Pyrazolo six-membered ring derivative and application thereof in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of drugs for treating diseases related to the activity or expression quantity of guanylate cyclase (sGC). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and their intermediates and preparation methods, as well as their use in the preparation of drugs for treating diseases related to sGC activity or expression level. Background Art

[0002] Nitric oxide (NO) signaling has pleiotropic effects in biology and plays a key function in cardiovascular homeostasis. The secretion of NO increases under the influence of mediators such as norepinephrine (NA), angiotensin, adenosine triphosphate or bradykinin. NO synthesis is also affected by many physical stimuli (Int. J. Mol. Sci. 2021, 22, 6029; Molecules 2021, 26, 3418).

[0003] The intracellular mechanism of action of NO is mainly through stimulating the activity of soluble guanylate cyclase (sGC). sGC is a heme-containing enzyme that can increase the level of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle, leading to vasodilation (Nat. Rev. Cardiol. 2018, 15, 292–316).

[0004] The NO / sGC / cGMP regulatory pathway plays an important role in the homeostasis of the cardiovascular system, respiratory system and organs such as the kidney, brain and liver. In addition to smooth muscle cells, cGMP also affects the functions of fibroblasts, cardiomyocytes, platelets, neurons and immune cells, regulating fibrosis, inflammatory responses and neurotransmission processes (Molecules 2023, 28, 861).

[0005] sGC modulators and sGC agonists are a class of drugs that can stimulate the formation of cGMP, and such drugs provide tools for studying the sGC regulatory mechanism 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 (Molecules 2023, 28, 861). Riociguat is the first sGC agonist to be marketed. In 2013, riociguat was approved for two indications: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (TEPH) (J. Med. Chem. 2017, 60, 5146 - 5161). In the 12 - week, multicenter, double - blind, randomized, placebo - controlled, pivotal PATENT - 1 study, compared with placebo, the incidences of the most common (≥3%) AEs in the riociguat treatment group were headache (27% vs 18%), dyspepsia / gastritis (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), vomiting (10% vs 7%), anemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%). Developing new sGC modulators or agonists to improve treatment efficacy or reduce toxic side effects has good application prospects. SUMMARY OF THE INVENTION

[0006] The object of the present invention is to provide a class of pyrrolo[2,3 - d]pyrimidine heterocyclic compounds or their pharmaceutically acceptable salts, and apply them to sGC modulators or agonists. The compounds in the present invention can effectively stimulate the activity of soluble guanylate cyclase (sGC) and can be used to treat diseases such as cardiovascular diseases, kidney diseases, or respiratory diseases.

[0007] The present invention provides a compound of the general formula (I) or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0008]

[0009] In some embodiments, the general formula (I) is selected from the general formulas (II), (III), (IV),

[0010]

[0011] In some embodiments, Z is selected from CH or N;

[0012] In some embodiments, A is selected from C 3-12 carbocyclic group or a 4 - to 12 - membered heterocyclic group;

[0013] In some embodiments, A is selected from phenyl, benzoC4-6 a carbocyclic ring, a 5- to 6-membered heteroaryl group, a benzo-4- to 7-membered heterocyclic group, or an 8- to 12-membered fused heterocyclic aryl group;

[0014] In some embodiments, A is selected from phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0015] In some embodiments, A is selected from phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0016] In some embodiments, A is selected from

[0017] In some embodiments, R 1 is selected from -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH;

[0018] In some embodiments, R 1 is selected from -M-(CR 1a R 1b ) r -COOH, -(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH;

[0019] In some embodiments, R 1 is selected from -M-COOH, -M-CR 1a R 1b -COOH, -(CR 1c R 1d ) s -COOH;

[0020] In some embodiments, R 1 is selected from -(CR 1c R 1d ) s -COOH;

[0021] In some embodiments, R 1 is selected from preferably selected from

[0022] In some embodiments, M is selected from a bond, C 3-12A carbocyclic group or a 4- to 12-membered heterocyclic group, the carbocyclic group or heterocyclic group being optionally substituted with 1 to 4 R k substituted;

[0023] In some embodiments, M is selected from a 4- to 7-membered heteromonocyclic ring, a 5- to 10-membered hetero-fused ring, a 6- to 12-membered heterospiro ring, a 7- to 10-membered heterobridged ring, a C 3-7 monocyclic alkyl group, a C 5-10 fused-ring alkyl group, a C 6-12 membered spiroalkyl group, a C 7-10 bridged-ring alkyl group, a C 6-10 aryl group or a 5- to 10-membered heteroaryl group, the carbocyclic group or heterocyclic group being optionally substituted with 1 to 4 R k substituted;

[0024] In some embodiments, M is selected from the following groups optionally substituted with 1 to 3 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0025] In some embodiments, R 2 is selected from a C 1-6 alkyl group or -C 0-4 alkylene-Q, the alkyl group or alkylene being optionally substituted with 1 to 6 R k substituted;

[0026] In some embodiments, R 2 is selected from a C 1-4 alkyl group or -C 0-2 alkylene-Q, the alkyl group or alkylene being optionally substituted with 1 to 6 R k substituted;

[0027] In some embodiments, R 2 is selected from methyl, ethyl, propyl, isopropyl, Q, -methylene-Q, -ethylene-Q, the methyl, ethyl, propyl, isopropyl, methylene, ethylene being optionally substituted with 1 to 6 R k substituted;

[0028] In some embodiments, R 2 is selected from

[0029] In some embodiments, is selected from

[0030] In some embodiments, is selected from

[0031] In some embodiments, Q is selected from C 3-12 a carbocyclic group or a 4- to 12-membered heterocyclic group, said carbocyclic group or heterocyclic group being optionally substituted with 1 to 4 R k substituents;

[0032] In some embodiments, Q is selected from a 4- to 7-membered hetero monocyclic ring, a 7- to 10-membered hetero fused ring, a 6- to 12-membered hetero spiro ring, a 7- to 10-membered hetero bridged ring, C 3-7 a monocyclic alkyl group, C 5-10 a fused ring alkyl group, C 6-12 a spiroalkyl group having [number of members], C 7-10 a bridged ring alkyl group, a benzo 4- to 6-membered heterocyclic group, a benzo C 4-6 a carbocyclic group, a 5-fused 5-membered heteroaryl group, a 5-fused 6-membered heteroaryl group, a 6-fused 6-membered heteroaryl group, a 5- to 6-membered heteroaryl group or a phenyl group, said Q being optionally substituted with 1 to 4 R k substituents;

[0033] In some embodiments, Q is selected from Q1 or Q2;

[0034] In some embodiments, Q1 is selected from the following groups optionally substituted with 1 to 4 R k substituents: a benzo 4- to 6-membered heterocyclic group, a benzo C 4-6 a carbocyclic group, a 5-fused 5-membered heteroaryl group, a 5-fused 6-membered heteroaryl group, a 6-fused 6-membered heteroaryl group, an 8- to 10-membered hetero fused ring group;

[0035] In some embodiments, Q1 is selected from the following groups optionally substituted with 1 to 3 R k substituents: benzocyclopentyl, benzocyclohexyl, pyridinocyclopentyl, pyridinocyclohexyl, quinolinyl, isoquinolinyl;

[0036] In some embodiments, Q1 is selected from the following groups optionally substituted with 1 to 3 R k substituents:

[0037] In some embodiments, Q2 is selected from the following groups optionally substituted with 1 to 4 R k substituents: a 4- to 7-membered hetero monocyclic ring, a 6- to 12-membered hetero spiro ring, a 7- to 10-membered hetero bridged ring, C 3-7 a monocyclic alkyl group, C 5-10 a fused ring alkyl group, C 6-12 a spiroalkyl group having [number of members], C 7-10 a bridged ring alkyl group, a 5- to 6-membered heteroaryl group or a phenyl group;

[0038] In some embodiments, Q2 is selected from the following groups optionally substituted with 1 to 3 R kThe following groups which are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl;

[0039] In some embodiments, R a 、R c 、R c1 、R b3 、R 1a 、R 1b 、R 1c 、R 1d 、R d1 、R d2 are 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, -O-C 3-8 carbocyclic group, -O-3- to 8-membered heterocyclic group, -NH-C 3-8 carbocyclic group, -NH-3- to 8-membered heterocyclic group, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-3- to 8-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k ;

[0040] In some embodiments, R a 、R c 、R c1 、R b3 、R 1a 、R 1b 、R 1c 、R 1d 、R d1 、R d2 are 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, -O-C3-6 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 substituted;

[0041] In some embodiments, R a , R c , R c1 , R b3 , R 1a , R 1b , R 1c , R 1d , R d1 , R d2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or the following groups optionally substituted by 1 to 4 R k : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;

[0042] In some embodiments, R a , R c , R c1 , R b3 , R 1a , R 1b , R 1c , R 1d , R d1 , R d2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or the following groups optionally substituted by 1 to 4 R k substituted: methyl, ethyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, cyclopropyl;

[0043] In some embodiments, R a , R c , R b3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, methyl, ethyl, methoxy, cyclopropyl;

[0044] In some embodiments, R c1Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, methoxy, methylthio, vinyl, ethynyl, cyclopropyl;

[0045] In some embodiments, R c1 is selected from R c2 ;

[0046] In some embodiments, R c2 is selected from CN, NH2, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-8 carbocyclic group, -O-3- to 8-membered heterocyclic group, -NH-C 3-8 carbocyclic group, -NH-3- to 8-membered heterocyclic group, -C 1-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-3- to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0047] In some embodiments, R c2 is selected from CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methylthio, vinyl, ethynyl, cyclopropyl;

[0048] In some embodiments, R d1 and R d2 , R 1a and R 1b or R 1c and R 1d together with the carbon atoms to which they are attached respectively form a C 3-12 carbocyclic group or a 4- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0049] In some embodiments, R d1 and R d2 , R 1a and R 1b or R 1c and R 1d together with the carbon atoms to which they are attached respectively form a C4-11 Cycloalkyl, 4- to 11-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 4 R k substituents;

[0050] In some embodiments, R d1 and R d2 , R 1a and R 1b or R 1c and R 1d together with the carbon atom to which it is attached form a C 4-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl are optionally substituted with 1 to 4 R k substituents;

[0051] In some embodiments, R d1 and R d2 together with the carbon atom to which it is attached form ring D, and ring D is optionally substituted with 1 to 4 R k substituents;

[0052] In some embodiments, R d1 and R d2 , R 1a and R 1b , R 1a and R 1b or R 1c and R 1d together with the carbon atom to which it is attached form the following groups optionally substituted with 1 to 3 R k substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl;

[0053] In some embodiments, ring D is selected from the following groups optionally substituted with 1 to 3 R k substituents: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl;

[0054] In some embodiments, R b1 , R b2 , R b4 are each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NHC 1-6 alkyl, N(C 1-6 alkyl)2, -NH-C 3-6 carbocyclic group, -NH-3- to 7-membered heterocyclic group, -C 0-4 alkylene-C 3-6Carbocyclic group, -C 0-4 Alkylene-3 to 7-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally substituted with 1 to 4 R k Substituted;

[0055] In some embodiments, R b1 , R b2 , R b4 Are each independently selected from H, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -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 or heterocyclic group is optionally substituted with 1 to 4 R k Substituted;

[0056] In some embodiments, R b1 , R b2 , R b4 Are each independently selected from H, deuterium, or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;

[0057] In some embodiments, R b1 , R b2 , R b4 Are each independently selected from H, deuterium, or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, methoxy, cyclopropyl;

[0058] In some embodiments, R b1 , R b2 , R b4 Are each independently selected from H, deuterium, CF3, CHF2, CH2F, methyl, ethyl, cyclopropyl; preferably H;

[0059] In some embodiments, Is selected from Which is connected to R 2 On the left;

[0060] In some embodiments, a, c, r, s are each independently selected from 0, 1, 2, 3, 4;

[0061] In some embodiments, s are each independently selected from 1, 2, 3;

[0062] In some embodiments, r are each independently selected from 0, 1, 2;

[0063] In some embodiments, a and c are each independently selected from 0, 1, 2;

[0064] In some embodiments, R k are 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, -O-C 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, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0065] In some embodiments, R k are 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, -O-C 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, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4substituted by a substituent of an alkoxy group;

[0066] In some embodiments, R k are 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, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH2, C 1-4 alkyl, C 1-4 substituted by a substituent of an alkoxy group;

[0067] In some embodiments, R k are 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, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0068] Optionally, the general formula (I) satisfies at least one of the following three conditions:

[0069] 1) R c1 is selected from CN, NH2, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-8 carbocyclic group, -O-3- to 8-membered heterocyclic group, -NH-C 3-8Carbocyclic group, -NH- 3- to 8-membered heterocyclic group, -C 1-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-3- to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k Substituted;

[0070] 2) R d1 Together with R d2 And the carbon atom to which it is attached form C 3-12 Carbocyclic group or 4- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k Substituted;

[0071] 3) R 2 Is selected from the following groups optionally substituted by 1 to 4 R k Substituted: benzo 4- to 6-membered heterocyclic group, benzo C 4-6 Carbocyclic group, 5-fused 5-membered heteroaryl group, 5-fused 6-membered heteroaryl group, 6-fused 6-membered heteroaryl group, 8- to 10-membered hetero-fused ring group.

[0072] As the first embodiment of the present invention, the compounds represented by the foregoing general formulas (I), (II), (III), (IV) or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0073] Z is selected from CH or N;

[0074] A is selected from C 3-12 Carbocyclic group or 4- to 12-membered heterocyclic group;

[0075] R 1 Is selected from -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH;

[0076] M is selected from a bond, C 3-12 Carbocyclic group or 4- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k Substituted;

[0077] R 2 Is selected from C 1-6 Alkyl or -C 0-4 Alkylene-Q, wherein the alkyl or alkylene is optionally substituted by 1 to 6 R k Substituted;

[0078] Q is selected from C 3-12A carbocyclic group or a 4- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 Rs k substituted;

[0079] R a 、R c 、R c1 、R b3 、R 1a 、R 1b 、R 1c 、R 1d 、R d1 、R d2 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, -O-C 3-8 carbocyclic group, -O-3- to 8-membered heterocyclic group, -NH-C 3-8 carbocyclic group, -NH-3- to 8-membered heterocyclic group, -C 0-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-3- to 8-membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 Rs k substituted;

[0080] Or R d1 and R d2 、R 1a and R 1b or R 1c and R 1d together with the carbon atom to which it is attached respectively form a C 3-12 carbocyclic group or a 4- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 Rs k substituted;

[0081] R b1 、R b2 、R b4 each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -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 with 1 to 4 Rs k substituted;

[0082] 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, -O-C 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 substituents selected from deuterium, halogen, ═O, CN, OH, NH2, C 1-6 alkyl, C 1-6 alkoxy;

[0083] a, c, r, s are each independently selected from 0, 1, 2, 3;

[0084] Provided that the general formula (I) satisfies at least one of the following three conditions:

[0085] 1) R c1 Selected from CN, NH2, halogen-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkoxy, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl)2, -O-C 3-8 carbocyclic group, -O-3- to 8-membered heterocyclic group, -NH-C 3-8 carbocyclic group, -NH-3- to 8-membered heterocyclic group, -C 1-4 alkylene-C 3-8 carbocyclic group, -C 0-4 alkylene-3- to 8-membered heterocyclic group, wherein the alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0086] 2) R d1 together with R d2 and the carbon atom to which it is attached form a C 3-12 carbocyclic group or 4- to 12-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0087] 3)R 2 Selected from optionally 1 to 4 R k substituted with the following groups: benzo 4-6 membered heterocyclic group, benzo C 4-6 carbocyclic group, 5-fused 5-membered heteroaryl group, 5-fused 6-membered heteroaryl group, 6-fused 6-membered heteroaryl group, 8-10 membered hetero-fused ring group.

[0088] As a second embodiment of the present invention, the compounds represented by the foregoing general formulas (I), (II), (III), (IV) or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

[0089] R 1 Selected from -M-(CR 1a R 1b ) r -COOH, -(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH;

[0090] s are each independently selected from 1, 2, 3;

[0091] A is selected from phenyl, benzo C 4-6 carbocycle, 5- to 6-membered heteroaryl group, benzo 4- to 7-membered heterocyclic group or 8-12 membered fused ring heteroaryl group;

[0092] M is selected from 4-7 membered hetero monocyclic ring, 5-10 membered hetero fused ring, 6-12 membered hetero spiro ring, 7-10 membered hetero bridged ring, C 3-7 monocyclic alkyl group, C 5-10 fused ring alkyl group, C 6-12 membered spiroalkyl group, C 7-10 bridged ring alkyl group, C 6-10 aryl group or 5-10 membered heteroaryl group, and the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituted;

[0093] Q is selected from 4-7 membered hetero monocyclic ring, 7-10 membered hetero fused ring, 6-12 membered hetero spiro ring, 7-10 membered hetero bridged ring, C 3-7 monocyclic alkyl group, C 5-10 fused ring alkyl group, C 6-12 membered spiroalkyl group, C 7-10 bridged ring alkyl group, benzo 4-6 membered heterocyclic group, benzo C 4-6 carbocyclic group, 5-fused 5-membered heteroaryl group, 5-fused 6-membered heteroaryl group, 6-fused 6-membered heteroaryl group, 5-6 membered heteroaryl group or phenyl, and the Q is optionally substituted with 1 to 4 R k substituted;

[0094] or R d1 with R d2 、R 1a with R 1b or R 1c with R 1d together with the carbon atom(s) to which it is attached form a cycloalkyl group or a 4- to 11-membered heteroalkyl group, and the cycloalkyl group and heteroalkyl group are optionally substituted with 1 to 4 R 4-11 substituents; k Substituted;

[0095] The remaining definitions are the same as those of the first embodiment of the present invention.

[0096] As the third embodiment of the present invention, the compounds represented by the foregoing general formulas (I), (II), (III), and (IV), or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0097] R 2 is selected from C 1-4 alkyl or -C 0-2 alkylene-Q, and the alkyl or alkylene is optionally substituted with 1 to 6 R k substituents;

[0098] R a 、R c 、R c1 、R b3 、R 1a 、R 1b 、R 1c 、R 1d 、R d1 、R d2 are 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, -O-C 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, and the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k substituents;

[0099] or Rd1 With R d2 、R 1a With R 1b Or R 1c With R 1d Together with the carbon atom(s) to which it is attached, form a C 4-11 cycloalkyl group or a 4- to 11-membered heteroalkyl group, where the cycloalkyl group and the heteroalkyl group are optionally substituted by 1 to 4 R k substituents;

[0100] R b1 、R b2 、R b4 Each independently selected from H, deuterium, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, NHC 1-4 alkyl group, N(C 1-4 alkyl)2, -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, where the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k substituents;

[0101] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 alkyl group, OC 1-4 alkyl group, SC 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, NHC 1-4 alkyl group, N(C 1-4 alkyl)2, -O-C 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, where the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 alkyl group, C 1-4 alkoxy group;

[0102] The remaining definitions are the same as in the first or second embodiment of the present invention.

[0103] As a fourth embodiment of the present invention, the compounds represented by the foregoing general formulas (I), (II), (III), and (IV), or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0104] R 2 is selected from methyl, ethyl, propyl, isopropyl, Q, -methylene-Q, -ethylene-Q, and the methyl, ethyl, propyl, isopropyl, methylene, and ethylene are optionally substituted by 1 to 6 R k substituents;

[0105] Q is selected from Q1 or Q2;

[0106] Q2 is selected from C 3-6 monocyclic alkyl, 4- to 6-membered hetero monocyclic, 5- to 6-membered heteroaryl, phenyl, and the Q2 is optionally substituted by 1 to 4 R k substituents;

[0107] Q1 is selected from benzo 4- to 6-membered heterocyclic group, benzo C 4-6 carbocyclic group, 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 6-fused 6-membered heteroaryl, 8- to 10-membered hetero-fused ring group, and the Q1 is optionally substituted by 1 to 4 R k substituents;

[0108] R 1 is selected from -M-COOH, -M-CR 1a R 1b -COOH, -(CR 1c R 1d ) s -COOH;

[0109] s are each independently selected from 1, 2;

[0110] R a 、R c 、R c1 、R b3 、R 1a 、R 1b 、R 1c 、R 1d 、R d1 、R d2 are each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or the following groups optionally substituted by 1 to 4 R k substituents: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;

[0111] Or Rd1 With R d2 , R 1a With R 1b Or R 1c With R 1d Together with the carbon atom to which it is attached, form a cycloalkyl group or a 4- to 7-membered heterocycloalkyl group, and the cycloalkyl group and the heterocycloalkyl group are optionally substituted with 1 to 4 R 4-7 ; k Substituted;

[0112] R b1 , R b2 , R b4 Each independently selected from H, deuterium or the following groups optionally substituted with 1 to 4 R k : methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;

[0113] 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, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Alkoxy;

[0114] The remaining definitions are the same as those in the first, second or third embodiment of the present invention.

[0115] As the fifth embodiment of the present invention, the compounds represented by the foregoing general formulas (I), (II), (III), (IV) or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0116] A is selected from phenyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0117] M is selected from those optionally substituted with 1 to 3 R kThe following groups which are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0118] R 2 Selected from methyl, ethyl, propyl, isopropyl, Q, -methylene-Q, -ethylene-Q, said R 2 Optionally substituted by 1 to 5 R k substituted;

[0119] Q is selected from Q1 or Q2;

[0120] Q1 is selected from the following groups which are optionally substituted by 1 to 3 R k : benzocyclopentyl, benzocyclohexyl, pyridinocyclopentyl, pyridinocyclohexyl, quinolinyl, isoquinolinyl;

[0121] Q2 is selected from the following groups which are optionally substituted by 1 to 3 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxanyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl;

[0122] R a 、R c 、R c1 、R b3 、R 1a 、R 1b 、R 1c 、R 1d 、R d1 、R d2 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2 or the following groups which are optionally substituted by 1 to 4 R k : methyl, ethyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, cyclopropyl;

[0123] Or R d1 and R d2 、R 1a and R 1b 、R 1a and R 1b or R 1c and R 1d respectively and the carbon atoms to which they are attached together form an optionally substituted by 1 to 3 Rk The following groups which are substituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl;

[0124] R b1 and R b2 and R b4 each independently selected from H, deuterium or the following groups which are optionally substituted by 1 to 3 R k : methyl, ethyl, cyclopropyl;

[0125] 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, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl are optionally substituted by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, ═O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0126] The remaining definitions are the same as those in the first, second, third or fourth embodiment of the present invention.

[0127] As the sixth embodiment of the present invention, the compounds represented by the foregoing general formulas (I), (II), (III), (IV) or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0128] A is selected from phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl;

[0129] R 1 is selected from preferably selected from

[0130] is selected from

[0131] R a and R c and R b3Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, methyl, ethyl, methoxy, cyclopropyl;

[0132] R c1 Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, methoxy, methylthio, vinyl, ethynyl, cyclopropyl;

[0133] R b1 、R b2 、R b4 Each independently selected from H, deuterium, CF3, CHF2, CH2F, methyl, ethyl, cyclopropyl;

[0134] a and c each independently selected from 0, 1, 2;

[0135] The remaining definitions are the same as those in the first, second, third, fourth or fifth embodiment of the present invention.

[0136] As the seventh embodiment of the present invention, the compounds represented by the foregoing general formulas (II), (III), (IV) or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,

[0137] R 1 Selected from -(CR 1c R 1d ) s -COOH, preferably selected from

[0138] Ring D is selected from the following groups optionally substituted by 1 to 3 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl;

[0139] R c2 Selected from CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methylthio, vinyl, ethynyl, cyclopropyl;

[0140] Q1 is selected from the following groups optionally substituted by 1 to 3 R k : benzocyclopentyl, benzocyclohexyl, pyridinocyclopentyl, pyridinocyclohexyl, quinolinyl, isoquinolinyl, preferably selected from those optionally substituted by 1 to 3 R k substituted

[0141] The remaining definitions are the same as those in the first, second, third, fourth, or fifth embodiment of the present invention.

[0142] The present invention relates to a compound as described below, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the compound is selected from one of the structures in Table E-1 as follows:

[0143] Table E-1

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable carrier.

[0151] The present invention relates to the use of the above-mentioned compound, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating diseases related to sGC.

[0152] The present invention relates to the use of the above-mentioned compound, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, or the above-mentioned pharmaceutical composition, in the preparation of a medicament for treating cardiovascular diseases, kidney diseases, or respiratory diseases.

[0153] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation contains a therapeutically effective amount of the compound described in the present invention, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "formulation specification").

[0154] The present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal in the present invention includes a human.

[0155] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, to some extent, alleviates one or more symptoms of a disease or disorder being treated (such as a cardiovascular 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 alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a compound disclosed herein that provides a clinically significant reduction in the symptoms of a disease. 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 - 600 mg, 1 - 1500 mg, 1 - 1000 mg, 1 - 800 mg, 1 - 600 mg, 2 - 600 mg, 3 - 600 mg, 4 - 600 mg, 5 - 600 mg, 6 - 600 mg, 10 - 600 mg, 20 - 600 mg, 25 - 600 mg, 30 - 600 mg, 40 - 600 mg, 50 - 600 mg, 60 - 600 mg, 70 - 600 mg, 75 - 600 mg, 80 - 600 mg, 90 - 600 mg, 100 - 600 mg, 200 - 600 mg, 1 - 500 mg, 2 - 500 mg, 3 - 500 mg, 4 - 500 mg, 5 - 500 mg, 6 - 500 mg, 10 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 40 - 500 mg, 50 - 500 mg, 60 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 200 - 500 mg, 250 - 500 mg, 300 - 500 mg, 400 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 2 - 300 mg, 5 - 300 mg, 10 - 300 mg, 20 - 300 mg, 25 - 300 mg, 30 - 300 mg, 40 - 300 mg, 50 - 300 mg, 60 - 300 mg, 70 - 300 mg, 75 - 300 mg, 80 - 300 mg, 90 - 300 mg, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 2 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 25 - 200 mg, 30 - 200 mg, 40 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 200 mg, 75 - 200 mg, 80 - 200 mg, 90 - 200 mg, 100 - 200 mg, 125 - 200 mg, 150 - 200 mg, 0.01 - 100 mg, 0.01 - 10 mg, 0.01 - 5 mg, 0.05 - 10 mg, 0.05 - 5 mg, 0.1 - 5 mg, 1 - 5 mg, 0.1 - 1 mg, 0.1 - 5 mg;.

[0156] In some embodiments, the pharmaceutical composition comprises, 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, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of the compound of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals.

[0157] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, the therapeutically effective amount being preferably 0.01 - 1500 mg, and the disease being preferably a cardiovascular disease.

[0158] A method for treating a disease in a mammal, the method comprising administering to a subject a drug, the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, in a daily dose of 0.01 - 1500 mg / day, which daily dose may 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, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 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.

[0159] The present invention relates to a kit, which may include a composition in single - dose or multi - dose form. The kit contains the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and the amount of the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as that in the above - mentioned pharmaceutical composition.

[0160] In the present invention, the amount of the compound of the present invention or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is converted in the form of free base in each case.

[0161] "Formulation specification" means the weight of the active ingredient contained in each vial, tablet or other unit preparation.

[0162] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0163] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, 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, where the isotopes of carbon include 12 C, 13 C and 14C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), and 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 15 N. Fluorine isotopes include 17 F, and 19 F. Chlorine isotopes include 35 Cl, and 37 Cl. Bromine isotopes include 79 Br, and 81 Br.

[0164] "CN" refers to the cyano group.

[0165] "Halogen" refers to F, Cl, Br, or I.

[0166] "Halogen-substituted" means substituted with F, Cl, Br, or I, including but not limited to being substituted with 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, or 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0167] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 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 their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0168] "Heteroalkyl" means that one or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced by heteroatoms (including but not limited to N, O, or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-H (where v is an integer from 1 to 5, X is independently selected from a bond or a heteroatom, the heteroatom includes but not limited to N, O, or S, and at least one X is selected from a heteroatom, and N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0169] "Alkylene" refers to a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH2) v-(v is an integer from 1 to 10), examples of alkylene groups include but are not limited to methylene, ethylene, propylene, butylene, etc.

[0170] "Heteroalkylene" means that one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms in a substituted or unsubstituted alkylene group are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)v-X-(CH2)v-X-(CH2)v-, where v is an integer from 1 to 5, and each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0171] "Cycloalkyl" means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms. Cycloalkyl can be monocyclic, fused-ring, bridged-ring and spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-spiro-cyclobutyl, adamantane, etc. Cycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0172] "Heterocycloalkyl" means a substituted or unsubstituted saturated heterocyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S or Se. The C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be monocyclic, fused-ring, bridged-ring and spiro-ring. Heterocycloalkyl can be attached to a heteroatom or a carbon atom. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0173] Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0174] "Alkenyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, etc.; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0175] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, and the main chain includes 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain and having 2 to 4 carbon atoms in the main chain. Examples of alkynyl 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, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0176] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0177] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0178] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. The optionally substituted C, N, S, or Se in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and the heterocyclic group can be attached to an aromatic or non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantyl, oxaspiro[3.3]heptyl,

[0179] "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0180] "Spirocycle" or "spirocyclic group" refers to a polycyclic group in which a single atom (referred to as a spiro atom) is shared between substituted or unsubstituted monocyclic rings. The number of ring atoms in the spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, 6 to 10, where 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 heteroatoms selected from N, O, or S(=O) n (n is 0, 1, or 2).

[0181]

[0182] "Spirocycle" or "spirocyclic group" can be monovalent, divalent, trivalent, or tetravalent.

[0183] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where 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. Each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, selected from N, S(=O) n or O, n is 0, 1, or 2). The number of ring atoms in the fused ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include

[0184] "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0185] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two non-directly connected atoms, which may contain 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, N, S(=O)n, or O, where n is 0, 1, 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

[0186] Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0187] "Carbospirocycle", "spirocarbocyclic group", "spirocarbonyl group", or "carbospirocyclic group" refers to a "spirocycle" whose ring system consists only of carbon atoms.

[0188] "Carbofused ring", "fused carbocyclic group", "fused carbonyl group", or "carbofused ring group" refers to a "fused ring" whose ring system consists only of carbon atoms.

[0189] "Carbocyclic bridged ring", "bridged carbocyclic group", "bridged carbocyclic radical" or "carbocyclic bridged group" means a "bridged ring" in which the ring system consists only of carbon atoms.

[0190] "Heteromonocyclic ring", "monocyclic heterocyclic group" or "heteromonocyclic group" means a "heterocyclic group" or "heterocyclic ring" of a monocyclic system.

[0191] "Fused heterocyclic ring", "fused heterocyclic group", "fused heterocyclic group with a fused ring" or "fused heterocyclic group with a fused heterocyclic ring" means a "fused ring" containing heteroatoms.

[0192] "Heterospiro ring", "heterospiro group", "spiro heterocyclic group" or "spiro heterocyclic group" means a "spiro ring" containing heteroatoms.

[0193] "Heterobridged ring", "heterobridged group", "bridged heterocyclic group" or "bridged heterocyclic radical" means a "bridged ring" containing heteroatoms.

[0194] "Aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and 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 carbocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring. "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0195] "Heteroaryl" or "heteroaromatic ring" means 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, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 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, benzopyridyl, pyrrolopyridyl, pyridone, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include The heteroaryl appearing in this article has the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aromatic ring.

[0196] "Substituted" or "substituted" means substituted 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, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R 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, spiro or paracyclic groups.

[0197] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the 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.

[0198] A ring of X-Y members (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, and X and Y are any integers selected from 4 to 20) includes rings of X, X + 1, X + 2, X + 3, X + 4…Y members. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a hetero-monocyclic ring, a hetero-fused ring, a hetero-spiro ring or a hetero-bridged ring. For example, a "4-7 membered hetero-monocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered hetero-monocyclic ring, and a "5-10 membered hetero-fused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered hetero-fused ring.

[0199] C x-y The carbocyclic ring (including an aryl group, a cycloalkyl group, a monocyclic carbocyclic ring, a spiro carbocyclic ring, a fused carbocyclic ring or a bridged carbocyclic ring) includes C x 、C x+1 、C x+2 、C x+3 、C x+4 …C y membered rings (where x is an integer, and 3 ≤ x < y, and y is any integer selected from 4 to 20), for example. Such as C 3-6 The "cycloalkyl group" means a C3, C4, C5 or C6 cycloalkyl group;

[0200] When a certain group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bonds, the number of H atoms at the site will correspondingly decrease according to the number of connected chemical bonds to form a group with the corresponding valence. For example Indicates that any connectable site on the piperidyl group can be connected to other groups through 1 chemical bond, including at least these 4 connection modes, even if H atoms are drawn on -N-, also includes For example Indicates that the R group on the piperidyl group can be located on C or on N, including at least

[0201] When the listed connecting groups do not specify their connection directions, their connection directions include connecting in the directions of the reading orders from left to right and from right to left. For example, for A-L-B, when L is selected from -M-W-, it includes A-M-W-B and A-W-M-B.

[0202] "Optionally" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "Optionally fluorine-substituted alkyl" means that the alkyl can but does not have to be fluorine-substituted, and the description includes the case where the alkyl is fluorine-substituted and the case where the alkyl is not fluorine-substituted.

[0203] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt of the compound of the present invention that retains the biological effectiveness and characteristics of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0204] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components, wherein "other chemical components" means pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0205] "Dosage form specification" means the weight of the active ingredient contained in each vial, tablet or other unit dosage form.

[0206] "Carrier" means a material that does not cause obvious irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0207] "Prodrug" means a compound of the present invention that can be metabolically converted in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0208] "Cocrystal" means a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein both the pure states of the API and the CCF are solids at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are multi-component crystals, including binary cocrystals formed between two neutral solids, as well as multi-component cocrystals formed between neutral solids and salts or solvates.

[0209] "Animal" means including mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.

[0210] "Stereoisomer" means an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0211] "Tautomer" means a functional group isomer produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-iminoalcohol tautomerism, etc.

[0212] "IC 50" is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component in that process, such as an enzyme, receptor, cell, etc.) by half.

[0213] Example 1: Preparation of Compound 1

[0214]

[0215] First step: Preparation of Compound 1B

[0216] Triethylsilane hydride (7.9 g, 68 mmol) was added to a solution of 4-bromo-6-fluoroindanone (Compound 1A, 6.2 g, 27 mmol) in trifluoroacetic acid (100 mL). After stirring at room temperature for 16 h, the mixture was concentrated under reduced pressure, and the reaction was quenched by adding water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain Compound 1B (5.1 g, yield: 88%).

[0217] 1 H NMR (400 MHz, CDCl3) δ 7.02 (dd, 1H), 6.88–6.77 (m, 1H), 2.98 (t, 2H), 2.87 (t, 2H), 2.16–2.02 (m, 2H).

[0218] Second step: Preparation of Compound 1C

[0219] At -78 °C, n-butyllithium (10 mL, 2.5 M in Hexanes) was added dropwise to a solution of Compound 1B (5 g, 23.3 mmol) in tetrahydrofuran (60 mL). After stirring for 15 min, N,N-dimethylformamide (2.55 g, 34.18 mmol) was slowly added. After addition, the mixture was stirred at room temperature for 1 h. The reaction was quenched by adding saturated ammonium chloride aqueous solution (50 mL), and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain Compound 1C (3 g, yield: 79%).

[0220] 1 H NMR (400 MHz, DMSO-d6) δ 10.12–10.01 (m, 1H), 7.47–7.34 (m, 2H), 3.16 (t, 2H), 2.89 (t, 2H), 2.16–2.02 (m, 2H).

[0221] Third step: Preparation of Compound 1D

[0222] Sodium borohydride (2.08 g, 54.87 mmol) was added to a methanol solution (30 mL) of Compound 1C (3 g, 18.27 mmol), and the reaction was carried out at room temperature for 1 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (50 mL), and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain Compound 1D (2.5 g, yield: 82%).

[0223] Step 4: Preparation of Compound 1E

[0224] Methanesulfonyl chloride (2.58 g, 22.61 mmol) was added to a dichloromethane solution (50 mL) of Compound 1D (2.5 g, 15.04 mmol) and DIPEA (5.83 g, 45.14 mmol), and the reaction was carried out at room temperature for 1 h. After monitoring the reaction by TLC and completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution (50 mL). The mixture was extracted with dichloromethane (40 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain Compound 1E (3.1 g, yield: 84%).

[0225] Step 5: Preparation of Compound 1F

[0226] Potassium carbonate (1.63 g, 11.78 mmol) was added to an acetonitrile solution (20 mL) of Compound 1E (960 mg, 3.94 mmol) and 6-chloro-indazole-3-carbonitrile (700 mg, 3.94 mmol), and the reaction was carried out at 90 °C for 1 h. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution (30 mL), and the mixture was extracted with ethyl acetate (40 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain Compound 1F (1 g, yield: 78%).

[0227] 1 H NMR (400 MHz, DMSO-d6) δ 8.36–8.26 (m, 1H), 8.04 (d, 1H), 7.54 (dd, 1H), 7.15–7.07 (m, 1H), 6.82 (dd, 1H), 5.84 (s, 2H), 2.93 (t, 2H), 2.80 (t, 2H), 2.19–2.00 (m, 2H).

[0228] Step 6: Preparation of 1G

[0229] Under an ice bath, ammonium chloride (820 mg, 15.32 mmol) was added to a 50 mL single-necked flask, toluene (20 mL) was added, and then trimethylaluminum (8 mL, 2 M) was slowly added dropwise. The temperature was raised to room temperature and the mixture was stirred for 3 h. Compound 1F (1 g, 3.07 mmol) was dissolved in toluene, added dropwise to the aforementioned reaction solution, and then the temperature was raised to 110 °C and stirred overnight. After cooling to room temperature, silica gel and 20 mL of methanol were added under an ice bath, stirred for 30 min, and then filtered. The filter cake was washed 3 times with methanol. The organic phases were combined, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 1G (700 mg, yield: 67%).

[0230] Step 7: Preparation of Compound 1H

[0231] At -78 °C, lithium diisopropylamide (60 mL, 2 M in THF) was added dropwise to a solution of methyl isobutyrate (10.18 g, 99.72 mmol) in tetrahydrofuran (500 mL). After stirring for 0.5 h, 3-iodobenzyl bromide (29.6 g, 8.76 mmol) was added. The temperature was slowly raised to room temperature and stirred for 1 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (400 mL). The mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain compound 1H (18 g, yield: 57%).

[0232] Step 8: Preparation of Compound 1I

[0233] At -78 °C, isopropylmagnesium chloride-lithium chloride complex (35 mL, 1.3 M in THF) was added dropwise to a solution of compound 1H (10 g, 31.4 mmol) in tetrahydrofuran (200 mL). After stirring for 35 min, ethyl 3,3-dicyano-2-methylacrylate (5.16 g, 31.43 mmol) (refer to synthesis1974, 9, 669) was slowly added. After addition, the mixture was transferred to room temperature and stirred for 1 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (100 mL). The mixture was extracted with ethyl acetate (80 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain compound 1I (5 g, yield: 45%).

[0234] Step 9: Preparation of Compound 1J

[0235] Potassium bicarbonate (0.61 g, 6.12 mmol) was added to a solution of Compound 1G (0.7 g, 2.04 mmol) and Compound 1I (0.73 g, 2.04 mmol) in tert-butanol (4 mL), and the mixture was stirred at 80 °C for 16 h. The reaction was quenched by adding water (10 mL), and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) to obtain Compound 1J (1 g, yield: 75%).

[0236] Step 10: Preparation of Compound 1

[0237] Lithium hydroxide (0.11 g, 4.59 mmol) was added to a solution of Compound 1J (300 mg, 0.46 mmol) in 1,4-dioxane (3 mL) and water (1 mL). After stirring at room temperature for 1 h, glacial acetic acid (390 mg, 6.5 mmol) was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 - 1 / 10) and then by reverse-phase column chromatography (mobile phase: acetonitrile / 0.1% TFA in water (V / V) = 5 / 95 - 50 / 50) to obtain Compound 1 (0.29 g).

[0238] LCMS m / z = 639.2 [M+H] +

[0239] Compound 1 was used for SFC preparation.

[0240] Preparation conditions:

[0241] Instrument: Waters 150Prep-SFC F

[0242] Column: Chiralcel Whelk column

[0243] Mobile phase: A for CO2; B for 0.1% NH3·H2O in EtOH and ACN

[0244] Gradient: B 65%

[0245] Flow rate: 100 mL / min

[0246] Back pressure: 100 bar

[0247] Column temperature: 25 °C

[0248] Wavelength: 220 nm

[0249] Cycle time: 3.2 min

[0250] Sample preparation: Compound concentration was 3 mg / ml, dissolved in ACN.

[0251] Analysis conditions:

[0252] Instrument: SHIMADZU LC - 30AD

[0253] Column: Chiralcel Whelk column

[0254] Mobile phase: A for CO2; B for 0.05% DEA in EtOH and ACN

[0255] Gradient: B 50%

[0256] Flow rate: 3 mL / min

[0257] Back pressure: 100 bar

[0258] Column temperature: 35 °C

[0259] Wavelength: 220 nm

[0260] After preparation and separation, components with the same retention time were combined, concentrated under reduced pressure and freeze - dried respectively to obtain Compound 1 - 1 (140.2 mg) and Compound 1 - 2 (135.5 mg).

[0261] Compound 1 - 1: Retention time 0.910 min (P1) under the analysis conditions.

[0262] LCMS m / z = 639.2 [M + H] +

[0263] 11H NMR (400 MHz, CDCl3) δ 8.90–8.63 (m, 1H), 8.27 (d, 1H), 7.27–7.20 (m, 2H), 7.12 (s, 1H), 7.06 (s, 1H), 7.04–6.95 (m, 2H), 6.82–6.64 (m, 1H), 6.34–6.21 (m, 1H), 5.42 (s, 2H), 5.07–4.65 (m, 2H), 2.80 (t, 2H), 2.72–2.57 (m, 4H), 2.06–1.94 (m, 2H), 1.75 (s, 3H), 1.11–1.00 (m, 6H).

[0264] Compound 1-2: Retention time 1.502 min (P2) under the analytical conditions.

[0265] LCMS m / z = 639.3 [M+H] +

[0266] 1 1H NMR (400 MHz, CDCl3) δ 8.91–8.60 (m, 1H), 8.28 (d, 1H), 7.27–7.20 (m, 2H), 7.11 (s, 1H), 7.06 (s, 1H), 7.04–6.96 (m, 2H), 6.80–6.69 (m, 1H), 6.34–6.21 (m, 1H), 5.42 (s, 2H), 5.05–4.72 (m, 2H), 2.80 (t, 2H), 2.72–2.57 (m, 4H), 2.05–1.94 (m, 2H), 1.76 (s, 3H), 1.10–1.01 (m, 6H).

[0267] Example 2: Preparation of Compound 2

[0268]

[0269] First step: Preparation of 2A

[0270] Dissolve 6-bromo-3-cyanoindazole (0.50 g, 2.25 mmol) in acetonitrile (20 mL), add 1,1,1,2,2-pentafluoro-4-iodobutane (1.36 g, 4.95 mmol) and potassium carbonate (1.55 g, 11.25 mmol), heat to 80 °C and stir for reaction for 16 h. Cool the reaction solution to room temperature, filter off the solid, wash the filter cake with dichloromethane 3 times, combine the organic phases, concentrate under reduced pressure, and purify the residue by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 5 / 1) to obtain Compound 2A (0.365 g, yield: 44%).

[0271] Second step: Preparation of 2B

[0272] Under an ice bath, ammonium chloride (4.55 g, 85.05 mmol) was added to a 500 mL single-necked flask, toluene (100 mL) was added, and trimethylaluminum (42.5 mL, 2 M) was slowly added dropwise. The temperature was raised to room temperature and the mixture was stirred for 3 h. Then compound 2A (6.26 g, 17.01 mmol) was dissolved in toluene and added dropwise to the reaction solution. The temperature was raised to 110 °C and the mixture was stirred for 6 h. After cooling to room temperature, silica gel and 500 mL of methanol were added under an ice bath, and the mixture was stirred for another 30 min. The mixture was filtered by suction, and the filter cake was washed three times with methanol. The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 2B (0.46 g, yield: 99%).

[0273] LCMS m / z = 385.3 [M+H] +

[0274] Step 3: Preparation of 2C

[0275] 2B (2.00 g, 5.19 mmol), zinc cyanide (0.61 g, 5.19 mmol), and tetrakis(triphenylphosphine)palladium (0.60 g, 0.52 mmol) were added to a solution of DMF (50 mL). The reaction was carried out at 100 °C for 16 h under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, the reaction solution was diluted with 500 mL of ethyl acetate, washed twice with water, and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain 2C (0.25 g, yield: 14%).

[0276] LCMS m / z = 332.1 [M+H] +

[0277] Step 4: Preparation of 2D

[0278] Compound 2C (0.20 g, 0.60 mmol), 1I (0.214 g, 0.60 mmol), and potassium bicarbonate (0.18 g, 1.80 mmol) were mixed and dissolved in tert-butanol (10 mL). The temperature was raised to 80 °C and the mixture was stirred overnight. After cooling to room temperature, it was directly concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 2D (0.30 g, yield: 78%).

[0279] LCMS m / z = 642.4 [M+H] +

[0280] Step 5: Preparation of Compound 2

[0281] Compound 2D (0.20 g, 0.31 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL). Lithium hydroxide hydrate (0.13 g, 3.10 mmol) was added, and the mixture was heated to 60 °C and stirred for 3 h. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the solution to acidic, and a white solid precipitated. The mixture was extracted with dichloromethane three times, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by a reverse-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95 - 50 / 50) to obtain Compound 2 (0.08 g, yield: 40%).

[0282] LCMS m / z = 628.30 [M+H] +

[0283] Biological test examples

[0284] 1. In vitro guanylate cyclase (sGC) enzyme activity detection experiment

[0285] First, 100 nL of compounds with different concentrations were transferred into a 384-well reaction plate (Greiner, Cat. No 784075) using Echo655 (LABCYTE, Cat#655), and the DMSO content was 1% at the final reaction concentration. 2 μL of sGC (ICE, Cat. No S2304F-H07SH2) was added to the 384-well reaction plate and centrifuged at 1000 rpm for 1 min. Subsequently, 1 μL of DETANONOate was added and incubated at 37 °C for 10 min. After incubation, 2 μL of GTP was added, centrifuged at 1000 rpm for 1 min, and reacted at 37 °C for 60 min. In the reaction system, the final concentrations of sGC, GTP, and DETANONOate were 1.5 nM, 5 μM, and 100 μM, respectively. After the reaction, 5 μL of the 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), and nonlinear regression curve fitting was performed using GraphPad Prism software to calculate the EC 50 value. Compound A (Example 1 in WO2010065275) was used as a positive reference compound, and the activation rate calculation formula is shown in Equation 1, where Low control is the TR-FRET signal value of 1 μM compound A, and High control is the TR-FRET signal value of the DMSO well.

[0286] stimulation% = (ave High control - cpd well) / (ave High control - aveLow control)*100% Equation 1

[0287] Table 1 Results of the enzymatic agonism and / or activation of test compounds on guanylate cyclase (sGC)

[0288] Compound Number <![CDATA[EC 50 (nM)]]> Compound 1 A Compound 2 A

[0289] Note: A < 30 nM, 30 nM ≤ B < 60 nM, 60 nM ≤ C < 200 nM

[0290] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good agonistic and / or activating effects on the enzymatic activity of guanylate cyclase (sGC).

[0291] 2: Pharmacokinetics test in rats (inhalation administration)

[0292] Purpose of the experiment: In this experiment, the test substance was administered to SD rats by single-dose inhalation, and the concentrations of the test substance in the plasma and lungs of the rats were measured to evaluate the pharmacokinetic characteristics and bioavailability of the test substance in rats.

[0293] Test animals: Male SD rats, 180 - 200 g. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0294] Test method: On the day of the experiment, (for each compound) the SD rats were randomly divided into 6 groups with 2 rats in each group. They were fasted but allowed water for 12 - 16 h one day before dosing and resumed feeding 4 h after dosing.

[0295]

[0296] The dose is calculated as the free base; (DMA: dimethylacetamide; HS-15 (Solutol): polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[0297] Plasma sampling: Blood was taken from the orbital cavity under isoflurane anesthesia before and after dosing and placed in an EDTAK2 centrifuge tube. Centrifuge at 6000 rpm at 4 °C for 10 min to collect plasma. Plasma collection time points: 0, 0.0833, 0.25, 0.5, 1, 2, 4, 7, 24 h.

[0298] Lung tissue sampling: The test animals in each group were euthanized by CO2 inhalation at 0.25, 0.5, 1, 4, 7, and 24 hours after drug administration. Then the animals were dissected, lung tissue was collected, rinsed with physiological saline, dried with filter paper, weighed using a balance, homogenized within 2 hours on wet ice, and homogenized with 6 times the volume of homogenate (50% methanol-water) (i.e., 1 g of tissue was added to 6 mL of homogenate).

[0299] Before analysis and detection, all samples were stored at -60 °C. The samples were quantitatively analyzed by LC-MS / MS.

[0300] Table 2-1 Pharmacokinetic parameters of the test compounds in rats (inhalation administration)

[0301] Test Compound <![CDATA[Lung AUC 0-t (h.ng.mL -1 )]]> <![CDATA[Lung AUC 0-t / Blood AUC 0-t > Lung Cmax (ng / mL) Compound 1-1 3337 667 2562 Control Compound 1 220 29.1 273

[0302] Conclusion: The compounds of the present invention, such as the example compounds, have good exposure and / or lung-blood ratio in the lungs of rats after inhalation administration.

[0303] Control compound 1:

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: Z is selected from CH or N; A is selected from C 3-12 Carbocyclic group or 4-12 membered heterocyclic group; R 1 Selected from -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH; M is selected from a bond, C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; R 2 Selected from C 1-6 Alkyl or -C 0-4 Alkylene-Q, the alkyl or alkylene group is optionally substituted by 1 to 6 R k replace; Q is selected from C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; R a , R c , R c1 , R b3 , R 1a , R 1b , R 1c , R 1d , R d1 , R d2 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 3-8 carbocyclic group, -O-3 to 8-membered heterocyclic group, -NH-C 3-8 carbocyclic group, -NH-3 to 8-membered heterocyclic group, -C 0-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-3 to 8 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; or R d1 With R d2 , R 1a With R 1b or R 1c With R 1d Together with the carbon atoms they are connected to form C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; R b1 , R b2 , R b4 are each independently selected from H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -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 carbocyclyl, -O-3 to 7 membered heterocyclyl, -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; a, c, r, s are each independently selected from 0, 1, 2, 3; The condition is that the general formula (I) satisfies at least one of the following three conditions: 1) R c1 Selected from CN, NH2, halogen-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-8 carbocyclic group, -O-3 to 8-membered heterocyclic group, -NH-C 3-8 carbocyclic group, -NH-3 to 8-membered heterocyclic group, -C 1-4 Alkylene-C 3-8 Carbocyclic group, -C 0-4 Alkylene-3 to 8-membered heterocyclic group, the alkylene, alkenyl, alkynyl, The carbocyclic or heterocyclic group is optionally substituted with 1 to 4 R k replace; 2) R d1 With R d2 Together with the carbon atom to which it is attached, it forms C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R k replace; 3) R 2 Selected from 1 to 4 R k Substituted groups: benzo 4-6 membered heterocyclic group, benzo C 4-6 Carbocyclic group, 5-membered 5-membered heteroaryl, 5-membered 6-membered heteroaryl, 6-membered 6-membered heteroaryl, 8-10 membered heterocyclic group.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 1 Selected from -M-(CR 1a R 1b ) r -COOH, -(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH; s are each independently selected from 1, 2, and 3; A is selected from phenyl, benzo 4-6 Carbocyclic ring, 5- to 6-membered heteroaryl, benzo 4- to 7-membered heterocyclic ring or 8- to 12-membered heterocyclic ring; M is selected from a 4-7 membered heteromonocyclic ring, a 5-10 membered heterocyclic ring, a 6-12 membered heterospirocyclic ring, a 7-10 membered heterobridged ring, 3-7 Monocyclic alkyl, C 5-10 Cycloalkyl, C 6-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, C 6-10 aryl or 5-10 membered heteroaryl, the carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; Q is selected from 4-7 membered heteromonocyclic ring, 7-10 membered heterocyclic ring, 6-12 membered heterospirocyclic ring, 7-10 membered heterobridged ring, C 3-7 Monocyclic alkyl, C 5-10 Cycloalkyl, C 6-12 Spirocycloalkyl, C 7-10 Bridged cycloalkyl, benzo 4-6 membered heterocyclic group, benzo C 4-6 carbocyclyl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 6- and 6-membered heteroaryl, 5- and 6-membered heteroaryl or phenyl, wherein Q is optionally substituted by 1 to 4 R k replace; or R d1 With R d2 , R 1a With R 1b or R 1c With R 1d Together with the carbon atoms they are connected to form C 4-11 Cycloalkyl, 4 to 11 membered heterocycloalkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 2 Selected from C 1-4 Alkyl or -C 0-2 Alkylene-Q, the alkyl or alkylene group is optionally substituted by 1 to 6 R k replace; R a , R c , R c1 , R b3 , R 1a , R 1b , R 1c , R 1d , R d1 , R d2 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; or R d1 With R d2 , R 1a With R 1b or R 1c With R 1d Together with the carbon atoms they are connected to form C 4-11 Cycloalkyl, 4 to 11 membered heterocycloalkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R b1 , R b2 , R b4 are each independently selected from H, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -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 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 deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 2 is selected from methyl, ethyl, propyl, isopropyl, Q, -methylene-Q, -ethylene-Q, wherein the methyl, ethyl, propyl, isopropyl, methylene, ethylene is optionally substituted by 1 to 6 R k replace; Q is selected from Q1 or Q2; Q2 is selected from C 3-6 monocycloalkyl, 4-6 membered heteromonocycle, 5-6 membered heteroaryl, phenyl, wherein Q2 is optionally substituted by 1 to 4 R k replace; Q1 is selected from benzo 4-6 membered heterocyclic group, benzo C 4-6 carbocyclic group, 5-membered and 5-membered heteroaryl group, 5-membered and 6-membered heteroaryl group, 6-membered and 6-membered heteroaryl group, 8-10-membered heterocyclic group, wherein Q1 is optionally substituted by 1 to 4 R k replace; R 1 Selected from -M-COOH, -M-CR 1a R 1b -COOH, -(CR 1c R 1d ) s -COOH; s are each independently selected from 1 and 2; R a , R c , R c1 , R b3 , R 1a , R 1b , R 1c , R 1d , R d1 , R d2 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; or R d1 With R d2 , R 1a With R 1b or R 1c With R 1d Together with the carbon atoms they are connected to form C 4-7 Cycloalkyl, 4 to 7 membered heterocycloalkyl, the cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R k replace; R b1 , R b2 , R b4 are each independently selected from H, deuterium or optionally substituted by 1 to 4 R k Substituted groups: methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl; 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 deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: A is selected from phenyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; M is selected from 1 to 3 R k Substituted groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, oxolanyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl; R 2 is selected from methyl, ethyl, propyl, isopropyl, Q, -methylene-Q, -ethylene-Q, wherein R 2 Optional 1 to 5 R k replace; Q is selected from Q1 or Q2; Q1 is selected from 1 to 3 R k Substituted groups include: benzocyclopentyl, benzocyclohexyl, pyridocyclopentyl, pyridocyclohexyl, quinolyl, isoquinolyl; Q2 is selected from 1 to 3 R k Substituted as follows: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, thienyl, furanyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl; R a , R c , R c1 , R b3 , R 1a , R 1b , R 1c , R 1d , R d1 , R d2 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: methyl, ethyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, cyclopropyl; or R d1 With R d2 , R 1a With R 1b , R 1a With R 1b or R 1c With R 1d Each of them and the carbon atom connected thereto together form an optionally substituted 1 to 3 R k Substituted groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl; R b1 , R b2 , R b4 are each independently selected from H, deuterium or optionally substituted by 1 to 3 R k Substituted groups: methyl, ethyl, cyclopropyl; 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; 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 with 1 to 3 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy.

6. The compound according to claim 5 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: A is selected from phenyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl; R 1 Selected from Selected from R a , R c , R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, methyl, ethyl, methoxy, cyclopropyl; R c1 Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CD3, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OCD3, methyl, ethyl, methoxy, methylthio, vinyl, ethynyl, cyclopropyl; R b1 , R b2 , R b4 Each is independently selected from H, deuterium, CF3, CHF2, CH2F, methyl, ethyl, cyclopropyl; a and c are each independently selected from 0, 1, and 2.

7. The compound according to 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.

8. 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 a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating a disease associated with sGC.

10. The use according to claim 9, wherein the disease is selected from cardiovascular disease, kidney disease or respiratory disease.

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