86D (0.35 g, yield: 60%). LC-MS (ESI): m / z = 619.3 [M+H] + .

[0629] Step 4: Compound 86D (0.35 g) was subjected to chiral SFC separation to yield compound 86 (pre-SFC preparative peak, 102 mg) and compound 87 (post-SFC preparative peak, 95 mg). SFC preparative method: 1. Apparatus: SFC Prep 150AP; Column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: CO2; Mobile phase B: Isopropanol (0.01% ammonia solution); b. Isocratic elution, mobile phase B content: 28%; c. Flow rate: 42 mL / min.

[0630] Compound 86 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.00(d,2H),7.85(d,2H),7.75(d,2H),7.45(d,2H),7.32(t,2H),7.25(dd,1H),7.22(dd,2H),6. 28(q,1H),5.06(dd,1H),4.69-4.54(m,1H),4.48(t,1H),3.97(td,2H),3.94-3.80(m,3H),2.55(d,3H); LC-MS(ESI):m / z=619.3[M+H] + .

[0631] Compound 87 (peak after SFC preparation): 1H NMR(400MHz,DMSO-d6)δ8.57(d,1H),8.00(d,2H),7.85(d,2H),7.75(d,2H),7.45(d,2H),7.32(t,2H),7.25(dd,1H),7.22(dd,2H),6. 27(q,1H),5.06(dd,1H),4.68-4.55(m,1H),4.47(t,1H),3.98(td,2H),3.94-3.80(m,3H),2.55(d,3H); LC-MS(ESI):m / z=619.3[M+H] + .

[0632] Example 88 and Example 89

[0633] Step 1: Dissolve compound 88A (600 mg, 3.22 mmol) in dichloromethane (10 mL). Add triethylamine (1.47 g, 14.50 mmol). After purging the nitrogen atmosphere three times, slowly add a solution of cyclopropylcarbonyl chloride (505 mg, 4.83 mmol) in dichloromethane (10 mL) dropwise in an ice bath. After the addition is complete, stir the reaction mixture in an ice bath for 30 min. Quench the reaction with water (50 mL) and extract twice with dichloromethane (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 88B (665 mg, yield: 81%). LC-MS (ESI): m / z = 199.3 [M+H-56] + .

[0634] Step 2: Dissolve compound 88B (665 mg, 2.61 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain compound 88C (645 mg, crude product), which was used directly in the next reaction.

[0635] Step 3: Compound 88C (645 mg, 2.61 mmol) was subjected to the same procedure as in Example 18, Step 1, to give Compound 88D (0.48 g, yield: 78%). LC-MS (ESI): m / z = 644.2 [M+H] + .

[0636] Step 4: Compound 88D (0.48 g) was subjected to chiral SFC separation to afford compound 88 (pre-SFC preparative peak, 204 mg) and compound 89 (post-SFC preparative peak, 195 mg). SFC preparative method: 1. Apparatus: SFC Prep 150AP; Column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: CO2; Mobile phase B: Isopropanol (0.01% ammonia solution); b. Isocratic elution, mobile phase B content: 20%; c. Flow rate: 40 mL / min.

[0637] Compound 88 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.38(d,1H),8.24(s,1H),7.99(d,2H),7.84(d,2H),7. 72(d,2H),7.44(d,2H),7.33(t,2H),7.25(t,1H),7.23-7.18(m,2H),5.05(dd, 1H),4.54-4.41(m,2H),4.28-4.15(m,1H),3.94(dd,1H),2.48-2.33(m,2H),2. 24-2.12(m,2H),1.50(dq,1H),0.68-0.60(m,4H); LC-MS(ESI):m / z=644.2[M+H] + .

[0638] Compound 89 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.38(d,1H),8.24(s,1H),7.99(d,2H),7.84(d,2H),7. 72(d,2H),7.44(d,2H),7.33(t,2H),7.25(t,1H),7.23-7.18(m,2H),5.05(dd, 1H),4.57-4.40(m,2H),4.28-4.14(m,1H),3.94(dd,1H),2.48-2.33(m,2H),2. 24-2.11(m,2H),1.50(dq,1H),0.68-0.60(m,4H); LC-MS(ESI):m / z=644.2[M+H] + .

[0639] Example 90 and Example 91

[0640] Step 1: Dissolve compound 90A (600 mg, 3.22 mmol) in dichloromethane (10 mL). Add triethylamine (1.47 g, 14.50 mmol). After purging the nitrogen atmosphere three times, slowly add a solution of cyclopropylcarbonyl chloride (505 mg, 4.83 mmol) in dichloromethane (10 mL) dropwise in an ice bath. After the addition is complete, stir the reaction mixture in an ice bath for 30 min. Quench the reaction with water (50 mL) and extract twice with dichloromethane (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 90B (650 mg, yield: 79%). LC-MS (ESI): m / z = 199.3 [M+H-56] + .

[0641] Step 2: Dissolve compound 90B (650 mg, 2.56 mmol) in dichloromethane (20 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 1.5 h. The reaction solution was concentrated under reduced pressure to obtain compound 90C (660 mg, crude product), which was used directly in the next reaction.

[0642] Step 3: Compound 90C (660 mg, 2.56 mmol) was subjected to the same procedure as in Example 18, Step 1, to give Compound 90D (0.41 g, yield: 67%). LC-MS (ESI): m / z = 644.2 [M+H] + .

[0643] Step 4: Compound 90D (0.41 g) was subjected to chiral SFC separation to afford compound 90 (pre-SFC preparative peak, 135 mg) and compound 91 (post-SFC preparative peak, 128 mg). SFC preparative method: 1. Apparatus: SFC Prep 150AP; Column: AS (19 mm × 250 mm); 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: a. Mobile phase A and B composition: Mobile phase A: CO2; Mobile phase B: Isopropanol (0.01% ammonia solution); b. Isocratic elution, mobile phase B content: 25%; c. Flow rate: 40 mL / min.

[0644] Compound 90 (peak before SFC preparation): 1H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.09(s,1H),7.99(d,2H),7.87(d,2H),7.73 (d,2H),7.47-7.41(m,2H),7.32(t,2H),7.25(t,1H),7.24-7.19(m,2H),5.05(dd ,1H),4.50(t,1H),4.03(dd,1H),3.97-3.90(m,1H),3.81(dd,1H),2.53(dd,3H), 2.10-1.93(m,2H),1.50(dq,1H),0.71-0.56(m,4H); LC-MS(ESI):m / z=644.2[M+H] + .

[0645] Compound 91 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.23(d,1H),8.09(s,1H),7.99(d,2H),7.87(d,2H),7.73 (d,2H),7.48-7.41(m,2H),7.32(t,2H),7.25(t,1H),7.24-7.19(m,2H),5.05(dd ,1H),4.50(t,1H),4.03(dd,1H),3.97-3.90(m,1H),3.81(dd,1H),2.53(dd,3H), 2.10-1.93(m,2H),1.50(dq,1H),0.72-0.54(m,4H); LC-MS(ESI):m / z=644.2[M+H] + .

[0646] Example 92, Example 93, Example 94 and Example 95

[0647] Step 1: Dissolve 1-methyl-2-oxopiperidine-4-carboxylic acid (314 mg, 2 mmol) in N,N-dimethylformamide (10 mL). HATU (1.14 g, 3 mmol), tert-butyloxycarbonylguanidine (477 mg, 3 mmol), and N,N-diisopropylethylamine (1.3 g, 10 mmol) were added sequentially. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, 40 mL of ethyl acetate was added to the system, and the mixture was washed with saturated brine (50 mL x 4). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 92A (368 mg, yield: 61.7%). LC-MS (ESI): m / z = 299.1 [M+H] + .

[0648] Step 2: Dissolve compound 92A (368 mg, 1.23 mmol) in dichloromethane (10 mL), add trifluoroacetic acid (4 mL), and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 92B (247 mg, crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 199.1 [M+H] + .

[0649] Step 3: Compound 1D (525 mg, 1 mmol) was dissolved in anhydrous acetonitrile (30 mL). Compound 92B (247 mg, crude) and N,N-diisopropylethylamine (2 mL) were added, respectively, and the mixture was reacted at 40°C for 0.5 h. After completion of the reaction as monitored by LCMS, the product was concentrated and the resulting residue was purified by silica gel column chromatography to afford compound 92C (256 mg, 37.2% yield).

[0650] Step 4: Chiral SFC separation of compound 92C afforded compound 92 (SFC retention time: 2.907 min, 28.6 mg), compound 93 (SFC retention time: 3.303 min, 22.1 mg), compound 94 (SFC retention time: 4.183 min, 29.9 mg), and compound 95 (SFC retention time: 4.955 min, 29.7 mg). SFC analysis: Instrument: SHIMADZU LC-20AD, Column: Chiral IK Column; Mobile Phase: A: n-Hexane, B: 0.1% IPA / min isopropanol and acetonitrile; Gradient: 35% B in A; Flow Rate: 1 mL / min, Column Temperature: 35°C, Wavelength: 220 nm.

[0651] Compounds 92 and 93 were prepared in the first step by SFC. Method: Instrument: Waters 150 Prep-SFC, Column: Chiral WHELK column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in isopropanol and acetonitrile; Gradient: 40% B in A; Flow rate: 120 mL / min, Column temperature: Room temperature, Wavelength: 220 nm, Cycle time: 4.8 min; Sample preparation: Sample concentration: 5 mg / mL, Acetonitrile and methanol solution injection: 3 mL each.

[0652] The remaining mixture was recovered and subjected to a second SFC preparation to obtain compounds 94 and 95. Method: Instrument: Waters 150Prep-SFC, Column: Chiral WHELK column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in isopropanol and acetonitrile; Gradient: 40% B in A; Flow rate: 120 mL / min, Column temperature: Room temperature, Wavelength: 220 nm, Cycle time: 3.5 min; Sample preparation: Sample concentration: 5 mg / mL, Acetonitrile and methanol solution injection: 3 mL each.

[0653] Compound 92 (SFC analysis retention time: 2.907 min): 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m, 2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H) ,3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2 .26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m / z=688.3[M+H] + .

[0654] Compound 93 (SFC analysis retention time: 3.303 min): 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m, 2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H) ,3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2 .26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m / z=688.3[M+H] + .

[0655] Compound 94 (SFC analysis retention time: 4.183 min): 1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m, 2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H) ,3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2 .26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m / z=688.3[M+H] + .

[0656] Compound 95 (SFC analysis retention time: 4.955 min): 1 H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.01(d,2H),7.82(d,2H),7.53-7.48(m, 2H),7.41-7.36(m,2H),7.35-7.20(m,5H),5.10-4.95(m,1H),4.59-4.40(m,1H) ,3.96-3.81(m,1H),3.28-3.19(m,2H),3.04-3.93(m,1H),2.80(s,3H),2.43-2 .26(m,2H),2.09-1.93(m,1H),1.86-1.72(m,1H); LC-MS(ESI):m / z=688.3[M+H] + .

[0657] Example 96 and Example 97

[0658] Step 1: Compound 96A (3.1 g, 14 mmol) (Synthesis reference: ACS Catalysis (2021), 11 (15), 9715-9721) was dissolved in 140 mL of anhydrous ethanol, and excess hydrazine hydrate was added. The mixture was refluxed for 6 h. After the reaction, the mixture was directly concentrated to obtain compound 96B (3.3 g, crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 237.1 [M+H] + .

[0659] Step 2: Compound 96B (3.3 g, crude product) was dispersed in anhydrous toluene, and ethyl (4-(trifluoromethyl)phenyl)sulfonyl)carbamate (3.86 g, 13 mmol) was added. The mixture was reacted at 100°C for 4 h. After the reaction was completed, the mixture was concentrated, and 100 mL of a mixture of petroleum ether and ethyl acetate (v / v = 3:1) was added to the resulting residue. The mixture was thoroughly shaken, filtered, and the filter cake was dried to obtain Compound 96C (3.1 g, two-step yield: 45.5%). LC-MS (ESI): m / z = 488.2 [M+H] + .

[0660] Step 3: Disperse compound 96C (3.1 g, 6.3 mmol) in anhydrous toluene, add phosphorus oxychloride (1.53 g, 10 mmol) and N,N-diisopropylethylamine (3.87 g, 30 mmol), and react at 100°C for 1 h. After completion of the reaction, concentrate the product, and purify the resulting residue by silica gel column chromatography to obtain compound 96D (2.8 g, yield: 88.1%). LC-MS (ESI): m / z = 506.1 [M+H] + .

[0661] Step 4: Compound 1C (127 mg, 1 mmol) was dissolved in anhydrous acetonitrile (30 mL), and compound 96D (505 mg, 1 mmol) and N,N-diisopropylethylamine (2 mL) were added, respectively. The mixture was reacted at 40°C for 0.5 h. After completion of the reaction as monitored by LCMS, the product was concentrated and the residue was purified by silica gel column chromatography to afford compound 96E (384 mg, 64.4% yield).

[0662] Step 5: Chiral SFC separation of compound 96E afforded compound 96 (SFC retention time: 1.747 min, 183.8 mg) and compound 97 (SFC retention time: 2.147 min, 181.6 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in ethanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 35% B gradient elution, flow rate: 120 mL / min, column temperature: room temperature, wavelength: 220 nm, cycle time: 4.0 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile and ethanol solution injection: 5 mL each.

[0663] Compound 96 (SFC analysis retention time: 1.747 min): 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.03(d,2H),7.82(d,2H),7.47-7.39(m,2H),7.35-7.18(m,5H),7.11(d,2H),5.05-4.95 (m,1H),5.53-4.41(m,1H),3.90-3.83(m,1H),2.23(s,3H),2.07-1.93(m,1H),0.97-0.80(m,4H); LC-MS(ESI):m / z=597.3[M+H] + .

[0664] Compound 97 (SFC analysis retention time: 2.147 min): 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.03(d,2H),7.82(d,2H),7.47-7.39(m,2H),7.35-7.18(m,5H),7.11(d,2H),5.05-4.95 (m,1H),5.53-4.41(m,1H),3.90-3.83(m,1H),2.23(s,3H),2.07-1.93(m,1H),0.97-0.80(m,4H); LC-MS(ESI):m / z=597.3[M+H] + .

[0665] Example 98 and Example 99

[0666] Step 1: In a 100 mL eggplant-shaped flask, compound 98A (530 mg, 2.37 mmol) (synthesized according to patent WO2023169481), benzyl mercaptan (440 mg, 3.5 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (87.7 mg, 0.12 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (138 mg, 0.24 mmol), and N,N-diisopropylethylamine (2 mL) were added in sequence. 20 mL of anhydrous toluene was then added, the atmosphere was purged with nitrogen, and the mixture was reacted at 100°C for 4 h. After completion of the reaction, the mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 98B (472 mg, yield: 72.1%).

[0667] Step 2: In a 50 mL eggplant-shaped flask, 98B (472 mg, 1.71 mmol) and N-chlorosuccinimide (0.9 g, 6.84 mmol) were added, followed by 10 mL of anhydrous acetic acid and 2 mL of water. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 98C (296 mg, yield: 69.1%).

[0668] Step 3: Dissolve compound 98C (296 mg, 1.2 mmol) in dichloromethane (10 mL) and add a 0.1 M amine solution in 1,4-dioxane (16 mL). Allow to react at room temperature for 2 h. After completion of the reaction, concentrate to yield compound 98D (287 mg, crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 234.0 [M+H] + .

[0669] Step 4: Compound 98D (287 mg, crude product) was dissolved in dichloromethane (10 mL), and ethyl chloroformate (194 mg, 1.8 mmol) and triethylamine (1 mL) were added. The mixture was allowed to react overnight at room temperature. After completion of the reaction, the pH was adjusted to 1-3 with 1 M hydrogen chloride solution. The organic phase was separated and concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 98E (267 mg, yield: 72.9%). LC-MS (ESI): m / z = 306.1 [M+H] + .

[0670] Step 5: Compound 98E (267 mg, 0.87 mmol) was dispersed in anhydrous toluene, and compound 22D (257 mg, 1 mmol) was added. The mixture was reacted at 100°C for 4 h. After the reaction was completed, the mixture was concentrated, and 100 mL of a mixture of petroleum ether and ethyl acetate (v / v = 3:1) was added to the resulting residue. The mixture was thoroughly shaken, filtered, and the filter cake was dried to obtain compound 98H (355 mg, yield: 79.1%). LC-MS (ESI): m / z = 514.3 [MH] -

[0671] Step 6: Disperse compound 98H (355 mg, 0.68 mmol) in anhydrous toluene, add phosphorus oxychloride (153 mg, 1 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol), and react at 100°C for 1 h. After completion of the reaction, concentrate the product, and purify the resulting residue by silica gel column chromatography to afford compound 98I (318 mg, yield: 87.6%). LC-MS (ESI): m / z = 612.2 [MH] - .

[0672] Step 7: Compound 1C (127 mg, 1 mmol) was dissolved in anhydrous acetonitrile (10 mL), and compound 98I (318 mg, 0.6 mmol) and N,N-diisopropylethylamine (2 mL) were added, respectively, and the mixture was reacted at 40°C for 0.5 h. After completion of the reaction as monitored by LCMS, the product was concentrated and the resulting residue was purified by silica gel column chromatography to afford compound 98J (187 mg, yield: 49.8%). LC-MS (ESI): m / z = 625.3 [M+H] + .

[0673] Step 8: Chiral SFC separation of compound 98J afforded compound 98 (pre-SFC preparative peak, 84.1 mg) and compound 99 (post-SFC preparative peak, 86.1 mg). SFC preparative method: Instrument: SFC Prep 150AP, Column: Chiral IK Column; Mobile phases: A: CO2, B: 0.1% NH3·H2O in isopropanol; Gradient: 50% B gradient elution, flow rate: 40 mL / min, column temperature: room temperature, wavelength: 220 nm, cycle time: 4.0 min; Sample preparation: Sample concentration: 5 mg / mL, DMF solution injection: 5 mL per injection.

[0674] Compound 98 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.85-7.80(m,2H),7.62(d,1H),7. 54-7.50(m,2H),7.42-7.37(m,2H),7.34-7.21(m,5H),5.08-4.98(m,1H) ,4.54-4.43(m,1H),3.92-3.82(m,1H),3.16-3.04(m,2H),2.70-2.54(m, 2H),2.05-1.92(m,1H),0.98-0.78(m,4H); LC-MS(ESI):m / z=625.3[M+H] + .

[0675] Compound 99 (peak after SFC preparation): 1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),7.85-7.80(m,2H),7.62(d,1H),7. 54-7.50(m,2H),7.42-7.37(m,2H),7.34-7.21(m,5H),5.08-4.98(m,1H) ,4.54-4.43(m,1H),3.92-3.82(m,1H),3.16-3.04(m,2H),2.70-2.54(m, 2H),2.05-1.92(m,1H),0.98-0.78(m,4H); LC-MS(ESI):m / z=625.3[M+H] + .

[0676] Example 100 and Example 101

[0677] Step 1: Compound 100A (3.5 g, 29.63 mmol) was added to a reaction flask, dissolved in THF (50 mL), and cooled to -15°C. Benzylmagnesium bromide (37 mL, 37.04 mmol) was then added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and react for 3 hours. 2 mol / L hydrochloric acid (30 mL) was then added and stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was diluted with water (200 mL) and extracted twice with ethyl acetate (100 mL x 2). The organic phases were combined, dried, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to yield compound 100B (2.2 g, yield: 35.15%). LC-MS (ESI): m / z = 212.1 [M+H] + .

[0678] Step 2: Compound 100B (1.2 g, 5.68 mmol) was added to a reaction flask and dissolved in methanol (20 mL). Formaldehyde solution (670 mg, 17.04 mmol), acetic acid (680 mg, 11.36 mmol), and piperidine (970 mg, 11.36 mmol) were then added. The atmosphere was purged with nitrogen three times and the reaction was carried out at 60°C for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to afford compound 100C (0.6 g, yield: 47.31%). LC-MS (ESI): m / z = 224.2 [M+H] + .

[0679] Step 3: Compound 100C (0.6 g, 2.69 mmol) was added to a reaction flask and dissolved in ethanol (10 mL). Hydrazine hydrate (336 mg, 5.38 mmol) was then added and reacted at 80°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 100D (0.5 g, yield: 78.37%). LC-MS (ESI): m / z = 238.1 [M+H] + .

[0680] Step 4: Compound 100D (0.5 g, 2.11 mmol) and compound 100H (627 mg, 2.11 mmol, synthesized with reference to patent WO2020236411A1) were added to a reaction flask, mixed with toluene (10 mL), and reacted at 120°C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 100E (240 mg, yield: 23.30%). LC-MS (ESI): m / z = 489.1 [M+H] + .

[0681] Step 5: Compound 100E (200 mg, 0.41 mmol) was added to a reaction flask and dissolved in toluene (10 mL). DIPEA (0.18 mL, 1.02 mmol) and phosphorus oxychloride (94 mg, 0.61 mmol) were then added, followed by reaction at 100°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 100F (100 mg, yield: 48.18%). LC-MS (ESI): m / z = 507.0 [M+H] + .

[0682] Step 6: Compound 100F (100 mg, 0.20 mmol), compound 1C (101 mg, 0.80 mmol), and DIPEA (0.35 mL, 2.0 mmol) were added to a reaction flask, dissolved in DCM (10 mL), and reacted at room temperature for 2 hours. After completion of the reaction, the product was concentrated under reduced pressure and purified by silica gel column chromatography to afford compound 100G (80 mg, yield: 66.93%). LC-MS (ESI): m / z = 598.3 [M+H] + .

[0683] Step 7: Chiral SFC separation of compound 100G afforded compound 100 (SFC retention time: 0.473 min, 12 mg) and compound 101 (SFC retention time: 0.714 min, 11 mg). SFC analysis: Instrument: SHIMADZU LC-30AD, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in methanol; Gradient: 40% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 6.2 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile-methanol mixture injection: 3.0 mL per injection.

[0684] Compound 100 (SFC analysis retention time: 0.473 min): 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.28(s,1H),8.05-8.00(m,2H),7.84-7.80(m,2H),7.67-7.58(m,2H),7.28-7.1 5(m,6H),5.05-4.99(m,1H),4.51-4.43(m,1H),3.93-3.87(m,1H),2.23(s,3H),2.02-1.95(m,1H),0.92-0.82(m,4H).

[0685] Compound 101 (SFC analysis retention time: 0.714 min): 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.28(s,1H),8.05-8.00(m,2H),7.84-7.79(m,2H),7.67-7.58(m,2H),7.28-7.1 5(m,6H),5.05-4.99(m,1H),4.51-4.43(m,1H),3.93-3.87(m,1H),2.23(s,3H),2.02-1.94(s,1H),0.92-0.82(m,4H).

[0686] Example 102 and Example 103

[0687] Step 1: Dissolve compound 102A (0.5 g, 4.8 mmol) and N-Boc-guanidine (1.14 g, 7.2 mmol) in N,N-dimethylformamide (15 mL). Add diisopropylethylamine (1.86 g, 14.4 mmol) and HATU (2.19 g, 5.76 mmol). Stir overnight at room temperature after addition. Add water (100 mL) and extract twice with ethyl acetate (50 mL). The combined organic phases are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield compound 102B (1.0 g, yield: 85.0%). LC-MS (ESI): m / z = 190.1 [M-56+H] + .

[0688] Step 2: Dissolve compound 102B (300 mg, 1.22 mmol) in dichloromethane (8 mL), add trifluoroacetic acid (4 mL), and stir at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 102C (500 mg crude product), which was used directly in the next reaction. LC-MS (ESI): m / z = 146.1 [M+H] + .

[0689] Step 3: Compound 1D (200 mg, 0.38 mmol) was dissolved in acetonitrile (10 mL). Compound 40C (500 mg, 1.22 mmol) and diisopropylethylamine (765 mg, 5.9 mmol) were added, respectively, and the mixture was heated to 40°C for 2 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford compound 102D (150 mg, yield: 62.2%).

[0690] Step 4: Chiral SFC separation of compound 102D afforded compound 102 (SFC retention time: 1.903 min, 61 mg) and compound 103 (SFC retention time: 2.181 min, 70 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral AD column; Mobile phase: A: CO2, B: 0.05% DEA in isopropanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral AD column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in isopropanol; Gradient: 35% B gradient elution, flow rate: 120 mL / min, column temperature: 25°C, wavelength: 220 nm, cycle time: 6.0 min; Sample preparation: Sample concentration: 10 mg / mL, acetonitrile-methanol mixture injection: 2.0 mL per injection.

[0691] Compound 102 (SFC analysis retention time: 1.903 min): 1 H NMR(400MHz, DMSO-d6)δ10.45(s,1H),8.04-8.02(m,2H),7.82-7.80(m,2H),7.54-7.51(m,2H),7.40-7.38(m,2H),7.32-7.20(m, 5H),5.05-5.01(m,1H),4.51-4.44(m,1H),3.90-3.86(m,1H),1.50-1.41(m,2H),1.40-1.32(m,2H); LC-MS(ESI):m / z=635.3[M+H] + .

[0692] Compound 103 (SFC analysis retention time: 2.181 min): 1 H NMR(400MHz, DMSO-d6)δ10.45(s,1H),8.04-8.02(m,2H),7.82-7.80(m,2H),7.54-7.51(m,2H),7.40-7.38(m,2H),7.32-7.19(m, 5H),5.05-5.01(m,1H),4.51-4.45(m,1H),3.90-3.85(m,1H),1.50-1.41(m,2H),1.40-1.32(m,2H); LC-MS(ESI):m / z=635.3[M+H] + .

[0693] Example 104 and Example 105

[0694] Step 1: Compound 104A (6 g, 40.50 mmol) was dissolved in dichloromethane (50 mL). Oxalyl chloride (12.85 g, 101.25 mmol) was slowly added under an ice-water bath. The reaction was allowed to proceed for 1 h, and the mixture was concentrated to yield the crude acyl chloride. N,O-Dimethylhydroxylamine hydrochloride (7.11 g, 72.9 mmol) and triethylamine (12.29 g, 121.5 mmol) were then dissolved in dichloromethane (50 mL). The resulting acyl chloride was dissolved in dichloromethane and slowly added to the reaction mixture. The reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction, the mixture was concentrated, and the resulting residue was purified by silica gel column chromatography to yield Compound 104B (5.5 g, 71% yield).

[0695] LC-MS (ESI): m / z = 192.1 [M+H] + .

[0696] Step 2: Compound 104B (5.4 g, 28.24 mmol) was dissolved in tetrahydrofuran (60 mL). After nitrogen substitution three times, benzylmagnesium bromide (16.55 g, 84.72 mmol) was slowly added portionwise at 0°C and allowed to react overnight at room temperature. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The organic phases were combined, concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 104C (4.2 g, yield: 67%). LC-MS (ESI): m / z = 223.2 [M+H] + .

[0697] Step 3: Compound 104C (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 reacted at 80°C for 5 hours. After completion of the reaction, the mixture was directly concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 104D (3.8 g, yield: 90%). LC-MS (ESI): m / z = 235.2 [M+H] + .

[0698] Step 4: Compound 104D (3.6 g, 15.37 mmol) was dissolved in ethanol (35 mL), followed by the addition of hydrazine hydrate (6.16 g, 122.96 mmol). The mixture was reacted at 80°C for 4 hours. After completion of the reaction, the mixture was concentrated and the resulting residue was purified by silica gel column chromatography to afford compound 104E (2.8 g, yield: 73%). LC-MS (ESI): m / z = 249.2 [M+H] + .

[0699] Step 5: Compound 104E (2.8 g, 11.28 mmol) and compound 100H (4.36 g, 14.66 mmol) were dissolved in toluene (40 mL) and reacted at 120°C for 5 hours. After completion of the reaction, the mixture was concentrated and the resulting residue was purified by silica gel column chromatography to afford compound 104G (4.2 g, yield: 75%). LC-MS (ESI): m / z = 500.1 [M+H] + .

[0700] Step 6: Compound 104G (4 g, 8.01 mmol) and ethyldiisopropylamine (2.59 g, 20.02 mmol) were dissolved in toluene (50 mL). Phosphorus oxychloride (1.84 g, 12.02 mmol) was then slowly added. The mixture was heated to 100°C under nitrogen for 3 hours. After completion of the reaction, the mixture was directly concentrated, and the resulting residue was purified by silica gel column chromatography to afford Compound 104H (2.8 g, yield: 67%). LC-MS (ESI): m / z = 518.1 [M+H] +.

[0701] Step 7: Compound 104H (0.15 g, 0.29 mmol), compound 1C (0.059 g, 0.46 mmol), and ethyldiisopropylamine (0.11 g, 0.87 mmol) were dissolved in N,N-dimethylformamide (8 mL) and reacted at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 104I (0.13 g, yield: 73%). LC-MS (ESI): m / z = 609.1 [M+H] + .

[0702] Step 8: Compound 104I (130 mg, 0.21 mmol) was subjected to chiral SFC separation to afford compound 104 (SFC retention time: 1.992 min, 58 mg) and compound 105 (SFC retention time: 2.349 min, 56 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral IK Column; Mobile Phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow Rate: 3.0 mL / min, Column Temperature: 35°C, Wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral IK Column; mobile phase: A: CO2, B: methanol; gradient: 40% B gradient; elution flow rate: 100 mL / min; column temperature: 25°C; wavelength: 220 nm; cycle time: 3.0 min; sample preparation: sample concentration 5 mg / mL, acetonitrile and dichloromethane mixed solution injection: 3.0 mL each time.

[0703] Compound 104 (SFC analysis retention time: 1.992 min): 1 H NMR (400MHz, DMSO-d6) δ8.02(d,2H),7.81(d,2H),7.38(d,1H),7.33-7.17(m,6H),7.01(d,1H),5.05-4.96(m,1H),4.51-4. 39(m,1H),3.90-3.80(m,1H),3.06(s,4H),1.99(s,1H),1.32-1.17(m,1H),0.99-0.79(m,4H); LC-MS(ESI):m / z=609.1[M+H] + .

[0704] Compound 105 (SFC analysis retention time: 2.349 min): 1H NMR (400MHz, DMSO-d6) δ8.02(d,2H),7.81(d,2H),7.38(d,1H),7.33-7.19(m,6H),7.01(d,1H),5.05-4.95(m,1H),4.52-4. 38(m,1H),3.90-3.80(m,1H),3.06(s,4H),1.98(s,1H),1.31-1.18(m,1H),0.98-0.77(m,4H); LC-MS(ESI):m / z=609.1[M+H] + .

[0705] Example 106 and Example 107

[0706] Step 1: Dissolve 3-N-tert-Butyloxycarbonylaminocyclobutylamine (1 g, 5.81 mmol) and triethylamine (1.76 g, 17.43 mmol) in dichloromethane (10 mL). Then slowly add Compound 106A (0.90 g, 6.39 mmol) dropwise. React at room temperature for 2 h. After completion of the reaction, concentrate the mixture, add 100 mL of ethyl acetate, and wash with saturated brine (50 mL x 4). The organic phase is collected, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by silica gel column chromatography to afford Compound 106B (1.2 g, yield: 74.78%).

[0707] Step 2: Dissolve compound 106B (0.3 g, 1.09 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.3 mL), and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure to obtain compound 106C (0.2 g crude product), which was used directly in the next reaction.

[0708] Step 3: Compound 106C (0.2 g crude product) was subjected to the same procedure as in Example 18, Step 1, to give Compound 106D (0.25 g, yield: 65.85%). LC-MS (ESI): m / z = 666.2 [M+H] + .

[0709] Step 4: Chiral SFC separation of compound 106D afforded compound 106 (pre-SFC elution, 80 mg) and compound 107 (post-SFC elution, 85 mg). SFC preparative method: Instrument: SFC Prep 150AP, Column: AS (19 mm x 250 mm); Mobile phase: A: CO2, B: 0.01% ammonia in isopropanol; Gradient: Isocratic, 50% B; Flow rate: 38 mL / min, Column temperature: 35°C, Wavelength: 220 nm, Cycle time: 5.0 min; Sample preparation: Sample concentration: 3 mg / mL, 5 mL of methanol solution injected per injection.

[0710] Compound 106 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.62(d,1H),8.01(d,2H),7.87(d,2H),7.75(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.20(m,3H),5.10-5.05(m,1H ),4.68-4.62(m,1H),4.54-4.49(m,H),4.08-3.92(m,5H),2.77-2.69(m, 1H),1.07-0.96(m,2H),0.95-0.91(m,2H); LC-MS(ESI):m / z=666.2[M+H] + .

[0711] Compound 107 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.62(d,1H),8.01(d,2H),7.87(d,2H),7.75(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.20(m,3H),5.10-5.05(m,1H ),4.68-4.62(m,1H),4.54-4.49(m,H),4.08-3.92(m,5H),2.77-2.69(m, 1H),1.07-0.96(m,2H),0.95-0.91(m,2H); LC-MS(ESI):m / z=666.2[M+H] + .

[0712] Example 108 and Example 109

[0713] Step 1: Dissolve 3-N-tert-Butyloxycarbonylaminocyclobutylamine (1 g, 5.81 mmol) and triethylamine (1.76 g, 17.43 mmol) in dichloromethane (10 mL). Then slowly add compound 108A (1.01 g, 5.81 mmol) dropwise. React at room temperature for 2 h. After completion of the reaction, concentrate the mixture, add 100 mL of ethyl acetate, and wash with saturated brine (50 mL x 4). The organic phase is collected, dried over anhydrous sodium sulfate, and the resulting residue is purified by silica gel column chromatography to afford compound 108B (1.1 g, yield: 68.55%).

[0714] Step 2: Dissolve compound 108B (0.2 g, 0.80 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (0.3 mL), and stir overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain compound 108C (0.2 g crude product), which was used directly in the next reaction.

[0715] Step 3: Compound 108C (0.2 g) was treated according to the first step of Example 18 to obtain compound 108D (0.27 g, yield: 74.01%). LC-MS (ESI): m / z = 640.2 [M+H] + .

[0716] Step 4: Chiral SFC separation of compound 108D afforded compound 108 (pre-SFC elution, 85 mg) and compound 109 (post-SFC elution, 87 mg). SFC preparative method: Instrument: SFC Prep 150AP, Column: AS (19 mm x 250 mm); Mobile phase: A: CO2, B: 0.01% ammonia in isopropanol; Gradient: Isocratic, 40% B; Flow rate: 40 mL / min, Column temperature: 35°C, Wavelength: 220 nm, Cycle time: 5.0 min; Sample preparation: Sample concentration: 3 mg / mL, 5 mL of methanol solution injected per injection.

[0717] Compound 108 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.01(d,2H),7.86(d,2H),7.74(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.19(m, 3H),5.10-5.05(m,1H),4.69-4.58(m,1H),4.53-4.47(m,1H),4.02-3.92(m,5H),3.03(s,3H); LC-MS(ESI):m / z=640.2[M+H] + .

[0718] Compound 109 (eluted after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ8.59(d,1H),8.01(d,2H),7.86(d,2H),7.74(d,2H),7.46(d,2H),7.35-7.31(m,2H),7.28-7.19(m, 3H),5.10-5.05(m,1H),4.69-4.58(m,1H),4.53-4.47(m,1H),4.02-3.92(m,5H),3.03(s,3H); LC-MS(ESI):m / z=640.2[M+H]+ .

[0719] Example 110 and Example 111

[0720] Step 1: Compound 110A (5.0 g, 26.45 mmol) was added to a reaction flask and dissolved in acetonitrile (100 mL). 1,2-Dibromoethane-d4 (5.08 g, 26.45 mmol) was then added and reacted at 85°C for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 110B (4.4 g, 75.92% yield). 1 H NMR (400MHz, DMSO-d6) δ7.06-7.04(m,1H), 6.99-6.95(m,1H), 6.84-6.80(m,1H).

[0721] Step 2: Compound 110B (4.4 g, 20.08 mmol), benzyl mercaptan (4.99 g, 40.16 mmol), Pd(dppf)Cl2 (1.46 g, 2.01 mmol), Xantphos (2.3 g, 4.02 mmol), and DIPEA (10.5 mL, 60.24 mmol) were added to a reaction flask, dissolved with toluene (100 mL), and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 100°C for 16 hours. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 110C (1.55 g, yield: 29.41%). 1 H NMR (400MHz, DMSO-d6) δ7.30-7.19(m,5H),6.85-6.93(m,1H),6.80-6.77(m,2H),4.11(s,2H).

[0722] Step 3: Compound 110C (1.5 g, 5.72 mmol) was added to a reaction flask and dissolved in 9:1 acetic acid:water (50 mL). N-chlorosuccinimide (3.1 g, 22.88 mmol) was then added and allowed to react at room temperature for 20 min. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford compound 110D (0.81 g, yield: 64.33%). 1 H NMR (400MHz, DMSO-d6) δ14.61(s,1H),7.08-7.02(m,2H),6.79-6.76(m,1H).

[0723] Step 4: Compound 110D (0.80 g, 3.63 mmol) was added to a reaction flask and dissolved in 1,4-dioxane (25 mL). DIPEA (3 mL) was then added and allowed to react at room temperature for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford compound 110E (0.75 g, 94.17% yield). 1 H NMR (400MHz, DMSO-d6) δ7.30-7.26(m,2H),7.19(s,2H),7.02-6.99(m,1H).

[0724] Step 5: Compound 110E (0.61 g, 2.78 mmol), ethyl chloroformate (0.60 g, 5.56 mmol), and potassium carbonate (1.15 g, 8.34 mmol) were added to a reaction flask, dissolved in acetonitrile (30 mL), and reacted at 85°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 110F (0.8 g, yield: 98.71%). LC-MS (ESI): m / z = 292.1 [M+H] + .

[0725] Step 6: Compound 64C (0.11 g, 0.43 mmol) and compound 110F (0.14 g, 0.47 mmol) were added to a reaction flask, dissolved in toluene (10 mL), and reacted at 120°C for 4 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 110G (0.2 g, yield: 92.99%). LC-MS (ESI): m / z = 502.1 [M+H] + .

[0726] Step 7: Compound 110G (0.2 g, 0.40 mmol) was dissolved in toluene (10 mL), followed by the addition of DIPEA (0.42 mL, 2.4 mmol) and phosphorus oxychloride (122 mg, 0.80 mmol). The mixture was reacted at 100°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford compound 110H (0.15 g, yield: 72.34%). LC-MS (ESI): m / z = 520.1 [M+H] + .

[0727] Step 8: Compound 110H (0.15 g, 0.29 mmol), compound 1C (0.15 g, 1.16 mmol), and DIPEA (0.5 mL, 2.9 mmol) were added to a reaction flask, dissolved in DCM (10 mL), and reacted at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to afford compound 110I (0.1 g, yield: 56.43%). LC-MS (ESI): m / z = 611.3 [M+H] + .

[0728] Step 9: Chiral SFC separation of compound 110I afforded compound 110 (pre-SFC preparative peak, 30 mg) and compound 111 (post-SFC preparative peak, 27 mg). SFC preparative method: 1. Apparatus: SFC prep 150AP, chromatographic column: IK (19 mm x 250 mm). 2. Dissolve the sample in methanol and filter through a 0.45 μm filter to prepare a sample solution. 3. Preparative chromatography conditions: Mobile phase A: CO2, mobile phase B: isopropanol, isocratic elution, mobile phase B content: 60%, flow rate: 38 mL / min.

[0729] Compound 110 (peak before SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.55-7.49(m,2H),7.42-7.37(m,2H),7.35-7.19(m,8H),6.90-6.85(m,1H),5.04 -4.97(m,1H),4.50-4.43(m,1H),3.87-3.79(m,1H),2.04-1.95(m,1H),0.92-0.82(m,4H); LC-MS(ESI):m / z=611.3[M+H] + .

[0730] Compound 111 (peak after SFC preparation): 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.55-7.49(m,2H),7.42-7.37(m,2H),7.34-7.19(m,8H),6.90-6.86(m,1H),5.04 -4.97(m,1H),4.50-4.41(m,1H),3.87-3.80(m,1H),2.05-1.94(m,1H),0.93-0.83(m,4H); LC-MS(ESI):m / z=611.3[M+H] + .

[0731] Example 112 and Example 113

[0732] Step 1: Dissolve compound 112A (5 g, 28.54 mmol) and triethylamine (8.66 g, 85.62 mmol) in dichloromethane (60 mL). Add ethyl chloroformate (4.03 g, 37.10 mmol) under an ice-water bath and allow to react overnight at room temperature. After completion, quench the reaction with saturated sodium bicarbonate solution. Adjust the mixture to acidic with dilute hydrochloric acid and extract three times with dichloromethane. The combined organic phases were concentrated to yield compound 112B (7 g crude product), which was used directly in the next step. LC-MS (ESI): m / z = 248.2 [M+H] + .

[0733] Step 2: Compound 112B (2 g, 8.09 mmol) and compound 22D (2.70 g, 10.52 mmol) were dissolved in toluene (25 mL) and reacted at 120°C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated. The resulting residue was slurried to afford compound 112C (3.6 g, yield: 97%). LC-MS (ESI): m / z = 458.2 [M+H] + .

[0734] Step 3: Compound 112C (1 g, 2.18 mmol) and DIPEA (0.70 g, 5.45 mmol) were dissolved in toluene (15 mL). Phosphorus oxychloride (0.50 g, 3.27 mmol) was then slowly added and the mixture was allowed to react at 100°C for 2 hours. After completion of the reaction, the mixture was concentrated and the resulting residue was purified by silica gel column chromatography to afford compound 112D (0.6 g, yield: 58%). LC-MS (ESI): m / z = 476.3 [M+H] + .

[0735] Step 4: Compound 112D (0.2 g, 0.42 mmol), compound 1C (0.080 g, 0.63 mmol), and DIPEA (0.16 g, 1.26 mmol) were dissolved in DMF (10 mL) and reacted at room temperature for 2 hours. After completion, the reaction was diluted with water and extracted three times with ethyl acetate. The combined organic phases were concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 112E (0.13 g, yield: 55%). LC-MS (ESI): m / z = 567.2 [M+H] + .

[0736] Step 5: Chiral SFC separation of compound 112E afforded compound 112 (SFC retention time: 2.100 min, 56 mg) and compound 113 (SFC retention time: 2.418 min, 56 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3 mL / min, Column temperature: 35°C, Wavelength: 254 nm. SFC preparation method: Instrument: Waters 150 Prep-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: 254 nm; Cycle time: 6.5 min; Sample preparation: Sample concentration: 5 mg / mL, methanol and acetonitrile solution injection: 3 mL each.

[0737] Compound 112 (SFC analysis retention time: 2.100 min): 1 H NMR (400MHz, DMSO-d6) δ7.93-7.84(m,2H),7.52(d,2H),7.43-7.37(m,2H),7.35-7.20(m,7H),5.07-4.97( m,1H),4.54-4.41(m,1H),3.91-3.82(m,1H),2.01(d,1H),0.96-0.80(m,4H); LC-MS(ESI):m / z=567.2[M+H] + .

[0738] Compound 113 (SFC analysis retention time: 2.418 min): 1 H NMR (400MHz, DMSO-d6) δ7.93-7.84(m,2H),7.53(d,2H),7.44-7.36(m,2H),7.34-7.20(m,7H),5.06-4.98( m,1H),4.55-4.42(m,1H),3.93-3.80(m,1H),2.03(d,1H),0.95-0.77(m,4H); LC-MS(ESI):m / z=567.2[M+H] + .

[0739] Example 114 and Example 115

[0740] Step 1: Compound 114A (560 mg, 5 mmol) was dissolved in N,N-dimethylformamide (20 mL). NaH (200 mg, 5 mmol) was added under a nitrogen atmosphere. Stirring was continued for 30 min, followed by the addition of compound 1D (526 mg, 1 mmol). After 10 min, the reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography to yield the target compound 114B (562 mg, yield: 93.3%). LC-MS (ESI): m / z = 602.2 [M+H] + .

[0741] Step 2: Dissolve compound 144B (562 mg, 0.9 mmol) in dichloromethane (10 mL), add triethylamine (1 mL) and cyclopropylcarbonyl chloride (104 mg, 1 mmol), and stir at room temperature for 10 min. The reaction solution was concentrated, and the resulting residue was separated by silica gel column chromatography to obtain compound 114C (171 mg, yield: 28.3%). LC-MS (ESI): m / z = 670.2 [M+H] + .

[0742] Step 3: Chiral resolution of compound 114C afforded compound 114 (SFC retention time: 2.034 min, 5.6 mg) and compound 115 (SFC retention time: 2.266 min, 6.1 mg). SFC analysis: Instrument: SHIMADZU LC-30AD SFC, 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: Waters 150 Prep-SFC, Column: Chiral IK Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in MeOH; Gradient: 35% B gradient elution flow rate: 120 mL / min, Column temperature: room temperature, Wavelength: 220 nm, Cycle time: 5.0 min; Sample preparation: Sample concentration: 2 mg / mL, Methanol solution injection: 2 mL each time.

[0743] Compound 114 (SFC analysis retention time: 2.034 min): 1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.15-7.02(m,13H),3.91(s,2H),3.07-2 .78(m,1H),2.19-2.07(m,1H),1.10-0.69(m,4H); LC-MS(ESI):m / z=670.2[M+H] + .

[0744] Compound 115 (SFC analysis retention time: 2.266 min): 1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.15-7.02(m,13H),3.91(s,2H),3.07-2 .78(m,1H),2.19-2.07(m,1H),1.10-0.69(m,4H); LC-MS(ESI):m / z=670.2[M+H] + .

[0745] Example 116, Example 117, Example 118 and Example 119

[0746] Step 1: Dissolve p-toluenesulfonamide (10 g, 58.4 mmol), ammonium persulfate (66.63 g, 292 mmol), and a selective fluorine reagent (82.76 g, 233.6 mmol) in acetonitrile (100 mL) and water (100 mL). Add silver nitrate (1.98 g, 11.68 mmol) at 0°C, then replace the atmosphere with nitrogen three times. Finally, raise the temperature to 80°C and react for 5 h. After the reaction, slowly add saturated sodium bicarbonate solution until no bubbles form. Then, extract with ethyl acetate (100 mL) three times. The organic phases are combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to yield a mixture of Compound 116B and Compound 118B (5 g).

[0747] Compound 116B: LC-MS (ESI): m / z = 190 [M+H] + Compound 118B: LC-MS (ESI): m / z = 206 [MH] - .

[0748] Step 2: A mixture of compounds 116B and 118B (1.5 g) and triethylamine (0.63 g, 2.15 mmol) was dissolved in dichloromethane (30 mL). Isopropyl chloroformate (0.98 g, 7.96 mmol) was slowly added dropwise and allowed to react at room temperature for 2 h. After the reaction, water (100 mL) was added to the system and the pH was adjusted to 3 with 1 M HCl. The mixture was then extracted three times with dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a mixture of compounds 116C and 118C (1.6 g), which was used directly in the next reaction.

[0749] Compound 116C: LC-MS (ESI): m / z = 274 [MH] - Compound 118C: LC-MS (ESI): m / z = 292 [MH] - .

[0750] Step 3: A mixture of compound 116C and compound 118C (0.5 g) and compound 22D (0.63 g, 2.15 mmol) were added to toluene (30 mL) under nitrogen protection, heated to 100°C and stirred overnight, then cooled and concentrated. The residue was purified by silica gel column chromatography to obtain a mixture of compound 116D and compound 118D (0.5 g).

[0751] Compound 116D: LC-MS (ESI): m / z = 470 [MH] - Compound 118D: LC-MS (ESI): m / z = 488 [MH] - .

[0752] Step 4: A mixture of 116D and compound 118D (0.5 g) and DIPEA (2.64 g, 20.4 mmol) were dissolved in toluene (10 mL), and then phosphorus oxychloride (1.56 g, 10.2 mmol) was slowly added dropwise. After the addition was completed, the system was protected by nitrogen and stirred at 100°C for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a mixture of compound 116E and compound 118E (0.4 g).

[0753] Compound 116E: LC-MS (ESI): m / z = 488 [MH] - Compound 118E: LC-MS (ESI): m / z = 506 [MH] - .

[0754] Step 5: A mixture of Compound 116E and Compound 118E (0.4 g) and triethylamine (0.16 mg, 1.58 mmol) was dissolved in DMF (8 mL), followed by the addition of Compound 1C (0.15 g, 1.19 mmol). After addition, the mixture was stirred at room temperature overnight. After completion of the reaction, water (50 mL) was added to the system, followed by extraction three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to afford Compound 116F (80 mg) and Compound 118F (51 mg).

[0755] Compound 116F: LC-MS (ESI): m / z=581 [M+H] + Compound 118F: LC-MS (ESI): m / z = 599 [M+H] + .

[0756] Step 6: Compound 116F was resolved by chiral SFC to afford compound 116 (pre-SFC elution, 22 mg) and compound 117 (post-SFC elution, 29 mg). SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO2, B: 0.05% DEA in 1% ethanol; Gradient: 5-40% B in A; Flow rate: 120 mL / min, Column temperature: 35°C, Wavelength: 220 nm, Cycle time: 6.8 min; Sample preparation: Sample concentration: 2 mg / mL, Methanol solution injection: 2 mL per injection.

[0757] Compound 118F was resolved by chiral SFC to give compound 118 (pre-SFC elution, 16 mg) and compound 119 (post-SFC elution, 16 mg). SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 5-40% B in A; Flow rate: 100 mL / min, Column temperature: 35°C, Wavelength: 220 nm, Cycle time: 3.6 min; Sample preparation: Sample concentration: 2 mg / mL, ethanol solution injection: 2 mL per injection.

[0758] Compound 116 (peak before SFC preparation): 1H NMR (400MHz, DMSO-d6) δ7.90-7.84(m,2H),7.54-7.46(m,4H),7.42-7.36(m,2H),7.34-7.20(m,5H),5.48(d,2H),5. 01-4.99(m,1H),4.50-4.44(m,1H),3.89-3.84(m,1H),2.00(s,1H),0.94-0.78(m,4H); LC-MS(ESI):m / z=581.1[M+H] + .

[0759] Compound 117 (peak after SFC preparation): 1 H NMR (400MHz, DMSO-d6) δ7.89-7.84(m,2H),7.55-7.45(m,4H),7.42-7.37(m,2H),7.34-7.20(m,5H),5.48(d,2H),5. 01-4.99(m,1H),4.50-4.44(m,1H),3.89-3.84(m,1H),2.00(s,1H),0.97-0.79(m,4H); LC-MS(ESI):m / z=581.1[M+H] + .

[0760] Compound 118 (peak before SFC preparation): 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.96(d,2H),7.65(d,2H),7.55-7.46(m,2H),7.44-7.35(m,2H),7.34-7.22(m,5H),7.22-6. 95(m,1H),5.04-5.00(m,1H),4.51-4.45(m,1H),3.90-3.85(m,1H),1.99(s,1H),0.95-0.81(m,4H); LC-MS(ESI):m / z=599.2[M+H] + .

[0761] Compound 119 (peak before SFC preparation): 1H NMR (400MHz, DMSO-d6) δ10.84(s,1H),7.96(d,2H),7.65(d,2H),7.53-7.49(m,2H),7.41-7.37(m,2H),7.33-7.22(m,5H),7.22-6. 95(m,1H),5.04-5.00(m,1H),4.51-4.45(m,1H),3.90-3.85(m,1H),1.99(s,1H),0.97-0.80(m,4H); LC-MS(ESI):m / z=599.2[M+H] + .

[0762] Example 120 and Example 121

[0763] Step 1: Compound 120A (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 sequentially to anhydrous methanol (50 mL), then heated to 80°C and stirred for 4 hours. The mixture was cooled and concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 120B (1.9 g, yield: 91%). LC-MS (ESI): m / z = 287.0 [M+H] + .

[0764] Step 2: Compound 120B (1.9 g, 6.62 mmol) and hydrazine hydrate (3.31 g, 52.96 mmol, 80% content) were added to anhydrous ethanol (50 mL) under nitrogen atmosphere. The mixture was heated to 80°C and stirred for 4 hours. The mixture was cooled, filtered, and the filter cake was washed with anhydrous ethanol and dried to obtain compound 120C (1.5 g, yield: 76%). LC-MS (ESI): m / z = 301.0 [M+H] + .

[0765] Step 3: Compound 120C (1.5 g, 4.98 mmol) and compound 120I (1.41 g, 4.98 mmol) were added to toluene (30 mL), heated to 100°C, and stirred for 2 hours. The mixture was cooled and concentrated, and the resulting residue was purified by silica gel column chromatography to afford compound 120D (2.4 g, yield: 87%). LC-MS (ESI): m / z = 552.1 [M+H] + .

[0766] Step 4: Compound 120D (600 mg, 1.09 mmol) and triisopropylsilyl acetylene (800 mg, 4.36 mmol) were dissolved in tetrahydrofuran (25 mL). Pd(PPh3)2Cl2 (77 mg, 0.11 mmol), cuprous iodide (21 mg, 0.11 mmol), and triethylamine (550 mg, 5.45 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the mixture was reacted at 60°C under nitrogen for 16 hours. After completion of the reaction, saturated aqueous ammonium chloride (20 mL) was added, and the mixture was extracted twice with ethyl acetate. The organic phases were combined and concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound 120E (200 mg, yield: 28%). LC-MS (ESI): m / z = 654.2 [M+H] + .

[0767] Step 5: To a 50 mL single-necked flask, add toluene (20 mL), followed by compound 120E (200 mg, 0.31 mmol) and DIPEA (120 mg, 0.93 mmol). Then, slowly add phosphorus oxychloride (140 mg, 0.93 mmol) dropwise. After the addition is complete, the system is protected with nitrogen and stirred at 100°C for 2 h. The reaction solution is cooled and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain compound 120F (100 mg, yield: 49%). LC-MS (ESI): m / z = 672.2 [M+H] + .

[0768] Step 6: Compound 120F (270 mg, 0.40 mmol) and dichloromethane (10 mL) were added to a 50 mL single-necked flask and dissolved. Compound 1C (140 mg, 0.60 mmol) was then added, followed by DIPEA (160 mg, 1.20 mmol). After completion of the addition, the mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue, stirred for 5 min, and extracted three times with dichloromethane. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield compound 120G (200 mg, yield: 65%). LC-MS (ESI): m / z = 763.3 [M+H] + .

[0769] Step 7: Compound 120G (200 mg, 0.26 mmol) was dissolved in 5 mL of tetrahydrofuran, and tetrabutylammonium fluoride (0.52 mL, 0.52 mmol, 1 M in THF) was added. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 120H (120 mg, yield: 75%). LC-MS (ESI): m / z = 607.2 [M+H] + .

[0770] Step 8: Compound 120H was further resolved by chiral SFC to afford compound 120 (SFC retention time: 1.957 min, 31 mg) and compound 121 (SFC retention time: 2.091 min, 20 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral Wheel Column; Mobile Phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow Rate: 3 mL / min, Column Temperature: 35°C, Wavelength: 220 nm. SFC preparation method: Instrument: Waters 150 Prep-SFC, Column: Chiral IC Column; Mobile phase: A: CO2, B: 0.1% NH3·H2O in ethanol; Gradient: 40% B gradient elution; Flow rate: 100 mL / min, Column temperature: 25°C, Wavelength: 220 nm, Cycle time: 3.8 min. Sample preparation: Sample concentration: 10 mg / mL, Methanol solution injection: 2.0 mL per injection.

[0771] Compound 120 (SFC analysis retention time: 1.957 min): 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.05-7.99(m,2H),7.85-7.78(m,2H),7.54-7.47(m,2H),7.44-7.37(m,2H),7.35-7.20(m,5H),5. 10-4.97(m,1H),4.56-4.43(m,1H),4.29(s,1H),3.93-3.82(m,1H),2.04-1.92(m,1H),0.95-0.81(m,4H); LC-MS(ESI):m / z=607.3[M+H] + .

[0772] Compound 121 (SFC analysis retention time: 2.091 min): 1 H NMR (400MHz, DMSO-d6) δ10.82(s,1H),8.05-7.99(m,2H),7.85-7.78(m,2H),7.54-7.47(m,2H),7.44-7.37(m,2H),7.35-7.20(m,5H),5. 10-4.97(m,1H),4.56-4.43(m,1H),4.29(s,1H),3.93-3.82(m,1H),2.04-1.92(m,1H),0.95-0.81(m,4H); LC-MS(ESI):m / z=607.3[M+H] + .

[0773] Example 122 and Example 123

[0774] Step 1: Dissolve compound 122A (2 g, 17.69 mmol) and BOC-guanidine (3.38 g, 21.23 mmol) in tetrahydrofuran (40 mL). Add triethylamine (5.36 g, 53.07 mmol) and then 1-n-propylphosphoric anhydride (16.88 g, 26.54 mmol). Stir at room temperature under nitrogen for 2 h. Quench the reaction with water (50 mL) and extract twice with ethyl acetate (50 mL). The organic phase is collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue is purified by column chromatography to yield compound 122B (1.6 g, yield: 36%). LC-MS (ESI): m / z = 255.1 [M+H] + .

[0775] Step 2: Compound 122B (1.6 g, 6.30 mmol) was dissolved in dichloromethane (35 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 16 h. The reaction was quenched with sodium hydroxide solution (50 mL) and extracted twice with dichloromethane (50 mL). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to afford compound 122C (459 mg, yield: 47%). LC-MS (ESI): m / z = 155.1 [M+H] + .

[0776] Step 3: Compound 122C (200 mg, 1.30 mmol) and compound 1D (666 mg, 1.30 mmol) were dissolved in DMF (10 mL). Sodium methoxide (210 mg, 3.90 mmol) was added and stirred at room temperature overnight. The reaction was quenched with water (40 mL) and extracted three times with dichloromethane (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to afford compound 122D (350 mg, yield: 42%). LC-MS (ESI): m / z = 644.2 [M+H] + .

[0777] Step 4: Compound 122D was further resolved by chiral SFC to yield compound 122 (SFC retention time: 0.831 min, 98.0 mg) and compound 123 (SFC retention time: 1.276 min, 96.9 mg). SFC analysis: Instrument: SHIMADZU LC-30AD SFC, Column: Chiral IX column; Mobile phase: A: CO2, B: 0.05% DEA in 1% ethanol; Gradient: 5%-40% B; Flow rate: 3 mL / min; Column temperature: 35°C; Wavelength: 220 nm. SFC preparative method: Instrument: Waters 150 Prep-SFC, Column: Chiral IK column; Mobile phase: A: CO2, B: Methanol; Gradient: 45% B; Flow rate: 120 mL / min; Column temperature: Room temperature; Wavelength: 220 nm; Cycle time: 6.5 min. Sample preparation: Sample concentration: 10 mg / mL; 2.0 mL of ethanol solution injected per injection.

[0778] Compound 122 (SFC analysis retention time: 0.831 min): 1 H NMR (400MHz, DMSO-d6)) δ8.70(s,1H),8.25(s,1H),8.03(d,2H),7.88(s,1H),7.80(d,2H),7.53(d,2H),7.37(d ,2H),7.34-7.17(m,5H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.92-3.88(m,1H); LC-MS(ESI):m / z=644.0[M+H] + .

[0779] Compound 123 (SFC analysis retention time: 1.276 min): 1 H NMR (400MHz, DMSO-d6)) δ8.70(s,1H),8.25(s,1H),8.03(d,2H),7.88(s,1H),7.80(d,2H),7.53(d,2H),7.37(d ,2H),7.34-7.17(m,5H),5.06-5.02(m,1H),4.54-4.48(m,1H),3.92-3.88(m,1H); LC-MS(ESI):m / z=644.0[M+H] + .

[0780] Example 124 and Example 125

[0781] Step 1: Compound 124A (2 g, 12.69 mmol) was dissolved in dichloromethane (50 mL). HATU (5.79 g, 15.23 mmol) and triethylamine (3.85 g, 38.07 mmol) were slowly added under an ice-water bath, followed by N,O-dimethylhydroxylamine hydrochloride (1.78 g, 18.3 mmol). The mixture was reacted at room temperature for 2 hours. Water (100 mL) was added, and the mixture was extracted with dichloromethane (50 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 124B (2.2 g, yield: 86%). LC-MS (ESI): m / z = 201.1 [M+H] + .

[0782] Step 2: Compound 124B (2.2 g, 10.97 mmol) was dissolved in tetrahydrofuran (60 mL). After nitrogen substitution three times, benzylmagnesium bromide (2.48 g, 14.46 mmol) was slowly added portionwise at 0°C and allowed to react overnight at room temperature. After completion, the reaction was diluted with water (80 mL), extracted with ethyl acetate (50 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 124C (1.8 g, yield: 71%). LC-MS (ESI): m / z = 232.2 [M+H] + .

[0783] Step 3: Compound 124C (1.6 g, 6.91 mmol), aqueous formaldehyde solution (2.59 g, 34.55 mmol), acetic acid (91 mg, 1.5 mmol), and piperidine (88 mg, 1.1 mmol) were dissolved in methanol (60 mL) and reacted at 80°C for 5 hours. After completion of the reaction, the mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124D (1 g, yield: 59%). LC-MS (ESI): m / z = 244.2 [M+H] + .

[0784] Step 4: Compound 124D (1.0 g, 2.99 mmol) was dissolved in ethanol (35 mL), and hydrazine hydrate (0.94 g, 14.95 mmol) was added. The mixture was reacted at 80°C for 4 hours. After completion of the reaction, the mixture was concentrated to afford compound 124E (1.2 g crude product), which was used directly in the next reaction.

[0785] LC-MS (ESI): m / z = 258.2 [M+H] + .

[0786] Step 5: Compound 124E (1.3 g, 5.04 mmol) and compound 100H (1.43 g, 5.04 mmol) were dissolved in toluene (40 mL) and reacted at 120°C for 5 hours. After completion of the reaction, the mixture was concentrated and the residue was purified by silica gel column chromatography to afford compound 124F (0.60 g, yield: 23%). LC-MS (ESI): m / z = 509.2 [M+H] + .

[0787] Step 6: Compound 124F (0.5 g, 0.98 mmol) and DIPEA (0.32 g, 2.45 mmol) were dissolved in toluene (20 mL). Phosphorus oxychloride (0.23 g, 1.47 mmol) was slowly added and the mixture was heated to 100°C under nitrogen for 1 hour. After completion of the reaction, the mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 124G (0.23 g, yield: 44%). LC-MS (ESI): m / z = 527.1 [M+H] + .

[0788] Step 7: Compound 124G (0.23 g, 0.44 mmol), compound 1C (0.11 g, 0.88 mmol), and DIPEA (0.17 g, 1.32 mmol) were dissolved in dichloromethane (10 mL) and reacted at room temperature for 3 hours. After completion of the reaction, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford compound 124H (0.08 g, yield: 29%). LC-MS (ESI): m / z = 618.1 [M+H] + .

[0789] Step 8: Compound 124H (80 mg) was separated by chiral SFC to afford compound 124 (SFC retention time: 2.130 min, 20 mg) and compound 125 (SFC retention time: 2.628 min, 21 mg). SFC analysis: Instrument: SHIMADZU LC-30AD sf, Column: Chiral WHELK Column; Mobile phase: A: CO2, B: 0.05% DEA in methanol; Gradient: 5-40% B in A; Flow rate: 3.0 mL / min, Column temperature: 35°C, Wavelength: 220 nm. SFC preparation method: instrument: Waters 150 Prep-SFC, column: Chiral WHELK Column; mobile phase: A: CO2, B: for ethanol; gradient: 50% B gradient; elution flow rate: 100 mL / min; column temperature: 25°C; wavelength: 220 nm; cycle time: 5.0 min; sample preparation: sample concentration 4 mg / mL, acetonitrile and ethanol mixed solution injection: 3.0 mL each time.

[0790] Compound 124 (SFC analysis retention time: 2.130 min): 1 H NMR(400MHz, DMSO-d6)δ10.83(s,1H),8.45(d,1H),8.03(d,2H),7.90-7.87(m,1H),7.82(d,2H),7.51(d,1H),7.35-7.23(m, 5H),5.12-5.05(m,1H),4.52(t,1H),3.93-3.89(m,1H),2.03-1.92(m,1H),0.97-0.76(m,4H); LC-MS(ESI):m / z=618.1[M+H] + .

[0791] Compound 125 (SFC analysis retention time: 2.628 min): 1 H NMR(400MHz,DMSO-d6)δ10.83(s,1H),8.45(d,1H),8.03(d,2H),7.91-7.88(m,1H),7.82(d,2H),7.51(d,1H),7.35-7.23(m, 5H),5.11-5.07(m,1H),4.53(t,1H),3.93-3.89(m,1H),2.02-1.94(m,1H),0.99-0.80(m,4H); LC-MS(ESI):m / z=618.1[M+H] + .

[0792] Example 126, Example 127, Example 128 and Example 129

[0793] Step 1: Compound 126A (2 g, 3.85 mmol, synthesized according to the literature Journal of Medicinal Chemistry, 60(3), 1126-1141), potassium vinyl trifluoroborate (1.03 g, 7.71 mmol), Pd(PPh3)4 (445 mg, 0.38 mmol) and cesium carbonate (3.76 g, 11.6 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (dioxane:H2O=10:1, total 110 mL). After nitrogen replacement three times, the mixture was stirred at 80°C for 4 h. After completion of the reaction, water (30 mL) was added to quench the reaction, and the mixture was extracted twice with 100 mL of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 126B (1.1 g, yield: 61%). LC-MS (ESI): m / z = 464.3 [MH] - .

[0794] Step 2: Compound 126B (1.1 g, 2.36 mmol) and NIS (586 mg, 2.60 mmol) were dissolved in 20 mL of anhydrous DCM and stirred at -10°C for 10 min under nitrogen. A solution of hydrogen fluoride in pyridine (270 mg, 260 mmol) was then slowly added dropwise at -10°C. The temperature was slowly restored from -10°C to room temperature and the reaction was continued for 1 h. After the reaction was complete, 20 mL of saturated aqueous sodium bicarbonate solution was slowly added dropwise under an ice bath. The phases were separated, and the aqueous phase was extracted once with 20 mL of dichloromethane. The organic phases were combined, dried, and concentrated. The resulting residue was separated by silica gel column chromatography to afford compound 126C (510 mg, a mixture containing starting material 126B). LC-MS (ESI): m / z = 609.9 [MH] - &464.3[MH] - .

[0795] Step 3: A mixture...

Claims

1. A compound represented by formula (I), formula (IV), formula (IV-a), or formula (IV-b), or a stereoisomer or pharmaceutically acceptable salt thereof, in, R1, R2, and R3 are each independently selected from 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 with 1-5 Ra; R A Selected from -L1-W1-L2-W2-R A1 , -C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ; L1, L2 are each independently selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, 3-6 membered cycloalkyl, wherein the alkyl, alkoxy, cycloalkyl may be further substituted by 1-4 substituents selected from halogen, CN, OH and NH2; W1 and W2 are each independently selected from a bond, -O-, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -C(=O)O-, -OC(=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(=O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-; The condition is that L1, L2, W1, and W2 are not bonds at the same time; R A1 Selected from deuterium, halogen, hydroxyl, cyano, nitro, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, 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 with 1-5 Ra; R W1 Selected from H, C 1-4 Alkyl, halogen, cyano; Ra is selected from deuterium, halogen, hydroxyl, cyano, amino, nitro, oxo, C 1-6 Alkyl, C 1-6 Alkyl subunit, C 1-6 Haloalkyl subunit, 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, 5-10 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-8 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-8 Cycloalkyl, -S(O)2C 3-8 Cycloalkyl or -S(O)2C 1-4 wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1 to 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; R A2 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-6 substituted with an alkoxy group; X1, X2, X3, X4 are selected from CH or N; Alternatively, two Ra on the same carbon atom together with the carbon atom to which it is attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl; Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from 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 selected from 0, 1, 2, 3, 4 or 5; m is selected from 1, 2, 3, 4 or 5; k is selected from 1, 2, 3, 4 or 5; And the compound of formula (I) satisfies the following conditions: (1)R A Not for (2)R A Selected from When R3 is not C 2-6 Alkynyl and C 1-6 Deuterated alkyl; (3) When m and k are both selected from 1, R1 and R3 are not simultaneously selected from halogen.

2. The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein R1, R2, and R3 are each independently selected from 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 with 1-5 Ra; n is selected from 0, 1, 2 or 3; m is selected from 1, 2 or 3; k is selected from 1, 2 or 3.

3. A compound of formula (I), formula (IV), formula (IV-a), or formula (IV-b) according to any one of claims 1 to 2, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R A Selected from -W1-L2-W2-R A1、 -C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 ; L2 is selected from a bond, C 1-4 Alkylene, C 2-4 Alkenylene, wherein the alkylene and alkenylene are optionally further substituted by 1-4 R L1 Replacement; R L1 Each independently selected from halogen, =O, C 1-4 Alkyl, 3-6 membered cycloalkyl, wherein the alkyl and cycloalkyl are optionally further substituted by 1-4 substituents selected from halogen; W1 and W2 are each independently selected from a bond, -NR W1 -、-(C=O)NR W1 -、-NR W1 (C=O)-、-NR W1 -NR w1 (C=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-; The condition is that L2, W1, and W2 are not bonds at the same time; R A1 Selected from deuterium, halogen, hydroxyl, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, 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 with 1-5 Ra; R W1 Selected from H, C 1-2 Alkyl, halogen, cyano; Ra is selected from deuterium, halogen, hydroxyl, cyano, oxo, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 1-3 Alkyl subunit, C 1-3 Haloalkyl subunit, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl, 5-6 membered heteroaryl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 3-6 Cycloalkyl, -S(O)2C 1-4 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted by 1 to 5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group; R A2 Selected from C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl, heteroaryl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group; Alternatively, two Ra on the same carbon atom together with the carbon atom to which it is attached form C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl; Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

4. The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 3, its stereoisomers, and pharmaceutically acceptable salts, wherein: R A Selected from -W1-W2-R A1 , -C 3-6 Cycloalkyl-R A1 or -3-6 membered heterocycloalkyl-R A1 , preferably R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-N=C(NH2)-NR W1 R A1 、-N=C(NH2)-R A1 、-NR W1 -R A1 、-N=S(=O)(C 1-6 Alkyl)-R A1 、-NR W1 S(O)2-NR W1 C(O)-R A1 、-NR W1 -S(O)(=NH)-R A1 、-N=C(CH3)-NR W1 R A1 、-N=C(NH2)-NR W1 -NR W1 C(O)-R A1 , -C 3-6 Cycloalkyl-R A1 、-3-6 membered heterocycloalkyl-R A1 ; W1 and W2 are each independently selected from a bond, -NR W1 -、-NR W1 -NR w1 (C=O)-, -(C=O)NR W1 -、-NR W1 (C=O)-, -S(O)2-, -S(O)2NR W1 -、-NR W1 S(O)2-, -S(O)(=NH)-, -N=C(NH2)-, -N=S(=O)(C 1-6 alkyl)-, -N=C(CH3)-; The condition is that W1 and W2 are not bonds at the same time; R A1 Selected from deuterium, halogen, cyano, C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, C 6-8 Aryl or 5-6 membered heteroaryl, wherein the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 1-5 Ra; R W1 Selected from H, C 1-2 Alkyl, cyano; Ra is selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, C 1-3 Alkyl subunit, C 1-3 Haloalkyl subunit, C 1-4 Deuterated alkyl, C 1-4 Haloalkyl, -C(O)C 1-4 Alkyl, -C(O)C 1-4 Deuterated alkyl, -NR W1 C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Deuterated alkyl, -S(O)2NH2, -S(O)2NHC 1-4 Alkyl, -C(O)C 3-6 Cycloalkyl, -C(O)NR W1 C 1-4 Alkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 3-6 Cycloalkyl or -S(O)2C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group; R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy, C 1-3 Alkyl subunit, C 1-3 Haloalkyl substituent or deuterated C 1-4 substituted with an alkoxy group; Alternatively, two Ra on the same carbon atom together with the carbon atom to which it is attached form C 2-6 Alkenyl, C 3-6 Cycloalkyl; Alternatively, two R1 or two R3 on different carbon atoms together with the carbon atom to which they are attached form a C 4-6 Cycloalkyl, 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, cyano, amino, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

5. The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein: R1 is selected from halogen, C 1-4 Alkyl, C 2-4 Alkynyl; R2 is selected from hydrogen; R3 is selected from deuterium, halogen, C 1-4 Halogenated alkyl, -SF5, C 2-4 Alkenyl, C 2-4 Alkynyl, wherein the alkenyl and alkynyl are optionally further substituted with 1-3 Ra; Alternatively, two R3 from different carbon atoms together with the carbon atom to which they are attached form C 4-6 Cycloalkyl, wherein the cycloalkyl is optionally further substituted by 1-5 groups selected from deuterium, halogen, C 1-4 Alkyl groups are substituted; X1, X2, X3, X4 are selected from CH or N; R A Selected from -N=C(NH2)-NR W1 C(O)-R A1 、-NR W1 -R A1 、-N=C(NH2)-NR W1 -NR W1 C(O)-R A1 ; R A1 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl or 5-6 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl or heteroaryl is optionally further substituted with 1-5 Ra; R W1 Selected from H, C 1-2 alkyl; Ra is selected from deuterium, halogen, oxo, C 1-4 Alkyl, -C(O)C 1-4 Alkyl, -NR W1 C(O)C 1-4 Alkyl, -S(O)2NH2, -C(O)C 3-6 Cycloalkyl, -NR W1 C(O)C 3-6 Cycloalkyl, -S(O)2C 1-4 Alkyl, -S(=O)(=NH)-C 1-4 Alkyl, wherein the alkyl, cycloalkyl is optionally further substituted by 1-5 groups selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl groups are substituted; R A2 Selected from C 3-6 Cycloalkyl, 5-6 membered heteroaryl, wherein the cycloalkyl and heteroaryl are optionally further substituted by 1-5 groups selected from deuterium, halogen, hydroxyl, oxo, C 1-4 Alkyl, halogenated C 1-4 Alkyl, deuterated C 1-4 Alkyl, C 1-4 Alkoxy, halogenated C 1-4 Alkoxy or deuterated C 1-4 substituted with an alkoxy group.

6. The compound of formula (I), formula (IV), formula (IV-a), formula (IV-b) according to claim 1, its stereoisomers, and pharmaceutically acceptable salts, wherein: R A Selected from: R A2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5-membered heteroaryl, 6-membered heteroaryl, 6-membered heterocycloalkyl, 5-membered heterocycloalkyl, 4-membered heterocycloalkyl are optionally further substituted by 1-5 selected from deuterium, hydroxyl, cyano, amino, methyl, ethyl, isopropyl, methoxy, ethoxy, F, Cl , oxo, methylidene, ethylidene, 1-methylethylidene, fluoromethylidene, difluoromethylidene, -CH2D, -CHD2, -CD3, -CH2CH2D, -CH2CHD2, -CH2CD3, -CHDCH2D, -CHDCHD2, -CHDCD3, -CD2CH2D, -CD2CHD2, -CD2CD3, -CH2F, -CHF2, -CF3, -CH -2CH2F, -CH2CHF2, -CH2CF3, -CHFCH2F, -CHFCHF2, -CHFCF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -OCHF2, -OCH2F, -OCF3, -OCH2CH2F, -OCH2CHF2, -OCH2CF3, -OCHFCH2F, -OCHFCHF2, -OCHFCF3, -OCF2CH2F, -OCF2CHF2, -OCF2CF3, -OCHD2, -OCH2D, -OCD3, -OCH2CH2D, -OCH2CHD2, -OCH2CD3, -OCHDCH2D, -OCHDCHD2, -OCHDCD3, -OCD2CH2D, -OCD2CHD2, -OCD2CD3.

7. A compound of formula (I), formula (IV), formula (IV-a), or formula (IV-b) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the structures in Table 1 or Table 2.

8. A pharmaceutical composition, wherein Containing the compound according to any one of claims 1 to 7, its stereoisomer, pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and / or excipient.

9. Use of the compound according to any one of claims 1 to 7, its stereoisomer, pharmaceutically acceptable salt or the composition according to claim 8 in the preparation of a medicament for treating a CB1-mediated disease.

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.

11. A pharmaceutical composition or pharmaceutical preparation, comprising 1-1000 mg of a compound selected from any one of claims 1-7 or a stereoisomer or a pharmaceutically acceptable salt thereof and a carrier and / or an excipient.

12. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a stereoisomer or a pharmaceutically acceptable salt thereof, the therapeutically effective amount preferably being 1 to 1000 mg, the disease preferably being obesity, diabetes, non-alcoholic and alcoholic fatty liver disease, diabetic nephropathy, metabolic syndrome, hyperlipidemia or gout.

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