Substituted 1,2,4-triazole derivatives and use thereof

Abstract

Provided in the present invention are a series of substituted 1,2,4-triazole derivatives and the use thereof, and specifically provided are a compound as shown in formula (I) and a pharmaceutically acceptable salt thereof.

Description

Substituted 1,2,4-triazole derivatives and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims priority to the prior patent application filed with the China National Intellectual Property Office on August 9, 2024 (application number CN2024110992280) and the prior patent application filed with the China National Intellectual Property Office on May 16, 2025 (application number CN2025106426078), the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

[0003] The present application relates to a series of substituted 1,2,4-triazole derivatives and their uses, in particular to compounds represented by formula (I) or (I-3), stereoisomers thereof and pharmaceutically acceptable salts thereof. BACKGROUND

[0004] Apelin receptor (APJ) is a member of the G protein-coupled receptor (GPCR) family, and Apelin is the endogenous ligand of APJ, which can simultaneously activate the G protein and β-arrestin pathway downstream of APJ, thereby exerting a wide range of physiological effects. The Apelin / APJ system exists in many tissues (such as heart, kidney, pancreas, lung, vasculature, central nervous system, liver, fat, gastrointestinal tract, brain, adrenal gland, endothelium and human plasma), has a wide range of physiological functions, and is involved in a variety of pathological processes. The Apelin / APJ system has an important regulatory effect on the health status of the cardiovascular, metabolic and muscle systems. In the cardiovascular system, it has a regulatory effect on angiogenesis, diastole and systole, and cardiac contraction. In addition, a number of studies have also shown that Apelin has a significant regulatory effect on muscle metabolism and function, and the muscle function of old mice with Apelin or its receptor (APLNR) gene knockout is significantly reduced. The secretion of Apelin decreases in an age-dependent manner, and restoring the reduced Apelin can greatly enhance muscle function. Other studies have shown that Apelin / APJ also plays an important regulatory role in the metabolic system, and can regulate food intake, regulate sugar uptake, lipid metabolism, and muscle metabolism. Due to the important physiological functions of the Apelin / APJ system, its disorder is also involved in the occurrence of a variety of diseases, for example, studies have shown that Apelin has the potential to treat heart failure, muscle function decline, pulmonary hypertension, non-specific pulmonary fibrosis, and related diseases such as glucose and lipid metabolism disorders; Apelin / APJ system is associated with the occurrence of diseases such as sepsis, septic shock, and renal failure.

[0005] Apelin is a precursor protein composed of 77 amino acids, which hydrolyzes to produce bioactive peptides of varying lengths, such as Apelin-36, Apelin-31, Apelin-17, and Apelin-13. The 36-residue form (Apelin-36) and the 13-residue peptide (Apelin-13) are the main forms of endogenous apelin peptides, but these peptides have short half-lives, making them difficult to use as drugs. Apelin is a balanced (non-biased) receptor agonist that can simultaneously activate the G protein and β-arrestin pathways of the APJ. Related studies have shown that the cardioprotective effects induced by apelin (such as promoting cardiac contractility) are mainly attributed to APJ G protein signaling, while APJ β-arrestin activation may lead to potential side effects such as myocardial hypertrophy and receptor desensitization. Therefore, developing G protein-biased APJ agonists as potential drugs for treating cardiovascular diseases such as heart failure is a hot research topic. Currently, small molecule agonists such as AMG-986 (also known as BGE-105) and ANPA-0073 have entered clinical research stages. AMG-986 is a balanced receptor agonist, while ANPA-0073 is a G protein-biased receptor agonist with weak activation of the β-arrestin pathway. However, no APJ agonist (also called apelin receptor agonist) has been approved for marketing to date. Therefore, developing novel APJ agonists for diseases involving apelin / APJ system dysregulation has significant clinical value and broad application prospects. Summary of the Invention

[0006] This invention provides compounds of formula (I), their stereoisomers, or pharmaceutically acceptable salts thereof.

[0007] in,

[0008] Ring A is arbitrarily selected by 1 or 2 Rs a Substituted 5-membered heteroaryl groups;

[0009] Ring B is selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0010] L1 does not exist, or L1 is selected from O, S, NR7 and optionally selected by one or more R. L1 Replacement C 1-4 alkyl;

[0011] L2 is selected from one or more Rs. L2 The following groups are substituted: C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 0-3 Alkyl-C3-10 Cycloalkyl-C 0-3 Alkyl and C 0-3 Alkyl-3-10 membered heterocycloalkyl-C 0-3 Alkyl, wherein L2is attached to S via a carbon atom; X is O or NR8;

[0012] R1is selected from the group consisting of phenyl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0013] R2is selected from the group consisting of H, D, F, Cl, Br, I, CN, and phenyl, 5-10 membered heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0014] each R3, each R4, and each R5is independently selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2, CN, SF5, and the following groups optionally substituted with 1 or more R3a: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0015] Alternatively, two R3are joined together to form the following group optionally substituted with 1 or more R3b: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl;

[0016] Alternatively, two R4are joined together to form the following group optionally substituted with 1 or more R4b: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl;

[0017] R6, R7, and R8are each independently selected from the group consisting of H and the following groups optionally substituted with 1 or more R6a: C 1-4 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocycloalkyl;

[0018] each Rais independently selected from the group consisting of H, D, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C3-8 cycloalkyl and 3-8 membered heterocycloalkyl;

[0019] each R L1 and each R L2 is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: C 1-4 alkyl, C2-4alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;

[0020] each R1a, each R2a, is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CN, SF5, and the following groups optionally substituted with 1 or more R: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NHCO-C 1-4 alkyl, -CONH-C 1-4 alkyl and -CO-C 1-4 alkyl;

[0021] each R3a, each R3b, each R4b, each R6a, is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CN, SF5, and the following groups optionally substituted with 1 or more R: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0022] or 2 R1aare linked together, or 2 R2aare linked together, each independently form the following groups optionally substituted with 1 or more R: C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0023] each R is independently selected from H, D, F, CI, Br, I, OH, NH2, CN, SF5, and the following groups optionally substituted with 1 or more F: C1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl;

[0024] m, n, p are each independently selected from 0, 1, 2 and 3;

[0025] provided that, when ring A is X is O, any one of the following conditions is met:

[0026] 1) two R3are linked together to form a C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl;

[0027] 2) two R3are linked together to form a phenyl or 5-6 membered heteroaryl, optionally substituted with 1 or more R3b, and simultaneously, two R4are linked together to form a phenyl or 5-6 membered heteroaryl, optionally substituted with 1 or more R4b.

[0028] In some embodiments of the present application, each R above is independently selected from H, D, F, Cl, OH, NH2, CN, CH3and CF3, and other variables are as defined in the present application.

[0029] In some embodiments of the present application, each R above is independently selected from H, F, Cl, OH, NH2, CN, CH3and CF3, and other variables are as defined in the present application.

[0030] In some embodiments of the present application, each R above is independently selected from F, and other variables are as defined in the present application.

[0031] In some embodiments of the present application, each Raabove is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3and cyclopropyl, and other variables are as defined in the present application.

[0032] In some embodiments of the present application, each Raabove is independently selected from H, F, Cl, Br, I, OH, NH2, CN and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3and cyclopropyl, and other variables are as defined in the present application.

[0033] In some technical solutions of the present invention, each of the above Ra is independently selected from H, D, F, Cl, CH3 and CF3, and other variables are as defined in the present invention.

[0034] In some technical solutions of the present invention, the above-mentioned R L1 The variables are independently selected from H, D, F, Cl, CH3 and CF3, respectively, and other variables are as defined in this invention.

[0035] In some technical solutions of the present invention, the above-mentioned R L2 The following groups are independently selected from H, D, F, Cl, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl and C 1-4 Alkoxy groups, and other variables as defined in this invention.

[0036] In some technical solutions of the present invention, the above-mentioned R L2 The groups are independently selected from H, D, F, Cl, CN and the following groups optionally substituted with one or more R: methyl, ethyl, methoxy and ethoxy, with other variables as defined in this invention.

[0037] In some technical solutions of the present invention, the above-mentioned R L2 The groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and the following groups optionally substituted with one or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, and cyclopropyl, with other variables as defined in this invention.

[0038] In some technical solutions of the present invention, the above-mentioned R L2 The variables are independently selected from H, D, F, Cl, CH3, CF3 and CH2CN, respectively, and other variables are as defined in this invention.

[0039] In some technical solutions of the present invention, the above-mentioned R L2 The groups are independently selected from H, F, Cl, Br, I, =O, OH, NH2, CN, and the following groups optionally substituted with one or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, and cyclopropyl, with other variables as defined in this invention.

[0040] In some technical solutions of the present invention, the above-mentioned R L2each R1a, each R2a, each R3a, each R3b, each R4b, and each R6a is independently selected from H, F, CI, CH3, CF3, and CH2CN, and the other variables are as defined herein.

[0041] In some embodiments of the application, each R1a, each R2a, each R3a, each R3b, each R4b, and each R6a is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl, and the other variables are as defined herein.

[0042] In some embodiments of the application, each R1a, each R2a, each R3a, each R3b, each R4b, and each R6a is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CH3, CH2CH3, OCH3, and OCH2CH3, and the other variables are as defined herein.

[0043] In some embodiments of the application, each R1a is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, -COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl, and the other variables are as defined herein.

[0044] In some embodiments of the application, each R1a is independently selected from H, D, F, CI, Br, I, OH, NH2, CN, -COCH3, -COCF3, CH3, CH2F, CHF2, CF3, CD3, CH2CH3, CH2CF3, CF2CH3, OCH3, OCF3, OCD3, OCH2CH3, and the other variables are as defined herein.

[0045] In some embodiments of the application, each R1a is independently selected from H, D, F, CI, CN, and C 1-3 alkyl optionally substituted with 1 or more R, and the other variables are as defined herein.

[0046] In some embodiments of the application, each R1ais independently selected from C 1-3 alkyl, and the other variables are as defined in the application.

[0047] In some embodiments of the application, each R1ais independently selected from C 1-3 alkyl, and the other variables are as defined in the application.

[0048] In some embodiments of the application, each R1ais independently selected from methyl or ethyl optionally substituted with 1 or more D or F, and the other variables are as defined in the application.

[0049] In some embodiments of the application, each R1ais independently selected from methyl or ethyl, and the other variables are as defined in the application.

[0050] In some embodiments of the application, each R2ais independently selected from H, D, F, Cl, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, -COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl, and the other variables are as defined in the application.

[0051] In some embodiments of the application, each R 2a is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, -COCH3, -COCF3, -COCD3, CH3, CH2F, CHF2, CF3, CD3, CH2CH3, CH2CF3, CF2CH3, OCH3, OCF3, OCD3, OCH2CH3, and the other variables are as defined in the application.

[0052] In some embodiments of the application, each R 2a is independently selected from H, D, F, Cl, CN, and C 1-3 alkyl optionally substituted with 1 or more R, and the other variables are as defined in the application.

[0053] In some embodiments of the application, each R 2a is independently selected from C 1-3alkyl, and the other variables are as defined in the application.

[0054] In some embodiments of the application each R 2a is independently selected from C 1-3 alkyl, and the other variables are as defined in the application.

[0055] In some embodiments of the application each R 2a is independently selected from C 1-3 alkyl, and the other variables are as defined in the application.

[0056] In some embodiments of the application each R 2a is independently selected from C

[0057] In some embodiments of the application each R 2a is independently selected from C

[0058] In some embodiments of the application the two R 1a together with the atom to which they are attached form a group selected from and the other variables are as defined in the application.

[0059] In some embodiments of the application the two R 1a together with the atom to which they are attached form a group selected from and the other variables are as defined in the application.

[0060] In some embodiments of the application the two R 2a together with the atom to which they are attached form a group selected from said are each independently optionally substituted with one or more R, and the other variables are as defined in the application.

[0061] In some embodiments of the application the two R 2a together with the atom to which they are attached form a group selected from and the other variables are as defined in the application.

[0062] In some embodiments of the application R1is selected from C 1asubstituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0063] In some embodiments of the application, R1is selected from and the other variables are as defined in the application.

[0064] In some embodiments of the application, R1is selected from and the other variables are as defined in the application.

[0065] In some embodiments of the application, R1is selected from and the other variables are as defined in the application.

[0066] In some embodiments of the application, R1is selected from 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0067] In some embodiments of the application, R1is selected from 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0068] In some embodiments of the application, R1is selected from 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0069] In some embodiments of the application, R1is selected from 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0070] In some embodiments of the application, R1is selected from 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0071] In some embodiments of the application, R1is selected from 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, and the other variables are as defined in the application.

[0072] In some embodiments of the application, R1is selected from Other variables are as defined in the application.

[0073] In some embodiments of the application, R1is selected from Other variables are as defined in the application.

[0074] In some embodiments of the application, R2is selected from optionally substituted 2a phenyl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, and 4-12 membered heterocycloalkyl, and other variables are as defined in the application.

[0075] In some embodiments of the application, R2is selected from optionally substituted 2a phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, benzimidazolyl, pyridopyrrolyl, pyrimidopyrrolyl, and 4-12 membered heterocycloalkyl, and other variables are as defined in the application.

[0076] In some embodiments of the application, R2is selected from optionally substituted 2a phenyl and 5-10 membered heteroaryl, and other variables are as defined in the application.

[0077] In some embodiments of the application, R2is selected from optionally substituted 2a phenyl or 5-6 membered heteroaryl, and other variables are as defined in the application.

[0078] In some embodiments of the application, R2is selected from optionally substituted 2a 5-6 membered heteroaryl, and other variables are as defined in the application.

[0079] In some embodiments of the application, R2is selected from optionally substituted 2a R2is selected from optionally substituted 2a phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, pyridopyrrolyl, pyrimidopyrrolyl, and 4-12 membered heterocycloalkyl, and other variables are as defined in the application.

[0080] In some embodiments of the application, R2is selected from H, F, Cl, Br, I, CN, and optionally substituted 2asubstituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, and oxazolyl, and the other variables are as defined in the application.

[0081] In some embodiments of the application, R2is selected from optionally substituted 2a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, and oxazolyl, and the other variables are as defined in the application.

[0082] In some embodiments of the application, R2is optionally substituted 2a substituted pyrimidinyl, pyridyl, pyrazinyl, and pyridazinyl, and the other variables are as defined in the application.

[0083] In some embodiments of the application, R2is optionally substituted 2a substituted pyrimidinyl, and the other variables are as defined in the application.

[0084] In some embodiments of the application, R2is optionally substituted 2a substituted pyrimidinyl, and the other variables are as defined in the application.

[0085] In some embodiments of the application, R2is optionally substituted

[0086] In some embodiments of the application, R2is selected from and the other variables are as defined in the application.

[0087] In some embodiments of the application, R2is selected from and the other variables are as defined in the application.

[0088] In some embodiments of the application, R2is selected from and the other variables are as defined in the application.

[0089] In some embodiments of the application, R2is and the other variables are as defined in the application.

[0090] In some embodiments of the application, R2is and the other variables are as defined in the application.

[0091] In some embodiments of the application, R2is selected from H, F, CI, Br, I, and CN, and the other variables are as defined in the application.

[0092] In some embodiments of the application, R2is selected from H, F, and CN, and the other variables are as defined in the application.

[0093] In some embodiments of the application, each R3, each R4, and each R5is independently selected from H, D, F, CI, Br, I, OH, NH2, and optionally substituted with 1, 2, 3, 4, or 5 R 3a substituted with 1, 2, 3, 4, or 5 R

[0094] In some embodiments of the application, each R3, each R4, and each R5is independently selected from H, D, F, CI, Br, I, OH, NH2, CH3, OCH3, CD3, OCD3, CF3, and OCF3, and the other variables are as defined in the application.

[0095] In some embodiments of the application, each R3, each R4, and each R5is independently selected from H, F, CI, Br, I, OH, NH2, CH3, OCH3, CF3, and OCF3, and the other variables are as defined in the application.

[0096] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form a 5-, 6-, or 7-membered ring that is optionally substituted with 1, 2, 3, 4, or 5 R 3b substituted with 1, 2, 3, 4, or 5 R and the other variables are as defined in the application.

[0097] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form a 5-, 6-, or 7-membered ring that is optionally substituted with 1, 2, 3, 4, or 5 R and the other variables are as defined in the application.

[0098] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form a 5-, 6-, or 7-membered ring that is optionally substituted with 1, 2, 3, 4, or 5 R 3b substituted with 1, 2, 3, 4, or 5 R

[0099] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form The other variables are as defined in the application.

[0100] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form The other variables are as defined in the application.

[0101] In some embodiments of the application, two R4on adjacent atoms together with the atoms to which they are attached form 4b the following groups optionally substituted with 1, 2, 3, 4, or 5 R The other variables are as defined in the application.

[0102] In some embodiments of the application, two R4on adjacent atoms together with the atoms to which they are attached form The other variables are as defined in the application.

[0103] In some embodiments of the application, two R4on adjacent atoms together with the atoms to which they are attached form 4b the following groups optionally substituted with 1, 2, 3, 4, or 5 R

[0104] In some embodiments of the application, two R4on adjacent atoms together with the atoms to which they are attached form The other variables are as defined in the application.

[0105] In some embodiments of the application, two R4on adjacent atoms together with the atoms to which they are attached form The other variables are as defined in the application.

[0106] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form 3b the following groups optionally substituted with 1, 2, 3, 4, or 5 R 4b the following groups optionally substituted with 1, 2, 3, 4, or 5 R the following groups optionally substituted with 1, 2, 3, 4, or 5 R

[0107] In some embodiments of the application, two R3on adjacent atoms together with the atoms to which they are attached form two R4on adjacent atoms together with the atoms to which they are attached form The other variables are as defined in the application.

[0108] In some embodiments of the application, ring B is selected from phenyl and 5-6 membered heteroaryl, and the other variables are as defined in the application.

[0109] In some embodiments of the application, ring B is selected from phenyl, pyridyl and pyrimidinyl, and the other variables are as defined in the application.

[0110] In some embodiments of the application, ring B is selected from phenyl, and the other variables are as defined in the application.

[0111] In some embodiments of the application, the structural unit is selected from E1and E2are each independently selected from the following groups optionally substituted with 1 or more R 3b substituted with 1 or more R ＝ substituted with 1 or more R ＝ substituted with 1 or more R ＝ substituted with 1 or more R ＝ substituted with 1 or more R

[0112] In some embodiments of the application, E1and E2are each independently selected from the following groups optionally substituted with 1 or more R 3b substituted with 1 or more R ＝ substituted with 1 or more R ＝ substituted with 1 or more R ＝ substituted with 1 or more R 3b substituted with 1 or more R

[0113] In some embodiments of the application, the structural unit is selected from wherein T1is selected from CR5and N; T2, T3, T4, T5are each independently selected from C and N; ring C1and ring C2are each independently selected from the following groups optionally substituted with 1 or more R 3b substituted with 1 or more R5-8 saturated cycloalkyl, C 5-8 cycloalkenyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; other variables are as defined in the application.

[0114] In some embodiments of the application, the structural unit is selected from wherein E1and E2are each independently selected from optionally substituted -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH 3b -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH ＝ -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH ＝ -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH ＝ -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH ＝ -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH

[0115] In some embodiments of the application, the structural unit is selected from other variables are as defined in the application.

[0116] In some embodiments of the application, the structural unit is selected from other variables are as defined in the application.

[0117] In some embodiments of the application, the structural unit is selected from other variables are as defined in the application.

[0118] In some embodiments of the application, the structural unit is selected from other variables are as defined in the application.

[0119] In some embodiments of the application, the structural unit is selected from other variables are as defined in the application.

[0120] In some embodiments of the application, the structural unit is wherein, is selected from a single bond and a double bond, E3 and E4 are independently selected from O and S, and other variables are as defined in the application.

[0121] In some embodiments of the application, the structural unit is In some embodiments of the application, the structural unit is wherein, is selected from a single bond and a double bond, and other variables are as defined in the application.

[0122] In some embodiments of the application, the structural unit is In some embodiments of the application, the structural unit is and other variables are as defined in the application.

[0123] In some embodiments of the application, X is O, and other variables are as defined in the application.

[0124] In some embodiments of the application, X is NH, and other variables are as defined in the application.

[0125] In some embodiments of the application, L1 is absent, and other variables are as defined in the application.

[0126] In some embodiments of the application, L2 is selected from the following groups optionally substituted with 1 or more R L2 substituted with 1 or more R C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, CH2-C 3-8 cycloalkyl and CH2-3-8 membered heterocycloalkyl, wherein L2 is attached to S through a carbon atom, and other variables are as defined in the application.

[0127] In some embodiments of the application, L2 is selected from the following groups optionally substituted with 1 or more R L2 substituted with 1 or more R 1-6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl and C 0-3 alkyl-C 3-10 cycloalkyl-C 0-3 alkyl, and other variables are as defined in the application.

[0128] In some embodiments of the application, L2 is selected from the following groups optionally substituted with 1 or more R L2 substituted with 1 or more R 1-6 alkyl, and other variables are as defined in the application.

[0129] In some embodiments of the application, L2 is selected from the following groups optionally substituted with 1 or more R L2 substituted with 1 or more R1-3 alkyl, and the other variables are as defined in the application.

[0130] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. L2 substituted CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, CH(CH3)CH(CH3), CH=CH, CH2CH=CH, C 3-6 cycloalkyl, and CH2-C 3- 8cycloalkyl, and the other variables are as defined in the application.

[0131] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0132] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0133] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application.

[0134] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0135] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0136] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0137] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0138] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. and the other variables are as defined in the application.

[0139] In some embodiments of the application, L2is selected from the group consisting of CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3), and the other variables are as defined in the application. L2 substituted CH2, CH2CH2, CH2CH2CH2, and CH(CH3)CH2, R2is selected from the group consisting of optionally substituted alkyl, and the other variables are as defined in the application. 2asubstituted phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, and other variables are as defined in the application.

[0140] In some embodiments of the application, L2 is R2 is selected from and other variables are as defined in the application.

[0141] In some embodiments of the application, L2 is R2 is selected from and other variables are as defined in the application.

[0142] In some embodiments of the application, ring A is selected from and other variables are as defined in the application.

[0143] In some embodiments of the application, ring A is selected from and other variables are as defined in the application.

[0144] In some embodiments of the application, ring A is selected from triazolyl, and other variables are as defined in the application.

[0145] In some embodiments of the application, ring A is selected from and other variables are as defined in the application.

[0146] In some embodiments of the application, ring A is selected from wherein 1 is connected to ring B, and other variables are as defined in the application.

[0147] In some embodiments of the application, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0148] T1 is selected from CR5 and N;

[0149] T2, T3, T4, T5 are each independently selected from C and N;

[0150] ring C1 and ring C2 are each independently selected from an optionally substituted group consisting of C 3b substituted C 5-8 cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0151] ring A, X, R1, R2, R5, R 3b , L2 are as defined in the application.

[0152] In some embodiments of the present application, the compound represented by the above formula (I-3), (I-4), (I-5) or (I-6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L2 is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R L2 substituted groups: CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2and CH(CH3)CH(CH3); R1is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R 1a substituted groups: CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2and CH(CH3)CH(CH3); R1is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R 2a substituted groups: CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2and CH(CH3)CH(CH3); R1is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R

[0153] In some embodiments of the present application, the compound represented by the above formula (I-3) or (I-6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0154] wherein,

[0155] T1is selected from CH and N; further, T1is selected from CH;

[0156] T2, T3, T4, T5are each independently selected from C and N; further, T2, T3, T4, T5are each independently selected from C;

[0157] ring C1and ring C2are each independently selected from C 5-8 cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; further, ring C1and ring C2are each independently selected from 5-8 membered heterocycloalkyl;

[0158] ring A is selected from 1,2,4-triazolyl;

[0159] X is selected from O and NH; further, X is selected from O;

[0160] R1is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R 1a substituted 5-6 membered heteroaryl;

[0161] R2is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R 2a substituted groups: CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2and CH(CH3)CH(CH3); R1is selected from the following groups optionally substituted by 1, 2, 3, 4 or 5 R

[0162] each R 1a is each independently selected from H, D, F, Cl, CN and C 1-3 alkyl;

[0163] each R 2a is each independently selected from H, D, F, Cl, CN and C1-3 alkyl;

[0164] L2is selected from optionally substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered heteroarylidene, each of which is optionally substituted with 1 or more R L2 substituted C1-6alkyl; 1-3 alkyl, each R L2 are each independently selected from H, D, F, Cl, CN, and optionally substituted methyl, ethyl, methoxy, and ethoxy with 1 or more R; further, L2is selected from CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3); still further, L2is selected from CH2CH2,

[0165] In some embodiments of the present application, the compound represented by the above formula (I-3) or (I-6), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0166] wherein r is selected from 1 and 2; ring C1, ring C2, T1, T2, T3, T4, T5, R1, R2, R L2 as defined in the present application.

[0167] In some embodiments of the present application, the compound represented by the above formula (I-3), (I-6), or (I-7), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0168] wherein,

[0169] r is selected from 1 and 2;

[0170] E1and E2are each independently selected from -CH2CH2O-, -CH ＝ CHO-, -CH2CH2S-, and -CH ＝ CHS-;

[0171] R1, R2, R5, R L2 as defined in the present application.

[0172] In some embodiments of the present application, the compound represented by the above formula (II-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1is selected from optionally substituted 5-6 membered heteroaryl; R2is selected from optionally substituted phenyl and 5-6 membered heteroaryl with 1, 2, 3, 4, or 5 R 1a substituted C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkenyl, 5-6 membered heteroaryl, and 5-6 membered heteroarylidene; other variables are as defined in the present application. 2a substituted phenyl and 5-6 membered heteroaryl; other variables are as defined in the present application.

[0173] In some technical solutions of the present invention, the compounds shown in formulas (I), (I-1), (I-2), (I-3), (I-6), (I-7), (II) or (II-1), their stereoisomers or pharmaceutically acceptable salts thereof are selected from:

[0174] in, Selected from single and double bonds;

[0175] E1 and E2 are independently selected from O and S, respectively;

[0176] R1 is selected from one or more R1s. 1a Substituted 5-6 aryl groups;

[0177] R2 is selected from one or more R2s. 2a Substituted phenyl or 5-6-membered heteroaryl;

[0178] R 1a R 2a As defined in this invention.

[0179] In some technical solutions of the present invention, the above-mentioned Selected from single bonds, other variables are as defined in this invention.

[0180] The present invention also provides the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,

[0181] in,

[0182] Ring A is arbitrarily selected by 1 or 2 Rs a Substituted 5-membered heteroaryl groups;

[0183] Ring B is selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0184] L1 does not exist, or L1 is selected from O, S, NR7 and optionally selected by one or more R. L1 Replacement C 1-4 alkyl;

[0185] L2 is selected from one or more Rs. L2 The following groups are substituted: C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 0-3 Alkyl-C 3-10 cycloalkyl-C 0-3 Alkyl and C 0-3 Alkyl-3-10 heterocyclic alkyl-C 0-3 alkyl;

[0186] X is either O or NR8;

[0187] R1 is selected from one or more R1s. 1a Substituted groups include: phenyl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0188] R2 is selected from H, F, Cl, Br, I, CN, and optionally one or more R 2a Substituted phenyl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0189] Each R3, each R4, and each R5 is independently selected from H, F, Cl, Br, I, OH, NH2, and optionally by one or more R... 3a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0190] Alternatively, two R3s connected together form a configuration that can be optionally bounded by one or more Rs. 3b The following groups are substituted: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0191] Alternatively, two R4s connected together form a configuration that can be optionally bounded by one or more Rs. 4b The following groups are substituted: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0192] R6, R7, and R8 are each independently selected from any H and selected by one or more Rs. 6a The following groups are substituted: C 1-4 Alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0193] Each R a The following groups are selected independently from H, F, Cl, Br, I, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0194] Each R L1 and each R L2 The following groups are independently selected from H, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0195] Each R 1a Each R 2a Each R 3a Each R 3b Each R 4b Each R 6a The following groups are independently selected from H, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0196] Or 2 Rs 1a Connected together, or two Rs 2a Linked together, they independently form the following groups, optionally substituted with one or more R groups: C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0197] Each R is independently selected from H, F, Cl, Br, I, OH, NH2, CN, and the following groups optionally substituted by one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0198] m, n, and p are independently selected from 0, 1, 2, and 3, respectively;

[0199] The condition is that when ring A is X is O, any one of the following conditions is met:

[0200] 1) two R3s are linked together to form an optionally substituted C 3b substituted C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl;

[0201] 2) two R3s are linked together to form an optionally substituted C 3b substituted phenyl or 5-6 membered heteroaryl, two R4s are linked together to form an optionally substituted C 4b substituted phenyl or 5-6 membered heteroaryl.

[0202] In some technical solutions of the present application, the compound represented by the above formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, wherein L2 is connected to S through a carbon atom.

[0203] In some technical solutions of the present application, the compound represented by the above formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is selected from:

[0204] wherein,

[0205] T1 is selected from CR5 and N;

[0206] T2, T3, T4 and T5 are selected from C and N;

[0207] R1 is optionally substituted 5-6 membered heteroaryl; 1a substituted 5-6 membered heteroaryl;

[0208] R2 is selected from optionally substituted phenyl or 5-6 membered heteroaryl; 2a substituted phenyl or 5-6 membered heteroaryl;

[0209] R5 is selected from H, F, Cl, CH3 and OCH3;

[0210] ring C1 and ring C2 are independently selected from optionally substituted C 3b substituted C 4-8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0211] ring A, each R 1a , each R 2a , each R 3b as defined in the present application.

[0212] In some technical solutions of the present application, the compound represented by the above formula (I) or (I-1), the stereoisomer thereof or the pharmaceutically acceptable salt thereof is selected from:

[0213] wherein,

[0214] R1is selected from H, F, Cl, CH3, and OCH3; 1a substituted 5-6 membered heteroaryl;

[0215] R2is selected from optionally substituted phenyl or 5-6 membered heteroaryl; 2a substituted 5-6 membered heteroaryl;

[0216] R5is selected from H, F, Cl, CH3, and OCH3;

[0217] E1and E2are each independently selected from optionally substituted -CH2CH2O-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-; 3b substituted -CH2CH2O-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-; ＝ substituted -CH2CH2O-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-; ＝ substituted -CH2CH2O-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-; ＝ substituted -CH2CH2O-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-;

[0218] ring A, each R 1a and each R 2a , each R 3b as defined in the present application.

[0219] In some embodiments of the present application, the compound represented by the above formula (I) or (I-1), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-2), (I-2a), (I-2b), (I-2c), or (I-2d); in some embodiments of the present application, the compound represented by formula (I-1a), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-2a); in some embodiments of the present application, the compound represented by formula (I-1b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from a compound of formula (I-2b).

[0220] In some embodiments of the present application, the compound represented by the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0221] wherein R1, R2, L2, X are as defined in the present application formula (I), ring C1, ring C2, T1, T2, T3, T4, T5 are as defined in the present application formula (I-1).

[0222] In some embodiments of the present application, the compound represented by the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0223] wherein,

[0224] T1is selected from CR5and N;

[0225] T2, T3, T4, T5 are selected from C and N;

[0226] R1is optionally substituted with 1 or more R 1a substituted 5-6 membered heteroaryl;

[0227] R2is selected from H, F, Cl, Br, I and CN;

[0228] R5is selected from H, F, Cl, CH3and OCH3;

[0229] L2is selected from optionally substituted with 1 or more R L2 substituted C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, -CH2-C 3-8 cycloalkyl and -CH2-3-8 membered heterocycloalkyl, wherein L2is attached to S through a carbon atom;

[0230] ring C1and ring C2are each independently selected from optionally substituted with 1 or more R 3b substituted C 4-8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0231] ring A is triazolyl;

[0232] each R 1a , each R L2 , each R 3b as defined in the present invention.

[0233] The present invention also has some technical solutions with any combination of the above variables.

[0234] The present invention also provides the compounds shown in Table A, stereoisomers thereof or pharmaceutically acceptable salts thereof.

[0235] In some technical solutions of the present invention, the compounds shown in Table A, stereoisomers thereof or pharmaceutically acceptable salts thereof are selected from the compounds of Table A1.

[0236] The compounds of Table A

[0237] The compounds of Table A1

[0238] The present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present application, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. Further, a pharmaceutically acceptable carrier is also included.

[0239] The present application also provides a pharmaceutical combination method comprising the compound of the present application, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and other drugs for use in the treatment of Apelin receptor agonist related diseases.

[0240] In some technical solutions of the present application, the other drugs in the above-mentioned pharmaceutical combination method include but are not limited to GLP-1 receptor agonists, GIP receptor agonists, GCG receptor agonists, and related dual-target, triple-target drugs, etc.

[0241] In some technical solutions of the present application, the above-mentioned GLP-1 receptor agonists include but are not limited to Semaglutide, Tirzepatide, Liraglutide, Orforglipron, etc.

[0242] The present application also provides the use of the above-mentioned compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating Apelin receptor agonist related diseases.

[0243] In some technical solutions of the present application, the above-mentioned Apelin receptor agonist related diseases include but are not limited to metabolic disorder diseases (such as obesity, insulin resistance, type 2 diabetes, etc.), cardiovascular diseases (such as heart failure, etc.), pulmonary hypertension and idiopathic pulmonary fibrosis, etc. lung diseases, muscle atrophy caused by long-term bedridden or other diseases, etc. muscle function decline diseases.

[0244] The present application also provides the following synthesis methods:

[0245] Method 1:

[0246] Method 2:

[0247] Technical effects

[0248] The compound of the present application can significantly activate the G protein signal downstream of the Apelin receptor, and some of the compounds have relatively weak effects on recruiting β-arrestin 2, have high selectivity, and are G protein biased Apelin receptor agonists.

[0249] The compound of the present application has high plasma protein binding ratio in different species plasma, shows strong plasma protein binding ability, has good stability in various species (especially human) liver microsomes and hepatocytes, has no obvious inhibition on main cytochrome P450 enzymes of human liver microsomes, has low risk of "drug-drug interaction", has no obvious inhibition on hERG, and has low clearance rate, long half-life, high oral exposure and high oral bioavailability in various species pharmacokinetic (PK) studies, has excellent pharmacokinetic properties, and has small species difference.

[0250] The compound of the present application can be combined with Semaglutide in a diet-induced mouse obesity (DIO) model, can further significantly reduce body weight, improve body composition, and further reduce the fasting blood glucose level of animals, exhibits good in vivo efficacy, and the combined efficacy is significantly better than the single drug effect of Semaglutide.

[0251] The compound of the present application also has good solubility, which is beneficial to oral administration and formulation development.

[0252] Definitions and Descriptions

[0253] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indefinite or unclear if not specifically defined, but should be understood according to the ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0254] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0255] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents, as discovered in the present invention, with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in their free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0256] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and their racemic mixtures and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention. The optical purity of a single-configuration compound can be expressed by optical rotation, chiral purity, and / or ee, etc. Chiral purity refers to the content determined by testing methods (such as GC, HPLC, SFC, NMR, etc.); ee refers to the percentage excess of isomers or enantiomers, which is the difference in the percentage content of the two isomers or enantiomers. For example, if SFC testing shows that the content of one isomer a is 90% and the content of another isomer b is 10%, then the chiral purity of isomer a is 90% and the ee value is 80%.

[0257] The compounds of the present application can exist as specific tautomers. Unless otherwise specified, the term "tautomer" or "tautomerically" refers to isomers of a functional group that result from the movement of one or more atoms in a molecule between two positions. Tautomers are a special class of functional group isomers. Tautomers can interconvert in a dynamic equilibrium, but usually one isomer predominates as the more stable form. For example, in solution, a chemical equilibrium between tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by reorganization of some bonding electrons. For example, a specific example of keto-enol tautomerization is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one, two tautomers. In some embodiments of the present application, are also tautomers of two forms.

[0258] Unless otherwise specified, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.

[0259] Unless otherwise specified, the term "cis-trans isomer" or "geometric isomer" is caused by a double bond or a ring-forming carbon atom single bond that cannot rotate freely.

[0260] Unless otherwise specified, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.

[0261] Unless otherwise specified, "(+)" indicates dextrorotation, "(-)" indicates levorotation, and "(±)" indicates racemization.

[0262] Unless otherwise specified, a wedge-shaped solid line bond and a wedge-shaped dashed line bond indicate the absolute configuration of a stereocenter, a straight solid line bond and a straight dashed line bond indicate the relative configuration of a stereocenter, a wavy line indicates a wedge-shaped solid line bond and / or a wedge-shaped dashed line bond or a wavy line indicates a straight solid line bond and / or a straight dashed line bond

[0263] ​Unless otherwise indicated, the carbon atom bearing an "*" is a chiral carbon atom, and exists in the form of a (R) or (S) single enantiomer or is enriched in one enantiomeric form. For example, denotes or or is enriched in one enantiomeric form.

[0264] Unless otherwise indicated, the term "enriched in one isomer," "isomerically enriched," "enriched in one enantiomer," or "enantiomerically enriched" means that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0265] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is present in the molecule, diastereomeric salts with appropriate optically active acids or bases are formed and the diastereomeric salt resolved by conventional means well known in the art, and the desired enantiomer recovered. In addition, separation of the enantiomers and diastereomers is often accomplished by the use of chromatography with a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamates from amines).

[0266] The compounds of the present application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterium- containing drugs. Deuterium-containing drugs have advantages over non-deuterium containing drugs in that they can have increased stability, increased efficacy, increased potency, increased bioavailability, and / or decreased toxicity. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0267] The term "substituted" means that any one or more hydrogen atoms on the designated atom is replaced with a substituent group, which can include heavy hydrogen and variations of hydrogen, as long as the valency of the designated atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. In some embodiments of the invention, "substituted" means that any one or more hydrogen atoms on a carbon atom or a nitrogen atom is replaced with a substituent group.

[0268] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not.

[0269] The term "optionally substituted" means that the group can or can not be substituted and that the types and number of substituents are any that are chemically possible, unless otherwise specified. In some embodiments of the invention, "optionally substituted with 1 or more R" means that the group can not be substituted, or can be substituted with 1, 2, 3, 4, 5, 6, 7, or 8 R. In some embodiments of the invention, "optionally substituted with 1 or more R" means that the group is optionally substituted with 1, 2, 3, 4, or 5 R. In some embodiments of the invention, "optionally substituted with 1 or more R" means that the group is optionally substituted with 1, 2, or 3 R.

[0270] When any variable (e.g., R) occurs more than one time in a compound or structure, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is designated as being substituted with 0-2 R, then the group optionally can be substituted with up to two R, and at each occurrence R is selected independently of its selection at every other occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0271] When the number of occurrences of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0272] When one of the variables is selected from a single bond or a bond, it means that the two groups to which it is attached are directly connected, such as when L is a bond in A-L-Z, it means that the structure is actually A-Z.

[0273] When a substituent is null, it means that the substituent is absent, such as when X is null in A-X, it means that the structure is actually A.

[0274] When the listed substituents do not specify which atom they are attached to the substituted group, they can be bonded to any of their atoms. For example, a pyridinium group, as a substituent, can be attached to the substituted group via any carbon atom on the pyridine ring. When the listed linking groups do not specify their attachment direction, the attachment direction is arbitrary. For example… The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the right-to-left reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0275] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line Indicated. Wherein, the key is represented by a straight dashed line. or wavy line When indicating a linking site, it can be a single bond, double bond, or triple bond, etc. For example, the straight solid line bond in -OCH3 indicates that the oxygen atom in this group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the text indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0276] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, and also any range from n to n+m. For example, C 1-12Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 etc., including C 1- 3. C 1-6 C 1-9 C 3-6 C 3-9 C 3-12 C 6-9 C 6-12 and C 9-12 Similarly, n to n+m membered rings represent rings with n to n+m atoms. For example, 3-12 membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, as well as 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings.

[0277] Unless otherwise specified, the term “halogen” or “halogen” itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0278] Unless otherwise specified, the term "alkyl" on its own or in combination with other terms refers to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 20 carbon atoms. It can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). The alkyl group includes C... 1-10 Alkyl, C 1-6 Alkyl, C 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl groups, examples of which include, but are not limited to, methyl (Me), methylene (CH2), methine (CH), ethyl (Et), propyl (including n-propyl and isopropyl), n-butyl, tert-butyl, n-pentyl, etc. In some embodiments of the present invention, the alkyl group is C24. 1-6 Alkyl groups, including C 1-2 C 1-3 C 1-4 C 2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkyl groups, etc.; in other technical solutions of the present invention, the alkyl group is C1, C2, C3, C4, C5, C6 alkyl groups, etc. 1-4 Alkyl groups, including C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkyl groups, etc.; in other technical solutions of the present invention, the alkyl group is C1, C2, C3, C4 alkyl group, etc. 1-3 Alkyl groups, including C1-2 , C 2-3 , C1, C2, C3alkyl, etc.

[0279] Unless otherwise specified, the term "alkenyl" by itself or in combination with other terms means a straight-chain or branched-chain hydrocarbon group consisting of 2 to 20 carbon atoms, containing at least one carbon-carbon double bond. It can be monovalent, divalent, or multivalent. The alkenyl group includes C 2-10 alkenyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 alkenyl, etc. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, 1-butenyl, isoprene, etc. In some embodiments of the present application, the alkenyl group is C 2-6 alkenyl, which includes C 2-3 , C 2-4 , C 2-5 , C2, C3, C4, C5, C6alkenyl, etc. In other embodiments of the present application, the alkenyl group is C 2-4 alkenyl, which includes C 2-3 , C2, C3, C4alkenyl, etc. In other embodiments of the present application, the alkenyl group is C 2-3 alkenyl, which includes C2and C3alkenyl, etc.

[0280] Unless otherwise specified, the term "alkynyl" by itself or in combination with other terms means a straight-chain or branched-chain hydrocarbon group consisting of 2 to 20 carbon atoms, containing at least one carbon-carbon triple bond. It can be monovalent, divalent, or multivalent. The alkynyl group includes C 2-10 alkynyl, C 2-6 alkynyl, C 2-5 alkynyl, C 2-4 alkynyl, C 2-3 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butyryl, etc. In some embodiments of the present application, the alkynyl group is C 2-6 alkynyl, which includes C 2-3 , C 2-4 , C 2-5 , C2, C3, C4, C5, C6alkynyl, etc. In other embodiments of the present application, the alkynyl group is C 2-4 alkynyl, which includes C 2-3 , C2, C3, C4alkynyl, etc. In other embodiments of the present application, the alkynyl group is C 2-3 alkynyl, which includes C2and C3alkynyl, etc.

[0281] Unless otherwise specified, the term "alkyl," by itself or in combination with another term, means those branched or unbranched saturated straight-chain monovalent hydrocarbon groups containing 1 to 20 carbon atoms. It can be monovalent, divalent, or multivalent. The alkyl groups include C 1-10 alkyl, C 1-6 alkyl, C 1-5 alkyl, C 1-4 alkyl, C 1-3 alkyl, and the like. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), and the like. In some embodiments of the application, the alkyl group is a C 1-6 alkyl group, including C 1-2 , C 1-3 , C 1-4 , C 2-3 , C 2-4 , C 2-5 , C1, C2, C3, C4, C5, C6 alkyl, and the like; in other embodiments of the application, the alkyl group is a C 1-4 alkyl group, including C 1-2 , C 1-3 , C 2-3 , C 2-4 , C1, C2, C3, C4 alkyl, and the like; in other embodiments of the application, the alkyl group is a C 1-3 alkyl group, including C 1-2 , C 2-3 , C1, C2, C3 alkyl, and the like.

[0282] Unless otherwise specified, the term "alkylthio," by itself or in combination with other terms, means those alkyl groups containing 1 to 20 carbon atoms connected to the rest of the molecule by a sulfur atom. It can be monovalent, divalent, or multivalent. The alkylthio groups include C 1-10 alkylthio, C 1-6 alkylthio, C 1-5 alkylthio, C 1-4 alkylthio, C 1-3 alkylthio, and the like. Examples of alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), and the like. In some embodiments of the application, the alkylthio group is a C 1-6 alkylthio group, including C 1-2 , C 1-3 , C 1-4 , C 2-3 , C 2-4 , C 2-5 , C1, C2, C3, C4, C5, C6 alkylthio, and the like; in other embodiments of the application, the alkylthio group is a C 1-4alkylthio, including C 1-2 alkylthio, including C 1-3 alkylthio, including C 2-3 alkylthio, including C 2-4 alkylthio, including C1, C2, C3, C4alkylthio, etc. 1-3 alkylthio, including C 1-2 alkylthio, including C 2-3 alkylthio, including C1, C2, C3alkylthio, etc.

[0283] Unless otherwise specified, the term "alkylamino," by itself or in combination with other terms, refers to those alkyl groups containing from 1 to 20 carbon atoms attached to the rest of the molecule through a nitrogen atom. It can be monovalent, divalent, or multivalent, including monoalkylamino and dialkylamino. The alkylamino groups include C 1-10 alkylamino, C 1-6 alkylamino, C 1-5 alkylamino, C 1-4 alkylamino, C 1-3 alkylamino, etc., examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, etc. In some embodiments of the application, the alkylamino is C 1-6 alkylamino, including C 1-2 alkylamino, including C 1-3 alkylamino, including C 1-4 alkylamino, including C 2-3 alkylamino, including C 2-4 alkylamino, including C 2-5 alkylamino, including C1, C2, C3, C4, C5, C6alkylamino, etc. In other embodiments of the application, the alkylamino is C 1-4 alkylamino, including C 1-2 alkylamino, including C 1-3 alkylamino, including C 2-3 alkylamino, including C 2-4 alkylamino, including C1, C2, C3, C4alkylamino, etc. In other embodiments of the application, the alkylamino is C 1-3 alkylamino, including C 1-2 alkylamino, including C 2-3 alkylamino, including C1, C2, C3alkylamino, etc.

[0284] Unless otherwise indicated, the term "cycloalkyl" by itself or in combination with other terms, means a saturated or partially unsaturated cyclic hydrocarbon radical of from 3 to 20 carbon atoms. It can be monovalent, divalent or multivalent. The cycloalkyl group can optionally contain one or more carbon-carbon double bonds or triple bonds, but no aromatic rings. The cycloalkyl group can be a saturated cycloalkyl group (meaning all rings are saturated), a cycloalkenyl group (meaning at least one double bond in a monocyclic or polycyclic ring system), and the like. The cycloalkyl group can be monocyclic, polycyclic (e.g., spiro, fused, bridged), and the like. Cycloalkyl groups include C3-C20cycloalkyl, C3-Ci0cycloalkyl, C3-C8cycloalkyl, C3-C6cycloalkyl, C3-C5cycloalkyl, C3-C4cycloalkyl, C4-C6cycloalkyl, C5-C6cycloalkyl, and the like. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. In some embodiments of the application, the cycloalkyl group is a C3-C6cycloalkyl group. 3-10 Cycloalkyl, C 3-8 Cycloalkyl, C 3-7 Cycloalkyl, C 3-6 Cycloalkyl, C 3-5 Cycloalkyl, C 4-6 Cycloalkyl, and the like. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like. In some embodiments of the application, the cycloalkyl group is a C3-C6cycloalkyl group. 3-6 Cycloalkyl, C 3- 5, C 4-5 , C 4-6 , C3, C4, C5, C6cycloalkyl, and the like.

[0285] Unless otherwise specified, the term "heterocycloalkyl," by itself or in combination with other terms, refers to a saturated or partially unsaturated cyclic group consisting of 3 to 20 ring atoms, 1, 2, 3, 4, 5, 6, 7, or 8 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms, wherein the carbon atoms are optionally substituted with oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)2, p is 1 or 2), and wherein the heteroatoms can occupy any available position of the heterocycloalkyl group including the position that is attached to the remainder of the molecule. It can be monovalent, divalent, or multivalent. The heterocycloalkyl group can optionally contain one or more double or triple bonds, but none of the rings is aromatic. The heterocycloalkyl group can be a saturated heterocycloalkyl group (meaning all rings are saturated), a heterocycloalkenyl group (meaning at least one carbon-carbon double bond is present in a monocyclic or polycyclic system), and the like. The heterocycloalkyl group includes 3-10 membered heterocycloalkyl, 3-8 membered heterocycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, 3-5 membered heterocycloalkyl, 4-6 membered heterocycloalkyl, and the like. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl and 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl and 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, and the like. In some embodiments of the application, 3-10 membered heterocycloalkyl includes 3-5 membered, 3-6 membered, 3-7 membered, 3-8 membered, 4-6 membered, 4-7 membered, 4-8 membered, 5-6 membered, 5-8 membered, 6-8 membered, 6-10 membered heterocycloalkyl, and the like. In some embodiments of the application, the heterocycloalkyl group is a 3-6 membered heterocycloalkyl group, which includes 3-5 membered, 4-5 membered, 4-6 membered, 3 membered, 4 membered, 5 membered, 6 membered heterocycloalkyl, and the like.

[0286] Unless otherwise specified, the terms "heteroaromatic ring" and "heteroaryl" are used interchangeably, and the term "heteroaryl" by itself or in conjunction with other terms refers to a monocyclic group or a polycyclic ring system consisting of 5 to 20 ring atoms having a conjugated pi-electron system, 1, 2, 3, 4, 5, 6, 7, or 8 of which are heteroatoms independently selected from O, S, and N, with the remainder being carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)2, p is 1 or 2). The heteroaryl group can be attached to the remainder of the molecule through a heteroatom or carbon atom, and it can be monovalent, divalent, or multivalent. The heteroaryl group includes 5-6 membered, 5-8 membered, 5-9 membered, 5-10 membered, 6-8 membered, 6-9 membered, 6-10 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heteroaryl. Examples of the heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thiophenyl (including 2-thiophenyl and 3-thiophenyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyridazinyl, pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), indolyl, indazolyl, pyrimidoimidazolyl, etc. In some embodiments of the present application, the heteroaryl group is a 5-10 membered heteroaryl group, which includes 5-6 membered, 5-8 membered, 5-9 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, 10 membered heteroaryl; in other embodiments of the present application, the heteroaryl group is a 5-6 membered heteroaryl group, which includes 5 membered and 6 membered heteroaryl.

[0287] Unless otherwise specified, the term "aromatic ring" is a cyclic group having a conjugated pi-electron system, which is overlaid by a delocalized pi-electron cloud between the atoms. In structural formulas, it can be written in the form of single and double bonds alternating, or it can be represented by o to represent the delocalized pi-electron cloud, while complying with the valence state of the atoms and the bonding rules of covalent bonds. For example, the structures represented by are the same; the structure represented by is the same. The aromatic ring can be a monocyclic ring, or a polycyclic ring system, wherein each ring of the polycyclic ring system is aromatic. Unless otherwise specified, the ring optionally contains 0, 1, or more heteroatoms or heteroatom groups independently selected from O, S, NH, and N.

[0288] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present application.

[0289] The compounds of the present application can be confirmed by conventional methods well known to those skilled in the art. If the present application relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD), a single crystal is grown and diffracted intensity data is collected using a Bruker D8 venture diffractometer with Cu Kα radiation, scanning mode: After the relevant data is collected, the crystal structure is further resolved using the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0290] Abbreviations used in the present application: XantPhos-Pd-G3 represents [9,9-dimethyl-4,5-bis(diphenylphosphoryl) xanthene][2-amino-1,1-diphenyl]palladium(II) methane sulfonate, CAS: 1445085-97-1; MC represents methyl cellulose; Saline represents physiological saline; Solutol represents polyethylene glycol-15 hydroxystearate; tween80 represents tween 80; PEG400 represents polyethylene glycol 400; HEPES represents 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; HBSS represents Hank's balanced salt buffer; NADPH represents reduced coenzyme II, also known as reduced nicotinamide adenine dinucleotide phosphate; PBS represents phosphate buffer.

[0291] The solvents used in the present application can be commercially available. The compounds are named according to the conventional naming principles in the art or using software naming, and commercially available compounds are named using the supplier's catalog name. BRIEF DESCRIPTION OF DRAWINGS

[0292] Figure 1: Body weight change graph of mice in DIO model in vivo efficacy experiment (I).

[0293] Figure 2: Body weight change graph of mice in DIO model in vivo efficacy experiment (II). DETAILED DESCRIPTION

[0294] The application will be described in detail below with examples, but it does not mean any unfavorable limitation to the application. The application has been described in detail herein, and the specific embodiment modes thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiment modes of the application without departing from the spirit and scope of the application.

[0295] Intermediate M1

[0296] Step 1: To a mixture of compound M1-1 (10 g, 77.79 mmol) and compound M1-2 (13.86 g, 85.56 mmol) in dioxane (100 mL) and water (10 mL) was added tris(dibenzylideneacetone)dipalladium (7.12 g, 7.78 mmol), tricyclohexylphosphine (4.36 g, 15.56 mmol) and potassium phosphate (49.53 g, 233.36 mmol) under nitrogen atmosphere at room temperature. The reaction was heated to 100 °C for 0.5 h. To the reaction was added ethyl acetate (500 mL), filtered, the filtrate was washed with water (50 mL) and saturated brine (50 mL) successively, the organic phase was collected, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (n-hexane: ethyl acetate = 1 / 0-10 / 1) to give compound M1-3. 1 H NMR (400 MHz, CDCl3) δ = 8.50 (s, 2H), 7.09-7.01 (m, 1H), 2.28 (s, 3H), 2.14-2.12 (m, 3H), 1.90 (dd, J = 0.8, 7.2 Hz, 3H).

[0297] Step 2: To a solution of compound M1-4 (9.08 g, 80.97 mmol) in dichloromethane (300 mL) was added sulfuryl chloride (10.93 g, 80.97 mmol) dropwise at 0 °C under nitrogen atmosphere. After the addition was completed, the reaction was stirred at 0 °C for 0.5 h. To the reaction was added compound M1-3 (10 g, 67.47 mmol) dropwise. After the addition was completed, the reaction was allowed to warm up to 25 °C slowly and was stirred for another 0.5 h. The reaction was added to saturated sodium bicarbonate solution (300 mL) slowly and extracted with dichloromethane (300 mL x 2). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (n-hexane: ethyl acetate = 10 / 1-1 / 1) to give compound M1-5. LCMS (m / z): 295.0 [M+1] + .

[0298] Step 3: To a solution of compound M1-5 (8.2 g, 27.82 mmol) in dichloromethane (160 mL) was added m-chloroperoxybenzoic acid (16.94 g, 83.45 mmol, 85% purity) portionwise at room temperature under nitrogen atmosphere. After the addition was complete, the reaction was stirred at room temperature for 0.5 h. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (100 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with water (50 mL) and saturated brine (50 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (n-hexane: ethyl acetate = 30 / 1-1 / 1) to give compound M1-6.

[0299] Step 4: To a solution of compound M1-6 (9.1 g, 27.85 mmol) in acetonitrile (50 mL) and water (50 mL) was added potassium carbonate (7.70 g, 55.69 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 40 °C for 2 h. To the reaction was added methanol (50 mL) and heated to 50 °C for 0.5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give compound M1-7.

[0300] Step 5: To a solution of compound M1-7 (8 g, 31.95 mmol) in water (80 mL) was added potassium acetate (3.14 g, 31.95 mmol) and hydroxylamine-O-sulfonic acid (7.23 g, 63.91 mmol) slowly at room temperature under nitrogen atmosphere. The reaction was heated to 40 °C for 12 h. The reaction was cooled to room temperature and extracted with dichloromethane (500 mL). The organic phase was concentrated under reduced pressure to give compound M1-8.

[0301] Step 6: To a solution of compound M1-8 (6.8 g, 29.92 mmol) in methanol (70 mL) was added bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (CAS: 35138-22-8, 242.98 mg, 598.37 µmol), (S)-1-{(RP)-2-[bis(1-naphthyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (CAS: 849924-44-3, 384.50 mg, 598.37 µmol), and zinc triflate (2.18 g, 5.98 mmol) successively at room temperature under nitrogen atmosphere. The reaction was replaced with hydrogen three times and stirred at 25 °C under hydrogen 50 psi for 12 h. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography (n-hexane: ethyl acetate = 10 / 1-0 / 1) to give a crude product. To the crude product was added ethanol (20 mL) and stirred at room temperature for 10 min. The reaction was filtered and the filter cake was dried to give compound M1. LCMS (m / z): 230.2 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) d = 8.61 (s, 2H), 6.83 (s, 2H), 3.77-3.61 (m, 2H), 2.25 (s, 3H), 1.32 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 7.2 Hz, 3H). SFC detection (Chromatographic column: Chiralpak AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase is supercritical CO2, B phase is methanol (0.05% diethylamine); Gradient (B%): 5%-40%) Retention time of compound M1 is 2.001 min, chiral purity is 96.19%.

[0302] Intermediate M2

[0303] Step 1: To a solution of compound M2-1 (100 g, 0.91 mol) and 1-bromo-2-chloroethane (521 g, 3.63 mol) in acetonitrile (1000 mL) was added potassium carbonate (628 g, 4.55 mol) portionwise slowly under nitrogen atmosphere at 25 °C, the reaction was warmed to 90 °C and stirred for 48 h. The reaction was filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-2:1) to give compound M2-2. LCMS (m / z): 235.0 [M+H] + .

[0304] Step 2: To a solution of compound M2-2 (39.0 g, 166 mmol) in acetic acid (300 mL) was added a solution of bromine (19.55 mL, 381 mmol) in acetic acid (100 mL) dropwise slowly at 0 °C under nitrogen atmosphere, the reaction was warmed to room temperature and stirred for 1 h. The reaction was poured into ice water (800 mL), stirred for 5 min and filtered, the filter cake was rinsed with acetic acid (50 mL), then the filter cake was dissolved in 200 mL of ethyl acetate, adjusted to pH = 7-8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL x 2), the combined organic phase was washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound M2-3.

[0305] Step 3: To tetrahydrofuran (150 mL) was added magnesium powder (12.8 g, 527 mmol) at 25 °C, then ethylmagnesium bromide (3 M tetrahydrofuran solution, 12.7 mL) was added dropwise slowly, after the addition was completed, the temperature was raised to 40 °C, a solution of compound M2-3 (68 g, 173 mmol) in tetrahydrofuran (400 mL) was added dropwise to the reaction system. After the addition was completed, the temperature was raised to 75 °C and reacted for 4 h. The reaction solution was cooled to 0 °C, diluted with dilute hydrochloric acid (1 M, 300 mL) and extracted with methyl tert-butyl ether (300 mL x 2), the combined organic phase was washed successively with sodium hydroxide aqueous solution (1 M, 200 mL) and brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to give compound M2-4. LCMS (m / z): 163.0 [M+H] + ; 1 H NMR (400 MHz, CDCl3) d = 6.96 (s, 1H), 6.30 (s, 1H), 4.57 (dt, J = 1.6, 8.8 Hz, 4H), 3.11 (br t, J = 8.4 Hz, 4H).

[0306] Step 4: Solution 1 was a solution of compound M2-4 (3 g, 18.50 mmol) and tetramethylethylenediamine (8.6 g, 74.78 mmol) in anhydrous tetrahydrofuran (60 mL); solution 2 was tert-butyllithium (1.3 M n-pentane, 54 mL, 70.2 mmol); solution 3 was 1,2-dibromo-1,1,2,2-tetrachloroethane (6.02 g, 18.49 mmol) in anhydrous tetrahydrofuran (60 mL); the fluid chemical steps were as follows:

[0307] Solution 1 was pumped into flow reactor 1 (3 min residence), flow reactor 2 (2.025 min residence) and flow reactor 3 (2.025 min residence) by pump 1 (22.818 mL / min) at 0 °C; solution 2 was pumped into flow reactor 1 (3 min residence), flow reactor 2 (2.025 min residence) and flow reactor 3 (2.025 min residence) by pump 2 (20.516 mL / min) at 0 °C; solution 3 was pumped into flow reactor 2 (2.025 min residence) and flow reactor 3 (2.025 min residence) by pump 3 (20.861 mL / min) at 0 °C; wherein pump 1 and pump 2 were started at the same time, 3 minutes later, pump 3 was started, and 4.05 min later the reaction mixture was collected.

[0308] After the reaction was completed, the reaction solution was cooled to 0°C, 100 mL of saturated ammonium chloride aqueous solution was added dropwise, extracted with ethyl acetate (200 mL x 2), the combined organic phase was washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to obtain compound M2-5. LCMS (m / z): 240.9, 243.0 [M+H] + .

[0309] Step 5: Under a nitrogen atmosphere, to a solution of compound M2-5 (1.1 g, 4.56 mmol) and compound M2-6 (1.65 g, 9.13 mmol) in toluene (5 mL) were added XantPhos-Pd-G3 (865 mg, 912 μmol), sodium tert-butoxide (1.32 g, 13.7 mmol) and tris(dibenzylideneacetone)dipalladium (417.82 mg, 456.28 μmol) successively, and after replacing nitrogen three times, the reaction system was warmed to 100°C for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by reverse phase column chromatography preparation (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 65%-70%) to obtain compound M2-7. LCMS (m / z): 342.0 [M+H] + .

[0310] Step 6: Under a nitrogen atmosphere, compound M2-7 (800 mg, 2.34 mmol) was dissolved in trifluoroacetic acid (8 mL) at 25°C, and reacted at room temperature for 4 hours. The reaction solution was adjusted to pH = 7-8 with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (50 mL x 2), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by reverse phase column chromatography preparation (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 30%-35%) to obtain compound M2. LCMS (m / z): 178.1 [M+H] + .

[0311] Intermediate M3

[0312] Solution 1 was a solution of compound M2-4 (1.0 g, 6.17 mmol) and tetramethylethylenediamine (2.87 g, 24.69 mmol) in tetrahydrofuran (20 mL); solution 2 was sec-butyllithium (1.3 M in n-hexane, 19.0 mL); solution 3 was isopropyl alcohol pinacolboronate (294 mg, 1.02 mmol) in tetrahydrofuran (20 mL); the fluidic chemistry steps were as follows:

[0313] Solution 1 was pumped by pump 1 (7.898 mL / min) into flow reactor 1 (3 min residence), flow reactor 2 (2.035 min residence) and flow reactor 3 (2.035 min residence) sequentially at 0 °C;

[0314] Solution 2 was pumped by pump 2 (7.102 mL / min) into flow reactor 1 (3 min residence), flow reactor 2 (2.035 min residence) and flow reactor 3 (2.035 min residence) sequentially at 0 °C;

[0315] Solution 3 was pumped by pump 3 (7.116 mL / min) into flow reactor 2 (2.035 min residence) and flow reactor 3 (2.035 min residence) sequentially at 0 °C;

[0316] Wherein, pump 1 and pump 2 were started at the same time, 3 minutes later, pump 3 was started, and after another 4.07 min, the reaction mixture was collected. The reaction solution was poured into saturated aqueous ammonium chloride solution (100 mL) at 0 °C, extracted with ethyl acetate (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to give compound M3. 1 H NMR (400 MHz, CD3OD) δ = 7.09-7.05 (m, 1H), 4.53 (t, J = 8.8 Hz, 4H), 3.08-3.03 (m, 4H), 1.32 (s, 12H).

[0317] Intermediate M4

[0318] Step 1: To a solution of compound M4-1 (6.00 g, 46.63 mmol) in anhydrous dichloromethane (100 mL) was added bis(4-methoxybenzyl)amine (10 g, 38.86 mmol) and triethylamine (5.11 g, 50.52 mmol) under nitrogen atmosphere at 0 °C. The reaction was stirred at room temperature for 1.5 h. Water (25 mL) was added to the reaction mixture and extracted with dichloromethane (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to give compound M4-2. 1 H NMR (400 MHz, CDC13) δ = 7.22 (d, J = 8.4 Hz, 4H), 6.88 (d, J = 8.4 Hz, 4H), 4.28 (s, 4H), 3.82 (s, 6H), 2.91 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H).

[0319] Step 2: To a solution of compound M4-2 (12 g, 34.34 mmol) in anhydrous tetrahydrofuran (125 mL) was added n-butyllithium (2.5 M in tetrahydrofuran, 17.86 mL) dropwise at -70 °C under nitrogen atmosphere. The reaction was stirred at -70 °C for 0.5 h. To the reaction was added p-trifluoromethylacetophenone (7.75 g, 41.21 mmol) dropwise at -70 °C. The reaction was stirred at -70 °C for another 1.5 h. The reaction was allowed to warm to room temperature. Water (40 mL) was added to the reaction and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative reverse phase column chromatography (column: Phenomenex luna C18 20-45 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40%-70%) to give compound M4-3. H NMR (400 MHz, CDC13) δ = 7.22 (d, J = 8.4 Hz, 4H), 6.88 (d, J = 8.4 Hz, 4H), 4.28 (s, 4H), 3.82 (s, 6H), 2.91 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H). 1 H NMR (400 MHz, DMSO-d6) δ = 7.75-7.58 (m, 4H), 7.13 (dd, J = 8.4, 17.0 Hz, 4H), 6.85 (t, J = 8.8 Hz, 4H), 5.70-5.47 (m, 1H), 4.44-4.21 (m, 2H), 4.09 (dd, J = 9.6, 15.2 Hz, 2H), 3.72 (d, J = 2.8 Hz, 6H), 3.61-3.46 (m, 1H), 1.80-1.62 (m, 3H), 1.22-0.91 (m, 3H).

[0320] Step 3: Under a nitrogen atmosphere, trifluoroacetic acid (184.20 g, 1.62 mol) was slowly added dropwise to a solution of compound M4-3 (12 g, 22.32 mmol) in anhydrous dichloromethane (60 mL). The reaction mixture was allowed to react at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40%-70%) to obtain compound M4-4. 1 H NMR (400MHz, DMSO-d6) δ = 7.77-7.61 (m, 4H), 6.65 (br s, 2H), 5.66 (br s, 1H), 3.51-3.43 (m, 1H), 1.62 (s, 3H), 1.21 (d, J = 7.0Hz, 3H).

[0321] Step 4: Under a nitrogen atmosphere, sulfuric acid (61.86 μL, 1.16 mmol) was slowly added dropwise to a solution of compound M4-4 (2.3 g, 7.74 mmol) in glacial acetic acid (21 mL). The reaction mixture was reacted at 90 °C for 12 hours. The reaction mixture was filtered, and the filtrate was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40%-70%) to obtain compound M4-5. 1 H NMR (400MHz, DMSO-d6) δ = 7.70 (s, 4H), 6.88 (s, 2H), 5.72 (s, 1H), 5.59 (s, 1H), 4.27 (q, J = 7.2Hz, 1H), 1.56 (d, J = 7.2Hz, 3H).

[0322] Step 5: Under a nitrogen atmosphere, 10% dry palladium on carbon (833.33 mg) was slowly added to an anhydrous methanol (100 mL) solution of compound M4-5 (1 g, 3.58 mmol) and glacial acetic acid (1.67 mL, 29.11 mmol). After three purgings with hydrogen, the reaction was carried out at 80 °C for 24 hours under a hydrogen atmosphere (50 psi). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40%-70%) to obtain compound M4. 1H NMR (400 MHz, CDC13) δ = 7.60 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 4.28 (s, 2H), 3.60-3.49 (m, 1H), 3.33 (quin, J = 6.8 Hz, 1H), 1.51 (d, J = 7.1 Hz, 3H), 1.33-1.27 (m, 3H).

[0323] Intermediate M5

[0324] Step 1: To a solution of compound M5-1 (6 g, 32.87 mmol) and compound M1-2 (5.86 g, 36.16 mmol) in dioxane (100 mL) was added tris(dibenzylideneacetone)dipalladium (2.41 g, 2.63 mmol), tricyclohexylphosphine (1.84 g, 6.57 mmol) and potassium phosphate aqueous solution (4 M, 24.65 mL) slowly in batches at room temperature under nitrogen atmosphere. The reaction was heated to 80 °C for 10 h. The reaction was concentrated under reduced pressure, 100 mL of ethyl acetate was added to the residue, filtered, the filtrate was washed with water (50 mL) and saturated brine (50 mL) successively, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (hexane: ethyl acetate = 100 / 1 - 50 / 1) to give compound M5-3. 1 H NMR (400 MHz, DMSO-d6) δ = 9.17 (s, 2H), 7.33 (q, J = 6.8 Hz, 1H), 2.09 (s, 3H), 1.92 (br d, J = 7.2 Hz, 3H).

[0325] Step 2: To a solution of compound M1-4 (1.33 g, 11.87 mmol) in dichloromethane (60 mL) was added sulfuryl chloride (SO2Cl2, 1.19 mL, 11.87 mmol) slowly dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for another 0.5 h. To the reaction was added compound M5-3 (2 g, 9.89 mmol) slowly, the reaction was stirred at 25 °C for 1.5 h. To the reaction was added sulfuryl chloride (989.02 μL, 9.89 mmol) again, stirred at 25 °C for 1 h. The reaction was slowly poured into 20 mL of saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (40 mL x 2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (hexane: ethyl acetate = 100 / 1 - 10 / 1) to give compound M5-4. LCMS (m / z): 348.9 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 9.33 (s, 2H), 8.64 (d, J = 4.8 Hz, 2H), 7.24 (t, J = 4.8 Hz, 1H), 5.21 (q, J = 6.8 Hz, 1H), 2.08 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H).

[0326] Step 3: To a solution of compound M5-4 (1.88 g, 5.39 mmol) in dichloromethane (40 mL) was added m-chloroperoxybenzoic acid (3.28 g, 16.17 mmol, 85% purity) portionwise at room temperature under nitrogen atmosphere. The reaction was stirred at room temperature for 12 h. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (30 mL x 2), the combined organic phase was washed with water (10 mL) and saturated brine (10 mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (hexane: ethyl acetate = 50 / 1-20 / 1) to give compound M5-5. LCMS (m / z): 380.9 [M+l] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 9.34 (s, 2H), 9.10 (d, J = 4.8 Hz, 2H), 7.89 (t, J = 4.8 Hz, 1H), 5.72 (q, J = 7.2 Hz, 1H), 2.29 (s, 3H), 1.70 (d, J = 7.2 Hz, 3H).

[0327] Step 4: To a mixture of compound M5-5 (1 g, 2.63 mmol) in acetonitrile (10 mL) and water (10 mL) was added potassium carbonate (725.94 mg, 5.25 mmol) at room temperature under nitrogen atmosphere. The reaction was warmed to 40 °C for 2 h. To the reaction was added 50 mL of methanol, and the reaction was continued to warm to 50 °C for 3 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to give compound M5-6.

[0328] Step 5: To a solution of compound M5-6 (0.9 g, 2.96 mmol) in water (20 mL) was added potassium acetate (290.23 mg, 2.96 mmol) and compound M5-7 (668.90 mg, 5.91 mmol) slowly at room temperature under nitrogen atmosphere. The reaction was warmed to 40 °C and stirred for 3 h. To the reaction was added dichloromethane (50 mL) to extract, and the organic phase was concentrated under reduced pressure to give compound M5-8. LCMS (m / z): 281.9 [M+l] + ; 1H NMR (400 MHz, DMSO-d6) δ = 9.35 (s, 2H), 7.30 (s, 2H), 2.39 (d, J = 1.2 Hz, 3H), 1.90 (d, J = 1.2 Hz, 3H).

[0329] Step 6: To a solution of compound M5-8 (0.5 g, 1.78 mmol) in methanol (10 mL) was added slowly in portions under nitrogen atmosphere at room temperature bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (CAS: 35138-22-8, 177.77 μmol), (S)-1-{(RP)-2-[bis(1- naphthyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (CAS: 849924-44-3, 177.77 μmol) and zinc triflate (129.25 mg, 355.55 μmol). After three times of hydrogen replacement, the reaction was stirred at 50 °C under hydrogen atmosphere (pressure 50 psi) for 12 hours. The reaction was concentrated under reduced pressure to give a crude product, which was purified by reverse phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water-acetonitrile; gradient (acetonitrile %): 18%-38%) to give compound M5. LCMS (m / z): 284.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 9.35 (s, 2H), 7.30 (s, 2H), 2.39 (d, J = 1.2 Hz, 3H), 1.90 (d, J = 1.2 Hz, 3H).

[0330] Intermediate M6

[0331] Step 1: To a solution of compound M6-1 (6 g, 26.55 mmol) and compound M1-2 (4.73 g, 29.20 mmol) in dioxane (50 mL) and water (5 mL) was added tris(dibenzylideneacetone)dipalladium (2.43 g, 2.65 mmol), tricyclohexylphosphine (1.49 g, 5.31 mmol) and potassium phosphate (16.91 g, 79.65 mmol) under nitrogen atmosphere at room temperature. The reaction was heated to 100 °C for 2 h. To the reaction was added 250 mL of ethyl acetate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (hexane: ethyl acetate = 100 / 1 - 50 / 1) to give compound M6-2. LCMS (m / z): 202.0 [M+1] + ; 1 H NMR (400 MHz, CDCl3) d = 8.72 (s, 1H), 7.78 (dd, J = 1.6, 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.08-5.91 (m, 1H), 2.06 (s, 3H), 1.86 (d, J = 6.8 Hz, 3H).

[0332] Step 2: To a solution of compound M1-4 (1.47 g, 13.12 mmol) in dichloromethane (60 mL) was added sulfuryl chloride (1.62 g, 12.03 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 h. To the reaction was added compound M6-2 (2.2 g, 10.94 mmol), and then the reaction was allowed to warm to 25 °C slowly. The reaction was stirred at 25 °C for 2 h. To the reaction was added sulfuryl chloride (885.54 mg, 6.56 mmol), and then the reaction was stirred at 25 °C for 2 h. The reaction was slowly added to 200 mL of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (hexane: ethyl acetate = 50 / 1 - 20 / 1) to give compound M6-3. LCMS (m / z): 347.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 9.03 (s, 1H), 8.62-8.45 (m, 2H), 8.35-8.21 (m, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.27-7.08 (m, 1H), 4.91-4.71 (m, 1H), 2.13 (s, 3H), 1.49 (d, J = 7.2 Hz, 3H).

[0333] Step 3: To a solution of compound M6-3 (2.9 g, 8.34 mmol) in dichloromethane (60 mL) was added m-chloroperoxybenzoic acid (5.08 g, 25.02 mmol, 85% purity) portionwise at room temperature under nitrogen atmosphere. After the addition was complete, the reaction was stirred at room temperature for 24 h. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (200 mL) and extracted with dichloromethane (100 mL x 2). The combined organic phase was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (hexanes: ethyl acetate = 10 / 1-2 / 1) to give compound M6-4. LCMS (m / z): 380.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.96-8.89 (m, 3H), 8.21 (dd, J = 2.2, 8.4 Hz, 1H), 7.76 (t, J = 4.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 5.10 (q, J = 7.2 Hz, 1H), 2.29 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H).

[0334] Step 4: To a solution of compound M6-4 (2.6 g, 6.85 mmol) in acetonitrile (13 mL) and water (13 mL) was added potassium carbonate (2.84 g, 20.54 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 40 °C for 2 h. Methanol (13 mL) was added and the reaction was heated to 50 °C for 2 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give compound M6-5. LCMS (m / z): 265.9 [M+1] + .

[0335] Step 5: To a solution of compound M6-5 (3.00 g, 6.92 mmol) in water (30 mL) was added potassium acetate (679.41 mg, 6.92 mmol) and compound M5-7 (1.57 g, 13.85 mmol) slowly at room temperature under nitrogen atmosphere. The reaction was heated to 30 °C for 4 h. The reaction was filtered and the filter cake was dried to give compound M6-6. LCMS (m / z): 281.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.63 (s, 1H), 7.96 (d, J = 1.2 Hz, 2H), 7.23 (s, 2H), 2.37 (d, J = 1.6 Hz, 3H), 1.83 (d, J = 1.6 Hz, 3H).

[0336] Step 6: To Pd / C (1 g, 10% purity) was added methanol followed by compound M6-6 (1 g, 3.57 mmol) at room temperature under argon atmosphere. After three times of hydrogen purging, the reaction was heated to 25 °C under hydrogen atmosphere (50 psi pressure) for 12 h. The reaction was filtered and the filtrate was concentrated to give a crude product which was purified by column chromatography (hexanes: ethyl acetate = 40 / 1 to 20 / 1) to give compound M6. LCMS (m / z): 283.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.68 (s, 1H), 7.99 (br d, J = 8.0 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 6.86 (s, 2H), 3.66 - 3.47 (m, 1H), 3.30 - 3.20 (m, 1H), 1.44 - 1.33 (m, 3H), 1.23 - 1.08 (m, 3H).

[0337] Step 7: To a solution of compound M6-6 (0.7 g, 2.50 mmol) in methanol (5 mL) was added (S)-1-{(RP)-2-[bis(1-naphthyl)phosphino]ferrocenyl}ethyl di-tert-butylphosphine (160.49 mg, 249.76 μmol), dichloro(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (101.42 mg, 249.76 μmol) and zinc triflate (181.59 mg, 499.52 μmol) at room temperature under argon atmosphere. After three times of hydrogen purging, the reaction was heated to 50 °C under hydrogen atmosphere (50 psi pressure) for 12 h. The reaction was filtered and the filtrate was concentrated to give a crude product which was purified by preparative reverse phase column chromatography (column: Phenomenex luna C18 (100 g); mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 0% to 25%) to give compound M6A. LCMS (m / z): 283.1 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.16 (dd, J = 1.6, 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 6.85 (s, 2H), 3.77-3.64 (m, 1H), 3.60-3.49 (m, 1H), 1.32 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H); F NMR (376 MHz, DMSO-d6) δ = -60.657; SFC detection (Chromolith® SpeedRay® column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 10% - 60%), Compound M6A contains 2 isomers, retention time is 1.019 min (content 87.30%) and 1.264 min (content 12.70%) respectively.

[0338] Intermediate M7

[0339] Step 1: To a solution of compound M7-1 (120 g, 842 mmol) in dichloromethane (1 L) was added diethylaminosulfur trifluoride (271 g, 1.68 mol) dropwise at 0 °C under nitrogen atmosphere, the reaction solution was warmed to 25 °C for 1 h. The reaction solution was slowly poured into saturated aqueous sodium bicarbonate solution (1 L) at 0 °C, then sodium carbonate solid was added to adjust the pH to 7-8, then extracted with dichloromethane (300 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-20:1) to give compound M7-2. 1 H NMR (400 MHz, CDCl3) δ = 8.79 (s, 2H), 6.79 (t, J = 55.2 Hz, 1H); 19 F NMR (376 MHz, CDCl3) δ (ppm) = -114.345.

[0340] Step 2: To a solution of compound M7-2 (80 g, 486 mmol), compound M1-2 (86.6 g, 535 mmol) and tricyclohexylphosphine (13.6 g, 48.6 mmol) in dioxane (1 L) was added potassium phosphate tribasic (5 M, 243 mL) and tris(dibenzylideneacetone)dipalladium (22.3 g, 24.3 mmol) under nitrogen atmosphere. The reaction was heated to 100 °C for 16 h. The reaction was allowed to cool to room temperature, filtered, the filtrate was diluted with 400 mL of water and extracted with ethyl acetate (300 mL x 3), the combined organic phase was washed with 500 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0) to give compound M7-3. 1 H NMR (400 MHz, CDC13) d = 8.79 (s, 2H), 7.27 (s, 1H), 6.73 (t, J = 55.2 Hz, 1H), 2.15 (s, 3H), 1.94 (d, J = 6.8 Hz, 3H); 19 F NMR (376 MHz, CDC13) d (ppm) = -113.296.

[0341] Step 3: To a solution of compound M1-4 (69.9 g, 623 mmol) in dichloromethane (1.3 L) was added sulfuryl chloride (72.1 g, 534 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 0.5 h, then a solution of compound M7-3 (5.4 g, 29.3 mmol) in dichloromethane (300 mL) was added dropwise to the reaction. The reaction was allowed to warm to 25 °C and stirred for 16 h. To the reaction was added 500 mL of saturated sodium bicarbonate solution and the pH was adjusted to 8 by adding sodium carbonate solid. The reaction was extracted with dichloromethane (500 mL x 3), the combined organic phase was washed with 500 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-3:2) to give compound M7-4. LCMS (m / z): 330.9 [M+H] + .

[0342] Step 4: To a solution of compound M7-4 (80 g, 242 mmol) in dichloromethane (1.5 L) was added m-chloroperoxybenzoic acid (147 g, 726 mmol, 85% purity) portionwise at 0 °C under nitrogen atmosphere. After the addition was completed, the reaction was allowed to warm to 25 °C and stirred for 16 h. To the reaction was added dichloromethane (200 mL), washed with saturated sodium bicarbonate solution (500 mL x 3) and saturated sodium chloride solution (500 mL) sequentially, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1-1:1) to give compound M7-5. LCMS (m / z): 363.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 9.09 (d, J = 4.8 Hz, 2H), 9.05 (s, 2H), 7.88 (t, J = 4.8 Hz, 1H), 7.23 (t, J = 54.8 Hz, 1H), 5.74 (q, J = 7.2 Hz, 1H), 2.29 (s, 3H), 1.69 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CDC13) d (ppm) = -113.615.

[0343] Step 5: To a solution of compound M7-5 (42 g, 116 mmol) in a mixture of methanol (210 mL), acetonitrile (210 mL) and water (210 mL) was added potassium carbonate (48.0 g, 347 mmol) at 50 °C under nitrogen atmosphere. The reaction was stirred at 50 °C for 4 h. The reaction was directly concentrated under reduced pressure to remove the organic solvents to give a crude mixture of compound M7-6. LCMS (m / z): 249.1 [M+H] + .

[0344] Step 6: To a solution of compound M7-6 (33.15 g, crude mixture) and compound M5-7 (26.2 g, 232 mmol) in water (330 mL) was added potassium acetate (11.4 g, 116 mmol) at 0 °C under nitrogen atmosphere. The reaction was allowed to warm to 40 °C and stirred for 2 h. The reaction was cooled to room temperature, filtered and the filtrate was extracted with dichloromethane (200 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give compound M7-7. LCMS (m / z): 264.0 [M+H] + .

[0345] Step 7: To a solution of compound M7-7 (5.6 g, 21.3 mmol), zinc triflate (773 mg, 2.13 mmol) and (S)-1-{(RP)-2-[bis(1-naphthyl)phosphino]ferrocenyl}ethyldi-tert- butylphosphine (432 mg, 1.06 mmol) in anhydrous methanol (100 mL) was added bis(1,5- cyclooctadiene)rhodium(I) tetrafluoroborate (683 mg, 1.06 mmol) under nitrogen atmosphere. After three times of hydrogen replacement, the reaction was stirred at 50 °C under hydrogen atmosphere (50 Psi) for 16 hours. The reaction was cooled to room temperature, filtered and the filtrate was concentrated to give a crude product. The crude product was separated by preparative reverse phase HPLC (column: Phenomenex luna C18 20-45 μm; mobile phase: water (0.1% ammonia) - acetonitrile; gradient (acetonitrile %): 52% to 100% in 5 min) to give compound M7. LCMS (m / z): 266.2 [M+H] Mobile phase: water (0.1% ammonia) - acetonitrile; gradient (acetonitrile %): 52% to 100% in 5 min) to give compound M7. LCMS (m / z): 266.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 8.99 (s, 2H), 7.20 (t, J = 54.8 Hz, 1H), 6.87 (s, 2H), 3.82 - 3.63 (m, 2H), 1.34 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H); 19 F NMR (376 MHz, CDC13) δ (ppm) = -112.942; SFC detection (column: Chiralpak AD-3 50 x 4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 10% to 60%), showed that compound M7 contained 2 isomers with retention times of 1.217 min (content 88.51%) and 1.067 min (content 11.49%) respectively.

[0346] Intermediate M8

[0347] Step 1: To a solution of compound M8-1 (5 g, 24.04 mmol) and compound M1-2 (5.84 g, 36.06 mmol) in dioxane (50 mL) was added tris(dibenzylideneacetone)dipalladium (2.20 g, 2.40 mmol), tricyclohexylphosphonium tetrafluoroborate (1.35 g, 4.81 mmol) and potassium phosphate tribasic (5 M, 14.42 mL) portionwise slowly under nitrogen at room temperature. The reaction was heated to 100 °C for 2 h. To the reaction was added ethyl acetate (200 mL), filtered, added water (100 mL) to the filtrate, extracted with ethyl acetate (80 mL x 3), washed the combined organic phase with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse-phase column chromatography (column: Phenomenex luna C18 1000 x 500 mm x 50 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50% - 70%) to give compound M8-2. LCMS (m / z): 184.2 [M+1] + ; 1 H NMR (400 MHz, CDC13) δ = 8.65 (d, J = 0.8 Hz, 1H), 7.77 (dd, J = 2.0, 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.82 - 6.43 (m, 1H), 5.97 (q, J = 6.8 Hz, 1H), 2.05 (s, 3H), 1.84 (d, J = 6.8 Hz, 3H); 19 F NMR (376 MHz, CDC13) δ = -115.225.

[0348] Step 2: To a solution of compound M1-4 (3.31 g, 29.48 mmol) in dichloromethane (40 mL) was added sulfuryl chloride (3.18 g, 23.58 mmol) dropwise at 0 °C under nitrogen. After the addition was completed, the reaction was stirred at 0 °C for 0.5 h. To the reaction was added compound M8-2 (3.6 g, 19.65 mmol) and the reaction was allowed to warm to 25 °C slowly for 0.5 h. The reaction was slowly added to water (100 mL) and extracted with dichloromethane (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (hexanes: ethyl acetate = 1 / 1 - 0 / 1) to give compound M8-3. LCMS (m / z): 330.0 [M+1] + .

[0349] Step 3: To a solution of compound M8-3 (5 g, 15.16 mmol) in dichloromethane (50 mL) was added m-chloroperoxybenzoic acid (9.23 g, 45.48 mmol, 85% purity) portionwise at 0 °C under nitrogen atmosphere. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 12 h. The reaction was slowly added to saturated aqueous sodium sulfite solution (400 mL) and extracted with dichloromethane (150 mL x 3). The combined organic phase was washed successively with saturated aqueous sodium sulfite solution (400 mL) and saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 1000 x 500 mm x 50 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50% - 70%) to give compound M8-4. LCMS (m / z): 362.0 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.91 (d, J = 4.8 Hz, 2H), 8.80 (s, 1H), 8.08 (br d, J = 7.6 Hz, 1H), 7.73 (t, J = 4.8 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.05 - 6.71 (m, 1H), 5.09 - 5.04 (m, 1H), 2.27 (s, 3H), 1.65 (d, J = 7.2 Hz, 3H).

[0350] Step 4: To a solution of compound M8-4 (900 mg, 2.49 mmol) in a mixture of acetonitrile (5 mL) and water (5 mL) was added potassium carbonate (687.62 mg, 4.98 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 40 °C for 2 h. Another 5 mL of methanol was added and the reaction was heated to 50 °C for 0.5 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give compound M8-5.

[0351] Step 5: To a solution of compound M8-5 (700 mg, 2.45 mmol) in water (10 mL) was added potassium acetate (240.75 mg, 2.45 mmol) and M5-7 (554.85 mg, 4.91 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 40 °C for 12 h. The reaction was directly separated by preparative reverse phase chromatography (column: Phenomenex luna C18 500 x 250 mm x 25 pm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 70% - 80%) to give compound M8-6. LCMS (m / z): 263.1 [M+1] + ; 1H NMR (400 MHz, CDC13) δ = 8.49 (s, 1H), 7.74-7.66 (m, 2H), 6.67 (t, J = 55.6 Hz, 1H), 4.83 (br s, 2H), 2.50-2.44 (m, 3H), 1.98 (d, J = 1.6 Hz, 3H); 19 F NMR (376 MHz, CDC13) δ = -115.834.

[0352] Step 6: To a solution of compound M8-6 (450 mg, 1.72 mmol) in methanol (10 mL) was added palladium on carbon (200 mg, 10% purity) in portions under nitrogen atmosphere at room temperature, after three times of hydrogen gas replacement, the reaction was carried out under hydrogen atmosphere (50 psi pressure) at 45 °C for 12 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase column chromatography (column: Phenomenex luna C18 250x250mmx25um; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 60%-80%) to give compound M8. LCMS (m / z): 265.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 8.60 (br s, 1H), 7.90 (dd, J = 2.0, 8.0 Hz, 1H), 7.68-7.59 (m, 1H), 7.07-6.79 (m, 3H), 3.65-3.40 (m, 1H), 3.28-3.15 (m, 1H), 1.43 (d, J = 7.2 Hz, 1H), 1.33 (d, J = 7.2 Hz, 2H), 1.21 (d, J = 7.2 Hz, 2H), 1.07 (d, J = 7.2 Hz, 1H); 19 F NMR (376 MHz, DMSO-d6) δ = -114.831.

[0353] Intermediate M9

[0354] Step 1: To a solution of compound 1-3 (12 g, 54.73 mmol) and cesium carbonate (23.18 g, 71.15 mmol) in anhydrous acetonitrile (240 mL) was added compound M9-1 (9.01 g, 65.68 mmol) under nitrogen atmosphere at 0 °C, the reaction was carried out at room temperature for 12 hours to give a acetonitrile solution of compound M9-2, which was used directly for the next step. LCMS (m / z): 357.1 [M+H] + .

[0355] Step 2: To a solution of compound M9-2 from step 1 in acetonitrile and a solution of compound 1-2 (12.40 g, 82.06 mmol) in anhydrous acetonitrile (200 mL) was added silver nitrate (14.2 g, 83.59 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 12 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give compound M9-3. LCMS (m / z): 474.2 [M+H] + .

[0356] Step 3: To a solution of compound M9-3 (22 g, 46.46 mmol) in anhydrous dioxane (1500 mL) was added trifluoroacetic acid (17.26 mL) at room temperature under nitrogen atmosphere. The reaction was stirred at 100 °C for 12 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 5:0, then dichloromethane: ethyl acetate = 1:1) to give compound M9-4. LCMS (m / z): 456.3 [M+H] + .

[0357] Step 4: To a solution of compound M9-4 (12 g, 26.34 mmol) in trifluoroacetic acid (60 mL) was added anisole (8.55 g, 79.03 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 100 °C for 12 h. The reaction was concentrated under reduced pressure to give the crude product, which was adjusted to pH 7.5-8 with 10% aqueous sodium bicarbonate solution (150 mL). The solid was collected by filtration after stirring for 15 min. The filter cake was dried to give compound M9-5. LCMS (m / z): 336.2 [M+H] + .

[0358] Step 5: To a solution of compound M9-5 (10.4 g, 31.01 mmol), benzyltriethylammonium bromide (25.33 g, 93.03 mmol) and sodium nitrite (42.79 g, 620.23 mmol) in dibromomethane (200 mL) was added dichloroacetic acid (5.10 mL, 62.02 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude product, which was isolated by preparative reverse phase chromatography (column: Phenomenex luna C18 (250 x 70 mm, 10 µm); mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40% - 80%) to give compound M9. 1H NMR (400 MHz, CDC13) δ = 8.44 (d, J = 1.2 Hz, 1H), 8.39 (d, J = 1.6 Hz, 1H), 7.97 (s, 1H), 7.09 (s, 1H), 4.67-4.56 (m, 2H), 4.55-4.45 (m, 2H), 3.25-3.10 (m, 4H), 2.35 (s, 3H). LCMS (m / z): 399.1, 401.1 [M+H] + .

[0359] Intermediate M10

[0360] Step 1: To a solution of compound M10-1 (18.0 g, 105 mmol) and 4-nitro pyrazole (17.7 g, 157 mmol) in anhydrous N,N-dimethylformamide (250 mL) was added potassium carbonate (28.9 g, 209 mmol) and cuprous iodide (1.99 g, 10.5 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 120 °C for 36 h. The reaction was poured into 400 mL of water and extracted with ethyl acetate (300 mL x 2), the combined organic phase was washed with saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was dissolved in 100 mL of ethyl acetate and stirred at room temperature for 10 min, filtered and the filter cake was dried to give compound M10-2. 1 H NMR (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 8.98 (d, J = 2.4 Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 2.41 (s, 3H).

[0361] Step 2: To a mixture of compound M10-2 (4.5 g, 22.0 mmol), ammonium chloride (1.41 g, 26.5 mmol) in ethanol (90 mL) and water (22 mL) was added iron powder (6.15 g, 110 mmol) portionwise slowly at 50 °C under nitrogen atmosphere. The reaction was heated to 80 °C for 1 h. The reaction was filtered and to the filtrate was added 50 mL of saturated aqueous sodium chloride solution and 30 mL of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (120 mL x 2), the combined organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound M10-3.

[0362] Step 3: A mixture of compound M10-3 (3.0 g, 17.2 mmol) and di-tert-butyl dicarbonate (15.0 g, 68.9 mmol) was stirred at 25 °C for 2 h under nitrogen atmosphere. The reaction was poured into 50 mL of water, extracted with ethyl acetate (20 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-3:1) to give compound M10-4. LCMS (m / z): 275.0 [M+1] + .

[0363] Step 4: To a solution of compound M10-4 (2.30 g, 8.38 mmol) in dichloromethane (50 mL) was added bromine (0.86 mL, 16.8 mmol) dropwise slowly at -40 °C under nitrogen atmosphere. The reaction was stirred at -40 °C for 0.5 h. The reaction was poured into ice saturated aqueous sodium sulfite solution (200 mL), extracted with dichloromethane (30 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-3:1) to give compound M10-5. 1 H NMR (400 MHz, CDC13) d = 8.68 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.17 (br s, 1H), 7.72 (s, 1H), 6.20 (br s, 1H), 2.44 (s, 3H), 1.55 (s, 9H).

[0364] Step 5: To a mixture of compound M10-5 (600 mg, 1.70 mmol), compound M3 (587 mg, 2.04 mmol) in dioxane (12 mL) and water (3 mL) was added potassium carbonate (470 mg, 3.40 mmol) and dichlorobis[di-tert-butyl-(4-dimethylamino phenyl)phosphine] palladium(II) (120 mg, 170 pmol) under nitrogen atmosphere, the reaction was purged with nitrogen for 3 times, and stirred at 100 °C for 1 h. The reaction was poured into water (10 mL), extracted with ethyl acetate (8 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-1:2) to give compound M10-6. LCMS (m / z): 435.3 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 8.30 (d, J = 1.2 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.08-8.00 (m, 1H), 7.95 (br s, 1H), 7.56 (t, J = 2.0 Hz, 1H), 7.12 (s, 1H), 4.51-4.40 (m, 2H), 4.18 (q, J = 8.8 Hz, 2H), 3.10-2.99 (m, 4H), 2.28 (s, 3H), 1.42 (br s, 9H).

[0365] Step 6: To a solution of compound M10-6 (500 mg, 1.15 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (3 mL) at room temperature under nitrogen atmosphere. The reaction was stirred at 25 °C for 1 h. The reaction was concentrated under reduced pressure to give a crude product, which was poured into 5 mL of ice sodium bicarbonate aqueous solution, extracted with ethyl acetate (7 mL x 2), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 2-7. 1 H NMR (400 MHz, DMSO-d6) δ = 8.21 (d, J = 1.2 Hz, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 7.36 (s, 1H), 7.07 (s, 1H), 4.53-4.41 (m, 2H), 4.19-4.09 (m, 2H), 3.91 (br s, 2H), 3.08-2.98 (m, 4H), 2.25 (s, 3H).

[0366] Step 7: To a solution of compound M10-7 (250 mg, 748 pmol) in dibromomethane (4 mL) was added tetrabutylammonium bromide (723 mg, 2.24 mmol) at room temperature under nitrogen atmosphere. The reaction was warmed to 60 °C, and isopentylnitrite (175 mg, 1.50 mmol) was added dropwise slowly. The reaction was stirred for 1 h. The reaction was poured into water (3 mL), extracted with ethyl acetate (5 mL x 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by preparative reverse phase column (column: Phenomenex luna C18 (250 x 70 mm, 10 pm); mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 25% - 60%) to give compound M10. LCMS (m / z): 398.1, 400.0 [M+1] + .

[0367] Intermediate M11

[0368] Step 1: To a solution of compound M11-1 (1 g, 10.51 mmol) in anhydrous N,N- dimethylformamide (10 mL) was added potassium carbonate (5.81 g, 42.05 mmol) at 25 °C for 0.5 h, then p-methoxybenzyl chloride (4.94 g, 31.54 mmol) was added dropwise slowly, the reaction mixture was continued to react at 25 °C for 12 h. The reaction mixture was filtered, the filtrate was separated by preparative reverse phase column chromatography (column: Phenomenex luna C18 (250 x 70 mm, 10 μm); mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 35% - 65%) to give compound M11-2. LCMS (m / z): 358.1 [M+23] + .

[0369] Step 2: To a solution of compound M11-2 (1 g, 2.98 mmol) in tetrahydrofuran (10 mL) was added n-butyllithium (2.5 M in tetrahydrofuran, 1.55 mL) dropwise at -70 °C, after the addition was completed, the reaction mixture was reacted at -70 °C for 0.5 h, then a solution of compound M11-3 (881.13 mg, 4.47 mmol) in tetrahydrofuran (2 mL) was added dropwise slowly, the reaction mixture was continued to react at -70 °C for 1.5 h. Water (20 mL) was added dropwise to the reaction mixture, extracted with ethyl acetate (15 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-2:1) to give compound M11-4. LCMS (m / z): 452.1 [M+H] + .

[0370] Step 3: To a solution of compound M11-4 (340 mg, 752.98 μmol) in anhydrous dichloromethane (1.7 mL) was added trifluoroacetic acid (5.22 g, 45.77 mmol) at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, dichloromethane (10 mL) was added to the residue, the pH was adjusted to 7-7.5 with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase column chromatography (column: Phenomenex luna C18 (250 x 70 mm, 10 μm); mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 35% - 65%) to give compound M11. LCMS (m / z): 212.0 [M+H] + .

[0371] Intermediate M12

[0372] Step 1: To a solution of compound M11-3 (2 g, 10.15 mmol) in acetonitrile (30 mL) was added compound M12-1 (979.50 mg, 4.49 mmol) under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1-5: 1) to give compound M12-2. LCMS (m / z): 192.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.69 (d, J = 1.2 Hz, 1H), 8.03-7.92 (m, 2H), 4.21 (s, 2H), 2.36 (s, 3H).

[0373] Step 2: To a solution of NCS (2.22 g, 16.65 mmol) and hydrochloric acid (2 M, 0.8 mL) in acetonitrile (4 mL) was added dropwise a solution of compound M12-2 (0.8 g, 4.16 mmol) in acetonitrile (1 mL) at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 30 min. The reaction was poured into ammonia water (6 mL) and the mixture was stirred at 0 °C for another 30 min. The reaction was diluted with water (20 mL) and adjusted to pH 3 with 4 N hydrochloric acid. The mixture was extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product which was purified by preparative reversed-phase column chromatography (column: Waters Xbridge C18 150*50mm*10um; mobile phase: water (10 mM NH4HCO3) - acetonitrile; gradient (acetonitrile %): 22%-52%) to give compound M12. LCMS (m / z): 197.9 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.71 (d, J = 1.6 Hz, 1H), 8.12-8.06 (m, 1H), 8.04-8.00 (m, 1H), 7.01 (s, 2H), 4.48 (s, 2H).

[0374] Intermediate M13

[0375] Step 1: To a solution of compound M13-1 (2.8 g, 15.34 mmol) and compound M1-2 (2.74 g, 16.94 mmol) in dioxane (40 mL) and water (4 mL) was added tricyclohexylphosphonium (860.35 mg, 3.07 mmol), potassium phosphate (9.77 g, 46.02 mmol) and tris(dibenzylideneacetone)dipalladium (1.4 g, 1.53 mmol) sequentially under nitrogen atmosphere at room temperature. The reaction was heated at 95 °C for 4.5 h. Water (100 mL) was added to the reaction mixture, which was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give compound M13-2. LCMS (m / z): 203.1 [M+H] + ; 1 H NMR (400 MHz, CDC13) d = 7.63 (dd, J = 1.2, 4.4 Hz, 1H), 7.10 (d, J = 16.0 Hz, 1H), 6.66 (dq, J = 1.2, 7.2 Hz, 1H), 2.26-2.23 (m, 3H), 1.97 (dd, J = 1.2, 7.2 Hz, 3H).

[0376] Step 2: To a solution of compound M1-4 (1.54 g, 13.75 mmol) in dichloromethane (28 mL) was added sulfuryl chloride (1.86 g, 13.75 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 1 h to give reaction solution 1. To reaction solution 1 was added a solution of compound M13-2 (2.78 g, 13.75 mmol) in dichloromethane (28 mL) dropwise. After the addition was completed, the reaction was allowed to warm to 25 °C slowly and stirred for 2 h. Another batch of reaction solution 1 was added at 0 °C and the reaction was continued at 25 °C for 15 h. The reaction was slowly added to saturated aqueous sodium bicarbonate solution (150 mL) and water (30 mL) was added. The mixture was extracted with dichloromethane (100 mL x 3). The combined organic phase was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give compound M13-3. LCMS (m / z): 348.9 [M+H] + .

[0377] Step 3: Under a nitrogen atmosphere at 0°C, m-chloroperoxybenzoic acid (3.39 g, 16.69 mmol, 85% purity) was added in portions to a dichloromethane (40 mL) solution of compound M13-3 (1.94 g, 5.56 mmol). After the addition was complete, the reaction solution was allowed to react at room temperature for 15 hours. At 0°C, the reaction solution was slowly added to a saturated sodium bicarbonate aqueous solution (100 mL) and a saturated sodium sulfite aqueous solution (100 mL), and extracted with dichloromethane (50 mL × 3). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1-0:1) to obtain compound M13-4. LCMS (m / z): 381.0 [M+H] + .

[0378] Step 4: Under a nitrogen atmosphere at room temperature, potassium carbonate (1.66 g, 12.02 mmol) was added to a mixed solution of compound M13-4 (1.83 g, 4.47 mmol) in acetonitrile (19 mL), methanol (19 mL), and water (13 mL). The reaction solution was heated to 50 °C and reacted for 3 hours. The reaction solution was concentrated under reduced pressure to obtain crude compound M13-5, which was used directly in the next step.

[0379] Step 5: Under a nitrogen atmosphere at room temperature, potassium acetate (474 ​​mg, 4.83 mmol) and compound M5-7 (1.09 g, 9.6 mmol) were added to an aqueous (15 mL) solution of compound M13-5 (1.46 g, crude product). The reaction solution was reacted at 40 °C for 4 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 6). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Spherical C18, 40-60 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 30% ) yielded compound M13-6. LCMS (m / z): 282.0 [M+H] + .

[0380] Step 6: Under an argon atmosphere at room temperature, add (S)-1-{(RP)-2-[bis(1-naphthyl)phosphine]ferrocene}ethyl di-tert-butylphosphine (41.12 mg, 64.0 μmol), rhodium (I) di(1,5-cyclooctadiene)tetrafluoroborate (25.99 mg, 64.0 μmol), and zinc trifluoromethanesulfonate (46.53 mg, 128 μmol) to a methanol (10 mL) solution of compound M13-6 (0.3 g, 1.07 mmol). The reaction solution is purged with hydrogen three times, and the reaction is carried out at 50 °C for 18 hours at a hydrogen pressure of 50 psi. The reaction solution is filtered, and the filtrate is reduced in pressure to obtain the crude product, which is then preparatively separated by reversed-phase column chromatography (column: Spherical C18, 40-60 μm). Mobile phase: water (0.1% ammonia water) - acetonitrile; gradient (acetonitrile %): 30% to get compound M13. LCMS (m / z): 284.0 [M+H] + SFC detection (Chromatographic column: Chiralpak AD-3 100 x 4.6 mm I.D., 3 μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 5% to 40%), compound M13 contains 2 isomers, the retention time is 3.517 min (content 60.19%) and 4.989 min (content 39.81%) respectively.

[0381] Example 001

[0382] Step 1: To a solution of compound 001-1 (10.0 g, 66.1 mmol) in methanol (100 mL) was added 85% hydrazine hydrate (7.79 g) slowly at 25 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure, the residue was added with n-hexane (100 mL) and stirred at room temperature for 30 min, filtered, the filter cake was washed with 50 mL petroleum ether and dried to give compound 001-2.

[0383] Step 2: To a solution of compound M2 (60 mg, 338 μmol) in dichloromethane (0.3 mL) and pure water (0.2 mL) was added sodium bicarbonate solid (56.9 mg, 677 μmol) and thiophosgene (42.8 mg, 372 μmol) slowly at 0 °C under nitrogen atmosphere. After stirring at 0 °C for 10 min, the reaction was warmed to 25 °C and stirred for 1 h. To the reaction was added water (10 mL), extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with 50 mL saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 001-3.

[0384] Step 3: To a solution of compound M2 (70 mg, 305 μmol) in acetonitrile (1 mL) was added compound 001-3 (73.6 mg, 336 μmol) and cesium carbonate (129 mg, 396 μmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h to give a reaction solution of compound 001-4 which was used directly in the next step.

[0385] Step 4: To the reaction solution of compound 001-4 from step 3 was added compound 001-2 (45.5 mg, 301 μmol) and silver nitrate (0.08 g, 471 μmol) at 0 °C under nitrogen atmosphere, and the reaction was stirred at 25 °C for 0.5 h. The reaction solution was added to acetonitrile (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give compound 001-5. LCMS (m / z): 566.1 [M+H] + .

[0386] Step 5: To a solution of compound 001-5 (170 mg, 300 μmol) in dioxane (1.5 mL) was added methanesulfonic acid (86.6 mg, 902 μmol) at 25 °C under nitrogen atmosphere, and the reaction was stirred at 100 °C for 3 h. The reaction was adjusted to pH = 7-8 by slowly adding saturated aqueous sodium bicarbonate solution, and then extracted with dichloromethane (50 mL x 2). The combined organic layers were washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by preparative reverse phase column (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: [water (0.5% ammonia water) - acetonitrile]; gradient (B%): 25% - 32%), and then by preparative reverse phase column (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (B%): 36% - 56%) to give compound 001. LCMS (m / z): 548.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.44 (s, 1H), 8.59 (s, 2H), 8.51 (d, J = 1.2 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 7.75 (s, 1H), 7.21 (s, 1H), 4.59 - 4.43 (m, 4H), 3.76 - 3.69 (m, 1H), 3.68 (br s, 1H), 3.18 - 3.08 (m, 4H), 2.29 (s, 3H), 2.24 (s, 3H), 1.27 (d, J = 7.2 Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H). SFC detection (column: Chiralpak AD-3 50*4.6mm I.D., 3 μm; mobile phase: A phase: supercritical CO2, B phase: isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20% - 60%), the retention time of compound 001 was 1.925 min, and the chiral purity was 97.31%.

[0387] Example 002

[0388] To a solution of compound M10 (30.0 mg, 75.3 μmol), compound M1 (51.8 mg, 226 μmol) and N,N-dimethylcyclohexanediamine (10.7 mg, 75.3 μmol) in dioxane (1.5 mL) was added potassium carbonate (31.2 mg, 226 μmol) and cuprous iodide (14.4 mg, 75.3 μmol) under nitrogen atmosphere at room temperature. The reaction was purged with nitrogen for 3 times and the reaction was heated to 100 °C for 16 h. The reaction was poured into water (4 mL) and extracted with ethyl acetate (4 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0-0:1) to give a crude product, which was further purified by preparative reverse phase column (column: Waters Xbridge 150 x 25 mm x 5 μm; mobile phase: [water (10 mM NH4HCO3) - acetonitrile]; gradient (acetonitrile %): 35%-65%) to give compound 002. LCMS (m / z): 547.1 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.92 (s, 1H), 8.59 (s, 2H), 8.32 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.04 (s, 1H), 4.49 (q, J = 8.4 Hz, 1H), 4.29 (q, J = 8.8 Hz, 1H), 4.17-4.00 (m, 2H), 3.66-3.51 (m, 2H), 3.01 (br t, J = 8.8 Hz, 2H), 2.98-2.77 (m, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.28 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H); SFC detection (column: Chiralpak IC-3 50*4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical CO2, B phase: ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 002 was 2.122 min with 97.43% chiral purity.

[0389] Example 003

[0390] To a solution of compound 001-5 (8.3 g, 14.67 mmol) in dioxane (830 mL) was added methanesulfonic acid (4.23 g, 44.02 mmol) slowly under nitrogen atmosphere, the reaction was heated to 100 °C and stirred for 8 h. The reaction was cooled to room temperature, concentrated under reduced pressure, dissolved in dichloromethane (500 mL), adjusted to pH = 8 by adding saturated aqueous sodium bicarbonate solution slowly, extracted with dichloromethane (500 mL x 2), the combined organic layer was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by column chromatography (dichloromethane: methanol = 100 / 1-20 / 1) to give a crude product. To the crude product was added a mixture of petroleum ether / ethanol (15 / 1, 20 mL) again, stirred at room temperature for 15 min, filtered, the mother liquor was separated by preparative reverse phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile; gradient (acetonitrile%): 38%-68%), to give a mixture of compound 001 and 003, which was further purified by SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: A phase is supercritical CO2, B phase is EtOH / acetonitrile / 0.1% ammonia water (ethanol and acetonitrile in a volume ratio of 4:1); gradient (B%): 50%) to give compound 003. LCMS (m / z): 546.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 8.58 (s, 2H), 8.35 (s, 1H), 8.25 (s, 1H), 8.15 (br d, J = 7.9 Hz, 1H), 7.79-7.74 (m, 1H), 7.63 (br s, 1H), 7.58 (s, 1H), 6.90 (dd, J = 2.1, 7.6 Hz, 1H), 4.66-4.55 (m, 1H), 4.54-4.46 (m, 1H), 3.90-3.83 (m, 1H), 3.71 (br d, J = 5.0 Hz, 1H), 3.30 (br d, J = 8.7 Hz, 2H), 2.23 (s, 3H), 2.20 (d, J = 1.6 Hz, 3H), 1.21 (dd, J = 7.2, 12.0 Hz, 3H), 1.03 (dd, J = 7.0, 16.7 Hz, 3H).

[0391] Example 004

[0392] Step 1: To a solution of compound M4 (70 mg, 305 μmol) in acetonitrile (5 mL) was added compound 001-3 (300 mg, 1.37 mmol) and cesium carbonate (580 mg, 1.78 mmol) slowly at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h to give a reaction solution of compound 004-1, which was used directly in the next step. LCMS (m / z): 501.1 [M+H] + .

[0393] Step 2: To the reaction solution of compound 004-1 above was added compound 001-2 (308 mg, 2.04 mmol) and silver nitrate (346 mg, 2.04 mmol) was added slowly in portions at 0 °C under nitrogen atmosphere. The mixture was stirred at 0 °C for 1 h. The reaction was diluted with 50 mL of acetonitrile and filtered. The filtrate was concentrated under reduced pressure to give compound 004-2. LCMS (m / z): 618.2 [M+H] + .

[0394] Step 3: To a solution of compound 004-2 (740 mg, 1.20 mmol) in dioxane (100 mL) was added methanesulfonic acid (345 mg, 3.59 mmol) at 100 °C under nitrogen atmosphere. The reaction was stirred at 100 °C for 3 h. The reaction was cooled to room temperature and concentrated under reduced pressure to give a crude product, which was purified by preparative reverse phase chromatography (column: Phenomenex luna C18 150 x 25 mm x 10 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 36% - 56%) to give compound 004. LCMS (m / z): 600.2 [M+H] + .

[0395] Step 4: Compound 004 was separated by SFC (column: REGIS (S, S) WHELK-O1 (250 mm x 25 mm, 10 μm; mobile phase: A phase: supercritical CO2, B phase: isopropanol (0.1% ammonia); gradient (B%): 35%) to give compound 004A and compound 004B. Compound 004A was characterized: LCMS (m / z): 600.2 [M+H] + ; 1H NMR (400 MHz, CDC13) δ = 11.07 (br s, 1H), 8.60-8.20 (m, 2H), 7.79 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 4.64-4.39 (m, 4H), 3.49 (t, J = 7.2 Hz, 1H), 3.25 (t, J = 7.2 Hz, 1H), 3.21-3.02 (m, 4H), 2.35 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 7.2 Hz, 3H). SFC detection (Chiralpak® IC column (S,S) Whelk-01 50*4.6 mm I.D., 3.5 μm; mobile phase: A phase is supercritical CO2, B phase is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) the retention time of compound 004A was 3.581 min with 98.98% chiral purity.

[0396] Compound 004B was characterized by LCMS (m / z): 600.2 [M+H] + ; 1 H NMR (400 MHz, CDC13) δ = 11.07 (br s, 1H), 8.60-8.20 (m, 2H), 7.79 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 4.64-4.39 (m, 4H), 3.49 (t, J = 7.2 Hz, 1H), 3.25 (t, J = 7.2 Hz, 1H), 3.21-3.02 (m, 4H), 2.35 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 7.2 Hz, 3H). SFC detection (Chiralpak® IC column (S,S) Whelk-01 50*4.6 mm I.D., 3.5 μm; mobile phase: A phase is supercritical CO2, B phase is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) the retention time of compound 004B was 3.806 min with 98.09% chiral purity.

[0397] Example 005

[0398] Step 1: To a solution of compound 001-3 (120 mg, 547.30 pmol) and cesium carbonate (231.82 mg, 711.49 pmol) in acetonitrile (4 mL) was added compound M5 (155.03 mg, 547.30 pmol) slowly at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h to give a solution of compound 005-1 in acetonitrile, which was used directly in the next step. LCMS (m / z): 503.1 [M+H] + .

[0399] Step 2: To the solution of compound 005-1 in acetonitrile from step 1 was added compound 001-2 (81.22 mg, 537.28 pmol) and silver nitrate (0.15 g, 883.01 pmol) portionwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2 h. To the reaction was added 50 mL of acetonitrile and the mixture was filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (dichloromethane:methanol = 100 / 1-10 / 1) to give compound 005-2. LCMS (m / z): 620.3 [M+H] + .

[0400] Step 3: To a solution of compound 005-2 (60 mg, 96.83 pmol) in dioxane (5 mL) was added methanesulfonic acid (20.76 pL, 290.50 pmol) slowly at 25 °C under nitrogen atmosphere. The reaction was stirred at 100 °C for 4 h. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (50 mL), and then the pH was adjusted to 7-8 by adding aqueous sodium bicarbonate solution slowly. The mixture was extracted with dichloromethane (30 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile %): 40%-70%) to give compound 005. LCMS (m / z): 602.1 [M+H] + ; SFC detection (column: Chiralpak IH-3 50*4.6mm I.D., 3pm; mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); gradient (B%): 20%-60%) Compound 005 contains 2 isomers with a ratio of about 5.5:1.

[0401] Step 4: Compound 005 was separated by SFC (Chromatographic column: ChiralPak IH, 250*50mm, 10pm; Mobile phase: A phase: Supercritical CO2, B phase: Ethanol (0.1% Ammonia); Gradient (B%): 45%) to give Compound 005A and Compound 005B.

[0402] Compound 005A was characterized by LCMS (m / z): 602.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.51-13.26 (m, 1H), 9.22-9.19 (m, 2H), 8.51-8.41 (m, 1H), 8.31-8.26 (m, 1H), 7.77-7.68 (m, 1H), 7.19 (br s, 1H), 4.59-4.43 (m, 4H), 3.91-3.70 (m, 2H), 3.17-3.09 (m, 4H), 2.30-2.26 (m, 3H), 1.32 (br d, J = 7.0 Hz, 3H), 1.21-1.14 (m, 3H); 19 F NMR (376 MHz, DMSO-d6) d = -60.720; Compound 005A was detected by SFC (Chromatographic column: Chiralpak IH-3 50*4.6mm I.D., 3pm; Mobile phase: A phase: Supercritical CO2, B phase: EtOH (0.05% Diethylamine); Gradient (B%): 20%-60%), the retention time was 0.877 min, and the chiral purity was 99.30%.

[0403] Compound 005B was characterized by LCMS (m / z): 602.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.44 (br s, 1H), 9.21 (d, J = 0.6 Hz, 2H), 8.51 (s, 1H), 8.30 (d, J = 1.9 Hz, 1H), 7.75 (s, 1H), 7.22 (s, 1H), 4.61-4.43 (m, 4H), 3.80-3.66 (m, 2H), 3.19-3.09 (m, 4H), 2.29 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) d = -60.712; SFC (Chiralpak IH-3 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical CO2, B phase: EtOH (0.05% diethylamine); gradient (B%): 20% - 60%) retention time of compound 005B: 1.224 min, chiral purity: 100%.

[0404] Example 006

[0405] Step 1: To a solution of compound M6 (453.18 mg, 1.61 mmol) in acetonitrile (20 mL) was added compound 001-3 (320 mg, 1.46 mmol) and cesium carbonate (618.18 mg, 1.90 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 16 h to give a solution of compound 006-1 in acetonitrile, which was used directly for the next step. LCMS (m / z): 502.1 [M+H] + .

[0406] Step 2: To the solution of compound 006-1 in acetonitrile from step 1 was added compound 001-2 (264.39 mg, 1.75 mmol) and a solution of silver nitrate (371.39 mg, 2.19 mmol) in acetonitrile (3 mL) dropwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2 h. To the reaction was added 50 mL of acetonitrile and the mixture was filtered. The filtrate was concentrated under reduced pressure and the crude was purified by column chromatography (dichloromethane: methanol = 40 / 1-30 / 1) to give compound 006-2. LCMS (m / z): 619.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 10.85-10.62 (m, 1H), 9.00-8.86 (m, 2H), 8.67-8.54 (m, 2H), 8.14 (br d, J = 1.9 Hz, 1H), 7.98-7.89 (m, 1H), 7.86-7.76 (m, 1H), 6.99 (br s, 1H), 4.63-4.39 (m, 4H), 3.75-3.56 (m, 1H), 3.11 (br t, J = 7.8 Hz, 4H), 2.38 (s, 3H), 1.41-1.31 (m, 3H), 1.20-1.09 (m, 3H).

[0407] Step 3: To a solution of compound 006-2 (600.00 mg, 969.89 pmol) in dioxane (10 mL) was added trifluoroacetic acid (360.23 pL, 4.85 mmol) under nitrogen atmosphere at 25 °C. The reaction was stirred at 100 °C for 4 h. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), adjusted to pH = 7-8 with saturated aqueous sodium bicarbonate solution, and separated. The aqueous phase was extracted with dichloromethane (30 mL x 2), and all organic phases were combined, washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative reverse-phase column chromatography (column: Phenomenex luna C18 150*25mm*10pm; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient (acetonitrile %): 40% - 70%) to give compound 006.

[0408] Step 4: Compound 006 was purified by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10pm); mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.1% ammonia water); gradient (B%): 50%) to give compound 006A and a mixture of compounds 006B / 006C / 006D. The mixture of compounds 006B / 006C / 006D was purified by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10pm); mobile phase: A phase: supercritical carbon dioxide, B phase: isopropanol (0.1% ammonia water); gradient (B%): 40%) to give a mixture of compounds 006B and 006C and compound 006D.

[0409] Compound 006A was characterized by LCMS (m / z): 601.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 13.61 - 13.28 (m, 1H), 8.58 (s, 1H), 8.49 (br s, 1H), 8.31 (s, 1H), 7.94 - 7.88 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.22 (s, 1H), 4.63 - 4.41 (m, 4H), 3.68 - 3.54 (m, 1H), 3.42 - 3.34 (m, 1H), 3.19 - 3.10 (m, 4H), 2.29 (s, 3H), 1.30 (d, J = 7.2 Hz, 3H), 1.15 (br d, J = 6.8 Hz, 3H). SFC Analysis Method 1 test (Column: Lux 3 pm Cellulose-4 50*4.6 mm I.D., 3 pm); Mobile Phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); Gradient (B%): 20%-60%), the retention time of compound 006A was 2.245 min, chiral purity 99.14%. SFC Analysis Method 2 test (Column: CHIRALPAK AD-3 50*4.6 mm I.D., 3 pm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); Gradient (B%): 30%), the retention time of compound 006A was 0.886 min.

[0410] Mixture of compounds 006B and 006C characterized: LCMS (m / z): 601.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 13.61 - 13.28 (m, 1H), 8.58 (s, 1H), 8.49 (br s, 1H), 8.31 (s, 1H), 7.94 - 7.88 (m, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.22 (s, 1H), 4.63 - 4.41 (m, 4H), 3.68 - 3.54 (m, 1H), 3.42 - 3.34 (m, 1H), 3.19 - 3.10 (m, 4H), 2.29 (s, 3H), 1.30 (d, J = 7.2 Hz, 3H), 1.15 (br d, J = 6.8 Hz, 3H). SFC Analysis Method 1 test (Column: Lux 3 pm Cellulose-4 50*4.6 mm I.D., 3 pm); Mobile Phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); Gradient (B%): 20%-60%), the retention time of compound 006A was 2.245 min, chiral purity 99.14%. SFC Analysis Method 2 test (Column: CHIRALPAK AD-3 50*4.6 mm I.D., 3 pm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); Gradient (B%): 30%), the retention time of compound 006A was 0.886 min.

[0411] Compound 006D was characterized by LCMS (m / z): 601.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.49 (br s, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 7.96-7.89 (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.23 (s, 1H), 4.62-4.44 (m, 4H), 3.63-3.54 (m, 1H), 3.42-3.35 (m, 1H), 3.20-3.07 (m, 4H), 2.30 (s, 3H), 1.30 (d, J = 7.2 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H). SFC Analysis Method 2 test (Chromatographic column: CHIRALPAK AD-3 50*4.6 mm I.D., 3 pm; Mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); Gradient (B%): 30%), the retention time of compound 006D was 1.370 min, and the chiral purity was 100%.

[0412] Example 007

[0413] Step 1: To a solution of compound 001-3 (2.5 g, 11.4 mmol) and compound M7 (3.3 g, 12.44 mmol) in acetonitrile (100 mL) was added cesium carbonate (4.83 g, 14.8 mmol) at 0 °C under nitrogen atmosphere, the reaction was warmed to 25 °C for 16 hours. The reaction was filtered, and the filter cake was dried to give compound 007-1. LCMS (m / z): 485.2 [M+H] + .

[0414] Step 2: To a solution of compound 007-1 (5.4 g, 11.14 mmol) and compound 001-2 (1.68 g, 11.1 mmol) in acetonitrile (200 mL) was added silver nitrate (2.9 g, 17.3 mmol) portionwise at 0 °C under nitrogen atmosphere, the reaction was stirred at 0 °C for 1 hour. The reaction was filtered, and the filter cake was washed with acetonitrile (100 mL x 3), and the mother liquor was concentrated under reduced pressure to give compound 007-2. LCMS (m / z): 602.2 [M+H] + .

[0415] Step 3: To a solution of compound 007-2 (6.1 g, 10.1 mmol) in dioxane (60 mL) was added trifluoroacetic acid (5.78 g, 50.7 mmol) dropwise at 0 °C under nitrogen atmosphere. The reaction was allowed to warm to 100 °C and stirred for 2 h. After the reaction was cooled to room temperature, it was filtered and the filtrate was concentrated to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 20-45 μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient (acetonitrile %): 45%) and high performance liquid chromatography preparative separation (column: Phenomenex Luna C18 150 x 25 mm x 10 μm; mobile phase: [water (0.225% formic acid) - acetonitrile]; gradient (acetonitrile %): 35% - 55%) to give compound 007. LCMS (m / z): 584.1 [M+H] ; + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.43 (s, 1H), 8.98 (s, 2H), 8.51 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.36 - 6.98 (m, 2H), 4.61 - 4.42 (m, 4H), 3.80 - 3.67 (m, 2H), 3.19 - 3.07 (m, 4H), 2.29 (s, 3H), 1.30 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, CD3CN) d (ppm) = -112.924. SFC detection (column: Chiralpak IH-3 50 x 4.6 mm I.D., 3 μm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 20% - 60%) showed that compound 007 contained 2 isomers with retention times of 1.504 min (content 84.40%) and 1.161 min (content 15.60%), respectively.

[0416] Step 4: Compound 007 was purified by SFC preparative purification (column: ChiralPak IH, 250 x 50 mm, 10 μm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.1% ammonia); gradient (B%): 50%) to give compound 007A and compound 007B. Compound 007A was characterized: LCMS (m / z): 584.2 [M+H] +SFC detection (ChiralPak IH-3 50x4.6mm I.D., 3μιη; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 007A was 1.161 min.

[0417] Compound 007B was characterized by LCMS (m / z): 584.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 13.43 (s, 1H), 8.98 (s, 2H), 8.51 (s, 1H), 8.31 (d, J = 2.0 Hz, 1H), 7.75 (s, 1H), 7.36-6.98 (m, 2H), 4.61-4.42 (m, 4H), 3.80-3.67 (m, 2H), 3.19 -3.07 (m, 4H), 2.29 (s, 3H), 1.30 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) δ (ppm) = -112.931. SFC detection (ChiralPak IH-3 50x4.6mm I.D., 3μιη; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 007B was 1.512 min, chiral purity 100%.

[0418] Example 008

[0419] Step 1: To a solution of compound 001-3 (250 mg, 1.14 mmol) and compound M8 (361.62 mg, 1.37 mmol) in acetonitrile (5 mL) was added cesium carbonate (482.95 mg, 1.48 mmol) under nitrogen atmosphere at room temperature. The reaction was stirred at room temperature for 2 hours to give a solution of compound 008-1 in acetonitrile, which was used directly in the next step. LCMS (m / z): 484.1 [M+1] + .

[0420] Step 2: To a solution of compound 008-1 (400.00 mg, 827.21 μmol) and compound 001-2 (125.05 mg, 827.21 μmol) in acetonitrile (10 mL) was added silver nitrate (180 mg, 105.96 mmol) portionwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 250x140mmx10μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 70% - 80%) to give compound 008-2. LCMS (m / z): 601.3 [M+1] + .

[0421] Step 3: To a solution of compound 008-2 (400.00 mg, 665.96 μmol) in dioxane (5 mL) was added trifluoroacetic acid (247.34 μL, 3.33 mmol) at room temperature under nitrogen atmosphere. The reaction was stirred at 100 °C for 12 h. The reaction was concentrated under reduced pressure to give a crude product, which was separated by preparative reverse phase chromatography (column: Phenomenex luna C18 250x140mmx10μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40% - 60%) to give compound 008. LCMS (m / z): 583.1 [M+1] + .

[0422] Step 4: Compound 008 (150 mg) was separated by SFC preparative separation (column: ChiralPak IH, 250x50mm, 10μm; mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.1% NH3H2O); gradient (B%): 40%) to give two crude products (compound 008-P1 and compound 008-P2). SFC detection (column: Chiralpak IH-3 50x4.6mm I.D. 3μm; mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.05% diethylamine); gradient (B%): 20% - 60%) showed that the retention time of compound 008-P1 was 1.041 min and the retention time of compound 008-P2 was 1.166 min.

[0423] Compound 008-P1 was further separated by SFC preparative separation (column: DAICEL CHIRALCEL OX (250mmx30mm, 10μm); mobile phase: A phase: supercritical carbon dioxide, B phase: MeOH (0.1% NH3H2O); gradient (B%): 60%) to give compound 008A and compound 008B.

[0424] Compound 008-P2 was further separated by SFC preparation (Chromatographic column: DAICEL CHIRALCEL OJ (250 mm x 30 mm, 10 pm); Mobile phase: A phase was supercritical carbon dioxide, B phase was EtOH (0.1% NH3-H2O); Gradient (B%): 10%) to give Compound 008C and Compound 008D.

[0425] Compound 008A characterization: LCMS (m / z): 583.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.49 (s, 1H), 8.50 (br d, J = 13.6 Hz, 2H), 8.31 (d, J = 1.6 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 6.91 (t, J = 54.8 Hz, 1H), 4.61 - 4.42 (m, 4H), 3.49 - 3.43 (m, 1H), 3.30 - 3.25 (m, 1H), 3.19 - 3.08 (m, 4H), 2.30 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H), 1.02 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) d = -114.801; SFC detection (Chromatographic column: Lux 3 pm Cellulose-4 50 x 4.6 mm I.D., 3 pm; Mobile phase: A phase was supercritical carbon dioxide, B phase was MeOH (0.05% diethylamine); Gradient (B%): 30% - 60%), the retention time of Compound 008A was 1.995 min, and the chiral purity was 100%.

[0426] Compound 008B characterization: LCMS (m / z): 583.2 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ = 13.52 (s, 1H), 8.51 (dd, J = 1.6, 8.0 Hz, 2H), 8.32 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 8.0 Hz, 1H), 7.78-7.74 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.24 (s, 1H), 6.93 (t, J = 55.2 Hz, 1H), 4.62-4.41 (m, 4H), 3.59 (br dd, J = 3.6, 7.2 Hz, 1H), 3.22-3.06 (m, 5H), 2.30 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H), 1.15 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) δ = -114.793; SFC detection (Column: Lux 3 pm Cellulose-4 50 x 4.6 mm I.D., 3 pm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is MeOH (0.05% diethylamine); Gradient (B%): 30% - 60%), the retention time of compound 008B was 2.231 min with 99.28% chiral purity.

[0427] Compound 008C characterization: LCMS (m / z): 583.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) δ = 13.48 (s, 1H), 8.50 (dd, J = 2.0, 14.0 Hz, 2H), 8.31 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 2.0, 8.0 Hz, 1H), 7.75 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 6.91 (t, J = 55.2 Hz, 1H), 4.61-4.42 (m, 4H), 3.49-3.40 (m, 1H), 3.31-3.26 (m, 1H), 3.14 (br t, J = 8.4 Hz, 4H), 2.30 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H), 1.02 (d, J = 7.0 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) δ = -114.801; SFC detection (Column: Chiralcel OJ-3 50 x 4.6 mm I.D. 3 pm; Mobile Phase: A phase is supercritical carbon dioxide, B phase is EtOH (0.05% diethylamine); Gradient (B%): 5% - 20%), the retention time of compound 008C was 2.162 min with 99.04% chiral purity.

[0428] Compound 008D Characterization: LCMS (m / z): 583.2 [M+1] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.52 (s, 1H), 8.51 (dd, J = 1.2, 7.2 Hz, 2H), 8.32 (d, J = 2.0 Hz, 1H), 7.84 (dd, J = 2.0, 8.0 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 6.93 (t, J = 55.2 Hz, 1H), 4.60 - 4.44 (m, 4H), 3.65 - 3.52 (m, 1H), 3.20 - 3.07 (m, 5H), 2.30 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H), 1.15 (d, J = 7.2 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) d = -114.793; SFC detection (column: Chiralcel OJ-3 50 x 4.6 mm I.D. 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: EtOH (0.05% diethylamine); gradient (B%): 5% - 20%), the retention time of compound 008D was 2.406 min, and the chiral purity was 99.68%.

[0429] Example 009

[0430] Step 1: To a solution of compound 009-1 (3 g, 13.69 mmol) in dimethylformamide (30 mL) was added N-iodosuccinimide (3.54 g, 15.74 mmol) under nitrogen atmosphere, the reaction was heated to 60 °C for 2 hours. The reaction was cooled to room temperature, water (100 mL) was added to the reaction, extracted with ethyl acetate (100 mL x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 0 / 1 ~ 5 / 1) to give compound 009-2. LCMS (m / z): 345.9 [M+1] + ; 1 H NMR (400 MHz, CDCl3) d = 7.72 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 6.85 (dd, J = 2.8, 8.8 Hz, 1H), 4.33 (br s, 2H); 19 F NMR (376 MHz, CDCl3) d = 62.81 (d, 4F), 84.64 - 83.85 (m, 1F).

[0431] Step 2: To a solution of compound 009-2 (2.4 g, 6.96 mmol) in methanol (30 mL) was added triethylamine (2.11 g, 20.87 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium chloride (508.91 mg, 695.51 μmol) under nitrogen atmosphere, and the reaction mixture was purged with carbon monoxide for three times. The reaction mixture was stirred at 80 °C for 17 h under carbon monoxide atmosphere (50 Psi). The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 0 / 1 ~ 10 / 1) to give compound 009-3. LCMS (m / z): 277.9 [M+1] + ; 1 H NMR (400 MHz, CDC13) d = 7.92 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 2.4, 8.8 Hz, 1H), 5.94 (br s, 2H), 3.91 (s, 3H); 19 F NMR (376 MHz, CDC13) d = 61.76 (d, 4F), 83.94 - 83.14 (m, 1F).

[0432] Step 3: To a solution of compound 009-3 (1.6 g, 5.77 mmol) and cuprous bromide (2.48 g, 17.32 mmol) in acetonitrile (20 mL) was added tert-butyl nitrite (893 mg, 8.66 mmol) under nitrogen atmosphere at 0 °C, and the reaction mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched by adding ice water (30 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated aqueous sodium bicarbonate solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 0 / 1 ~ 10 / 1) to give compound 009-4. 1 H NMR (400 MHz, CDC13) d = 8.06 (d, J = 2.0 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.77 (dd, J = 2.0, 8.8 Hz, 1H), 3.98 (s, 3H).

[0433] Step 4: To a solution of compound 009-4 in anhydrous dioxane (20 mL) was added bis(pinacolato)diboron (1.16 g, 4.57 mmol), potassium acetate (1.50 g, 15.25 mmol), and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (311.24 mg, 381.13 μmol) under nitrogen atmosphere. The reaction mixture was purged with nitrogen for three times, and stirred at 80 °C for 2 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 10 / 1 ~ 4 / 1) to give compound 009-5.1 H NMR (400 MHz, CDC13) δ = 8.01 (d, J = 8.8 Hz, 1H), 7.85-7.77 (m, 2H), 3.95 (s, 3H), 1.44 (s, 12H).

[0434] Step 5: To a solution of compound 009-5 (1.4 g, 3.61 mmol) and sodium hydroxide (144.26 mg, 3.61 mmol) in tetrahydrofuran (25 mL) was added hydrogen peroxide (10.07 g, 100.66 mmol, 34% purity) at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 2 h. To the reaction was added saturated aqueous sodium sulfite solution (50 mL), and extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 009-6. 1 H NMR (400 MHz, CDC13) δ = 8.01 (d, J = 8.8 Hz, 1H), 7.85-7.77 (m, 2H), 3.95 (s, 3H), 1.44 (s, 12H).

[0435] Step 6: To a mixture of compound 009-6 (1 g, 3.59 mmol) and diisopropylethylamine (1.39 g, 10.78 mmol) was added bromomethyl methyl ether (898 mg, 7.19 mmol) at 25 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1 / 0 ~ 5 / 1) to give compound 009-7. 1 H NMR (400 MHz, CDC13) δ = 8.01 (d, J = 8.8 Hz, 1H), 7.85-7.77 (m, 2H), 3.95 (s, 3H), 1.44 (s, 12H).

[0436] Step 7: To a solution of compound 009-7 (0.9 g, 2.79 mmol) in methanol (10 mL) was added hydrazine hydrate (8.46 mL, 165.67 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at 25 °C for 17 h. To the reaction was added hydrochloric acid (1 N, 0.5 mL) to quench, and extracted with dichloromethane (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1 / 0 ~ 10 / 1) to give compound 009-8. 1H NMR (400 MHz, CDC13) δ = 8.81 (br s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 2.0, 8.8 Hz, 1H), 5.39 (s, 2H), 3.56 (s, 3H).

[0437] Step 8: To a solution of compound 001-4 (312 mg, 695.56 pmol) and compound 009-8 (224 mg, 695 pmol) in acetonitrile (5 mL) was added silver nitrate (570 mg, 3.36 mmol) portionwise at 0 °C under nitrogen atmosphere. The reaction was stirred at 0 °C for 2 h. The reaction was filtered, the filter cake was washed with acetonitrile (10 mL x 3), and the filtrate was concentrated under reduced pressure. The residue was separated by reverse phase column chromatography (column: Phenomenex luna C18 150*40mm*15pm; mobile phase: water (0.225% formic acid) - acetonitrile; gradient (acetonitrile %): 55% - 85%) to give compound 009-9. LCMS (m / z): 737.2 [M+l] + .

[0438] Step 9: To a solution of compound 009-9 (180 mg, 244.32 pmol) in anhydrous dioxane (2 mL) was added trifluoroacetic acid (90.74 pL, 1.22 mmol) at room temperature under nitrogen atmosphere. The reaction was heated to 100 °C for 4 h. The reaction was cooled to room temperature and separated by reverse phase column chromatography (column: Phenomenex Luna C18 150*25mm*10pm; mobile phase: water (0.225% formic acid) - acetonitrile; gradient (acetonitrile %): 47% - 77%) to give compound 009. LCMS (m / z): 675.1 [M+l] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.25 (br s, 1H), 10.96 - 10.68 (m, 1H), 8.65 - 8.52 (m, 2H), 7.44 (br d, J = 7.6 Hz, 1H), 7.36 (br d, J = 7.6 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.07 (s, 1H), 4.58 - 4.38 (m, 2H), 4.36 - 4.17 (m, 2H), 3.76 (br dd, J = 3.2, 7.2 Hz, 1H), 3.67 (br d, J = 3.2 Hz, 1H), 3.15 - 2.89 (m, 4H), 2.24 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H), 1.16 (br d, J = 6.8 Hz, 3H).

[0439] Example 010

[0440] Step 1: To a solution of compound M9 (200 mg, 500.95 μmol), compound M6A (212.11 mg, 751.43 μmol) and trans-N,N-dimethylcyclohexyl-1,2-diamine (427.54 mg, 1.50 mmol) in dioxane (6 mL) was added cuprous iodide (286.22 mg, 1.50 mmol) and cesium carbonate (489.66 mg, 1.50 mmol) under nitrogen atmosphere. The reaction was stirred at 100 °C for 2 h. The reaction was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10 / 1-10 / 1) and then by reverse phase column chromatography (preparative) (column: Phenomenex luna C18 (100 g); mobile phase: [water-(0.1% formic acid)-acetonitrile]; gradient (acetonitrile %): 0%-25%) to give compound 010.

[0441] Step 2: Compound 010 was separated by SFC (column: REGIS (s,s) WHELK-O1 (250 mm*30 mm, 10 μm); mobile phase: A phase: supercritical carbon dioxide, B phase: isopropyl alcohol / acetonitrile (4:1) + 0.1% ammonia; gradient (B%): 25%) to give compound 010A and compound 010B.

[0442] Characterization of compound 010A: LCMS (m / z): 601.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ = 13.61 - 13.36 (m, 1H), 8.90 (s, 1H), 8.58 - 8.48 (m, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.14 (dd, J = 1.8, 8.4 Hz, 1H), 7.75 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 4.62 - 4.43 (m, 4H), 3.77 - 3.66 (m, 1H), 3.55 - 3.45 (m, 1H), 3.19 - 3.10 (m, 4H), 2.30 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H), 1.17 (d, J = 7.0 Hz, 3H); F NMR (376 MHz, DMSO-d6) δ = -60.627; SFC detection (Chiralpak® IC column: (S,S) Whelk-01 50*4.6 mm I.D., 3.5 μm; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), Compound 010A had a retention time of 1.188 min with a chiral purity of 100%. Compound 010B had a retention time of 1.267 min with a chiral purity of 74.87%. + ; 1 H NMR (400 MHz, DMSO-d6) δ = 8.87 (br s, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 8.11 (br d, J = 7.0 Hz, 1H), 7.69 (br s, 1H), 7.46 (br d, J = 8.2 Hz, 1H), 7.17 (s, 1H), 4.55 - 4.40 (m, 4H), 3.70 (br s, 1H), 3.56 - 3.55 (m, 1H), 3.12 (br d, J = 8.6 Hz, 4H), 2.26 (br s, 3H), 1.29 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 7.0 Hz, 3H); F NMR (376 MHz, DMSO-d6) δ = -60.627; SFC detection (Chiralpak® IC column: (S,S) Whelk-01 50*4.6 mm I.D., 3.5 μm; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropyl alcohol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), Compound 010B had a retention time of 1.267 min with a chiral purity of 74.87%.

[0443] Example 011

[0444] Step 1: To a mixture of compound M13 (140 mg, 494.23 pmol) and compound M9 (130 mg, 325.62 pmol) in dioxane (3 mL) and N,N-dimethylacetamide (1 mL) was added (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (97.26 mg, 683.80 pmol), cesium carbonate (265.23 mg, 814.05 pmol) and cuprous iodide (124.03 mg, 651.24 pmol) under nitrogen atmosphere at room temperature. The reaction was stirred at 95 °C for 1 h. The reaction was filtered, the filtrate was concentrated under reduced pressure to give a crude product, which was separated by preparative reversed-phase column chromatography (column: Spherical C18, 40-60 pm, 150 mm x 21.9 mm, column temperature: 30 °C; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50% to 95% in 10 min, then 95% to 100% in 1 min, 100% for 1 min, 100% to 50% in 1 min, 50% for 1 min; flow rate: 15 mL / min) to give compound 011. LCMS (m / z): 602.2 [M+H] Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50% to 95% in 10 min, then 95% to 100% in 1 min, 100% for 1 min, 100% to 50% in 1 min, 50% for 1 min; flow rate: 15 mL / min) to give compound 011. LCMS (m / z): 602.2 [M+H] + .

[0445] Step 2: Compound 011 (75 mg) was separated by SFC preparative (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: isopropyl alcohol / acetonitrile (4: 1) + 0.1% ammonia water; gradient (B%): 40%) to give compound 011A and compound 011B.

[0446] Compound 011A was characterized by LCMS (m / z): 602.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.49 (br s, 1H), 8.50 (br s, 1H), 8.31 (br s, 1H), 8.19 (br d, J = 8.4 Hz, 1H), 7.89 (br d, J = 8.4 Hz, 1H), 7.74 (br s, 1H), 7.21 (br s, 1H), 4.65-4.40 (m, 4H), 3.88-3.81 (m, 1H), 3.69-3.61 (m, 1H), 3.22-3.07 (m, 4H), 2.29 (br s, 3H), 1.36 (br d, J = 6.4 Hz, 3H), 1.24 (br d, J = 6.4 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) d = -65.54; SFC detection (Chromolith Speed ROD column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), retention time of compound 011A: 1.560 min, chiral purity: 100%.

[0447] Compound 011B characterization: LCMS (m / z): 602.1 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) d = 13.48 (br s, 1H), 8.48 (br s, 1H), 8.30 (br s, 1H), 8.19 (br d, J = 8.8 Hz, 1H), 7.88 (br d, J = 8.8 Hz, 1H), 7.73 (br s, 1H), 7.20 (br s, 1H), 4.60-4.41 (m, 4H), 3.89-3.81 (m, 1H), 3.74-3.65 (m, 1H), 3.20-3.06 (m, 4H), 2.28 (br s, 3H), 1.36 (br d, J = 6.4 Hz, 3H), 1.23 (br d, J = 6.4 Hz, 3H); 19 F NMR (376 MHz, DMSO-d6) d = -65.53; SFC detection (Chromolith Speed ROD column: Chiralpak IG-3 50*4.6 mm I.D., 3 pm; mobile phase: A phase: supercritical carbon dioxide, B phase: ethanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), retention time of compound 011B: 1.947 min, chiral purity: 99.22%.

[0448] Control compound

[0449] Biological test data

[0450] Test Example 1: Determination of the effect of a compound on the Apelin receptor

[0451] In this study, a CHO cell line stably expressing the Apelin receptor was used, incubated with different concentrations of test compounds, and the agonistic effect of the compounds on the Apelin receptor was determined by means of the HTRF cAMP kit.

[0452] Experimental method:

[0453] (1) According to the method described in the literature (J. Med. Chem. 2016, 59, 1122-1137), the following compounds were synthesized: Ultra cAMP Kit instruction book to prepare 1x Stimulation Buffer for use.

[0454] (2) Gradient dilution of positive control and test compound to 10 concentrations.

[0455] (3) Culture the stable cell line to 80% confluence, trypsinize to collect cells, count and seed 10 μL / well in a 384-well plate, then Echo655 dispensing, 10 nL per well, and incubate at 37℃ for 10 minutes.

[0456] (4) Continue to dispense 10 nL of 0.6 mM Forskolin, and incubate for 30 minutes to induce cAMP production.

[0457] (5) Dilute Eu-cAMP to 4x working concentration with Detection buffer, and add 4 μL / well to the corresponding experimental wells.

[0458] (6) ULight TM -anti-cAMP antibody is diluted to 4x working concentration with Detection buffer, and 4 μL / well is added to the corresponding experimental wells, and after centrifugation, incubate at room temperature for 1 hour.

[0459] (7) After incubation, use a microplate reader to detect the reading values at 665 nm and 620 nm under excitation at 330 nm. Plot the signal values against the compound concentrations, perform curve fitting and EC 50 calculations.

[0460] The experimental results are shown in Table 1. Wherein, A represents EC 50 ≤1 nM (further A+ represents EC 50 ≤0.1 nM), B represents 1 nM < EC 50 ≤100 nM (further B+ represents 1 nM < EC 50 ≤20 nM), C represents EC 50 >100 nM.

[0461] Conclusion: The compound of the present application can significantly activate the cAMP signal downstream of the Apelin receptor.

[0462] Test Example 2: Effect of test compound on Apelin receptor recruiting β-arrestin 2

[0463] In this study, HEK293T-APJ-βArrestin2 stable cell line was used, and by acting with different concentrations of test compound, Nano- Live Cell Substrates kit, by NanoBiT method to detect the change of fluorescence intensity, to study the ability of the test substance to recruit β-arrestin 2 of human Apelin receptor.

[0464] Test method:

[0465] (1) On the first day, HEK293T-APJ-βArrestin2 cells were cultured to 80% confluence, and the cells were collected by trypsinization treatment, counted and inoculated in 96-well plates (CAT#3603) at 30,000 cells / well, with Opti-MEM+4%FBS as the culture medium, and incubated overnight.

[0466] (2) On the second day, the positive drug and the test compound were gradiently diluted (10 concentrations) with Opti-MEM.

[0467] (3) When the cell density reached about 80%, according to the Live Cell Substrates instructions, the substrate was diluted 20 times, and 20 μL / well was added to the wells and shaken well.

[0468] (4) 10 μL of the diluted 10× compound was added to the corresponding experimental wells, and incubated in the dark for 10 minutes.

[0469] (5) After incubation, the luminescence signal value was read by a microplate reader.

[0470] (6) The signal value was plotted against the compound concentration, and the curve fitting and EC 50 values were calculated by nonlinear regression method using GraphPad Prism software.

[0471] After calculating the EC 50 values of the compound for recruiting β-arrestin 2 and for agonizing the cAMP pathway, the ratio of the two (the EC 50 value of the compound for recruiting β-arrestin 2 divided by the APJ cAMP EC 50 value) was calculated to evaluate the bias of the compound agonism.

[0472] The experimental results are shown in Table 1. Among them, A represents EC 50 ≤1nM (further A+ represents EC 50 ≤0.1nM), B represents 1nM<EC 50 ≤100nM (further B+ represents 1nM<EC 50 <20nM), and C represents EC 50 ​> 100 nM; + means 1 < ratio < 10, ++ means 10 < ratio < 50, +++ means ratio > 50.

[0473] Table 1 Test results of agonistic activity of compounds of the present application on Apelin receptor

[0474] Conclusion: The compounds of the present application can significantly activate the cAMP signal downstream of Apelin receptor; some of the compounds have strong effects on recruiting β-arrestin 2, and are G protein balanced Apelin receptor agonists; and some of the compounds have relatively weak effects on recruiting β-arrestin 2, and are G protein biased Apelin receptor agonists.

[0475] Test Example 3: Thermodynamic solubility experiment

[0476] An appropriate amount of test compound and control compound powder was weighed into a Mini-UniPrep vial, and 450 μL of medium (Na2HPO4 / NaH2PO4 solution at different pH) was added. After adding the medium, the piston of the Mini-UniPrep filter was pressed to the liquid surface, so that the medium and the compound were in full contact during the incubation process, and the sample was vortexed for at least two minutes. Then, the sample was placed on a shaking plate at a speed of 800 rpm for 24 hours at room temperature to achieve solubility equilibrium. After incubation, the sample was placed in a centrifuge and centrifuged at 4000 rpm for 10 minutes at 25°C. The sample after centrifugation was pressed and filtered to obtain the filtrate, which was diluted as needed, and 200 μL of sample solution was transferred to a deep-well 96-well plate. The concentration of the sample filtrate was quantitatively determined by LC-UV, LC-ELSD or LC-MS / MS system. The thermodynamic solubility of the corresponding compound can be calculated according to the determined filtrate concentration.

[0477] The experimental results are shown in Table 2 below. The experimental results show that the compounds of the present application have good solubility at different pH, and the solubility is significantly better than that of the reference compound BGE-105. Specifically, compared with BGE-105, the solubility of compound 001 at each pH is 4.9-11.6 times that of BGE-105, the solubility of compound 005 at each pH is 1.7-10.9 times that of BGE-105, and the solubility of compound 007B at each pH is 3.6-24.4 times that of BGE-105.

[0478] Table 2 Solubility of compounds in sodium phosphate buffer at different pH

[0479] Conclusion: The compounds of the present application have good solubility, which is beneficial to oral administration and formulation development.

[0480] Test Example 4: Plasma protein binding experiment (equilibrium dialysis method)

[0481] The frozen CD-1 mice and human plasma were thawed in flowing cold tap water. After the plasma was completely thawed, it was centrifuged at 3220xg for 5 minutes and the supernatant and precipitate were removed. 597 μL of the above blank plasma of each species was taken, 3 μL of the working solution of the test sample or control sample was added and mixed thoroughly to obtain a plasma sample with a test sample and control sample concentration of 2 μM (n = 1). The concentration of the organic phase DMSO was 0.5%. The sample was mixed thoroughly before proceeding to the next step.

[0482] 50 μL of the plasma sample of the test sample and control sample was taken into the sample receiving plate (n = 3), 50 μL of blank PBS was immediately added, and then 600 μL of the termination solution was added to the T0 sample of the test sample and control sample, respectively, and stored at 2-8°C, waiting for subsequent processing with other dialyzed samples.

[0483] 100 μL of the plasma sample of the test sample and control sample was added to the dosing end of each dialysis well (n = 3), and 100 μL of blank PBS was added to the receiving end corresponding to the dialysis well. The dialysis plate was placed in a 5% CO2incubator and incubated at 37°C with about 100 rpm shaking for 4 hours.

[0484] After dialysis, 50 μL of the dialyzed PBS sample and the dialyzed plasma sample (n = 3) was taken into a new 96-well plate (sample receiving plate). The corresponding volume of the corresponding blank plasma or PBS was added to the sample so that the final volume of each sample well was 100 μL, and the volume ratio of plasma to PBS was 1:1. All samples were subjected to protein precipitation and then analyzed by LC-MS / MS.

[0485] The experimental results show that the binding ratio of compounds 001, 005, and 007B in mouse plasma is greater than 94%, and the binding ratio in human plasma is greater than 98%.

[0486] Conclusion: The plasma protein binding ratio of the compound of the present application in different species of plasma is high, which shows strong binding ability with plasma proteins.

[0487] Test Example 5: Liver microsomal metabolic stability

[0488] The test substance was dissolved in DMSO to prepare a 10 mM DMSO solution, and then diluted with 100% acetonitrile to 100 μM to obtain a working solution (organic phase content: 99% acetonitrile, 1% DMSO).

[0489] Two 96-well incubation plates were prepared and named T60 incubation plate and NCF60 incubation plate, respectively.

[0490] Add 445 μL of microsomes working solution (0.56 mg / mL of liver microsomal protein concentration) to each well of T60 incubation plate and NCF60 incubation plate, respectively, and then pre-incubate the above plates in a 37°C water bath for about 10 minutes.

[0491] After pre-incubation, add 5 μL of test compound or control compound working solution to each well of T60 incubation plate and NCF60 incubation plate, respectively, and mix well.

[0492] Start the reaction by adding 50 μL of potassium phosphate buffer to each well of NCF60 incubation plate, and add 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) and 6 μL of NADPH regenerating system working solution to each well of T0 termination plate, and then take 54 μL of sample from T60 incubation plate to T0 termination plate (T0 sample production). In blank plate, only add 54 μL of microsomes working solution, 6 μL of NADPH regenerating system working solution and 180 μL of stop solution. Start the reaction by adding 44 μL of NADPH regenerating system working solution to each well of T60 incubation plate. Therefore, in the samples of test compound or control compound, the final concentrations of compound, testosterone, diclofenac and propafenone are 1 μM, the concentration of liver microsomes is 0.5 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system are 0.01% (v / v) and 0.99% (v / v), respectively.

[0493] After incubation for a suitable time (e.g. 5, 15, 30, 45 and 60 minutes), add 180 μL of stop solution (200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile) to each well of termination plate, and then take 60 μL of sample from T60 incubation plate or NCF60 incubation plate to terminate the reaction.

[0494] Centrifuge all sample plates at 3220 x g for 20 minutes, and then take 80 μL of supernatant from each well and dilute in 240 μL of pure water for liquid chromatography tandem mass spectrometry analysis. The in vitro elimination rate constant ke of test compound and control compound is obtained by converting the ratio of peak area of compound to internal standard in the following formula into the percentage of remaining. The in vitro liver microsomal intrinsic clearance (CLint) is calculated by ke. int (mic) = 0.693 / T int (mic) = 0.693 / T 1 / 2 / microsomal protein content (mg / mL of microsomal concentration at incubation). The experimental results are shown in Table 3.

[0495] Table 3 Test results of liver microsomal metabolic stability of compounds of the present application

[0496] Conclusion: The compounds of this invention exhibit good metabolic stability in liver microsomes of various genera (especially human).

[0497] Test Example 6: Hepatocyte Metabolic Stability

[0498] Prepare several 96-well sample precipitate plates, named T0, T15, T30, T60, T90, T0-MC, T90-MC, and blank matrix, respectively. Preheat the resuscitation and incubation media in a 37°C water bath. Remove the frozen hepatocytes from the liquid nitrogen container and immediately immerse them in the 37°C water bath (approximately 90 seconds). After the frozen portion has thawed and loosened, pour them into centrifuge tubes containing 40 mL of resuscitation media, gently inverting to resuspend the cells in the resuscitation media. Centrifuge at 100 × g for 5 minutes at room temperature, remove the supernatant, resuspend the hepatocytes in an appropriate volume of incubation media, and calculate cell viability using trypan blue staining. Add 198 μL of the hepatocyte suspension (0.51 × 10⁻⁶ m³ / h) to the centrifuge tubes. 6 (cells / mL) were added to the preheated incubation plate. For the culture medium control group, 198 μL of incubation medium without hepatocytes was added to the T0-MC and T120-MC incubation plates. All incubation plates were pre-incubated in a 37°C incubator for 10 minutes.

[0499] Then add 2 μL of the test sample and control compound working solution, mix well, and immediately place the incubation plate in the shaker inside the incubator and start the timer to begin the reaction. Prepare two replicate samples for each time point of each compound. The incubation conditions are 37°C, saturated humidity, and 5% CO2.

[0500] In the test system, the final concentration of the test sample was 1 μM, the final concentration of the control was 3 μM, and the final concentration of hepatocytes was 0.5 × 10⁻⁶. 6 The final concentration of total organic solvents was 0.96%, with DMSO at a final concentration of 0.1%. At the end of incubation at the corresponding time points, the incubation plate was removed, and 25 μL of the mixture of compound and control compound with cells was added to a sample plate containing 125 μL of stop solution (acetonitrile solution containing 200 ng / mL tolbutamide and labetalol). For blank sample plates, 25 μL of hepatocyte-free incubation medium was added directly. After sealing all sample plates, they were shaken at 600 rpm for 10 minutes on a shaker, followed by centrifugation at 3220 × g for 20 minutes. The supernatants of the test and control samples were diluted with ultrapure water at a ratio of 1:3. All samples were analyzed by LC / MS / MS after mixing.

[0501] Conclusion: The compounds of this invention exhibit good metabolic stability in various types of hepatocytes, showing moderate or slow metabolism.

[0502] Test Example 7: Study on Inhibition of Cytochrome P450 Enzyme (CYP)

[0503] Objective: To determine the inhibitory effect of the test compound on the activity of human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).

[0504] Method: The test compound (10.0 mM) was gradiently diluted to prepare a working solution (100x final concentration) with concentrations (mM) of 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150 and 0.00500, and a working solution of each positive inhibitor of P450 isozyme (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (with midazolam as a probe substrate)) and its specific substrate mixture was prepared; human liver microsomes stored in a refrigerator below -60℃ were thawed on ice, and then dissolved completely, diluted with potassium phosphate buffer (PB) to prepare a working solution with a certain concentration (0.253 mg / mL).

[0505] 20.0 μL of the substrate mixture was added to the reaction plate (20.0 μL of PB was added to the blank well), and then 158 μL of the human liver microsome working solution was added to the reaction plate, which was placed on ice for use; at this time, 2.00 μL of each concentration of the test compound (N=1) and the specific inhibitor (N=2) was added to the corresponding well, and the non-inhibitor (no test compound or positive inhibitor) group was added to the corresponding organic solvent as a control group sample (the test compound control sample was DMSO:MeOH=1:1, and the positive control sample was DMSO:MeOH=1:9); after pre-incubation at 37℃ for 10 min, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate, which was incubated at 37℃ for 10 min; 400 μL of pre-cooled acetonitrile solution (containing an internal standard) was added to terminate the reaction; the reaction plate was placed on a shaker and shaken for 10 min to mix; then it was centrifuged at 4℃ and 4000 rpm for 20 min; 200 μL of supernatant was added to 100 μL of water for sample dilution; finally, the plate was sealed and shaken for 10 min to mix, and then subjected to LC-MS / MS detection.

[0506] The experimental results show that the IC 50 of all the compounds 001 and 007 on human liver microsomal cytochrome P450 isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) is greater than 50 μM.

[0507] Conclusion: The compounds of the present application have no obvious inhibitory effect on the five main cytochrome P450 enzymes of human liver microsomes, and the risk of "drug-drug interaction" is low.

[0508] Test Example 8: hERG test

[0509] CHO cells stably expressing hERG were cultured in 35 mm cell culture dishes in a 37°C, 5% CO2 incubator and passaged every 48 hours at a 1:5 ratio. On the day of the experiment, the cell culture medium was aspirated and the cells were rinsed once with extracellular solution and then treated with 0.25% Trypsin-EDTA (Invitrogen) solution for 3-5 minutes at room temperature. The trypsin solution was aspirated and the cells were resuspended in extracellular solution and then transferred to experimental dishes for electrophysiological recording.

[0510] The test compound was prepared as a 20 mM stock solution in DMSO and then serially diluted 1:3 in DMSO. For each test concentration, 10 μL of the compound DMSO solution was added to 20 μL of DMSO, and then 10 μL of each serially diluted compound DMSO solution was added to 4990 μL of extracellular solution to give a final concentration of 500-fold dilution.

[0511] CHO cells stably expressing hERG potassium channels were used to record hERG potassium currents using the whole-cell voltage clamp technique at room temperature. After obtaining the whole-cell recording, the cells were clamped at -100 mV and a step voltage was applied to induce hERG potassium currents (IhERG) from -100 mV to +20 mV for 2 s, repolarized to -50 mV for 1 s, and then returned to -100 mV. This voltage stimulation was applied every 5 s, and after the hERG potassium current was stable (1 min), the drug administration process was started. Each test concentration of the compound was administered for at least 1 min to reach a steady state or for a maximum of 3 min, and at least 2 cells were tested for each concentration (n≥2).

[0512] Data analysis was performed using pClamp and Excel software. The degree of inhibition of hERG potassium currents (peak hERG tail current induced at -50 mV) by different concentrations of the compound was calculated using the following formula: Inhibition% = [1 - (I / I0)] x 100%. Where Inhibition% represents the inhibition rate of the compound on hERG potassium current, and I and I0 represent the amplitude of hERG potassium current after and before drug administration, respectively. GraphPad Prism 8 was used to plot and calculate IC 50 . The experimental results show that the hERG IC 50 of compounds 001, 005, and 007 are all greater than 40 μM.

[0513] Conclusion: The compounds of the present application have no significant inhibition on hERG.

[0514] Test Example 9: Mouse PK study

[0515] Male C57BL / 6 mice, 6 animals, were divided into 2 groups, 3 animals in each group. The vehicle for intravenous injection (iv) group was 5% DMSO / 50% PEG400 / 45% 5% glucose; the vehicle for oral administration (po) group was 0.5% MC / 0.2% Tween80 / water. Whole blood was collected at 5 min (only iv group), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, respectively, and the whole blood was placed in an anticoagulant tube containing EDTA-K2, and plasma was prepared by centrifugation. The concentration of the test molecule in the plasma was quantitatively detected by LC-MS / MS, and the PK parameters were calculated by Phoenix WinNonlin.

[0516] The experimental results are shown in Table 4. Among them, CL represents the clearance, Vdss represents the distribution volume, T 1 / 2 is the half-life, AUC 0-last represents the area under the whole blood concentration-time curve from 0 to the last quantifiable time point; and F represents the bioavailability.

[0517] Table 4. PK test results of the compound of the present application in mice

[0518] Conclusion: The compound of the present application exhibits high oral exposure and good bioavailability in mouse PK, and has excellent pharmacokinetic properties.

[0519] Test Example 10: Rat PK study

[0520] Male SD rats, 6 animals, were divided into 2 groups, 3 animals in each group. The vehicle for intravenous injection (iv) group was 5% DMSO / 50% PEG400 / 45% 5% glucose; the vehicle for oral administration (po) group was 0.5% MC / 0.2% Tween80 / water. Whole blood was collected at 5 min (only iv group), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, respectively, and the whole blood was placed in an anticoagulant tube containing EDTA-K2, and plasma was prepared by centrifugation. The concentration of the test molecule in the plasma was quantitatively detected by LC-MS / MS, and the PK parameters were calculated by Phoenix WinNonlin.

[0521] The experimental results are shown in Table 5. The experimental results show that the compound of the present application has very high oral exposure and oral bioavailability, which is significantly better than BGE-105. Specifically, the oral exposure of compound 001 is 2.9 times that of BGE-105, the dose-normalized oral exposure of compound 004A is 2.8 times that of BGE-105, and the oral bioavailability of compounds 001, 004A and 007B is 1.3 times, 2.5 times and 2.2 times that of BGE-105, respectively.

[0522] Table 5. PK test results of the compound of the present application in rats

[0523] Conclusion: The compounds of the present application all exhibit lower clearance, longer half-life, higher oral exposure and higher oral bioavailability in rat PK, and have excellent pharmacokinetic properties.

[0524] Test Example 11: Dog PK study

[0525] Male beagle dogs, 6, were divided into 2 groups, 3 animals in each group. The iv group solvent was normal saline; the po group solvent was 0.5% MC / 0.2% Tween80 / water. Whole blood was collected at 5 min (only iv group), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration, and the whole blood was placed in an anticoagulant tube containing EDTA-K2, and centrifuged to prepare plasma. The concentration of the test molecule in the plasma was quantitatively detected by LC-MS / MS, and the PK parameters were calculated by Phoenix WinNonlin.

[0526] The experimental results are shown in Table 6. The experimental results show that the compounds of the present application have low clearance, long half-life, high oral exposure, and high oral bioavailability, which are significantly better than BGE-105. Specifically, the clearance of compounds 001 and 007B is low (about 55% of BGE-105), the oral exposure is high (2.7 times and 4.8 times of BGE-105, respectively), and the oral bioavailability is high (1.5 times and 2.7 times of BGE-105, respectively).

[0527] Table 6: Dog PK test results of the compounds of the present application

[0528] Conclusion: The compounds of the present application all exhibit lower clearance, longer half-life, higher oral exposure and higher oral bioavailability in dog PK, and have excellent pharmacokinetic properties.

[0529] Test Example 12: In vivo efficacy (I)

[0530] Purpose of the experiment:

[0531] The efficacy of the test compound in combination with semaglutide in a diet-induced obesity (DIO) mouse model.

[0532] Experimental method:

[0533] 6-week-old male C57BL / 6J mice were fed with high-fat granular feed for 16 weeks, and the body weight was greater than 50 grams. After one week of adaptive feeding, the experiment started (recorded as Day 0), and the body weight and food remaining were weighed in the morning of Day 0, and the body fat of the animals was detected by MRI. After the body fat detection, the animals were changed to cages and fasted, and the fasting blood glucose of the animals was detected after 6 hours. Then, the DIO mice were grouped according to the body weight, fasting blood glucose, and body fat results: DIO model control group (Vehicle group) and test group. At the same time, C57BL / 6 mice were selected as the normal control group (Normal group) according to the body weight, FBG (fasting blood glucose), and body fat results.

[0534] Day 1 started dosing, and the dosing time was 21 days. The Normal group and the Vehicle group were the dosing vehicle; test group 1: Semaglutide was dissolved in normal saline and injected subcutaneously, and the dosing dose was 10 nmol / kg, once every three days; test group 2: the compound was dissolved in the vehicle, and the concentration was 1.1 g / L, and the continuous free water administration was performed every day. The specific dosing scheme is shown in Table 7. The body weight of the mice was recorded every day, and the food intake / water intake was recorded, and then the body fat (Day 20) and fasting blood glucose (Day 17) of the mice were detected at the end of the experiment.

[0535] Table 7: Dosing scheme of in vivo efficacy

[0536] The experimental results are shown in Table 8, and the body weight changes of the mice are shown in Figure 1. The experimental results show that, compared with the DIO model control group, the combination of compound 001 and Semaglutide can further significantly reduce the body weight, and the weight loss effect is better than that of Semaglutide alone. At the same time, the combination of compound 001 and Semaglutide can further reduce the fat / body weight ratio of the animals, and increase the lean body weight / body weight ratio and the lean body weight / fat weight ratio, and the effect is better than that of Semaglutide alone. The combination of compound 001 and Semaglutide can also further reduce the fasting blood glucose level of the animals.

[0537] Table 8: Test results of body composition of mice in the in vivo efficacy experiment combined with Semaglutide

[0538] Note: All data are presented as mean ± standard error, *P<0.05, ****P<0.0001, compared with test group 1, One-Way ANOVA.

[0539] Conclusion: In the diet-induced obesity (DIO) model, the compound of the present application combined with Semaglutide can further significantly reduce body weight, improve body composition, and further reduce the fasting blood glucose level of animals, showing good in vivo efficacy, and the efficacy of combination is significantly better than that of Semaglutide alone.

[0540] Test Example 13: In vivo efficacy (two)

[0541] Purpose of the experiment:

[0542] The efficacy of the test compound combined with Semaglutide in the diet-induced obesity (DIO) model of mice.

[0543] Experimental method:

[0544] After 16 weeks of feeding high-fat granular feed to 6-week-old male C57BL / 6J mice, the body weight is greater than 50 grams, and the mice are used for the test. After one week of adaptive feeding, the experiment begins (recorded as Day 0), and the body weight and food remaining are weighed in the morning on Day 0, and the animal body fat is detected using MRI. After the body fat detection is completed, the animals are changed to cages and fasted, and the fasting blood glucose of the animals is detected after 6 hours. Then, according to the body weight, fasting blood glucose, and body fat results, the DIO mice are grouped: DIO model control group (Vehicle group) and test group. At the same time, according to the body weight, FBG (fasting blood glucose), and body fat results, C57BL / 6 mice are selected as the normal control group (Normal group).

[0545] Day 1 starts the administration, and the administration time is 21 days. The Normal group and the Vehicle group are the administration vehicle; the specific administration scheme of the control group and the test group is shown in Table 9. The body weight of the mice is weighed and recorded every day, and the food and water intake is recorded, and then the body fat (Day 18) and fasting blood glucose (Day 17) of the mice are detected.

[0546] Table 9: In vivo efficacy administration scheme

[0547] The experimental results are shown in Table 10, and the weight change of the mice is shown in Figure 2. The experimental results show that, compared with the DIO model control group, the compound 001 combined with Semaglutide can further significantly reduce the body weight, reduce the fat / body weight ratio of the animals, and increase the lean body weight / body weight ratio and the lean body weight / fat weight ratio, and present a dose-dependent effect, and the weight loss effect is better than that of Semaglutide alone; the weight loss effect of the administration of 0.55 g / L of the compound 001 is equivalent to that of 1.1 g / L of BGE-105, and the weight loss effect of the administration of the same dose (1.1 g / L) of the compound 001 is significantly better than that of BGE-105. At the same time, the compound 001 combined with Semaglutide can further reduce the fasting blood glucose level of the animals.

[0548] Table 10: Test results of body composition and blood glucose of mice in in vivo pharmacodynamic experiments

[0549] Note: All data are presented as mean ± standard error, *P < 0.05, **P < 0.01, ****P < 0.0001, compared with test group 1, One-Way ANOVA.

[0550] Conclusion: The compound of the present application combined with Semaglutide in the diet-induced mouse obesity (DIO) model can further significantly reduce the body weight, improve the body composition, and further reduce the fasting blood glucose level of the animals, and exhibits good in vivo pharmacodynamic effect, and the pharmacodynamic effect under the same dose is significantly better than that of BGE-105.

Claims

a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is an optionally substituted 5-membered heteroaryl a substituted 5-membered heteroaryl; Ring B is selected from C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl, and 5-10 membered heteroaryl; L1is absent, or, L1is selected from O, S, NR7, and optionally substituted C L1 substituted C 1-4 alkyl; L2is selected from the group consisting of optionally substituted C L2 alkyl, C 1-6 alkenyl, C 2-4 alkynyl, C 2-4 alkyl-C 0-3 cycloalkyl-C 3-10 alkyl and C 0-3 alkyl and C 0-3 alkyl-3-10 membered heterocycloalkyl-C 0-3 alkyl, wherein L2is attached to S via a carbon atom; X is O or NR8; R1is selected from optionally substituted phenyl, 5-10 membered heteroaryl, C 1a substituted phenyl, 5-10 membered heteroaryl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl; R2is selected from H, D, F, CI, Br, I, CN, and optionally substituted phenyl, 5-10 membered heteroaryl, C 2a substituted phenyl, 5-10 membered heteroaryl, C 3-8 cycloalkyl, and 3-8 membered heterocycloalkyl; Each R3, each R4, and each R5 is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, SF5, and optionally by one or more R 3a The following groups are substituted: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; Alternatively, two R3s connected together form a configuration that can be optionally bounded by one or more Rs. 3b The following groups are substituted: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; or two R4are joined together to form an optionally substituted 4b substituted C 4-8 cycloalkyl, 4-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; R6, R7and R8are each independently selected from H and optionally substituted with 1 or more R 6a substituted C 1-4 alkyl, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl; Each R a The following groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl; each R L1 and each R L2 The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; each R 1a , each R 2a is independently selected from H, D, F, CI, Br, I, =0, OH, NH2, CN, SF5, and the following groups optionally substituted with 1 or more R: C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, -NHCO-C 1-4 alkyl, -CONH-C 1-4 alkyl, and -CO-C 1-4 alkyl; each R 3a , each R 3b , each R 4b , each R 6a is independently selected from H, D, F, Cl, Br, I, =0, OH, NH2, CN, SF5, and an optionally substituted group selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl; or 2 R 1a connected together, or 2 R 2a connected together, each independently form the following group optionally substituted with 1 or more R: C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; Each R is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, SF5, and the following groups optionally substituted with one or more F: C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Alkylamino, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups; m, n, p are each independently selected from 0, 1, 2 and 3; provided that when ring A is when X is O, any one of the following conditions is met: 1) two R3are joined together to form an optionally substituted C 3b substituted C 4-8 cycloalkyl or 4-8 membered heterocycloalkyl; 2) two R3are joined together to form an optionally substituted phenyl or 5-6 membered heteroaryl 3b substituted phenyl or 5-6 membered heteroaryl, and two R4are joined together to form an optionally substituted phenyl or 5-6 membered heteroaryl 4b substituted phenyl or 5-6 membered heteroaryl. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R is independently selected from H, D, F, Cl, OH, NH2, CN, CH3and CF3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R a are each independently selected from the group consisting of H, D, F, CI, Br, I, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3, and cyclopropyl; further, each R a are each independently selected from the group consisting of H, D, F, CI, CH3, and CF3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R L2 are each independently selected from the group consisting of H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, and cyclopropyl; further, each R L2 are each independently selected from the group consisting of H, D, F, CI, CH3, CF3, and CH2CN. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, Each R 1a The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, -COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, and aziridine; further, each R 1a Each of the following is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, -COCH3, -COCF3, CH3, CH2F, CHF2, CF3, CD3, CH2CH3, CH2CF3, CF2CH3, OCH3, OCF3, OCD3, OCH2CH3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, Each R 2a The following groups are independently selected from H, D, F, Cl, Br, I, =O, OH, NH2, CN, and optionally substituted with one or more R groups: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, -COCH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, and aziridine; further, each R 2a Each of the following is independently selected from H, D, F, Cl, Br, I, OH, NH2, CN, -COCH3, -COCF3, -COCD3, CH3, CH2F, CHF2, CF3, CD3, CH2CH3, CH2CF3, CF2CH3, OCH3, OCF3, OCD3, OCH2CH3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, each R 3a , each R 3b , each R 4b , each R 6a is independently selected from the group consisting of H, D, F, CI, Br, I, =0, OH, NH2, CN, and the following groups optionally substituted with 1 or more R: CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, and azetidinyl; further, each R 3a , each R 3b , each R 4b , each R 6a is independently selected from the group consisting of H, D, F, CI, Br, I, OH, NH2, CH3, CH2CH3, OCH3and OCH2CH3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, R1is selected from the group consisting of optionally substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; further, R1is selected from the group consisting of 1a substituted phenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl; further, R1is selected from the group consisting of The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R2 is selected from one or more R2 values. 2a Substituted groups include: phenyl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic alkyl groups; further, R2 is selected from those optionally surrounded by one or more R groups. 2a The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, pyridopyrroleyl, pyrimidopyrroleyl, and 4-12 membered heterocyclic alkyl groups; furthermore, R2 is selected from... The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, each R3, each R4, and each R5is independently selected from H, D, F, Cl, Br, I, OH, NH2, and optionally substituted with one or more R 3a substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted with one or more R substituted The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, two R3on adjacent atoms together with the atoms to which they are attached form a 5- to 7-membered ring containing zero to 3 heteroatoms selected from N, O, and S, and optionally substituted with 1 or more R 3b substituted with one or more R The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, two R4on adjacent atoms together with the atoms to which they are attached form a 5- to 7-membered ring containing 0-2 heteroatoms selected from the group consisting of O, N, and S, and optionally substituted with 1 or more R 4b substituted with 1 or more R4; further, two R4on adjacent atoms together with the atoms to which they are attached form a 5- to 7-membered ring containing 0-2 heteroatoms selected from the group consisting of O, N, and S, and optionally substituted with 1 or more R The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1, wherein, Ring B is selected from phenyl and 5-6 membered heteroaryl; further, Ring B is selected from phenyl, pyridyl and pyrimidyl; still further, Ring B is selected from phenyl. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, Structural unit selected from the group consisting of wherein T1is selected from CR5and N, T2, T3, T4, T5are each independently selected from C and N, ring C1and ring C2are each independently selected from an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring, wherein the carbocyclyl or heterocyclyl ring is optionally substituted with 1 or more R 3b substituted C 5-8 saturated cycloalkyl, C 5-8 cycloalkenyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; further, structural unit selected from the group consisting of Still further, the structural unit For The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, L2is selected from the group consisting of optionally substituted CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, CH(CH3)CH(CH3), CH=CH, CH2CH=CH, L2 substituted CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, CH(CH3)CH(CH3), CH=CH, CH2CH=CH, C 3-6 cycloalkyl and CH2-C 3-8 cycloalkyl; further, L2is selected from CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3); still further, L2is selected from CH2CH2, The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, Ring A is selected from Further, ring A is selected from wherein, 1 is connected with Ring B. The compound, stereoisomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 16, is selected from: wherein, T1is selected from CR5and N; T2, T3, T4, T5are each independently selected from C and N; Rings C1and C2are each independently selected from an optionally substituted 3b substituted C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 3- to 6-membered 5-8 substituted C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 3- to 6-membered Rings A, X, R1, R2, R5, R 3b L2 is as defined in any one of claims 1 to 16. The compound of formula (I-3) or (I-6), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 17, wherein: T1is selected from CH and N; further, T1is selected from CH; T2, T3, T4, T5are each independently selected from C and N; further, T2, T3, T4, T5are each independently selected from C; Ring C1 and ring C2 are independently selected from C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl; furthermore, the C1 and C2 rings are each independently selected from 5-8 membered heterocycloalkyl groups; Ring A is selected from 1,2,4-triazolyl; X is selected from O and NH; further, X is selected from O; R1 is selected from one or more R1s. 1a Substituted 5-6 aryl groups; R2 is selected from any 1, 2, 3, 4 or 5 Rs. 2a The following groups are substituted: phenyl and 5-6 membered heteroaryl groups; each R is independently selected from the group consisting of H, D, F, Cl, CN, and C1-6alkyl optionally substituted with 1 or more R; 1a each R is independently selected from the group consisting of H, D, F, Cl, CN, and C1-6alkyl optionally substituted with 1 or more R; 1-3 C1-6alkyl; each R is independently selected from the group consisting of H, D, F, Cl, CN, and C1-6alkyl optionally substituted with 1 or more R; 2a each R is independently selected from the group consisting of H, D, F, Cl, CN, and C1-6alkyl optionally substituted with 1 or more R; 1-3 C1-6alkyl; L2 is selected from one or more Rs. L2 Replacement C 1-3 Alkyl groups, each R L2 The group L2 is independently selected from H, D, F, Cl, CN, and optionally substituted with one or more R groups: methyl, ethyl, methoxy, and ethoxy; further, L2 is selected from CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3); even further, L2 is selected from CH2CH2, The compound of formula (I-3) or (I-6), stereoisomer thereof, or pharmaceutically acceptable salt thereof according to claim 18, is selected from: wherein r is selected from 1 and 2; Ring C1, Ring C2, T1, T2, T3, T4, T5, R1, R2, R L2 As defined in claim 18. The compound of formula (I-7), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 19, is selected from: wherein, r is selected from 1 and 2; E1 and E2 are independently selected from -CH2CH2O- and -CH2CH2O-, respectively. ＝ CHO-, -CH2CH2S- and -CH ＝ CHS-; R1, R2, R5, R L2 As defined in claim 19. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 20, is selected from: wherein is selected from single bond and double bond; E3and E4are each independently selected from O and S; R1, R2are as defined in claim 20. a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as shown in Table A and / or Table A1. Use of a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 22 in the manufacture of a medicament for the treatment of a disease associated with an agonist of the Apelin receptor.

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