Pyrazole carboxylic acid derivative and use thereof in medicine

Abstract

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

Description

Pyrazole carboxylic acid derivatives and their applications in medicine Technical Field

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

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

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

[0004] sGC modulators and sGC agonists are a class of drugs that stimulate cGMP formation. They provide tools for studying the regulatory mechanisms of sGC and its role in pathological mechanisms. The development of sGC modulators or agonists has made it possible to develop drugs that directly target diseased blood vessels, myocardium, kidneys, and other organs. The development of novel sGC modulators or agonists holds great promise for exploring the therapeutic value and broader therapeutic potential of sGC targets across diverse indications.

[0005] Summary of the Invention

[0006] The present invention aims to provide a novel compound of general formula (I) or its stereoisomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods thereof, and their use in the preparation of drugs for treating diseases associated with sGC.

[0007] The compound of the present invention has good pharmacokinetic properties, better liver microsome stability, oral performance and good safety.

[0008] The present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0009] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h) or (II-i).

[0010] In some embodiments, represents an aromatic ring or a non-aromatic ring;

[0011] In some embodiments, C1 is selected from a 5-6 membered heterocyclic ring;

[0012] In some embodiments, Selected from

[0013] In some embodiments, X1 is selected from CR 1 or N;

[0014] In some embodiments, X2 is selected from CR 2 or N;

[0015] In some embodiments, X3 is selected from CR 3 or N;

[0016] In some embodiments, X4 is selected from CR 4 or N;

[0017] In some embodiments, X5 is selected from CR 5 or N;

[0018] In some embodiments, X6 is selected from CR 6 or N;

[0019] In some embodiments, X7 is selected from CR 7 or N;

[0020] In some embodiments, X8 is selected from CR 8 or N;

[0021] In some embodiments, X1 is selected from CR 1 or N, X2 is selected from CR 2 or N, X3 selected from CR 3 or N, X4 selected from CR 4 or N, X5 selected from CR 5 or N, X6 selected from CR 6or N, X7 selected from CR 7 or N, X8 selected from CR 8 or N;

[0022] In some embodiments, Selected from C 3-12 A 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 a replace;

[0023] In some embodiments, Selected from 1 to 4 R a Substituted with the following groups: C 3-6 Monocyclic alkyl, C 3-6 Monocyclic alkenyl, C 5-11 Spiroalkyl, C 4-10 Cycloalkyl, C 5-10 Bridged cycloalkyl, 4 to 6 membered monocyclic heterocycloalkyl, 4 to 6 membered monocyclic heterocycloalkenyl, C 5-11 Spiroheterocycloalkyl, C 4-10 Heterocycloalkyl or C 5-10 bridged heterocycloalkyl;

[0024] In some embodiments, Selected from 1 to 4 R a Substituted groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, azetidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, s1, s2, s3, s4, and s5 are each independently selected from 0 or 1;

[0025] In some embodiments, Selected from 1 to 4 R a Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0026] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, halogen, OH, CN, NH2, C1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0027] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c 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;

[0028] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、Ra 、R b1 、R b2 、R c Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0029] In some embodiments, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;

[0030] In some embodiments, R a Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, -CH2-cyclopropyl;

[0031] In some embodiments, R a Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl;

[0032] In some embodiments, R 7 With R a Together with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0033] In some embodiments, R 7 With Ra Together with the atoms to which it is attached, it forms a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0034] In some embodiments, R 7 With R a Together with the atoms to which it is attached, it forms a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0035] In some embodiments, R 7 With R a Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group;

[0036] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0037] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 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 0-2Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0038] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0039] In some embodiments, R 2a Selected from H, deuterium, F, Br, CHF2, methyl, ethyl, isopropyl, cyclopropyl;

[0040] In some embodiments, X 1a Select N or CR 1a ;

[0041] In some embodiments, X 3a Select N or CR 3a ;

[0042] In some embodiments, X 4a Select N or CR 4a ;

[0043] In some embodiments, R 1a 、R 3a or R 4a Each is independently selected from deuterium, F, Cl, Br, CHF2, methyl, ethyl, isopropyl, cyclopropyl;

[0044] In some embodiments, Selected from 1 to 4 R a Substituted groups:

[0045] In some embodiments, R 8a Selected from deuterium, F, Br, CF3, CHF2, cyclopropyl;

[0046] In some embodiments, R b1 Each is independently selected from H, deuterium, F, Cl, Br, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, cyclopropyl;

[0047] In some embodiments, R b1 or R b2 is selected from H, deuterium, F, CH2F, CF3 or CHF2;

[0048] In some embodiments, R b1 Selected from CF3 or CHF2;

[0049] In some embodiments, R b2 Selected from H;

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

[0051] Optionally, 1) R 2 Not Cl, CF3;

[0052] or 2) at least one of X1, X2, X3, X4, X5, and X8 is selected from N;

[0053] or 3) R 1 、R 3 、R 4 At least one of them is not H;

[0054] or 4) Not selected m is selected from 0, 1, 2, 3, 4;

[0055] or 5) R 7 With R a Together with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0056] or 6) when R b1 Selected from CHF2, R b2 Selected from H, Selected from R c are each independently selected from H or halogen, Selected from m is selected from 0, 1, 2, 3, 4, X1 is selected from CH, X3 is selected from CH, X4 is selected from CH, X2 is selected from CR2 , R 2 is selected from Cl or CF3, X6 or X7 is selected from CH, CF or N, X5 is selected from CR 5 , X8 selected from CR 8 When R 5 or R 8 At least one of them is not H or C 1-4 alkyl.

[0057] Optionally, 1) R 2 Not Cl, CF3;

[0058] or 2) at least one of X1, X2, X3, X4, X5, and X8 is selected from N;

[0059] or 3) R 1 、R 3 、R 4 At least one of them is not H;

[0060] or 4) Not selected m is selected from 0, 1, 2, 3, 4;

[0061] or 5) R 7 With R a Together with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0062] or 6) when R b1 Selected from CHF2, R b2 Selected from H, Selected from R c are each independently selected from H or halogen, Selected from m is selected from 0, 1, 2, 3, 4, X1 is selected from CH, X3 is selected from CH, X4 is selected from CH, X2 is selected from CR 2 , R 2 is selected from Cl or CF3, X6 or X7 is selected from CH, CF or N, X5 is selected from CR 5 , X8 selected from CR 8 When R 5 or R 8 At least one of them is not H or C 1-4 alkyl;

[0063] or 7) when Selected from When R a Not for C 1-4 Alkylcarbonyl or optionally substituted C 3-6 Cycloalkyl.

[0064] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0065] X1 selected from CR 1 or N, X2 is selected from CR 2 or N, X3 selected from CR 3 or N, X4 selected from CR 4 or N, X5 selected from CR 5 or N, X6 selected from CR 6 or N, X7 selected from CR 7 or N, X8 selected from CR 8 or N;

[0066] Selected from C 3-12 A 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 a replace;

[0067] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0068] or R 7 With R aTogether with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0069] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 7 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-3 to 7 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0070] n is selected from 0, 1, 2, 3, 4;

[0071] The condition is,

[0072] 1) R 2 Not Cl, CF3;

[0073] or 2) at least one of X1, X2, X3, X4, X5, and X8 is selected from N;

[0074] or 3) R 1 、R 3 、R 4 At least one of them is not H;

[0075] or 4) Not selected m is selected from 0, 1, 2, 3, 4;

[0076] or 5) R 7 With R a Together with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0077] or 6) when R b1 Selected from CHF2, R b2 Selected from H, Selected from R c are each independently selected from H or halogen, Selected from m is selected from 0, 1, 2, 3, 4, X1 is selected from CH, X3 is selected from CH, X4 is selected from CH, X2 is selected from CR 2 , R 2 is selected from Cl or CF3, X6 or X7 is selected from CH, CF or N, X5 is selected from CR 5 , X8 selected from CR 8 When R 5 or R 8 At least one of them is not H or C 1-4 alkyl;

[0078] or 7) when Selected from When R a Not for C 1-4 Alkylcarbonyl or optionally substituted C 3-6 Cycloalkyl.

[0079] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0080] Selected from 1 to 4 R a Substituted with the following groups: C 3-6 Monocyclic alkyl, C 3-6 Monocyclic alkenyl, C 5-11 Spiroalkyl, C 4-10 Cycloalkyl, C 5-10 Bridged cycloalkyl, 4 to 6 membered monocyclic heterocycloalkyl, 4 to 6 membered monocyclic heterocycloalkenyl, C 5-11 Spiroheterocycloalkyl, C 4-10 Heterocycloalkyl or C 5-10 bridged heterocycloalkyl;

[0081] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-4 Alkyl, OC 1-4Alkyl, 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;

[0082] or R 7 With R a Together with the atoms to which it is attached, it forms a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0083] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 Carbocyclic group, -NH-3 to 6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent.

[0084] The remaining definitions are the same as those of the first embodiment of the present invention.

[0085] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0086] Selected from 1 to 4 R a Substituted groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, azetidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl,

[0087] s1, s2, s3, s4, and s5 are each independently selected from 0 or 1;

[0088] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R a 、R b1 、R b2 、R c Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, or optionally 1 to 4 R k Substituted groups include: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, and phenyl;

[0089] or R 7 With R a Together with the atoms to which it is attached, it forms a 5-6 membered carbocyclic ring or a 5-6 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace;

[0090] R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C1-4 substituted by an alkoxy substituent.

[0091] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0092] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0093] Selected from 1 to 4 R a Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0094] or R 7 With R a Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group.

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

[0096] As a fifth embodiment of the present invention, the compound represented by the following general formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h) or (II-i) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0097] R 2a Selected from H, deuterium, F, Br, CHF2, methyl, ethyl, isopropyl, cyclopropyl;

[0098] X 1a Select N or CR 1a ;

[0099] X 3a Select N or CR 3a ;

[0100] X 4a Select N or CR 4a ;

[0101] R 1a 、R 3a or R 4a Each is independently selected from deuterium, F, Cl, Br, CHF2, methyl, ethyl, isopropyl, cyclopropyl;

[0102] Selected from 1 to 4 Ra Substituted groups:

[0103] R a Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, Methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, -CH2-cyclopropyl; R a1 Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl;

[0104] R 8a Selected from deuterium, F, Br, CF3, CHF2, cyclopropyl;

[0105] Selected from

[0106] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0107] As a sixth embodiment of the present invention, the compound represented by the following general formula (III-a) or (III-f) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0108] R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl;

[0109] R a Selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, -CH2-cyclopropyl;

[0110] R b1 Each is independently selected from H, deuterium, F, Cl, Br, CH2F, CHF2, CF3, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0111] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1 below:

[0112] Table E-1

[0113] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0114] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the above-mentioned pharmaceutical compositions for preparing drugs for treating diseases associated with sGC.

[0115] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions for preparing drugs for treating cardiovascular diseases, kidney diseases or respiratory diseases, preferably pulmonary hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, chronic kidney disease or non-proliferative diabetic retinopathy.

[0116] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0117] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0118] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate to some extent one or more symptoms of the disease or condition being treated (e.g., cardiovascular disease, kidney disease, or respiratory disease drugs, preferably pulmonary hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, chronic kidney disease, or non-proliferative diabetic retinopathy). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 0.01-1500 mg, 0.01-1000 mg, 0.01-800 mg, 0.01-600 mg, 0.1-1500 mg, 0.1-1000 mg, 0.1-800 mg, 0.1-600mg、1-1500mg、1-1000mg、1-800mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、 20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、0.01-100mg、0.01-50mg、0.01-10mg、0.01-5mg、0.05-10mg、0.05-5mg、0.1-5mg、1-5mg、0.1-1mg、0.1-5mg;.

[0119] In some embodiments, the pharmaceutical composition includes but is not limited to 0.01-1500 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.3 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg , 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 300mg of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0120] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, preferably 0.01-1500 mg. The disease is preferably cardiovascular disease, kidney disease, or respiratory disease, preferably pulmonary hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, chronic kidney disease, or non-proliferative diabetic retinopathy.

[0121] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 0.01-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 0.01-1500 mg / day, 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 2 5-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 0.01 mg / day, 0.05 mg / day, 0.1 mg / day, 0.15 mg / day, 0.2 mg / day, 0.3 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day.

[0122] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0123] The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0124] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0125] Synthesis method 1:

[0126] PG1, PG2, and PG4 are each independently selected from an amino protecting group, and PG3 are each independently selected from a hydroxyl protecting group;

[0127] R D-1 、R D-2 Each independently selected from C 1-6 alkyl;

[0128] R D-3Each is independently selected from a halogen or a leaving group, preferably Br, I, OTf;

[0129] R D-4 each independently selecting an oxygen-containing leaving group;

[0130] R D-5 、R D-6 Each independently selected from H or C 1-6 alkyl;

[0131] is selected from 4 to 12-membered nitrogen-containing heterocyclic groups, the nitrogen-containing heterocyclic groups are optionally substituted by 1 to 4 R a replace;

[0132] The definitions of the remaining groups are consistent with those in the description of the present invention;

[0133] The compound of general formula (D-1-1) is subjected to reductive amination reaction to obtain the compound of general formula (D-1-2);

[0134] The compound of formula (D-1-2) is obtained by removing the amino protecting group to obtain the compound of formula (D-1-3);

[0135] The compound of the general formula (D-1-3) and the compound of the general formula (D-1-4) undergo a cyclization reaction to obtain the compound of the general formula (D-1-5);

[0136] The compound of formula (D-1-5) is obtained by removing the amino protecting group to obtain the compound of formula (D-1-6);

[0137] The compound of general formula (D-1-6) and the compound of general formula (D-1-7) are reacted through coupling reaction or substitution reaction to obtain the compound of general formula (D-1-8);

[0138] The compound of formula (D-1-8) is obtained by removing the hydroxyl protecting group to obtain the compound of formula (D-1-9);

[0139] The compound of general formula (D-1-9) is subjected to a substitution reaction to obtain a compound of general formula (D-1-10);

[0140] The compound of general formula (D-1-10) and the compound of general formula (D-1-11) or the compound of general formula (D-1-12) are subjected to a coupling reaction to obtain a compound of general formula (D-1-13);

[0141] The compound of formula (D-1-13) is obtained by removing the amino protecting group to obtain the compound of formula (D-1-14);

[0142] The compound of general formula (D-1-14) is subjected to reductive amination reaction, condensation reaction, substitution reaction, or coupling reaction to obtain the compound of general formula (D-1-15);

[0143] The compound of general formula (D-1-13) can be subjected to hydrolysis reaction or hydrogenation reaction to obtain the compound of general formula (I).

[0144] Synthesis method 2:

[0145] The compound of general formula (D-1-10) and the compound of general formula (D-2-1) or the compound of general formula (D-2-2) are reacted by coupling to obtain the compound of general formula (D-2-3);

[0146] The compound of general formula (D-2-3) can be subjected to hydrolysis reaction or hydrogenation reaction to obtain the compound of general formula (I).

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

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

[0149] "CN" refers to cyano.

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

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

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

[0153] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, including but not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0154] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0155] "Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)v-, where v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0156] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0157] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0158] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0159] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 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, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0160] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0161] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0162] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0163] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2).

[0164] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0165] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0166] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0167] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0168] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0169] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0170] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0171] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0172] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0173] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0174] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0175] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0176] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-Ra , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0177] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0178] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0179] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to a C3, C4, C5 or C6 cycloalkyl group.

[0180] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0181] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0182] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0183] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0184] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0185] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0186] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0187] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0188] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0189] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0190] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0191] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0192] “IC 50 "It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0193] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0194] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0195] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0196] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0197] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0198] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0199] The * next to the chemical bond indicates that the chirality of the chiral atom is R or S;

[0200] Boc: tert-butoxycarbonyl;

[0201] Ts: p-toluenesulfonyl;

[0202] Cbz: benzyloxycarbonyl;

[0203] TMS: trimethylsilyl.

[0204] Example 1:

[0205] Step 1: Synthesis of 1A

[0206] 2-Bromo-4-chloro-6-fluorophenol (2.2 g, 9.76 mmol), 4-methoxybenzyl chloride (1.60 g, 10.22 mmol), potassium carbonate (4.05 g, 29.30 mmol) and acetone (30 mL) were added to the reaction flask and heated in an oil bath at 70°C overnight. The mixture was cooled to room temperature and filtered. An appropriate amount of silica gel was added to the filtrate, which was then concentrated under reduced pressure. The product was purified by column chromatography with eluent: PE / EA = 100 / 0 to 90 / 10 to obtain 1A (2.8 g, yield: 83%).

[0207] Step 2: Synthesis of 1C

[0208] 1A (0.60 g, 1.74 mmol), 1B (CAS: 2781965-82-8, synthesis reference patent: WO2022122910, 0.48 g, 1.74 mmol), Pd2DBa3 (CAS: 60748-47-2, 0.16 g, 0.17 mmol), (R)-SEGPHOS (0.21 g, 0.35 mmol), cesium carbonate (1.70 g, 5.22 mmol) and 1,4-dioxane (15 mL) were added to the reaction flask, purged with nitrogen three times, heated in an oil bath at 100°C overnight, cooled to room temperature, filtered, and the filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. Purification by column chromatography (eluent: PE-EA = 100-0 to 90-10) gave 1C (0.34 g, yield: 36%).

[0209] Step 3: 1D synthesis

[0210] 1C (0.34 g, 0.63 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. Dichloromethane (20 mL) was added and the mixture was washed with saturated aqueous sodium bicarbonate. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 1D (0.20 g, yield: 76%).

[0211] Step 4: Synthesis of 1E

[0212] 1D (0.20 g, 0.48 mmol), triethylamine (0.15 g, 1.44 mmol) and dichloromethane solution (8 mL) were added to the reaction flask. The mixture was cooled to about -30°C and a dichloromethane solution (2 mL) of trifluoromethanesulfonic anhydride (0.27 g, 0.96 mmol) was added dropwise. The temperature was naturally raised to react for 1 hour. Dichloromethane (10 mL) was added and the mixture was washed with saturated sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 1E (0.24 g, yield: 91%).

[0213] Step 5: Synthesis of 1F

[0214] 1E (0.24 g, 0.44 mmol), 4-[4-(N-BOC)piperazin-1-yl]phenylboronic acid pinacol ester (0.26 g, 0.66 mmol), tetrakistriphenylphosphine palladium (0.10 g, 0.088 mmol), sodium carbonate (0.14 g, 1.32 mmol), toluene (6 mL), ethanol (6 mL), water (3 mL) were added to the reaction flask and ventilated three times with nitrogen. The mixture was stirred in an oil bath at 95° C. under nitrogen protection overnight. The mixture was cooled to room temperature, and ethyl acetate (30 mL) and water (20 mL) were added and stirred to separate the layers. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 1F (0.18 g, yield: 62%).

[0215] Step 6: Synthesis of 1G

[0216] 1F (0.18 g, 0.27 mmol) and dichloromethane (3 mL) were added to the reaction flask, and trifluoroacetic acid (2 mL) was added with stirring. The reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added and the mixture was washed once with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 1G (0.15 g, yield: 99%).

[0217] LCMS m / z=562.3[M+1] +

[0218] Step 7: Synthesis of 1H

[0219] 1G (0.15 g, 0.27 mmol), isobutyraldehyde (0.097 g, 1.34 mmol) and dichloromethane (10 mL) were added to the reaction flask and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.17 g, 0.80 mmol) and glacial acetic acid (48 mg, 0.80 mmol) were added and stirred at room temperature overnight. Dichloromethane (10 mL) was added and the mixture was washed with saturated sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 80-20 to give 1H (0.12 g, yield: 72%).

[0220] LCMS m / z=618.3[M+1] +

[0221] Step 8: Synthesis of Compound 1

[0222] 1H (0.12 g, 0.19 mmol), lithium hydroxide monohydrate (0.080 g, 1.91 mmol), 1,4-dioxane (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was stirred at room temperature overnight. Dichloromethane (30 mL) and water (20 mL) were added, and the pH was adjusted to 2-3 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography. The eluent was DCM-CH3OH = 100-0 to 90-10 to obtain compound 1 (0.09 g, yield: 80%).

[0223] LCMS m / z=590.3[M+1] +

[0224] Compound 1 (400 mg) was used for chiral separation and purification:

[0225] Preparation conditions: Instrument: Waters 150 Prep-SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, B for isopropanol (0.1% ammonia solution); Gradient: B for 30%; Flow rate: 120 ml / min; Back pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm; Cycle time: 4.5 min;.

[0226] Analytical conditions: Instrument: SHIMADZU LC-30AD SFC; Chromatographic column: AD; Mobile phase: A for CO2, Mobile phase: B for isopropanol (0.05% DEA); Gradient: B for 5-40%; Flow rate: 3 ml / min; Column temperature: 35°C; Detection wavelength: 220 nm.

[0227] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to obtain compound 1-1 (116.1 mg) and compound 1-2 (151.9 mg).

[0228] Compound 1-1: retention time 1.598 min under analytical conditions, LCMS m / z = 590.2 [M+H] +

[0229] 1H NMR(400MHz,CD3OD)δ7.75(s,1H),7.66(t,1H),7.38-7.28(m,2H),7.08-6 .99(m,2H),6.95-6.82(m,2H),4.39-4.25(m,1H),3.52-3.38(m,4H),3.28 -3.18(m,5H),3.17-3.09(m,1H),3.00(t,1H),2.83(d,2H),2.71-2.59(m, 1H),2.22-2.07(m,1H),2.04-1.72(m,3H),1.64-1.45(m,1H),1.06(d,6H).

[0230] Compound 1-2: retention time 1.959 min under analytical conditions, LCMS m / z = 590.2 [M+H] +

[0231] 1 H NMR(400MHz,CD3OD)δ7.75(s,1H),7.66(t,1H),7.37-7.28(m,2H),7.07-7. 00(m,2H),6.95-6.83(m,2H),4.41-4.24(m,1H),3.52-3.38(m,4H),3.28-3. 17(m,5H),3.17-3.08(m,1H),3.06-2.95(m,1H),2.82(d,2H),2.72-2.59(m ,1H),2.21-2.06(m,1H),2.04-1.70(m,3H),1.64-1.47(m,1H),1.06(d,6H).

[0232] Example 2:

[0233] Step 1: Synthesis of 2A

[0234] 2-Bromo-4-fluorophenol (3.3 g, 17.32 mmol), 4-methoxybenzyl chloride (2.71 g, 17.32 mmol), potassium carbonate (7.18 g, 51.96 mmol) and acetone (50 mL) were added to the reaction flask and heated in an oil bath at 70°C overnight. The mixture was cooled to room temperature and filtered. An appropriate amount of silica gel was added to the filtrate, which was then concentrated under reduced pressure. The product was purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 2A (3.8 g, yield: 71%).

[0235] Step 2: Synthesis of 2B

[0236] 2A (0.75 g, 2.41 mmol), 1B (0.66 g, 2.41 mmol), Pd2DBa3 (0.22 g, 0.24 mmol), (R)-SEGPHOS (0.29 g, 0.48 mmol), cesium carbonate (2.36 g, 7.25 mmol) and 1,4-dioxane (15 mL) were added to the reaction flask and ventilated with nitrogen three times. The mixture was heated in an oil bath at 100°C overnight and cooled to room temperature. The filtrate was filtered and an appropriate amount of silica gel was added to the filtrate, which was then concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 2B (0.45 g, yield: 37.08%).

[0237] LCMS m / z=504.2[M+1] +

[0238] Step 3: Synthesis of 2C

[0239] 2B (0.45 g, 0.89 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The reaction was stirred at room temperature overnight and concentrated to dryness under reduced pressure. Dichloromethane (20 mL) was added, and the organic phase was washed with saturated aqueous sodium bicarbonate solution. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 2C (0.32 g, yield: 94%).

[0240] Step 4: 2D synthesis

[0241] 2C (0.32 g, 0.83 mmol), triethylamine (0.26 g, 2.52 mmol) and dichloromethane solution (8 mL) were added to the reaction flask. The mixture was cooled to about -30°C and a dichloromethane solution (2 mL) of trifluoromethanesulfonic anhydride (0.47 g, 1.67 mmol) was added dropwise. The temperature was naturally raised to react for 1 hour. Dichloromethane (10 mL) was added and the mixture was washed with saturated sodium bicarbonate aqueous solution. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 2D (0.31 g, yield: 72%).

[0242] LCMS m / z=516.2[M+1] +

[0243] Step 5: Synthesis of 2E

[0244] To the reaction flask were added 2D (0.31 g, 0.60 mmol), 4-[4-(N-BOC)piperazin-1-yl]phenylboronic acid pinacol ester (0.35 g, 0.90 mmol), tetrakistriphenylphosphine palladium (0.14 g, 0.12 mmol), sodium carbonate (0.19 g, 1.79 mmol), toluene (6 mL), ethanol (6 mL), and water (3 mL). The mixture was ventilated three times with nitrogen and stirred in an oil bath at 95° C. under nitrogen protection overnight. The mixture was cooled to room temperature, and ethyl acetate (30 mL) and water (20 mL) were added, stirred, and the layers were separated. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography with PE-EA = 100-0 to 80-20 to give 2E (0.06 g, yield: 16%).

[0245] LCMS m / z=628.3[M+1] +

[0246] Step 6: Synthesis of 2F

[0247] 2E (62 mg, 0.096 mmol) and dichloromethane (3 mL) were added to the reaction flask, and trifluoroacetic acid (1 mL) was added with stirring. The reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added, and the mixture was washed once with saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2F (40 mg, yield: 77%).

[0248] Step 7: Synthesis of 2G

[0249] 2F (40 mg, 0.076 mmol), isobutyraldehyde (28 mg, 0.38 mmol), and dichloromethane (5 mL) were added to the reaction flask and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (48 mg, 0.23 mmol) and glacial acetic acid (23 mg, 0.23 mmol) were added and the mixture was stirred at room temperature overnight. Dichloromethane (10 mL) was added and the mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. Purification by column chromatography (eluent: PE-EA = 100-0 to 80-20) afforded 2G (30 mg, yield: 68%).

[0250] LCMS m / z=584.3[M+1] +

[0251] Step 8: Synthesis of Compound 2

[0252] 2G (30 mg, 0.051 mmol), lithium hydroxide monohydrate (21 mg, 0.51 mmol), 1,4-dioxane (3 mL) and water (1 mL) were added to the reaction flask and stirred at room temperature overnight. Dichloromethane (30 mL) and water (20 mL) were added and the pH was adjusted to 2-3 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer and concentrated under reduced pressure. The mixture was purified by column chromatography with eluent: DCM-CH3OH = 100-0 to 90-10 to give compound 2 (10 mg, yield: 35%).

[0253] LCMS m / z=556.3[M+1] +

[0254] 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.50(t,1H),7.34(d,2H),7.31-7.21(m,1 H),7.07(d,2H),6.99-6.85(m,2H),4.40-4.30(m,1H),4.01-3.74(m,2H),3.69- 3.53(m,2H),3.25-3.09(m,5H),3.08-2.97(m,4H),2.62-2.52(m,1H),2.21-2.0 8(m,1H),2.05-1.80(m,2H),1.76-1.59(m,1H),1.47-1.31(m,1H),1.00(d,6H).

[0255] Example 3:

[0256] Step 1: Synthesis of 3A

[0257] 3-Bromo-4-hydroxybenzaldehyde (3 g, 14.89 mmol), 4-methoxybenzyl chloride (2.45 g, 15.63 mmol), potassium carbonate (4.12 g, 29.71 mmol) and DMF (30 mL) were added to the reaction flask and heated in an oil bath at 50°C for 4 hours. The mixture was cooled to room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with saturated aqueous sodium chloride solution. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 3A (4.5 g, yield: 94%).

[0258] Step 2: Synthesis of 3B

[0259] 3A (4.30 g, 13.39 mmol) and dichloromethane (40 mL) were added to the reaction flask, and a solution of DAST (4.32 g, 26.78 mmol) in dichloromethane (10 mL) was added dropwise under ice-water bath cooling. The reaction was stirred at room temperature for 5 hours. Methanol (10 mL) was added dropwise under ice-water bath cooling to quench the reaction. The reaction solution was washed with saturated sodium bicarbonate aqueous solution. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 3B (4 g, yield: 87%).

[0260] Step 3: Synthesis of 3C

[0261] 3B (1 g, 2.91 mmol), 1B (0.80 g, 2.91 mmol), Pd2DBa3 (0.27 g, 0.29 mmol), (R)-SEGPHOS (0.36 g, 0.58 mmol), cesium carbonate (2.84 g, 8.73 mmol) and 1,4-dioxane (20 mL) were added to the reaction flask and purged with nitrogen three times. The reaction was heated in an oil bath at 100°C overnight, cooled to room temperature, filtered, and the filtrate was added with an appropriate amount of silica gel and concentrated under reduced pressure. Purification was performed by column chromatography with eluent: PE-EA = 100-0 to 90-10 to obtain 3C (0.7 g, yield: 45%).

[0262] Step 4: 3D synthesis

[0263] 3C (0.7 g, 1.31 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The reaction was stirred at room temperature overnight and concentrated under reduced pressure to dryness. Dichloromethane (20 mL) was added and the mixture was washed with saturated aqueous bicarbonate solution. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 3D (0.3 g, yield: 55%).

[0264] Step 5: Synthesis of 3E

[0265] 3D (0.3 g, 0.72 mmol), triethylamine (0.22 g, 2.17 mmol) and dichloromethane solution (8 mL) were added to the reaction flask. The mixture was cooled to about -30°C and a dichloromethane solution (2 mL) of trifluoromethanesulfonic anhydride (0.41 g, 1.45 mmol) was added dropwise. The temperature was naturally raised to react for 1 hour. Dichloromethane (10 mL) was added and the mixture was washed with saturated sodium bicarbonate aqueous solution. An appropriate amount of silica gel was added to the organic layer, which was then concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 3E (0.28 g, yield: 71%).

[0266] Step 6: Synthesis of 3F

[0267] To the reaction flask were added 3E (0.28 g, 0.51 mmol), 4-[4-(N-BOC)piperazin-1-yl]phenylboronic acid pinacol ester (0.30 g, 0.77 mmol), tetrakistriphenylphosphine palladium (0.12 g, 0.10 mmol), sodium carbonate (0.16 g, 1.53 mmol), toluene (6 mL), ethanol (6 mL), and water (3 mL). The mixture was ventilated three times with nitrogen and stirred in an oil bath at 95°C under nitrogen protection overnight. The mixture was cooled to room temperature, and ethyl acetate (30 mL) and water (20 mL) were added, stirred, and the layers separated. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography with PE-EA (100-0 to 80-20) as the eluent to give 3F (0.25 g, yield: 74%).

[0268] Step 7: 3G synthesis

[0269] 3F (0.25 g, 0.38 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added, and the mixture was washed once with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3G (0.18 g, yield: 85%).

[0270] LCMS m / z=560.3[M+1] +

[0271] Step 8: Synthesis of 3H

[0272] To the reaction flask were added 3G (0.18 g, 0.32 mmol), isobutyraldehyde (0.12 g, 1.66 mmol), and dichloromethane (10 mL). The mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.20 g, 0.94 mmol) and glacial acetic acid (0.058 g, 0.97 mmol) were added and the reaction was stirred at room temperature overnight. Dichloromethane (10 mL) was added and the mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. Purification by column chromatography (eluent: PE-EA = 100-0 to 80-20) afforded 3H (0.18 g, yield: 81%).

[0273] LCMS m / z=616.4[M+1] +

[0274] Step 9: Synthesis of compound 3

[0275] 3H (0.16 g, 0.26 mmol), lithium hydroxide monohydrate (0.11 g, 2.6 mmol), 1,4-dioxane (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was stirred at room temperature overnight. Dichloromethane (30 mL) and water (20 mL) were added, and the pH was adjusted to 2-3 with 1N hydrochloric acid. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography. Eluent: DCM-CH3OH = 100-0 to 90-10 to obtain compound 3 (0.12 g, yield: 79%).

[0276] LCMS m / z=588.3[M+1] +

[0277] Compound 3 (350 mg) was used for chiral separation and purification:

[0278] Preparation conditions: Instrument: Waters 150 Prep-SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, B for isopropanol (0.1% ammonia solution); Gradient: B for 35%; Flow rate: 110 ml / min; Back pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm; Cycle time: 3 min.

[0279] Analytical conditions: Instrument: SHIMADZU LC-30AD SFC; Column: AD; Mobile phase: A for CO2, Mobile phase: B for isopropanol (0.05% DEA); Gradient: B from 5-40%; Flow rate: 3 ml / min; Column temperature: 35°C; Detection wavelength: 220 nm. After preparative separation, fractions with identical retention times were combined and concentrated under reduced pressure to yield compound 3-1 (126.1 mg) and compound 3-2 (178.4 mg).

[0280] Compound 3-1: retention time 1.592 min under analytical conditions, LCMS m / z = 588.3 [M+H] +

[0281] 1H NMR(400MHz,CD3OD)δ7.76(s,1H),7.67(t,1H),7.53-7.47(m,2H),7.29-7.18(m,3H),7.08 -7.00(m,2H),6.72(t,1H),4.53-4.38(m,1H),3.50-3.38(m,4H),3.27-3.11(m,6H),3.06- 2.97(m,1H),2.78(d,2H),2.76-2.64(m,1H),2.20-2.06(m,1H),2.06-1.77(m,3H),1.74-1.58(m,1H),1.05(d,6H).

[0282] Compound 3-2: retention time 1.918 min under analytical conditions, LCMS m / z = 588.3 [M+H] +

[0283] 1 H NMR (400MHz, CD3OD) δ7.75(s,1H),7.68(t,1H),7.52(d,2H),7.33-7.18(m,3H),7.05(d,2H),6.73(t,1H),4.55-4.39(m,1H),3.49-3.38(m, 4H),3.28-3.10(m,6H),3.01(t,1H),2.77(d,2H),2.74-2.65(m,1H), 2.19-2.07(m,1H),2.07-1.77(m,3H),1.74-1.56(m,1H),1.05(d,6H).

[0284] Example 4:

[0285] Step 1: Preparation of 4A

[0286] 2-Bromo-6-fluorophenol (3.3 g, 17.32 mmol), 4-methoxybenzyl chloride (2.71 g, 17.32 mmol), and potassium carbonate (7.18 g, 52.04 mmol) were added to acetone (50 mL). The mixture was stirred in an oil bath at 70°C overnight. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 10 / 1) to provide compound 4A (3.8 g, yield: 70%).

[0287] Step 2: Preparation of 4B

[0288] Compound 4A (1 g, 3.21 mmol) and 1B (0.92 g, 3.37 mmol) were added to 1,4-dioxane (15 mL). Pd2(dba)3 (0.29 g, 0.32 mmol), 4,4'-bis-1,3-benzodioxolane-5,5'-diylbis(diphenylphosphine) ((R)-SEGPHOS) (0.39 g, 0.64 mmol), and cesium carbonate (2.61 g, 8.01 mmol) were also added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 100°C and stirred overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was added with ethyl acetate and water, stirred, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 2 / 1) to afford compound 4B (0.54 g, yield: 33%).

[0289] LCMS m / z=504.3[M+H] +

[0290] Step 3: Preparation of 4C

[0291] 4B (0.54 g, 1.07 mmol) was dissolved in DCM (10 mL), and TFA (0.61 g, 5.35 mmol) was added. The reaction was stirred at room temperature overnight. The majority of the solvent was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate and washed once with water, once with saturated sodium bicarbonate solution, and finally once with saturated brine. The residue was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0-2 / 1) to afford compound 4C (0.38 g, yield: 92%).

[0292] LCMS m / z=384.4[M+H] +

[0293] Step 4: 4D preparation

[0294] 4C (0.38 g, 0.99 mmol) was dissolved in DCM (5 mL), and triethylamine (0.30 g, 2.97 mmol) was added. Trifluoromethanesulfonic anhydride (0.56 g, 1.98 mmol) was added dropwise in an ice-water bath, and the mixture was stirred at room temperature overnight. Dichloromethane and water were added, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0-10 / 1) to afford compound 4D (0.45 g, yield: 88%).

[0295] LCMS m / z=516.1[M+H] +

[0296] Step 5: Preparation of 4E

[0297] 4D (0.22 g, 0.43 mmol) and 4-[4-(N-BOC)piperazin-1-yl]phenylboronic acid pinacol ester (0.25 g, 0.65 mmol) were dissolved in toluene (3 mL), ethanol (3 mL), and water (1 mL). Tetrakistriphenylphosphine palladium (0.099 g, 0.086 mmol) and sodium carbonate (0.14 g, 1.29 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and the mixture was stirred overnight. The mixture was cooled to room temperature and filtered through celite. The filtrate was added with ethyl acetate and water, and the mixture was separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 4E (0.15 g, yield: 55%).

[0298] LCMS m / z=628.3[M+H] +

[0299] Step 6: Preparation of 4F

[0300] 4E (0.15 g, 0.24 mmol) was dissolved in 4M HCl / 1,4-dioxane solution (5 mL) and stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 4F (0.12 g, yield: 94%).

[0301] LCMS m / z=528.6[M+H] +

[0302] Step 7: Preparation of 4G

[0303] 4F (0.12 g, 0.23 mmol) and isobutyraldehyde (0.033 g, 0.46 mmol) were dissolved in DCM (5 mL), and glacial acetic acid (0.055 g, 0.92 mmol) was added. The mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (0.15 g, 0.71 mmol) was added. The reaction was allowed to react at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 4G (0.12 g, yield: 89%).

[0304] LCMS m / z=584.3[M+H] +

[0305] Step 8: Preparation of compound 4

[0306] Compound 4G (0.12 g, 0.21 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (0.088 g, 3.67 mmol) was added and stirred at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to obtain compound 4 (90 mg, yield: 77%).

[0307] LCMS m / z=556.2[M+H] +

[0308] 1 H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.52(t,1H),7.37-7.23(m,3H),7.07(d ,2H),6.97-6.87(m,2H),4.44-4.27(m,1H),3.91-3.80(m,2H),3.66-3.56(m ,2H),3.24-3.10(m,5H),3.08-2.97(m,4H),2.60-2.52(m,1H),2.22-2.09(m ,1H),2.01-1.80(m,2H),1.74-1.62(m,1H),1.44-1.36(m,1H),1.02(d,6H).

[0309] Example 5:

[0310] Step 1: Synthesis of 5A

[0311] 2-Bromo-4-chlorophenol (25 g, 120.54 mmol), 4-methoxybenzyl chloride (18.88 g, 120.54 mmol), potassium carbonate (33.32 g, 241.08 mmol) and acetone (300 mL) were added to the reaction flask and heated in an oil bath at 70°C overnight. The mixture was cooled to room temperature and filtered. An appropriate amount of silica gel was added to the filtrate, which was then concentrated under reduced pressure. The product was purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 5A (30 g, yield: 76%).

[0312] Step 2: Synthesis of 5B

[0313] 5A (12 g, 36.63 mmol), 1B (10.1 g, 36.63 mmol), Pd2DBa3 (3.35 g, 3.66 mmol), (R)-SEGPHOS (4.47 g, 7.33 mmol), cesium carbonate (35.80 g, 109.93 mmol) and 1,4-dioxane (150 mL) were added to the reaction flask, purged with nitrogen three times, heated in an oil bath at 100°C overnight, cooled to room temperature, added with an appropriate amount of silica gel, and concentrated under reduced pressure. Purification was performed by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 5B (10 g, yield: 53%).

[0314] Step 3: Synthesis of 5C

[0315] 5B (10 g, 19.23 mmol) and dichloromethane (50 mL) were added to the reaction flask, and trifluoroacetic acid (40 mL) was added with stirring. The reaction was stirred at room temperature overnight and concentrated under reduced pressure. Dichloromethane (100 mL) was added and the mixture was washed with saturated aqueous sodium bicarbonate. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 5C (6.5 g, yield: 85%).

[0316] Step 4: 5D synthesis

[0317] 5C (5 g, 12.51 mmol), triethylamine (3.80 g, 37.53 mmol) and dichloromethane solution (50 mL) were added to the reaction flask. The mixture was cooled to about -30°C and a dichloromethane solution (10 mL) of trifluoromethanesulfonic anhydride (4.1 g, 14.5 mmol) was added dropwise. The temperature was naturally raised to react for 1 hour, and the mixture was washed with saturated sodium bicarbonate aqueous solution. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. The mixture was purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 5D (4.60 g, yield: 69%).

[0318] Step 5: Synthesis of 5F

[0319] Compound 5E (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and BOC2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain the racemate of compound 5F (3.4 g, yield: 82%).

[0320] The racemate of 5F was subjected to chiral separation as follows:

[0321] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0322] 2. Dissolve the sample in methanol and filter with a 0.45 μm filter to prepare a sample solution.

[0323] 3. Preparative chromatographic conditions: a. Mobile phases consisted of a system of A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content was 20%; c. Flow rate was 40 mL / min.

[0324] Peak time: chiral isomer 1 (compound 5F-1): 5.7 min, chiral isomer 2 (compound 5F-2): 6.47 min.

[0325] According to MicroED structure determination, compound 5F-1 has R configuration and compound 5F-2 has S configuration.

[0326] LCMS m / z=307.3[M+1] +

[0327] Step 6: 5G Synthesis

[0328] 5F-2 (3 g, 9.79 mmol) and acetonitrile (40 mL) were added to the reaction flask, and NBS (1.83 g, 10.28 mmol) was added in batches with stirring. The reaction was stirred at room temperature for 1 hour. After adding an appropriate amount of silica gel, the product was concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to obtain 5G (1.9 g, yield: 50%).

[0329] Step 7: Synthesis of 5H

[0330] 5G (0.8 g, 2.08 mmol), pinacol diboron (1.06 g, 4.18 mmol), Pd(dppf)Cl2 (0.30 g, 0.42 mmol), potassium acetate (0.61 g, 6.22 mmol) and 1,4-dioxane (15 mL) were added to the reaction flask and ventilated with nitrogen three times. The reaction was heated in an oil bath at 95 ° C. under nitrogen protection overnight. The reaction was cooled to room temperature, and an appropriate amount of silica gel was added, followed by concentration under reduced pressure and purification by column chromatography (eluent: PE-EA = 100-0 to 90-10) to give 5H (0.47 g, yield: 52%).

[0331] Step 8: Synthesis of 5I

[0332] 5D (0.38 g, 0.71 mmol), 5H (0.46 g, 1.06 mmol), tetrakistriphenylphosphine palladium (0.16 g, 0.14 mmol), sodium carbonate (0.23 g, 2.13 mmol), toluene (6 mL), ethanol (6 mL), and water (3 mL) were added to the reaction flask and ventilated three times with nitrogen. The mixture was stirred in an oil bath at 95°C under nitrogen protection overnight. The mixture was cooled to room temperature, and ethyl acetate (30 mL) and water (20 mL) were added and stirred to separate the layers. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography with eluent: PE-EA = 100-0 to 90-10 to give 5I (0.37 g, yield: 61%).

[0333] LCMS m / z=688.3[M+1] +

[0334] Step 9: Synthesis of 5J

[0335] 5I (0.37 g, 0.54 mmol) and dichloromethane (5 mL) were added to the reaction flask, and trifluoroacetic acid (3 mL) was added with stirring. The reaction was stirred at room temperature for 2 hours, and the mixture was concentrated under reduced pressure. Dichloromethane (20 mL) was added, and the mixture was washed once with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 5J (0.29 g).

[0336] Step 10: 5K Synthesis

[0337] 5J (0.29 g, 0.49 mmol), isobutyraldehyde (0.17 g, 2.41 mmol), and dichloromethane (10 mL) were added to the reaction flask and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.31 g, 1.47 mmol) and glacial acetic acid (0.088 g, 1.47 mmol) were added and the reaction was stirred at room temperature for approximately 48 hours. Dichloromethane (10 mL) was added and the mixture was washed with saturated aqueous sodium bicarbonate. The organic layer was added with an appropriate amount of silica gel and concentrated under reduced pressure. Purification was performed by column chromatography using PE-EA (100-0 to 80-20) as the eluent to afford 5K (0.17 g).

[0338] LCMS m / z=644.4[M+1] +

[0339] Step 11: Synthesis of compound 5

[0340] 5K (0.17 g, 0.26 mmol), lithium hydroxide monohydrate (0.11 g, 2.6 mmol), 1,4-dioxane (3 mL) and water (1 mL) were added to the reaction flask, and the reaction was stirred at room temperature overnight. Dichloromethane (30 mL), water (20 mL) and 1N hydrochloric acid were added to adjust the pH to 2-3. An appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure and purified by column chromatography. The eluent was DCM-CH3OH = 100-0 to 90-10 to obtain compound 5 (0.08 g).

[0341] LCMS m / z=616.3[M+1] +

[0342] Compound 5 (400 mg) was used for chiral separation and purification:

[0343] Preparation conditions: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, B for isopropanol (0.1% ammonia solution); Gradient: B for 50%; Flow rate: 100 ml / min; Back pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm; Cycle time: 2.9 min.

[0344] Analytical conditions: Instrument: SHIMADZU LC-30AD SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, Mobile phase: B for isopropanol (0.05% DEA); Gradient: B for 5-40%; Flow rate: 3 mL / min; Column temperature: 35°C; Detection wavelength: 220 nm.

[0345] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to give compound 5-1 (174 mg) and compound 5-2 (191.4 mg).

[0346] Compound 5-1: retention time 1.755 min under analytical conditions, LCMS m / z = 616.6 [M+H] +

[0347] 1H NMR (400MHz, CD3OD / CDCl3(v / v)=1 / 1)δ7.86(s,1H),7.59(t,1H),7.18-7.10(m,1 H),7.09-6.97(m,3H),6.59(d,1H),4.50-4.37(m,1H),3.80(d,1H),3.32-3.20(m, 3H),3.20-3.02(m,4H),2.91-2.79(m,1H),2.78-2.62(m,2H),2.61-2.43(m,3H),2 .25(t,1H),2.10-1.89(m,4H),1.87-1.72(m,2H),1.64-1.46(m,1H),1.02(d,6H).

[0348] Compound 5-2: retention time 2.284 min under analytical conditions, LCMS m / z = 616.7 [M+H] +

[0349] 1 H NMR (400MHz, CD3OD / CDCl3(v / v)=1 / 1)δ7.86(s,1H),7.62(t,1H),7.18-6.99(m, 4H),6.59(d,1H),4.50-4.35(m,1H),3.88-3.70(m,1H),3.34-3.26(m,2H),3.26 -3.00(m,5H),2.97-2.83(m,1H),2.79-2.63(m,2H),2.61-2.43(m,3H),2.26(t, 1H),2.12-1.89(m,4H),1.87-1.69(m,2H),1.64-1.46(m,1H),1.09-0.98(m,6H).

[0350] Example 6:

[0351] Step 1: Preparation of 6A

[0352] Compound 5F-1 (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 ml), and NBS (0.81 g, 4.57 mmol) was added. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 0:1-1:9) to obtain 6A (1.6 g, yield: 91%).

[0353] Step 2: Preparation of 6B

[0354] Compound 6A (0.6 g, 1.56 mmol) and pinacol diboron (0.59 g, 2.35 mmol) were dissolved in 1,4-dioxane (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.23 g, 0.31 mmol) and potassium acetate (0.46 g, 4.69 mmol) were added. The nitrogen atmosphere was replaced three times. Under nitrogen protection, the temperature was raised to 100°C and the reaction was stirred overnight. After cooling to room temperature, ethyl acetate and water were added and stirred to separate the layers. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to obtain compound 6B (0.45 g, yield: 66%).

[0355] LCMS m / z=433.3[M+H] +

[0356] Step 3: Preparation of 6C

[0357] 5D (0.22 g, 0.41 mmol) and 6B (0.27 g, 0.61 mmol) were dissolved in toluene (3 mL), ethanol (3 mL), and water (1 mL). Tetrakistriphenylphosphine palladium (0.095 g, 0.082 mmol) and sodium carbonate (0.13 g, 1.23 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and the mixture was stirred and reacted overnight. The mixture was cooled to room temperature and filtered through celite. The filtrate was added with ethyl acetate and water, and the mixture was stirred to separate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 6C (0.23 g, yield: 81%).

[0358] LCMS m / z=688.3[M+H] +

[0359] Step 4: Preparation of 6D

[0360] 6C (0.23 g, 0.33 mmol) was dissolved in 4M HCl / 1,4-dioxane solution (5 mL) and stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate were added, followed by stirring and separation. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 6D (0.18 g, yield: 92%).

[0361] LCMS m / z=588.2[M+H] +

[0362] Step 5: Preparation of 6E

[0363] 6D (0.18 g, 0.31 mmol) and isobutyraldehyde (0.045 g, 0.62 mmol) were dissolved in DCM (5 mL), and glacial acetic acid (0.074 g, 1.24 mmol) was added. The mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (0.2 g, 0.93 mmol) was added. The reaction was allowed to react at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 6E (0.17 g, yield: 85%).

[0364] LCMS m / z=644.3[M+H] +

[0365] Step 6: Preparation of compound 6

[0366] Compound 6E (0.17 g, 0.26 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide (0.11 g, 2.59 mmol) was added and stirred at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. 20 mL of ethyl acetate was added, and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to obtain compound 6 (0.14 g, yield: 87%).

[0367] LCMS m / z=616.2[M+1] +

[0368] Compound 6 (140 mg) was subjected to chiral separation and prepared as follows:

[0369] Instrument: SFC Prep 150AP; Chromatographic column: AD (19 mm × 250 mm).

[0370] The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution.

[0371] Preparative chromatographic conditions: a. Mobile phase consists of A and B system: mobile phase A: CO2; mobile phase B: methanol (0.1% ammonia solution); b. Isocratic elution, mobile phase B content is 35%; c. Flow rate: 30 mL / min.

[0372] After preparative separation, the fractions with the same retention time were combined and concentrated under reduced pressure to give compound 6-1 (30 mg) and compound 6-2 (70 mg).

[0373] Compound 6-1: Retention time 8.4 min according to the preparation method, LCMS m / z = 616.2 [M+1] +

[0374] 1 H NMR(400MHz,DMSO-d6)δ7.77(s,1H),7.73(t,1H),7.17-7.00(m,4H),6.67(d,1H),4.40-4.26(m,1H),3.81-3.71(m,1H),3.20- 3.14(m,1H),3.09-2.54(m,9H),2.13-1.98(m,3H),1.97-1.68(m,6H),1.67-1.53(m,1H),1.45-1.31(m,1H),0.95-0.83(m,6H).

[0375] Compound 6-2: Retention time 9.6 min under the preparation method, LCMS m / z=616.2[M+1] +

[0376] 1 H NMR(400MHz,CD3OD)δ7.79(s,1H),7.66(t,1H),7.15-6.95(m,4H),6.70(d,1H),4.41 -4.31(m,1H),4.07-3.93(m,1H),3.60-3.50(m,1H),3.49-3.42(m,1H),3.38-3.32(m, 1H),3.21-3.11(m,2H),3.10-2.90(m,3H),2.89-2.77(m,3H),2.76-2.63(m,3H),2.2 5-2.10(m,1H),2.06-1.90(m,3H),1.85-1.72(m,2H),1.64-1.47(m,1H),1.07(d,6H).

[0377] Example 7:

[0378] Step 1: Preparation of 7B

[0379] Compound 7A (2 g, 5.45 mmol) (synthesis method reference WO2009050236) and pinacol diboron (2.08 g, 8.18 mmol) were dissolved in 1,4-dioxane (30 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.40 g, 0.55 mmol) and potassium acetate (1.60 g, 16.35 mmol) were added. The atmosphere was purged with nitrogen three times. Under nitrogen protection, the mixture was heated to 100°C and stirred overnight. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to obtain compound 7B (1.1 g, yield: 48%).

[0380] LCMS m / z=415.3[M+H] +

[0381] Step 2: Preparation of 7C

[0382] 5D (0.40 g, 0.75 mmol) and 7B (0.47 g, 1.13 mmol) were dissolved in toluene (6 mL), ethanol (6 mL), and water (2 mL). Tetrakistriphenylphosphine palladium (0.17 g, 0.15 mmol) and sodium carbonate (0.24 g, 2.25 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and the mixture was stirred overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was added with ethyl acetate and water, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to afford compound 7C (0.4 g, yield: 79%).

[0383] LCMS m / z=670.3[M+H] +

[0384] Step 3: Preparation of 7D

[0385] 7C (0.4 g, 0.60 mmol) was dissolved in 4M HCl / 1,4-dioxane (5 mL) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 7D (0.34 g, yield: 99%).

[0386] LCMS m / z=570.3[M+H] +

[0387] Step 5: Preparation of 7E

[0388] 7D (0.34 g, 0.60 mmol) and isobutyraldehyde (0.087 g, 1.2 mmol) were dissolved in DCM (10 mL). Glacial acetic acid (0.14 g, 2.4 mmol) was added, and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (0.38 g, 1.80 mmol) was added, and the reaction was allowed to react at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 7E (0.3 g, yield: 79%).

[0389] LCMS m / z=626.3[M+H] +

[0390] Step 6: Preparation of compound 7

[0391] Compound 7E (0.3 g, 0.48 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide monohydrate (0.20 g, 4.77 mmol) was added and stirred at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to obtain compound 7 (0.14 g, yield: 48%).

[0392] LCMS m / z=598.2[M+1] +

[0393] Compound 7 (100 mg) was subjected to chiral separation. The preparation method is as follows:

[0394] Instrument: SFC Prep 150AP; Chromatographic column: AD (19 mm × 250 mm).

[0395] The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution.

[0396] Preparative chromatographic conditions: a. Mobile phase consists of A and B system: mobile phase A: CO2; mobile phase B: methanol / ethanol (ammonia 0.1%) = 1 / 1; b. Isocratic elution, mobile phase B content is 30%; c. Flow rate: 40 mL / min.

[0397] After preparative separation, the fractions with the same retention time were combined and concentrated under reduced pressure to give compound 7-1 (30 mg) and compound 7-2 (25 mg).

[0398] Compound 7-1: Retention time 12.3 min under preparation method, LCMS m / z=598.2[M+1] +

[0399] 1 H NMR(400MHz,CD3OD)δ7.71(s,1H),7.70(t,1H),7.48-7.42(m,2H),7.15-7.01(m,3H), 6.98-6.90(m,2H),4.46-4.35(m,1H),4.12-3.98(m,2H),3.77-3.63(m,2H),3.30-3.23 (m,2H),3.21-3.10(m,2H),2.99-2.84(m,3H),2.76-2.65(m,1H),2.31-2.21(m,2H),2. 21-2.08(m,3H),2.05-1.97(m,1H),1.96-1.81(m,2H),1.74-1.59(m,1H),1.11(t,6H).

[0400] Compound 7-2: Retention time 17.1 min under the preparation method, LCMS m / z = 598.2 [M+1] +

[0401] 1 H NMR(400MHz,CD3OD)δ7.71(s,1H),7.70(t,1H),7.49-7.40(m,2H),7.15-7.01(m,3H), 6.99-6.89(m,2H),4.46-4.31(m,1H),4.16-3.96(m,2H),3.80-3.62(m,2H),3.29-3.23 (m,2H),3.22-3.10(m,2H),2.99-2.85(m,3H),2.76-2.65(m,1H),2.30-2.21(m,2H),2. 21-2.08(m,3H),2.06-1.97(m,1H),1.96-1.81(m,2H),1.74-1.57(m,1H),1.11(d,6H).

[0402] Example 8:

[0403] Step 1: Preparation of 8A-P1 and 8A-P2

[0404] Compound 8A (synthesis method reference DOI: 10.1021 / acs.oprd.9b00364) was subjected to chiral separation. The separation method is as follows:

[0405] Instrument: SFC Prep 150 AP; Chromatographic column: Daicel AD-H (19 mm × 250 mm);

[0406] The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution.

[0407] Preparative chromatography conditions: mobile phase A: CO2, mobile phase B: methanol; isocratic elution, mobile phase B content 25%; flow rate 40 ml / min.

[0408] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to give compound 8A-P1 and compound 8A-P2.

[0409] Compound 8A-P1: retention time 4.65 min under the preparation method;

[0410] Compound 8A-P2: retention time under the preparation method is 5.85 min.

[0411] Step 2: Preparation of 8B

[0412] Compound 8A-P2 (0.6 g, 3.19 mmol) was dissolved in dichloromethane (30 mL), and Boc anhydride (1.39 g, 6.4 mmol) and 4-dimethylaminopyridine (0.39 g, 3.19 mmol) were added. The mixture was stirred at room temperature overnight. The reaction solution was washed with 50 mL of 0.5N hydrochloric acid, 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) = 0:1-1:9) to obtain compound 8B (0.8 g, yield: 87%).

[0413] Step 3: Preparation of 8C

[0414] Compound 8B (0.78 g, 2.70 mmol) was dissolved in acetonitrile (20 ml), and NBS (0.53 g, 2.97 mmol) was added. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 0:1-1:9) to obtain compound 8C (0.86 g, yield: 87%).

[0415] LCMS m / z=367.5[M+1] +

[0416] Step 4: Preparation of 8D

[0417] 8C (0.5 g, 1.36 mmol) and pinacol diboron (1.69 g, 2.72 mmol) were dissolved in 1,4-dioxane (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.20 g, 0.27 mmol) and potassium acetate (0.40 g, 4.08 mmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 95°C under nitrogen protection and stirred overnight. The mixture was cooled to room temperature, an appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 90 / 10) to obtain compound 8D (0.6 g, yield: 53%).

[0418] Step 5: Preparation of 8E

[0419] 5D (0.39 g, 0.73 mmol) and 8D (0.45 g, 1.09 mmol) were dissolved in toluene (6 mL), ethanol (6 mL), and water (3 mL). Tetrakistriphenylphosphine palladium (0.17 g, 0.15 mmol) and sodium carbonate (0.23 g, 2.19 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 95°C and stirred overnight. After cooling to room temperature, ethyl acetate and water were added and stirred. The layers were separated, and an appropriate amount of silica gel was added to the organic phase, which was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to afford compound 8E (0.31 g, yield: 63%).

[0420] Step 6: Preparation of 8F

[0421] 8E (0.31 g, 0.46 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. After concentration under reduced pressure, dichloromethane and saturated aqueous sodium bicarbonate were added, and the layers were separated by stirring. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 8F (0.24 g).

[0422] LCMS m / z=570.4[M+H] +

[0423] Step 7: Preparation of 8G

[0424] 8F (0.24 g, 0.42 mmol) and isobutyraldehyde (0.15 g, 2.10 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.27 g, 1.26 mmol) and glacial acetic acid (0.076 g, 1.26 mmol) were added and allowed to react at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate were added, stirred, and the layers were separated. An appropriate amount of silica gel was added to the organic phase, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to afford compound 8G (0.16 g, yield: 61%).

[0425] LCMS m / z=626.3[M+H] +

[0426] Step 8: Preparation of Compound 8

[0427] Compound 8G (0.16 g, 0.26 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide monohydrate (0.11 g, 2.6 mmol) was added and the mixture was stirred at room temperature overnight. Dichloromethane and water were added, and the pH of the reaction mixture was adjusted to 2-3 with 1N aqueous hydrochloric acid. The layers were separated, and an appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 0-90 / 10) to afford compound 8 (0.02 g, yield: 13%).

[0428] LCMS m / z=598.5[M+1] +

[0429] Compound 8 (380 mg) was used for chiral separation and purification:

[0430] Preparation conditions: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, B for isopropanol and acetonitrile (0.1% ammonia solution); Gradient: B for 55%; Flow rate: 100 ml / min; Back pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm; Cycle time: 4.0 min.

[0431] Analytical conditions: Instrument: SHIMADZU LC-30AD SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, Mobile phase: B for isopropanol (0.05% DEA); Gradient: B for 5-40%; Flow rate: 3 mL / min; Column temperature: 35°C; Detection wavelength: 220 nm.

[0432] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to give compound 8-1 (161.7 mg) and compound 8-2 (189.9 mg).

[0433] Compound 8-1: retention time 1.841 min under analytical conditions, LCMS m / z = 598.4 [M+H] +

[0434] 1 H NMR(400MHz,CD3OD)δ7.76(s,1H),7.67(t,1H),7.32-7.28(m,1H),7.22-7.15(m,1H),7.14 -7.08(m,1H),7.07-6.99(m,2H),6.94-6.86(m,1H),4.48-4.35(m,1H),4.10-3.97(m,1H),3 .53-3.45(m,1H),3.45-3.36(m,1H),3.30-3.25(m,1H),3.23-3.11(m,2H),3.09-2.84(m,4H ),2.82-2.56(m,5H),2.22-2.08(m,1H),2.06-1.73(m,5H),1.72-1.56(m,1H),1.06(d,6H).

[0435] Compound 8-2: retention time 2.431 min under analytical conditions, LCMS m / z = 598.6 [M+H] +

[0436] 1 H NMR(400MHz,CD3OD)δ7.76(s,1H),7.66(t,1H),7.36-7.28(m,1H),7.23-7.14(m,1H),7.14-7.08(m, 1H),7.07-6.97(m,2H),6.96-6.87(m,1H),4.51-4.36(m,1H),4.11-3.96(m,1H),3.53-3.45(m,1H),3 .43-3.34(m,1H),3.26-3.18(m,2H),3.18-3.10(m,1H),3.10-3.01(m,1H),3.00-2.83(m,3H),2.81-2 .56(m,5H),2.19-2.08(m,1H),2.06-1.90(m,3H),1.89-1.74(m,2H),1.72-1.56(m,1H),1.06(d,6H).

[0437] Example 9:

[0438] Step 1: Preparation of 9A

[0439] 8A-P1 (1.1 g, 5.86 mmol) and isobutyraldehyde (0.84 g, 11.68 mmol) were dissolved in DCM (20 mL). Glacial acetic acid (1.05 g, 17.52 mmol) was added, and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (4.95 g, 23.36 mmol) was added, and the reaction was allowed to react at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 2 / 1) to provide compound 9A (0.5 g, yield: 35%).

[0440] LCMS m / z=245.1[M+H] +

[0441] Step 2: Preparation of 9B

[0442] Compound 9A (0.5 g, 2.05 mmol) was dissolved in acetonitrile (10 ml), and NBS (0.36 g, 2.05 mmol) was added. After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v:v) = 0:1-1:9) to obtain 9B (0.53 g, yield: 79%).

[0443] LCMS m / z=323.0[M+H] +

[0444] Step 3: Preparation of 9C

[0445] Compound 9B (0.53 g, 1.64 mmol) and pinacol diboron (0.62 g, 2.46 mmol) were dissolved in 1,4-dioxane (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.24 g, 0.33 mmol) and potassium acetate (0.48 g, 4.92 mmol) were added. The atmosphere was purged with nitrogen three times. Under nitrogen protection, the mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the mixture was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to obtain compound 9C (0.45 g, yield: 74%).

[0446] LCMS m / z=371.5[M+H] +

[0447] Step 4: Preparation of 9D

[0448] 5D (0.45 g, 0.85 mmol) and 9C (0.47 g, 1.27 mmol) were dissolved in toluene (6 mL), ethanol (6 mL), and water (2 mL). Tetrakistriphenylphosphine palladium (0.2 g, 0.17 mmol) and sodium carbonate (0.27 g, 2.55 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and the mixture was stirred overnight. The mixture was cooled to room temperature and filtered through celite. The filtrate was added with ethyl acetate and water, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 9D (80 mg, yield: 15%).

[0449] LCMS m / z=626.3[M+H] +

[0450] Step 5: Preparation of compound 9

[0451] Compound 9D (80 mg, 0.13 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL). Lithium hydroxide monohydrate (0.055 g, 1.3 mmol) was added and stirred at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to obtain compound 9 (50 mg, yield: 65%).

[0452] LCMS m / z=598.2[M+1] +

[0453] Compound 9 (500 mg) was used for chiral separation and purification:

[0454] Preparation conditions: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, B for isopropanol (0.1% ammonia solution); Gradient: B for 50%; Flow rate: 100 ml / min; Back pressure: 100 bar; Column temperature: Room temperature; Detection wavelength: 220 nm; Cycle time: 3.6 min.

[0455] Analytical conditions: Instrument: SHIMADZU LC-30AD SFC; Chromatographic column: Chiral AD column; Mobile phase: A for CO2, Mobile phase: B for isopropanol (0.05% DEA); Gradient: B for 5-40%; Flow rate: 3 mL / min; Column temperature: 35°C; Detection wavelength: 220 nm.

[0456] After preparative separation, fractions with the same retention time were combined and concentrated under reduced pressure to give compound 9-1 (198.7 mg) and compound 9-2 (242.9 mg).

[0457] Compound 9-1: retention time 1.903 min under analytical conditions, LCMS m / z = 598.3 [M+H] +

[0458] 1 H NMR(400MHz,CD3OD)δ7.80-7.74(m,1H),7.64(t,1H),7.35-7.29(m,1H),7.21-7.15(m,1H),7.14- 7.08(m,1H),7.07-6.99(m,2H),6.95-6.87(m,1H),4.49-4.39(m,1H),4.12-4.01(m,1H),3.55-3. 46(m,1H),3.45-3.36(m,1H),3.28-3.19(m,2H),3.18-3.11(m,1H),3.10-2.85(m,4H),2.84-2.57 (m,5H),2.20-2.08(m,1H),2.07-1.89(m,3H),1.89-1.74(m,2H),1.72-1.57(m,1H),1.06(d,6H).

[0459] Compound 9-2: retention time 2.468 min under analytical conditions, LCMS m / z = 598.3 [M+H] +

[0460] 1H NMR(400MHz,CD3OD)δ7.76(s,1H),7.68(t,1H),7.35-7.26(m,1H),7.22-7.15(m,1H),7.14 -7.08(m,1H),7.07-6.98(m,2H),6.95-6.85(m,1H),4.47-4.33(m,1H),4.11-3.94(m,1H),3 .53-3.45(m,1H),3.44-3.36(m,1H),3.30-3.24(m,1H),3.24-3.10(m,2H),3.09-2.83(m,4H ),2.82-2.53(m,5H),2.21-2.08(m,1H),2.07-1.71(m,5H),1.71-1.56(m,1H),1.06(d,6H).

[0461] Example 10:

[0462] Step 1: Preparation of 10A

[0463] 10A-1 (CAS: 2760247-54-7, synthesis reference WO2022029617, 1 g, 2.72 mmol) and pinacol diboron (1.38 g, 5.44 mmol) were dissolved in 1,4-dioxane (20 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.40 g, 0.54 mmol) and potassium acetate (0.80 g, 8.16 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the mixture was heated to 95°C and stirred overnight. The mixture was cooled to room temperature, an appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 100 / 0 to 90 / 10) to obtain compound 10A (0.6 g, yield: 53%).

[0464] Step 2: Preparation of 10B

[0465] 5D (0.50 g, 0.94 mmol) and 10A (0.58 g, 1.41 mmol) were dissolved in toluene (6 mL), ethanol (6 mL), and water (3 mL). Tetrakistriphenylphosphine palladium (0.22 g, 0.19 mmol) and sodium carbonate (0.30 g, 2.83 mmol) were added. The atmosphere was replaced with nitrogen three times, and the mixture was heated to 95°C under nitrogen and stirred overnight. After cooling to room temperature, ethyl acetate and water were added, stirred, and the layers were separated. An appropriate amount of silica gel was added to the organic phase, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to afford compound 10B (0.4 g, yield: 63%).

[0466] Step 3: Preparation of 10C

[0467] 10B (0.4 g, 0.60 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to dryness. Dichloromethane and saturated aqueous sodium bicarbonate were added, stirred, and the layers separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 10C (0.3 g).

[0468] LCMS m / z=570.3[M+H] +

[0469] Step 5: Preparation of 10D

[0470] 10C (0.32 g, 0.56 mmol) and isobutyraldehyde (0.21 g, 2.85 mmol) were dissolved in DCM (5 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.36 g, 1.68 mmol) and glacial acetic acid (0.10 g, 1.68 mmol) were added and allowed to react at room temperature overnight. Dichloromethane and saturated aqueous sodium bicarbonate were added, stirred, and the layers were separated. An appropriate amount of silica gel was added to the organic phase, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 100 / 0 to 80 / 20) to afford compound 10D (0.3 g, yield: 79%).

[0471] LCMS m / z=626.3[M+H] +

[0472] Step 6: Preparation of compound 10

[0473] Compound 10D (0.17 g, 0.27 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide monohydrate (0.11 g, 2.7 mmol) was added and the mixture was stirred at room temperature overnight. Dichloromethane and water were added, and the pH of the reaction mixture was adjusted to 2-3 with 1N aqueous hydrochloric acid. The layers were separated, and an appropriate amount of silica gel was added to the organic layer, which was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 100 / 0 to 90 / 10) to afford compound 10 (0.02 g, yield: 12%).

[0474] LCMS m / z=598.3[M+1] +

[0475] 1H NMR(400MHz,DMSO-d6)δ7.96(s,1H),7.56(t,1H),7.40(d,2H),7.17(d,1 H),7.12-6.99(m,2H),6.85(d,2H),4.63-4.50(m,1H),4.34-4.16(m,2H), 3.35-3.30(m,2H),3.11-2.96(m,2H),2.49-2.42(m,2H),2.37-2.28(m,2 H),2.07-1.79(m,8H),1.77-1.63(m,2H),1.58-1.39(m,1H),0.84(d,6H).

[0476] Example 11: Preparation of Compound 11

[0477] Step 1: Preparation of 11B

[0478] Compound 11A (3.5 g, 10.35 mmol) (synthesis method reference WO2021255212) and pinacol diboron (3.94 g, 15.52 mmol) were dissolved in DMSO (30 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.85 g, 1.03 mmol) and potassium acetate (3.05 g, 31.05 mmol) were added. The atmosphere was purged with nitrogen three times. Under nitrogen protection, the mixture was heated to 100°C and stirred overnight. The mixture was cooled to room temperature and extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-10 / 1) to obtain compound 11B (2.6 g, yield: 66%).

[0479] Step 2: Preparation of 11C

[0480] 5D (1.1 g, 2.07 mmol) and 11B (1.2 g, 3.1 mmol) were dissolved in toluene (9 mL), ethanol (9 mL), and water (3 mL). Tetrakistriphenylphosphine palladium (0.48 g, 0.41 mmol) and sodium carbonate (0.66 g, 6.21 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and the mixture was stirred overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was added with ethyl acetate and water, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to afford compound 11C (0.77 g, yield: 58%).

[0481] LCMS m / z=641.3[M+H] +

[0482] Step 3: Preparation of 11D

[0483] 11C (0.77 g, 1.2 mmol) was dissolved in 4 M HCl / 1,4-dioxane (8 mL) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 11D (0.61 g).

[0484] LCMS m / z=541.3[M+H] +

[0485] Step 5: Preparation of 11E

[0486] 11D (0.2 g, 0.37 mmol) and isobutyraldehyde (0.08 g, 1.11 mmol) were dissolved in DCM (5 mL). Glacial acetic acid (0.044 g, 0.74 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.235 g, 1.11 mmol) was added, and the reaction was allowed to react at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 4 / 1) to afford compound 11E (0.157 g, yield: 71%).

[0487] LCMS m / z=597.3[M+H] +

[0488] Step 6: Preparation of compound 11

[0489] Compound 11E (0.06 g, 0.1 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide monohydrate (0.042 g, 1 mmol) was added, and the mixture was stirred at 60°C for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a flash column (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to provide the trifluoroacetate salt of compound 11 (0.015 g).

[0490] LCMS m / z=569.3[M+H] +

[0491] 1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.69-7.55(m,4H),7.50(t,1H),7.27-7.05(m ,3H),6.34-6.10(m,1H),4.56-4.34(m,1H),4.16-4.00(m,1H),3.87-3.64(m,2H), 3.36-3.15(m,2H),3.12-2.96(m,4H),2.96-2.71(m,2H),2.62(t,1H),2.24-2.09( m,1H),2.06-1.83(m,2H),1.79-1.66(m,1H),1.59-1.36(m,1H),1.11-0.93(m,6H).

[0492] Example 12: Preparation of Compound 12

[0493] Step 1: Preparation of 12A

[0494] Compound 11E (0.04 g, 0.067 mmol) was dissolved in methanol (3 mL), and triphenylphosphine rhodium chloride (6.2 mg, 0.0067 mmol) was added. The atmosphere was replaced with hydrogen three times, and the temperature was raised to 50°C with stirring overnight. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 3 / 1) to obtain compound 12A (22 mg, yield: 55%).

[0495] LCMS m / z=599.1[M+H] +

[0496] Step 2: Preparation of compound 12

[0497] Compound 12A (22 mg, 0.037 mmol) was dissolved in a mixed solvent of 1,4-dioxane (1.5 mL) and water (0.5 mL). Lithium hydroxide monohydrate (15.53 mg, 0.37 mmol) was added, and the mixture was stirred at 60°C for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a flash column (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to provide the trifluoroacetate salt of compound 12 (5 mg).

[0498] LCMS m / z=571.1[M+H] +

[0499] 1H NMR(400MHz,DMSO-d6)δ7.94(s,1H),7.54(d,2H),7.48(t,1H),7.30(d,2H),7.23-7.06(m,3H),4.54-4.31(m,1H),3.71-3.55(m,2H),3.2 3-3.14(m,1H),3.12-2.90(m,6H),2.90-2.77(m,1H),2.65(t,1H),2.23-1.84(m,7H),1.80-1.64(m,1H),1.56-1.38(m,1H),1.00(d,6H).

[0500] Example 13:

[0501] Step 1: Preparation of 13A

[0502] Compound 11D (0.33 g, 0.61 mmol) and 2-iodopropane (0.31 g, 1.83 mmol) were dissolved in acetonitrile (10 mL). N,N-diisopropylethylamine (0.24 g, 1.83 mmol) was added, and the mixture was heated to 60°C with stirring for 2 h. After cooling to room temperature, ethyl acetate and water were added for extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-4 / 1) to obtain compound 13A (0.17 g, yield: 48%).

[0503] LCMS m / z=583.1[M+H] +

[0504] Step 2: Preparation of compound 13

[0505] Compound 13A (0.05 g, 0.086 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide monohydrate (0.036 g, 0.86 mmol) was added, and the mixture was stirred at 60°C for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a flash column (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to provide the trifluoroacetate salt of compound 13 (0.008 g).

[0506] LCMS m / z=555.3[M+H] +

[0507] 1H NMR(400MHz,DMSO-d6)δ7.95(s,1H),7.68-7.53(m,4H),7.50(t,1H),7.29 -7.09(m,3H),6.36-6.20(m,1H),4.53-4.36(m,1H),3.99-3.83(m,2H),3.7 1-3.56(m,2H),3.29-3.14(m,2H),3.05(t,2H),2.97-2.72(m,2H),2.62(t, 1H),2.07-1.83(m,2H),1.79-1.69(m,1H),1.56-1.41(m,1H),1.33(d,6H).

[0508] Example 14: Preparation of Compound 14

[0509] Step 1: Preparation of 14A

[0510] Compound 13A (0.12 g, 0.21 mmol) was dissolved in methanol (5 mL), and triphenylphosphine rhodium chloride (19.43 mg, 0.021 mmol) was added. The atmosphere was replaced with hydrogen three times, and the temperature was raised to 50°C with stirring and the reaction was allowed to proceed overnight. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0 to 3 / 1) to obtain compound 14A (40 mg, yield: 33%).

[0511] LCMS m / z=585.3[M+H] +

[0512] Step 2: Preparation of compound 14

[0513] Compound 14A (40 mg, 0.068 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL). Lithium hydroxide monohydrate (28.53 mg, 0.68 mmol) was added, and the mixture was stirred at 60°C for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a flash column (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to provide the trifluoroacetate salt of compound 14 (8 mg).

[0514] LCMS m / z=557.3[M+H] +

[0515] 1H NMR(400MHz,DMSO-d6)δ7.93(s,1H),7.54(d,2H),7.47(t,1H),7.29(d,2H),7.22-7.09(m,3H),4.48-4.28(m,1H),3.5 5-3.45(m,2H),3.24-2.82(m,7H),2.66(t,1H),2.18-1.82(m,6H),1.81-1.64(m,1H),1.59-1.41(m,1H),1.30(d,6H).

[0516] Example 15: Preparation of Compound 15

[0517] Step 1: Preparation of 15B

[0518] 15A (1.9 g, 5.86 mmol) (synthesis method, see WO2017181117) was dissolved in a 4 M HCl / 1,4-dioxane solution (10 mL) and stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and ethyl acetate and saturated sodium bicarbonate aqueous solution were added with stirring to separate the layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 15B (1 g).

[0519] LCMS m / z=223.9[M+H] +

[0520] Step 2: Preparation of 15C

[0521] 15B (1 g, 4.46 mmol) and isobutyraldehyde (0.64 g, 8.92 mmol) were dissolved in DCM (10 mL). Glacial acetic acid (1.07 g, 17.84 mmol) was added, and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (2.84 g, 13.38 mmol) was added, and the reaction was allowed to react at room temperature overnight. Ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0 to 5 / 1) to afford compound 15C (0.84 g, yield: 67%).

[0522] LCMS m / z=280.0[M+H] +

[0523] Step 3: Preparation of 15D

[0524] Compound 15C (0.84 g, 3.00 mmol) and pinacol diboron (1.52 g, 6 mmol) were dissolved in 1,4-dioxane (10 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.22 g, 0.30 mmol) and potassium acetate (0.88 g, 9 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the mixture was heated to 100°C and stirred overnight. After cooling to room temperature, the mixture was extracted with ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to obtain compound 15D (0.16 g, yield: 16%).

[0525] LCMS m / z=328.3[M+H] +

[0526] Step 4: Preparation of 15E

[0527] 5D (0.16 g, 0.30 mmol) and 15D (0.15 g, 0.45 mmol) were dissolved in toluene (3 mL), ethanol (3 mL), and water (1 mL). Tetrakistriphenylphosphine palladium (0.069 g, 0.060 mmol) and sodium carbonate (0.095 g, 0.90 mmol) were added. The atmosphere was replaced with nitrogen three times. Under nitrogen protection, the temperature was raised to 100°C and the mixture was stirred overnight. The mixture was cooled to room temperature and filtered through celite. The filtrate was added with ethyl acetate and water, stirred, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (v / v) = 1 / 0-5 / 1) to afford compound 15E (50 mg, yield: 28%).

[0528] LCMS m / z=583.3[M+H] +

[0529] Step 5: Preparation of 15F

[0530] Compound 15E (50 mg, 0.086 mmol) was dissolved in methanol (2 mL), and 10 mL of 6N hydrochloric acid and palladium on carbon (2.03 g, 1.90 mmol) were added. The atmosphere was replaced with hydrogen three times, and the reaction was allowed to proceed overnight under a hydrogen atmosphere (balloon pressure). The reaction solution was filtered through celite and washed three times with methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (v / v) = 1 / 0-10 / 1) to afford compound 15F (20 mg, yield: 39%).

[0531] LCMS m / z=585.3[M+H] +

[0532] Step 6: Preparation of compound 15

[0533] Compound 15F (20 mg, 0.034 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL). Lithium hydroxide monohydrate (15 mg, 0.36 mmol) was added and stirred at room temperature for 3 h. The pH of the reaction solution was adjusted to 3-4 with 1N aqueous hydrochloric acid. Ethyl acetate was added, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a reverse phase column (mobile phase: acetonitrile / 0.1% TFA water (v / v) = 0 / 100 to 50 / 50) to obtain compound 15 trifluoroacetate (3 mg).

[0534] LCMS m / z=557.1[M+H] +

[0535] Control compound 1:

[0536] Biological test cases

[0537] 1. CHO-KI / sGC cell cGMP detection experiment

[0538] Stably transfected CHO-K1 cells expressing sGCα1 / β1 heterodimers were constructed and designated CHO-KI / sGC. CHO-KI / sGC cells were cultured in complete culture medium (FK12 + 10% FBS + 1% double-stranded antibody + 0.5 mg / mL hygromycin + 0.25 mg / mL G418). On the day of assay, cells were reselected in EAB assay buffer (EBSS assay buffer + 5 mL MgCl2 + 10 mM HEPES + 0.05% BSA) at a cell density of 2.25 x 10 5 0.5 mM IBMX was added to prevent cGMP degradation.

[0539] After the cells were pre-incubated with 1 pM diethylenetriamine / nitric oxide (EDTA-NO) at room temperature for 30 minutes, different concentrations of compounds were added and incubated at 37°C for 1 hour. After the incubation, the reaction was terminated and the intracellular cGMP content was detected according to the instructions of the Cisbio kit (CisBio, 62GM2PEC). The maximum cGMP production relative to the positive compound was calculated according to formula (1), where RLU compound The reading for the test compound is RLU reference is the maximum reading for positive compounds.

[0540] Activation % = RLU compound / RUL reference *100% Formula (1)

[0541] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good stimulating effect on the cGMP production in CHO-KI / sGC cells.

[0542] 2. In vitro guanylate cyclase (sGC) enzyme activity assay

[0543] First, 100 nL of compound at various concentrations was transferred to a 384-well plate (Greiner, Cat. No. 784075) using an Echo655 (LABCYTE, Cat. No. 655). DMSO was added to a final reaction concentration of 1%. 2 μL of sGC (ICE, Cat. No. S2304F-H07SH2) was added to the plate and centrifuged at 1000 rpm for 1 minute. Then, 1 μL of DETA NONOate was added and incubated at 37°C for 10 minutes. Following incubation, 2 μL of GTP was added, the reaction was centrifuged at 1000 rpm for 1 minute, and the reaction was incubated at 37°C for 60 minutes. The final concentrations of sGC, GTP, and DETA NONOate in the reaction system were 1.5 nM, 5 μM, and 100 μM, respectively. After the reaction, 5 μL of detection mixture (PerkinElmer, Cat. No. 62GM2PEG) was added and incubated at room temperature for 60 min. The TR-FRET signal (Ratio: 665 / 620 nm) was read using a microplate reader (BMG, Cat. No. PHERAstar FSX). Nonlinear regression curve fitting was performed using GraphPad Prism software to calculate the EC 50 Compound A (Example 1 in WO2010065275) was used as the positive reference compound, and the activation rate calculation formula was shown in Formula 2-1, where the Low control was the TR-FRET signal value of 1 μM compound A, and the High control was the TR-FRET signal value of the DMSO well.

[0544] stimulation%=(ave High control-cpd well) / (ave High control-ave Low control)*100% Formula 2-1

[0545] Table 2-1 Results of enzymatic stimulation and / or activation of guanylate cyclase (sGC) by test compounds

[0546] Note: A<20nM, 20nM≤B<50nM, 50nM≤C<200nM

[0547] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good agonistic and / or activating effects on the activity of guanylate cyclase (sGC).

[0548] Test Example 3: Pharmacokinetic Test in Mice

[0549] Experimental purpose: This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, measured the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in mice.

[0550] Experimental animals: Male ICR mice, 20-35 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0551] Experimental Methods: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted overnight before administration, but not water. Food was resumed 4 hours after administration.

[0552] *Dosage is based on free form;

[0553] Sampling: Blood was collected from the eye socket at designated time points and placed in EDTAK2 centrifuge tubes. The tubes were centrifuged at 5000 rpm for 10 min to collect plasma.

[0554] Time points for plasma collection in G1 group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h;

[0555] Time points for plasma collection in G2 group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, and 24 h;

[0556] All samples were stored below -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0557] Table 3-1 PK data of test compound in mice

[0558] *Note: Compounds were administered ig (orally).

[0559] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in mice.

[0560] Test Example 4: Pharmacokinetic Test in Rat

[0561] Experimental animals: Male SD rats, 180-200 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0562] Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted overnight before administration, but not with water. Food was resumed 4 hours after administration.

[0563] Note: Intravenous administration solvent: 5% DMA + 5% HS-15 + 90% NS or 10% DMA + 10% HS-15 + 80% NS;

[0564] The vehicle for oral administration was: 5% DMSO + 5% Solutol + 10% PEG 400 + 80% (20% SBE-β-CD).

[0565] Blood was collected from the eye socket at designated time points and placed in EDTAK2 centrifuge tubes. The tubes were centrifuged at 5000 rpm for 10 min to collect plasma.

[0566] Blood was collected from the venous group at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours; from the oral gavage group at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours. All samples were stored below -60°C before analysis. Quantitative analysis was performed using LC-MS / MS.

[0567] Table 4-1 PK data of test compound in rats

[0568] *Note: Compounds were administered ig (orally).

[0569] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in rats.

[0570] 5. hERG potassium channel effect test

[0571] Experimental platform: electrophysiology manual patch clamp system

[0572] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0573] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0574] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0575] Inhibition%=[1-(I / Io)]×100%

[0576] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0577] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation:

[0578] Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope))

[0579] Among them, X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom

[0580] and Top are the minimum and maximum inhibition percentages, respectively.

[0581] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on hERG potassium ion channels.

[0582] 6.CYP450 enzyme inhibition test

[0583] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0584] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on CYP450 enzymes or have a weak inhibitory effect.

[0585] 7. Pharmacodynamic study on relaxation of thoracic aorta rings in SD rats

[0586] Eight-week-old, SPF-qualified male Sprague-Dawley rats were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. Upon arrival, they were acclimated for at least one week. Rats were weighed and randomly assigned to groups based on body weight before the experiment. On the day of the experiment, rats were deeply anesthetized with Zotai 50 (20 mg / kg, ip) and xylazine (8 mg / kg, ip). The thorax was then rapidly opened, and the aorta was carefully isolated. The descending aorta was then cut and placed in a culture dish containing saturated oxygen (95% O₂ + 5% CO₂) in KH₄ solution. Connective tissue on the vessel surface was removed, and vascular rings approximately 3–5 mm long were prepared. Using a custom-made hook, the rings were suspended in an isolated tissue perfusion bath containing 37°C constant-temperature KH₄ solution, saturated with oxygen, and connected to a tension transducer (JZ101H, Chengdu Instrument Factory). The tension transducer was then connected to a multi-channel electrophysiological signal recorder (RM6240E, Chengdu Instrument Factory). The vascular rings were rinsed with KH solution and allowed to equilibrate under a 3g basic tension for 90 minutes, after which 10 -6 The vascular rings were pre-contracted with 100 M of norepinephrine and allowed to reach a stable tension. The test compounds were then added sequentially to the bath in a concentration gradient from low to high to relax the rings. Each addition was separated by 5 minutes, and changes in the tension of the thoracic aorta rings were observed. The percentage of relaxation at each concentration was calculated.

[0587] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant dilating effect on rat thoracic aorta rings.

[0588] 8. Blood Pressure Telemetry in SHR Rats

[0589] Implantation of the telemeter blood pressure implant: The day before surgery, the DSI implant was disinfected (soaked in 2% glutaraldehyde solution for 8-10 hours); the animal was weighed and anesthetized with thiazine (8 mg / kg, ip.) + Zotai 50 (20 mg / kg, ip.); the animal was fasted the day before surgery; the implant was implanted on the first day of the experiment, and the procedure was as follows: the abdominal skin of the rat was sterile disinfected, a longitudinal incision was made, the abdominal organs were separated, the abdominal aorta was exposed, the blood pressure sensitive probe catheter of the implant was inserted into the abdominal aorta, and the implant was sealed with biological glue for hemostasis. The implant was then fixed to the abdominal wall, and the muscles and skin were sutured, disinfected, and meloxicam was administered subcutaneously for analgesia; the animal was placed in a constant temperature (37°C) incubator after surgery. After the animal was fully awake (autonomic movement was restored), it was returned to the cage and housed individually. Within 3 days after surgery, 4-8 mg / kg of gentamicin sulfate was injected subcutaneously every day for infection prevention, and meloxicam was injected subcutaneously for analgesia.

[0590] Blood Pressure Monitoring: Baseline blood pressure was measured for 24 hours approximately 10 days after postoperative recovery. Rats were grouped according to their baseline blood pressure and then administered medication. Blood pressure was monitored for 24 hours after a single oral dose. Changes in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate were recorded over a 24-hour period. The raw data were used to calculate the mean systolic blood pressure, mean diastolic blood pressure, mean arterial pressure, and mean heart rate over a defined time period (typically 30 minutes). A P value of less than 0.05 was considered statistically significant.

[0591] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant effect on lowering blood pressure in rats.

[0592] 9. Beagle Dog Pharmacokinetic Test

[0593] Test animals: Male beagle dogs, about 8-11 kg, 5-6 per compound.

[0594] Test method: On the test day, 5-6 beagle dogs were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0595] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0596] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.)

[0597] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 5000 rpm at 4°C for 10 minutes. Blood was collected from both the intravenous and oral gavage groups in the G1 and G2 groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0598] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

[0599] 10. Monkey Pharmacokinetic Test

[0600] Test animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound.

[0601] Test method: On the test day, 4-6 monkeys / compound were randomly divided into groups according to body weight. The monkeys were fasted for 14-18 hours before administration and fed 4 hours after administration.

[0602] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC.

[0603] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% methylcellulose aqueous solution.

[0604] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0605] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in monkeys.

[0606] 11. Mouse liver microsome stability test

[0607] At 37°C, 1 μM of the test compound was incubated with mouse liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the mouse liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0608] Conclusion: The compound of the present invention has good stability in mouse liver microsomes.

[0609] 12. Rat microsome stability test

[0610] At 37°C, 1 μM of the test compound was incubated with rat liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the rat liver microsome solution was calculated by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0611] Biological test results:

[0612] Conclusion: The compound of the present invention has good stability in rat liver microsomes. Compared with the control compound 1, its clearance rate in rat liver microsomes is significantly slowed down and its half-life is significantly prolonged.

[0613] 13. Monkey microsome stability test

[0614] At 37°C, 1 μM of the test compound was incubated with monkey liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the monkey liver microsome solution was calculated by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0615] Conclusion: The compounds of the present invention have good stability in monkey liver microsomes.

[0616] 14. Canine microsome stability test

[0617] At 37°C, 1 μM of the test compound was incubated with canine liver microsomes (0.5 mg / mL) supplemented with an NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the canine liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0618] Conclusion: The compounds of the present invention have good stability in canine liver microsomes.

[0619] 15. Human microsome stability test

[0620] At 37°C, 1 μM of the test compound was incubated with human liver microsomes (0.5 mg / mL) supplemented with NADPH regeneration system for 5, 10, 20, 30, and 60 minutes. The concentration of the test compound in the resulting samples was determined by LC-MS / MS. The half-life (T) of the compound in the human liver microsome solution was obtained by calculating the remaining percentage of the compound at each time point. 1 / 2 ) and intrinsic clearance (CL int(mic) ).

[0621] Conclusion: The compounds of the present invention have good stability in human liver microsomes.

[0622] 16.Caco2 permeability test

[0623] The experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (5μM) was added to the dosing port hole on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port hole. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS / MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficient for transport from the apical side to the basolateral side and from the basolateral side to the apical side of the monolayer cells, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

[0624] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Caco2 permeability.

[0625] 17. Rat toxicity experiment

[0626] Experimental Animals: 120 Sprague-Dawley rats were purchased, with a planned use of 106, half male and half female. Animals were 6-7 weeks old and weighed 180-220 g at the time of dosing, with individual weights within ±20% of the mean body weight. Rats were acclimated for at least 3 days prior to the experiment. The experiments were divided into vehicle control and compound dose-selective groups (each dose constituted a group). The main experimental group consisted of 10 rats per group (4 rats per group for the recovery period), and the TK group consisted of 6 rats per group, half male and half female.

[0627] Experimental process:

[0628] General clinical observation: Close observation was conducted 0-6 hours after administration on the day of administration, and at least twice a day (once in the morning and once in the afternoon) during the subsequent administration and recovery periods.

[0629] Body weight: Measure once before administration, and then weigh once on D4, D7, D11, and D14 during the administration period, and once during the recovery period.

[0630] Food intake: Measure twice during the dosing period and once during the recovery period. Measure the amount of feed given to each cage on day 1 and the remaining feed at approximately the same time on day 2. The difference between the two is the total food intake for each cage over 24 hours. Divide this by the number of animals per cage to obtain the total food intake for each animal over 24 hours.

[0631] Serum biochemical index detection:

[0632] Test animals: surviving animals in the main experiment;

[0633] Testing time: the day of autopsy at the end of drug administration and recovery period;

[0634] Blood collection method: Fast for at least 8 hours before blood collection. About 1.0 ml of blood is collected from the jugular vein without anticoagulation. The blood sample is centrifuged to obtain serum. Serum biochemical indicators are tested using a Roche Cobas C311 fully automatic biochemical analyzer. Specific test indicators are as follows:

[0635] Hematological index detection:

[0636] Test animals: surviving animals in the main experiment;

[0637] Testing time: the day of autopsy at the end of drug administration and recovery period;

[0638] Blood collection method: About 1.0 ml of blood was collected from the jugular vein and anticoagulated with EDTA-K2. Hematological parameters were tested using a Siemens ADVIA 2120i blood analyzer. Specific test indicators are as follows:

[0639] Toxicokinetic testing:

[0640] Animals in the TK satellite group underwent TK blood sampling on days 1 and 14 of the experiment;

[0641] The blood collection intervals were: before medication, and 0.25h, 0.5h, 1h, 2h, 4h, 8h, 24h, and 48h after medication (48h was the last medication for blood collection); the blood collection intervals for the HSK38966 BID medication group were: before medication, and 0.5h, 1h, 2h, 4h, 6.5h, 7h, 8h, 24h, and 48h after the first medication of the day (48h was the last medication for blood collection).

[0642] Sampling animals: All surviving TK animals in the drug administration group

[0643] Sampling site: jugular vein

[0644] Sampling volume: about 0.2mL

[0645] Anticoagulant: EDTA-K2

[0646] Blood sample processing: Whole blood samples were temporarily stored in an ice box before centrifugation, centrifuged at 2-8°C with a centrifugal force of approximately 1800×g for 10 minutes, and stored below -20°C until sent for testing.

[0647] Gross anatomy and organ weights:

[0648] All animals that died unexpectedly and were euthanized by the main experimental group were required to be autopsied.

[0649] When an animal is found dead, it can be stored in a refrigerator at 2-8°C and dissected as soon as possible within 24 hours.

[0650] Twenty-four hours after the last dose (D15), blood samples were collected from the jugular vein. The animals were anesthetized with 20% urethane and euthanized by exsanguination from the abdominal aorta. A gross necropsy was performed. Gross observations were performed during the necropsy, including but not limited to the presence of abnormalities in the animal's body surface, body orifices, cranial cavity, thoracic cavity, abdominal cavity, pelvic cavity, and their contents. If abnormalities were found, the location, color, shape, and size of the abnormal tissue or organ were recorded promptly.

[0651] During autopsy, the required organ weights were recorded, and the organ / body weight coefficient and organ / brain weight coefficient were calculated.

[0652] Histopathological examination:

[0653] The following tissues and / or organs were collected during autopsy and fixed with 10% formalin solution (Davidson's fixative was used for testis / epididymis) and histopathological examination was performed if necessary.

[0654] Statistical methods:

[0655] Statistics were performed using SPSS 23. Means and standard deviations were calculated for body weight, hematological parameters, serum biochemical parameters, organ weights, and coefficients for each group, and statistical analysis was performed according to the following methods: ① Levene's test was used to test for homogeneity of variance. If the variances were homogeneous (P>0.05), one-way analysis of variance (ANOVA) was performed. If the variances were unequal (P≤0.05), Dunnett's t3 test was used for inter-group comparisons (at the 0.05 and 0.01 levels). ② If the ANOVA results showed statistical differences (P≤0.05), Dunnett's t test was used for inter-group comparisons (at the 0.05 and 0.01 levels). If the ANOVA results showed no statistical differences (P>0.05), statistical analysis was terminated.

[0656] Experimental records and preservation:

[0657] Test plan, animal grouping record form, test sample receipt record form, test sample preparation record form, animal weight and drug administration operation record form, animal daily observation record form, organ weighing record form, and experimental animal dissection record form.

[0658] Conclusion: The compound of the present invention has good safety in rats at the set dosage.

[0659] 18. Assessment of renal function by analyzing proteinuria (urine protein to creatine ratio, uPCR) in female rats

[0660] RenTG / L-NAME-supplemented female rats were treated with placebo (set as 100%) or compound, and the urine protein to creatinine ratio of the rats was detected and calculated.

[0661] Conclusion: The compounds of the present invention can reduce proteinuria in RenTG / L-NAME-supplemented female rats.

[0662] 19.CYP3A4 induction activity test (PXR activation)

[0663] Objective: The purpose of this study was to evaluate the potential of test compounds to induce the activity of drug-metabolizing enzymes by activating PXR in vitro.

[0664] 1. Cell seeding

[0665] 1) DPX2 cells were cultured in growth medium containing 10% fetal bovine serum.

[0666] 2) DPX2 cells were cultured in a T-75 culture flask in an incubator at 37°C, 5% CO2, and 95% relative humidity. The cells were digested when they covered 80-90% of the bottom of the culture flask.

[0667] 3) Wash the surface of the T-75 cultured cells with 10 mL of PBS, aspirate the PBS, add 3-5 mL of trypsin, and digest at 37°C for 5 minutes or until the cells are digested and suspended. Add an excess of culture medium containing fetal bovine serum to terminate the trypsin digestion.

[0668] 4) Transfer the cell suspension to a conical-bottom centrifuge tube and centrifuge at 150g for 5 minutes at room temperature. Carefully aspirate the supernatant and resuspend the cells in treatment medium to a concentration of 3.2 × 105 cells / mL (incubation time: 24 hours, seeding density: 4.0 × 105 cells / mL). Add 25 μL of the cell suspension to each well of a 384-well cell culture plate. Incubate the plate in an incubator at 95% humidity, 37°C, and 5% CO2 for 24 hours.

[0669] 2. Compound preparation

[0670] 1) Prepare 1000× stock solutions of the test compound, positive control (rifampicin), and negative control (propranolol) in DMSO. The final concentrations of the positive control (rifampicin) are 1 μM and 10 μM, and the final concentration of the negative control (propranolol) is 10 μM. The final concentrations of the test compound are 10, 1, 0.1 μM, or the EC50 (30, 10, 3, 1, 0.3, 0.1 μM). The final DMSO concentration is 0.1%.

[0671] 2) Remove the cell culture plate from the incubator and directly add 25 nL of the positive or negative control drug or test compound stock solution using an Echo. Set up three replicates for each concentration. Return the cell plate to the incubator and continue incubation for 48 hours (24 hours).

[0672] 3) Before beginning experiments with the substrate, inspect cell morphology and monolayer integrity to ensure the monolayer is of acceptable quality for your studies.

[0673] 3. Quantitative detection of PXR activation

[0674] 1) 48 hours after drug treatment (24 hours), cultures can be used for quantitative detection of PXR activation.

[0675] 2) CellTiter-Fluor TM Equilibrate the Cell Viability Assay Kit and One-Glo Luciferase Reagent to room temperature. Add GF-AFC Substrate (10 μL) to Assay Buffer (10 ml) to create a 2X reagent, which is then diluted with 10 ml of PBS to a 1X reagent. Add ONE-Glo Luciferase Substrate to ONE-Glo Luciferase Assay Buffer.

[0676] 3) Take out the culture plate from the incubator, discard the culture medium, and add 1X CellTiter-Fluor TM The reagent was poured into the sample tank, and 25 μL of the reagent was added to each well of the culture plate using a pipetting workstation, and then placed in the incubator for incubation for 30 minutes.

[0677] 4) Remove the cell culture plate from the incubator, cool it slightly to room temperature, and measure the fluorescence value using an automatic quantitative microplate reader with an excitation wavelength of 400 nm and an emission wavelength of 505 nm.

[0678] 5) Pour ONE-Glo reagent into the sample reservoir, add 25 μL to each well, gently mix the plate, incubate at room temperature for 5 minutes, and measure the luminescence value.

[0679] 4. Data Analysis

[0680] All data were calculated using Microsoft Excel.

[0681] 1) Luciferase activity is expressed as RFU / RLU, where RLU is the average luminescence intensity of three replicates of each compound at each concentration, and RFU is the average fluorescence intensity of three replicates of each compound at each concentration.

[0682] The activation fold of mRNA was calculated using the following formula:

[0683] Fold activation=(RLU test / RFU test) / (RLUvehicle / RFUvehicle)

[0684] 2) The cell viability percentage of the compound was calculated according to the following formula:

[0685] Cell Viability%=(RFUtest / RFUvehicle)×100

[0686] 3) The percentage relative to the positive control drug is calculated according to the following formula:

[0687] Percent of positive control (%) = (Fold activation test / Fold activationPositive control) × 100

[0688] Conclusion: The compounds of the present invention have no obvious induction effect on CYP3A4.

[0689] 20.CYP3A4 induction activity test (enzyme activity and mRNA)

[0690] The purpose of this research project is to evaluate the effects of the test substances on the enzyme activities and gene expression levels of cytochrome P450 isozymes CYP1A2, CYP2B6 and CYP3A4 by in vitro hepatocyte induction experiments.

[0691] Cryopreserved human hepatocytes from three donors were incubated with the test compound at varying concentrations (≥5 concentration points) at 37°C for 48 hours, with fresh culture medium replaced every 24 hours. Lactate dehydrogenase release was measured in the culture medium after 24 and 48 hours of incubation to assess potential cytotoxic effects of the test compound. The concentration of the test compound in the culture medium was measured at 0, 5, and 24 hours after the second dose to assess the concentration of the parent drug in the culture medium of the human hepatocytes. After incubation of the cryopreserved human hepatocytes from the three donors with the test compound for 48 hours, the culture medium was removed, and the cells were washed with Hank's balanced salt solution (HBSS) preheated to 37°C. The enzyme-specific substrate was then added and incubated at 37°C for 30 minutes. Liquid chromatography-tandem mass spectrometry was used to quantify the amount of metabolites produced by each substrate. Real-time quantitative PCR was used to assess gene expression levels in the cells.

[0692] Conclusion: The compounds of the present invention have no obvious induction effect on CYP3A4.

[0693] 21. P-gp transporter inhibition test

[0694] This project uses the MDR1-MDCKⅡ monolayer cell model to evaluate the inhibitory effect of the test substance on the activity of P-glycoprotein transporter.

[0695] In the experiment, MDR1-MDCKⅡ cells were seeded into 96-well cell plates and cultured for 7 consecutive days before being used for transport experiments. Digoxin (a known P-gp substrate) was administered bidirectionally in the presence and absence of the test substance and incubated with different concentrations (0-30μM) of the test substance. After incubation for 150 minutes, the receiving end samples were collected and the digoxin content in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). By calculating the efflux ratio (ER) of digoxin in the presence and absence of the test substance, the percentage of P-gp transport activity of MDR1-MDCKⅡ cells under the action of different test concentrations of the test substance (%VC (Vehicle Control, solvent control), the percentage of P-gp transport activity in the presence and absence of the test substance) was obtained, and the half-maximal inhibitory concentration (IC50) was calculated from this. 50 ).

[0696] Conclusion: The compounds of the present invention have no obvious inhibitory effect on P-gp transporter.

[0697] 22. BCRP transporter inhibition

[0698] The purpose of this study was to evaluate the inhibitory effect of the test compounds on the activity of breast cancer resistance protein transporter using the Caco-2 monolayer cell model.

[0699] In the experiment, Caco-2 cells were seeded into 96-well cell plates and cultured for 22 days before being used for transport experiments. 5.00 μM estrone 3-sulfate (a BCRP substrate) was administered bidirectionally with or without the test substance. The cells were incubated with different concentrations (0-30 μM) of the test substance. After 120 minutes of incubation, the receiving end samples were collected and the content of estrone 3-sulfate in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). By calculating the efflux ratio (ER) of estrone 3-sulfate with and without the test substance, the percentage of BCRP transport activity of Caco-2 cells under the action of different test concentrations of the test substance (%VC (Vehicle Control, solvent control), the percentage of BCRP transport activity with and without the test substance) was obtained, and the half-maximal inhibitory concentration (IC) was calculated from this. 50 ).

[0700] Conclusion: The compounds of the present invention have no significant inhibitory effect on BCRP transporter.

[0701] 23. SLC transporter inhibition

[0702] The aim of this study was to evaluate the inhibitory effects of test substances on the activities of the transporters OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1, and MATE2-K.

[0703] HEK293-OATP1B1, OATP1B3, OAT1, OAT3, OCT, MATE1, and MATE2-K cells were incubated with and without the analyte (0-30 μM) for the corresponding time, and samples were collected. The substrate content in the samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The transport activity of the transporter in the presence and absence of the analyte was calculated to obtain the percentage of transporter activity of the transporter cells under the action of different concentrations of the analyte (% VC (Vehicle Control, solvent control), the percentage of transporter activity in the presence and absence of the analyte), and the half-maximal inhibitory concentration (IC) was calculated from this. 50 ).

[0704] Conclusion: The compounds of the present invention have no obvious inhibitory effect on SLC transporters.

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein: X1 from CR 1 or N, X2 is selected from CR 2 or N, X3 selected from CR 3 or N, X4 selected from CR 4 or N, X5 selected from CR 5 or N, X6 selected from CR 6 or N, X7 is selected from CR 7 or N, X8 selected from CR 8 or N; Selected from C 3-12 A carbocyclic group or a 4- to 12-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R a replace; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b1 , R b2 , R c Each independently selected from H, deuterium, halogen, OH, CN, NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 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 R k replace; or R 7 With R a Together with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring 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; n is selected from 0, 1, 2, 3, 4; The condition is, 1) R 2 Not Cl, CF3; or 2) at least one of X1, X2, X3, X4, X5, and X8 is selected from N; or 3) R 1 , R 3 , R 4 At least one of them is not H; or 4) Not selected from m is selected from 0, 1, 2, 3, 4; or 5) R 7 With R a Together with the atoms to which it is attached, it forms a 4-8 membered carbocyclic ring or a 4-8 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; or 6) when R b1 Selected from CHF2, R b2 Selected from H, Selected from R c are each independently selected from H or halogen, Selected from m is selected from 0, 1, 2, 3, 4, X1 is selected from CH, X3 is selected from CH, X4 is selected from CH, X2 is selected from CR 2 , R 2 is selected from Cl or CF3, X6 or X7 is selected from CH, CF or N, and X5 is selected from CR 5 , X8 is selected from CR 8 When R 5 or R 8 At least one of them is not H or C 1-4 alkyl; or 7) when Selected from When R a Not for C 1-4 Alkylcarbonyl or optionally substituted C 3-6 Cycloalkyl.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Selected from 1 to 4 R a Substituted with the following groups: C 3-6 Monocyclic alkyl, C 3-6 Monocyclic alkenyl, C 5-11 Spirocycloalkyl, C 4-10 Cycloalkyl, C 5-10 bridged cycloalkyl, 4- to 6-membered monocyclic heterocycloalkyl, 4- to 6-membered monocyclic heterocycloalkenyl, C 5-11 Spiroheterocycloalkyl, C 4-10 Heterocycloalkyl or C 5-10 Bridged heterocycloalkyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b1 , R b2 , R c 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 7 With R a Together with the atoms to which it is attached, it forms a 4-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 carbocyclic group, -O-3 to 6 membered heterocyclic group, -NH-C 3-6 carbocyclic group, -NH-3 to 6-membered heterocyclic group, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-3 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2, or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, Selected from 1 to 4 R a Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, azetidinyl, pyrrolidinyl, piperidinyl, azocyclohexenyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, s1, s2, s3, s4, s5 are each independently selected from 0 or 1; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b1 , R b2 , R c Each independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, or optionally 1 to 4 R k Substituted groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, isopropoxy, vinyl, ethynyl, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, phenyl; or R 7 With R a Together with the atoms to which it is attached, it forms a 5-6-membered carbocyclic ring or a 5-6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, phenyl is optionally substituted by 1 to 4 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.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, Selected from 1 to 4 R a Substituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or R 7 With R a Together with the atoms to which it is attached, it forms a 5-6 membered heterocyclic group.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (II-a), (II-b), (II-c), (II-d), (II-e), (II-f), (II-g), (II-h) or (II-i), R 2a is selected from H, deuterium, F, Br, CHF2, methyl, ethyl, isopropyl, cyclopropyl; X 1a Select from N or CR 1a ; X 3a Select from N or CR 3a ; X 4a Select from N or CR 4a ; R 1a , R 3a or R 4a Each is independently selected from deuterium, F, Cl, Br, CHF2, methyl, ethyl, isopropyl, cyclopropyl; Selected from 1 to 4 R a Substituted with the following groups: R a is selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, -CH2-cyclopropyl; R a1 is selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, NHCH3, methyl, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl; R 8a Selected from deuterium, F, Br, CF3, CHF2, cyclopropyl; Selected from The remaining definitions are the same as those in claim 4.

6. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-1.

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

8. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating a disease associated with sGC.

9. The use according to claim 8, wherein the disease is selected from cardiovascular disease, kidney disease or respiratory disease, preferably pulmonary hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, chronic kidney disease or non-proliferative diabetic retinopathy.

10. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 7, the therapeutically effective amount preferably being 0.01-1500 mg, and the disease preferably being a cardiovascular disease, a kidney disease or a respiratory disease.

Images