Pyrazole carboxylic acid derivative and pharmaceutical use thereof

Abstract

A pyrazole carboxylic acid derivative and the pharmaceutical use thereof, in particular, a compound represented by formula (I) or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and the use thereof in the preparation of a drug for treating sGC-related diseases.

Description

Pyrazole carboxylic acid derivatives and their applications in medicine Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and relates to pyrazolecarboxylic acid derivatives and their applications in medicine. Specifically, a pyrazolecarboxylic acid derivative and its application in medicine is provided, specifically a compound represented by formula (I) or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as its application in the preparation of drugs for treating diseases related to sGC. Background Art

[0002] Nitric oxide (NO) signaling has pleiotropic effects in biology and plays a key role in cardiovascular homeostasis. NO secretion is increased under the influence of mediators such as norepinephrine (NA), angiotensin, adenosine triphosphate (ATP), or bradykinin. NO synthesis is also influenced by a variety of physical stimuli.

[0003] The intracellular mechanism of action of NO is primarily through stimulation of soluble guanylate cyclase (sGC). sGC is a heme-containing enzyme that elevates cyclic 3'-5'-guanosine monophosphate (cGMP) levels in smooth muscle, leading to vasodilation. The NO / sGC / cGMP regulatory pathway plays a crucial role in the homeostasis of the cardiovascular and respiratory systems, as well as organs such as the kidneys, brain, and liver. In addition to smooth muscle cells, cGMP also influences the function of fibroblasts, cardiomyocytes, platelets, neurons, and immune cells, regulating fibrosis, inflammatory responses, and neurotransmission.

[0004] sGC modulators and sGC agonists are a class of drugs that stimulate cGMP formation. These drugs provide tools for studying the regulatory mechanisms of sGC and its role in pathological mechanisms. The development of sGC modulators or agonists has made it possible to develop drugs that directly target diseased blood vessels, myocardium, kidneys, and other organs. Riociguat, the first sGC agonist to be marketed, was approved in 2013 for two indications: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (TEPH). The development of novel sGC modulators or agonists, exploring the therapeutic value and broader therapeutic potential of sGC targets in different indications, holds great promise for future applications. Summary of the Invention

[0005] The present invention aims to provide a novel compound of general formula (I) or its stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases associated with sGC.

[0006] The compounds of the present invention have good sGC enzymatic agonist and / or activator activity, also exhibit good agonist and / or activator activity at the cellular level, have a significant vasodilator effect, have a good blood pressure lowering effect, good pharmacokinetic properties (for example, good stability in liver microsome stability tests, low clearance rate in animals, high oral exposure AUC, and good bioavailability) and good safety (for example, no significant inhibitory effect on hERG potassium ion channels), and have no significant inhibitory activity on some transporters (such as SLC, BCRP, and P-gp).

[0007] The present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0008] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib) or (Ic).

[0009] In some embodiments, z1 is selected from 0, 1, 2, or 3;

[0010] In some embodiments, z2 is selected from 0, 1, 2, 3, or 4;

[0011] In some embodiments, X5 is selected from CR 5 or N, X6 selected from CR 6 or N;

[0012] In some embodiments, Y1 is selected from N or CR y1 ;

[0013] In some embodiments, Y1 is selected from N or CH;

[0014] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0015] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0016] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R kSubstituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0017] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0018] In some embodiments, R 1 、R 3 、R 4 、R 5 、R 6 Each is independently selected from H, deuterium, F, Cl, Br, methyl, CF3;

[0019] In some embodiments, R 2 Selected from F, Cl, Br, methyl, CF3;

[0020] In some embodiments, R a 、R c 、R b2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3;

[0021] In some embodiments, R b1 Selected from CF3 or CHF2;

[0022] In some embodiments, Z is selected from 4 to 12 membered heterocycloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z Substituted, the alkyl group is optionally replaced by 1 to 4 substituents selected from deuterium, OH, CN, and NH2;

[0023] In some embodiments, Z is selected from 4 to 7 membered heterocycloalkyl, C 3-6 Cycloalkyl, C 2-4 Alkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z Substituted, the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2;

[0024] In some embodiments, Z is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl is optionally replaced by 1 to 4 R z Substitution, the ethyl, propyl, isopropyl group is optionally substituted by 1 to 4 substituents selected from deuterium, OH, CN, NH2;

[0025] In some embodiments, Selected from

[0026] In some embodiments, Z1 is selected from C 2-6 Alkyl, optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2;

[0027] In some embodiments, Selected from

[0028] In some embodiments, Ring A is selected from C 3-6 Cycloalkyl or 4 to 12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R z replace;

[0029] In some embodiments, Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl is optionally substituted by 1 to 4 R z replace;

[0030] In some embodiments, Selected from

[0031] In some embodiments, R z Each independently selected from deuterium, halogen, OH, CN, NH2, C1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0032] In some embodiments, R z Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0033] In some embodiments, R z Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0034] In some embodiments, R zEach is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, CF3, ethyl, isopropyl, methoxy, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl;

[0035] In some embodiments, R z Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3;

[0036] In some embodiments, R z1 is selected from methyl, deuterated methyl, halomethyl, preferably methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F;

[0037] In some embodiments, R z2 Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0038] In some embodiments, R z2 Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3, deuterated methyl, halomethyl, preferably deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F;

[0039] In some embodiments, Selected from

[0040] In some embodiments, R A Selected from halogen, C 1-6 Alkyl, OH, CN, NH2, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0041] In some embodiments, R A Selected from halogen, C 1-4 Alkyl, OH, CN, NH2, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0042] In some embodiments, R A is selected from F, Cl, Br, I, OH, CN, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, NHCH3, N(CH3)2, NH(CH2CH3), N(CH2CH3)2, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-tetrahydrofuranyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-azetidinyl, -NH-oxetanyl, -NH- Pyrrolidinyl, -NH-tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-tetrahydrofuranyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k replace;

[0043] In some embodiments, R A is selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, wherein the ethyl, propyl, isopropyl is optionally replaced by 1 to 4 R k replace;

[0044] In some embodiments, R A1 Selected from -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0045] In some embodiments, R A1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl is optionally substituted by 1 to 4 R z replace;

[0046] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0047] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0048] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0049] In some embodiments, n is selected from 0, 1, 2, 3, 4;

[0050] In some embodiments, m is selected from 0, 1, 2, 3, 4;

[0051] Provided that, when Z is selected from C 2-6 When alkyl, R A Selected from -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace.

[0052] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0053] X5 selected from CR 5 or N, X6 selected from CR 6 or N;

[0054] Y1 is selected from N or CR y1 ;

[0055] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0056] Z is selected from 4 to 12 membered heterocycloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z Substituted, the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2;

[0057] R z Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0058] R A Selected from halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0059] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0060] n is selected from 0, 1, 2, 3, 4;

[0061] m is selected from 0, 1, 2, 3, 4;

[0062] The condition is,

[0063] When Z is selected from C 2-6 When alkyl, R A Selected from -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace.

[0064] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0065] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0066] R z Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0067] Z is selected from 4 to 7 membered heterocycloalkyl, C 3-6 Cycloalkyl, C 2-4 Alkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z Substituted, the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2;

[0068] R A Selected from halogen, C 1-4 Alkyl, OH, CN, NH2, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0069] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0070] The remaining definitions are the same as those of the first embodiment of the present invention.

[0071] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0072] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0073] Z is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl are optionally replaced by 1 to 4 R z Substitution, the ethyl, propyl, isopropyl group is optionally substituted by 1 to 4 substituents selected from deuterium, OH, CN, NH2;

[0074] R z Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R kSubstituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl; R A is selected from F, Cl, Br, I, OH, CN, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, NHCH3, N(CH3)2, NH(CH2CH3), N(CH2CH3)2, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-tetrahydrofuranyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-azetidinyl, -NH-oxetanyl, -NH- Pyrrolidinyl, -NH-tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-tetrahydrofuranyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k replace;

[0075] R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

[0076] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0077] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0078] Selected from

[0079] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0080] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the compound represented by the general formula (I) is selected from the compounds represented by the general formula (Ia), (Ib) or (Ic),

[0081] Y1 is selected from N or CH;

[0082] Z1 chooses C 2-6 Alkyl, optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2;

[0083] R A1 Selected from -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0084] Ring A is selected from C 3-6 Cycloalkyl or 4 to 12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R z replace;

[0085] R A Selected from halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0086] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0087] R z Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0088] R z1 is selected from methyl, deuterated methyl, and halomethyl;

[0089] R z2 Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy;

[0090] z1 is selected from 0, 1, 2 or 3;

[0091] z2 is selected from 0, 1, 2, 3 or 4.

[0092] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0093] As a sixth embodiment of the present invention, the compounds represented by the above-mentioned general formula (Ia), (Ib), (Ic) or their stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0094] R 1 、R 3 、R 4 、R 5 、R 6 Each is independently selected from H, deuterium, F, Cl, Br, methyl, CF3;

[0095] R 2 Selected from F, Cl, Br, methyl, CF3;

[0096] R a 、R c 、R b2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3;

[0097] R z Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3; R b1 Selected from CF3 or CHF2;

[0098] Selected from

[0099] Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl is optionally substituted by 1 to 4 R z replace;

[0100] R A is selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, wherein the ethyl, propyl, isopropyl is optionally replaced by 1 to 4 R k replace;

[0101] R z1 Selected from methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F;

[0102] R z2Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3, deuterated methyl, halomethyl, preferably deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F;

[0103] Preferably, Selected from

[0104] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0105] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below:

[0106] Table E-1

[0107] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0108] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0109] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the above-mentioned pharmaceutical compositions for preparing drugs for treating diseases associated with sGC.

[0110] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating cardiovascular diseases, kidney diseases (such as chronic kidney disease) or respiratory diseases (such as pulmonary hypertension, pulmonary hypertension or chronic obstructive pulmonary disease).

[0111] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0112] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0113] As used herein, "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein that will alleviate to some extent one or more symptoms of the disease or condition being treated, such as cardiovascular disease, kidney disease, or respiratory disease (e.g., pulmonary hypertension, pulmonary hypertension, or chronic obstructive pulmonary disease). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 0.01-1500 mg, 0.01-1000 mg, 0.01-800 mg, 0.01-600 mg, 0.1-1500 mg, 0.1-1000 mg, 0.1-800 mg, 0.1-600mg、1-1500mg、1-1000mg、1-800mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、0.01-100mg、0.01-50mg、0.01-10mg、0.01-5mg、0.05-10mg、0.05-5mg、0.1-5mg、1-5mg、0.1-1mg、0.1-5mg;.

[0114] In some embodiments, the pharmaceutical composition includes but is not limited to 0.01-1500 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.3 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg , 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0115] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, preferably 0.01-1500 mg. The disease is preferably cardiovascular disease, renal disease (e.g., chronic kidney disease) or respiratory disease (e.g., pulmonary hypertension, pulmonary hypertension or chronic obstructive pulmonary disease).

[0116] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 0.01-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 0.01-1500 mg / day, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 2 5-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 0.01 mg / day, 0.05 mg / day, 0.1 mg / day, 0.15 mg / day, 0.2 mg / day, 0.3 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0117] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0118] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0119] Synthesis method 1:

[0120] PG1, PG2, and PG4 are each independently selected from an amino protecting group, and PG3 are each independently selected from a hydroxyl protecting group;

[0121] R D-1 、R D-2 Each independently selected from C 1-6 alkyl;

[0122] R D-3 Each is independently selected from a halogen or a leaving group, preferably Br, I, OTf;

[0123] RD-4 each independently selecting an oxygen-containing leaving group;

[0124] R D-5 、R D-6 Each independently selected from H or C 1-6 alkyl;

[0125] The definitions of the remaining groups are consistent with those in the specification;

[0126] The compound of general formula (D-1-1) is subjected to reductive amination reaction to obtain the compound of general formula (D-1-2);

[0127] The compound of formula (D-1-2) is obtained by removing the amino protecting group to obtain the compound of formula (D-1-3);

[0128] The compound of the general formula (D-1-3) and the compound of the general formula (D-1-4) undergo a cyclization reaction to obtain the compound of the general formula (D-1-5);

[0129] The compound of formula (D-1-5) is obtained by removing the amino protecting group to obtain the compound of formula (D-1-6);

[0130] The compound of general formula (D-1-6) and the compound of general formula (D-1-7) are reacted through coupling reaction or substitution reaction to obtain the compound of general formula (D-1-8);

[0131] The compound of formula (D-1-8) is obtained by removing the hydroxyl protecting group to obtain the compound of formula (D-1-9);

[0132] The compound of general formula (D-1-9) is subjected to a substitution reaction to obtain a compound of general formula (D-1-10);

[0133] The compound of general formula (D-1-10) and the compound of general formula (D-1-11) or the compound of general formula (D-1-12) are subjected to a coupling reaction to obtain a compound of general formula (D-1-13);

[0134] The compound of formula (D-1-13) is obtained by removing the amino protecting group to obtain the compound of formula (D-1-14);

[0135] The compound of general formula (D-1-14) is subjected to reductive amination reaction, substitution reaction, or coupling reaction to obtain the compound of general formula (D-1-15);

[0136] The compound of the general formula (D-1-15) can be subjected to a hydrolysis reaction or a hydrogenation reaction to obtain a compound of the general formula (D-1).

[0137] Synthesis method 2:

[0138] PG5 and PG6 are each independently selected from an amino protecting group;

[0139] R D-2-1 、R D-2-2 Each is independently selected from a halogen or a leaving group, preferably Br, I, Cl, OTf;

[0140] The definitions of the remaining groups are consistent with those in the specification;

[0141] The compound of general formula (D-2-1) is subjected to reductive amination reaction, substitution reaction, or coupling reaction to obtain the compound of general formula (D-2-2);

[0142] The compound of formula (D-2-2) is obtained by removing the amino protecting group to obtain the compound of formula (D-2-3);

[0143] The compound of general formula (D-2-3) and the compound of general formula (D-2-4) are reacted by coupling reaction or substitution reaction to obtain the compound of general formula (D-2-5);

[0144] The compound of general formula (D-2-5) is reacted through coupling reaction or substitution reaction to obtain the compound of general formula (D-2-6) or the compound of general formula (D-2-7);

[0145] The compound of formula (D-2-6) or the compound of formula (D-2-7) is respectively reacted with the compound of formula (D-1-10) to obtain the compound of formula (D-2-8);

[0146] The compound of the general formula (D-2-8) can be subjected to a hydrolysis reaction or a hydrogenation reaction to obtain a compound of the general formula (D-2).

[0147] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0148] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0149] "CN" refers to cyano.

[0150] "Halogen" refers to F, Cl, Br or I.

[0151] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0152] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0153] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0154] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0155] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0156] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two or three, carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, and the like; alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

[0157] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three, carbon-carbon triple bonds, with a backbone comprising from 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like; alkynyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0158] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0159] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0160] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0161] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2).

[0162] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0163] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0164] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0165] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0166] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0167] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R cR is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0168] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0169] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0170] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to a C3, C4, C5 or C6 cycloalkyl group.

[0171] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0172] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0173] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0174] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0175] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0176] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0177] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0178] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0179] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0180] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0181] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0182] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers. DETAILED DESCRIPTION

[0183] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0184] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0185] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0186] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0187] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0188] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0189] Boc: tert-butyloxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl;

[0190] (R)-SEGPHOS: 5,5'-bis(diphenylphosphoryl)-4,4'-di-1,3-biphenyl (CAS: 244261-66-3);

[0191] Pd2(dba)3: tris(dibenzylideneacetone)dipalladium (CAS: 60748-47-2).

[0192] The * next to the chemical bond indicates that the chirality of the chiral atom is R or S;

[0193] Example 1: Preparation of Compound 1

[0194] Step 1: Synthesis of 1A

[0195] 2-Bromo-4-chlorophenol (25 g, 120.54 mmol), 4-methoxybenzyl chloride (18.88 g, 120.54 mmol), potassium carbonate (33.32 g, 241.08 mmol) and acetone (300 mL) were added to a reaction flask and reacted at 70°C overnight. The mixture was cooled to room temperature and filtered. An appropriate amount of silica gel was added to the filtrate and the mixture was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 1A (30 g, yield: 76%).

[0196] Step 2: Synthesis of 1C

[0197] 1A (12 g, 36.63 mmol), 1B (10.1 g, 36.63 mmol) (CAS: 2781965-82-8, synthesis reference patent: WO2022122910), Pd2(dba)3 (3.35 g, 3.66 mmol), (R)-SEGPHOS (4.47 g, 7.33 mmol), cesium carbonate (35.80 g, 109.93 mmol) and 1,4-dioxane (150 mL) were added to the reaction flask and ventilated with nitrogen three times. The reaction was carried out at 100°C overnight, cooled to room temperature, and an appropriate amount of silica gel was added and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 90-10) to obtain 1C (10 g, yield: 53%).

[0198] Step 3: 1D synthesis

[0199] 1C (10 g, 19.23 mmol) and dichloromethane (50 mL) were added to a reaction flask, and trifluoroacetic acid (40 mL) was added with stirring. The reaction was allowed to react at room temperature overnight, and the mixture was concentrated under reduced pressure. Dichloromethane (100 mL) was added, and the mixture was washed with saturated aqueous sodium bicarbonate. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 1D (6.5 g, yield: 85%).

[0200] Step 4: Synthesis of 1E

[0201] 1D (5 g, 12.51 mmol), triethylamine (3.80 g, 37.53 mmol) and dichloromethane solution (50 mL) were added to the reaction flask. A dichloromethane solution (10 mL) of trifluoromethanesulfonic anhydride (4.1 g, 14.5 mmol) was added dropwise at about -30°C. The mixture was naturally warmed to room temperature and reacted for 1 hour, then washed with saturated sodium bicarbonate aqueous solution. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 1E (4.60 g, yield: 69%).

[0202] Step 5: Synthesis of 1F

[0203] 1E (0.9 g, 1.69 mmol), 4-[4-(N-BOC)piperazin-1-yl]phenylboronic acid pinacol ester (0.98 g, 2.54 mmol), tetrakistriphenylphosphine palladium (0.39 g, 0.34 mmol), sodium carbonate (0.54 g, 5.07 mmol), toluene (6 mL), ethanol (6 mL), and water (3 mL) were added to the reaction flask. The mixture was reacted at 95° C. under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 1F (0.78 g, yield: 71%).

[0204] Step 6: Synthesis of 1G

[0205] 1F (0.95 g, 1.47 mmol) and dichloromethane (6 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The mixture was reacted at room temperature for 2 h, concentrated under reduced pressure, and dichloromethane was added. The mixture was washed once with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1G (0.75 g).

[0206] LCMS m / z=544.1[M+1] +

[0207] Step 7: Synthesis of 1H

[0208] 1G (240 mg, 0.44 mmol) and 1-BOC-3-azetidinone (150 mg, 0.88 mmol) were dissolved in 1,2-dichloroethane (10 mL). Glacial acetic acid (105.69 mg, 1.76 mmol) was added and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (279.76 mg, 1.32 mmol) was added and allowed to react at room temperature overnight. Dichloromethane was then added and the mixture was washed with saturated aqueous sodium bicarbonate. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure. The residue was purified by column chromatography (eluent: PE-EA = 100-0 to 50-50) to afford 1H (0.28 g, yield: 90%).

[0209] LCMS m / z=699.2[M+H] +

[0210] Step 8: Synthesis of 1I

[0211] 1H (0.28 g, 0.40 mmol) and dichloromethane (6 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The reaction was carried out at room temperature for 2 h, and the mixture was concentrated under reduced pressure. After adding dichloromethane, the mixture was washed once with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1I (0.23 g).

[0212] LCMS m / z=599.1[M+1] +

[0213] Step 9: Synthesis of 1J

[0214] 1I (210 mg, 0.44 mmol) and acetone (41 mg, 0.88 mmol) were dissolved in 1,2-dichloroethane (10 mL). Glacial acetic acid (0.063 g, 1.05 mmol) was added and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was then added and allowed to react overnight at room temperature. Dichloromethane was added and the mixture was washed with saturated sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to afford 1J (110 mg, yield: 48%).

[0215] LCMS m / z=641.2[M+1] +

[0216] Step 10: Synthesis of Compound 1

[0217] 1J (110 mg, 0.26 mmol), lithium hydroxide monohydrate (0.071 g, 2.6 mmol), 1,4-dioxane (3 mL), and water (1 mL) were added to the reaction flask. After reacting at room temperature overnight, dichloromethane and water were added, and the pH was adjusted to 4-5 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure. The residue was purified using a reverse phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 0 / 100-50 / 50) to obtain compound 1 trifluoroacetate (80 mg).

[0218] LCMS m / z=613.1[M+1] +

[0219] Example 2: Preparation of Compound 2

[0220] Step 1: Synthesis of 2A

[0221] Dissolve 1G (300 mg, 0.55 mmol) and cyclopropyl ketone (115.66 mg, 1.38 mmol) in methanol (10 mL). Add 2 drops of glacial acetic acid and sodium cyanoborohydride (86.41 mg, 1.38 mmol). React at 70°C under nitrogen overnight. Add cyclopropyl ketone (115.66 mg, 1.38 mmol) and sodium cyanoborohydride (86.41 mg, 1.38 mmol). React at 70°C for 8 h. Add cyclopropyl ketone (115.66 mg, 1.38 mmol) and sodium cyanoborohydride (86.41 mg, 1.38 mmol). React at 70°C overnight. Dichloromethane was added, and the mixture was washed with saturated aqueous sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to give 2A (160 mg, yield: 47%).

[0222] LCMS m / z=612.4[M+1] +

[0223] Step 2: Synthesis of compound 2

[0224] To a reaction flask were added 2A (0.16 g, 0.26 mmol), lithium hydroxide monohydrate (0.11 g, 2.6 mmol), 1,4-dioxane (6 mL), and water (2 mL). After reacting at room temperature overnight, dichloromethane and water were added. The pH was adjusted to 4-5 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to afford compound 2 (100 mg, 65% yield).

[0225] LCMS m / z=584.3[M+1] +

[0226] 1 H NMR(400MHz,CD3OD)δ7.78(s,1H),7.60(t,1H),7.52-7.44(m,2H),7.16-7.10(m,1H) ,7.10-6.99(m,4H),4.50-4.37(m,1H),3.85-3.38(m,8H),3.24-3.11(m,2H),2.98(t, 1H),2.84-2.62(m,2H),2.08-1.78(m,3H),1.73-1.57(m,1H),1.51(d,3H),1.15-1.0 1(m,1H),0.95-0.84(m,1H),0.84-0.74(m,1H),0.74-0.62(m,1H),0.43-0.31(m,1H).

[0227] Example 2-1: Preparation of compound 2-1:

[0228] Step 1: Preparation of 2-0-A and 2-0-B

[0229] Compound 2-0 (2.0 g) was subjected to chiral separation as follows:

[0230] Preparation method: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Gradient: B for 35%; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm.

[0231] After preparative separation, fractions with the same retention time were combined, concentrated under reduced pressure and lyophilized to give 2-0-A (916 mg) and 2-0-B (826 mg).

[0232] Analytical method: Instrument: SHIMADZU LC-30AD SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 5-40%; Flow rate: 3 mL / min; Back pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm.

[0233] Compound 2-0-A: Retention time 1.4 min under analytical method,

[0234] Compound 2-0-B: retention time under the analytical method was 1.6 min.

[0235] Step 2: Synthesis of 2-1-B

[0236] 2-0-B (0.4 g, 1.29 mmol), pinacol diboron (655 mg, 2.58 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (210.69 mg, 0.26 mmol), potassium acetate (379.8 mg, 3.87 mmol) and 1,4-dioxane (10 mL) were added to the reaction flask in sequence. The reaction was carried out at 80 ° C. under nitrogen protection overnight, cooled to room temperature, filtered, and the filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 50-50) to give 2-1-B (0.32 g, yield: 69%).

[0237] LCMS m / z=357.4[M+1] +

[0238] Step 3: Synthesis of 2-1-C

[0239] 1E-R (150 mg, 0.28 mmol), 2-1-B (108.75 mg, 0.31 mmol), tetrakistriphenylphosphine palladium (64.71 mg, 0.056 mmol), sodium carbonate (89.03 mg, 0.84 mmol), toluene (3 mL), ethanol (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. An appropriate amount of silica gel was added to the organic layer and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 95-5) to give 2-1-C (132 mg, yield: 76%).

[0240] LCMS m / z=612.5[M+1] +

[0241] Step 4: Synthesis of compound 2-1

[0242] 2-1-C (130 mg, 0.21 mmol), lithium hydroxide monohydrate (0.088 g, 2.1 mmol), 1,4-dioxane (4.5 mL), and water (1.5 mL) were added to a reaction flask. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford the product, compound 2-1 (10 mg, yield: 8%).

[0243] LCMS m / z=584.5[M+1] +

[0244] 1 H NMR(400MHz,CD3OD)δ7.80(s,1H),7.53(t,1H),7.51-7.44(m,2H),7.15-7.09(m,1H) ,7.09-7.00(m,4H),4.52-4.37(m,1H),3.88-3.38(m,8H),3.25-3.06(m,2H),2.98(t, 1H),2.87-2.56(m,2H),2.09-1.74(m,3H),1.72-1.56(m,1H),1.50(d,3H),1.14-1.0 1(m,1H),0.93-0.82(m,2H),0.82-0.73(m,1H),0.73-0.62(m,1H),0.43-0.30(m,1H).

[0245] Compound 2-1 and compound 2-3 are diastereoisomers, one of which has the structure Another one is

[0246] Example 2-2: Preparation of compound 2-2:

[0247] Step 1: Synthesis of 2-2-A

[0248] 1E-S (200 mg, 0.38 mmol), 2-1-B (147.58 mg, 0.41 mmol), tetrakistriphenylphosphine palladium (87.82 mg, 0.076 mmol), sodium carbonate (120.83 mg, 1.14 mmol), toluene (3 mL), ethanol (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C. under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 95-5) to give 2-2-A (150 mg, yield: 65%).

[0249] LCMS m / z=612.1[M+1] +

[0250] Step 3: Synthesis of compound 2-2

[0251] 2-2-A (150 mg, 0.25 mmol), lithium hydroxide monohydrate (0.1 g, 2.5 mmol), 1,4-dioxane (4.5 mL), and water (1.5 mL) were added to a reaction flask. The reaction was allowed to react overnight at room temperature. The pH was adjusted to 4-5 with 1N hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) and then by preparative HPLC (instrument: Waters 2767 preparative liquid phase; column: XBridge@Prep C18 (30 mm × 150 mm); mobile phase composition: acetonitrile, water (containing 0.1% trifluoroacetic acid)). The preparative solution was lyophilized to obtain the trifluoroacetate salt of compound 2-2 (15 mg).

[0252] LCMS m / z=584.0[M+1] +

[0253] 2-2-A (300 mg, 0.49 mmol), lithium hydroxide monohydrate (0.21 g, 4.9 mmol), 1,4-dioxane (9 mL), and water (3 mL) were added to a reaction flask. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 30 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was isolated and purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 2-2 (150 mg, yield: 52%).

[0254] LCMS m / z=584.0[M+1] +

[0255] 1 H NMR(400MHz,CD3OD)δ7.78(s,1H),7.67(t,1H),7.53-7.46(m,2H),7.19-7.13(m,1H) ,7.13-7.03(m,4H),4.51-4.37(m,1H),3.76-3.40(m,8H),3.27-3.12(m,2H),2.98(t, 1H),2.85-2.65(m,2H),2.10-1.80(m,3H),1.78-1.60(m,1H),1.53(d,3H),1.19-1.0 4(m,1H),0.98-0.85(m,1H),0.85-0.75(m,1H),0.75-0.65(m,1H),0.47-0.31(m,1H).

[0256] Compound 2-2 and compound 2-4 are diastereoisomers, one of which has the structure Another one is

[0257] Example 2-3: Preparation of Compound 2-3

[0258] Step 1: Synthesis of 2-3-B

[0259] 2-0-A (0.2 g, 0.65 mmol), diboronic acid pinacol ester (330 mg, 2.54 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (106 mg, 0.13 mmol), potassium acetate (191 mg, 1.95 mmol) and 1,4-dioxane (10 mL) were added to the reaction flask in sequence, ventilated with nitrogen three times, and reacted at 80 ° C under nitrogen protection overnight. The mixture was cooled to room temperature and filtered. The filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 50-50) to give 2-3-B (0.12 g, yield: 52%).

[0260] LCMS m / z=357.4[M+1] +

[0261] Step 2: Synthesis of 2-3-C

[0262] 1E-R (100 mg, 0.19 mmol), 2-3-B (80 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (44 mg, 0.038 mmol), sodium carbonate (60 mg, 0.57 mmol), toluene (6 mL), ethanol (6 mL) and water (3 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. An appropriate amount of silica gel was added to the organic layer and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 95-5) to give 2-3-C (80 mg, yield: 70%).

[0263] LCMS m / z=612.5[M+1] +

[0264] Step 3: Synthesis of compound 2-3

[0265] To a reaction flask were added 2-3-C (80 mg, 0.13 mmol), lithium hydroxide monohydrate (0.036 g, 1.3 mmol), 1,4-dioxane (2 mL), and water (1 mL). After reacting at room temperature overnight, dichloromethane and water were added, and the pH was adjusted to 4-5 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure. The residue was purified using a reverse phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 0 / 100 to 50 / 50) to afford the trifluoroacetate salt of compound 2-3 (50 mg).

[0266] LCMS m / z=584.5[M+1] +

[0267] Example 2-4: Preparation of Compound 2-4

[0268] Step 1: Synthesis of 2-4-A

[0269] 1E-S (130 mg, 0.24 mmol), 2-3-B (93 mg, 0.26 mmol), tetrakistriphenylphosphine palladium (55 mg, 0.048 mmol), sodium carbonate (76 mg, 0.72 mmol), toluene (6 mL), ethanol (6 mL), water (3 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. After adding an appropriate amount of silica gel to the organic layer, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 95-5) to give 2-4-A (120 mg, yield: 80%).

[0270] LCMS m / z=612.1[M+1] +

[0271] Step 3: Synthesis of Compound 2-4

[0272] To a reaction flask were added 2-4-A (120 mg, 0.196 mmol), lithium hydroxide monohydrate (0.054 g, 1.96 mmol), 1,4-dioxane (2 mL), and water (1 mL). The mixture was allowed to react overnight at room temperature, followed by the addition of dichloromethane and water. The pH was adjusted to 4-5 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure. The residue was purified using a reverse phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 0 / 100 to 50 / 50) to afford the trifluoroacetic acid salt of compound 2-4 (50 mg).

[0273] LCMS m / z=584.0[M+1] +

[0274] Example 3: Preparation of Compound 3

[0275] Step 1: Synthesis of 3A

[0276] 1-(4-Bromophenyl)piperazine (650 mg, 2.70 mmol) and 1-(1-fluorocyclopropyl)ethanone (550 mg, 5.4 mmol) were dissolved in methanol (20 mL). Glacial acetic acid (0.2 mL) and sodium cyanoborohydride (420 mg, 6.75 mmol) were added and the mixture was allowed to react at 70°C overnight under nitrogen. 1-(1-Fluorocyclopropyl)ethanone (550 mg, 5.4 mmol) and sodium cyanoborohydride (420 mg, 6.75 mmol) were then added and the mixture was allowed to react at 70°C for 8 h. Dichloromethane was added and the mixture was washed with saturated sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 10 / 1) to obtain 3A (200 mg, yield: 23%).

[0277] Step 2: Synthesis of 3B

[0278] 3A (0.2 g, 0.61 mmol), pinacol diboron (309.81 mg, 1.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (99.63 mg, 0.12 mmol), potassium acetate (179.6 mg, 1.83 mmol) and 1,4-dioxane (5 mL) were added to the reaction flask in sequence. The reaction was carried out at 80°C under nitrogen protection overnight, cooled to room temperature, filtered, and the filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 50-50) to give 3B (0.15 g, yield: 66%).

[0279] LCMS m / z=375.1[M+1] +

[0280] Step 2: Synthesis of 3C

[0281] 1E (200 mg, 0.38 mmol), 3B (155 mg, 0.41 mmol), tetrakistriphenylphosphine palladium (87.82 mg, 0.076 mmol), sodium carbonate (120.83 mg, 1.14 mmol), toluene (3 mL), ethanol (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was carried out at 95°C under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 80-20) to give 3C (120 mg, yield: 51%).

[0282] LCMS m / z=630.0[M+1]+

[0283] Step 3: Synthesis of compound 3

[0284] To a reaction flask, 3C (120 mg, 0.19 mmol), lithium hydroxide monohydrate (0.08 g, 1.9 mmol), 1,4-dioxane (3 mL), and water (1 mL) were added. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10 / 1) to afford the product, compound 3 (50 mg, yield: 44%).

[0285] LCMS m / z=602.1[M+1] +

[0286] Example 3-1: Preparation of compound 3-1:

[0287] Step 1: Preparation of 3-0

[0288] Dissolve 3-0-1 (2.6 g, 9.37 mmol) and 1-(1-fluorocyclopropyl)ethanone (0.96 g, 9.37 mmol) in methanol (30 mL), add 2 drops of glacial acetic acid and sodium cyanoborohydride (1.18 g, 18.74 mmol), and react at 70°C under nitrogen overnight. Add 1-(1-fluorocyclopropyl)ethanone (550 mg, 5.4 mmol) and sodium cyanoborohydride (420 mg, 6.75 mmol), and react at 70°C for 8 h. Add 1-(1-fluorocyclopropyl)ethanone (550 mg, 5.4 mmol) and sodium cyanoborohydride (420 mg, 6.75 mmol), and react at 70°C for 8 h. The reaction solution was cooled to room temperature, and dichloromethane was added. The mixture was washed once with saturated aqueous sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (V / V) = 1 / 0-10 / 1) to give 3-0 (900 mg, yield: 29%).

[0289] Step 2: Preparation of 3-0-A and 3-0-B

[0290] Compound 3-0 (900 mg) was subjected to chiral separation as follows:

[0291] Preparation method: Instrument: CAS-05-Prep-SFC-F; Chromatographic column: AD column; Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; Flow rate: 100 mL / min; Column temperature: room temperature; Detection wavelength: 220 nm.

[0292] After preparative separation, the fractions with the same retention time were combined, concentrated under reduced pressure and lyophilized to give 3-0-A (373.2 mg) and 3-0-B (323.9 mg).

[0293] Analytical method: Instrument: CAS-05-ANA-SFC-D; Chromatographic column: AD column; Mobile phase: A for CO2; B for 0.05% MNH3 in methanol; Flow rate: 3 mL / min; Column temperature: 35°C; Detection wavelength: 220 nm.

[0294] Compound 3-0-A: Retention time 1.8 min under analytical method,

[0295] Compound 3-0-B: retention time 2.1 min under the analytical method.

[0296] Step 3: Synthesis of 3-1-B

[0297] 3-0-A (0.17 g, 0.52 mmol), diboronic acid pinacol ester (264 mg, 1.04 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (84.93 mg, 0.1 mmol), potassium acetate (153.1 mg, 1.56 mmol) and 1,4-dioxane (6 mL) were added to the reaction flask in sequence. The reaction was carried out at 80 ° C. under nitrogen protection overnight, cooled to room temperature, filtered, and the filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 98-2) to give 3-1-B (0.19 g, yield: 98%).

[0298] LCMS m / z=375.3[M+1] +

[0299] Step 4: Synthesis of 3-1-C

[0300] 1E-R (200 mg, 0.38 mmol), 3-1-B (170.68 mg, 0.46 mmol), tetrakistriphenylphosphine palladium (87.82 mg, 0.076 mmol), sodium carbonate (120.83 mg, 1.14 mmol), toluene (3 mL), ethanol (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. An appropriate amount of silica gel was added to the organic layer and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 98-2) to give 3-1-C (200 mg, yield: 84%).

[0301] LCMS m / z=630.4[M+1] +

[0302] Step 5: Synthesis of compound 3-1

[0303] To a reaction flask, 3-1-C (200 mg, 0.32 mmol), lithium hydroxide monohydrate (0.13 g, 3.2 mmol), 1,4-dioxane (4.5 mL), and water (1.5 mL) were added. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 30 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford the product, compound 3-1 (100 mg, yield: 52%).

[0304] LCMS m / z=602.2[M+1] +

[0305] 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.54(t,1H),7.47(d,2H),7.14-6.99(m, 3H),6.95(d,2H),4.47-4.23(m,1H),3.61-3.26(m,8H),3.24-3.03(m,3H),2 .94(t,1H),2.73(t,1H),2.09-1.91(m,2H),1.88-1.77(m,1H),1.73-1.60(m ,1H),1.55(d,3H),1.47-1.33(m,1H),1.17-0.98(m,2H),0.70-0.56(m,1H).

[0306] Compound 3-1 and compound 3-3 are diastereoisomers, one of which has the structure Another one is

[0307] Example 3-2: Preparation of Compound 3-2

[0308] Step 1: Synthesis of 3-2-B

[0309] 1E-S (200 mg, 0.38 mmol), 3-1-B (170.68 mg, 0.46 mmol), tetrakistriphenylphosphine palladium (87.82 mg, 0.076 mmol), sodium carbonate (120.83 mg, 1.14 mmol), toluene (3 mL), ethanol (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C. under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 98-2) to give 3-2-B (230 mg, yield: 97%).

[0310] LCMS m / z=630.4[M+1] +

[0311] Step 2: Synthesis of compound 3-2

[0312] To a reaction flask, 3-2-B (230 mg, 0.36 mmol), lithium hydroxide monohydrate (0.15 g, 3.6 mmol), 1,4-dioxane (4.5 mL), and water (1.5 mL) were added. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 30 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford the product, compound 3-2 (100 mg, yield: 46%).

[0313] LCMS m / z=602.3[M+1] +

[0314] 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.56(t,1H),7.48(d,2H),7.15-7.00( m,3H),6.95(d,2H),4.50-4.31(m,1H),3.59-3.26(m,8H),3.25-2.93(m, 4H),2.70(t,1H),2.09-1.91(m,2H),1.87-1.77(m,1H),1.74-1.59(m,1H ),1.53(d,3H),1.41-1.29(m,1H),1.19-0.97(m,2H),0.72-0.54(m,1H).

[0315] Compound 3-2 and compound 3-4 are diastereoisomers, one of which has the structure Another one is

[0316] Example 3-3: Preparation of compound 3-3:

[0317] Step 1: Synthesis of 3-3-B

[0318] 3-0-B (0.3 g, 0.92 mmol), pinacol diboron (467 mg, 1.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride dichloromethane complex (150 mg, 0.18 mmol), potassium acetate (271 mg, 2.76 mmol) and 1,4-dioxane (10 mL) were added to the reaction flask in sequence. The reaction was carried out at 80 ° C. under nitrogen protection overnight, cooled to room temperature, filtered, and the filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 98-2) to give 3-3-B (0.33 g, yield: 96%).

[0319] LCMS m / z=375.3[M+1] +

[0320] Step 2: Synthesis of 3-3-C

[0321] 1E-R (240 mg, 0.45 mmol), 3-3-B (180 mg, 0.48 mmol), tetrakistriphenylphosphine palladium (104 mg, 0.090 mmol), sodium carbonate (143 mg, 1.35 mmol), toluene (4 mL), ethanol (4 mL) and water (2 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. An appropriate amount of silica gel was added to the organic layer and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 98-2) to give 3-3-C (180 mg, yield: 63%).

[0322] LCMS m / z=630.4[M+1] +

[0323] Step 3: Synthesis of compound 3-3

[0324] To a reaction flask, 3-3-C (180 mg, 0.29 mmol), lithium hydroxide monohydrate (0.12 g, 2.9 mmol), 1,4-dioxane (4.5 mL), and water (1.5 mL) were added. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 30 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford the product, compound 3-3 (120 mg, yield: 69%).

[0325] LCMS m / z=602.3[M+1] +

[0326] 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.56(t,1H),7.49(d,2H),7.15-7.00( m,3H),6.95(d,2H),4.49-4.33(m,1H),3.56-3.25(m,8H),3.24-2.92(m, 4H),2.70(t,1H),2.07-1.91(m,2H),1.87-1.75(m,1H),1.74-1.57(m,1H ),1.51(d,3H),1.39-1.29(m,1H),1.16-0.95(m,2H),0.73-0.51(m,1H).

[0327] Example 3-4: Preparation of compound 3-4:

[0328] Step 1: Synthesis of 3-4-A

[0329] 1E-S (200 mg, 0.38 mmol), 3-3-B (150 mg, 0.40 mmol), tetrakistriphenylphosphine palladium (88 mg, 0.076 mmol), sodium carbonate (121 mg, 1.14 mmol), toluene (4 mL), ethanol (4 mL) and water (2 mL) were added to the reaction flask, and the reaction was carried out at 95 ° C. under nitrogen protection overnight. After cooling to room temperature, ethyl acetate (30 mL) and water (20 mL) were added and extracted. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: DCM-MeOH = 100-0 to 98-2) to give 3-4-A (170 mg, yield: 71%).

[0330] LCMS m / z=630.4[M+1] +

[0331] Step 3: Synthesis of compound 3-4

[0332] To a reaction flask, 3-4-A (170 mg, 0.27 mmol), lithium hydroxide monohydrate (0.11 g, 2.7 mmol), 1,4-dioxane (4.5 mL), and water (1.5 mL) were added. The reaction was allowed to react at room temperature overnight. The pH was adjusted to 4-5 with 1N hydrochloric acid. 30 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 10:1) to afford the product, compound 3-4 (110 mg, yield: 67%).

[0333] LCMS m / z=602.2[M+1] +

[0334] 1 H NMR(400MHz, CDCl3)δ7.84(s,1H),7.53(t,1H),7.47(d,2H),7.14-7.00(m, 3H),6.95(d,2H),4.43-4.29(m,1H),3.58-3.25(m,8H),3.21-3.01(m,3H),2 .94(t,1H),2.74(t,1H),2.07-1.93(m,2H),1.90-1.79(m,1H),1.75-1.59(m ,1H),1.55(d,3H),1.44-1.34(m,1H),1.17-0.98(m,2H),0.72-0.53(m,1H).

[0335] Control compound 1: Control compound 2:

[0336] Biological test cases

[0337] 1. CHO-KI / sGC cell cGMP detection experiment

[0338] Stably transfected CHO-K1 cells expressing sGCα1 / β1 heterodimers were constructed and designated CHO-KI / sGC. CHO-KI / sGC cells were cultured in complete culture medium (FK12 + 10% FBS + 1% double-stranded antibody + 0.5 mg / mL hygromycin + 0.25 mg / mL G418). On the day of assay, cells were reselected in EAB assay buffer (EBSS assay buffer + 5 mL MgCl2 + 10 mM HEPES + 0.05% BSA) at a cell density of 2.25 x 10 5 0.5 mM IBMX was added to prevent cGMP degradation.

[0339] After the cells were pre-incubated with 1 pM diethylenetriamine / nitric oxide (EDTA-NO) at room temperature for 30 minutes, different concentrations of compounds were added and incubated at 37°C for 1 hour. After the incubation, the reaction was terminated and the intracellular cGMP content was detected according to the instructions of the Cisbio kit (CisBio, 62GM2PEC). The maximum cGMP production relative to the positive compound was calculated according to formula (1-1), where RLU compound The reading for the test compound is RLU reference The maximum reading of the positive compound. Activation% = RLU compound / RUL reference *100% formula (1-1)

[0340] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good stimulating effect on the cGMP production in CHO-KI / sGC cells.

[0341] 2. In vitro guanylate cyclase (sGC) enzyme activity assay

[0342] First, 100 nL of compound at various concentrations was transferred to a 384-well plate (Greiner, Cat. No. 784075) using an Echo655 (LABCYTE, Cat. No. 655). DMSO was added to a final reaction concentration of 1%. 2 μL of sGC (ICE, Cat. No. S2304F-H07SH2) was added to the plate and centrifuged at 1000 rpm for 1 minute. Then, 1 μL of DETA NONOate was added and incubated at 37°C for 10 minutes. Following incubation, 2 μL of GTP was added, the reaction was centrifuged at 1000 rpm for 1 minute, and the reaction was incubated at 37°C for 60 minutes. The final concentrations of sGC, GTP, and DETA NONOate in the reaction system were 1.5 nM, 5 μM, and 100 μM, respectively. After the reaction, 5 μL of detection mixture (PerkinElmer, Cat. No. 62GM2PEG) was added and incubated at room temperature for 60 min. The TR-FRET signal (Ratio: 665 / 620 nm) was read using a microplate reader (BMG, Cat. No. PHERAstar FSX). Nonlinear regression curve fitting was performed using GraphPad Prism software to calculate the EC 50 Compound A (Example 1 in WO2010065275) was used as the positive reference compound, and the activation rate calculation formula was shown in Formula 2-1, where the Low control was the TR-FRET signal value of 1 μM compound A, and the High control was the TR-FRET signal value of the DMSO well.

[0343] stimulation%=(ave High control-cpd well) / (ave High control-ave Low control)*100% Formula 2-1

[0344] Table 1: Results of enzymatic agonism and / or activation of guanylate cyclase (sGC) by test compounds

[0345] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an agonistic and / or activating effect on the activity of guanylate cyclase (sGC).

[0346] Test Example 3: Pharmacokinetic Test in Mice

[0347] Experimental purpose: This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, measured the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in mice.

[0348] Experimental animals: Male ICR mice, 20-35 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0349] Experimental Methods: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted overnight before administration, but not water. Food was resumed 4 hours after administration. * The dose is based on the free form;

[0350] Sampling: Blood was collected from the eye socket at designated time points and placed in EDTAK2 centrifuge tubes. The tubes were centrifuged at 5000 rpm for 10 min to collect plasma.

[0351] Time points for plasma collection in G1 group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h;

[0352] Time points for plasma collection in G2 group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h;

[0353] All samples were stored below -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0354] Table 3-1 PK data of test compound in mice *Note: Compounds were administered ig (orally).

[0355] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in mice.

[0356] Test Example 4: Pharmacokinetic Test in Rat

[0357] Experimental animals: Male SD rats, 180-200 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0358] Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted overnight before administration, but not with water. Food was resumed 4 hours after administration. Note: Intravenous administration solvent: 5% DMA + 5% HS-15 + 90% NS or 10% DMA + 10% HS-15 + 80% NS;

[0359] The vehicle for oral administration was: 5% DMSO + 5% Solutol + 10% PEG 400 + 80% (20% SBE-β-CD).

[0360] Blood was collected from the eye socket at designated time points and placed in EDTAK2 centrifuge tubes. The tubes were centrifuged at 5000 rpm for 10 min to collect plasma.

[0361] Blood was collected from the venous group at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours; from the oral gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours. All samples were stored below -60°C before analysis. Quantitative analysis was performed using LC-MS / MS.

[0362] Table 4-1 PK data of test compound in rats *Note: Compounds were administered ig (orally).

[0363] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in rats.

[0364] 5. hERG potassium channel effect test

[0365] Experimental platform: electrophysiology manual patch clamp system

[0366] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0367] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0368] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0369] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0370] Compound IC 50 The results were calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0371] Among them, X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom

[0372] and Top are the minimum and maximum inhibition percentages, respectively.

[0373] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on hERG potassium ion channels.

[0374] 6. CHO / sGC cell cGMP detection experiment

[0375] Stably transfected CHO cells expressing sGCα1 / β1 heterodimers were constructed and named CHO / sGC. They were cultured in complete medium (RPMI-1640 + 10% FBS + 1% P + 500 μg / mL G418 + 500 μg / mL HB). On the day of the assay, cells were reselected in assay buffer (EBSS assay buffer + 5 mL MgCl2 + 10 mM HEPES + 0.05% BSA) at a cell density of 2 x 10 5 0.5 mM IBMX was added to prevent cGMP degradation.

[0376] After preincubation of cells with 20 μM diethylenetriamine / nitric oxide (EDTA-NO) at 37°C for 30 minutes, different concentrations of compound (0.38 nM, 1.526 nM, 6.1 nM, 24.4 nM, 97.656 nM, 390.6 nM, 1.56 μM, 6.25 μM, 25 μM, 100 μM) were added and incubated at room temperature for 1 hour. After the incubation, the reaction was terminated and the intracellular cGMP content was measured according to the Cisbio kit instructions (CisBio, 62GM2PEC). The amount of cGMP produced relative to compound A (Example 1 in WO2010065275) was calculated according to formula (6-1). Sample cGMP is the reading of the test compound, Low control cGMP is the 1% DMSO control, and High control cGMP is the reading at a 10 μM dose of compound A. %Activity=(Sample cGMP-Low control GMP) / (High control cGMP-Low control cGMP)*100% Formula (6-1)

[0377] The maximum activation (%) was the measured value, and the concentrations of 50% and 80% absolute activation values ​​were calculated using GraphPad Prism 8.0.1 software.

[0378] Table 2: Results of compounds stimulating and / or activating cGMP production in CHO / sGC cells

[0379] Conclusion: The compounds of the present invention, such as the example compounds, have a good agonistic and / or activating effect on the cGMP production of CHO / sGC cells, and the agonistic and / or activating effect is better than that of control compound 1 and control compound 2.

[0380] 7. Pharmacodynamic study on relaxation of thoracic aorta rings in SD rats

[0381] Eight-week-old, SPF-qualified male Sprague-Dawley rats were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Upon arrival, they were acclimated for at least one week. Rats were weighed and randomly assigned to groups based on body weight before the experiment. On the day of the experiment, rats were deeply anesthetized with Zotai 50 (20 mg / kg, ip) and xylazine (8 mg / kg, ip). The thorax was then rapidly opened, and the aorta was carefully isolated. The descending aorta was then cut and placed in a culture dish containing saturated oxygen (95% O₂ + 5% CO₂) in KH₄ solution. Connective tissue on the vessel surface was removed, and vascular rings approximately 3–5 mm long were prepared. Using a custom-made hook, the rings were suspended in an isolated tissue perfusion bath containing 37°C constant-temperature KH₄ solution, saturated with oxygen, and connected to a tension transducer (JZ101H, Chengdu Instrument Factory). The tension transducer was then connected to a multi-channel electrophysiological signal recorder (RM6240E, Chengdu Instrument Factory). The vascular rings were rinsed with KH solution and allowed to equilibrate under a 3g basic tension for 90 minutes, after which 10 -6 The vascular rings were pre-contracted with 100 M of norepinephrine and allowed to reach a stable tension. The test compounds were then added sequentially to the bath in a concentration gradient from low to high to relax the rings. Each addition was separated by 5 minutes, and changes in the tension of the thoracic aorta rings were observed. The percentage of relaxation at each concentration was calculated.

[0382] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant dilating effect on rat thoracic aorta rings.

[0383] 8. Blood Pressure Telemetry in SHR Rats

[0384] Implantation of the telemeter blood pressure implant: The day before surgery, the DSI implant was disinfected (soaked in 2% glutaraldehyde solution for 8-10 hours); the animal was weighed and anesthetized with thiazine (8 mg / kg, ip.) + Zotai 50 (20 mg / kg, ip.); the animal was fasted the day before surgery; the implant was implanted on the first day of the experiment, and the procedure was as follows: the abdominal skin of the rat was sterile disinfected, a longitudinal incision was made, the abdominal organs were separated, the abdominal aorta was exposed, the blood pressure sensitive probe catheter of the implant was inserted into the abdominal aorta, and the implant was sealed with biological glue for hemostasis. The implant was then fixed to the abdominal wall, and the muscles and skin were sutured, disinfected, and meloxicam was administered subcutaneously for analgesia; the animal was placed in a constant temperature (37°C) incubator after surgery. After the animal was fully awake (autonomic movement was restored), it was returned to the cage and housed individually. Within 3 days after surgery, 4-8 mg / kg of gentamicin sulfate was injected subcutaneously every day for infection prevention, and meloxicam was injected subcutaneously for analgesia.

[0385] Blood Pressure Monitoring: Baseline blood pressure was measured for 24 hours approximately 10 days after postoperative recovery. Rats were grouped according to their baseline blood pressure and then administered medication. Blood pressure was monitored for 24 hours after a single oral dose. Changes in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate were recorded over a 24-hour period. The raw data were used to calculate the mean systolic blood pressure, mean diastolic blood pressure, mean arterial pressure, and mean heart rate over a defined time period (typically 30 minutes). A P value of less than 0.05 was considered statistically significant.

[0386] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant effect on lowering blood pressure in rats.

[0387] 9. Beagle Dog Pharmacokinetic Test

[0388] Test animals: Male beagle dogs, about 8-11 kg, 5-6 per compound.

[0389] Test method: On the test day, 5-6 beagle dogs were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration. Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0390] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.)

[0391] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm at 4°C for 10 minutes. Blood was collected from both the intravenous and oral gavage groups in the G1 and G2 groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0392] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

[0393] 10. Monkey Pharmacokinetic Test

[0394] Test animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound.

[0395] Test method: On the day of the test, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration. Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0396] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

[0397] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0398] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in monkeys.

[0399] 11. Mouse liver microsome stability test

[0400] At 37°C, 1 μM of the test compound was incubated with mouse liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the mouse liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0401] Conclusion: The compound of the present invention has good stability in mouse liver microsomes.

[0402] 12. Rat microsome stability test

[0403] At 37°C, 1 μM of the test compound was incubated with rat liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the rat liver microsome solution was calculated by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0404] Biological test results:

[0405] Conclusion: The compound of the present invention has good stability in rat liver microsomes. Compared with the control compound 1, its clearance rate in rat liver microsomes is significantly slowed down and its half-life is significantly prolonged.

[0406] 13. Monkey microsome stability test

[0407] At 37°C, 1 μM of the test compound was incubated with monkey liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the monkey liver microsome solution was calculated by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0408] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good stability in monkey liver microsomes.

[0409] 14. Canine microsome stability test

[0410] At 37°C, 1 μM of the test compound was incubated with canine liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the canine liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0411] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good stability in canine liver microsomes.

[0412] 15. Human microsome stability test

[0413] At 37°C, 1 μM of the test compound was incubated with human liver microsomes (0.5 mg / mL) supplemented with NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the human liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0414] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good stability in human liver microsomes.

[0415] 16.Caco2 permeability test

[0416] The experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (5μM) was added to the dosing port hole on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port hole. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS / MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficient for transport from the apical side to the basolateral side and from the basolateral side to the apical side of the monolayer cells, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

[0417] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Caco2 permeability.

[0418] 17. Assessment of renal function by analyzing proteinuria (urine protein to creatine ratio, uPCR) in female rats

[0419] RenTG / L-NAME-supplemented female rats were treated with placebo (set as 100%) or compound, and the urine protein to creatinine ratio of the rats was detected and calculated.

[0420] Conclusion: The compounds of the present invention, such as the compounds of the Examples, can lead to a reduction in proteinuria in RenTG / L-NAME-supplemented female rats.

[0421] 18.CYP3A4 induction activity test (PXR activation)

[0422] Objective: The purpose of this study was to evaluate the potential of test compounds to induce the activity of drug-metabolizing enzymes by activating PXR in vitro.

[0423] 1. Cell seeding

[0424] 1) DPX2 cells were cultured in growth medium containing 10% fetal bovine serum.

[0425] 2) DPX2 cells were cultured in a T-75 culture flask in an incubator at 37°C, 5% CO2, and 95% relative humidity. The cells were digested when they covered 80-90% of the bottom of the culture flask.

[0426] 3) Wash the surface of the T-75 cultured cells with 10 mL of PBS, aspirate the PBS, add 3-5 mL of trypsin, and digest at 37°C for 5 minutes or until the cells are digested and suspended. Add an excess of culture medium containing fetal bovine serum to terminate the trypsin digestion.

[0427] 4) Transfer the cell suspension to a conical-bottom centrifuge tube and centrifuge at 150g for 5 minutes at room temperature. Carefully aspirate the supernatant and resuspend the cells in treatment medium to a concentration of 3.2 × 105 cells / mL (incubation time: 24 hours, seeding density: 4.0 × 105 cells / mL). Add 25 μL of the cell suspension to each well of a 384-well cell culture plate. Incubate the plate in an incubator at 95% humidity, 37°C, and 5% CO2 for 24 hours.

[0428] 2. Compound preparation

[0429] 1) Prepare 1000× stock solutions of the test compound, positive control (rifampicin), and negative control (propranolol) in DMSO. The final concentrations of the positive control (rifampicin) are 1 μM and 10 μM, and the final concentration of the negative control (propranolol) is 10 μM. The final concentrations of the test compound are 10, 1, 0.1 μM, or the EC50 (30, 10, 3, 1, 0.3, 0.1 μM). The final DMSO concentration is 0.1%.

[0430] 2) Remove the cell culture plate from the incubator and directly add 25 nL of the positive or negative control drug or test compound stock solution using an Echo. Set up three replicates for each concentration. Return the cell plate to the incubator and continue incubation for 48 hours (24 hours).

[0431] 3) Before initiating experiments using the substrate, inspect cell morphology and monolayer integrity to ensure the monolayer is of acceptable quality for studies.

[0432] 3. Quantitative detection of PXR activation

[0433] 1) 48 hours after treatment (24 hours), cultures can be used for quantitative detection of PXR activation.

[0434] 2) CellTiter-Fluor TM Equilibrate the Cell Viability Assay Kit and One-Glo Luciferase Reagent to room temperature. Add GF-AFC Substrate (10 μL) to Assay Buffer (10 ml) to create a 2X reagent, which is then diluted with 10 ml of PBS to a 1X reagent. Add ONE-Glo Luciferase Substrate to ONE-Glo Luciferase Assay Buffer.

[0435] 3) Take out the culture plate from the incubator, discard the culture medium, and add 1X CellTiter-Fluor TM The reagent was poured into the sample tank, and 25 μL of the reagent was added to each well of the culture plate using a pipetting workstation, and then placed in the incubator for incubation for 30 minutes.

[0436] 4) Remove the cell culture plate from the incubator, cool it slightly to room temperature, and measure the fluorescence value using an automatic quantitative microplate reader with an excitation wavelength of 400 nm and an emission wavelength of 505 nm.

[0437] 5) Pour ONE-Glo reagent into the sample reservoir, add 25 μL to each well, gently mix the plate, incubate at room temperature for 5 minutes, and measure the luminescence value.

[0438] 4. Data Analysis

[0439] All data were calculated using Microsoft Excel.

[0440] 1) Luciferase activity is expressed as RFU / RLU, where RLU is the average luminescence intensity of three replicates of each compound at each concentration, and RFU is the average fluorescence intensity of three replicates of each compound at each concentration.

[0441] The activation fold of mRNA was calculated using the following formula:

[0442] Fold activation=(RLU test / RFU test) / (RLUvehicle / RFUvehicle)

[0443] 2) The cell viability percentage of the compound was calculated according to the following formula:

[0444] Cell Viability%=(RFUtest / RFUvehicle)×100

[0445] 3) The percentage relative to the positive control drug is calculated according to the following formula:

[0446] Percent of positive control (%) = (Fold activation test / Fold activationPositive control) × 100

[0447] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant induction effect on CYP3A4.

[0448] 19.CYP3A4 induction activity test (enzyme activity and mRNA)

[0449] The purpose of this research project is to evaluate the effects of the test substances on the enzyme activities and gene expression levels of cytochrome P450 isozymes CYP1A2, CYP2B6 and CYP3A4 by in vitro hepatocyte induction experiments.

[0450] Cryopreserved human hepatocytes from three donors were incubated with the test compound at varying concentrations (≥5 concentration points) at 37°C for 48 hours, with fresh culture medium replaced every 24 hours. Lactate dehydrogenase release was measured in the culture medium after 24 and 48 hours of incubation to assess potential cytotoxic effects of the test compound. The concentration of the test compound in the culture medium was measured at 0, 5, and 24 hours after the second dose to assess the concentration of the parent drug in the culture medium of the human hepatocytes. After incubation of the cryopreserved human hepatocytes from the three donors with the test compound for 48 hours, the culture medium was removed, and the cells were washed with Hank's balanced salt solution (HBSS) preheated to 37°C. The enzyme-specific substrate was then added and incubated at 37°C for 30 minutes. Liquid chromatography-tandem mass spectrometry was used to quantify the amount of metabolites produced by each substrate. Real-time quantitative PCR was used to assess gene expression levels in the cells.

[0451] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant induction effect on CYP3A4.

[0452] 20. P-gp transporter inhibition test

[0453] This project uses the MDR1-MDCKⅡ monolayer cell model to evaluate the inhibitory effect of the test substance on the activity of P-glycoprotein transporter.

[0454] In the experiment, MDR1-MDCKⅡ cells were seeded into 96-well cell plates and cultured for 7 consecutive days before being used for transport experiments. Digoxin (a known P-gp substrate) was administered bidirectionally in the presence and absence of the test substance and incubated with different concentrations (0-30μM) of the test substance. After incubation for 150 minutes, the receiving end samples were collected and the digoxin content in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). By calculating the efflux ratio (ER) of digoxin in the presence and absence of the test substance, the percentage of P-gp transport activity of MDR1-MDCKⅡ cells under the action of different test concentrations of the test substance (%VC (Vehicle Control, solvent control), the percentage of P-gp transport activity in the presence and absence of the test substance) was obtained, and the half-maximal inhibitory concentration (IC50) was calculated from this. 50 ).

[0455] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the P-gp transporter.

[0456] 21. BCRP transporter inhibition

[0457] The purpose of this study was to evaluate the inhibitory effect of the test compounds on the activity of breast cancer resistance protein transporter using the Caco-2 monolayer cell model.

[0458] In the experiment, Caco-2 cells were seeded into 96-well cell plates and cultured for 22 days before being used for transport experiments. 5.00 μM estrone 3-sulfate (a BCRP substrate) was administered bidirectionally with or without the test substance. The cells were incubated with different concentrations (0-30 μM) of the test substance. After 120 minutes of incubation, the receiving end samples were collected and the content of estrone 3-sulfate in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). By calculating the efflux ratio (ER) of estrone 3-sulfate with and without the test substance, the percentage of BCRP transport activity of Caco-2 cells under the action of different test concentrations of the test substance (%VC (Vehicle Control, solvent control), the percentage of BCRP transport activity with and without the test substance) was obtained, and the half-maximal inhibitory concentration (IC) was calculated from this. 50 ).

[0459] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the BCRP transporter.

[0460] 22. SLC transporter inhibition

[0461] The aim of this study was to evaluate the inhibitory effects of test substances on the activities of the transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1, and MATE2-K.

[0462] HEK293-OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1, and MATE2-K cells were incubated with and without the analyte (0-30 μM) for the corresponding time, and samples were collected. The substrate content in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The transport activity of the transporter in the presence and absence of the analyte was calculated to obtain the percentage of transporter activity of the transporter cells under the action of different concentrations of the analyte (% VC (Vehicle Control, solvent control), the percentage of transporter activity in the presence and absence of the analyte), and the half-maximal inhibitory concentration (IC) was calculated from this. 50 ).

[0463] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on SLC transporters.

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein: X5 selected from CR 5 or N, X6 selected from CR 6 or N; Y1 is selected from N or CR y1 ; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Z is selected from 4 to 12 membered heterocycloalkyl, C 3-6 Cycloalkyl, C 2-6 Alkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z Substituted, the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2; R z Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R A Selected from halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; n is selected from 0, 1, 2, 3, 4; m is selected from 0, 1, 2, 3, 4; The condition is, When Z is selected from C 2-6 When alkyl, R A Selected from -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R z Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Z is selected from 4 to 7 membered heterocycloalkyl, C 3-6 Cycloalkyl, C 2-4 Alkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z Substituted, the alkyl group is optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2; R A Selected from halogen, C 1-4 Alkyl, OH, CN, NH2, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

3. The compound according to claim 2, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c 、R y1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl; Z is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl, and the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, ethyl, propyl, isopropyl are optionally replaced by 1 to 4 R z Substitution, the ethyl, propyl, isopropyl group is optionally substituted by 1 to 4 substituents selected from deuterium, OH, CN, NH2; R z Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl; R A is selected from F, Cl, Br, I, OH, CN, NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl, NHCH3, N(CH3)2, NH(CH2CH3), N(CH2CH3)2, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-azetidinyl, -O-oxetanyl, -O-pyrrolidinyl, -O-tetrahydrofuranyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-azetidinyl, -NH-oxetanyl, -NH- Pyrrolidinyl, -NH-tetrahydrofuranyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-azetidinyl, -CH2-oxetanyl, -CH2-pyrrolidinyl, -CH2-tetrahydrofuranyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-azetidinyl, -CH2CH2-oxetanyl, the CH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl are optionally substituted by 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Preferably, Selected from 4. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib) or (Ic), Y1 is selected from N or CH; Z1 chooses C 2-6 Alkyl, optionally substituted with 1 to 4 substituents selected from deuterium, OH, CN, and NH2; R A1 Selected from -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, said carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Ring A is selected from C 3-6 Cycloalkyl or 4 to 12 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl being optionally substituted by 1 to 4 R z replace; R A Selected from halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl; R z Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl; R z1 is selected from methyl, deuterated methyl, and halomethyl; R z2 Each independently selected from deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 haloalkoxy; z1 is selected from 0, 1, 2 or 3; z2 is selected from 0, 1, 2, 3 or 4.

5. The compound according to claim 4, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: R 1 、R 3 、R 4 、R 5 、R 6 Each is independently selected from H, deuterium, F, Cl, Br, methyl, CF3; R 2 Selected from F, Cl, Br, methyl, CF3; R a 、R c 、R b2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3; R z Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3; R b1 Selected from CF3 or CHF2; Selected from Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or morpholinyl is optionally substituted by 1 to 4 R z replace; R A is selected from F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, wherein the ethyl, propyl, isopropyl is optionally replaced by 1 to 4 R k replace; R z1 Selected from methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F; R z2 Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CF3, deuterated methyl, halomethyl, preferably deuterium, F, Cl, Br, I, OH, CN, NH2, methyl, CD3, CHD2, CH2D, CF3, CHF2, CH2F; Preferably, Selected from 6. The compound of claim 1 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures in Table E-1.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 0.01-1500 mg of the compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

8. Use of the compound of any one of claims 1 to 6, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or the pharmaceutical composition of claim 7, for the preparation of a medicament for treating a disease associated with sGC, preferably the disease is selected from cardiovascular disease, renal disease (e.g., chronic kidney disease), or respiratory disease (e.g., pulmonary hypertension, pulmonary hypertension, or chronic obstructive pulmonary disease).

9. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 7, wherein the therapeutically effective amount is preferably 0.01-1500 mg, and the disease is preferably cardiovascular disease, renal disease (e.g., chronic kidney disease), or respiratory disease (e.g., pulmonary hypertension, pulmonary hypertension, or chronic obstructive pulmonary disease).

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