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

Abstract

The present application provides a series of substituted 1,2,4-triazole derivatives and their applications, and specifically provides a compound shown in formula (I) and a pharmaceutically acceptable salt thereof.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to two earlier patent applications filed with the China National Intellectual Property Administration on August 9, 2024 (application number CN2024110992280) and on May 16, 2025 (application number CN2025106426078), the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a series of substituted 1,2,4-triazole derivatives and their applications, particularly to compounds of formula (I) or (I-3), their stereoisomers, and pharmaceutically acceptable salts thereof. Background Technology

[0004] Apelin receptor (APJ) is a member of the G protein-coupled receptor (GPCR) family. Apelin is an endogenous ligand of APJ, which can simultaneously activate downstream G proteins and β-arrestin pathways, thereby exerting a wide range of physiological effects. The Apelin / APJ system is present in many tissues (e.g., heart, kidney, pancreas, lung, vascular system, central nervous system, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma), possessing a wide range of physiological functions and participating in various pathological processes. The Apelin / APJ system plays an important regulatory role in cardiovascular, metabolic, and muscle health. In the cardiovascular system, it regulates angiogenesis, vasodilation and vasoconstriction, as well as cardiac contraction. Furthermore, multiple studies have demonstrated the significant regulatory effect of Apelin on muscle metabolism and function; aged mice with knockout of the Apelin or its receptor (APLNR) gene showed significantly reduced muscle function. Apelin secretion decreases in an age-dependent manner, and restoring reduced Apelin levels can greatly enhance muscle function. Other studies have shown that Apelin / APJ also plays an important regulatory role in the metabolic system, regulating food intake, glucose uptake, lipid metabolism, and muscle metabolism. Due to the vital physiological functions of the Apelin / APJ system, its dysregulation is also involved in the development of various diseases. For example, studies have shown that Apelin has the potential to treat heart failure, muscle weakness, pulmonary hypertension, nonspecific pulmonary fibrosis, and disorders of glucose and lipid metabolism; the Apelin / APJ system is associated with 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]

[0008] in,

[0009] Ring A is arbitrarily selected by 1 or 2 Rs a Substituted 5-membered heteroaryl groups;

[0010] Ring B is selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0011] 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;

[0012] 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, C0-3 Alkyl-C 3-10 cycloalkyl-C 0-3 Alkyl and C 0-3 Alkyl-3-10 heterocyclic alkyl-C 0-3 Alkyl group, wherein L2 is bonded to S via a carbon atom;

[0013] X is either O or NR8;

[0014] 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;

[0015] R2 is selected from H, D, 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;

[0016] 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;

[0017] 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;

[0018] 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;

[0019] R6, R7, and R8 are independently selected from H and arbitrarily 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;

[0020] Each R aThe 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;

[0021] Each R 1a Each R 2a The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, 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, 5-6 membered heteroaryl, -NHCO-C 1-4 Alkyl, -CONH-C 1-4 Alkyl and -CO-C 1-4 alkyl;

[0022] Each R 3a Each R 3b Each R 4b Each R 6a The following groups are selected independently from H, D, F, Cl, Br, I, =O, OH, NH2, CN, SF5, 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 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0023] 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;

[0024] 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;

[0025] m, n, and p are independently selected from 0, 1, 2, and 3, respectively;

[0026] The condition is that when ring A is When X is 0, any one of the following conditions must be met:

[0027] 1) Two R3s connected together form an array that can be optionally bounded by one or more Rs 3b Replacement C 4-8 cycloalkyl or 4-8 membered heterocyclic alkyl;

[0028] 2) Two R3s connected together form an array that can be optionally bounded by one or more Rs. 3b Substituted phenyl or 5-6-membered heteroaryl groups, wherein two R4 groups are linked together to form an optional R4 group. 4b Substituted phenyl or 5-6 heteroaryl groups.

[0029] In some technical solutions of the present invention, each of the above R is independently selected from H, D, F, Cl, OH, NH2, CN, CH3 and CF3, and other variables are as defined in the present invention.

[0030] In some technical solutions of the present invention, each of the above R is independently selected from H, F, Cl, OH, NH2, CN, CH3 and CF3, and other variables are as defined in the present invention.

[0031] In some technical solutions of the present invention, each of the above R is independently selected from F, and other variables are as defined in the present invention.

[0032] In some technical solutions of the present invention, the above-mentioned R aThe groups are independently selected from H, D, F, Cl, Br, I, OH, NH2, CN and the following groups optionally substituted with one or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3 and cyclopropyl, with other variables as defined in this invention.

[0033] In some technical solutions of the present invention, the above-mentioned R a The groups are independently selected from H, F, Cl, Br, I, OH, NH2, CN and the following groups optionally substituted with one or more R: CH3, CH2CH3, vinyl, ethynyl, OCH3, OCH2CH3 and cyclopropyl, with other variables as defined in this invention.

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

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] In some technical solutions of the present invention, the above-mentioned R L2 The variables are independently selected from H, F, Cl, CH3, CF3 and CH2CN, respectively, and other variables are as defined in this invention.

[0042] In some technical solutions of the present invention, the above-mentioned R 1a Each R 2a Each R 3a Each R 3b Each R 4b Each R 6a 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, C(CH3)3, vinyl, ethynyl, OCH3, OCH2CH3, OC(CH3)2, SCH3, SCH2CH3, NHCH3, NHCH2CH3, N(CH3)2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxacyclobutyl, and aziridine, with other variables as defined in this invention.

[0043] In some technical solutions of the present invention, the above-mentioned R 1a Each R 2a Each R 3a Each R 3b Each R 4b Each R 6a Each of the following is independently selected from H, D, F, Cl, Br, I, OH, NH2, CH3, CH2CH3, OCH3 and OCH2CH3, and other variables as defined in this invention.

[0044] In some technical solutions of the present invention, the above-mentioned R 1aThe 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, 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, with other variables as defined in this invention.

[0045] In some technical solutions of the present invention, the above-mentioned 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. Other variables are as defined in this invention.

[0046] In some technical solutions of the present invention, the above-mentioned R 1a The components are independently selected from H, D, F, Cl, CN, and C, which are optionally substituted by one or more R. 1-3 Alkyl groups, and other variables as defined in this invention.

[0047] In some technical solutions of the present invention, the above-mentioned R 1a Each is independently selected from C, which is arbitrarily replaced by one or more R. 1-3 Alkyl groups, and other variables as defined in this invention.

[0048] In some technical solutions of the present invention, the above-mentioned R 1a Each is independently selected from C, which is arbitrarily replaced by one or more D, F, or CN. 1-3 Alkyl groups, and other variables as defined in this invention.

[0049] In some technical solutions of the present invention, the above-mentioned R 1a Each is independently selected from methyl or ethyl groups optionally substituted with one or more D or F, and other variables are as defined in this invention.

[0050] In some technical solutions of the present invention, the above-mentioned R 1a Each is independently selected from methyl or ethyl, and other variables are as defined in this invention.

[0051] In some technical solutions of the present invention, the above-mentioned R 2aThe 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, 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, with other variables as defined in this invention.

[0052] In some technical solutions of the present invention, the above-mentioned 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. Other variables are as defined in this invention.

[0053] In some technical solutions of the present invention, the above-mentioned R 2a The components are independently selected from H, D, F, Cl, CN, and C, which are optionally substituted by one or more R. 1-3 Alkyl groups, and other variables as defined in this invention.

[0054] In some technical solutions of the present invention, the above-mentioned R 2a Each is independently selected from C, which is arbitrarily replaced by one or more R. 1-3 Alkyl groups, and other variables as defined in this invention.

[0055] In some technical solutions of the present invention, the above-mentioned R 2a Each is independently selected from C, which is arbitrarily replaced by one or more F or CN. 1-3 Alkyl groups, and other variables as defined in this invention.

[0056] In some technical solutions of the present invention, the above-mentioned R 2a Each is independently selected from C, which is arbitrarily replaced by one or more D, F, or CN. 1-3 Alkyl groups, and other variables as defined in this invention.

[0057] In some technical solutions of the present invention, the above-mentioned R 2a Each is independently selected from methyl or ethyl groups optionally substituted with one or more D or F, and other variables are as defined in this invention.

[0058] In some technical solutions of the present invention, the above-mentioned R 2aEach is independently selected from methyl or ethyl groups optionally substituted with one or more F groups, and other variables are as defined in this invention.

[0059] In some technical solutions of the present invention, the above two Rs 1a Together with the atoms attached to them, they form the following groups, which may be optionally substituted with one or more R groups: Other variables are as defined in this invention.

[0060] In some technical solutions of the present invention, the above two Rs 1a Together with the atoms they are connected to form Other variables are as defined in this invention.

[0061] In some technical solutions of the present invention, the above two Rs 2a Together with the atoms they are connected to form The Each variable can be independently and arbitrarily replaced by one or more R variables, and other variables are as defined in this invention.

[0062] In some technical solutions of the present invention, the above two Rs 2a The atoms they are connected together form Other variables are as defined in this invention.

[0063] In some technical solutions of the present invention, the above-mentioned R1 is selected from one or more R1s. 1a The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrroleyl, thiazolyl, oxazolyl, indolyl, inzolyl, benzimidazolyl, benzopyrazolyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and morpholinyl, with other variables as defined in this invention.

[0064] In some technical solutions of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0065] In some technical solutions of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0066] In some technical solutions of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0067] In some technical solutions of the present invention, the above-mentioned R1 is optionally represented by one or more R... 1a Substituted phenyl or 5-6 heteroaryl groups, other variables as defined in this invention.

[0068] In some technical solutions of the present invention, the above-mentioned R1 is optionally represented by one or more R... 1a The substituted 5-6 heteroaryl groups, and other variables as defined in this invention.

[0069] In some technical solutions of the present invention, the above-mentioned R1 is selected from one or more R1s. 1a The following groups may be substituted: pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, pyrazolyl, thiazolyl, and oxazolyl, with other variables as defined in this invention.

[0070] In some technical solutions of the present invention, the above-mentioned R1 is selected from one or more R1s. 1a The following groups may be substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, with other variables as defined in this invention.

[0071] In some technical solutions of the present invention, the above-mentioned R1 is selected from one or more R1s. 1a The following groups may be substituted: pyridinyl and pyridazinyl, and other variables as defined in this invention.

[0072] In some technical solutions of the present invention, the above-mentioned R1 is selected from one or more R1s. 1a The substituted pyridinyl group, and other variables as defined in this invention.

[0073] In some technical solutions of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0074] In some technical solutions of the present invention, R1 is selected from... Other variables are as defined in this invention.

[0075] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2a Substituted groups include: phenyl, 5-10 heteroaryl, C 3-8 Cycloalkyl and 4-12 membered heterocyclic alkyl groups, other variables as defined in this invention.

[0076] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2a The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, benzimidazolyl, pyridopyrroleyl, and 4-12 membered heterocyclic alkyl groups, with other variables as defined in this invention.

[0077] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2aThe following groups may be substituted: phenyl and 5-10 heteroaryl groups, and other variables as defined in this invention.

[0078] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2a Substituted phenyl or 5-6 heteroaryl groups, other variables as defined in this invention.

[0079] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2a The substituted 5-6 heteroaryl groups, and other variables as defined in this invention.

[0080] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2a The following groups are substituted: R2 is selected from those optionally replaced by one or more R groups. 2a The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, benzimidazolyl, benzothiazolyl, benzopyrazolyl, pyridopyrroleyl, pyrimidopyrroleyl and 4-12 membered heterocyclic alkyl groups, and other variables as defined in this invention.

[0081] In some technical solutions of the present invention, the R2 is selected from H, F, Cl, Br, I, CN, and optionally one or more R 2a The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, oxazolyl, and thiazolyl, with other variables as defined in this invention.

[0082] In some technical solutions of the present invention, the above-mentioned R2 is selected from one or more R... 2a The following groups may be substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, pyrazolyl, pyrroleyl, thiazolyl, and oxazolyl, with other variables as defined in this invention.

[0083] In some technical solutions of the present invention, R2 is optionally replaced by one or more R 2a The substituted pyrimidinyl, pyridinyl, pyrazinyl, and pyridazinyl groups, and other variables as defined in this invention.

[0084] In some technical solutions of the present invention, R2 is optionally replaced by one or more R 2a The substituted pyrimidin group, and other variables as defined in this invention.

[0085] In some technical solutions of the present invention, R2 is optionally represented by 1, 2 or 3 Rs. 2a The substituted pyrimidin group, and other variables as defined in this invention.

[0086] In some technical solutions of the present invention, R2 is a pyrimidinyl group that is optionally substituted with 1, 2 or 3 F groups, and other variables are as defined in the present invention.

[0087] In some technical solutions of the present invention, R2 is selected from... Other variables are as defined in this invention.

[0088] In some technical solutions of the present invention, R2 is selected from... Other variables are as defined in this invention.

[0089] In some technical solutions of the present invention, R2 is selected from... Other variables are as defined in this invention.

[0090] In some technical solutions of the present invention, R2 is... Other variables are as defined in this invention.

[0091] In some technical solutions of the present invention, R2 is... Other variables are as defined in this invention.

[0092] In some technical solutions of the present invention, R2 is selected from H, F, Cl, Br, I and CN, and other variables are as defined in the present invention.

[0093] In some technical solutions of the present invention, R2 is selected from H, F and CN, and other variables are as defined in the present invention.

[0094] In some technical solutions of the present invention, each of R3, R4 and R5 is independently selected from H, D, F, Cl, Br, I, OH, NH2 and optionally selected by one or more R 3a The following groups may be substituted: 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, oxacyclobutyl, and aziridine, with other variables as defined in this invention.

[0095] In some technical solutions of the present invention, each of R3, R4 and R5 is independently selected from H, D, F, Cl, Br, I, OH, NH2, CH3, OCH3, CD3, OCD3, CF3 and OCF3, and other variables are as defined in the present invention.

[0096] In some technical solutions of the present invention, each of R3, R4 and R5 is independently selected from H, F, Cl, Br, I, OH, NH2, CH3, OCH3, CF3 and OCF3, and other variables are as defined in the present invention.

[0097] In some technical solutions of the present invention, the two R3s on the adjacent atoms, together with the atoms they are connected to, form a structure optionally bounded by one or more Rs. 3b The following groups are substituted: Other variables are as defined in this invention.

[0098] In some technical solutions of the present invention, the two R3s on the adjacent atoms together with the atoms they are connected to form Other variables are as defined in this invention.

[0099] In some technical solutions of the present invention, the two R3s on the adjacent atoms, together with the atoms they are connected to, form a configuration optionally bounded by 1, 2, 3, 4, or 5 Rs. 3b The following groups may be substituted: oxepyl, oxepenyl, thioepyl or thioepenyl, and other variables as defined in this invention.

[0100] In some technical solutions of the present invention, the two R3s on the adjacent atoms together with the atoms they are connected to form Other variables are as defined in this invention.

[0101] In some technical solutions of the present invention, the two R3s on the adjacent atoms together with the atoms they are connected to form Other variables are as defined in this invention.

[0102] In some technical solutions of the present invention, the two R4s on the adjacent atoms, together with the atoms they are connected to, form a structure optionally bounded by one or more R4s. 4b The following groups are substituted: Other variables are as defined in this invention.

[0103] In some technical solutions of the present invention, the two R4 atoms on the adjacent atoms are formed together with the atoms they are connected to. Other variables are as defined in this invention.

[0104] In some technical solutions of the present invention, the two R4s on the adjacent atoms, together with the atoms they are connected to, form a structure optionally bounded by one or more R4s.4b The following groups may be substituted: oxepyl, oxepylenyl, thioepyl or thioepylenyl, and other variables as defined in this invention.

[0105] In some technical solutions of the present invention, the two R4 atoms on the adjacent atoms are formed together with the atoms they are connected to. Other variables are as defined in this invention.

[0106] In some technical solutions of the present invention, the two R4 atoms on the adjacent atoms are formed together with the atoms they are connected to. Other variables are as defined in this invention.

[0107] In some technical solutions of the present invention, the two R3s on the adjacent atoms, together with the atoms they are connected to, form a configuration optionally bounded by 1, 2, 3, 4, or 5 Rs. 3b The following groups are substituted: oxepyl, oxepenyl, thioepenyl, or thioepenyl, with two R4 groups on adjacent atoms forming a group optionally substituted by 1, 2, 3, 4, or 5 R4 groups. 4b The following groups may be substituted: oxepyl, oxepenyl, thioepyl or thioepenyl, and other variables as defined in this invention.

[0108] In some technical solutions of the present invention, the two R3s on the adjacent atoms together with the atoms they are connected to form The two R4 atoms on adjacent atoms together with the atoms they are connected to form Other variables are as defined in this invention.

[0109] In some technical solutions of the present invention, the above-mentioned ring B is selected from phenyl and 5-6-membered heteroaryl groups, and other variables are as defined in the present invention.

[0110] In some technical solutions of the present invention, the above-mentioned ring B is selected from phenyl, pyridyl and pyrimidinyl, and other variables are as defined in the present invention.

[0111] In some technical solutions of this invention, the ring B is selected from phenyl, and other variables are as defined in this invention.

[0112] In some technical solutions of the present invention, the above-mentioned structural unit Selected from E1 and E2 are each independently selected from one or more R. 3b The following groups are substituted: -CH2CH2O-, -CH ＝ CHO-、-N ＝ CHO-、-CH＝ NO-, -CH2OCH2-, -CH2CH2S-, -CH ＝ CHS-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-, with other variables as defined in this invention.

[0113] In some technical solutions of the present invention, E1 and E2 are each independently selected from one or more R. 3b The following groups are substituted: -CH2CH2O-, -CH ＝ CHO-、-N ＝ CHO-、-CH ＝ NO-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH-, and -CH2NHCH2-, with other variables as defined in this invention.

[0114] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Wherein, T1 is selected from CR5 and N; T2, T3, T4, and T5 are independently selected from C and N respectively; ring C1 and ring C2 are independently selected from one or more Rs. 3b The following groups are substituted: C 5-8 Saturated cycloalkyl, C 5-8 Cycloalkenyl, 5-8 membered heterocyclic alkyl, phenyl or 5-6 membered heteroaryl; other variables as defined in this invention.

[0115] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Among them, E1 and E2 are independently selected from one or more R. 3b The following groups are substituted: -CH2CH2CH2-, -CH2CH=CH-, -CH2CH2O-, -CH ＝ CHO-、-N ＝ CHO-、-CH ＝ NO-, -CH2OCH2-, -CH2CH2S-, -CH ＝ CHS-, -CH2SCH2-, -CH2CH2NH- and -CH2NHCH2-; other variables are as defined in this invention.

[0116] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0117] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0118] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0119] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0120] In some technical solutions of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0121] In some technical solutions of the present invention, the above-mentioned structural unit for in, The variables are selected from single and double bonds, with E3 and E4 independently selected from O and S, respectively. Other variables are as defined in this invention.

[0122] In some technical solutions of the present invention, the above-mentioned structural unit for in, Selected from single and double bonds, other variables are as defined in this invention.

[0123] In some technical solutions of the present invention, the above-mentioned structural unit for Other variables are as defined in this invention.

[0124] In some technical solutions of the present invention, X is 0, and other variables are as defined in the present invention.

[0125] In some technical solutions of this invention, X is NH, and other variables are as defined in this invention.

[0126] In some technical solutions of this invention, L1 is not present, and other variables are as defined in this invention.

[0127] In some technical solutions of the present invention, the L2 mentioned above is selected from one or more R. L2 The following groups are substituted: CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, CH(CH3)CH(CH3), CH=CH, CH2CH=CH. C 3-6Cycloalkyl, 3-8 membered heterocyclic alkyl, CH2-C 3-8 Cycloalkyl and CH2-3-8-membered heterocyclic alkyl, wherein L2 is attached to S via a carbon atom, and other variables are as defined in this invention.

[0128] In some technical solutions of the present invention, the L2 mentioned above is selected from one or more R. L2 The following groups are substituted: C 1-6 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group and C 0-3 Alkyl-C 3-10 cycloalkyl-C 0-3 Alkyl groups, and other variables as defined in this invention.

[0129] In some technical solutions of the present invention, the L2 mentioned above is selected from one or more R. L2 Replacement C 1-6 Alkyl groups, and other variables as defined in this invention.

[0130] In some technical solutions of the present invention, the L2 mentioned above is selected from one or more R. L2 Replacement C 1-3 Alkyl groups, and other variables as defined in this invention.

[0131] In some technical solutions of the present invention, the L2 mentioned above is selected from one or more R. L2 The following groups are 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 groups, and other variables as defined in this invention.

[0132] In some technical solutions of the present invention, L2 is selected from... Other variables are as defined in this invention.

[0133] In some technical solutions of the present invention, L2 is selected from... Other variables are as defined in this invention.

[0134] In some technical solutions of the present invention, L2 is selected from CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2 and CH(CH3)CH(CH3), and other variables are as defined in the present invention.

[0135] In some technical solutions of this invention, the L2 mentioned above is selected from CH2CH2, Other variables are as defined in this invention.

[0136] In some technical solutions of this invention, the L2 mentioned above is selected from CH2CH2, Other variables are as defined in this invention.

[0137] In some technical solutions of the present invention, L2 is... Other variables are as defined in this invention.

[0138] In some technical solutions of the present invention, L2 is... Other variables are as defined in this invention.

[0139] In some technical solutions of the present invention, L2 is... Other variables are as defined in this invention.

[0140] In some technical solutions of the present invention, the L2 mentioned above is selected from one or more R. L2 The following groups are substituted: CH2, CH2CH2, CH2CH2CH2 and CH(CH3)CH2, where R2 is selected from those substituted by one or more R groups. 2a The following groups may be substituted: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, oxazolyl, and thiazolyl, with other variables as defined in this invention.

[0141] In some technical solutions of the present invention, L2 is... R2 is selected from Other variables are as defined in this invention.

[0142] In some technical solutions of the present invention, L2 is... R2 is selected from Other variables are as defined in this invention.

[0143] In some technical solutions of the present invention, the ring A is selected from... Other variables are as defined in this invention.

[0144] In some technical solutions of the present invention, the ring A is selected from... Other variables are as defined in this invention.

[0145] In some technical solutions of this invention, the above-mentioned ring A is selected from triazole groups, and other variables are as defined in this invention.

[0146] In some technical solutions of the present invention, the ring A is selected from... Other variables are as defined in this invention.

[0147] In some technical solutions of the present invention, the ring A is selected from... In this context, bit 1 is connected to ring B, and other variables are as defined in this invention.

[0148] In some technical solutions of the present invention, the compound shown in formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0149]

[0150] T1 is selected from CR5 and N;

[0151] T2, T3, T4, and T5 are each independently selected from C and N;

[0152] Rings C1 and C2 are each independently selected from one or more R's. 3b The following groups are substituted: C 5-8 Cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0153] Rings A, X, R1, R2, R5, R 3b L2 is as defined in this invention.

[0154] In some technical solutions of the present invention, the compounds shown in formulas (I-3), (I-4), (I-5), or (I-6), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein L2 is selected from compounds optionally surrounded by 1, 2, 3, 4, or 5 Rs. L2 The following groups are substituted: CH2, CH2CH2, CH2CH2CH2, CH(CH3)CH2, and CH(CH3)CH(CH3); R1 is selected from those substituted by one or more R groups. 1a The following groups are substituted: phenyl and 5-10 heteroaryl groups; R2 is selected from those optionally replaced by 1, 2, 3, 4 or 5 R groups. 2a The following groups may be substituted: phenyl and 5-10 heteroaryl groups; X is O; other variables are as defined in this invention.

[0155] In some technical solutions of the present invention, the compounds shown in formulas (I-3) or (1-6), their stereoisomers, or their pharmaceutically acceptable salts, are used.

[0156]

[0157] in,

[0158] T1 is selected from CH and N; furthermore, T1 is selected from CH;

[0159] T2, T3, T4, and T5 are each independently selected from C and N; furthermore, T2, T3, T4, and T5 are each independently selected from C.

[0160] Ring C1 and ring C2 are independently selected from C 5-8Cycloalkyl, 5-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl; further, ring C1 and ring C2 are each independently selected from 5-8 membered heterocycloalkyl;

[0161] Ring A is selected from 1,2,4-triazolyl;

[0162] X is selected from O and NH; furthermore, X is selected from O;

[0163] R1 is selected from one or more R1s. 1a Substituted 5-6 aryl groups;

[0164] 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;

[0165] Each R 1a The components are independently selected from H, D, F, Cl, CN, and C, which are optionally substituted by one or more R. 1-3 alkyl;

[0166] Each R 2a The components are independently selected from H, D, F, Cl, CN, and C, which are optionally substituted by one or more R. 1-3 alkyl;

[0167] 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,

[0168] In some technical solutions of the present invention, the compounds shown in formula (I-3) or (I-6), their stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0169]

[0170] Where r is selected from 1 and 2; ring C1, ring C2, T1, T2, T3, T4, T5, R1, R2, R L2 As defined in this invention.

[0171] In some technical solutions of the present invention, the compounds shown in formulas (I-3), (I-6), or (I-7), their stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0172]

[0173] in,

[0174] r is selected from 1 and 2;

[0175] E1 and E2 are independently selected from -CH2CH2O- and -CH2CH2O-, respectively. ＝ CHO-, -CH2CH2S- and -CH ＝ CHS-;

[0176] R1, R2, R5, R L2 As defined in this invention.

[0177] In some technical solutions of the present invention, the compound shown in formula (II-1), its stereoisomer, or its pharmaceutically acceptable salt, wherein R1 is selected from one or more R... 1a The substituted 5-6 heteroaryl group; R2 is selected from 1, 2, 3, 4 or 5 R groups. 2a The following groups may be substituted: phenyl and 5-6 heteroaryl groups; other variables are as defined in this invention.

[0178] 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:

[0179]

[0180] in, Selected from single and double bonds;

[0181] E1 and E2 are independently selected from O and S, respectively;

[0182] R1 is selected from one or more R1s. 1a Substituted 5-6 aryl groups;

[0183] R2 is selected from one or more R2s. 2a Substituted phenyl or 5-6-membered heteroaryl;

[0184] R 1a R 2a As defined in this invention.

[0185] In some technical solutions of the present invention, the above-mentioned Selected from single bonds, other variables are as defined in this invention.

[0186] The present invention also provides the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof,

[0187]

[0188] in,

[0189] Ring A is arbitrarily selected by 1 or 2 Rs a Substituted 5-membered heteroaryl groups;

[0190] Ring B is selected from C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, naphthyl and 5-10 membered heteroaryl;

[0191] 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;

[0192] 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;

[0193] X is either O or NR8;

[0194] 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;

[0195] 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;

[0196] 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;

[0197] Alternatively, two R3s connected together form a configuration that can be optionally bounded by one or more Rs. 3bThe following groups are substituted: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0198] 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;

[0199] 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;

[0200] 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, C 3-8 Cycloalkyl and 3-8 membered heterocyclic alkyl groups;

[0201] 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;

[0202] 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 1-4Alkylamino, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl;

[0203] 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;

[0204] 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;

[0205] m, n, and p are independently selected from 0, 1, 2, and 3, respectively;

[0206] The condition is that when ring A is When X is 0, any one of the following conditions must be met:

[0207] 1) Two R3s connected together form an array that can be optionally bounded by one or more Rs 3b Replacement C 4-8 cycloalkyl or 4-8 membered heterocyclic alkyl;

[0208] 2) Two R3s connected together form an array that can be optionally bounded by one or more Rs. 3b Substituted phenyl or 5-6-membered heteroaryl groups, two R4 groups linked together to form an optional R4 group. 4b Substituted phenyl or 5-6 heteroaryl groups.

[0209] In some technical solutions of the present invention, the compound shown in formula (I), its stereoisomer or its pharmaceutically acceptable salt, wherein L2 is linked to S through a carbon atom.

[0210] In some technical solutions of the present invention, the compound shown in formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0211]

[0212] in,

[0213] T1 is selected from CR5 and N;

[0214] T2, T3, T4, and T5 are selected from C and N;

[0215] R1 is arbitrarily selected by one or more R1s 1a Substituted 5-6 aryl groups;

[0216] R2 is selected from one or more R2s. 2a Substituted phenyl or 5-6-membered heteroaryl;

[0217] R5 is selected from H, F, Cl, CH3 and OCH3;

[0218] Rings C1 and C2 are each independently selected from one or more R's. 3b The following groups are substituted: C 4-8 Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0219] Ring A, each R 1a Each R 2a Each R 3b As defined in this invention.

[0220] In some technical solutions of the present invention, the compound shown in formula (I) or (I-1), its stereoisomer, or its pharmaceutically acceptable salt is selected from:

[0221]

[0222] in,

[0223] R1 is arbitrarily selected by one or more R1s 1a Substituted 5-6 aryl groups;

[0224] R2 is selected from one or more R2s. 2a Substituted phenyl or 5-6-membered heteroaryl;

[0225] R5 is selected from H, F, Cl, CH3 and OCH3;

[0226] E1 and E2 are each independently selected from one or more R... 3b The following groups are substituted: -CH2CH2O-, -CH ＝ CHO-、-N ＝ CHO-、-CH ＝ NO-, -CH2OCH2-, -CH2CH2S-, -CH2SCH2-, -CH2CH2NH- and -CH2NHCH2-;

[0227] Ring A, each R 1a and each R 2a Each R 3b As defined in this invention.

[0228] In some technical solutions of the present invention, the compound represented by formula (I) or (I-1), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from compounds of formula (I-2), (I-2a), (I-2b), (I-2c), or (I-2d); in some technical solutions of the present invention, the compound represented by formula (I-1a), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from compounds of formula (I-2a); in some technical solutions of the present invention, the compound represented by formula (I-1b), its stereoisomer, or a pharmaceutically acceptable salt thereof is selected from compounds of formula (I-2b).

[0229] In some technical solutions of the present invention, the compound shown in formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0230]

[0231] Wherein, R1, R2, L2, X are as defined in formula (I) of the present invention, and rings C1, C2, T1, T2, T3, T4, T5 are as defined in formula (I-1) of the present invention.

[0232] In some technical solutions of the present invention, the compound shown in formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof are selected from:

[0233]

[0234] in,

[0235] T1 is selected from CR5 and N;

[0236] T2, T3, T4, and T5 are selected from C and N;

[0237] R1 is arbitrarily selected by one or more R1s 1a Substituted 5-6 aryl groups;

[0238] R2 is selected from H, F, Cl, Br, I, and CN;

[0239] R5 is selected from H, F, Cl, CH3 and OCH3;

[0240] L2 is selected from one or more Rs. L2 The following groups are substituted: C 3-6 Cycloalkyl, 3-8 membered heterocyclic alkyl, -CH2-C 3-8 Cycloalkyl and -CH2-3-8-membered heterocycloalkyl, wherein L2 is attached to S via a carbon atom;

[0241] Rings C1 and C2 are each independently selected from one or more R's. 3b The following groups are substituted: C 4-8Cycloalkyl, 4-8 membered heterocycloalkyl, phenyl or 5-6 membered heteroaryl;

[0242] Ring A is a triazole group;

[0243] Each R 1a Each R L2 Each R 3b As defined in this invention.

[0244] Some technical solutions of this invention are derived from arbitrary combinations of the above-mentioned variables.

[0245] The present invention also provides the compounds shown in Table A, their stereoisomers, or pharmaceutically acceptable salts thereof.

[0246] In some technical solutions of the present invention, the compounds shown in Table A, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from the compounds in Table A1.

[0247] Table A Compounds

[0248]

[0249]

[0250]

[0251]

[0252] Table A1 Compounds

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention, its stereoisomer, or a pharmaceutically acceptable salt thereof. Further, it also includes a pharmaceutically acceptable carrier.

[0261] The present invention also provides a method for drug combination therapy, comprising the use of the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof, in combination with other drugs in the treatment of apelin receptor agonist-related diseases.

[0262] In some technical solutions of the present invention, the other drugs in the above-mentioned drug combination methods include, but are not limited to, GLP-1 receptor agonists, GIP receptor agonists, GCG receptor agonists, and related dual-target and tri-target drugs.

[0263] In some technical solutions of the present invention, the above-mentioned GLP-1 receptor agonists include, but are not limited to, semaglutide, tirzepatide, liraglutide, and orforglipron.

[0264] The present invention also provides the use of the above-mentioned compounds, their stereoisomers or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases associated with Apelin receptor agonists.

[0265] In some technical solutions of the present invention, the aforementioned Apelin receptor agonist-related diseases include, but are not limited to, metabolic disorders (such as obesity, insulin resistance, type 2 diabetes, etc.), cardiovascular diseases (such as heart failure, etc.), pulmonary diseases such as pulmonary hypertension and idiopathic pulmonary fibrosis, and muscle atrophy and other muscle function decline diseases caused by long-term bed rest or other diseases.

[0266] The present invention also provides the following synthesis methods:

[0267] Method 1:

[0268]

[0269] Method 2:

[0270]

[0271] Technical effect

[0272] The compounds of this invention can significantly activate G protein signaling downstream of the Apelin receptor. Some of these compounds have a relatively weaker effect on recruiting β-arrestin 2 and exhibit high selectivity, making them G protein-biased Apelin receptor agonists.

[0273] The compounds of this invention exhibit high plasma protein binding rates in plasmas of various species, demonstrating strong plasma protein binding capacity. They also exhibit good stability in liver microsomes and hepatocytes of various genera (especially humans). They do not show significant inhibitory effects on the major cytochrome P450 enzymes in human liver microsomes, resulting in a low risk of drug-drug interactions. They do not significantly inhibit hERG. In pharmacokinetic (PK) studies of various genera, they have demonstrated low clearance rates, long half-lives, high oral exposures, and high oral bioavailability, exhibiting excellent pharmacokinetic properties with minimal species differences.

[0274] When the compound of this invention is used in combination with semaglutide in a diet-induced obesity (DIO) mouse model, it can further significantly reduce body weight, improve body composition, and further reduce fasting blood glucose levels in animals, demonstrating good in vivo efficacy. Moreover, the efficacy of the combination is significantly better than that of semaglutide alone.

[0275] The compounds of this invention also have good solubility, which is beneficial for oral administration and formulation development.

[0276] Definitions and Explanations

[0277] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0278] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0279] 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.

[0280] 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%.

[0281] The compounds of this invention can exist in specific tautomers. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to functional group isomers resulting from the rapid movement of one or more atoms in a molecule between two positions. A tautomer is a special type of functional group isomer. Tautomers can interconvert and exist in dynamic equilibrium, but usually exist primarily in the more stable isomer form. For example, chemical equilibrium of tautomers can be achieved in solution. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions involving the rearrangement of some bonding electrons. For example, a specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one. In some technical solutions of the present invention, and These are also two forms of tautomers.

[0282] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0283] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0284] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0285] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0286] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key and / or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and / or straight dashed key

[0287] Unless otherwise stated, carbon atoms marked with an asterisk (*) are chiral carbon atoms, existing as a single enantiomer (R) or (S) or enriched with one enantiomer. For example, express or Or it may contain an enantiomer.

[0288] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean 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%.

[0289] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0290] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0291] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, which can include deuterium and hydrogen variants, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are substituted. In some embodiments of the present invention, "substituted" refers to the substitution of one or more hydrogen atoms on a carbon or nitrogen atom by a substituent.

[0292] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0293] The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on the basis of chemical feasibility. In some technical solutions of the present invention, "optionally substituted by one or more Rs" means that it may not be substituted by Rs, or it may be substituted by 1, 2, 3, 4, 5, 6, 7, or 8 Rs. In some technical solutions of the present invention, "optionally substituted by one or more Rs" means that it may be substituted by 1, 2, 3, 4, or 5 Rs. In some technical solutions of the present invention, "optionally substituted by one or more Rs" means that it may be substituted by 1, 2, or 3 Rs.

[0294] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0295] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0296] When one of the variables is selected as a single bond or a bond, it means that the two groups it connects are directly connected. For example, when L in ALZ is a bond, it means that the structure is actually AZ.

[0297] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, it means that the structure is actually A.

[0298] 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.

[0299] 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.

[0300] 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.

[0301] Unless otherwise specified, the term “halogen” or “halogen” itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.

[0302] 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 C 1-2C 2-3 C1, C2, C3 alkyl groups, etc.

[0303] Unless otherwise specified, the term "alkenyl" on its own or in combination with other terms refers to a straight-chain or branched hydrocarbon group consisting of 2 to 20 carbon atoms and containing at least one carbon-carbon double bond. It can be monovalent, divalent, or polyvalent. The alkenyl group includes C... 2-10 alkenyl, C 2-6 alkenyl, C 2-5 alkenyl, C 2-4 alkenyl, C 2-3 Alkenyl groups, etc., examples of which include, but are not limited to, vinyl, propenyl, 1-butenyl, and cis-butadienyl. In some technical solutions of the present invention, the alkenyl group is C... 2-6 alkenyl groups, which include C 2-3 C 2-4 C 2-5 C2, C3, C4, C5, C6 alkenyl groups, etc.; in other technical solutions of the present invention, the alkenyl group is C 2-4 alkenyl groups, which contain C 2-3 C2, C3, C4 alkenyl groups, etc.; in other technical solutions of the present invention, the alkenyl group is C 2-3 Alkenyl groups, including C2 and C3 alkenyl groups, etc.

[0304] Unless otherwise specified, the term "alkynyl" on its own or in combination with other terms refers to a straight-chain or branched hydrocarbon group consisting of 2 to 20 carbon atoms and containing at least one carbon-carbon triple bond. It can be monovalent, divalent, or polyvalent. The alkynyl group includes C... 2-10 alkynyl group, C 2-6 alkynyl group, C 2-5 alkynyl group, C 2-4 alkynyl group, C 2-3 Alkyne groups, etc., examples of which include, but are not limited to, ethynyl, propynyl, 1-butynyl, etc. In some technical solutions of the present invention, the alkynyl group is C. 2-6 Alkyne groups, which include C 2-3 C 2-4 C 2-5 C2, C3, C4, C5, C6 alkynyl groups, etc.; in other technical solutions of the present invention, the alkynyl group is C 2-4 Alkyne group, which includes C 2-3 C2, C3, C4 alkynyl groups, etc.; in some other technical solutions of the present invention, the alkynyl group is C 2-3 Alkyne groups, including C2 and C3 alkynyl groups, etc.

[0305] Unless otherwise specified, the term "alkoxy" on its own, or in combination with other terms, refers to alkyl groups comprising 1 to 20 carbon atoms that are attached to the remainder of a molecule by an oxygen atom. It can be monovalent, divalent, or polyvalent. The alkoxy group includes C... 1-10 Alkoxy, C 1-6 Alkoxy, C 1-5 Alkoxy, C 1-4 Alkoxy, C 1-3 Alkoxy groups, etc., examples of which include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), etc. In some technical solutions of the present invention, the alkoxy group is C 1-6 Alkoxy groups, which include C 1-2 C 1-3 C 1-4 C 2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkoxy groups, etc.; in other technical solutions of the present invention, the alkoxy group is C 1-4 Alkoxy groups, which include C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkoxy groups, etc.; in other technical solutions of the present invention, the alkoxy group is C 1-3 Alkoxy groups, which include C 1-2 C 2-3 C1, C2, C3 alkoxy groups, etc.

[0306] Unless otherwise specified, the term "alkathioyl" on its own or in combination with other terms refers to alkyl groups comprising 1 to 20 carbon atoms that are attached to the remainder of a molecule by a sulfur atom. It can be monovalent, divalent, or polyvalent. The alkathioyl group includes C... 1-10 Alkylthio, C 1-6 Alkylthio, C 1-5 Alkylthio, C 1-4 Alkylthio, C 1-3 Alkylthio groups, etc., examples of which include, but are not limited to, methylthio, ethylthio, and propylthio (including n-propylthio and isopropylthio). In some technical solutions of the present invention, the alkylthio group is C10. 1-6 Alkylthio groups, which include 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 groups, etc.; in some other technical solutions of the present invention, the alkylthio group is C1, C2, C3, C4, C5, C6 alkylthio groups, etc. 1-4Alkylthio groups, which include C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkylthio groups, etc.; in some other technical solutions of the present invention, the alkylthio group is C1, C2, C3, C4, etc. 1-3 Alkylthio groups, which include C 1-2 C 2-3 C1, C2, C3 alkylthio groups, etc.

[0307] Unless otherwise specified, the term "alkylamino" on its own or in combination with other terms refers to alkyl groups comprising 1 to 20 carbon atoms that are attached to the remainder of a molecule by a nitrogen atom. They can be monovalent, divalent, or polyvalent, including monoalkylamino and dialkylamino groups. The alkylamino group comprises C... 1-10 Alkylamino, C 1-6 Alkylamino, C 1-5 Alkylamino, C 1-4 Alkylamino, C 1-3 Alkylamino groups, etc., examples of which include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, etc. In some technical solutions of the present invention, the alkylamino group is C 1-6 Alkylamino, which includes C 1-2 C 1-3 C 1-4 C 2-3 C 2-4 C 2-5 C1, C2, C3, C4, C5, C6 alkylamino groups, etc.; in some other technical solutions of the present invention, the alkylamino group is C1, C2, C3, C4, C5, C6, etc. 1-4 Alkylamino, which includes C 1-2 C 1-3 C 2-3 C 2-4 C1, C2, C3, C4 alkylamino groups, etc.; in some other technical solutions of the present invention, the alkylamino group is C 1-3 Alkylamino, which includes C 1-2 C 2-3 C1, C2, C3 alkylamino, etc.

[0308] Unless otherwise specified, the term "cycloalkyl" on its own or in combination with other terms refers to a saturated or partially unsaturated cyclic hydrocarbon group consisting of 3 to 20 carbon atoms. It can be monovalent, divalent, or polyvalent. The cycloalkyl group may optionally contain one or more carbon-carbon double or triple bonds, but all rings must not be aromatic. The cycloalkyl group can be a saturated cycloalkyl group (meaning all rings are saturated), or a cycloalkenyl group (meaning a monocyclic or polycyclic system containing at least one double bond), etc. The cycloalkyl group can be monocyclic or polycyclic (e.g., spirocyclic, fused, bridged rings), etc. The cycloalkyl group includes C... 3-10 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl, C 4-6 Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl. In some embodiments of the present invention, the cycloalkyl group is C10. 3-6 cycloalkyl groups, including C 3-5 C 4-5 C 4-6 C3, C4, C5, C6 cycloalkyl groups, etc.

[0309] Unless otherwise specified, the term "heterocyclic alkyl" on its own or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 20 ring atoms, wherein 1, 2, 3, 4, 5, 6, 7, or 8 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., C(O)), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)2, p is 1 or 2), and the heteroatoms may occupy the connection positions between the heterocyclic alkyl group and the rest of the molecule. It can be monovalent, divalent, or polyvalent. The heterocyclic alkyl group may optionally contain one or more double or triple bonds, but all rings are not aromatic rings. The heterocyclic alkyl group may be a saturated heterocyclic alkyl group (meaning all rings are saturated), or a heterocyclic alkenyl group (meaning a monocyclic or polycyclic system containing at least one carbon-carbon double bond), etc. The heterocyclic alkyl groups include 3-10-membered heterocyclic alkyl groups, 3-8-membered heterocyclic alkyl groups, 3-7-membered heterocyclic alkyl groups, 3-6-membered heterocyclic alkyl groups, 3-5-membered heterocyclic alkyl groups, 4-6-membered heterocyclic alkyl groups, etc. Examples of heterocyclic alkyl groups include, but are not limited to, azacyclic butyl, oxacyclic butyl, thiocyclic butyl, pyrrolidinyl, pyrazolyl, imidazolyl, tetrahydrothiophene (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc. In some technical solutions of this invention, the 3-10 membered heterocyclic alkyl group 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, and 6-10 membered heterocyclic alkyl groups. In some technical solutions of this invention, the heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group, which includes 3-5 membered, 4-5 membered, 4-6 membered, 3 membered, 4 membered, 5 membered, and 6 membered heterocyclic alkyl groups.

[0310] Unless otherwise specified, the terms "heteroaryl ring" and "heteroaryl" are used interchangeably. The term "heteroaryl," either alone or in combination with other terms, refers to a monocyclic group or polycyclic ring system consisting of 5 to 20 ring atoms with a conjugated π-electron system, wherein 1, 2, 3, 4, 5, 6, 7, or 8 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)₂, p is 1 or 2). The heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom, and can be monovalent, divalent, or polyvalent. The heteroaryl groups include 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, and 10-membered heteroaryl groups. Examples of the heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl). (e.g., tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, etc.), pyrazinyl, pyrazinyl, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), indoleyl, indazoleyl, pyrimidinimidazoleyl, etc. In some technical solutions of the present invention, the heteroaryl group is a 5-10 ternaryl group, including 5-6 ternary, 5-8 ternary, 5-9 ternary, 5 ternary, 6 ternary, 7 ternary, 8 ternary, 9 ternary, and 10 ternary heteroaryl groups; in other technical solutions of the present invention, the heteroaryl group is a 5-6 ternary heteroaryl group, including 5 ternary and 6 ternary heteroaryl groups.

[0311] Unless otherwise specified, the term "aromatic ring" refers to a cyclic group with a conjugated π-electron system, whose atoms are covered by a delocalized π-electron cloud. In the structural formula, when conforming to the rules of atomic valence and covalent bonding, it can be written in the form of alternating single and double bonds, or it can be written using... This represents the delocalized π-electron cloud. For example, the structural formula... The structures represented are all the same; structural formula The structures represented are all identical. The aromatic ring can be a monocyclic or polycyclic system, wherein each ring in a polycyclic system is aromatic. Unless otherwise specified, the ring optionally contains 0, 1, or more heteroatoms or heterogroups independently selected from O, S, NH, and N.

[0312] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0313] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0314] The abbreviations used in this invention are as follows: XantPhos-Pd-G3 represents methanesulfonic acid [9,9-dimethyl-4,5-bis(diphenylphospho)oxanthracene][2-amino-1,1-diphenyl]palladium(II), CAS: 1445085-97-1; MC represents methylcellulose; Saline represents physiological saline; Solutol represents polyethylene glycol-15-hydroxystearate; Tween80 represents Tween 80; PEG400 represents polyethylene glycol 400; HEPES represents 4-hydroxyethylpiperazine 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.

[0315] The solvents used in this invention are commercially available. Compounds are named according to conventional naming principles in the art or using… Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0316] Figure 1 Figure 1: Changes in body weight of mice in the in vivo drug efficacy experiment of the DIO model.

[0317] Figure 2 Figure 2: Body weight changes in mice during in vivo drug efficacy experiments using the DIO model. Detailed Implementation

[0318] The present invention will be described in detail below with reference to embodiments, but this does not imply any adverse limitation on the invention. The present invention has been described in detail, and specific embodiments thereof have been disclosed. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope thereof.

[0319] Intermediate M1

[0320]

[0321] Step 1: Under a nitrogen atmosphere at room temperature, tris(diphenylmethyleneacetone)dipalladium (7.12 g, 7.78 mmol), tricyclohexylphosphine (4.36 g, 15.56 mmol), and potassium phosphate (49.53 g, 233.36 mmol) were added to a mixed solution of dioxane (100 mL) and water (10 mL) of compounds M1-1 (10 g, 77.79 mmol) and M1-2 (13.86 g, 85.56 mmol). The reaction solution was heated to 100 °C and reacted for 0.5 hours. Ethyl acetate (500 mL) was added to the reaction solution, and the mixture was filtered. The filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (n-hexane: ethyl acetate = 1 / 0-10 / 1) to obtain compound M1-3. 1 H NMR (400MHz, 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, 7.2Hz, 3H).

[0322] Step 2: Under a nitrogen atmosphere at 0°C, slowly add thioyl chloride (10.93 g, 80.97 mmol) dropwise to dichloromethane (300 mL) containing compound M1-4 (9.08 g, 80.97 mmol). After the addition is complete, the reaction mixture is allowed to react at 0°C for 0.5 hours. Then, slowly add compound M1-3 (10 g, 67.47 mmol) dropwise to the reaction system. After the addition is complete, slowly raise the temperature to 25°C and continue the reaction for 0.5 hours. Slowly add the reaction mixture to a saturated sodium bicarbonate solution (300 mL), extract with dichloromethane (300 mL × 2), combine the organic phases, wash successively with water (50 mL) and saturated brine (50 mL), dry to anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure to obtain the crude product, and purify by column chromatography (n-hexane: ethyl acetate = 10 / 1-1 / 1) to obtain compound M1-5. LCMS(m / z): 295.0 [M+1] + .

[0323] Step 3: Under a nitrogen atmosphere at room temperature, m-chloroperoxybenzoic acid (16.94 g, 83.45 mmol, 85% purity) was added in portions to a dichloromethane (160 mL) solution of compound M1-5 (8.2 g, 27.82 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 0.5 hours. The reaction solution was then slowly added to a saturated sodium bicarbonate aqueous solution (100 mL), and extracted with dichloromethane (100 mL × 2). The organic phases were combined and washed successively with water (50 mL) and saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (n-hexane: ethyl acetate = 30 / 1-1 / 1) to obtain compound M1-6.

[0324] Step 4: Under a nitrogen atmosphere at room temperature, potassium carbonate (7.70 g, 55.69 mmol) was added to a solution of compound M1-6 (9.1 g, 27.85 mmol) in acetonitrile (50 mL) and water (50 mL). The reaction solution was heated to 40 °C and reacted for 2 hours. Then, methanol (50 mL) was added to the reaction solution, and the temperature was raised to 50 °C and reacted for half an hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound M1-7.

[0325] Step 5: Under a nitrogen atmosphere at room temperature, potassium acetate (3.14 g, 31.95 mmol) and hydroxylamine-O-sulfonic acid (7.23 g, 63.91 mmol) were slowly added to an aqueous solution (80 mL) of compound M1-7 (8 g, 31.95 mmol). The reaction solution was heated to 40 °C and reacted for 12 hours. After the reaction solution cooled to room temperature, it was extracted with dichloromethane (500 mL), and the organic phase was concentrated under reduced pressure to obtain compound M1-8.

[0326] Step 6: Under a nitrogen atmosphere at room temperature, add rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (I) (CAS: 35138-22-8, 242.98 mg, 598.37 μmol), (S)-1-{(RP)-2-[bis(1-naphthyl)phosphine]ferrocene}ethyl di-tert-butylphosphine (CAS: 849924-44-3, 384.50 mg, 598.37 μmol), and zinc trifluoromethanesulfonate (2.18 g, 5.98 mmol) sequentially to a methanol (70 mL) solution of compound M1-8 (6.8 g, 29.92 mmol). Replace the solution with hydrogen three times. React at 25 °C for 12 hours under a hydrogen pressure of 50 psi. Concentrate the reaction solution under reduced pressure. Purify the residue by column chromatography (n-hexane:ethyl acetate = 10 / 1-0 / 1) to obtain the crude product. Add 20 mL of ethanol to the crude product, stir at room temperature for 10 min, filter, and dry the filter cake to obtain compound M1. LCMS (m / z): 230.2 [M+1] + ; 1¹H NMR (400MHz, DMSO-d6) δ=8.61(s,2H),6.83(s,2H),3.77-3.61(m,2H),2.25(s,3H),1.32(d,J=7.2Hz,3H),1.20(d,J=7.2Hz,3H). SFC detection (column: Chiralpak AD-3 50*4.6mm ID,3μm; mobile phase: A phase is supercritical CO2, B phase is methanol (0.05% diethylamine); gradient (B%): 5%-40%)) showed that the retention time of compound M1 was 2.001 min, and the chiral purity was 96.19%.

[0327] intermediate M2

[0328]

[0329] Step 1: Under a nitrogen atmosphere at 25°C, potassium carbonate (628 g, 4.55 mol) was slowly added in portions 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). The reaction mixture was heated to 90°C and stirred for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1-2:1) to obtain compound M2-2. LCMS (m / z): 235.0 [M+H] + .

[0330] Step 2: Under a nitrogen atmosphere at 0°C, slowly add a solution of liquid bromine (19.55 mL, 381 mmol) in acetic acid (100 mL) to a solution of compound M2-2 (39.0 g, 166 mmol) in acetic acid (300 mL). After the addition is complete, heat to room temperature and react for 1 hour. Pour the reaction solution into ice water (800 mL), stir for 5 minutes, and filter. Rinse the filter cake with acetic acid (50 mL), then dissolve the filter cake in 200 mL of ethyl acetate. Adjust the pH to 7-8 with saturated sodium bicarbonate solution, and extract with ethyl acetate (100 mL × 2). Wash the combined organic phases with 300 mL of saturated brine, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound M2-3.

[0331] Step 3: Under a nitrogen atmosphere at 25°C, magnesium powder (12.8 g, 527 mmol) was added to tetrahydrofuran (150 mL), followed by the slow addition of ethyl magnesium bromide (3 M tetrahydrofuran solution, 12.7 mL). After the addition was complete, the temperature was raised to 40°C, and a tetrahydrofuran solution (400 mL) of compound M2-3 (68 g, 173 mmol) was added dropwise to the reaction system. After the addition was complete, the temperature was raised to 75°C and the reaction was carried out for 4 hours. The reaction solution was cooled to 0°C, quenched dropwise with dilute hydrochloric acid (1 M, 300 mL), and extracted with methyl tert-butyl ether (300 mL × 2). The combined organic phases were 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 obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-4:1) to obtain compound M2-4. LCMS(m / z): 163.0 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 6.96 (s, 1H), 6.30 (s, 1H), 4.57 (dt, J = 1.6, 8.8Hz, 4H), 3.11 (br t, J = 8.4Hz, 4H).

[0332] Step 4: Solution 1 is an anhydrous tetrahydrofuran (60 mL) solution of compound M2-4 (3 g, 18.50 mmol) and tetramethylethylenediamine (8.6 g, 74.78 mmol); Solution 2 is tert-butyllithium (1.3 M n-pentane, 54 mL, 70.2 mmol); Solution 3 is an anhydrous tetrahydrofuran (60 mL) solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (6.02 g, 18.49 mmol); the fluid chemistry steps are as follows:

[0333] At 0°C, solution 1 was pumped sequentially into flow reactor 1 (holding time 3 min), flow reactor 2 (holding time 2.025 min), and flow reactor 3 (holding time 2.025 min) by pump 1 (22.818 mL / min); at 0°C, solution 2 was pumped sequentially into flow reactor 1 (holding time 3 min), flow reactor 2 (holding time 2.025 min), and flow reactor 3 (holding time 2.025 min) by pump 2 (20.516 mL / min); at 0°C, solution 3 was pumped sequentially into flow reactor 2 (holding time 2.025 min) and flow reactor 3 (holding time 2.025 min) by pump 3 (20.861 mL / min); pumps 1 and 2 were started simultaneously, pump 3 was started after 3 minutes, and the reaction mixture was collected after another 4.05 minutes.

[0334] After the reaction was complete, the reaction solution was cooled to 0℃ and added dropwise to 100 mL of saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0-3:1) to give compound M2-5. LCMS (m / z): 240.9, 243.0 [M+H] + .

[0335] Step 5: Under a nitrogen atmosphere at 25°C, XantPhos-Pd-G3 (865 mg, 912 μmol), sodium tert-butoxide (1.32 g, 13.7 mmol), and tris(dibenzylacetone)palladium (417.82 mg, 456.28 μmol) were added sequentially to a toluene (5 mL) solution of compound M2-5 (1.1 g, 4.56 mmol) and compound M2-6 (1.65 g, 9.13 mmol). After purging with nitrogen three times, the reaction system was heated to 100°C and reacted for 4 hours. The reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 65%-70%) to give compound M2-7. LCMS (m / z): 342.0 [M+H] + .

[0336] Step 6: Under a nitrogen atmosphere at 25°C, reactant M2-7 (800 mg, 2.34 mmol) was dissolved in trifluoroacetic acid (8 mL) and reacted at room temperature for 4 hours. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution, then extracted with dichloromethane (50 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound M2 was preparatively separated by reversed-phase column chromatography (column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 30%-35%). LCMS (m / z): 178.1 [M+H] + .

[0337] intermediate M3

[0338]

[0339] Solution 1 was a tetrahydrofuran (20 mL) solution of compound M2-4 (1.0 g, 6.17 mmol) and tetramethylethylenediamine (2.87 g, 24.69 mmol); Solution 2 was sec-butyllithium (1.3 M n-hexane solution, 19.0 mL); Solution 3 was a tetrahydrofuran (20 mL) solution of isopropoxide benzoyl borate (294 mg, 1.02 mmol); the fluid chemistry steps are as follows:

[0340] At 0°C, solution 1 was pumped sequentially into flow reactor 1 (holding time 3 min), flow reactor 2 (holding time 2.035 min), and flow reactor 3 (holding time 2.035 min) by pump 1 (7.898 mL / min);

[0341] At 0°C, solution 2 was pumped sequentially into flow reactor 1 (holding time 3 min), flow reactor 2 (holding time 2.035 min), and flow reactor 3 (holding time 2.035 min) by pump 2 (7.102 mL / min);

[0342] At 0°C, solution 3 was pumped sequentially into flow reactor 2 (residence time 2.035 min) and flow reactor 3 (residence time 2.035 min) by pump 3 (7.116 mL / min);

[0343] Pumps 1 and 2 were started simultaneously. After 3 minutes, pump 3 was started, and the reaction mixture was collected after another 4.07 minutes. At 0°C, the reaction solution was poured into a saturated ammonium chloride aqueous solution (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to obtain compound M3. 1 HNMR (400MHz, CD3OD) δ = 7.09-7.05 (m, 1H), 4.53 (t, J = 8.8Hz, 4H), 3.08-3.03 (m, 4H), 1.32 (s, 12H).

[0344] intermediate M4

[0345]

[0346] Step 1: Under a nitrogen atmosphere at 0°C, compound M4-1 (6.00 g, 46.63 mmol) was added to a solution of bis(4-methoxybenzyl)amine (10 g, 38.86 mmol) and triethylamine (5.11 g, 50.52 mmol) in anhydrous dichloromethane (100 mL). The reaction mixture was allowed to react at room temperature for 1.5 hours. Water (25 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:0-5:1) to obtain compound M4-2. 1 H NMR (400MHz, CDCl3) δ = 7.22 (d, J = 8.4Hz, 4H), 6.88 (d, J = 8.4Hz, 4H), 4.28 (s, 4H), 3.82 (s, 6H), 2.91 (q, J = 7.6Hz, 2H), 1.32 (t, J = 7.6Hz, 3H).

[0347] Step 2: Under a nitrogen atmosphere at -70°C, 17.86 mL of 2.5 M tetrahydrofuran solution was slowly added dropwise to a 125 mL solution of anhydrous tetrahydrofuran containing compound M4-2 (12 g, 34.34 mmol). The reaction mixture was kept at -70°C for 0.5 hours. Then, 7.75 g, 41.21 mmol of p-trifluoromethylacetophenone was slowly added dropwise to the reaction mixture at -70°C, and the reaction was continued at -70°C for 1.5 hours. The reaction mixture was brought to room temperature, 40 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, 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 M4-3. 1 H NMR (400MHz, DMSO-d6) δ=7.75-7.58(m,4H),7.13(dd,J=8.4,17.0Hz,4H),6.85(t,J=8.8Hz,4H),5.70-5.47(m,1H),4.44- 4.21(m,2H),4.09(dd,J=9.6,15.2Hz,2H),3.72(d,J=2.8Hz,6H),3.61-3.46(m,1H),1.80-1.62(m,3H),1.22-0.91(m,3H).

[0348] 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).

[0349] 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).

[0350] 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 C1820-45 μm). Mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40%-70%) to obtain compound M4. 1H NMR (400MHz, CDCl3) δ = 7.60 (d, J = 8.1Hz, 2H), 7.39 (d, J = 8.1Hz, 2H), 4.28 (s, 2H), 3. 60-3.49(m,1H),3.33(quin,J=6.8Hz,1H),1.51(d,J=7.1Hz,3H),1.33-1.27(m,3H).

[0351] intermediate M5

[0352]

[0353] Step 1: Under a nitrogen atmosphere at room temperature, tris(diphenylmethyleneacetone)dipalladium (2.41 g, 2.63 mmol), tricyclohexylphosphine (1.84 g, 6.57 mmol), and potassium phosphate aqueous solution (4 M, 24.65 mL) were slowly added in portions to a dioxane (100 mL) solution of compound M5-1 (6 g, 32.87 mmol) and compound M1-2 (5.86 g, 36.16 mmol). The reaction solution was heated to 80 °C and reacted for 10 hours. The reaction solution was concentrated under reduced pressure, and 100 mL of ethyl acetate was added to the residue. The mixture was filtered, and the filtrate was washed successively with water (50 mL) and saturated brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (hexane:ethyl acetate = 100 / 1 - 50 / 1) to obtain compound M5-3. 1 H NMR (400MHz, DMSO-d6) δ = 9.17 (s, 2H), 7.33 (q, J = 6.8Hz, 1H), 2.09 (s, 3H), 1.92 (br d, J = 7.2Hz, 3H).

[0354] Step 2: Under a nitrogen atmosphere at 0°C, sulfuryl chloride (SO₂Cl₂, 1.19 mL, 11.87 mmol) was slowly added dropwise to a dichloromethane (60 mL) solution of compound M1-4 (1.33 g, 11.87 mmol). After the addition was complete, the reaction solution was stirred at 0°C for 0.5 hours. Compound M5-3 (2 g, 9.89 mmol) was slowly added to the reaction solution, and the temperature was raised to 25°C and stirred for 1.5 hours. Then, sulfuryl chloride (989.02 μL, 9.89 mmol) was added to the reaction solution, and the mixture was stirred at 25°C for 1 hour. The reaction solution was slowly poured into 20 mL of saturated sodium bicarbonate aqueous solution and extracted with dichloromethane (40 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (hexane:ethyl acetate = 100 / 1-10 / 1) to obtain compound M5-4. LCMS(m / z): 348.9 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 9.33 (s, 2H), 8.64 (d, J = 4.8Hz, 2H), 7.24 (t, J = 4.8Hz, 1H), 5.21 (q, J = 6.8Hz, 1H), 2.08 (s, 3H), 1.57 (d, J = 6.8Hz, 3H).

[0355] Step 3: Under a nitrogen atmosphere at room temperature, m-chloroperoxybenzoic acid (3.28 g, 16.17 mmol, 85% purity) was added in portions to a dichloromethane (40 mL) solution of compound M5-4 (1.88 g, 5.39 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction solution was slowly added to a saturated sodium bicarbonate aqueous solution (50 mL), and extracted with dichloromethane (30 mL × 2). The combined organic phases were washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (hexane:ethyl acetate = 50 / 1-20 / 1) to obtain compound M5-5. LCMS (m / z): 380.9 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ = 9.34 (s, 2H), 9.10 (d, J = 4.8Hz, 2H), 7.89 (t, J = 4.8Hz, 1H), 5.72 (q, J = 7.2Hz, 1H), 2.29 (s, 3H), 1.70 (d, J = 7.2Hz, 3H).

[0356] Step 4: Under a nitrogen atmosphere at room temperature, potassium carbonate (725.94 mg, 5.25 mmol) was added to a mixed solution of compound M5-5 (1 g, 2.63 mmol) in acetonitrile (10 mL) and water (10 mL). The reaction solution was heated to 40 °C and reacted for 2 hours. Then, 50 mL of methanol was added to the reaction solution, and the temperature was raised to 50 °C, and the reaction was continued for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound M5-6.

[0357] Step 5: Under a nitrogen atmosphere at room temperature, potassium acetate (290.23 mg, 2.96 mmol) and compound M5-7 (668.90 mg, 5.91 mmol) were slowly added to an aqueous solution (20 mL) of compound M5-6 (0.9 g, 2.96 mmol). The reaction mixture was heated to 40 °C and stirred for 3 hours. Dichloromethane (50 mL) was added to the reaction mixture for extraction, and the organic phase was concentrated under reduced pressure to obtain compound M5-8. LCMS (m / z): 281.9 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 9.35 (s, 2H), 7.30 (s, 2H), 2.39 (d, J = 1.2Hz, 3H), 1.90 (d, J = 1.2Hz, 3H).

[0358] Step 6: Under a nitrogen atmosphere at room temperature, slowly add in portions di(1,5-cyclooctadiene)tetrafluoroborate rhodium(I) (CAS: 35138-22-8, 177.77 μmol), (S)-1-{(RP)-2-[bis(1-naphthyl)phosphine]ferrocene}ethyl di-tert-butylphosphine (CAS: 849924-44-3, 177.77 μmol), and zinc trifluoromethanesulfonate (129.25 mg, 355.55 μmol) to a methanol (10 mL) solution of compound M5-8 (0.5 g, 1.78 mmol). After three hydrogen purgings, react at 50 °C for 12 hours under a hydrogen atmosphere (50 psi pressure). The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by reversed-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 ¹H NMR (400MHz, DMSO-d6) δ=9.23(s,2H), 6.89(s,2H), 3.77-3.65(m,2H), 1.36(d,J=6.8Hz,3H), 1.27(d,J=6.8Hz,3H); SFC detection (column: Chiralpak AD-350×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 10%-60%), the retention time of compound M5 was 0.918 min, the chiral purity was 83.78%; the retention time of the isomer was 0.688 min.

[0359] intermediate M6

[0360]

[0361] Step 1: Under a nitrogen atmosphere at room temperature, tris(diphenylmethyleneacetone)dipalladium (2.43 g, 2.65 mmol), tricyclohexylphosphine (1.49 g, 5.31 mmol), and potassium phosphate (16.91 g, 79.65 mmol) were added sequentially to dioxane (50 mL) and water (5 mL) of compounds M6-1 (6 g, 26.55 mmol) and M1-2 (4.73 g, 29.20 mmol). The reaction solution was heated to 100 °C and reacted for 2 hours. 250 mL of ethyl acetate was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (hexane:ethyl acetate = 100 / 1 - 50 / 1) to obtain compound M6-2. LCMS (m / z): 202.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 7.78 (dd, J = 1.6, 8.4Hz, 1H), 7.60 (d, J = 8.4Hz, 1H), 6.08-5.91 (m, 1H), 2.06 (s, 3H), 1.86 (d, J = 6.8Hz, 3H).

[0362] Step 2: Under a nitrogen atmosphere at 0°C, sulfuryl chloride (1.62 g, 12.03 mmol) was slowly added dropwise to a solution of compound M1-4 (1.47 g, 13.12 mmol) in dichloromethane (60 mL). After the addition was complete, the reaction solution was allowed to react at 0°C for 0.5 hours. Then, compound M6-2 (2.2 g, 10.94 mmol) was added to the reaction solution, and the temperature was slowly raised to 25°C, and the reaction was allowed to proceed for 2 hours. Next, sulfuryl chloride (885.54 mg, 6.56 mmol) was added to the reaction solution, and the reaction was allowed to proceed at 25°C for 2 hours. The reaction solution was then slowly added to 200 mL of saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (100 mL × 2), and the organic phases were combined. The mixture was washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (hexane:ethyl acetate = 50 / 1-20 / 1) to obtain compound M6-3. LCMS(m / z): 347.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 9.03 (s, 1H), 8.62-8.45 (m, 2H), 8.35-8.21 (m, 1H), 7.83 (d, J =8.4Hz,1H),7.27-7.08(m,1H),4.91-4.71(m,1H),2.13(s,3H),1.49(d,J=7.2Hz,3H).

[0363] Step 3: Under a nitrogen atmosphere at room temperature, m-chloroperoxybenzoic acid (5.08 g, 25.02 mmol, 85% purity) was added in portions to a dichloromethane (60 mL) solution of compound M6-3 (2.9 g, 8.34 mmol). After the addition was complete, the mixture was reacted at room temperature for 24 hours. The reaction solution was then slowly added to a saturated sodium bicarbonate aqueous solution (200 mL), and extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (hexane:ethyl acetate = 10 / 1-2 / 1) to obtain compound M6-4. LCMS (m / z): 380.1 [M+1] + ; 1 H NMR(400MHz, DMSO-d6)δ=8.96-8.89(m,3H),8.21(dd,J=2.2,8.4Hz,1H),7.76(t,J=4.8H z, 1H), 7.73 (d, J = 8.4Hz, 1H), 5.10 (q, J = 7.2Hz, 1H), 2.29 (s, 3H), 1.66 (d, J = 7.2Hz, 3H).

[0364] Step 4: Under a nitrogen atmosphere at room temperature, potassium carbonate (2.84 g, 20.54 mmol) was added to a solution of compound M6-4 (2.6 g, 6.85 mmol) in acetonitrile (13 mL) and water (13 mL). The reaction solution was heated to 40 °C and reacted for 2 hours. Then, methanol (13 mL) was added, and the reaction was heated to 50 °C and reacted for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound M6-5. LCMS (m / z): 265.9 [M+1] + .

[0365] Step 5: Under a nitrogen atmosphere at room temperature, potassium acetate (679.41 mg, 6.92 mmol) and compound M5-7 (1.57 g, 13.85 mmol) were slowly added to an aqueous solution (30 mL) of compound M6-5 (3.00 g, 6.92 mmol). The reaction mixture was heated to 30 °C and reacted for 4 hours. The reaction mixture was filtered, and the filter cake was collected and dried to obtain compound M6-6. LCMS (m / z): 281.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.63 (s, 1H), 7.96 (d, J = 1.2Hz, 2H), 7.23 (s, 2H), 2.37 (d, J = 1.6Hz, 3H), 1.83 (d, J = 1.6Hz, 3H).

[0366] Step 6: Under an argon atmosphere at room temperature, methanol was added to Pd / C (1 g, 10% purity), followed by compound M6-6 (1 g, 3.57 mmol). After three hydrogen purgings, the mixture was reacted at 25°C for 12 hours under a hydrogen atmosphere (50 psi pressure). The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by column chromatography (hexane:ethyl acetate = 40 / 1-20 / 1) to obtain compound M6. LCMS (m / z): 283.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.68 (s, 1H), 7.99 (br d, J = 8.0Hz, 1H), 7.84 (t, J = 7.6Hz, 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).

[0367] Step 7: Under an argon atmosphere at room temperature, (S)-1-{(RP)-2-[bis(1-naphthyl)phosphine]ferrocene}ethyl di-tert-butylphosphine (160.49 mg, 249.76 μmol), rhodium di(1,5-cyclooctadiene)tetrafluoroborate (I) (101.42 mg, 249.76 μmol), and zinc trifluoromethanesulfonate (181.59 mg, 499.52 μmol) were added to a methanol (5 mL) solution of compound M6-6 (0.7 g, 2.50 mmol). The mixture was purged with hydrogen three times, and the reaction was carried out at 50 °C for 12 hours under a hydrogen atmosphere (50 psi pressure). The reaction solution was filtered, and the filtrate was concentrated to obtain a crude product, which was then purified by reversed-phase column chromatography (column: Phenomenex luna C18 (100 g); mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient (acetonitrile %): 0%-25%) to give compound M6A. LCMS (m / z): 283.1 [M+1] + ; 1¹H NMR (400MHz, DMSO-d6) δ = 8.90 (s, 1H), 8.16 (dd, J = 1.6, 8.4Hz, 1H), 7.56 (d, J = 8.4Hz, 1H), 6.85 (s, 2H), 3.77–3.64 (m, 1H), 3.60–3.49 (m, 1H), 1.32 (d, J = 7.0Hz, 3H), 1.23 (d, J = 7.0Hz, 3H); F NMR (376MHz, DMSO-d6) δ = -60.657; SFC detection (column: Chiralpak AD-3 50×4.6mm) ID, 3 μm; Mobile phase: Phase A is supercritical carbon dioxide, Phase B is ethanol (0.05% diethylamine); Gradient (B%): 10%-60%), Compound M6A contains two isomers with retention times of 1.019 min (content 87.30%) and 1.264 min (content 12.70%), respectively.

[0368] intermediate M7

[0369]

[0370] Step 1: Under a nitrogen atmosphere at 0°C, diethylaminosulfur trifluoride (271 g, 1.68 mol) was added dropwise to a dichloromethane (1 L) solution of compound M7-1 (120 g, 842 mmol). The reaction solution was heated to 25°C and reacted for 1 hour. At 0°C, the reaction solution was slowly poured into a saturated sodium bicarbonate aqueous solution (1 L), and sodium carbonate solid was added to adjust the pH to 7-8. The solution was then extracted with dichloromethane (300 mL × 3). The combined organic phases were washed with a saturated sodium chloride aqueous solution (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-20:1) to obtain compound M7-2. 1 H NMR (400MHz, CDCl3) δ = 8.79 (s, 2H), 6.79 (t, J = 55.2Hz, 1H); 19 F NMR (376MHz, CDCl3) δ (ppm) = -114.345.

[0371] Step 2: Under a nitrogen atmosphere, potassium phosphate aqueous solution (5M, 243mL) and tris(benzylacetone) palladium (22.3g, 24.3mmol) were added to a dioxane (1L) solution of compound M7-2 (80g, 486mmol), compound M1-2 (86.6g, 535mmol), and tricyclohexylphosphine (13.6g, 48.6mmol). The reaction solution was heated to 100℃ and reacted for 16 hours. After the reaction solution cooled to room temperature, it was filtered. The filtrate was diluted with 400mL of water and extracted with ethyl acetate (300mL × 3). The combined organic phases were washed with 500mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0) to obtain compound M7-3. 1 H NMR (400MHz, CDCl3) δ = 8.79 (s, 2H), 7.27 (s, 1H), 6.73 (t, J = 55.2Hz, 1H), 2.15 (s, 3H), 1.94 (d, J = 6.8Hz, 3H); 19 F NMR (376MHz, CDCl3) δ (ppm) = -113.296.

[0372] Step 3: Under a nitrogen atmosphere at 0°C, sulfonyl chloride (72.1 g, 534 mmol) was slowly added dropwise to a solution of compound M1-4 (69.9 g, 623 mmol) in dichloromethane (1.3 L). The reaction mixture was stirred at 0°C for 0.5 hours. Then, a solution of compound M7-3 (5.4 g, 29.3 mmol) in dichloromethane (300 mL) was slowly added dropwise. The reaction mixture was then heated to 25°C and reacted for 16 hours. 500 mL of saturated sodium bicarbonate solution was added to the reaction mixture, followed by adjustment of the pH to 8 with sodium carbonate solid. The mixture was extracted with dichloromethane (500 mL × 3). The combined organic phases were washed with 500 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-3:2) to obtain compound M7-4. LCMS (m / z): 330.9 [M+H] + .

[0373] Step 4: Under a nitrogen atmosphere at 0°C, m-chloroperoxybenzoic acid (147 g, 726 mmol, 85% purity) was slowly added in portions to a solution of compound M7-4 (80 g, 242 mmol) in dichloromethane (1.5 L). After the addition was complete, the reaction solution was heated to 25°C and reacted for 16 hours. Dichloromethane (200 mL) was added to the reaction solution, followed by washing with saturated sodium bicarbonate solution (500 mL × 3) and saturated sodium chloride aqueous solution (500 mL). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. This crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-1:1) to obtain compound M7-5. LCMS (m / z): 363.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 9.09 (d, J = 4.8Hz, 2H), 9.05 (s, 2H), 7.88 (t, J = 4.8Hz, 1H) ,7.23(t,J=54.8Hz,1H),5.74(q,J=7.2Hz,1H),2.29(s,3H),1.69(d,J=7.2Hz,3H); 19 F NMR (376MHz, CDCl3) δ (ppm) = -113.615.

[0374] Step 5: Under a nitrogen atmosphere, potassium carbonate (48.0 g, 347 mmol) was added to a mixed solution of compound M7-5 (42 g, 116 mmol) in methanol (210 mL), acetonitrile (210 mL), and water (210 mL). The reaction solution was heated to 50 °C and reacted for 4 hours. The reaction solution was then directly concentrated under reduced pressure to remove the organic solvent, yielding a crude mixture of compound M7-6. LCMS (m / z): 249.1 [M+H] + .

[0375] Step 6: Under a nitrogen atmosphere at 0°C, potassium acetate (11.4 g, 116 mmol) was added to an aqueous solution of compound M7-6 (33.15 g, crude mixture) and compound M5-7 (26.2 g, 232 mmol) in 330 mL of water. The reaction mixture was heated to 40°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was extracted with dichloromethane (200 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound M7-7. LCMS (m / z): 264.0 [M+H] + .

[0376] Step 7: Under a nitrogen atmosphere, add rhodium (I) di(1,5-cyclooctadiene)tetrafluoroborate (683 mg, 1.06 mmol) to an anhydrous methanol (100 mL) solution of compound M7-7 (5.6 g, 21.3 mmol), zinc trifluoromethanesulfonate (773 mg, 2.13 mmol), and (S)-1-{(RP)-2-[bis(1-naphthyl)phosphine]ferrocene}ethyl di-tert-butylphosphine (432 mg, 1.06 mmol). After purging with hydrogen three times, react for 16 hours at 50 °C under a hydrogen atmosphere (50 Psi). Cool the reaction solution to room temperature, filter, concentrate the filtrate to obtain the crude product, and preparatively separate the crude product by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Mobile phase: water (0.1% ammonia) - acetonitrile; gradient (acetonitrile %): 52%) yielded compound M7. LCMS (m / z): 266.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.99 (s, 2H), 7.20 (t, J = 54.8Hz, 1H), 6.87 (s, 2H), 3.82-3.63 (m, 2H), 1.34 (d, J = 6.8Hz, 3H), 1.25 (d, J = 6.8Hz, 3H); 19 F NMR (376MHz, CDCl3) δ (ppm) = -112.942; SFC detection (column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 10%-60%), showed that compound M7 contains two isomers with retention times of 1.217 min (content 88.51%) and 1.067 min (content 11.49%), respectively.

[0377] intermediate M8

[0378]

[0379] Step 1: Under a nitrogen atmosphere at room temperature, tris(diphenylmethyleneacetone)palladium (2.20 g, 2.40 mmol), tricyclohexylphosphine (1.35 g, 4.81 mmol), and potassium phosphate aqueous solution (5 M, 14.42 mL) were slowly added in portions to a dioxane (50 mL) solution of compound M8-1 (5 g, 24.04 mmol) and compound M1-2 (5.84 g, 36.06 mmol). The reaction solution was heated to 100 °C and reacted for 2 hours. Ethyl acetate (200 mL) was added to the reaction solution, and the mixture was filtered. Water (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 1000 × 500 mm × 50 μm; mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 50%-70%) to obtain compound M8-2. LCMS (m / z): 184.2 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ = 8.65 (d, J = 0.8Hz, 1H), 7.77 (dd, J = 2.0, 8.4Hz, 1H), 7.56 (d, J = 8. 0Hz,1H),6.82-6.43(m,1H),5.97(q,J=6.8Hz,1H),2.05(s,3H),1.84(d,J=6.8Hz,3H); 19 F NMR (376MHz, CDCl3) δ=-115.225.

[0380] Step 2: Under a nitrogen atmosphere at 0°C, sulfuryl chloride (3.18 g, 23.58 mmol) was slowly added dropwise to dichloromethane (40 mL) containing compound M1-4 (3.31 g, 29.48 mmol). After the addition was complete, the reaction solution was allowed to react at 0°C for 0.5 hours. Then, compound M8-2 (3.6 g, 19.65 mmol) was added to the reaction solution, and the temperature was slowly raised to 25°C for 0.5 hours. The reaction solution was then slowly added to water (100 mL), and extracted with dichloromethane (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (hexane:ethyl acetate = 1 / 1-0 / 1) to obtain compound M8-3. LCMS (m / z): 330.0 [M+1] + .

[0381] Step 3: Under a nitrogen atmosphere at 0°C, m-chloroperoxybenzoic acid (9.23 g, 45.48 mmol, 85% purity) was slowly added in portions to dichloromethane (50 mL) containing compound M8-3 (5 g, 15.16 mmol). After the addition was complete, the reaction mixture was allowed to react at room temperature for 12 hours. The reaction mixture was then slowly added to a saturated sodium sulfite aqueous solution (400 mL), and extracted with dichloromethane (150 mL × 3). The combined organic phases were then washed successively with a saturated sodium sulfite aqueous solution (400 mL) and a saturated brine solution (150 mL). The mixture was dried over anhydrous sodium sulfate, 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 1000 × 500 mm × 50 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 50%-70%) to obtain compound M8-4. LCMS(m / z): 362.0 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.91 (d, J = 4.8Hz, 2H), 8.80 (s, 1H), 8.08 (br d,J=7.6Hz,1H),7.73(t,J=4.8Hz,1H),7.47(d,J=8.2Hz,1H),7.05-6.71(m,1H),5.09-5.04(m,1H),2.27(s,3H),1.65(d,J=7.2Hz,3H).

[0382] Step 4: Under a nitrogen atmosphere at room temperature, potassium carbonate (687.62 mg, 4.98 mmol) was added to a mixed solution of compound M8-4 (900 mg, 2.49 mmol) in acetonitrile (5 mL) and water (5 mL). The reaction solution was heated to 40 °C and reacted for 2 hours. Then, 5 mL of methanol was added, and the reaction was heated to 50 °C and reacted for 0.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound M8-5.

[0383] Step 5: Under a nitrogen atmosphere at room temperature, potassium acetate (240.75 mg, 2.45 mmol) and M5-7 (554.85 mg, 4.91 mmol) were added to 10 mL of water containing compound M8-5 (700 mg, 2.45 mmol). The reaction solution was heated to 40 °C and reacted for 12 hours. The reaction solution was directly separated by reversed-phase column chromatography (column: Phenomenex luna C18 500 × 250 mm × 25 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 70%-80%) to obtain compound M8-6. LCMS (m / z): 263.1 [M+1] + ; 1H NMR (400MHz, CDCl3) δ = 8.49 (s, 1H), 7.74-7.66 (m, 2H), 6.67 (t, J = 55.6Hz, 1H), 4.83 (br s, 2H), 2.50-2.44 (m, 3H), 1.98 (d, J = 1.6Hz, 3H); 19 F NMR (376MHz, CDCl3) δ=-115.834.

[0384] Step 6: Under a nitrogen atmosphere at room temperature, palladium on carbon (200 mg, 10% purity) was added in portions to a methanol (10 mL) solution of compound M8-6 (450 mg, 1.72 mmol). After three purgings with hydrogen, the reaction was carried out at 45 °C for 12 hours under a hydrogen atmosphere (50 psi pressure). The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound M8 was then preparatively separated by reversed-phase column chromatography (column: Phenomenexluna C18 250 × 250 mm × 25 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 60%-80%). LCMS (m / z): 265.1 [M+1] + ; 1 H NMR(400MHz,DMSO-d6)δ=8.60(br s,1H),7.90(dd,J=2.0,8.0Hz,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=7.2Hz,1H),1.33(d,J=7.2Hz,2H),1.21(d,J=7.2Hz,2H),1.07(d,J=7.2Hz,1H); 19 F NMR (376MHz, DMSO-d6) δ = -114.831.

[0385] intermediate M9

[0386]

[0387] Step 1: Under a nitrogen atmosphere at 0°C, compound M9-1 (9.01 g, 65.68 mmol) was added to an anhydrous acetonitrile (240 mL) solution of compounds 1-3 (12 g, 54.73 mmol) and cesium carbonate (23.18 g, 71.15 mmol). The reaction solution was reacted at room temperature for 12 hours to obtain an acetonitrile solution of compound M9-2, which was directly used in the next step. LCMS (m / z): 357.1 [M+H] + .

[0388] Step 2: Under a nitrogen atmosphere at 0°C, silver nitrate (14.2 g, 83.59 mmol) was added to an acetonitrile solution of compound M9-2 obtained in Step 1 and an anhydrous acetonitrile solution of compound 1-2 (12.40 g, 82.06 mmol) (200 mL). The reaction mixture was allowed to react at room temperature for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound M9-3. LCMS (m / z): 474.2 [M+H] + .

[0389] Step 3: Under a nitrogen atmosphere at room temperature, trifluoroacetic acid (17.26 mL) was added to an anhydrous dioxane (1500 mL) solution of compound M9-3 (22 g, 46.46 mmol). The reaction solution was reacted at 100 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 5:0, followed by dichloromethane: ethyl acetate = 1:1) to obtain compound M9-4. LCMS (m / z): 456.3 [M+H] + .

[0390] Step 4: Under a nitrogen atmosphere at room temperature, anisole (8.55 g, 79.03 mmol) was added to a trifluoroacetic acid (60 mL) solution of compound M9-4 (12 g, 26.34 mmol). The reaction solution was reacted at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The pH of the crude product was adjusted to 7.5-8 with a 10% sodium bicarbonate aqueous solution (150 mL), and a solid precipitated. The mixture was stirred for 15 min and filtered. The filter cake was collected, and acetonitrile (20 mL) and petroleum ether (30 mL) were added. The mixture was stirred at room temperature for 15 min, filtered, and the filter cake was dried to obtain compound M9-5. LCMS (m / z): 336.2 [M+H] + .

[0391] Step 5: Under a nitrogen atmosphere at 0°C, dichloroacetic acid (5.10 mL, 62.02 mmol) was slowly added dropwise 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 200 mL of dibromomethane. The reaction mixture was reacted at room temperature for 2 hours. The reaction mixture 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 (250 × 70 mm, 10 μm); mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 40%-80%) to obtain compound M9. 1H NMR (400MHz, CDCl3) δ = 8.44 (d, J = 1.2Hz, 1H), 8.39 (d, J = 1.6Hz, 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] + .

[0392] Intermediate M10

[0393]

[0394] Step 1: Under a nitrogen atmosphere at room temperature, potassium carbonate (28.9 g, 209 mmol) and cuprous iodide (1.99 g, 10.5 mmol) were added to an anhydrous N,N-dimethylformamide (250 mL) solution of compound M10-1 (18.0 g, 105 mmol) and 4-nitropyrazole (17.7 g, 157 mmol). The nitrogen atmosphere was purged three times, and the reaction mixture was heated to 120 °C and reacted for 36 hours. The reaction mixture was poured into 400 mL of water and extracted with ethyl acetate (300 mL × 2). The combined organic phases were washed with saturated brine (400 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. 100 mL of ethyl acetate was added to the crude product, and the mixture was stirred at room temperature for 10 min. The mixture was filtered, and the filter cake was dried to obtain compound M10-2. 1 H NMR (400MHz, DMSO-d6) δ = 9.70 (s, 1H), 8.98 (d, J = 2.4Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.21 (s, 1H), 2.41 (s, 3H).

[0395] Step 2: Under a nitrogen atmosphere at 50°C, iron powder (6.15 g, 110 mmol) was slowly added in portions to a mixed solution of compound M10-2 (4.5 g, 22.0 mmol), ammonium chloride (1.41 g, 26.5 mmol), ethanol (90 mL), and water (22 mL). The reaction solution was heated to 80°C and reacted for 1 hour. The reaction solution was filtered, and 50 mL of saturated sodium chloride aqueous solution and 30 mL of saturated sodium bicarbonate aqueous solution were added to the filtrate. The mixture was extracted with ethyl acetate (120 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound M10-3.

[0396] Step 3: Under a nitrogen atmosphere at room temperature, a mixture of compound M10-3 (3.0 g, 17.2 mmol) and di-tert-butyl dicarbonate (15.0 g, 68.9 mmol) was reacted at 25 °C for 2 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (20 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to give compound M10-4. LCMS (m / z): 275.0 [M+1] + .

[0397] Step 4: Under a nitrogen atmosphere at -40°C, liquid bromine (0.86 mL, 16.8 mmol) was slowly added dropwise to a dichloromethane (50 mL) solution of compound M10-4 (2.30 g, 8.38 mmol). The reaction mixture was reacted at -40°C for 0.5 hours. The reaction mixture was then poured into an ice-cold saturated sodium sulfite aqueous solution (200 mL), extracted with dichloromethane (30 mL × 2), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to obtain compound M10-5. 1 H NMR (400MHz, CDCl3) δ = 8.68 (d, J = 2.0Hz, 1H), 8.49 (d, J = 0.8Hz, 1H), 8.17 (br s, 1H), 7.72 (s, 1H), 6.20 (br s, 1H), 2.44 (s, 3H), 1.55 (s, 9H).

[0398] Step 5: Under a nitrogen atmosphere at room temperature, potassium carbonate (470 mg, 3.40 mmol) and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (120 mg, 170 μmol) were added to a mixed solution of compound M10-5 (600 mg, 1.70 mmol), compound M3 (587 mg, 2.04 mmol), dioxane (12 mL), and water (3 mL). Nitrogen was purged three times, and the reaction mixture was heated to 100 °C and reacted for 1 hour. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (8 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Purification by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-1:2) yielded compound M10-6. LCMS (m / z): 435.3 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 8.30 (d, J = 1.2Hz, 1H), 8.11 (d, J = 2.4Hz, 1H), 8.08-8.00 (m, 1H), 7.95 (br s,1H),7.56(t,J=2.0Hz,1H),7.12(s,1H),4.51-4.40(m,2H),4.18(q,J=8.8Hz,2H),3.10-2.99(m,4H),2.28(s,3H),1.42(br s,9H).

[0399] Step 6: Under a nitrogen atmosphere at room temperature, add 3 mL of trifluoroacetic acid to a 3 mL solution of compound M10-6 (500 mg, 1.15 mmol) in dichloromethane. React the solution at 25 °C for 1 hour. Concentrate the reaction solution under reduced pressure to obtain a crude product, then add 5 mL of ice-cold sodium bicarbonate aqueous solution and extract with ethyl acetate (7 mL × 2). Combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 2-7. 1 H NMR (400MHz, DMSO-d6) δ = 8.21 (d, J = 1.2Hz, 1H), 8.08 (d, J = 2.4Hz, 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).

[0400] Step 7: Under a nitrogen atmosphere at room temperature, add tetrabutylammonium bromide (723 mg, 2.24 mmol) to a solution of compound M10-7 (250 mg, 748 μmol) in dibromomethane (4 mL). Heat to 60 °C and slowly add isoamyl nitrite (175 mg, 1.50 mmol) dropwise to the reaction solution, stirring for 1 hour. Pour the reaction solution into water (3 mL), extract with ethyl acetate (5 mL × 3), and dry the combined organic layers with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. Preparatively separate by reversed-phase column chromatography (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 25%-60%) to obtain compound M10. LCMS (m / z): 398.1, 400.0 [M+1] + .

[0401] intermediate M11

[0402]

[0403] Step 1: Under a nitrogen atmosphere, potassium carbonate (5.81 g, 42.05 mmol) was added to an anhydrous N,N-dimethylformamide (10 mL) solution of compound M11-1 (1 g, 10.51 mmol). The reaction was carried out at 25 °C for 0.5 h. Then, p-methoxybenzyl chloride (4.94 g, 31.54 mmol) was slowly added dropwise to the reaction solution, and the reaction mixture was continued to react at 25 °C for 12 h. The reaction solution was filtered, and the filtrate was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 35%-65%) to obtain compound M11-2. LCMS (m / z): 358.1 [M+23] + .

[0404] Step 2: Under a nitrogen atmosphere at -70°C, n-butyllithium (2.5M tetrahydrofuran solution, 1.55mL) was added dropwise to a tetrahydrofuran (10mL) solution of compound M11-2 (1g, 2.98mmol). After the addition was complete, the reaction solution was reacted at -70°C for 0.5 hours. Then, a tetrahydrofuran (2mL) solution of compound M11-3 (881.13mg, 4.47mmol) was slowly added dropwise to the reaction solution, and the reaction solution was reacted at -70°C for another 1.5 hours. Water (20mL) was added dropwise to the reaction solution, and the mixture was extracted with ethyl acetate (15mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-2:1) to obtain compound M11-4. LCMS (m / z): 452.1 [M+H] + .

[0405] Step 3: Under a nitrogen atmosphere, trifluoroacetic acid (5.22 g, 45.77 mmol) was added to a solution of compound M11-4 (340 mg, 752.98 μmol) in anhydrous dichloromethane (1.7 mL), and the reaction was carried out at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and dichloromethane (10 mL) was added to the residue. The pH was adjusted to 7-7.5 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 (250 × 70 mm, 10 μm); mobile phase: water (0.1% formic acid)-acetonitrile; gradient (acetonitrile %): 35%-65%) to obtain compound M11. LCMS (m / z): 212.0 [M+H] + .

[0406] intermediate M12

[0407]

[0408] Step 1: Under a nitrogen atmosphere, compound M12-1 (979.50 mg, 4.49 mmol) was added to a solution of compound M11-3 (2 g, 10.15 mmol) in acetonitrile (30 mL). The reaction mixture was reacted at 25 °C for 12 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (60 mL × 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. This crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1-5:1) to obtain compound M12-2. LCMS (m / z): 192.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.69 (d, J = 1.2Hz, 1H), 8.03-7.92 (m, 2H), 4.21 (s, 2H), 2.36 (s, 3H).

[0409] Step 2: Under a nitrogen atmosphere at 0°C, add dropwise a solution of compound M12-2 (0.8 g, 4.16 mmol) in acetonitrile (1 mL) to a solution of NCS (2.22 g, 16.65 mmol) and hydrochloric acid (2 M, 0.8 mL) in acetonitrile (4 mL). Stir the reaction mixture at 0°C for 30 minutes. Pour the reaction mixture into ammonia water (6 mL), and continue stirring the mixture at 0°C for 30 minutes. Water (20 mL) was added to the reaction solution, and the pH was adjusted to 3 with 4N hydrochloric acid. The solution was then extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then preparatively separated by reversed-phase column chromatography (column: Waters Xbridge C18 150*50 mm*10 μm; mobile phase: water (10 mM NH4HCO3)-acetonitrile; gradient (acetonitrile %): 22%-52%) to obtain compound M12. LCMS (m / z): 197.9 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.71 (d, J = 1.6Hz, 1H), 8.12-8.06 (m, 1H), 8.04-8.00 (m, 1H), 7.01 (s, 2H), 4.48 (s, 2H).

[0410] Intermediate M13

[0411]

[0412] Step 1: Under a nitrogen atmosphere at room temperature, tricyclohexylphosphine (860.35 mg, 3.07 mmol), potassium phosphate (9.77 g, 46.02 mmol), and tris(diphenylmethyleneacetone)dipalladium (1.4 g, 1.53 mmol) were added sequentially to a solution of dioxane (40 mL) and water (4 mL) of compounds M13-1 (2.8 g, 15.34 mmol) and M1-2 (2.74 g, 16.94 mmol). The reaction solution was reacted at 95 °C for 4.5 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound M13-2 was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1). LCMS (m / z): 203.1 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 7.63 (dd, J = 1.2, 4.4Hz, 1H), 7.10 (d, J = 16.0Hz, 1H), 6.66 (dq, J = 1.2, 7.2Hz, 1H), 2.26-2.23 (m, 3H), 1.97 (dd, J = 1.2, 7.2Hz, 3H).

[0413] Step 2: Under a nitrogen atmosphere at 0°C, sulfonyl chloride (1.86 g, 13.75 mmol) was slowly added dropwise to a dichloromethane (28 mL) solution of compound M1-4 (1.54 g, 13.75 mmol). The reaction solution was reacted at 0°C for 1 hour to obtain reaction solution 1. A dichloromethane (28 mL) solution of compound M13-2 (2.78 g, 13.75 mmol) was then slowly added dropwise to reaction solution 1. After the addition was complete, the temperature was slowly raised to 25°C, and the reaction was carried out for 2 hours. Another batch of reaction solution 1 was added at 0°C, and the reaction was continued at 25°C for 15 hours. The reaction solution was slowly added to a saturated sodium bicarbonate aqueous solution (150 mL), followed by water (30 mL). The mixture was extracted with dichloromethane (100 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 = 5:1) to obtain compound M13-3. LCMS(m / z): 348.9 [M+H] + .

[0414] 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] + .

[0415] 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.

[0416] 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] + .

[0417] 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) - acetonitrile; gradient (acetonitrile %): 30% ) yielded compound M13. LCMS (m / z): 284.0 [M+H] + SFC detection (column: Chiralpak AD-3 100×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 5%-40%), compound M13 contains two isomers with retention times of 3.517 min (content 60.19%) and 4.989 min (content 39.81%), respectively.

[0418] Example 001

[0419]

[0420] Step 1: Under a nitrogen atmosphere at 25°C, slowly add 7.79 g of 85% hydrazine hydrate to a methanol (100 mL) solution of compound 001-1 (10.0 g, 66.1 mmol). Stir the reaction mixture at 25°C for 12 hours. Concentrate the reaction mixture under reduced pressure, add 100 mL of n-hexane to the residue, stir at room temperature for 30 minutes, filter, wash the filter cake with 50 mL of petroleum ether, and dry the filter cake to obtain compound 001-2.

[0421] Step 2: Under a nitrogen atmosphere at 0°C, sodium bicarbonate solid (56.9 mg, 677 μmol) and phosgene (42.8 mg, 372 μmol) were slowly added sequentially to a solution of compound M2 (60 mg, 338 μmol) in dichloromethane (0.3 mL) and pure water (0.2 mL). The mixture was stirred at 0°C for 10 min, then heated to 25°C and reacted for 1 hour. Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound 001-3.

[0422] Step 3: Under a nitrogen atmosphere at 0°C, add compound 001-3 (73.6 mg, 336 μmol) and cesium carbonate (129 mg, 396 μmol) to a 1 mL solution of compound M2 (70 mg, 305 μmol) in acetonitrile (1 mL). Stir the reaction solution at 25°C for 12 hours to obtain the reaction solution of compound 001-4, which can be directly used in the next step.

[0423] Step 4: Under a nitrogen atmosphere at 0°C, add compound 001-2 (45.5 mg, 301 μmol) and silver nitrate (0.08 g, 471 μmol) to the reaction solution of compound 001-4 obtained in Step 3. Heat to 25°C and stir for 0.5 hours. Add the reaction solution to acetonitrile (50 mL), filter, and concentrate the filtrate under reduced pressure to obtain compound 001-5. LCMS (m / z): 566.1 [M+H] + .

[0424] Step 5: Under a nitrogen atmosphere at 25°C, add methanesulfonic acid (86.6 mg, 902 μmol) to a solution of compound 001-5 (170 mg, 300 μmol) in dioxane (1.5 mL). Stir the reaction mixture at 100°C for 3 hours. Slowly add saturated sodium bicarbonate aqueous solution to the reaction mixture to adjust the pH to 7-8, then extract with dichloromethane (50 mL × 2). Wash the combined organic layers with saturated brine (100 mL × 2), dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was preparatively separated by reversed-phase column chromatography (column: Waters Xbridge 150×25mm×5μm; mobile phase: [water (0.5% ammonia)-acetonitrile]; gradient (B%): 25%-32%), followed by further preparative separation by reversed-phase column chromatography (column: Phenomenex luna C18 150×25mm×10μm; mobile phase: [water (0.1% formic acid)-acetonitrile]; gradient (B%): 36%-56%) to obtain compound 001. LCMS (m / z): 548.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 13.44 (s, 1H), 8.59 (s, 2H), 8.51 (d, J = 1.2Hz, 1H), 8.31 (d, J =1.6Hz,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=7.2Hz,3H),1.14(d,J=7.2Hz,3H). SFC detection (column: Chiralpak AD-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical CO2, phase B is 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%.

[0425] Example 002

[0426]

[0427] Under a nitrogen atmosphere at room temperature, potassium carbonate (31.2 mg, 226 μmol), cuprous iodide (14.4 mg, 75.3 μmol), and compound M1 (51.8 mg, 226 μmol) were added to a dioxane (1.5 mL) solution of N,N-dimethylcyclohexanediamine (10.7 mg, 75.3 μmol). The nitrogen atmosphere was purged three times, and the reaction mixture was heated to 100 °C and reacted for 16 hours. The reaction mixture was then poured into water (4 mL), extracted with ethyl acetate (4 mL × 3), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:0-0:1) to obtain a crude product, which was then preparatively separated by reversed-phase column chromatography (column: Waters Xbridge 150×25mm×5μm; mobile phase: [water (10mMNH4HCO3)-acetonitrile]; gradient (acetonitrile%): 35%-65%) to obtain compound 002. LCMS (m / z): 547.1 [M+1] + ; 1 HNMR (400MHz, DMSO-d6) δ = 8.92 (s, 1H), 8.59 (s, 2H), 8.32 (d, J = 1.2Hz, 1H), 8.15 (d, J = 2.4Hz, 1H), 7.77 (s, 1H), 7.6 2(s,1H),7.04(s,1H),4.49(q,J=8.4Hz,1H),4.29(q,J=8.8Hz,1H),4.17-4.00(m,2H),3.66-3.51(m,2H),3.01(br The chiral purity of compound 002 was 2.122 min, with wavelengths of 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), and 0.96 (d, J = 6.8 Hz, 3H). SFC detection (column: Chiralpak IC-3 50*4.6 mm ID, 3 μm; mobile phase: A phase was supercritical CO2, B phase was ethanol (0.05% diethylamine); gradient (B%): 20%–60%).

[0428] Example 003

[0429]

[0430] Under a nitrogen atmosphere, methanesulfonic acid (4.23 g, 44.02 mmol) was slowly added to a dioxane (830 mL) solution of compound 001-5 (8.3 g, 14.67 mmol). The reaction mixture was heated to 100 °C and stirred for 8 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, dissolved in 500 mL of dichloromethane, and the pH was adjusted to 8 by slowly adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane (500 mL × 2), and the combined organic layers were washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100 / 1-20 / 1) to obtain the crude product. A petroleum ether / ethanol (15 / 1, 20 mL) mixture was added to the crude product, stirred at room temperature for 15 min, filtered, and the mother liquor was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.1% trifluoroacetic acid)-acetonitrile; gradient (acetonitrile%): 38%-68%), yielding a mixture of compounds 001 and 003. This mixture was then purified by SFC (column: DAICELCHIRALPAK IC (250mm*30mm, 10μm); mobile phase: A phase was supercritical CO2, B phase was EtOH / acetonitrile / 0.1% ammonia (ethanol and acetonitrile volume ratio 4:1); gradient (B%): 50%), yielding compound 003. LCMS (m / z): 546.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.58 (s, 2H), 8.35 (s, 1H), 8.25 (s, 1H), 8.15 (br d, J = 7.9Hz, 1H), 7.79-7.74 (m, 1H), 7.63 (br s,1H),7.58(s,1H),6.90(dd,J=2.1,7.6Hz,1H),4.66-4.55(m,1H),4.54-4.46(m,1H),3.90-3.83(m,1H),3.71(br d,J=5.0Hz,1H),3.30(br d, J=8.7Hz, 2H), 2.23 (s, 3H), 2.20 (d, J=1.6Hz, 3H), 1.21 (dd, J=7.2, 12.0Hz, 3H), 1.03 (dd, J=7.0, 16.7Hz, 3H).

[0431] Example 004

[0432]

[0433] Step 1: Under a nitrogen atmosphere at 0°C, slowly add compound 001-3 (300 mg, 1.37 mmol) and cesium carbonate (580 mg, 1.78 mmol) to a 5 mL solution of acetonitrile (70 mg, 305 μmol) of compound M4. Stir the reaction solution at 25°C for 12 hours to obtain the reaction solution of compound 004-1, which can be used directly in the next step. LCMS (m / z): 501.1 [M+H] + .

[0434] Step 2: Under a nitrogen atmosphere at 0°C, compound 001-2 (308 mg, 2.04 mmol) was added to the reaction solution of compound 004-1, followed by slow, partial addition of silver nitrate (346 mg, 2.04 mmol). The mixture was stirred at 0°C for 1 hour. The reaction solution was diluted with 50 mL of acetonitrile, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 004-2. LCMS (m / z): 618.2 [M+H] + .

[0435] Step 3: Under a nitrogen atmosphere, methanesulfonic acid (345 mg, 3.59 mmol) was added to a 100 mL solution of dioxane (740 mg, 1.20 mmol) of compound 004-2. The reaction mixture was heated to 100 °C and stirred for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. Compound 004 was purified by reversed-phase column chromatography (column: Phenomenex luna C18 150 × 25 mm × 10 μm; mobile phase: [water (0.1% formic acid) - acetonitrile]; gradient (acetonitrile %): 36%-56%). LCMS (m / z): 600.2 [M+H] + .

[0436] Step 4: Compound 004 was separated by SFC (REGIS(S,S)WHELK-O1 column (250mm*25mm, 10μm; mobile phase: A phase is supercritical CO2, B phase is isopropanol (0.1% ammonia); gradient (B%): 35%) to obtain compounds 004A and 004B. Characterization of compound 004A: LCMS (m / z): 600.2 [M+H] + ; 1H NMR (400MHz, CDCl3) δ = 11.07 (brs, 1H), 8.60-8.20 (m, 2H), 7.79 (s, 1H), 7.54 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 7.03 (s, 1H), 4.64- 4.39(m,4H),3.49(t,J=7.2Hz,1H),3.25(t,J=7.2Hz,1H),3.21-3.02(m,4H),2.35(s,3H),1.50(d,J=7.2Hz,3H),1.16(d,J=7.2Hz,3H). SFC analysis (Chromatographic column (S,S)Whelk-O1 50*4.6mm ID, 3.5μm; mobile phase: A phase is supercritical CO2, B phase is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that the retention time of compound 004A was 3.581 min and the chiral purity was 98.98%.

[0437] Characterization of compound 004B: LCMS (m / z): 600.2 [M+H] + ; 1 H NMR (400MHz, CDCl3) δ = 11.01 (s, 1H), 8.48 (s, 1H), 8.39 (d, J = 1.6Hz, 1H), 7.80 (s, 1H), 7.54 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 7.04 (s, 1H) ,4.63-4.40(m,4H),3.49(t,J=7.2Hz,1H),3.25(t,J=7.2Hz,1H),3.20- 3.06 (m, 4H), 2.36 (s, 3H), 1.51 (d, J = 7.2Hz, 3H), 1.16 (d, J = 7.2Hz, 3H). SFC analysis (Chromatographic column (S,S) Welk-O1 50*4.6mm ID, 3.5μm; mobile phase: A phase is supercritical CO2, B phase is isopropanol (0.05% diethylamine); gradient (B%): 5%-40%) showed that the retention time of compound 004B was 3.806 min and the chiral purity was 98.09%.

[0438] Example 005

[0439]

[0440]

[0441] Step 1: Under a nitrogen atmosphere at 0°C, compound 001-3 (120 mg, 547.30 μmol) and cesium carbonate (231.82 mg, 711.49 μmol) were slowly added to a 4 mL acetonitrile solution of compound M5 (155.03 mg, 547.30 μmol). The reaction mixture was stirred at 25°C for 12 hours to obtain an acetonitrile solution of compound 005-1, which was directly used for the next reaction. LCMS (m / z): 503.1 [M+H] + .

[0442] Step 2: Under a nitrogen atmosphere at 0°C, compound 001-2 (81.22 mg, 537.28 μmol) was added to an acetonitrile solution of compound 005-1 obtained in Step 1, followed by the addition of silver nitrate (0.15 g, 883.01 μmol) in portions. After the addition was complete, the reaction solution was stirred at 0°C for 2 hours. 50 mL of acetonitrile was added to the reaction solution, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 100 / 1-10 / 1) to obtain compound 005-2. LCMS (m / z): 620.3 [M+H] + .

[0443] Step 3: Under a nitrogen atmosphere at 25°C, methanesulfonic acid (20.76 μL, 290.50 μmol) was slowly added to a dioxane (5 mL) solution of compound 005-2 (60 mg, 96.83 μmol). The reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL). Then, sodium bicarbonate aqueous solution was slowly added to adjust the pH to 7-8, followed by extraction with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile%): 40%-70%) to obtain compound 005. LCMS(m / z): 602.1 [M+H] + SFC detection (Column: Chiralpak IH-3 50*4.6mm ID, 3μm; Mobile phase: Phase A is supercritical CO2, Phase B is EtOH (0.05% diethylamine); Gradient (B%): 20%-60%) Compound 005 contains two isomers in a ratio of approximately 5.5:1.

[0444] Step 4: Compound 005 was separated by SFC (column: ChiralPak IH, 250*50mm, 10μm; mobile phase: phase A is supercritical CO2, phase B is ethanol (0.1% ammonia); gradient (B%): 45%) to obtain compound 005A and compound 005B.

[0445] Characterization of compound 005A: LCMS (m / z): 602.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6)δ=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=7.0Hz,3H),1.21-1.14(m,3H); 19 FNMR (376MHz, DMSO-d6) δ=-60.720; SFC detection (column: Chiralpak IH-3 50*4.6mm ID, 3μm; mobile phase: A phase is supercritical CO2, B phase is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 005A was 0.877 min, and the chiral purity was 99.30%.

[0446] Characterization of compound 005B: LCMS (m / z): 602.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=13.44(brs,1H),9.21(d,J=0.6Hz,2H),8.51(s,1H),8.30(d,J=1.9Hz,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=7.0Hz,3H),1.21(d,J=6.9Hz,3H); 19F NMR (376MHz, DMSO-d6) δ=-60.712; SFC detection (column: Chiralpak IH-3 50*4.6mm ID, 3μm; mobile phase: A phase is supercritical CO2, B phase is EtOH (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 005B is 1.224 min, and the chiral purity is 100%.

[0447] Example 006

[0448]

[0449]

[0450] Step 1: Under a nitrogen atmosphere at 0°C, compound 001-3 (320 mg, 1.46 mmol) and cesium carbonate (618.18 mg, 1.90 mmol) were added to a 20 mL acetonitrile solution of compound M6 (453.18 mg, 1.61 mmol). The reaction mixture was stirred at 25°C for 16 hours to obtain an acetonitrile solution of compound 006-1, which was used directly in the next step. LCMS (m / z): 502.1 [M+H] + .

[0451] Step 2: Under a nitrogen atmosphere at 0°C, compound 001-2 (264.39 mg, 1.75 mmol) was added to an acetonitrile solution of compound 006-1 obtained in Step 1, followed by the dropwise addition of a 3 mL acetonitrile solution containing silver nitrate (371.39 mg, 2.19 mmol). The reaction mixture was stirred at 0°C for 2 hours after the addition was complete. 50 mL of acetonitrile was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane:methanol = 40 / 1-30 / 1) to obtain compound 006-2. LCMS (m / z): 619.4 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 10.85-10.62 (m, 1H), 9.00-8.86 (m, 2H), 8.67-8.54 ( m,2H),8.14(brd,J=1.9Hz,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=7.8Hz,4H),2.38(s,3H),1.41-1.31(m,3H),1.20-1.09(m,3H).

[0452] Step 3: Under a nitrogen atmosphere at 25°C, trifluoroacetic acid (360.23 μL, 4.85 mmol) was added to a 10 mL solution of dioxane (10 mL) containing compound 006-2 (600.00 mg, 969.89 μmol). The reaction mixture was stirred at 100°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (500 mL). The pH was adjusted to 7-8 with a saturated sodium bicarbonate aqueous solution. The mixture was separated, and the aqueous phase was extracted again with dichloromethane (30 mL × 2). All organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reversed-phase column chromatography (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient (acetonitrile%): 40%-70%) to obtain compound 006.

[0453] Step 4: Compound 006 was purified by SFC (column: DAICL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.1% ammonia); gradient (B%): 50%) to obtain a mixture of compounds 006A and 006B / 006C / 006D. The mixture of compounds 006B / 006C / 006D was further purified by SFC (column: DAICL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.1% ammonia); gradient (B%): 40%) to obtain a mixture of compounds 006B and 006C and compound 006D.

[0454] Characterization of compound 006A: LCMS (m / z): 601.2 [M+H] + ; 1H NMR (400MHz, 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=8.2Hz,1H),7.74(s,1H),7.22(s,1H),4.63-4.41(m,4 H),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=7.2Hz,3H),1.15(br d,J=6.8Hz,3H). SFC analysis method 1 (column: Lux 3μm Cellulose-4 50*4.6mm ID, 3μm); mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 006A is 2.245 min, and the chiral purity is 99.14%. SFC analysis method 2 (column: CHIRALPAK AD-350*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 30%), the retention time of compound 006A is 0.886 min.

[0455] Characterization of a mixture of compounds 006B and 006C: LCMS (m / z): 601.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=13.60-13.39(m,1H),8.63-8.47(m,2H),8.30(d,J=1.4Hz,1H),7.93(br d,J=9.2Hz,1H),7.80(d,J=8.2Hz,1H),7.75(s,1H),7.23(s,1H),4.62-4.42(m,4H),3.57-3.47(m,1 H), 3.40-3.34 (m, 1H), 3.19-3.09 (m, 4H), 2.29 (s, 3H), 1.40 (d, J = 7.2Hz, 3H), 1.04 (d, J = 7.0Hz, 3H). SFC analysis method 2 test (chromatographic column: CHIRALPAK AD-3 50*4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 30%), the retention time of compound 006B was 1.016 min (content was 46.15%); the retention time of compound 006C was 1,189 min (content was 50.81%).

[0456] Characterization of compound 006D: LCMS (m / z): 601.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 13.49 (brs, 1H), 8.58 (s, 1H), 8.51 (s, 1H), 8.32 (s, 1H), 7.96-7.89 (m, 1H), 7.83 (d, J = 8.2Hz, 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 = 7.2Hz, 3H), 1.16 (d, J = 6.8Hz, 3H). SFC analysis method 2 test (chromatographic column: CHIRALPAK AD-3 50*4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 30%), the retention time of compound 006D is 1.370 min, and the chiral purity is 100%.

[0457] Example 007

[0458]

[0459] Step 1: Under a nitrogen atmosphere at 0°C, cesium carbonate (4.83 g, 14.8 mmol) was added to a 100 mL solution of acetonitrile containing compound 001-3 (2.5 g, 11.4 mmol) and compound M7 (3.3 g, 12.44 mmol). The reaction mixture was heated to 25°C and reacted for 16 hours. The reaction mixture was filtered, and the filter cake was dried to obtain compound 007-1. LCMS (m / z): 485.2 [M+H] + .

[0460] Step 2: Under a nitrogen atmosphere at 0°C, silver nitrate (2.9 g, 17.3 mmol) was slowly added in portions to a 200 mL solution of acetonitrile containing compounds 007-1 (5.4 g, 11.14 mmol) and 001-2 (1.68 g, 11.1 mmol). The reaction mixture was reacted at 0°C for 1 hour. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (100 mL × 3). The mother liquor was concentrated under reduced pressure to obtain compound 007-2. LCMS (m / z): 602.2 [M+H] + .

[0461] Step 3: Under a nitrogen atmosphere at 0°C, trifluoroacetic acid (5.78 g, 50.7 mmol) was added dropwise to a dioxane (60 mL) solution of compound 007-2 (6.1 g, 10.1 mmol). The reaction solution was heated to 100°C and reacted for 2 hours. After the reaction solution cooled to room temperature, it was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 20-45 μm). Compound 007 was prepared and separated by high performance liquid chromatography (HPLC) using a mobile phase of [water (0.225% formic acid)-acetonitrile] and a gradient (acetonitrile %) of 45%. The LCMS (m / z) result was 584.1 [M+H]. + ; 1 H NMR (400MHz, DMSO-d6) δ=13.43(s,1H),8.98(s,2H),8.51(s,1H),8.31(d,J=2.0Hz,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=7.2Hz,3H),1.19(d,J=7.2Hz,3H); 19 F NMR (376MHz, CD3CN) δ (ppm) = -112.924. SFC detection (column: Chiralpak IH-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 20%-60%) showed that compound 007 contains two isomers with retention times of 1.504 min (content 84.40%) and 1.161 min (content 15.60%), respectively.

[0462] Step 4: Compound 007 was purified by SFC (column: ChiralPak IH, 250×50mm, 10μm; mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.1% ammonia); gradient (B%): 50%) to obtain compounds 007A and 007B. Characterization of compound 007A: LCMS (m / z): 584.2 [M+H] +SFC detection (column: ChiralPak IH-350×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 007A was 1.161 min.

[0463] Characterization of compound 007B: LCMS (m / z): 584.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=13.43(s,1H),8.98(s,2H),8.51(s,1H),8.31(d,J=2.0H z,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=7.2Hz,3H),1.19(d,J=7.2Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ (ppm) = -112.931. SFC detection (column: ChiralPak IH-3 50×4.6mm ID, 3μm; mobile phase: A phase is supercritical carbon dioxide, B phase is ethanol (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 007B was 1.512 min, and the chiral purity was 100%.

[0464] Example 008

[0465]

[0466] Step 1: Under a nitrogen atmosphere at room temperature, cesium carbonate (482.95 mg, 1.48 mmol) was added to a 5 mL solution of acetonitrile containing compound 001-3 (250 mg, 1.14 mmol) and compound M8 (361.62 mg, 1.37 mmol). The reaction was allowed to proceed at room temperature for 2 hours to obtain an acetonitrile solution of compound 008-1, which was used directly in the next step. LCMS (m / z): 484.1 [M+1] + .

[0467] Step 2: Under a nitrogen atmosphere at 0°C, silver nitrate (180 mg, 105.96 mmol) was slowly added in portions to a 10 mL solution of acetonitrile containing compound 008-1 (400.00 mg, 827.21 μmol) and compound 001-2 (125.05 mg, 827.21 μmol). The reaction mixture was reacted at 0°C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 008-2 was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 250 × 140 mm × 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 70%-80%). LCMS (m / z): 601.3 [M+1] + .

[0468] Step 3: Under a nitrogen atmosphere at room temperature, trifluoroacetic acid (247.34 μL, 3.33 mmol) was added to a 5 mL solution of dioxane (5 mL) containing compound 008-2 (400.00 mg, 665.96 μmol). The reaction solution was reacted at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 250 × 140 mm × 10 μm; mobile phase: water (0.1% formic acid) - acetonitrile; gradient (acetonitrile %): 40%-60%) to obtain compound 008. LCMS (m / z): 583.1 [M+1] + .

[0469] Step 4: Compound 008 (150 mg) was prepared and separated by SFC (column: Chiralpak IH, 250×50 mm, 10 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.1% NH3·H2O); gradient (B%): 40%) to obtain two crude products (compound 008-P1 and compound 008-P2). SFC detection (column: Chiralpak IH-3 50×4.6 mm I.D. 3 μm; mobile phase: phase A is supercritical carbon dioxide, phase B is 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).

[0470] Compound 008-P1 was further prepared and separated by SFC (column: DAICEL CHIRALCEL OX (250mm×30mm, 10μm); mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.1% NH3·H2O); gradient (B%): 60%) to obtain compounds 008A and 008B.

[0471] Compound 008-P2 was further prepared and separated by SFC (column: DAICEL CHIRALCEL OJ (250mm×30mm, 10μm); mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.1% NH3·H2O); gradient (B%): 10%) to obtain compounds 008C and 008D.

[0472] Characterization of compound 008A: LCMS (m / z): 583.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 13.49 (s, 1H), 8.50 (br d,J=13.6Hz,2H),8.31(d,J=1.6Hz,1H),7.87-7.80(m,1H),7.75(s,1H),7.60(d,J=8.0Hz,1H),7.23(s,1H),6.91(t,J=54.8Hz,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=7.2Hz,3H),1.02(d,J=7.2Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-114.801; SFC detection (column: Lux 3μm Cellulose-4 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 30%-60%), the retention time of compound 008A was 1.995 min, and the chiral purity was 100%.

[0473] Characterization of compound 008B: LCMS (m / z): 583.2 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ=13.52(s,1H),8.51(dd,J=1.6,8.0Hz,2H),8.32(d,J=2.0Hz,1H),7.84(dd,J=2.0,8.0H z,1H),7.78-7.74(m,1H),7.63(d,J=8.4Hz,1H),7.24(s,1H),6.93(t,J=55.2Hz,1H),4.62-4.41(m,4H),3.59(br dd,J=3.6,7.2Hz,1H),3.22-3.06(m,5H),2.30(s,3H),1.29(d,J=7.2Hz,3H),1.15(d,J=7.2Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-114.793; SFC detection (column: Lux 3μm Cellulose-4 50×4.6mm ID, 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is MeOH (0.05% diethylamine); gradient (B%): 30%-60%), the retention time of compound 008B was 2.231 min, and the chiral purity was 99.28%.

[0474] Characterization of compound 008C: LCMS (m / z): 583.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 13.48 (s, 1H), 8.50 (dd, J = 2.0, 14.0Hz, 2H), 8.31 (d, J = 2.0Hz, 1H), 7.83 (dd, J = 2.0, 8.0Hz, 1H), 7.75 (s, 1H),7.60(d,J=8.0Hz,1H),7.23(s,1H),6.91(t,J=55.2Hz,1H),4.61-4.42(m,4H),3.49-3.40(m,1H),3.31-3.26(m,1H),3.14(br t,J=8.4Hz,4H),2.30(s,3H),1.39(d,J=7.2Hz,3H),1.02(d,J=7.0Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-114.801; SFC detection (column: Chiralcel OJ-3 50×4.6mm ID3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is EtOH (0.05% diethylamine); gradient (B%): 5%-20%), the retention time of compound 008C was 2.162 min, and the chiral purity was 99.04%.

[0475] Characterization of compound 008D: LCMS (m / z): 583.2 [M+1] + ; 1 H NMR (400MHz, DMSO-d6) δ = 13.52 (s, 1H), 8.51 (dd, J = 1.2, 7.2Hz, 2H), 8.32 (d, J=2.0Hz,1H),7.84(dd,J=2.0,8.0Hz,1H),7.76(s,1H),7.63(d,J=8.0Hz,1H) ,7.23(s,1H),6.93(t,J=55.2Hz,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=7.2Hz,3H),1.15(d,J=7.2Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-114.793; SFC detection (column: Chiralcel OJ-3 50×4.6mm ID3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is 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%.

[0476] Example 009

[0477]

[0478] Step 1: Under a nitrogen atmosphere, N-iodosuccinimide (3.54 g, 15.74 mmol) was added to a solution of compound 009-1 (3 g, 13.69 mmol) in dimethylformamide (30 mL). The reaction mixture was heated to 60 °C and reacted for 2 hours. The reaction mixture was cooled to room temperature, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 0 / 1 to 5 / 1) to give compound 009-2. LCMS (m / z): 345.9 [M+1] + ; 1 HNMR (400MHz, CDCl3) δ = 7.72 (d, J = 8.8Hz, 1H), 7.10 (d, J = 2.8Hz, 1H), 6.85 (dd, J = 2.8, 8.8Hz, 1H), 4.33 (br s, 2H); 19 F NMR (376MHz, CDCl3) δ = 62.81 (d, 4F), 84.64-83.85 (m, 1F).

[0479] Step 2: Under a nitrogen atmosphere, triethylamine (2.11 g, 20.87 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (508.91 mg, 695.51 μmol) were added to a methanol (30 mL) solution of compound 009-2 (2.4 g, 6.96 mmol). The mixture was purged three times with carbon monoxide, and the reaction was carried out at 80 °C for 17 hours under a carbon monoxide atmosphere (50 Psi). The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 0 / 1 to 10 / 1) to give compound 009-3. LCMS (m / z): 277.9 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ = 7.92 (d, J = 8.8Hz, 1H), 7.06 (d, J = 2.0Hz, 1H), 6.98 (dd, J = 2.4, 8.8Hz, 1H), 5.94 (br s, 2H), 3.91 (s, 3H); 19 F NMR (376MHz, CDCl3) δ = 61.76 (d, 4F), 83.94-83.14 (m, 1F).

[0480] Step 3: Under a nitrogen atmosphere at 0°C, tert-butyl nitrite (893 mg, 8.66 mmol) was added 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), and the reaction was carried out at 60°C for 2 hours. The reaction solution was quenched with ice water (30 mL), extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated sodium bicarbonate aqueous solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate = 0 / 1 to 10 / 1) to obtain compound 009-4. 1 H NMR (400 MHz, CDCl3) δ = 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).

[0481] Step 4: Under a nitrogen atmosphere, bis(diphenylphosphine) dioxane boronic acid ester (1.16 g, 4.57 mmol), potassium acetate (1.50 g, 15.25 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium(II) dichloromethane complex (311.24 mg, 381.13 μmol) were added to anhydrous dioxane (20 mL) solvent of compound 009-4. The mixture was purged with nitrogen three times and reacted at 80 °C for 2 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10 / 1 to 4 / 1) to obtain compound 009-5. 1 H NMR (400MHz, CDCl3) δ = 8.01 (d, J = 8.8Hz, 1H), 7.85-7.77 (m, 2H), 3.95 (s, 3H), 1.44 (s, 12H).

[0482] Step 5: Under a nitrogen atmosphere at 0°C, hydrogen peroxide (10.07 g, 100.66 mmol, 34% purity) was added to a tetrahydrofuran (25 mL) solution of compound 009-5 (1.4 g, 3.61 mmol) and sodium hydroxide (144.26 mg, 3.61 mmol), and the mixture was stirred at 25°C for 2 hours. A saturated aqueous solution of sodium sulfite (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 009-6. 1 H NMR (400MHz, CDCl3) δ = 10.88 (s, 1H), 7.93 (br d, J = 8.8Hz, 1H), 7.41 (d, J = 2.0Hz, 1H), 7.28 (br d, J = 2.4Hz, 1H), 4.01 (s, 3H).

[0483] Step 6: Under a nitrogen atmosphere, bromomethyl methyl ether (898 mg, 7.19 mmol) was added to a mixed solution of compound 009-6 (1 g, 3.59 mmol) and diisopropylethylamine (1.39 g, 10.78 mmol). The reaction solution was reacted at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 1 / 0 to 5 / 1) to obtain compound 009-7. 1 H NMR (400MHz, CDCl3) δ=7.83 (d, J=8.8Hz, 1H), 7.62 (d, J=2.0Hz, 1H), 7.48-7.41 (m, 1H), 5.35-5.24 (m, 2H), 4.00-3.92 (m, 3H), 3.60-3.50 (m, 3H).

[0484] Step 7: Under a nitrogen atmosphere at 0°C, hydrazine hydrate (8.46 mL, 165.67 mmol) was added to a methanol (10 mL) solution of compound 009-7 (0.9 g, 2.79 mmol). The reaction solution was reacted at 25°C for 17 hours. The reaction solution was quenched with hydrochloric acid (1 N, 0.5 mL), and then extracted with dichloromethane (60 mL × 3). The combined organic phases were 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 to 10 / 1) to obtain compound 009-8. 1 H NMR (400MHz, CDCl3) δ = 8.81 (br s, 1H), 8.29 (d, J = 8.8Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.53 (dd, J = 2.0, 8.8Hz, 1H), 5.39 (s, 2H), 3.56 (s, 3H).

[0485] Step 8: Under a nitrogen atmosphere at 0°C, silver nitrate (570 mg, 3.36 mmol) was slowly added in portions to an acetonitrile (5 mL) solution of compound 001-4 (312 mg, 695.56 μmol) and compound 009-8 (224 mg, 695 μmol). The reaction mixture was reacted at 0°C for 2 hours. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (10 mL × 3). The filtrate was concentrated under reduced pressure, and the residue was preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 150*40 mm*15 μm; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile %): 55%-85%) to obtain compound 009-9. LCMS (m / z): 737.2 [M+1] + .

[0486] Step 9: Under a nitrogen atmosphere, trifluoroacetic acid (90.74 μL, 1.22 mmol) was added to a 2 mL solution of anhydrous dioxane containing compound 009-9 (180 mg, 244.32 μmol). The reaction mixture was heated to 100 °C and reacted for 4 hours. After cooling to room temperature, compound 009 was preparatively separated by reversed-phase column chromatography (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: water (0.225% formic acid)-acetonitrile; gradient (acetonitrile %): 47%-77%). LCMS (m / z): 675.1 [M+1] + ; 1H NMR (400MHz, DMSO-d6) δ = 13.25 (br s, 1H), 10.96-10.68 (m, 1H), 8.65-8.52 (m, 2H), 7.44 (br s, 1H), 7.36 (br d,J=7.6Hz,1H),7.25(d,J=1.6Hz,1H),7.07(s,1H),4.58-4.38(m,2H),4.36-4.17(m,2H),3.76(br dd,J=3.2,7.2Hz,1H),3.67(br d,J=3.2Hz,1H),3.15-2.89(m,4H),2.24(s,3H),1.29(d,J=7.2Hz,3H),1.16(br d, J = 6.8 Hz, 3H).

[0487] Example 010

[0488]

[0489] Step 1: Under a nitrogen atmosphere at 25°C, cuprous iodide (286.22 mg, 1.50 mmol), cesium carbonate (489.66 mg, 1.50 mmol), and 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 a dioxane (6 mL) solution were added. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was then concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:methanol = 10 / 1-10 / 1), and then preparatively separated by reversed-phase column chromatography (column: Phenomenex luna C18 (100g); mobile phase: [water-(0.1% formic acid)-acetonitrile]; gradient (acetonitrile%): 0%-25%) to obtain compound 010.

[0490] Step 2: Compound 010 was prepared and separated by SFC (column: REGIS(s,s)WHELK-O1 (250mm*30mm, 10μm); mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (4:1) + 0.1% ammonia; gradient (B%): 25%) to obtain compound 010A and compound 010B.

[0491] Characterization of compound 010A: LCMS (m / z): 601.2 [M+H] + ; 1H NMR (400MHz, DMSO-d6) δ = 13.61-13.36 (m, 1H), 8.90 (s, 1H), 8.58-8.48 (m, 1H), 8.32(d,J=2.0Hz,1H),8.14(dd,J=1.8,8.4Hz,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=7.2Hz,3H),1.17(d,J=7.0Hz,3H); F NMR (376MHz, DMSO-d6) δ = -60.627; SFC detection (column: (S,S)Whelk-O1 50*4.6mm ID, 3.5μm; mobile phase A: supercritical carbon dioxide; mobile phase B: isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%). The retention time of compound 010A was 1.188 min, and its chiral purity was 100%. Characterization of compound 010B: LCMS (m / z): 601.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ = 8.87 (br s, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 8.11 (br d, J = 7.0Hz, 1H), 7.69 (br s, 1H), 7.46 (br d,J=8.2Hz,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=8.6Hz,4H),2.26(br s,3H),1.29(d,J=7.0Hz,3H),1.11(d,J=7.0Hz,3H); F NMR (376MHz, DMSO-d6) δ=-60.627; SFC detection (column: (S,S)Whelk-O1 50*4.6mm ID, 3.5μm; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), the retention time of compound 010B was 1.267 min, and the chiral purity was 74.87%.

[0492] Example 011

[0493]

[0494] Step 1: Under a nitrogen atmosphere at room temperature, (1R,2R)-(-)-N,N-dimethylcyclohexane-1,2-diamine (97.26 mg, 683.80 μmol), cesium carbonate (265.23 mg, 814.05 μmol), and cuprous iodide (124.03 mg, 651.24 μmol) were added to a mixed solution of dioxane (3 mL) and N,N-dimethylacetamide (1 mL) of compound M13 (140 mg, 494.23 μmol) and compound M9 (130 mg, 325.62 μmol). The reaction solution was reacted at 95 °C for 1 hour. The reaction solution was filtered, and the filtrate was reduced in pressure to obtain the crude product. The crude product 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 %): 50% yielded compound 011. LCMS (m / z): 602.2 [M+H] + .

[0495] Step 2: Compound 011 (75 mg) was prepared and separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm; mobile phase: A phase is supercritical carbon dioxide, B phase is isopropanol / acetonitrile (4:1) + 0.1% ammonia; gradient (B%): 40%) to obtain compound 011A and compound 011B.

[0496] Characterization of compound 011A: LCMS (m / z): 602.2 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=13.49(brs,1H),8.50(br s,1H),8.31(br s,1H),8.19(br d,J=8.4Hz,1H),7.89(br d,J=8.4Hz,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=6.4Hz,3H),1.24(br d,J=6.4Hz,3H); 19F NMR (376MHz, DMSO-d6) δ=-65.54; SFC detection (column: Chiralpak IG-3 50*4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), retention time of compound 011A: 1.560 min, chiral purity is 100%.

[0497] Characterization of compound 011B: LCMS (m / z): 602.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ=13.48(brs,1H),8.48(br s,1H),8.30(br s,1H),8.19(br d,J=8.8Hz,1H),7.88(br d,J=8.8Hz,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=6.4Hz,3H),1.23(br d,J=6.4Hz,3H); 19 F NMR (376MHz, DMSO-d6) δ=-65.53; SFC detection (column: Chiralpak IG-3 50*4.6mm I.D., 3μm; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol / acetonitrile (0.05% diethylamine); gradient (B%): 20%-60%), retention time of compound 011B: 1.947 min, chiral purity is 99.22%.

[0498] control compound

[0499]

[0500] Biological test data

[0501] Test Example 1: Determining the effect of a compound on the apelin receptor

[0502] This study used a CHO cell line that stably expresses the Apelin receptor and incubated it with different concentrations of test compounds. The activation of the Apelin receptor by the compounds was determined using an HTRF cAMP kit.

[0503] Experimental methods:

[0504] (1) According to Prepare 1×Stimulation Buffer according to the Ultra cAMP Kit instructions.

[0505] (2) The positive control and the test compound were serially diluted to 10 concentrations.

[0506] (3) The stable cell line was cultured to 80% confluence, and the cells were collected by trypsin digestion. After counting, 10 μL / well was seeded into a 384-well plate, and then Echo655 was administered at 10 nL per well. The plate was then incubated at 37°C for 10 minutes.

[0507] (4) Continue to inject 10 nL of 0.6 mM Forskolin and incubate for 30 minutes to induce cAMP production.

[0508] (5) Dilute Eu-cAMP to 4× working concentration with detection buffer and add 4 μL / well to the corresponding experimental well.

[0509] (6) ULight TM The anti-cAMP antibody was diluted to a working concentration of 4× with detection buffer, and 4 μL / well was added to the corresponding experimental well. After centrifugation, the mixture was incubated at room temperature for 1 hour.

[0510] (7) After incubation, the readings at 665 nm and 620 nm were detected using a microplate reader under excitation at 330 nm. Curve fitting and EC20 analysis were performed by plotting the signal values ​​against the compound concentration. 50 calculate.

[0511] The experimental results are shown in Table 1. Where A represents EC 50 ≤1nM (further A+ indicates EC) 50 ≤0.1nM), B represents 1nM <EC 50 ≤100nM (further B+ indicates 1nM) <EC 50 ≤20nM), C represents EC 50 >100nM.

[0512] Conclusion: The compounds of this invention can significantly activate cAMP signaling downstream of the Apelin receptor.

[0513] Test Example 2: Testing the effect of compounds on the recruitment of β-arrestin 2 by the apelin receptor.

[0514] This study used the HEK293T-APJ-βArrestin2 stable cell line and, through interaction with different concentrations of test compounds, utilized Nano- The Live Cell Substrates kit was used to investigate the ability of test substances to recruit β-arrestin 2 by detecting changes in fluorescence intensity using the NanoBiT method.

[0515] Test method:

[0516] (1) On the first day, HEK293T-APJ-βArrestin2 cells were cultured to 80% confluence, and cells were collected by trypsin digestion. After counting, they were seeded into 96-well plates (CAT#3603) at 30,000 cells / well. The culture medium was Opti-MEM + 4% FBS, and the cells were incubated overnight.

[0517] (2) On the second day, the positive drug and the test compound were serially diluted (10 concentrations) with Opti-MEM.

[0518] (3) When the cell density reaches approximately 80%, according to According to the Live Cell Substrates instructions, dilute the substrate 20 times and add it to the well at a rate of 20 μL / well, then shake well.

[0519] (4) Take 10 μL of the diluted 10× compound and add it to the corresponding experimental well. Incubate in the dark for 10 minutes.

[0520] (5) After incubation, the Luminescence signal value is read using an ELISA reader.

[0521] (6) By plotting the signal values ​​against the compound concentrations, curve fitting and EC were performed using the nonlinear regression method in GraphPad Prism software. 50 calculate.

[0522] The EC50 values ​​of the compound's effect on recruiting β-arrestin 2 and its agonistic activity on the cAMP pathway were calculated. 50 Then, the ratio of the two was calculated (the compound recruits β-arrestin 2EC). 50 Value divided by APJ cAMP EC 50 The ratio is used to assess the agonistic tendency of compounds.

[0523] The experimental results are shown in Table 1. Where A represents EC 50 ≤1nM (further A+ indicates EC) 50 ≤0.1nM), B represents 1nM <EC 50 ≤100nM (further B+ indicates 1nM) <EC 50 <20nM), C represents EC 50>100nM; + indicates 1 < ratio ≤ 10, ++ indicates 10 < ratio ≤ 50, and +++ indicates ratio > 50.

[0524] Table 1. Results of the test on the agonistic activity of the compounds of the present invention against the Apelin receptor.

[0525] 001 A+ A + 003 A+ A + 004A B C + 004B B C + 005 A B+ + 005B A B+ ++ 006D A B +++ 007B A+ B ++ 008D A B ++ 010A A A + 011A A B+ ++ 011B B C +++ BGE-105 A+ A+ +

[0526] Conclusion: The compounds of this invention can significantly activate cAMP signaling downstream of the apelin receptor; some of the compounds also have a strong recruitment effect on β-arrestin 2, and are G protein balanced apelin receptor agonists; while some compounds have a relatively weaker recruitment effect on β-arrestin 2 and have high selectivity, and are G protein biased apelin receptor agonists.

[0527] Test Example 3: Thermodynamic Solubility Experiment

[0528] Weigh appropriate amounts of the test compound and control compound powder into Mini-UniPrep vials, and add 450 μL of medium (Na2HPO4 / NaH2PO4 solutions at different pH values) to each. After adding the medium, press the stopcock of the Mini-UniPrep filter to the liquid surface to ensure full contact between the medium and the compound during incubation, and vortex the sample for at least two minutes. Then, place the sample vial on a shaker at 800 rpm and incubate at room temperature for 24 hours to reach dissolution equilibrium. After incubation, place the sample in a centrifuge and centrifuge at 4000 rpm for 10 minutes at 25°C. Filter the centrifuged sample to obtain the filtrate, dilute as needed, and transfer 200 μL of the sample solution to a 96-well deep-well plate. Quantitatively determine the concentration of the sample filtrate using an LC-UV, LC-ELSD, or LC-MS / MS system. The thermodynamic solubility of the corresponding compound can be calculated based on the determined filtrate concentration.

[0529] The experimental results are shown in Table 2 below. The results show that the compounds of this invention exhibit good solubility at different pH values, and are significantly better than the reference compound BGE-105. Specifically, compared to BGE-105, compound 001 has a solubility at all pH values ​​that is 4.9 to 11.6 times that of BGE-105, compound 005 has a solubility at all pH values ​​that is 1.7 to 10.9 times that of BGE-105, and compound 007B has a solubility at all pH values ​​that is 3.6 to 24.4 times that of BGE-105.

[0530] Table 2 Solubility of compounds in sodium phosphate buffer at different pH values

[0531]

[0532] Conclusion: The compounds of this invention have good solubility, which is beneficial for oral administration and formulation development.

[0533] Test Example 4: Plasma Protein Binding Assay (Balanced Dialysis Method)

[0534] Frozen CD-1 mouse and human plasma were thawed in running cold tap water. After complete thawing, the plasma was centrifuged at 3220×g for 5 minutes to remove suspended solids and precipitates. 597 μL of blank plasma from each species was taken, and 3 μL of the working solution of the test sample or control was added and mixed thoroughly to obtain plasma samples (n=1) with a concentration of 2 μM for both the test sample and control. The concentration of DMSO in the organic phase was 0.5%. The samples were thoroughly mixed before proceeding to the next step.

[0535] Transfer 50 μL of plasma samples from the test sample and control sample into a sample receiving plate (n=3), immediately add 50 μL of blank PBS, and then add 600 μL of stop solution to the T0 samples of the test sample and control sample respectively, and store at 2-8℃, waiting to be processed together with other dialysis samples.

[0536] Add 100 μL of test sample and control plasma sample to the administration end of each dialysis well (n=3), and add 100 μL of blank PBS to the receiving end of the corresponding dialysis well. Place the dialysis plate in a 5% CO2 incubator and incubate at 37°C with shaking at approximately 100 rpm for 4 hours.

[0537] After dialysis, 50 μL of dialysis-processed PBS and dialysis-processed plasma (n=3) were transferred to a new 96-well plate (sample receiving plate). The corresponding volume of blank plasma or PBS was added to each sample to make a final volume of 100 μL per well, with a plasma to PBS volume ratio of 1:1. All samples were analyzed by LC-MS / MS after protein precipitation.

[0538] Experimental results showed that compounds 001, 005, and 007B had a binding rate of over 94% in mouse plasma and over 98% in human plasma.

[0539] Conclusion: The compounds of this invention exhibit high plasma protein binding rates in the plasma of different species, demonstrating strong plasma protein binding ability.

[0540] Test Example 5: Hepatic Microsomal Metabolic Stability

[0541] The test substance was prepared into a 10 mM DMSO solution with DMSO, and then diluted to 100 μM with 100% acetonitrile to obtain the working solution (organic phase content: 99% acetonitrile, 1% DMSO).

[0542] Prepare two 96-well incubation plates, and name them T60 incubation plate and NCF60 incubation plate respectively.

[0543] Add 445 μL of microsomal working solution (liver microsomal protein concentration of 0.56 mg / mL) to both T60 and NCF60 incubation plates, and then place the incubation plates in a 37°C water bath for pre-incubation for about 10 minutes.

[0544] After the pre-incubation is completed, add 5 μL of the working solution of the test sample or control compound to the T60 incubation plate and the NCF60 incubation plate respectively, and mix well.

[0545] To initiate the reaction, add 50 μL of potassium phosphate buffer to each well of the NCF60 incubation plate. In the T0 stop plate, add 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labenoyl in acetonitrile) and 6 μL of NADPH regeneration working solution. Transfer 54 μL of sample from the T60 incubation plate to the T0 stop plate (T0 sample generation). In the blank plate, add only 54 μL of microsomal working solution, 6 μL of NADPH regeneration working solution, and 180 μL of stop solution. To initiate the reaction, add 44 μL of NADPH regeneration working solution to each well of the T60 incubation plate. Therefore, in the sample of the test or control compound, the final reaction concentrations of the 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.

[0546] After incubation for appropriate times (e.g., 5, 15, 30, 45, and 60 minutes), add 180 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labenoyl in acetonitrile) to each well of the stop plate. Then, remove 60 μL of sample from the T60 or NCF60 incubation plate to terminate the reaction.

[0547] All sample plates were shaken well and centrifuged at 3220×g for 20 minutes. Then, 80 μL of the supernatant from each well was diluted to 240 μL of pure water for liquid chromatography-tandem mass spectrometry analysis. The in vitro elimination rate constant ke for the test and control compounds was calculated by converting the ratio of the compound's peak area to the internal standard peak area into a residual percentage using the formula below. The in vitro intrinsic clearance rate of liver microsomes (CL) was calculated using ke. int (mic)), the calculation formula is: CL int (mic) = 0.693 / T 1 / 2 / Microsomal protein content (microsomal concentration during incubation, mg / mL). Experimental results are shown in Table 3.

[0548] Table 3 Results of liver microsomal metabolic stability tests of the compounds of this invention

[0549]

[0550] Conclusion: The compounds of this invention exhibit good metabolic stability in liver microsomes of various genera (especially human).

[0551] Test Example 6: Hepatocyte Metabolic Stability

[0552] 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.

[0553] 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.

[0554] 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.

[0555] Conclusion: The compounds of this invention exhibit good metabolic stability in various types of hepatocytes, showing moderate or slow metabolism.

[0556] Test Example 7: Study on Inhibition of Cytochrome P450 Enzyme (CYP)

[0557] Objective: To determine the inhibitory effect of the test compound on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).

[0558] Experimental methods: The test compound (10.0 mM) was serially diluted to prepare working solutions (100 × final concentration), with working solution concentrations (mM) of 5.00, 1.50, 0.500, 0.150, 0.0500, 0.0150 and 0.00500. At the same time, working solutions of positive inhibitors and specific substrate mixtures of P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (with midazolam as the probe substrate)) were prepared. Human liver microsomes stored at below -60°C were thawed on ice until all human liver microsomes were dissolved, and then diluted with potassium phosphate buffer (PB) to prepare a certain concentration of working solution (0.253 mg / mL).

[0559] Add 20.0 μL of substrate mixture to the reaction plate (add 20.0 μL of PB to the blank well), then add 158 μL of human liver microsome working solution to the reaction plate. Place the reaction plate on ice and set aside. At this time, add 2.00 μL of each concentration of the test compound (N=1) and specific inhibitor (N=2) to the corresponding well. For the inhibitor-free group (no test compound or positive inhibitor), add the corresponding organic solvent as the control sample (the test compound control sample is DMSO:MeOH = 1:1, and the positive control samples are all DMSO:MeOH = 1:9). Preheat the reaction plate in a 37°C water bath. After incubation for 10 min, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate and incubated in a 37°C water bath for 10 min. The reaction was terminated by adding 400 μL of pre-cooled acetonitrile solution (containing internal standard). The reaction plate was placed on a shaker and shaken for 10 min to mix. Then, it was centrifuged at 4°C and 4000 rpm for 20 min. 200 μL of the supernatant was added to 100 μL of water to dilute the sample. Finally, the plate was sealed, shaken for 10 min to mix, and then detected by LC-MS / MS.

[0560] Experimental results showed that compounds 001 and 007 had an IC50 inhibitory effect on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4). 50 All are greater than 50 μM.

[0561] Conclusion: The compounds of this invention do not have a significant inhibitory effect on the five major cytochrome P450 enzymes in human liver microsomes, and the risk of drug-drug interactions is low.

[0562] Test Example 8: hERG Test

[0563] CHO cells stably expressing hERG were cultured in 35 mm diameter cell culture dishes at 37°C in a 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, the cells were rinsed once with extracellular fluid, and then 0.25% Trypsin-EDTA (Invitrogen) solution was added for digestion at room temperature for 3-5 minutes. The digestion solution was aspirated, the cells were resuspended in extracellular fluid, and then transferred to experimental dishes for electrophysiological recording.

[0564] The compound to be tested was prepared into a 20 mM stock solution using DMSO, and then serially diluted 3 times with DMSO, i.e., 10 μL was added to 20 μL of DMSO. Then, 10 μL of the serially diluted compound DMSO solution was added to 4990 μL of extracellular fluid. The final concentration to be tested was obtained by 500-fold dilution.

[0565] CHO cells stably expressing the hERG potassium channel were used to record hERG potassium channel currents at room temperature using whole-cell voltage-clamp technique. After obtaining whole-cell recordings, the cells were clamped at -100 mV. The step voltage to induce hERG potassium current (IhERG) was applied from -100 mV with a 2-s depolarization voltage to +20 mV, then repolarized to -50 mV for 1 second before returning to -100 mV. This voltage stimulation was applied every 5 seconds. Once the hERG potassium current stabilized (1 minute), the drug administration process began. Each test concentration of the compound was administered for at least 1 minute to steady state or for a maximum of 3 minutes, and at least 2 cells (n≥2) were tested for each concentration.

[0566] Data analysis was performed using pClamp and Excel software. The inhibition degree of different compound concentrations on the hERG potassium current (the peak hERG tail current induced at -50mV) was calculated using the following formula: Inhibition% = [1 – (I / I0)] × 100%. Wherein, Inhibition% represents the inhibition rate of the compound on the hERG potassium current, and I and I0 represent the amplitude of the hERG potassium current before and after drug administration, respectively. IC was calculated using GraphPad Prism 8 for plotting. 50 Experimental results show that compounds 001, 005, and 007 have hERG IC 50 All are greater than 40 μM.

[0567] Conclusion: The compounds of this invention do not significantly inhibit hERG.

[0568] Test Example 9: Mouse PK Study

[0569] Six male C57 BL / 6 mice were divided into two groups of three. The intravenous (iv) group received 5% DMSO / 50% PEG400 / 45% 5% glucose as the solvent; the oral (po) group received 0.5% MC / 0.2% Tween 80 / water as the solvent. Whole blood was collected at 5 min (iv only), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The whole blood was placed in anticoagulant tubes containing EDTA-K2 and centrifuged to prepare plasma. The concentration of the test substance molecules in the plasma was quantitatively detected by LC-MS / MS, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin.

[0570] The experimental results are shown in Table 4. Where: CL represents the clearance rate, Vdss represents the distribution volume, and T... 1 / 2 For half-life, AUC 0-last The area under the whole blood concentration-time curve is represented from 0 to the last quantifiable time point; F represents bioavailability.

[0571] Table 4. Mouse PK test results of the compounds of the present invention.

[0572]

[0573] Conclusion: The compounds of this invention exhibit high oral exposure and good bioavailability in mouse pharmacokinetic studies, demonstrating excellent pharmacokinetic properties.

[0574] Test Example 10: Rat PK Study

[0575] Six male SD rats were randomly divided into two groups of three animals each. The intravenous (iv) group received 5% DMSO / 50% PEG400 / 45% 5% glucose as the solvent; the oral (po) group received 0.5% MC / 0.2% Tween 80 / water as the solvent. Whole blood was collected at 5 min (iv only), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The whole blood was placed in anticoagulant tubes containing EDTA-K2 and centrifuged to prepare plasma. The concentration of the test substance molecules in the plasma was quantitatively detected by LC-MS / MS, and the pharmacokinetic parameters were calculated using PhoenixWinNonlin.

[0576] The experimental results are shown in Table 5. The results show that the compounds of this invention have very high oral exposure and oral bioavailability, significantly superior to 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 are 1.3 times, 2.5 times, and 2.2 times that of BGE-105, respectively.

[0577] Table 5. Results of rat pK test of the compounds of the present invention.

[0578]

[0579] Conclusion: The compounds of this invention exhibited low clearance, long half-life, high oral exposure and high oral bioavailability in rat pharmacokinetic studies, demonstrating excellent pharmacokinetic properties.

[0580] Test Example 11: Canine PK Study

[0581] Six male beagle dogs were divided into two groups of three animals each. The intravenous (iv) group received physiological saline as the solvent; the oral (po) group received 0.5% MC / 0.2% Tween 80 / water as the solvent. Whole blood was collected at 5 min (iv only), 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. The whole blood was placed in anticoagulant tubes containing EDTA-K2 and centrifuged to prepare plasma. The concentration of the test substance molecules in the plasma was quantitatively detected by LC-MS / MS, and the pharmacokinetic parameters were calculated using Phoenix WinNonlin.

[0582] The experimental results are shown in Table 6. The results show that the compounds of this invention exhibit low clearance rates, long half-lives, high oral exposures, and high oral bioavailability, significantly superior to BGE-105. Specifically, compounds 001 and 007B showed low clearance rates (approximately 55% of BGE-105), high oral exposures (2.7 times and 4.8 times that of BGE-105, respectively), and high oral bioavailability (1.5 times and 2.7 times that of BGE-105, respectively).

[0583] Table 6. Beagle PK test results of the compound of the present invention.

[0584]

[0585] Conclusion: The compounds of this invention exhibited low clearance, long half-life, high oral exposure, and high oral bioavailability in canine PK, demonstrating excellent pharmacokinetic properties.

[0586] Test Example 12: In vivo drug efficacy (Part 1)

[0587] Experimental objective:

[0588] The efficacy of the compound in combination with semaglutide was tested in a diet-induced obesity (DIO) mouse model.

[0589] Experimental methods:

[0590] Six-week-old male C57BL / 6J mice, weighing over 50 grams after being fed a high-fat pelleted diet for 16 weeks, were used for this test. The experiment began one week after acclimatization (Day 0). On the morning of Day 0, body weight and remaining food were measured, and body fat was assessed using MRI. After body fat measurement, the animals were transferred to different cages and fasted. Fasting blood glucose was measured 6 hours later. Based on body weight, fasting blood glucose, and body fat results, the DIO mice were divided into two groups: a DIO model control group (Vehicle group) and a test group. Simultaneously, C57BL / 6 mice were selected as the normal control group (Normal group) based on body weight, fasting blood glucose, and body fat results.

[0591] Dosing began on Day 1 and continued for 21 days. The Normal and Vehicle groups used the prescribed solvents. In Test Group 1, Semaglutide was dissolved in physiological saline and injected subcutaneously at a dose of 10 nmol / kg every three days. In Test Group 2, the compound was dissolved in a solvent at a concentration of 1.1 g / L and administered via free access to water daily. Specific dosing regimens are shown in Table 7. Mouse weight and food / water intake were recorded daily. Body fat (Day 20) and fasting blood glucose (Day 17) were measured at the experimental endpoint.

[0592] Table 7: In vivo drug efficacy dosing regimen

[0593]

[0594] The experimental results are shown in Table 8, and the changes in mouse body weight are shown in [Table 8]. Figure 1 The experimental results showed that, compared with the DIO model control group, the combination of compound 001 and semaglutide significantly reduced body weight, which was better than the weight loss effect of semaglutide alone. At the same time, the combination of compound 001 and semaglutide further reduced the fat / body weight ratio of animals, while increasing the lean body weight / body weight ratio and the lean body weight / fat weight ratio, which was better than the effect of semaglutide alone. The combination of compound 001 and semaglutide also further reduced the fasting blood glucose level of animals.

[0595] Table 8: Results of in vivo pharmacodynamic studies in mice using semaglutide in combination with other drugs.

[0596] Note: All data are presented as mean ± standard error, *P<0.05, ****P<0.0001, compared with test group 1, one-way ANOVA.

[0597] Conclusion: In a diet-induced obesity (DIO) model in mice, the combination of the compound of this invention with semaglutide can further significantly reduce body weight, improve body composition, and further reduce fasting blood glucose levels, demonstrating good in vivo efficacy. Moreover, the efficacy of the combination is significantly better than that of semaglutide alone.

[0598] Test Example 13: In vivo drug efficacy (Part 2)

[0599] Experimental objective:

[0600] The efficacy of the compound in combination with semaglutide was tested in a diet-induced obesity (DIO) mouse model.

[0601] Experimental methods:

[0602] Six-week-old male C57BL / 6J mice, weighing over 50 grams after being fed a high-fat pelleted diet for 16 weeks, were used for this test. The experiment began one week after acclimatization (Day 0). On the morning of Day 0, body weight and remaining food were measured, and body fat was assessed using MRI. After body fat measurement, the animals were transferred to different cages and fasted. Fasting blood glucose was measured 6 hours later. Based on body weight, fasting blood glucose, and body fat results, the DIO mice were divided into two groups: a DIO model control group (Vehicle group) and a test group. Simultaneously, C57BL / 6 mice were selected as the normal control group (Normal group) based on body weight, fasting blood glucose, and body fat results.

[0603] Dosing began on Day 1 and continued for 21 days. The Normal and Vehicle groups used the same solvent; the specific dosing regimens for the control and test groups are shown in Table 9. Mouse weight, food intake / water intake were recorded daily, followed by measurement of body fat (Day 18) and fasting blood glucose (Day 17).

[0604] Table 9: In vivo drug efficacy dosing regimen

[0605]

[0606] The experimental results are shown in Table 10, and the changes in mouse body weight are shown in [Table 10]. Figure 2The experimental results showed that, compared with the DIO model control group, the combination of compound 001 and semaglutide significantly reduced body weight, decreased the fat / body weight ratio, and increased the lean body weight / body weight ratio and the lean body weight / fat weight ratio, exhibiting a dose-dependent effect and showing better weight loss than semaglutide alone. The weight loss effect of compound 001 at a dose of 0.55 g / L was comparable to that of BGE-105 at a dose of 1.1 g / L, and the weight loss effect of compound 001 at the same dose (1.1 g / L) was significantly better than that of BGE-105. Furthermore, the combination of compound 001 and semaglutide also further reduced the fasting blood glucose level in the animals.

[0607] Table 10: Results of body composition and blood glucose levels in mice during in vivo pharmacodynamic experiments.

[0608]

[0609] 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.

[0610] Conclusion: When the compound of this invention is used in combination with semaglutide in a diet-induced obesity (DIO) mouse model, it can further significantly reduce body weight, improve body composition, and further reduce fasting blood glucose levels, demonstrating good in vivo efficacy. At the same dose, its efficacy is significantly better than that of BGE-105.

Claims

1. The compound shown in formula (I-7), its stereoisomers, or pharmaceutically acceptable salts thereof, ， in, r is selected from 1 and 2; Selected from and R5 is H; R1 is randomly selected by one or more R1s 1a Substituted 5-6 aryl groups; R2 is selected from any 1, 2, 3 or 4 Rs. 2a The following groups are substituted: phenyl and 5-6 membered heteroaryl groups; Each R 1a The components are independently selected from H, F, Cl, CN, and C, which are optionally substituted by one or more R. 1-3 alkyl; Each R 2a The components are independently selected from H, F, Cl, CN, and C, which are optionally substituted by one or more R. 1-3 alkyl; Each R L2 The following groups are selected independently from H, F, Cl, CN and optionally substituted with one or more R groups: methyl, ethyl, methoxy and ethoxy; Each R is independently selected from H, F, Cl, OH, NH2, CN, CH3 and CF3; Compound of formula (I-7) is not , , , , , , , , , , , , , , or .

2. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Each R L2 They were independently selected from H, F, Cl, CH3, CF3 and CH2CN, respectively.

3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R 1a The following groups are independently selected from H, F, Cl, CN and optionally substituted by one or more R groups: CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2.

4. The compound according to claim 3, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R 1a They are independently selected from H, F, Cl, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3 and CF2CH3, respectively.

5. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, Each R 2a The following groups are independently selected from H, F, Cl, CN and optionally substituted by one or more R groups: CH3, CH2CH3, CH2CH2CH3 and CH(CH3)2.

6. The compound according to claim 5, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, Each R 2a They are independently selected from H, F, Cl, CN, CH3, CH2F, CHF2, CF3, CH2CH3, CH2CF3 and CF2CH3, respectively.

7. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R1 is selected from one or more R1s. 1a The following groups are substituted: pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.

8. The compound according to claim 7, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R1 is selected from , , , , , , , , , , , , , and .

9. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, R2 is selected from any 1, 2, 3 or 4 Rs. 2a The following groups are substituted: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, imidazoleyl, pyrazolyl, oxazolyl, and thiazolyl.

10. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, R2 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

11. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from the following compounds: and .

12. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, selected from the following compounds: and .

13. The use of the compound of any one of claims 1 to 12, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a medicament for treating diseases associated with Apelin receptor agonists, wherein the diseases associated with Apelin receptor agonists are muscle atrophy, metabolic disorders, cardiovascular diseases, pulmonary hypertension or idiopathic pulmonary fibrosis caused by prolonged bed rest.

14. The application of claim 13, wherein the metabolic disorder is obesity, insulin resistance, or type 2 diabetes.

15. The application of claim 13, wherein the cardiovascular disease is heart failure.

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