Pyrrolo[2,3-d]pyrimidine-4-amine derivatives and their pharmaceutical applications

Abstract

Pyrrolo[2,3-d]pyrimidine-4-amine derivatives and their pharmaceutical applications, specifically the compound shown in formula (I) or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and their applications in the manufacture of pharmaceuticals for treating diseases associated with sGC. [C1] TIFF2026521484000125.tif37156

Description

[Technical Field]

[0001] The present invention belongs to the pharmaceutical field and specifically concerns the compound shown in formula (I) or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and its application in the manufacture of pharmaceuticals for treating diseases related to sGC. [Background technology]

[0002] Nitric oxide (NO) signaling has diverse biological functions and plays a crucial role in cardiovascular steady state. NO secretion increases under the influence of mediators such as norepinephrine (NA), angiotensin, adenosine triphosphate, or bradykinin. NO synthesis is also influenced by numerous physical stimuli (Int.J.Mol.Sci.2021,22,6029, Molecules 2021,26,3418).

[0003] The intracellular mechanism of action of NO is primarily by stimulating the activity of soluble guanylate cyclase (sGC). sGC is a heme-containing enzyme that can increase the levels of cyclic 3'-5'-guanosine monophosphate (cGMP) in smooth muscle, leading to vasodilation (Nat. Rev. Cardiol. 2018, 15, 292-316). The NO / sGC / cGMP regulatory pathway plays a crucial role in the steady state of the cardiovascular and respiratory systems and organs (e.g., kidneys, brain, and liver). In addition to smooth muscle cells, cGMP further influences the function of fibroblasts, cardiomyocytes, platelets, neurons, and immune cells, regulating fibrosis, inflammatory responses, and neurotransmission processes (Molecules 2023, 28, 861).

[0004] sGC modulators and sGC agonists are a class of drugs that can stimulate cGMP formation, and such drugs provide tools for studying their effects in sGC regulatory mechanisms and pathological mechanisms. Research and development of sGC modulators or agonists has made it possible to develop drugs that directly target diseased blood vessels, myocardium, kidneys, and other organs (Molecules 2023, 28, 861). Riociguat was the first sGC agonist to be launched, and in 2013, Riociguat received approval for two indications: pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (TEPH) (J.Med.Chem. 2017, 60, 5146-5161). In a 12-week, multicenter, double-blind, randomized, placebo-controlled, importance patent-1 study, the most common (≧3%) adverse events (AEs) in the riociguat treatment group compared to placebo were headache (27% vs. 18%), dyspepsia / gastritis (21% vs. 8%), dizziness (20% vs. 13%), nausea (14% vs. 11%), diarrhea (12% vs. 8%), hypotension (10% vs. 4%), vomiting (10% vs. 7%), anemia (7% vs. 2%), gastroesophageal reflux disease (5% vs. 2%), and constipation (5% vs. 1%). Research and development of novel sGC modulators or agonists to improve therapeutic efficacy or reduce toxic side effects has promising application prospects. [Overview of the project] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide a compound described by general formula (I) having a novel structure, or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates thereof, as well as methods for producing them, and applications in the production of pharmaceuticals for treating diseases related to sGC.

[0006] The compound of the present invention has a good stimulating effect on the cGMP production of LNCap cells and exhibits good pulmonary pharmacokinetic performance, for example, pulmonary AUC and / or ventilation-perfusion ratio are superior to control 1, and it has advantages in pulmonary targeting and reduction of systemic side effects. [Means for solving the problem]

[0007] The present invention provides compounds represented by general formula (I) or their stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals. [ka] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (II), [ka] In some embodiments, the compound represented by general formula (I) or (II) is selected from the compounds represented by general formula (III-1) or (III-2), [ka] In some embodiments, R is [ka] Selected from, In some embodiments, R is [ka] Selected from, In some embodiments, Z is selected from CH or N. In some embodiments, Z1 or Z2 are independently selected from CH or N, and at least one of Z1 and Z2 is selected from N. In some embodiments, X1 or X2 are independently selected from O or S. In some embodiments, A is C 3-12 Selected from a carbocyclic group or a 4- to 12-membered heterocyclic group, In some embodiments, A is C 3-11 Cycloalkyl groups, 4-11 member heterocycloalkyl groups, C 6-10Selected from an aryl group or a 5- to 10-member heteroaryl group, In some embodiments, A is C 3-6 Selected from a cycloalkyl group, a 4- to 6-member heterocycloalkyl group, C 6-10 Selected from an aryl group or a 5- to 10-member heteroaryl group, In some embodiments, A is optionally substituted with 1 to 4 R a Selected from the group consisting of a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an oxetanyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a phenyl group, a pyrrolyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, and a pyridazinyl group; In some embodiments, A is optionally substituted with 1 to 4 R a Selected from a phenyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, and a pyridazinyl group; In some embodiments, R 1 is selected from -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s -COOH; In some embodiments, R 1 is

Chemical formula

[0008] As a first embodiment of the present invention, a compound represented by the above-described general formula (I) or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, R is [ka] Selected from, Z is selected from CH or N. Z1 or Z2 is independently selected from CH or N, and at least one of Z1 and Z2 is selected from N. X1 or X2 is independently selected from O or S. A is C 3-12Selected from a carbocyclic group or a 4- to 12-membered heterocyclic group, R 1 is, -M-(CR 1a R 1b ) r -(CR 1c R 1d ) s - Selected from COOH, M is bond, C 3-12 Selected from a carbocyclic group or a 4- to 12-membered heterocyclic group, the carbocyclic group or heterocyclic group optionally has 1 to 4 R m Replaced by, R 2 C 1-6 Alkyl alkyl group or -C 1-6 Selected from alkylene-Q, the alkyl group or alkylene group optionally comprises 1 to 10 R groups. k Replaced by, Q is C 3-12 Selected from a carbocyclic group or a 4- to 12-membered heterocyclic group, the carbocyclic group or heterocyclic group optionally has 1 to 4 R q Replaced by, R a , R c , R m , R q , R b3 , R 1a , R 1b , R 1c , R 1d These are H, deuterium, halogen, OH, CN, NH2, and C, respectively, independently. 1-6 Alkyl alkyl groups, OC 1-6 Alkyl, SC 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,-OC 3-6 Carbon ring group, -O-3~7 membered heterocyclic group, -NH-C 3-6 Carbon ring group, -NH-3~7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 carbocyclic group, -C 0-4Selected from alkylene-3 to 7-membered heterocyclic groups, the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group optionally contains 1 to 4 R k Replaced by, or R 1a and R 1b or R 1c and R 1d Each of them, along with the carbon atoms linked to them, is C 3-12 A carbocyclic group or a 4-12 membered heterocyclic group is formed, and the carbocyclic group or heterocyclic group optionally has 1-4 R k Replaced by, R b1 , R b2 , R b4 These are H, deuterium, OH, CN, NH2, and C, respectively, independently. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,-NH-C 3-6 Carbon ring group, -NH-3~7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 carbocyclic group, -C 0-4 Selected from alkylene-3 to 7-membered heterocyclic groups, the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group optionally contains 1 to 4 R k Replaced by, R k These are H, deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, and C, respectively, independently. 1-6 Alkyl alkyl groups, OC 1-6 Alkyl, SC 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,-OC 3-6 Carbon ring group, -O-3~7 membered heterocyclic group, -NH-C 3-6 Carbon ring group, -NH-3~7 membered heterocyclic group, -C 0-4 Alkylene-C 3-6 carbocyclic group, -C 0-4The alkylene group is selected from 3- to 7-membered heterocyclic groups, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally be deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl alkyl group, C 1-6 Substituted with 1 to 4 substituents selected from alkoxy groups, a, c, r, and s are each independently selected from 0, 1, 2, 3, and 4.

[0009] As a second embodiment of the present invention, a compound represented by the above-described general formula (I) or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, A is C 3-11 Cycloalkyl groups, 4-11 member heterocycloalkyl groups, C 6-10 Selected from an aryl group or a 5-10 membered heteroaryl group, M is bond, C 3-11 Cycloalkyl groups, 4-11 member heterocycloalkyl groups, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group optionally have 1-4 R m Replaced by, R 2 C 1-5 Alkyl alkyl group or -C 1-4 Selected from alkylene-Q, the alkyl group or alkylene group optionally comprises 1 to 8 R groups. k Replaced by, Q is C 3-11 Cycloalkyl groups, 4-11 member heterocycloalkyl groups, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group optionally have 1-4 R q Replaced by, R a , R c , R m , R q , R b3 , R 1a , R1b , R 1c , R 1d These are H, deuterium, halogen, OH, CN, NH2, and C, respectively, independently. 1-4 Alkyl alkyl groups, OC 1-4 Alkyl, SC 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2,-OC 3-6 Carbon ring group, -O-3~6 membered heterocyclic group, -NH-C 3-6 Carbon ring group, -NH-3~6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 carbocyclic group, -C 0-2 Selected from alkylene-3 to 6-membered heterocyclic groups, the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group optionally contains 1 to 4 R k Replaced by, or R 1a and R 1b or R 1c and R 1d Each of them, along with the carbon atoms linked to them, is C 3-11 A cycloalkyl group or a 4-11 member heterocycloalkyl group is formed, and the cycloalkyl group or heterocycloalkyl group optionally has 1-4 R k Replaced by, R b1 , R b2 , R b4 These are H, deuterium, OH, CN, NH2, and C, respectively, independently. 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2,-NH-C 3-6 Carbon ring group, -NH-3~6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 carbocyclic group, -C 0-2 Selected from alkylene-3 to 6-membered heterocyclic groups, the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group optionally contains 1 to 4 Rk Replaced by, R k These are H, deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, and C, respectively, independently. 1-4 Alkyl alkyl groups, OC 1-4 Alkyl, SC 1-4 Alkyl alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2,-OC 3-6 Carbon ring group, -O-3~6 membered heterocyclic group, -NH-C 3-6 Carbon ring group, -NH-3~6 membered heterocyclic group, -C 0-2 Alkylene-C 3-6 carbocyclic group, -C 0-2 The alkylene group is selected from 3- to 6-membered heterocyclic groups, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group can be optionally deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl alkyl group, C 1-4 Substituted with 1 to 4 substituents selected from alkoxy groups, Other definitions are the same as those in the first embodiment of the present invention.

[0010] A third embodiment of the present invention is a compound represented by the general formula (I) described above, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, A is C 3-6 Cycloalkyl groups, 4-6 member heterocycloalkyl groups, C 6-10 Selected from an aryl group or a 5-10 membered heteroaryl group, M is bond, C 3-6 Cycloalkyl groups, 4-6 member heterocycloalkyl groups, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group optionally have 1-4 R m Replaced by, R 2 C 1-4 Alkyl alkyl group or -C1-3 Selected from alkylene-Q, the alkyl group or alkylene group optionally comprises 1 to 6 R groups. k Replaced by, Q is C 3-6 Cycloalkyl groups, 4-6 member heterocycloalkyl groups, C 6-10 Selected from aryl groups or 5-10 membered heteroaryl groups, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group optionally have 1-4 R q Replaced by, R a , R c , R m , R q , R b3 , R 1a , R 1b , R 1c , R 1d Each of these is independently H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k The group substituted with is selected from the following groups: methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, vinyl group, ethinyl group, methylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, and phenyl group. or R 1a and R 1b or R 1c and R 1d Each of them, along with the carbon atoms linked to them, is C 3-7 A cycloalkyl group or a 4-7 membered heterocycloalkyl group is formed, and the cycloalkyl group or heterocycloalkyl group optionally has 1-4 R k Replaced by, R b1 , R b2 , R b4 Each of these independently consists of H, deuterium, OH, CN, NH2, or optionally 1 to 4 R kThe group selected from the following substituted groups is a methyl group, ethyl group, propyl group, isopropyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, and phenyl group. R k These are, independently, deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, methylthio group, vinyl group, ethinyl group, propynyl group, propargyl group, cyclopropyl group, cyclobutyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, pyrazolyl group, pyrrolyl group, morphol The group is selected from the yl group and the phenyl group, and the methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, methylthio group, vinyl group, ethinyl group, propynyl group, propargyl group, cyclopropyl group, cyclobutyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, pyrazolyl group, pyrrolyl group, morpholinyl group, and phenyl group may optionally be deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl alkyl group, C 1-4 Substituted with 1 to 4 substituents selected from alkoxy groups, Other definitions are the same as those in the first or second embodiment of the present invention.

[0011] A fourth embodiment of the present invention is a compound represented by the general formula (I) described above, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, A can choose 1 to 4 R aThe group selected from the following substituted groups is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, phenyl group, pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. M is bonded, or optionally 1 to 4 R m The group selected from the following substituted groups is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, phenyl group, pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. R 2 The group is selected from methyl, ethyl, propyl, butyl, methylene-Q, ethylene-Q, and propylene-Q, and the methyl, ethyl, propyl, butyl, methylene, ethylene, and propylene groups can optionally contain 1 to 6 R groups. k Replaced by, Q is an optional selection of 1 to 4 R's. q The group selected from the following substituted groups is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, phenyl group, pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. R a , R c , R m , R q , R b3 , R 1a , R 1b , R1c , R 1d Each of these is independently H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, or optionally 1 to 4 R k Selected from substituted methyl, ethyl, methoxy, and cyclopropyl groups, or R 1a and R 1b or R 1c and R 1d Each of these, along with the carbon atoms linked to them, optionally contains 1 to 4 R atoms. k Substituted with the following groups, they form the following groups: cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, tetrahydrofuranyl group, and tetrahydropyranyl group. R b1 , R b2 , R b4 Each of these independently consists of H, deuterium, OH, CN, NH2, or optionally 1 to 4 R k Selected from substituted methyl, ethyl, methoxy, and cyclopropyl groups, R k Each is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, methylthio group, vinyl group, ethinyl group, propynyl group, propargyl group, cyclopropyl group, cyclobutyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, pyrazolyl group, pyrrolyl group, morpholinyl group, and phenyl group, and the methyl The groups, ethyl groups, propyl groups, isopropyl groups, methoxy groups, ethoxy groups, methylthio groups, vinyl groups, ethynyl groups, propynyl groups, propargyl groups, cyclopropyl groups, cyclobutyl groups, azetidinyl groups, oxetanyl groups, pyrrolidinyl groups, piperidinyl groups, pyrazolyl groups, pyrrolyl groups, morpholinyl groups, and phenyl groups are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, methyl groups, ethyl groups, methoxy groups, and ethoxy groups. Other definitions are the same as those in the first, second or third embodiment of the present invention.

[0012] As a fifth embodiment of the present invention, it is a compound represented by the aforementioned general formula (I) or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, A is optionally a phenyl group, thiazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group which is substituted with 1 to 4 R a and is selected from the groups of phenyl group, thiazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0013] A sixth embodiment of the present invention is a compound represented by the above-described general formula (I) or its stereoisomer, tautomer, deuteride, 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), [ka] A is selected from the following groups: phenyl group, thiazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. R is [ka] Selected from, R 2 teeth, [ka] Selected from, R a , R c Each of these is independently selected from H, deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, CF3, CHF2, CH2F, methyl group, ethyl group, methoxy group, and cyclopropyl group. a and c are each independently selected from 0, 1, or 2.

[0014] As a seventh embodiment of the present invention, a compound represented by the above-described general formula (I) or (II), or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) or (II) is selected from the compounds represented by general formula (III-1) or (III-2), [ka] Other definitions are the same as those corresponding to any one of the first to sixth embodiments of the present invention.

[0015] The present invention relates to the following compounds or their stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from one of the structures in Table E-1 below.

[0016] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] ​​​​​​​​​​​ [Table 1-16] [Table 1-17] [Table 1-18] [Table 1-19] [Table 1-20] [Table 1-21] [Table 1-22] [Table 1-23] [Table 1-24] [Table 1-25] [Table 1-26] [Table 1-27] [Table 1-28]

[0017] The present invention relates to pharmaceutical compositions, which include the above-mentioned compounds or their stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and pharmaceutically acceptable carriers.

[0018] The present invention relates to the application of the above compound or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the above pharmaceutical composition, in the manufacture of pharmaceuticals for treating diseases related to sGC.

[0019] The present invention relates to the application of the above compound or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or pharmaceutical compositions, in the manufacture of pharmaceuticals for the treatment of cardiovascular diseases, kidney diseases, or respiratory diseases, wherein the diseases are preferably pulmonary arterial hypertension, pulmonary hypertension, or chronic obstructive pulmonary disease.

[0020] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises a therapeutically effective amount of the compound described in the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and pharmaceutical excipients. The pharmaceutical composition may be in the form of a unit formulation (the amount of the active ingredient in the unit formulation is also called the "formulation specification").

[0021] The present invention further provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound described in the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal described in the present invention includes a human.

[0022] The “effective dose” or “therapeutic effective dose” as used in this application refers to administering a sufficient amount of the compound disclosed herein that, to some extent, alleviates one or more symptoms of the disease or condition being treated (e.g., cardiovascular disease). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desirable change in the biological system. For example, an “effective dose” for therapeutic use is the amount of the compound disclosed herein that is necessary to provide a clinically significant reduction in disease symptoms. Examples of therapeutic effective doses include 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.It contains 1-5 mg, but is not limited to those. In some embodiments, the pharmaceutical composition is available in doses of 0.01-1500 mg, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.3 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, and 7 This includes, but is not limited to, 5 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, and 300 mg of the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

[0023] A method for treating a disease in a mammal, comprising administering a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal to a subject, wherein the therapeutically effective amount is preferably 0.01 to 1500 mg, and the disease is preferably a cardiovascular disease.

[0024] A method for treating a disease in a mammal, comprising administering to a subject a daily dose of 0.01 to 1500 mg / day of the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein the daily dose may be a single dose or a divided dose, and in some embodiments, the daily dose is 0.01 to 1500 mg / day, 10 to 1500 mg / day, 10 to 1000 mg / day, 10 to 800 mg / day, 25 to 800 mg / day, 50 to 800 mg / day, 100 to 800 mg / day, 200 to 800 mg / day The daily dose includes, but is not limited to, mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, and 200-400 mg / day. In some embodiments, the daily dose includes, but is not limited to, 0.01 mg / day, 0.05 mg / day, 0.1 mg / day, 0.15 mg / day, 0.2 mg / day, 0.3 mg / day, 0.5 mg / day, 1 mg / day, 2 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, and 800 mg / day.

[0025] The present invention relates to a kit, which may include a single-dose or multi-dose composition, which includes the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein the amount of the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals is the same as the amount in the pharmaceutical composition.

[0026] In the present invention, the amounts of the compound of the present invention or its stereoisomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals are, in each case, calculated in terms of free base form.

[0027] "Formulation specifications" refer to the weight of the active ingredient contained in one unit formulation, one tablet formulation, or any other unit formulation.

[0028] Synthesis method 1: [ka] R d-11 Each of them is independent of C 1-6 Selected from alkyl groups, R d-12 It is selected from halogens, preferably selected from I and Br. The definitions of other bases are consistent with those described in the specification of this invention. Compound (D-1-3) is obtained by an addition reaction between a compound of general formula (D-1-1) and a compound of general formula (D-1-2). A compound of general formula (D-1-3) and a compound of general formula (D-1-4) are cyclized to obtain a compound of general formula (D-1-5). Compound (D-1-5) is subjected to hydrolysis to obtain compound (I).

[0029] Unless otherwise stated, the terms used in the specification and claims of this application have the following meanings:

[0030] The carbon, hydrogen, oxygen, sulfur, nitrogen, or F, Cl, Br, I related to the groups and compounds described in the present invention all include their isotopic states, and the carbon, hydrogen, oxygen, sulfur, or nitrogen related to the groups and compounds described in the present invention can be optionally replaced with one or more corresponding isotopes, where the isotope of carbon is, 12 C and, 13 C and, 14 It contains C, and its isotopes include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called tritium), and its isotopes include 16 O and, 17 O and, 18 It contains O, and the sulfur isotopes are 32 S and, 33 S and, 34 S and, 36 It contains S, and the nitrogen isotope is, 14 N and 15 It contains N, and the isotopes of fluorine are 17 F and, 19It contains F, and the isotopes of chlorine are 35 Cl and, 37 It contains Cl, and the isotope of bromine is, 79 Br and, 81 Includes Br.

[0031] "Halogen" refers to F, Cl, Br, or I.

[0032] "Halogen substitution" refers to substitution with F, Cl, Br, or I, and includes, but is 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 substitution" is abbreviated as "halogenation."

[0033] "Alkyl group" refers to a substituted or unsubstituted linear or branched saturated aliphatic hydrocarbon group, including, but not limited to, alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 1 to 4 carbon atoms. Non-limiting examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, neobutyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and their various branched isomers, and the definition of alkyl group as described herein is consistent with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0034] An alkylene group is a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, -(CH2) v - (where v is an integer from 1 to 10) and examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene, and butylene groups.

[0035] "Cycloalkyl group" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl groups. The definition of cycloalkyl groups as used herein is as described above. Cycloalkyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0036] "Heterocycloalkyl group" refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group containing 3 to 10 atoms or 3 to 8 atoms, but is not limited to these, and may contain 1 to 3 heteroatoms selected from N, O, or S, and the selectively substituted N and S in the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group may be linked to a heteroatom or a carbon atom, may be linked to an aromatic ring or a non-aromatic ring, and may have a crosslinking ring or spiro ring linked to it. Non-limiting examples include oxylanyl group, azilidinyl group, oxetanyl group, azetidinyl group, tetrahydrofuranyl group, tetrahydro-2H-pyranyl group, dioxolanyl group, dioxanyl group, pyrrolidinyl group, piperidinyl group, imidazolidinyl group, oxazolidinyl group, oxadinyl group, morpholinyl group, hexahydropyrimidinyl group, and piperazinyl group. The heterocycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.

[0037] An "alkenyl group" is a substituted or unsubstituted linear and branched unsaturated hydrocarbon group that has at least one, generally 1, 2, or 3 carbon-carbon double bonds, and the main chain contains 2 to 10, 2 to 6, or 2 to 4 carbon atoms, but is not limited to these. Examples of alkenyl groups include vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-1-butenyl group, 2-methyl-1-butenyl group, and 2-methyl-3-butenyl group. This includes, but is not limited to, the following: the nyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-methyl-1-pentenyl group, 2-methyl-1-pentenyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-heptenyl group, 1-octenyl group, 3-octenyl group, 1-nonenyl group, 3-nonenyl group, 1-decenyl group, 4-decenyl group, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene. The definition of an alkenyl group described herein is consistent with this definition. The alkenyl group may be monovalent, divalent, trivalent, or tetravalent.

[0038] An "alkynyl group" refers to a substituted or unsubstituted linear and branched unsaturated hydrocarbon group which has at least one, usually 1, 2, or 3 carbon-carbon triple bonds, and the main chain may contain 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms, but is not limited to these. Examples of alkynyl groups include ethynyl group, propargyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1- This includes, but is not limited to, methyl-1-butynyl group, 2-methyl-1-butynyl group, 2-methyl-3-butynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group, 1-methyl-1-pentynyl group, 2-methyl-1-pentynyl group, 1-heptynyl group, 2-heptynyl group, 3-heptynyl group, 4-heptynyl group, 1-octinyl group, 3-octinyl group, 1-noninyl group, 3-noninyl group, 1-dequinyl group, 4-dequinyl group, etc., and the alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0039] The term "propynyl group" refers to the 1-propynyl group and the 2-propynyl group.

[0040] "Alkoxy group" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, n-hexyloxy group, cyclopropoxy group, and cyclobutoxy group.

[0041] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3-8 membered monocyclic ring, a 4-12 membered dicyclic ring, or a 10-15 membered tricyclic ring, and the carbocyclic group may be linked to the aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may optionally be a monocyclic ring, a crosslinked ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl group, 1-cyclopentyl-2-alkenyl group, 1-cyclopentyl-3-alkenyl group, cyclohexyl group, 1-cyclohexyl-2-alkenyl group, 1-cyclohexyl-3-alkenyl group, cyclohexenyl group, benzene ring, naphthalene ring, [ka] It includes. The "carbocyclic group" or "carbocyclic ring" may be monovalent, divalent, trivalent, or tetravalent.

[0042] "Heterocyclic group" or "heterocyclic ring" refers to a substituted or unsubstituted, saturated or unsaturated, aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic ring, a 4- to 12-membered dicyclic ring, or a 10- to 15-membered tricyclic system, and contains one or more heteroatoms (including but not limited to 2, 3, 4, or 5) selected from N, O, or S, and the selectively substituted N and S in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group may be linked to a heteroatom or carbon atom, the heterocyclic group may be linked to an aromatic ring or a non-aromatic ring, and the heterocyclic group may be linked to a crosslinking ring or a spiro ring. Non-limiting examples include oxylanyl group, azilidinyl group, oxetanyl group, azetidinyl group, 1,3-dioxolanyl group, 1,4-dioxolanyl group, 1,3-dioxanyl group, azacycloheptyl group, pyridyl group, furyl group, thienyl group, pyranyl group, N-alkylpyrrolyl group, pyrimidinyl group, pyrazinyl group, pyridadinyl group, imidazolyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group, 1,3-dithianyl group, dihydrofuryl group, dihydropyranyl group, dithiolanyl group, tetrahydrofuranyl group, tetrahydrofuranyl group, tetra Lahydropyrrolyl group, tetrahydroimidazolyl group, tetrahydrothiazolyl group, tetrahydropyranyl group, benzimidazolyl group, benzopyridyl group, pyrrolopyridyl group, benzodihydrofuryl group, pyrrolyl group, pyrazolyl group, thiazolyl group, oxazolyl group, pyrazinyl group, indazolyl group, benzothienyl group, benzofuryl group, benzopyrrolyl group, benzimidazolyl group, benzothiazolyl group, benzoxazolyl group, benzopyridyl group, benzopyrimidinyl group, benzopyradinyl group, piperazinyl group, azabicyclo[3.2.1]octyl group, azabicyclo[5.2.0]nonyl group, oxatricyclo[5.3.1.1]dodecyl group, azaadamantyl group, oxapiro[3.3]heptyl group, [ka] This includes the "heterocyclic group" or "heterocyclic ring" which may be monovalent, divalent, trivalent, or tetravalent.

[0043] A "spiro ring" or "spiro ring group" refers to a polycyclic group that shares one atom (called a spiro atom) between substituted or unsubstituted monorings. The number of ring atoms in a spiro ring system includes, but is not limited to, 5-20, 6-14, 6-12, or 6-10. Here, one or more rings may contain 0 or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and may optionally contain 1-5 heteroatoms selected from N, O, or S(=O)n. [ka] The "spiro ring" or "spiro ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0044] A "fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares adjacent atom pairs with other rings in the system, where one or more rings may contain zero 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 fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (N, S(=O) n Or, it may include, but is not limited to, those selected from O, and may also include n being 0, 1, or 2. The number of ring atoms in the fused ring system may include, but is not limited to, 5-20, 5-14, 5-12, or 5-10. Non-restrictive examples are, [ka] This includes the following: The "fused ring" or "fused ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0045] A "bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing two atoms in any two rings that are not directly linked, and may contain zero or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from or 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 may include, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. A non-restrictive example is: [ka] Contains cubane and adamantane. The "crosslinking ring" or "crosslinking ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0046] "Carbon spiro ring," "spiro ring carbon ring group," "spiro carbon ring group," or "carbon spiro ring group" refers to a "spiro ring" whose ring system consists only of carbon atoms.

[0047] "Carbon fused ring," "fused ring carbon ring group," "fused carbon ring group," or "carbon fused ring group" refers to a "fused ring" whose ring system consists only of carbon atoms.

[0048] "Carbon bridged ring," "bridged ring carbon ring group," "bridged carbon ring group," or "carbon bridged ring group" refers to a "bridged ring" whose ring system consists only of carbon atoms.

[0049] "Heterocyclic monoring," "monocyclic heterocyclic group," or "heterocyclic monoring group" refers to a monocyclic "heterocyclic group" or "heteroring."

[0050] "Heterofused ring," "heterofused ring group," "fused ring heterocyclic group," or "heterofused ring group" refers to a "fused ring" containing a heteroatom.

[0051] "Heterospiro ring," "heterospiro ring group," "spirocyclic heterocyclic group," or "spiroheterocyclic group" all refer to a "spiro ring" containing a heteroatom.

[0052] "Heterocrosslinked ring," "heterocrosslinked ring group," "crosslinked ring heterocrossed group," or "crosslinked heterocrossed group" refers to a "crosslinked ring" containing a heteroatom.

[0053] An "aryl group" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and the number of ring atoms in the aromatic ring may be 6 to 18, 6 to 12, or 6 to 10 carbon atoms, but is not limited to these. An aryl ring can be fused with a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring linked to the basic skeleton is an aryl ring, and non-limiting examples include a benzene ring, a naphthalene ring, [ka] The compound includes the "aryl group" or "aromatic ring," which may be monovalent, divalent, trivalent, or tetravalent. If it is divalent, trivalent, or tetravalent, the linking site is on the aryl ring.

[0054] A "heteroaryl group" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 groups (including, but not limited to, N, O, or S(=O)n, where n is 0, 1, or 2) selected from or containing heteroatoms, and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10, or 5 to 6. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl groups, furyl groups, thienyl groups, pyridyl groups, pyranyl groups, N-alkylpyrrolyl groups, pyrimidinyl groups, pyrazinyl groups, pyridadinyl groups, imidazolyl groups, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be condensed with a saturated or unsaturated carbocyclic or heterocyclic ring, where the ring linked to the basic skeleton is a heteroaryl ring, and non-limiting examples include, [ka] This includes. The definition of a heteroaryl group as described herein is consistent with this definition. A heteroaryl group may be monovalent, divalent, trivalent, or tetravalent. If it is divalent, trivalent, or tetravalent, the linking site is on the heteroaryl ring.

[0055] "Substituting" or "being substituted" means being substituted with one or more substituents (including, but not limited to, two, three, four, or five), and substituents include H, F, Cl, Br, I, alkyl groups, cycloalkyl groups, alkoxy groups, haloalkyl groups, thiol groups, hydroxyl groups, nitro groups, mercapto groups, amino groups, cyano groups, isocyano groups, aryl groups, heteroaryl groups, heterocyclic groups, crosslinked ring groups, spirocyclic groups, fused ring groups, hydroxyalkyl groups, =O, carbonyl groups, aldehydes, carboxylic acids, formic acid esters, and -(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 -Alkenil-R a , OR d or -(CH2) m -Alkinil-R a (where m and n are 0, 1, or 2), arylthio group, thiocarbonyl group, silyl group, or -NR b R c This includes, but is not limited to, the base R b and R c The group is independently selected from H, hydroxyl group, amino group, carbonyl group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, sulfonyl group, and trifluoromethanesulfonyl group, with R being one option. b and R c It can form a 5- or 6-membered cycloalkyl group or a heterocyclic group. a and R d Each of these groups is independently selected from aryl groups, heteroaryl groups, alkyl groups, alkoxy groups, cycloalkyl groups, heterocyclic groups, carbonyl groups, ester groups, crosslinked ring groups, spirocyclic groups, or fused ring groups.

[0056] "Containing 1 to 5 heteroatoms selected from O, S, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.

[0057] "Substituted with 1 to X substituents selected from..." means substituted with 1, 2, 3,..., X substituents, where X is selected from any integer from 1 to 10. For example, "substituted with 1 to 4 R k " means substituted with 1, 2, 3, or 4 R k "For example, "substituted with 1 to 5 substituents selected from..." means substituted with 1, 2, 3, 4, or 5 substituents selected from.... For example, "the heterocyclic ring is optionally substituted with 1 to 4 substituents selected from D or F" means that the heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents selected from D or F.

[0058] A ring of X to Y members (3 ≤ X < Y, where Y is selected from any integer from 4 to 12) includes rings of X, X + 1, X + 2, X + 3, X + 4,..., Y members. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterofused ring, a heterospiro ring, or a heterobridged ring. For example, "a 4 - 7 member heteromonocyclic ring" means a 4 - member, 5 - member, 6 - member, or 7 - member heteromonocyclic ring, and "a 5 - 10 member heterofused ring" means a 5 - member, 6 - member, 7 - member, 8 - member, 9 - member, or 10 - member heterofused ring.

[0059] "Optionally" or "optionally selected" means that the event or circumstance described thereafter may occur, but not necessarily, and the description includes both the case where the event or circumstance occurs and the case where it does not occur. For example, "an alkyl group optionally substituted with F" means that the alkyl group may be substituted with F, but not necessarily, indicating that it includes both the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0060] "Pharmacologically acceptable salt" or "the pharmaceutically acceptable salt" refers to a salt obtained by a reaction in which the compound of the present invention maintains the biological efficacy and properties of the free acid or free base, and by a reaction in which the free acid is reacted with a non-toxic inorganic base or organic base, or by a reaction in which the free base is reacted with a non-toxic inorganic acid or organic acid.

[0061] A "carrier" refers to a material that does not cause significant irritation to living organisms and does not cause the biological activity and properties of the administered compound to be lost.

[0062] A "cocrystal" refers to a crystalline body formed when an active pharmaceutical ingredient (API) and a cocrystal compound (CCF) are bonded together by hydrogen bonds or other non-covalent bonds, where the pure states of the API and CCF are both solids at room temperature, and a fixed stoichiometric ratio exists between each component. Cocrystals are multi-component crystalline bodies, including not only binary cocrystals formed between two neutral solids, but also multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0063] "Animals" include mammals such as humans, companion animals, zoo animals, and livestock, and preferably refers to humans, horses, or dogs.

[0064] "Stereoisomers" refer to isomers that arise from different arrangements of atoms in a molecule, and include cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0065] A "tautomer" refers to a functional isomer produced when an atom in a molecule rapidly moves between two positions. Examples include keto-enol isomers and amide-imide alcohol isomers. [Modes for carrying out the invention]

[0066] The following embodiments illustrate the technical concept of the present invention in detail, but the scope of protection of the present invention is included therein, but not limited thereto.

[0067] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacement (δ) was 10 -6 The values ​​were given in units of (ppm). NMR measurements were performed using nuclear magnetometers (Bruker Avance III 400 and Bruker Avance 300), with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD) as the measurement solvents, and tetramethylsilane (TMS) as the internal standard. MS measurements were performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)). HPLC measurements were performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM). Thin-layer chromatography silica gel plates are used in Yantai Huanghai HSGF 254 Or Qingdao GF 254 For thin-layer chromatography (TLC) using silica gel plates, plates with a thickness of 0.15 mm to 0.20 mm are used, while for the separation and purification of products by thin-layer chromatography, plates with a thickness of 0.4 mm to 0.5 mm are used. Column chromatography typically uses silica gel of 200-300 mesh size from Yantai Huanghai as the support material.

[0068] Example 1: [ka] Step 1: Manufacturing of 1A Compound isobutyryl chloride (7 g, 65.67 mmol) was dissolved in THF (40 mL), cooled to -70°C, and potassium tert-butoxide-tetrahydrofuran solution (72 mL, 1 N) was slowly added. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 10 minutes. Then, 100 mL of water and 50 mL of methyl tert-butyl ether were added in sequence, and the mixture was separated. The organic layer was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next step.

[0069] Step 2: Manufacturing of 1B Compound 1A (7.77 g, 53.89 mmol) was dissolved in THF (80 mL), the mixture was purged three times with nitrogen gas, and the temperature was lowered to -70°C. A solution of LDA in tetrahydrofuran (80 mL, 1 N) was slowly added dropwise. After the addition was complete, stirring was continued for 30 minutes, and then the temperature was raised to 0°C and stirred for 10 minutes. The temperature was lowered to -70°C, and a solution of 3-iodobenzyl bromide (16 g, 53.89 mmol) in tetrahydrofuran was slowly added. After the addition was complete, stirring was continued for 1 hour. The mixture was allowed to rise naturally to room temperature, 20 mL of saturated ammonium chloride aqueous solution was added to quench the reaction, 100 mL of water and 100 mL of methyl tert-butyl ether were added, and the mixture was stirred to form layers. The organic layer was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100 to 5 / 100) to obtain compound 1B (6.3 g, yield: 32%). 1 H NMR (400MHz, CDCl3) δ7.56-7.51(m,2H),7.14-7.09(m,1H),7.02-6.95(m,1H),2.75(s,2H),1.45(s,9H),1.13(s,6H).

[0070] Step 3: Manufacturing of 1C Compound 1B (5.8 g, 16.10 mmol) was dissolved in THF (20 mL), purged three times with nitrogen gas, cooled to -70°C, and isopropylmagnesium chloride-lithium tetrahydrofuran chloride solution (24 mL, 1 N) was slowly added dropwise. After the addition was complete, the temperature was raised to 0°C and stirred for 10 minutes, then cooled to -70°C, and diethyl oxalate (3.53 g, 24.15 mmol) was slowly added dropwise. After the addition was complete, the temperature was allowed to rise naturally to room temperature and stirred for 10 minutes. The reaction was quenched with 10 mL of saturated ammonium chloride aqueous solution, extracted with 50 mL of methyl tert-butyl ether and 50 mL of water, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100~8 / 100) to obtain compound 1C (4.2 g, yield: 78%).

[0071] Step 4: Manufacturing 1D Compound 1C (2.4 g, 7.18 mmol) was dissolved in a mixed solvent of ethanol (30 mL) and water (1 mL). Malononitrile (1.90 g, 28.79 mmol) and β-alanine (0.064 g, 0.72 mmol) were added sequentially, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100 to 10 / 100) to obtain compound 1D (2.56 g, yield: 93%).

[0072] Step 5: Manufacturing of 1E Compound 1D (2.56 g, 6.69 mmol) was dissolved in THF (15 mL), cooled to -70°C under nitrogen gas protection, and a solution of methylmagnesium chloride in tetrahydrofuran (2.7 mL, 3 N) was slowly added dropwise. After the addition was complete, stirring was continued at this temperature for 10 minutes, and the reaction was quenched with 10 mL of 1 N hydrochloric acid. 30 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred to form a layer. The organic phase was washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100 to 10 / 100) to obtain compound 1E (2.13 g, yield: 79%).

[0073] Step 6: Manufacturing on the 1st floor Compound 1E (0.54 g, 1.36 mmol), S-methylisothiourea sulfate (0.26 g, 1.36 mmol, CAS: 867-44-7), and potassium bicarbonate (0.54 g, 5.39 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, 20 mL of ethyl acetate was added, and the mixture was washed with 10 mL of saturated brine. The organic layer was removed, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5~1 / 2) to obtain compound 1F (0.45 g, yield: 75%). LCMS m / z = 443.2[M+H] +

[0074] Step 7: Manufacturing 1G Compound 1F (0.44 g, 0.99 mmol) was dissolved in THF (5 mL), and metachloroperbenzoic acid (0.34 g, 1.97 mmol, wt%=85%) was added at room temperature. After adding the compound, stirring was continued for 2 hours. 10 mL of saturated sodium thiosulfate aqueous solution was added and stirred for 20 minutes. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of ethyl acetate was added for extraction, and the organic layer was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1 G (a mixture of 1 G-1 and 1 G-2), which was used directly in the next step. LCMS m / z = 457.2 [MH] - and LCMS m / z = 473.2 [MH] -

[0075] Step 8: 1H Manufacturing Compounds 1,1,1,2,2-pentafluoro-4-iodobutane (2 g, 7.29 mmol), phthalimide (1.07 g, 7.29 mmol), and potassium carbonate (1.51 g, 10.94 mmol) were mixed and dissolved in DMF (20 mL). The mixture was heated to 80°C and stirred for 3 hours. After cooling to room temperature, 40 mL of MTBE and 40 mL of water were added and stirred to form layers. The organic layer was washed with saturated brine (20 mL x 4), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10~1 / 5) to obtain compound 1H (0.5 g, yield: 23%).

[0076] Step 9: Manufacturing of 1I hydrochloride Compound 1H (0.5 g, 1.71 mmol) was dissolved in ethanol (5 mL), hydrazine hydrate (0.12 g, 1.98 mmol, wt%=80%) was added, and the mixture was heated to 78°C and stirred for 2 hours. After cooling to room temperature, 10 mL of ethyl acetate was added, the mixture was filtered, the filter cake was washed with 5 mL of ethyl acetate, the filtrates were combined, 1 mL of 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was concentrated under reduced pressure to obtain the hydrochloride salt of compound 1I, which was used directly in the next step. LCMS m / z = 164.10[M+H] +

[0077] Step 10: Manufacturing 1J Compound 4-chloro-2-fluoronitrobenzene (0.33 g, 1.87 mmol) and the hydrochloride salt of compound 1I (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL), diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was heated to 60°C and stirred for 4 hours. After cooling to room temperature, 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 1J (0.43 g, yield: 72%). LCMS m / z=319.1[M+H] +

[0078] Step 11: Manufacturing 1K Compound 1J (0.43g, 1.35 mmol) was dissolved in a mixed solvent of ethanol (6mL) and water (2mL). Ammonium chloride (0.73g, 13.64 mmol) and iron powder (0.76g, 13.54 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20mL of dichloromethane. The filtrates were combined, and 20mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 1K (0.3g, yield: 77%). LCMS m / z = 289.10[M+H] +

[0079] Step 12: Manufacturing 1L Compound 1K (0.3g, 1.04 mmol) was dissolved in DCM (5 mL), diisopropylethylamine (0.41g, 3.14 mmol) was added, and triphosgene solid (0.12g, 0.42 mmol) was gradually added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes, and 20 mL of dichloromethane was added for extraction. The organic layer was washed with 20 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10~1 / 2) to obtain 1 L of compound (0.2 g, yield: 61%). LCMS m / z=315.0[M+H] +

[0080] Step 13: Manufacturing 1M 1 L (0.2 g, 0.64 mmol) of the compound, 1 G (0.46 g), and potassium carbonate (0.18 g, 1.29 mmol) were mixed and dissolved in DMF (3 mL). The mixture was heated to 100°C and stirred for 16 hours, then heated to 120°C and stirred for a further 24 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added and stirred to form layers. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-100 / 3). The resulting residue was further purified by reverse-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain 1 M of the compound (55 mg, yield: 12%). LCMS m / z = 709.70[M+H] +

[0081] Step 14: Preparation of Compound 1 Compound 1M (0.052 g, 0.073 mmol) was placed in a 50 mL single-necked flask, TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 4) to obtain Compound 1 (34 mg, yield: 71%).

[0082] Step 15: Compounds 1-1 and 1-2 Compound 1 (30 mg) was taken and used for chiral separation and purification. Preparative conditions: Instrument: Waters 150ap, Chromatography column: ChoralPak IC 19*250 5um, Column temperature: 35°C, Mobile phase: A is CO2, B is isopropanol, Gradient: B 24%, Back pressure: 95 bar, Cycle: 3.6 min, Detection wavelength: 210 nm, Flow rate: 40 ml / min.

[0083] Analytical conditions: Instrument: Shimadzu LC-20AD, Chromatography column: CHIRALPAK AD-H 4.6*250mm 5um, Mobile phase A: n-hexane, Mobile phase B: ethanol, Flow rate: 1 ml / min, Column temperature: 35℃, Detection wavelength: 210 nm, Sample input volume: 10 μL, Run time: 20 min, Isocratic elution: n-hexane:ethanol = (80:20).

[0084] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 1-1 (10 mg) and compound 1-2 (10 mg).

[0085] Compound 1-1: Retention time under analytical conditions was 5.1 min, and LCMS m / z = 653.1 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ7.83(d,1H),7.53(d,1H),7.28-7.21(m,1H),7.16-7.03(m,4H),6 .78-6.48(m,2H),4.24(t,2H),2.85-2.65(m,4H),1.78(s,3H),1.07(s,3H),1.03(s,3H).

[0086] Compound 1-2: Retention time under analytical conditions was 7.5 min, LCMS m / z = 653.1 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ7.83(d,1H),7.53(d,1H),7.28-7.21(m,1H),7.16-7.03(m,4H),6 .78-6.48(m,2H),4.24(t,2H),2.85-2.65(m,4H),1.78(s,3H),1.07(s,3H),1.03(s,3H).

[0087] Example 2: [ka] Step 1: Manufacturing 2A Compound 2-(dicyanomethyl)-2-methylmalonate diethyl (CAS: 1350855-72-9) (1 g, 4.20 mmol), S-methylisothiourea sulfate (0.79 g, 4.2 mmol), and potassium bicarbonate (1.68 g, 16.78 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, 30 mL of ethyl acetate was added, and the mixture was washed with 20 mL of saturated brine. The organic layer was removed, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5~1 / 2) to obtain compound 2A (0.9 g, yield: 76%). LCMS m / z = 283.20[M+H] +

[0088] Step 2: Manufacturing of 2B Compound 2A (0.9 g, 3.19 mmol) was dissolved in methanol (5 mL), 10 mL of 7 N ammonia-methanol solution was added, the temperature was raised to 40°C, and the mixture was stirred overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure to obtain compound 2B, which was used directly in the next step. LCMS m / z=254.1[M+H] +

[0089] Step 3: Manufacturing of 2C Compound 2B (0.85 g, 3.36 mmol) and Lawson's reagent (1.49 g, 3.70 mmol) were mixed and dissolved in toluene (15 mL). After addition, the mixture was purged three times with nitrogen gas, heated to 100°C, and stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 2C (0.52 g, yield: 57%).

[0090] Step 4: 2D Manufacturing Compound 4-chloro-2,2-dimethylpenta-4-enoate (2 g, 11.29 mmol, CAS: 86799-85-1) was dissolved in a mixed solvent of ethanol (10 mL) and water (10 mL). NBS (2.21 g, 12.42 mmol) was gradually added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 1 hour. The reaction was quenched by slowly adding 10 mL of saturated sodium bicarbonate aqueous solution, and the mixture was extracted with 20 mL of MTBE. The organic phase was then washed with saturated sodium bicarbonate aqueous solution (10 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was used directly in the next step.

[0091] Step 5: Manufacturing of 2E Compounds 2C (0.5 g, 1.86 mmol) and 2D (0.66 g, 2.79 mmol) were mixed and dissolved in ethanol (10 mL), and the mixture was heated to 60°C and stirred overnight. After cooling to room temperature, 30 mL of ethyl acetate and 20 mL of saturated sodium bicarbonate aqueous solution were added, the mixture was stirred for 10 minutes, and the liquid-liquid was separated. The organic layer was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain compound 2E (0.55 g, yield: 73%). LCMS m / z = 408.70[M+H] +

[0092] Step 6: Manufacturing on the 2nd floor Compound 2E (0.55 g, 1.35 mmol) was dissolved in tetrahydrofuran (5 mL), and methachloroperbenzoic acid (0.47 g, 2.72 mmol) was added at room temperature. After adding the compound, stirring was continued for 2 hours. 10 mL of saturated sodium thiosulfate aqueous solution was added and stirred for 20 minutes. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of ethyl acetate was added and stirred to form layers. The organic layer was washed with 10 mL of saturated brine, the organic layer was removed, dried over sodium sulfate, filtered, and concentrated to obtain 2F (a mixture of 2F-1 and 2F-2), which was used directly in the next step. LCMS m / z=424.1[M+H] + and LCMS m / z=440.1[M+H] +

[0093] Step 7: Manufacturing 2G 1 L of compound (0.12 g, 0.38 mmol), 2F (0.19 g), and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (3 mL). The mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added and stirred to form layers. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 3) to obtain compound 2 G (54 mg, yield: 21%). LCMS m / z = 674.1[M+H] +

[0094] Step 8: Preparation of Compound 2 Compound 2G (0.054g, 0.080 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), lithium hydroxide (0.019 g, 0.79 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1N hydrochloric acid, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate salt of compound 2 (31 mg). LCMS m / z = 660.0[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),7.81(d,1H),7.52(d,1H),7.25(s,1H),7.13(dd,1H),7. 09-6.96(m,2H),4.22(t,2H),2.93(s,2H),2.81-2.65(m,2H),1.81(s,3H),1.14-1.04(m,6H).

[0095] Preparation of Compound 2-1 and Compound 2-2: [ka] 31 mg of the trifluoroacetate of compound 2 was taken and used for chiral separation and purification. Preparative chromatography conditions: instrument: SFC Prep 150 AP, chromatography column: IG (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: mobile phase A: CO2, mobile phase B: methanol (containing 0.5% aqueous ammonia). Isocratic elution was performed, with a mobile phase B content of 30% and a flow rate of 52 ml / min.

[0096] Analytical conditions: Instrument: UPC2, chromatographic column: IG (3 mm × 50 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Gradient elution was performed, with a mobile phase B content of 10% to 40% and a time of 5 min. Isocratic elution was performed, with a mobile phase B content of 40% and a flow rate of 1.5 ml / min.

[0097] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 2-1 (10 mg) and compound 2-2 (15 mg).

[0098] Compound 2-1: Retention time under analytical conditions was 2.3 min, and LCMS m / z = 660.0 [M + H]. + That was the case.

[0099] Compound 2-2: Retention time under analytical conditions was 2.7 min, and LCMS m / z = 660.0 [M + H]. + That was the case.

[0100] Example 3: [ka] Step 1: Manufacturing 3A Pyridazine (3g, 37.50 mmol) was dissolved in chloroform (60 mL), trifluoromethanesulfonic acid anhydride (12.59 g, 44.63 mmol) was slowly added, and the mixture was stirred at room temperature for 1 hour. Then cyanotrimethylsilane (15.81 g, 159.26 mmol) was added, the temperature was raised to 60°C, and the reaction was carried out for 3 hours. After cooling, N-methylmorpholine (4.93 g, 48.75 mmol) was added, the temperature was raised again to 60°C, and the reaction was carried out overnight. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution, and DCM was added for two extractions. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 13) to obtain compound 3A (2.5 g, yield: 63%). LCMS m / z = 106.20[M+H] +

[0101] Step 2: Production of 3B hydrochloride Compound 3A (2 g, 19.03 mmol) was dissolved in methanol (10 mL), and 10 mL of 6N hydrochloric acid and palladium carbon (2.03 g, 1.90 mmol) were added. The mixture was purged three times with hydrogen gas and reacted overnight in a hydrogen gas environment. The reaction solution was filtered through diatomaceous earth, washed three times with methanol, and the filtrate was concentrated under reduced pressure to obtain the hydrochloride salt of compound 3B, which was used directly in the next step.

[0102] Step 3: Manufacturing of 3C The hydrochloride salt of compound 3B (1.1 g, 7.52 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.73 g, 9.02 mmol) were dissolved in DMF (20 mL), HATU (5.72 g, 15.04 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (2.92 g, 22.56 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 10) to obtain compound 3C (700 mg, yield: 32%).

[0103] Step 4: 3D Manufacturing Compound 3C (700 mg, 2.47 mmol) was dissolved in DCE (100 mL), phosphorus oxychloride (1.31 mL, 14.35 mmol) was added, and the mixture was heated to reflux and reacted overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure, water was carefully and slowly added to the residue, and the mixture was stirred for 5 minutes. Ethyl acetate was added, and the mixture was stirred to form a layer. The aqueous layer was treated with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100~20 / 100) to obtain compound 3D (350 mg, yield: 53%). LCMS m / z = 266.30[M+H] +

[0104] Step 5: Manufacturing of 3E Compound 3D (350 mg, 1.32 mmol) was dissolved in DCM (10 mL), NBS (246.68 mg, 1.39 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. Water was added, the mixture was stirred to form layers, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100 to 50 / 100) to obtain compound 3E (430 mg, yield: 94%). LCMS m / z = 344.30[M+H] +

[0105] Step 6: Manufacturing on the 3rd floor Compound 3E (400 mg, 1.16 mmol) and zinc cyanide (272.46 mg, 2.32 mmol) were added to a 50 mL pouring flask. Then, zinc powder (151.75 mg, 2.32 mmol), 1,1'-bis(diphenylphosphin)ferrocene (385.85 mg, 0.70 mmol), and tris(dibenzylidene-BASE acetone)dipalladium (318.67 mg, 0.35 mmol) were added, followed by the addition of N,N-dimethylacetamide (10 mL). The mixture was then protected with nitrogen gas, heated to 120 °C, and stirred for 2 hours. The reaction mixture was diluted with 50 mL of ethyl acetate, washed three times with water, washed once with saturated sodium chloride, dried the organic phase over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 3F (320 mg, yield: 95%) was obtained by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 2 / 1). LCMS m / z = 291.1[M+H] +

[0106] Step 7: Manufacturing 3G Under ice bath conditions, ammonium chloride (275.47 mg, 5.15 mmol) was added to a 50 mL pouring flask, toluene (10 mL) was added, and then trimethylaluminum (2.58 mL, 2 M, toluene solution) was slowly added dropwise. The mixture was heated to room temperature and stirred for 3 hours to allow the reaction to proceed. Compound 3F (300 mg, 1.03 mmol) was dissolved in toluene and added dropwise to the reaction mixture. The mixture was heated to 110°C and stirred overnight. After cooling to room temperature, silica gel and 20 mL of methanol were added under ice bath conditions. Stirring continued for 30 minutes, and the mixture was filtered by suction. The filtered cake was washed three times with methanol, the organic phases were combined, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 3G (190 mg, yield: 60%). LCMS m / z = 308.50[M+H] +

[0107] Step 8: 3H Manufacturing Diethyl 2-bromo-2-methylmalonate (20.00 g, 79.02 mmol) and malononitrile (5.22 g, 79.02 mmol) were dissolved in tetrahydrofuran (120 mL), and potassium tert-butoxide (8.87 g, 79.02 mmol) was gradually added under ice bath conditions. After the addition was complete, the temperature was raised to 85°C and the mixture was stirred for 16 hours. The reaction mixture was cooled to room temperature, the solid was removed by suction filtration, the filter cake was washed with dichloromethane, the organic phases were combined, and the mixture was concentrated under reduced pressure. The mixture was then purified by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain compound 3H (4.94 g, yield: 26%). LCMS m / z=239.1[M+H] +

[0108] Step 9: Manufacturing of 3I Compound 3G (190 mg, 0.62 mmol), 3H (177.25 mg, 0.74 mmol), and potassium bicarbonate (124.15 mg, 1.24 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, it was concentrated under direct reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 3I (250 mg, yield: 80%).

[0109] Step 10: Manufacturing 3J Compound 3I (250 mg, 0.50 mmol) was dissolved in methanol (5 mL), and 5 mL of 7N ammonia / methanol solution was added. The mixture was reacted overnight at 40°C. The mixture was concentrated under reduced pressure to obtain compound 3J (230 mg, yield: 97%). LCMS m / z = 471.1[M+H] +

[0110] Step 11: Manufacturing 3K Compound 3J (230 mg, 0.49 mmol) was dissolved in toluene (5 mL), and Lawesson's Reagent (237.83 mg, 0.59 mmol) was added. After adding the reagents, the temperature was raised to 80°C and the mixture was stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 5 / 1) to obtain compound 3K (200 mg, yield: 83%). LCMS m / z = 487.0[M+H] +

[0111] Step 12: Manufacturing 3L Compound 3K (200 mg, 0.41 mmol) was dissolved in ethanol (5 mL), and 2D (145.81 mg, 0.61 mmol) was added. After adding the compound, the temperature was raised to 80°C and the mixture was stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 5 / 1) to obtain 3 L of compound (200 mg, yield: 78%). LCMS m / z = 625.1[M+H] +

[0112] Step 13: Preparation of Compound 3 3 L of compound (200 mg, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL). Lithium hydroxide hydrate (134.27 mg, 3.2 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and the solid was precipitated. The mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50). The preparative solution was treated with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, concentrated under reduced pressure, and further water and acetonitrile were added. The mixture was freeze-dried to obtain compound 3 (100 mg, yield: 51%). LCMS m / z = 611.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ12.38-11.89(m,1H),11.33(s,1H),9.00(dd,1H),8.45(dd,1H),7.24(s,1 H),6.99(dd,1H),6.78(br.s,1H),3.42-3.34(m,2H),2.96-2.76(m,4H),1.79(s,3H),1.11(s,6H).

[0113] Preparation of Compound 3-1 and Compound 3-2: [ka] Compound 3 (100 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: mobile phase A: CO2, mobile phase B: methanol (ammonia water 0.05%), b. Isocratic elution, with mobile phase B content at 30%, c. Flow rate: 54 mL / min.

[0114] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 3-1 (35 mg) and compound 3-2 (35 mg).

[0115] Compound 3-1: Retention time under fractional separation conditions was 3.33 min, and LCMS m / z = 611.2 [M+1]. + That was the case.

[0116] Compound 3-2: Retention time under fractional separation conditions was 8.60 min, and LCMS m / z = 611.2 [M+1]. + That was the case.

[0117] Example 4: [ka] Step 1: Manufacturing 4A Compounds 2-bromo-5-chlorobenzoate methyl (2 g, 8.02 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.69 g, 8.82 mmol) were dissolved in THF (40 mL), and sodium bis(trimethylsilyl)amide (12 mL, 2 M, 24.06 mmol) was added at -78 °C. After addition, the mixture was stirred at the same temperature for 15 min and reacted, then the temperature was raised to 0 °C and the reaction was continued for 2 hours. 1N hydrochloric acid (60 mL) was added to quench the reaction, and the mixture was stirred overnight at room temperature. Ethyl acetate was added for extraction, the organic phase was washed twice with saturated sodium bicarbonate solution, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 20) to obtain compound 4A (1.6 g, yield: 54%).

[0118] Step 2: Manufacturing of 4B Compound 4A (1.6 g, 4.38 mmol) was dissolved in methanol (10 mL), and aminoguanidine hydrochloride (0.72 g, 6.54 mmol) and boron trifluoride diethyl ether (1.1 mL, 8.91 mmol) were added. The mixture was heated to 100°C in a sealed tube and reacted for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 4B, which was used directly in the next step. LCMS m / z = 421.0[M+H] +

[0119] Step 3: Manufacturing of 4C Compound 4B (1.6 g, 3.80 mmol), 3H (1.81 g, 7.6 mmol), and potassium tert-butoxide (0.43 g, 3.8 mmol) were mixed and dissolved in tert-butanol (15 mL). The mixture was heated to 130°C in a sealed tube and stirred for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form a layer. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 4C (550 mg, yield: 23%). LCMS m / z = 613.0[M+H] +

[0120] Step 4: 4D Manufacturing Compound 4C (550 mg, 0.90 mmol) was dissolved in DMF (10 mL), and N,N-dimethylethylenediamine (119 mg, 1.35 mmol) and cuprous iodide (34.28 mg, 0.18 mmol) were added. The mixture was purged three times with nitrogen gas and reacted for 2 hours under nitrogen gas protection. Ethyl acetate and water were added, the mixture was stirred, and then layered. The organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 4D (170 mg, yield: 35%). LCMS m / z = 533.30[M+H] +

[0121] Step 5: Manufacturing of 4E Compound 4D (170 mg, 0.32 mmol) was dissolved in methanol (3 mL), and 3 mL of 7 M ammonia-methanol solution was added. The mixture was reacted overnight at 40°C. The mixture was concentrated under reduced pressure to obtain compound 4E (160 mg). LCMS m / z = 504.1[M+H] +

[0122] Step 6: Manufacturing on the 4th floor Compound 4E (160 mg, 0.32 mmol) was dissolved in toluene (5 mL), and Lawesson's Reagent (155.32 mg, 0.38 mmol) was added. After adding the reagents, the temperature was raised to 80°C and the mixture was stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 5 / 1) to obtain compound 4F (160 mg, yield: 96%). LCMS m / z = 520.50[M+H] +

[0123] Step 7: Manufacturing 4G Compound 4F (160 mg, 0.31 mmol) was dissolved in ethanol (5 mL), and 2D (110.25 mg, 0.46 mmol) was added. After adding the compounds, the temperature was raised to 80°C and the mixture was stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 5 / 1) to obtain compound 4G (110 mg, yield: 53%).

[0124] Step 8: Preparation of Compound 4 Compound 4G (110 mg, 0.17 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL), lithium hydroxide hydrate (71.33 mg, 1.7 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and the solid was precipitated. The mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50) to obtain the trifluoroacetate of compound 4 (90 mg). LCMS m / z = 644.0[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.85(d,1H),8.10(d,1H),7.55(dd,1H),7.24(s,1H),7. 21-7.01(m,2H),3.37-3.24(m,2H),2.93(s,2H),2.87-2.70(m,2H),1.81(s,3H),1.11(s,6H).

[0125] Preparation of Compound 4-1 and Compound 4-2: [ka] Compound 4 (90 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: mobile phase A: CO2, mobile phase B: methanol (ammonia water 0.05%), b. Isocratic elution, with mobile phase B content at 25%, c. Flow rate: 50 mL / min.

[0126] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 4-1 (20 mg) and compound 4-2 (20 mg).

[0127] Compound 4-1: Retention time under fractional separation conditions was 3.80 min, and LCMS m / z = 644.1 [M+1]. + That was the case.

[0128] Compound 4-2: Retention time under fractional separation conditions was 10.10 min, and LCMS m / z = 644.0 [M+1]. + That was the case.

[0129] Example 5: [ka] Referencing the synthesis methods of Examples 1 and 4, trifluoroacetate (15 mg) of compound 5 was obtained. LCMS m / z = 604.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.21(s,1H),9.19(dd,1H),8.67(dd,1H),7.58(dd,1H),7.25(t,1H),7.19-7.03(m,3H),6 .99-6.39(m,2H),3.44-3.33(m,2H),3.01-2.84(m,2H),2.84-2.69(m,2H),1.79(s,3H),1.06(s,3H),1.03(s,3H).

[0130] Example 6: [ka] Step 1: Manufacturing 6A 5-Chloro-2-bromo-3-nitropyridine (5.00 g, 21.08 mmol) and tert-butyl cyanoacetate (4.32 g, 30.57 mmol) were dissolved in N,N-dimethylformamide (100 mL) solution, potassium carbonate (7.87 g, 56.92 mmol) was added, and after adding the potassium carbonate, the temperature was raised to 100°C and the mixture was stirred for 1 hour. The reaction mixture was cooled to room temperature, water was added to dissolve the potassium carbonate, and dilute hydrochloric acid was added to adjust the pH to 2. A pale yellow solid precipitated, which was filtered by suction, the filter cake was washed three times with water, the filter cake was redissolved with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain compound 6A (3.04 g, yield: 48%).

[0131] Step 2: Manufacturing of 6B In a 100 mL reaction flask, 26 mL of concentrated hydrochloric acid was added to 20 mL of water, and 6A (3.04 g, 10.21 mmol) was added to suspend the compound. Then glacial acetic acid (24 mL) was added, and after the addition was complete, the temperature was raised to 80°C and the mixture was stirred for 30 minutes. The reaction mixture was cooled to room temperature, water was added to quench the reaction, 500 mL of ethyl acetate was added, and the mixture was stirred to form a layer. The organic phase was washed three times with water, the organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure. Compound 6B (1.4 g, yield: 69%) was obtained by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1). LCMS m / z = 198.1[M+H] +

[0132] Step 3: Manufacturing of 6C Compound 6B (1.20 g, 6.07 mmol) was dissolved in tetrahydrofuran (30 mL), zinc powder (1.99 g, 30.35 mmol) was added, and then an aqueous solution of ammonium chloride (1.62 g, 30.35 mmol) (5 mL) was added dropwise. The mixture was stirred at room temperature for 0.5 hours to allow the reaction to proceed. 1 mL of aqueous ammonia and 10 mL of water were added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Compound 6C (0.91 g, yield: 89%) was obtained by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 1 / 1). LCMS m / z=168.1[M+H] +

[0133] Step 4: Manufacturing of 6D Compound 6C (0.61 g, 3.64 mmol) was dissolved in concentrated hydrochloric acid (3 mL) and water (15 mL). Sodium nitrite (0.41 g, 5.93 mmol) was added under an ice bath, and the mixture was stirred at room temperature for 16 hours. A yellow solid precipitated, which was then filtered by suction to obtain the solid. The solid was further dissolved in glacial acetic acid (6 mL), and the mixture was heated to 100°C and reacted for 2 hours. The mixture was concentrated under reduced pressure, and the residue was directly purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1) to obtain compound 6D (0.24 g, yield: 37%). LCMS m / z = 179.10[M+H] +

[0134] Step 5: Manufacturing of 6E Compound 6D (0.34 g, 1.89 mmol) and 1,1,1,2,2-pentafluoro-4-iodobutane (1.14 g, 4.16 mmol) were dissolved in acetonitrile (15 mL), potassium carbonate (1.31 g, 9.45 mmol) was added, the mixture was heated to 100 °C, stirred for 16 hours, and the reaction was allowed to proceed. The reaction mixture was cooled to room temperature, the solid was removed by suction filtration, the filter cake was washed three times with dichloromethane, the organic phases were combined, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 5 / 1) to obtain compound 6E (0.44 g, yield: 71%). LCMS m / z = 325.00[M+H] +

[0135] Step 6: Manufacturing of 6F Under ice bath conditions, ammonium chloride (0.36 g, 6.80 mmol) was added to a 500 mL pouring flask, toluene (30 mL) was added, and then trimethylaluminum (3.9 mL, 2 M, toluene solution) was slowly added dropwise. The mixture was heated to room temperature and stirred for 3 hours to allow the reaction to proceed. Compound 6E (0.44 g, 1.36 mmol) was dissolved in toluene and added dropwise to the reaction mixture. The mixture was heated to 110°C and stirred for 6 hours. The mixture was cooled to room temperature, and under ice bath conditions, silica gel and 100 mL of methanol were added. Stirring continued for 30 minutes, and the mixture was filtered by suction. The filtered cake was washed three times with methanol, the organic phases were combined, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 6F (0.46 g, yield: 99%). LCMS m / z=342.0[M+H] +

[0136] Step 7: Preparation of Compound 6F-0 Lithium diisopropylamide (60 mL, 2 M in THF) was added dropwise to a solution of methyl isobutyrate (10.18 g, 99.72 mmol) in tetrahydrofuran (500 mL) at -78°C. The mixture was stirred at -78°C for 0.5 hours, then 3-iodobenzyl bromide (29.6 g, 99.69 mmol) was added. The mixture was slowly heated to room temperature and stirred for 1 hour. A saturated aqueous solution of ammonium chloride (400 mL) was added to quench the mixture. The mixture was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100 to 1 / 10) to obtain compound 6F-0 (18 g, yield: 57%). 1 H NMR (400MHz, CDCl3) δ7.57-7.44(m,2H),7.10-7.03(m,1H),6.99(t,1H),3.66(s,3H),2.78(s,2H),1.18(s,6H).

[0137] Step 8: Preparation of Compound 6F-1 At -78°C, isopropylmagnesium chloride-lithium chloride complex (35 mL, 1.3 M in THF) was added dropwise to a solution of compound 6F-0 (10 g, 31.4 mmol) in tetrahydrofuran (200 mL), and after stirring for 30 minutes, ethyl 3,3-dicyano-2-methacrylate (synthesis was described in synthesis, 1974:9,669) (5.16 g, 31.43 mmol) was slowly added. After the addition was complete, the mixture was transferred to room temperature and stirred for 1 hour. Saturated ammonium chloride aqueous solution (100 mL) was added to quench the mixture, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1 / 100~1 / 10) to obtain compound 6F-1 (5 g, yield: 45%).

[0138] Step 9: Manufacturing 6G Compounds 6F (0.10 g, 0.29 mmol), 6F-1 (0.10 g, 0.29 mmol), and potassium bicarbonate (0.09 g, 0.87 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, the mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 6G (0.16 g). LCMS m / z = 652.2[M+H] +

[0139] Step 10: Preparation of Compound 6 Compound 6G (0.16g, 0.25 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL), lithium hydroxide hydrate (0.10 g, 2.50 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and a white solid precipitated. The mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50) to obtain compound 6 (0.14 g, yield: 87%). LCMS m / z = 638.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.20(s,1H),8.68-8.57(m,2H),7.25(t,1H),7.16-7.04(m,3H),6.46(s ,2H),4.86(t,2H),3.05-2.88(m,2H),2.84-2.70(m,2H),1.79(s,3H),1.07(s,3H),1.03(s,3H).

[0140] Preparation of Compound 6-1 and Compound 6-2: [ka] Compound 6 (140 mg) was taken and used for chiral separation and purification. Preparative chromatography conditions: Instrument: SFC Prep 150 AP, Chromatography column: IG (19 mm * 250 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: Methanol (0.05% aqueous ammonia). b. Isocratic elution was performed, and the content of mobile phase B was 30%. c. The flow rate was 54 ml / min.

[0141] Analytical method: 1. Instrument: UPC2, chromatographic column: IG (3 mm × 50 mm), 2. Sample solution was prepared by dissolving the sample in methanol and filtering through a 0.45 μm filter, 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia), b. Gradient elution was performed, with mobile phase B content ranging from 10% to 40%, and the elution time being 5 min, c. The flow rate was 1.5 ml / min.

[0142] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 6-1 (55 mg) and compound 6-2 (40 mg).

[0143] Compound 6-1: Retention time under analytical conditions was 2.824 mins, and LCMS m / z = 638.1 [M + H]. + That was the case.

[0144] Compound 6-2: Retention time under analytical conditions was 4.098 mins, and LCMS m / z = 638.1 [M + H]. + That was the case.

[0145] Example 7: [ka] Compound 7 (0.073 g) was obtained by referring to the synthesis of Example 6. LCMS m / z = 622.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.12(s,1H),9.20(d,1H),8.28(d,1H),7.33-7.20(m,1H),7.14-7.03(m,3H),6.5 2-6.30(m,2H),5.00(t,2H),3.10-2.93(m,2H),2.86-2.68(m,2H),1.80(s,3H),1.07(s,3H),1.03(s,3H).

[0146] Example 8: [ka] Step 1: Manufacturing 8A Compound 21D (0.5 g, 1.44 mmol), S-methylisothiourea sulfate (0.27 g, 1.44 mmol), and potassium bicarbonate (0.58 g, 5.76 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, 20 mL of ethyl acetate was added, and the mixture was washed with 10 mL of saturated brine. The organic layer was removed, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was beaten with 15 mL of methyl tert-butyl ether / petroleum ether (V / V=1 / 4) to obtain compound 8A (0.4 g). LCMS m / z = 392.1[M+H] +

[0147] Step 2: Manufacturing of 8B Compound 8A (0.52 g, 1.33 mmol) was dissolved in THF (5 mL), and methachloroperbenzoic acid (0.46 g, 2.66 mmol) was added at room temperature. After adding the compound, stirring was continued for 2 hours. 10 mL of saturated sodium thiosulfate aqueous solution was added and stirred for 20 minutes. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of ethyl acetate was added for extraction, the organic layer was washed with 10 mL of saturated brine, the organic layer was removed, dried over sodium sulfate, filtered, and concentrated to obtain compound 8B, which was used directly in the next step.

[0148] Step 3: Manufacturing of 8C 1 L of compound (0.12 g, 0.38 mmol), 8B (0.23 g, 0.57 mmol), and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 8C (54 mg, yield: 21%). LCMS m / z = 658.2[M+H] +

[0149] Step 4: Preparation of Compound 8 Compound 8C (0.054 g, 0.082 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), lithium hydroxide (0.020 g, 0.83 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1N hydrochloric acid aqueous solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 8 (30 mg, yield: 56%). LCMS m / z = 644.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),7.80(d,1H),7.75(s,1H),7.53(d,1H),7.15-7.10(m,1 H),6.91-6.67(m,2H),4.23(t,2H),2.83-2.62(m,4H),1.81(s,3H),1.11(s,3H),1.09(s,3H).

[0150] Example 9: [ka] Step 1: Manufacturing 9A The hydrochloride salt of compound 1I (0.5 g, 2.51 mmol) and 2-fluoro-3-nitropyridine (0.36 g, 2.51 mmol) were dissolved in DMSO (5 mL), DIPEA (0.97 g, 7.53 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 30 mL of methyl tert-butyl ether and 30 mL of water were added for extraction, the organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 9A (0.62 g, yield: 86%). LCMS m / z = 286.30[M+H] +

[0151] Step 2: Manufacturing of 9B Compound 9A (0.62 g, 2.17 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (1.16 g, 21.69 mmol) and iron powder (1.21 g, 21.66 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 9B (0.48 g, yield: 86%).

[0152] Step 3: Manufacturing of 9C Compound 9B (0.48 g, 1.88 mmol) was dissolved in THF (10 mL), and N,N'-carbonyldiimidazole (0.46 g, 2.84 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 hours. 20 mL of dichloromethane was added, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10 to 1 / 2) to obtain compound 9C (0.32 g, yield: 60%). LCMS m / z=282.1[M+H] +

[0153] Step 4: Manufacturing of 9D Compound 9C (0.12 g, 0.43 mmol), 1 G (0.30 g), and potassium carbonate (0.12 g, 0.87 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 9D (0.2 g, yield: 68%). LCMS m / z = 676.3[M+H] +

[0154] Step 5: Preparation of Compound 9 Compound 9D (0.20 g, 0.30 mmol) was placed in a 50 mL pouring flask, trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 5). The resulting crude product was further purified by column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to obtain compound 9 (80 mg, yield: 43%). LCMS m / z = 620.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.50-11.90(m,1H),11.22(s,1H),8.29-8.23(m,1H),8.15-8.09(m,1H),7.28-7.21(m,1 H),7.18-7.03(m,4H),6.80-6.44(m,2H),4.25(t,2H),2.92-2.70(m,4H),1.78(s,3H),1.07(s,3H),1.03(s,3H).

[0155] Preparation of Compound 9-1 and Compound 9-2: [ka] Compound 9 (80 mg) was used for chiral separation and purification. Preparative chromatography conditions: Instrument: SFC Prep 150 AP, Chromatography column: IG (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Isocratic elution was performed, with a mobile phase B content of 25% and a flow rate of 44 ml / min.

[0156] Analytical conditions: Instrument: UPC2, chromatographic column: IG (3 mm × 50 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Gradient elution was performed, with a mobile phase B content of 10% to 40% and a time of 5 min. Isocratic elution was performed, with a mobile phase B content of 40% and a flow rate of 1.5 ml / min.

[0157] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 9-1 (25 mg) and compound 9-2 (35 mg).

[0158] Compound 9-1: Retention time under analytical conditions was 1.9 min, and LCMS m / z = 620.2 [M + H]. + That was the case.

[0159] Compound 9-2: Retention time under analytical conditions was 2.2 min, and LCMS m / z = 620.2 [M + H]. + That was the case.

[0160] Example 10: [ka] Referencing the synthesis methods of Example 9 and Example 2, trifluoroacetate (15 mg) of compound 10 was obtained. LCMS m / z = 627.2[M+H] + 1 H NMR(400MHz,DMSO-d6)11.57(s,1H),8.28-8.22(m,1H),8.15-8.09(m,1H),7.26(s,1H),7.18-7.12(m ,1H),7.12-7.02(m,2H),4.24(t,2H),2.93(s,2H),2.89-2.73(m,2H),1.81(s,3H),1.14-1.05(m,6H).

[0161] Example 11: [ka] Step 1: Manufacturing 11A The hydrochloride salt of compound 1I (0.5 g, 2.51 mmol) and 2,4-difluoronitrobenzene (0.40 g, 2.51 mmol) were dissolved in DMSO (5 mL), DIPEA (0.98 g, 7.58 mmol) was added, and the mixture was stirred at room temperature for 4 hours. 30 mL of methyl tert-butyl ether and 30 mL of water were added for extraction, the organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 11A (0.62 g, yield: 82%).

[0162] Step 2: Manufacturing of 11B Compound 11A (0.62 g, 2.05 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (1.10 g, 20.56 mmol) and iron powder (1.14 g, 20.42 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 11B (0.48 g, yield: 86%). LCMS m / z = 273.30[M+H] +

[0163] Step 3: Manufacturing of 11C Compound 11B (0.48 g, 1.76 mmol) was dissolved in THF (10 mL), and N,N'-carbonyldiimidazole (0.43 g, 2.66 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 hours. 20 mL of dichloromethane was added, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10~1 / 2) to obtain compound 11C (0.3 g, yield: 57%). LCMS m / z=299.1[M+H] +

[0164] Step 4: Manufacturing of 11D Compounds 11C (0.14 g, 0.47 mmol), 8B (0.29 g, 0.70 mmol), and potassium carbonate (0.13 g, 0.94 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 100 °C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 11D (0.07 g, yield: 23%). LCMS m / z = 642.3[M+H] +

[0165] Step 5: Manufacturing of Compound 11 Compound 11D (0.070 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (3 mL) and water (1 mL), lithium hydroxide (0.026 g, 1.09 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 11 (20 mg, yield: 29%). LCMS m / z = 628.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.50-11.80(m,1H),11.49(s,1H),7.87-7.79(m,1H),7.75(s,1H),7.39-7.30(m,1H) ,6.98-6.87(m,1H),6.87-6.60(m,2H),4.22(t,2H),2.80-2.60(m,4H),1.81(s,3H),1.11(s,3H),1.09(s,3H).

[0166] Example 12: [ka] Step 1: Manufacturing 12A Compound 2-chloro-3-nitro-5-fluoropyridine (0.33 g, 1.87 mmol) and the hydrochloride salt of compound 1I (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL), diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was heated to 60°C and stirred for 4 hours. After cooling to room temperature, 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 12A (0.42 g, yield: 74%).

[0167] Step 2: Manufacturing of 12B Compound 12A (0.4 g, 1.32 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.07 mmol) and iron powder (0.74 g, 13.25 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 12B (0.3 g, yield: 83%).

[0168] Step 3: Manufacturing 12C Compound 12B (0.3 g, 1.1 mmol) was dissolved in THF (5 mL), and N,N'-carbonyldiimidazole (0.54 g, 3.3 mmol) was gradually added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of dichloromethane was added for extraction, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10~1 / 2) to obtain compound 12C (0.2 g, yield: 61%). LCMS m / z=300.1[M+H] +

[0169] Step 4: Manufacturing 12D Compound 2E (0.3 g, 0.74 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.8 mL), lithium hydroxide hydrate (0.17 g, 7.16 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and a white solid precipitated. The mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50) to obtain compound 12D (0.25 g, yield: 86%).

[0170] Step 5: Manufacturing of 12E Compound 12D (0.25 g, 0.64 mmol) was dissolved in tetrahydrofuran (7 mL), and metachloroperbenzoic acid (0.33 g, 1.92 mmol) was added at room temperature. After the addition, stirring was continued for 2 hours. 10 mL of saturated sodium thiosulfate aqueous solution was added and stirred for 20 minutes, then 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes, and 20 mL of ethyl acetate was added and stirred to form layers. The organic layer was washed with 10 mL of saturated brine, the organic layer was removed, dried over sodium sulfate, filtered, and concentrated to obtain compound 12E, which was used directly in the next step.

[0171] Step 6: Preparation of Compound 12 Compounds 12C (0.05 g, 0.17 mmol), 12E (0.072 g, 0.17 mmol), and potassium carbonate (0.047 g, 0.34 mmol) were mixed and dissolved in DMF (3 mL). The mixture was heated to 100°C and stirred for 16 hours, then heated to 120°C and stirred for a further 24 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added and stirred to form layers. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 3). The resulting residue was further purified by reverse-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to obtain compound 12 (10 mg, yield: 9%). LCMS m / z = 645.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.35(dd,1H),8.17-8.13(m,1H),7.26(s,1H),7.22- 7.02(m,2H),4.22(t,2H),2.93(s,2H),2.88-2.72(m,2H),1.81(s,3H),1.16-1.04(m,6H).

[0172] Preparation of Compound 12-1 and Compound 12-2: [ka] Compound 12 (110 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: Methanol (0.05% aqueous ammonia), b. Isocratic elution occurred, with a mobile phase B content of 12%, and c. The flow rate was 40 ml / min.

[0173] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 12-1 (50 mg) and compound 12-2 (50 mg).

[0174] Compound 12-1: Retention time under fractional separation conditions was 9.62 min, and LCMS m / z = 645.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.35(dd,1H),8.18-8.10(m,1H),7.26(s,1H),7.23- 7.01(m,2H),4.22(t,2H),2.93(s,2H),2.88-2.71(m,2H),1.80(s,3H),1.16-1.03(m,6H).

[0175] Compound 12-2: Retention time under fractional separation conditions was 13.68 min, and LCMS m / z = 645.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.35(dd,1H),8.19-8.12(m,1H),7.26(s,1H),7.22- 7.05(m,2H),4.22(t,2H),2.93(s,2H),2.88-2.71(m,2H),1.81(s,3H),1.16-1.02(m,6H).

[0176] Example 13: [ka] Step 1: Manufacturing of 13B Compound 2-chloro-3-nitro-5-fluoropyridine (0.3 g, 1.87 mmol) and compound 13A (0.21 g, 1.87 mmol) were dissolved in DMSO (5 mL), diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was heated to 60°C and stirred for 4 hours. After cooling to room temperature, 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 13B (0.4 g, yield: 84%).

[0177] Step 2: Manufacturing of 13C Compound 13B (0.4 g, 1.58 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.73 g, 13.64 mmol) and iron powder (0.76 g, 13.54 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 13C (0.3 g, yield: 85%).

[0178] Step 3: Manufacturing of 13D Compound 13C (0.3 g, 1.34 mmol) was dissolved in THF (15 mL), and N,N'-carbonyldiimidazole (0.65 g, 4.01 mmol) was gradually added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of dichloromethane was added for extraction, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10~1 / 2) to obtain compound 13D (0.24 g, yield: 72%). LCMS m / z = 250.2[M+H] +

[0179] Step 4: Preparation of Compound 13 Compounds 13D (40 mg, 0.16 mmol), 12E (68 mg, 0.16 mmol), and potassium carbonate (44 mg, 0.32 mmol) were mixed and dissolved in DMF (3 mL). The mixture was heated to 100°C and stirred for 16 hours, then heated to 120°C and stirred for a further 24 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added and stirred to form layers. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 3). The resulting residue was further purified by reverse-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to obtain compound 13 (20 mg, yield: 21%). LCMS m / z = 595.3[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),8.28(dd,1H),8.13-8.07(m,1H),7.26(s,1H),7.22-7.01(m,2 H),3.74(d,2H),2.93(s,2H),1.97-1.86(m,1H),1.81(s,3H),1.74-1.52(m,5H),1.26-0.92(m,11H).

[0180] Example 14: [ka] Step 1: Manufacturing 14A Compound 2,3-difluoronitrobenzene (0.3 g, 1.87 mmol) and the hydrochloride salt of compound 1I (0.37 g, 1.87 mmol) were dissolved in DMSO (5 mL), diisopropylethylamine (0.73 g, 5.61 mmol) was added, and the mixture was heated to 60°C and stirred for 4 hours. After cooling to room temperature, 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 14A (0.4 g, yield: 71%).

[0181] Step 2: Manufacturing of 14B Compound 14A (0.4 g, 1.35 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.7 g, 13.07 mmol) and iron powder (0.74 g, 13.25 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 14B (0.3 g, yield: 84%).

[0182] Step 3: Manufacturing of 14C Compound 14B (0.3 g, 1.1 mmol) was dissolved in THF (10 mL), and N,N'-carbonyldiimidazole (0.54 g, 3.3 mmol) was gradually added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of dichloromethane was added for extraction, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10~1 / 2) to obtain compound 14C (0.2 g, yield: 61%). LCMS m / z=299.1[M+H] +

[0183] Step 4: Manufacturing of 14D Compound 14C (0.1 g, 0.34 mmol), 2F (0.15 g), and potassium carbonate (0.094 g, 0.68 mmol) were mixed and dissolved in DMF (3 mL). The mixture was heated to 100°C and stirred for 16 hours, then heated to 120°C and stirred for a further 24 hours. The mixture was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 3). The resulting residue was further purified by reverse-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to obtain compound 14D (20 mg, yield: 9%).

[0184] Step 5: Preparation of trifluoroacetate of compound 14 Compound 14D (20 mg, 0.03 mmol) was dissolved in a mixed solvent of 1,4-dioxane (0.5 mL) and water (0.1 mL), lithium hydroxide hydrate (12.6 mg, 0.3 mmol) was added, the temperature was raised to 60°C, and the mixture was stirred for 3 hours. The mixture was cooled to room temperature, and dilute hydrochloric acid was added under an ice bath to adjust the acidity. The solid was precipitated, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50). The preparative solution was treated with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, concentrated under reduced pressure, and then appropriate amounts of water and acetonitrile were added. The mixture was freeze-dried to obtain the trifluoroacetate salt of compound 14 (10 mg). LCMS m / z = 644.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.57(s,1H),7.64-7.56(m,1H),7.26(s,1H),7.14-7.04(m ,4H),4.29(t,2H),2.93(s,2H),2.82-2.62(m,2H),1.82(s,3H),1.15-1.05(m,6H).

[0185] Preparation of Compound 14-1 and Compound 14-2 Compound 14 (100 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: Methanol (0.05% aqueous ammonia), b. Isocratic elution occurred, with a mobile phase B content of 20%, and c. The flow rate was 40 ml / min.

[0186] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 14-1 (40 mg) and compound 14-2 (40 mg). [ka]

[0187] Compound 14-1: Retention time under fractional separation conditions was 5.40 min, and LCMS m / z = 644.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),7.64-7.56(m,1H),7.26(s,1H),7.16-6.99(m ,4H),4.29(t,2H),2.93(s,2H),2.81-2.64(m,2H),1.82(s,3H),1.15-1.05(m,6H).

[0188] Compound 14-2: Retention time under fractional separation conditions was 8.53 min, and LCMS m / z = 644.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.48(s,1H),7.64-7.55(m,1H),7.26(s,1H),7.20-6.95(m ,4H),4.29(t,2H),2.93(s,2H),2.82-2.62(m,2H),1.82(s,3H),1.18-1.01(m,6H).

[0189] Example 15: [ka] Step 1: Manufacturing 15A Compound 2,3-difluoronitrobenzene (0.23 g, 1.87 mmol) and compound 15A (0.3 g, 1.87 mmol) were dissolved in DMSO (5 mL), diisopropylethylamine (0.71 g, 5.49 mmol) was added, and the mixture was heated to 60°C and stirred for 4 hours. After cooling to room temperature, 30 mL of MTBE and 30 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 1 / 10) to obtain compound 15B (0.4 g, yield: 81%).

[0190] Step 2: Manufacturing 15C Compound 15B (0.4 g, 1.51 mmol) was dissolved in a mixed solvent of ethanol (6 mL) and water (2 mL). Ammonium chloride (0.81 g, 15.1 mmol) and iron powder (0.84 g, 15.1 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 10 to 3 / 10) to obtain compound 15C (0.3 g, yield: 85%).

[0191] Step 3: Manufacturing of 15D Compound 15C (0.3 g, 1.28 mmol) was dissolved in THF (10 mL), and N,N'-carbonyldiimidazole (0.62 g, 3.84 mmol) was gradually added under ice bath conditions. After the addition was complete, the mixture was allowed to rise naturally to room temperature and stirred for 2 hours. 10 mL of saturated sodium bicarbonate aqueous solution was added and stirred for 10 minutes. 20 mL of dichloromethane was added for extraction, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 10~1 / 2) to obtain compound 15D (0.2 g, yield: 60%). LCMS m / z=261.2[M+H] +

[0192] Step 4: Manufacturing of 15E Compound 15D (0.15 g, 0.58 mmol), 2F (0.25 g), and potassium carbonate (0.16 g, 1.16 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 100°C and stirred for 16 hours, then heated to 120°C and stirred for a further 24 hours. The mixture was cooled to room temperature, 20 mL of ethyl acetate and 20 mL of water were added, and the mixture was stirred to form layers. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 3). The resulting residue was further purified by reverse-phase column chromatography (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100 to 60 / 40) to obtain compound 15E (0.1 g, yield: 28%).

[0193] Step 5: Manufacturing of Compound 15 Compound 15E (100 mg, 0.16 mmol) was dissolved in a mixed solvent of 1,4-dioxane (2 mL) and water (1 mL), lithium hydroxide hydrate (38 mg, 1.6 mmol) was added, the temperature was raised to 60°C, and the mixture was stirred for 3 hours. The mixture was cooled to room temperature, and dilute hydrochloric acid was added under an ice bath to adjust the acidity. The solid was precipitated, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50). The preparative solution was treated with saturated sodium bicarbonate aqueous solution, extracted with dichloromethane, concentrated under reduced pressure, and then appropriate amounts of water and acetonitrile were added. The mixture was freeze-dried to obtain the trifluoroacetate salt of compound 15 (20 mg). LCMS m / z = 606.2[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.59(s,1H),7.61(d,1H),7.40-7.31(m,1H),7.29-6.91(m,8H),5.23(s,2H),2.93(s,2H),1.82(s,3H),1.10(s,6H).

[0194] Preparation of Compound 15-1 and Compound 15-2: Compound 15 (200 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: mobile phase A: CO2, mobile phase B: methanol (0.05% aqueous ammonia), b. Isocratic elution, with mobile phase B content at 40%, c. Flow rate: 40 mL / min.

[0195] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 15-1 (70 mg) and compound 15-2 (80 mg).

[0196] Compound 15-1: Retention time under fractional separation conditions was 7.38 min, and LCMS m / z = 606.2 [M+1]. + That was the case.

[0197] Compound 15-2: Retention time under fractional separation conditions was 11.93 min, and LCMS m / z = 606.2 [M+1]. + That was the case.

[0198] Example 16: [ka] Compound 16 (20 mg) was obtained by referring to the synthesis in Example 8. LCMS m / z = 628.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),7.75(s,1H),7.63-7.56(m,1H),7.13-7.05(m,2H), 6.96-6.68(m,2H),4.29(t,2H),2.82-2.60(m,4H),1.82(s,3H),1.10(s,3H),1.09(s,3H).

[0199] Example 17: [ka] Step 1: Manufacturing 17A Compounds 2-bromo-5-fluorobenzoate methyl (5 g, 21.43 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (5.66 g, 23.57 mmol) were dissolved in THF (100 mL). Sodium bis(trimethylsilyl)amide (32.1 mL, 2 M, 64.28 mmol) was added at -78 °C, and the mixture was stirred at the same temperature for 15 min to allow the reaction to proceed. The temperature was then raised to 0 °C and the reaction was continued for 2 hours. 1N hydrochloric acid (160 mL) was added to quench the reaction, and the mixture was stirred overnight at room temperature. Ethyl acetate was added for extraction, the organic phase was washed twice with saturated sodium bicarbonate aqueous solution, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 20) to obtain compound 17A (2.9 g, yield: 38%).

[0200] Step 2: Manufacturing of 17B Compound 17A (2 g, 5.73 mmol) was dissolved in methanol (20 mL), and aminoguanidine hydrochloride (0.95 g, 8.59 mmol) and boron trifluoride diethyl ether (1.41 mL, 11.46 mmol) were added. The mixture was heated to 100°C in a sealed tube and reacted for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 17B, which was used directly in the next step. LCMS m / z = 405.10[M+H]+

[0201] Step 3: Manufacturing of 17C Compound 17B (1 g, 2.47 mmol), 3H (1.18 g, 4.94 mmol), and potassium tert-butoxide (0.28 g, 2.47 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was heated to 130°C in a sealed tube and stirred for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form a layer. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 17C (320 mg, yield: 21%).

[0202] Step 4: Manufacturing of 17D Compound 17C (300 mg, 0.50 mmol) was dissolved in DMF (5 mL), and N,N-dimethylethylenediamine (66.11 mg, 0.75 mmol) and cuprous iodide (19.04 mg, 0.10 mmol) were added. The mixture was purged three times with nitrogen gas and reacted for 2 hours under nitrogen gas protection. Ethyl acetate and water were added, the mixture was stirred, and then layered. The organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 17D (190 mg, yield: 73%).

[0203] Step 5: Manufacturing of 17E Compound 17D (190 mg, 0.37 mmol) was dissolved in methanol (3 mL), and 3 mL of 7 M ammonia-methanol solution was added. The mixture was reacted overnight at 40°C. The mixture was concentrated under reduced pressure to obtain compound 17E (180 mg). LCMS m / z = 488.30[M+H] +

[0204] Step 6: Manufacturing 17F Compound 17E (180 mg, 0.37 mmol) was dissolved in toluene (5 mL), and Lawesson's Reagent (224.48 mg, 0.55 mmol) was added. After adding the reagent, the temperature was raised to 80°C and the mixture was stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 5 / 1) to obtain compound 17F (170 mg, yield: 91%). LCMS m / z = 504.20[M+H] +

[0205] Step 7: Manufacturing 17G Compound 17F (170 mg, 0.34 mmol) was dissolved in ethanol (5 mL), and 2D (110.25 mg, 0.46 mmol) was added. After adding the compounds, the temperature was raised to 80°C and the mixture was stirred overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 5 / 1) to obtain compound 17G (150 mg, yield: 68%). LCMS m / z = 642.40[M+H] +

[0206] Step 8: Preparation of Compound 17 Compound 17G (150 mg, 0.23 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL), lithium hydroxide hydrate (96.51 mg, 2.3 mmol) was added, the mixture was heated to 60°C, and stirred for 3 hours. The mixture was cooled to room temperature, and dilute hydrochloric acid was added under an ice bath to adjust the acidity. The solid was precipitated, extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was further purified by preparative HPLC (instrument: waters AutoP preparative liquid, chromatography column: SunFire@ Prep C18 (19 mm × 250 mm), mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 5 mM ammonium acetate)) to obtain compound 17 (65 mg, yield: 45%). LCMS m / z = 628.20[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.26-12.02(m,1H),11.52(s,1H),8.87(dd,1H),7.81(dd,1H),7.47-7.39(m,1H),7 .25(s,1H),7.20-7.00(m,2H),3.30-3.24(m,2H),2.93(s,2H),2.88-2.66(m,2H),1.81(s,3H),1.10(s,6H).

[0207] Preparation of Compound 17-1 and Compound 17-2: Compound 17 (60 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: mobile phase A: CO2, mobile phase B: methanol (0.05% aqueous ammonia), b. Isocratic elution, with mobile phase B content at 30%, c. Flow rate: 45 mL / min.

[0208] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 17-1 (15 mg) and compound 17-2 (20 mg). [ka]

[0209] Compound 17-1: Retention time under fractional separation conditions was 3.33 min, and LCMS m / z = 628.0 [M+1]. + That was the case. 1H NMR(400MHz,DMSO-d6)δ12.24-12.11(m,1H),11.52(s,1H),8.87(dd,1H),7.81(dd,1H),7.49-7.38(m,1H),7 .25(s,1H),7.21-7.01(m,2H),3.30-3.24(m,2H),2.93(s,2H),2.87-2.69(m,2H),1.82(s,3H),1.11(s,6H).

[0210] Compound 17-2: Retention time under fractional separation conditions was 7.02 min, and LCMS m / z = 628.0 [M+1]. + That was the case.

[0211] Example 18: [ka] Compound 18 (100 mg) was obtained by referring to the synthesis of Examples 3 and 6. LCMS m / z = 604.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.55-11.75(m,1H),11.14(s,1H),8.97(d,1H),8.50(s,1H),7.28-7.21(m,1H),7.18 -7.00(m,4H),6.72-6.35(m,2H),3.46-3.35(m,2H),2.95-2.69(m,4H),1.79(s,3H),1.06(s,3H),1.02(s,3H).

[0212] Example 19: [ka] Step 1: Manufacturing of 19A The hydrochloride salt of compound 3B (2.83 g, 19.41 mmol) and o-fluorophenylacetic acid (2 g, 12.94 mmol) were dissolved in DMF (20 mL), HATU (7.38 g, 19.41 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (5.02 g, 38.81 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 0 to 100 / 10) to obtain compound 19A (420 mg, yield: 13%). LCMS m / z = 246.2[M+H] +

[0213] Step 2: Manufacturing of 19B Compound 19A (420 mg, 1.71 mmol) was dissolved in DCE (20 mL), phosphorus oxychloride (0.91 mL, 9.94 mmol) was added, and the mixture was heated to reflux and reacted overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure, water was carefully and slowly added to the residue, and the mixture was stirred for 5 minutes. Ethyl acetate was added, and the mixture was stirred to form a layer. The aqueous layer was treated with saturated sodium bicarbonate aqueous solution, and then extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was directly purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100~20 / 100) to obtain compound 19B (250 mg, yield: 64%). LCMS m / z = 228.1[M+H] +

[0214] Step 3: Manufacturing of 19C Compound 19B (250 mg, 1.10 mmol) was dissolved in DCM (10 mL), NBS (215.36 mg, 1.21 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. Water was added, the mixture was stirred to form layers, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100 to 50 / 100) to obtain compound 19C (280 mg, yield: 83%). LCMS m / z = 305.90[M+H] +

[0215] Step 4: Manufacturing of 19D Compound 19C (280 mg, 0.91 mmol) and zinc cyanide (220 mg, 2.06 mmol) were added to a 50 mL single-mouthed flask. Zinc powder (150 mg, 2.29 mmol), 1,1'-bis(diphenylphosphin)ferrocene (302.69 mg, 0.55 mmol), and tris(dibenzylidene-BASE acetone)dipalladium (250 mg, 0.27 mmol) were then added. N,N-dimethylacetamide (10 mL) was added, the mixture was protected with nitrogen gas, and the temperature was raised to 120 °C and stirred for 2 hours. The reaction mixture was diluted with 50 mL of ethyl acetate, washed three times with water, and washed once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Compound 19D (210 mg, yield: 91%) was obtained by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 2 / 1). LCMS m / z = 253.10[M+H] +

[0216] Step 5: Manufacturing of 19E Under ice bath conditions, ammonium chloride (221.98 mg, 4.15 mmol) was added to a 50 mL pouring flask, toluene (10 mL) was added, and then trimethylaluminum (2.07 mL, 2 M, toluene solution) was slowly added dropwise. The mixture was heated to room temperature and stirred for 3 hours to allow the reaction to proceed. Compound 19D (210 mg, 0.83 mmol) was dissolved in toluene and added dropwise to the reaction mixture. The mixture was heated to 110°C and stirred overnight. After cooling to room temperature, silica gel and 20 mL of methanol were added under ice bath conditions, and stirring continued for 30 minutes. The mixture was filtered by suction, the filter cake was washed three times with methanol, the organic phases were combined, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 19E (200 mg, yield: 89%). LCMS m / z = 270.2[M+H] +

[0217] Step 6: Manufacturing of 19F Compound 19E (100 mg, 0.37 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxypropyl)thiazole-2-yl)-2-methylpropionate (CAS: 2101649-65-2, synthesis route referred to patent US20170174693) (201.70 mg, 0.55 mmol), and potassium bicarbonate (111.13 mg, 1.11 mmol) were mixed and dissolved in tert-butanol (5 mL), heated to 80°C, and stirred overnight. After cooling to room temperature, the mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 19F (190 mg, yield: 87%). LCMS m / z = 587.2[M+H] +

[0218] Step 7: Preparation of Compound 19 Compound 19F (190 mg, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (3 mL), lithium hydroxide hydrate (134.27 mg, 3.2 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50) to obtain the trifluoroacetate of compound 19 (160 mg). LCMS m / z = 573.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.50-11.80(m,1H),11.41(s,1H),8.97(d,1H),8.46(d,1H),7.36-7.1 0(m,5H),7.04(dd,1H),6.98-6.79(m,2H),4.51(s,2H),2.93(s,2H),1.79(s,3H),1.10(s,6H).

[0219] Preparation of Compound 19-1 and Compound 19-2: Compound 19 (140 mg) was chiral separated and purified under the following conditions: Instrument: Waters 150 Prep-SFC, Chromatography column: AD, Column temperature: 35°C, Mobile phase: A is CO2, B is methanol / acetonitrile (0.1% aqueous ammonia), Gradient: B is 55%, Back pressure: 100 bar, Cycle: 5.3 min, Detection wavelength: 220 nm, Flow rate: 100 ml / min.

[0220] Analytical conditions: Instrument: SHIMADZU LC-30AD sf, Chromatography column: AD, Mobile phase A is CO2, Mobile phase B is methanol and acetonitrile (0.05% DEA), Flow rate: 3 ml / min, Column temperature: 35°C, Detection wavelength: 220 nm.

[0221] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 19-1 (56 mg) and compound 19-2 (61 mg). [ka]

[0222] Compound 19-1: Retention time under analytical conditions was 0.519 min, and LCMS m / z = 573.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ10.96-9.69(m,1H),9.00(dd,1H),8.43(dd,1H),7.38-7.06(m,5 H),6.98(dd,1H),6.89-6.70(m,2H),4.49(s,2H),2.93(s,2H),1.78(s,3H),1.09(s,6H).

[0223] Compound 19-2: Retention time under analytical conditions was 1.553 min, and LCMS m / z = 573.1 [M + H]. + That was the case. 1H NMR(400MHz,DMSO-d6)δ11.85-11.05(m,1H),9.00(dd,1H),8.43(dd,1H),7.37-7.09(m,5 H),6.98(dd,1H),6.87-6.71(m,2H),4.49(s,2H),2.93(s,2H),1.78(s,3H),1.09(s,6H).

[0224] Example 20: [ka] Compound 20 (0.035 g) was obtained by referring to the synthesis of Example 6 and Example 21. LCMS m / z = 645.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.50-11.80(m,1H),11.55(s,1H),8.66-8.61(m,2H),7.26 (s,1H),6.90(br.s,2H),4.86(t,2H),3.04-2.86(m,4H),1.81(s,3H),1.10(s,6H).

[0225] Example 21: [ka] Step 1: Manufacturing of 21A Ethyl 2-cyanopropionate (5.00 g, 39.32 mmol) was added to a 100 mL reaction flask, and trimethylchlorosilane (8.54 g, 78.64 mmol) was added dropwise under ice bath conditions, followed by the dropwise addition of water (1.42 g, 78.64 mmol). After the addition was complete, the mixture was stirred at room temperature for 4 hours. 50 mL of water was added to the reaction mixture, followed by the addition of n-hexane for extraction. The solution was then separated, the aqueous phase was collected, the solution was made alkaline with saturated sodium bicarbonate aqueous solution, and the organic phase was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 21A (1.46 g, yield: 25%). LCMS m / z = 146.1[M+H] +

[0226] Step 2: Manufacturing of 21B Compounds 2D (0.50 g, 2.11 mmol) and 21A (0.31 g, 2.15 mmol) were dissolved in ethyl acetate (10 mL), and silver trifluoromethanesulfonate (0.54 g, 2.11 mmol) was added. After adding the compounds, the temperature was raised to 90°C under light-shielding conditions and the mixture was stirred for 2 hours. The reaction mixture was cooled to room temperature, and the solid was removed by suction filtration. The filtration cake was washed three times with dichloromethane, the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain compound 21B (0.30 g, yield: 31%) by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1). LCMS m / z = 284.40[M+H] +

[0227] Step 3: Manufacturing of 21C Compound 21B (0.30 g, 1.06 mmol) was dissolved in tetrahydrofuran (10 mL), protected with nitrogen gas, and lithium bistrimethylsilylamide (0.59 mL, 1.17 mmol, 2 M) was added dropwise under an ice bath. The mixture was reacted at the same temperature for 0.5 hours, and then N-bromosuccinimide (0.21 g, 1.17 mmol) was added. After the addition was complete, the mixture was reacted under an ice bath for another 0.5 hours. The reaction was quenched with saturated ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then compound 21C (0.217 g, yield: 56%) was obtained by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1). LCMS m / z = 362.40[M+H] +

[0228] Step 4: Manufacturing of 21D Compound 21C (0.217 g, 0.60 mmol) and malononitrile (0.079 g, 1.20 mmol) were dissolved in tetrahydrofuran (10 mL), and DBU (0.18 g, 1.20 mmol) was added dropwise under ice bath conditions. After the addition was complete, the mixture was reacted under ice bath conditions for 0.5 hours. The reaction was quenched with saturated ammonium chloride, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 21D (0.16 g, yield: 76%) was obtained by high-performance column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 3 / 1). LCMS m / z=348.1[M+H] +

[0229] Step 5: Manufacturing of 21E Compounds 6F (0.10 g, 0.29 mmol), 21D (0.10 g, 0.29 mmol), and potassium bicarbonate (0.087 g, 0.87 mmol) were mixed and dissolved in tert-butanol (10 mL). The mixture was heated to 80°C and stirred for 16 hours to allow the reaction to proceed. After cooling to room temperature, the mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain compound 21E (0.142 g, yield: 76%). LCMS m / z = 643.2[M+H] +

[0230] Step 6: Preparation of Compound 21 Compound 21E (0.142 g, 0.22 mmol) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (5 mL), lithium hydroxide hydrate (0.092 g, 2.2 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and a white solid precipitated. The mixture was extracted three times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50) to obtain compound 21 (0.095 g, yield: 67%). LCMS m / z = 629.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.50-11.80(m,1H),11.47(s,1H),8.65-8.61(m,2H),7.75(s,1H),6.79-6. 41(m,2H),4.86(t,2H),3.08-2.87(m,2H),2.73-2.61(m,2H),1.82(s,3H),1.11(s,3H),1.09(s,3H).

[0231] Example 22: [ka] Referencing the synthesis of Examples 6, 20, and 21, trifluoroacetate (0.031 g) of compound 22 was obtained. LCMS m / z = 611.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.59(s,1H),8.76(d,1H),8.52(d,1H),7.67-7.59(m,1H),7.2 7(s,1H),7.13-6.90(m,2H),4.92(t,2H),3.05-2.89(m,4H),1.83(s,3H),1.11(s,6H).

[0232] Example 23: [ka] Referring to the synthesis of Examples 6, 20, and 21, trifluoroacetate (0.021 g) of compound 23 was obtained. LCMS m / z = 573.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.71(d,1H),8.40(d,1H),7.62-7.51(m,1H),7.44-7.32(m ,1H),7.30-7.12(m,4H),7.05-6.80(m,2H),5.86(s,2H),2.93(s,2H),1.81(s,3H),1.10(s,6H).

[0233] Example 24: [ka] Compound 24 (0.117 g) was obtained by referring to the synthesis of Examples 6, 20, and 21. LCMS m / z = 591.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ13.00-11.60(m,1H),11.53(s,1H),8.70(d,1H),8.39(d,1H),7.63-7.51(m,1H),7.46-7.35(m,1H) ,7.26(s,1H),7.23-7.13(m,1H),7.08-6.98(m,1H),6.98-6.82(m,2H),5.91(s,2H),2.94(s,2H),1.82(s,3H),1.10(s,6H).

[0234] Example 25: [ka] Compound 25 (250 mg) was obtained by referring to the synthesis of Examples 6, 20, and 21. LCMS m / z = 645.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.35-11.95(m,1H),11.43(s,1H),9.31(s,1H),8.35(s,1H),7 .28(s,1H),6.89(br.s,2H),4.98(t,2H),3.09-2.88(m,4H),1.83(s,3H),1.10(s,6H).

[0235] Example 26: [ka] Compound 26 (100 mg) was obtained by referring to the synthesis of Examples 6, 20, and 21. LCMS m / z = 629.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.16(br.s,1H),11.37(s,1H),9.31(s,1H),8.35(s,1H),7.76(s,1H),6.73-6 .45(m,2H),4.98(t,2H),3.08-2.91(m,2H),2.75-2.61(m,2H),1.84(s,3H),1.12(s,3H),1.10(s,3H).

[0236] Example 27: [ka] Referencing the synthesis of Example 16, trifluoroacetate (10 mg) of compound 27 was obtained. LCMS m / z = 578.3[M+H] +

[0237] Example 28: [ka] Referring to the synthesis in Example 15, trifluoroacetate (20 mg) of compound 28 was obtained. LCMS m / z = 623.5 [MH] - 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.37(dd,1H),8.15-8.05(m,1H),7.44-7.30(m,1 H),7.25(s,1H),7.21-7.00(m,4H),5.18(s,2H),2.93(s,2H),1.81(s,3H),1.10(s,6H).

[0238] Example 29: [ka] Compound 29 (6 mg) was obtained by referring to the synthesis in Example 5. LCMS m / z = 611.1[M+H] + 1H NMR(400MHz,DMSO-d6)δ11.87-11.06(m,1H),9.17(d,1H),8.67(d,1H),7.56(dd,1H) ,7.32-7.07(m,3H),3.41-3.33(m,2H),2.99-2.81(m,4H),1.81(s,3H),1.10(s,6H).

[0239] Example 30: [ka] Referencing the synthesis methods of Examples 6, 20, and 21, we obtained 170 mg of the trifluoroacetate salt of compound 30. LCMS m / z = 629.1[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H),9.23(s,1H),8.31(s,1H),7.26(s,1 H),6.88(s,2H),5.00(t,2H),3.10-2.86(m,4H),1.82(s,3H),1.10(s,6H).

[0240] Example 31: [ka] Step 1: Manufacturing of 31A Compound 11C (0.14 g, 0.47 mmol), 2F (0.30 g), and potassium carbonate (0.13 g, 0.94 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 31A (70 mg, yield: 23%). LCMS m / z = 658.3[M+H] +

[0241] Step 2: Preparation of Compound 31 Compound 31A (0.070 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (10 mL) and water (3 mL), lithium hydroxide (0.026 g, 1.09 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 31 (20 mg, yield: 28%). LCMS m / z = 644.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),7.83(dd,1H),7.35(dd,1H),7.26(s,1H),7.17-6.99(m, 2H),6.96-6.87(m,1H),4.22(t,2H),2.93(s,2H),2.83-2.63(m,2H),1.81(s,3H),1.10(s,6H).

[0242] Preparation of Compound 31-1 and Compound 31-2: Compound 31 (180 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: Mobile phase A: CO2, Mobile phase B: methanol / isopropanol = 1 / 1 (ammonia water 0.05%), b. Isocratic elution, with mobile phase B content at 25%, c. Flow rate: 40 mL / min.

[0243] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 31-1 (75 mg) and compound 31-2 (80 mg). [ka]

[0244] Compound 31-1: Retention time under fractional separation conditions was 4.37 min, and LCMS m / z = 644.2 [M+1]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),7.83(dd,1H),7.35(dd,1H),7.26(s,1H),7.14-6.98(m, 2H),6.96-6.86(m,1H),4.21(t,2H),2.93(s,2H),2.84-2.64(m,2H),1.81(s,3H),1.10(s,6H).

[0245] Compound 31-2: Retention time under fractional separation conditions was 6.45 min, and LCMS m / z = 644.2 [M+1]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ7.83(dd,1H),7.35(dd,1H),7.25(s,1H),7.12-7.00(m,2H),6. 95-6.87(m,1H),4.22(t,2H),2.93(s,2H),2.82-2.63(m,2H),1.81(s,3H),1.10(s,6H).

[0246] Example 32: [ka] Step 1: Manufacturing 32A Compounds 2-bromo-5-chlorobenzoate methyl (5 g, 20.07 mmol) and o-fluorophenylacetic acid (3.40 g, 22.08 mmol) were dissolved in THF (100 mL). Sodium bis(trimethylsilyl)amide (25.09 mL, 2 M, 50.17 mmol) was added at -78 °C, and the mixture was stirred at the same temperature for 15 minutes to allow the reaction to proceed. The temperature was then raised to 0 °C and the reaction was continued for 2 hours. 1N hydrochloric acid (150 mL) was added to quench the reaction, and the mixture was stirred overnight at room temperature. Ethyl acetate was added for extraction, the organic phase was washed twice with saturated sodium bicarbonate solution, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 20) to obtain compound 32A (5.7 g, yield: 86%). LCMS m / z=327.0[M+H] +

[0247] Step 2: Manufacturing of 32B Compound 32A (3 g, 9.16 mmol) was dissolved in methanol (30 mL), and aminoguanidine hydrochloride (1.52 g, 13.75 mmol) and boron trifluoride diethyl ether (2.26 mL, 18.32 mmol) were added. The mixture was heated to 100°C in a sealed tube and reacted for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 32B, which was used directly in the next step. LCMS m / z = 383.3[M+H] +

[0248] Step 3: Manufacturing of 32C Compound 32B (600 mg, 1.56 mmol) was dissolved in DMF (10 mL), and N,N-dimethylethylenediamine (206.27 mg, 2.34 mmol) and cuprous iodide (148.55 mg, 0.78 mmol) were added. The mixture was purged three times with nitrogen gas and reacted for 4 hours under nitrogen gas protection. Ethyl acetate and water were added, the mixture was stirred, and then layered. The organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 32C (200 mg, yield: 49%). LCMS m / z=261.2[M+H] +

[0249] Step 4: Manufacturing of 32D Compound 32C (60 mg, 0.23 mmol), 2F (107.15 mg), and cesium carbonate (149.88 mg, 0.46 mmol) were mixed and dissolved in DMF (3 mL). The mixture was heated to 100°C and stirred for 40 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 32D (60 mg, yield: 42%). LCMS m / z = 620.2[M+H] +

[0250] Step 5: Preparation of Compound 32 Compound 32D (60 mg, 0.097 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1.5 mL), lithium hydroxide (40.70 mg, 0.97 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1N hydrochloric acid aqueous solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate salt of compound 32 (15 mg). LCMS m / z = 606.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.85(d,1H),7.82(d,1H),7.53(dd,1H),7. 39(t,1H),7.35-7.02(m,6H),4.40(s,2H),2.93(s,2H),1.81(s,3H),1.10(s,6H).

[0251] Preparation of Compound 32-1 and Compound 32-2: Compound 32 (65 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: mobile phase A: CO2, mobile phase B: isopropanol (0.05% aqueous ammonia), b. Isocratic elution, with mobile phase B content at 40%, c. Flow rate: 40 mL / min.

[0252] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 32-1 (20 mg) and compound 32-2 (25 mg).

[0253] Compound 32-1: Retention time under fractional separation conditions was 7.40 min, and LCMS m / z = 606.0 [M+1]. + That was the case.

[0254] Compound 32-2: Retention time under fractional separation conditions was 11.97 min, and LCMS m / z = 606.0 [M+1]. + That was the case.

[0255] Example 33: [ka] Referring to the synthesis in Example 17, trifluoroacetate (15 mg) of compound 33 was obtained. LCMS m / z = 612.3[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.86(dd,1H),7.81(dd,1H),7.75(s,1H),7.47-7.37(m,1H),7.20-6. 46(m,2H),3.35-3.23(m,2H),2.87-2.72(m,2H),2.71-2.61(m,2H),1.81(s,3H),1.11(s,3H),1.09(s,3H).

[0256] Example 34: [ka] Referring to the synthesis in Example 4, trifluoroacetate (8 mg) of compound 34 was obtained. LCMS m / z = 590.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.49(s,1H),8.84(d,1H),7.82(d,1H),7.74(s,1H),7.52(dd,1H),7.42-7.27(m,2H) ,7.24-7.13(m,2H),7.03-6.65(m,2H),4.40(s,2H),2.71-2.58(m,2H),1.81(s,3H),1.11(s,3H),1.08(s,3H).

[0257] Example 35: [ka] Step 1: Manufacturing of 35B Compound 35A (CAS: 1361570-31-1, synthesis referred to US2013210824) (1 g, 3.23 mmol) was dissolved in DMSO (5 mL), sodium chloride (0.29 g, 4.93 mmol) and water (0.5 mL) were added in sequence, and the mixture was heated to 160 °C and stirred for 30 min. After cooling to room temperature, 10 mL of water and 20 mL of ethyl acetate were added for extraction, the organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 35B (0.7 g, yield: 86%).

[0258] Step 2: Manufacturing 35C Compound 35B (0.7g, 2.79 mmol) was dissolved in ethylene glycol (7 mL), hydrazine hydrate (1.24 g, 19.75 mmol, wt%=80%) was added, the temperature was raised to 100°C and stirred for 30 minutes, then the temperature was raised to 120°C and stirred for 2 hours. The mixture was cooled to room temperature, and 14 mL of water was slowly added dropwise while stirring to precipitate the solid. The mixture was filtered, and the filtered cake was dried under reduced pressure to obtain compound 35C (0.35 g, yield: 51%). LCMS m / z=246.1[M+H] +

[0259] Step 3: Manufacturing of 35D Compound 35C (0.1 g, 0.41 mmol), 2F (0.21 g), and potassium carbonate (0.057 g, 0.41 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 35D (0.22 g, yield: 88%). LCMS m / z = 605.1[M+H] +

[0260] Step 4: Preparation of Compound 35 Compound 35D (0.22 g, 0.36 mmol) was dissolved in a mixed solvent of 1,4-Dioxane (3 mL) and water (2 mL), lithium hydroxide (0.086 g, 3.59 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 35 (0.15 g, yield: 70%). LCMS m / z = 591.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.19(s,1H),11.55(s,1H),9.04(dd,1H),8.68(d,1H),7.42 -7.35(m,1H),7.33-7.05(m,6H),4.43(s,2H),2.93(s,2H),1.81(s,3H),1.11(s,6H).

[0261] Preparation of Compound 35-1 and Compound 35-2: Compound 35 (140 mg) was used for chiral separation and purification. Preparative chromatography conditions: Instrument: SFC Prep 150 AP, Chromatography column: IG (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Isocratic elution was performed, with a mobile phase B content of 30% and a flow rate of 54 ml / min.

[0262] Analytical conditions: Instrument: UPC2, chromatographic column: IG (3 mm × 50 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Gradient elution was performed, with a mobile phase B content of 10% to 40% and a time of 5 min. Isocratic elution was performed, with a mobile phase B content of 40% and a flow rate of 1.5 ml / min.

[0263] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 35-1 (60 mg) and compound 35-2 (70 mg).

[0264] Compound 35-1: Retention time under analytical conditions was 3.4 min, and LCMS m / z = 591.1 [M + H]. + That was the case.

[0265] Compound 35-2: Retention time under analytical conditions was 5.2 min, and LCMS m / z = 591.1 [M + H]. + That was the case.

[0266] Example 36: [ka] Step 1: Manufacturing 36A Compound 2,3-difluorophenylacetic acid (1 g, 5.81 mmol) was dissolved in methanol (10 mL), p-toluenesulfonic acid monohydrate (0.11 g, 0.58 mmol) was added, and the mixture was heated to reflux and reacted for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was dissolved in 20 mL of ethyl acetate. The organic layer was washed sequentially with saturated sodium bicarbonate aqueous solution (10 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step.

[0267] Step 2: Manufacturing of 36B Compound 36A (1.11 g, 5.95 mmol) was dissolved in THF (10 mL), and LiHMDS (7.14 mmol, 7.14 mL, 1 N) was slowly added dropwise under an ethanol dry ice bath. After the addition was complete, the mixture was stirred at -70°C for 1 hour. At this temperature, a 10 mL THF solution of 3,5-difluoropyridinyl chloride (CAS: 1048340-35-7, synthesis referred to WO2011158149) (1.27 g, 7.14 mmol) was slowly added dropwise. After the addition was complete, the mixture was allowed to rise naturally to room temperature, 10 mL of saturated ammonium chloride aqueous solution was added to quench the mixture, and 20 mL of ethyl acetate was added for extraction. The organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 36B (0.5 g, yield: 26%).

[0268] Step 3: Manufacturing 36C Compound 36B (0.5 g, 1.53 mmol) was dissolved in DMSO (5 mL), and sodium chloride (0.13 g, 2.29 mmol) and water (0.5 mL) were added in sequence. The mixture was heated to 160 °C and stirred for 30 min. After cooling to room temperature, 10 mL of water and 20 mL of ethyl acetate were added for extraction. The organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 20) to obtain compound 36C (0.3 g, yield: 73%).

[0269] Step 4: Manufacturing of 36D Compound 36C was dissolved in ethylene glycol (4 mL), hydrazine hydrate (0.49 g, 7.86 mmol, wt%=80%) was added, the temperature was raised to 100°C and stirred for 30 minutes, then the temperature was raised to 120°C and stirred for 2 hours. The mixture was cooled to room temperature, stirred, and 8 mL of water was slowly added dropwise to precipitate the solid. The mixture was filtered, and the filtered cake was dried under reduced pressure to obtain compound 36D (0.14 g, yield: 48%). LCMS m / z = 264.3[M+H] +

[0270] Step 5: Manufacturing of 36E Compound 36D (0.1 g, 0.38 mmol), 2F (0.19 g), and potassium carbonate (0.10 g, 0.76 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 36E (0.2 g, yield: 84%). LCMS m / z = 623.2[M+H] +

[0271] Step 6: Preparation of Compound 36 Compound 36E (0.2 g, 0.32 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL), lithium hydroxide (0.077 g, 3.2 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl, 20 mL of ethyl acetate was added, 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 silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 36 (0.12 g, yield: 61%). LCMS m / z = 609.2[M+H]+ 1 H NMR(400MHz,DMSO-d6)δ12.19(s,1H),11.54(s,1H),9.05(dd,1H),8.69(d, 1H),7.42-7.02(m,6H),4.49(s,2H),2.93(s,2H),1.81(s,3H),1.11(s,6H).

[0272] Preparation of Compound 36-1 and Compound 36-2: Compound 36 (100 mg) was used for chiral separation and purification. Preparative chromatography conditions: Instrument: SFC Prep 150 AP, Chromatography column: IG (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Isocratic elution was performed, with a mobile phase B content of 30% and a flow rate of 54 ml / min.

[0273] Analytical conditions: Instrument: UPC2, chromatographic column: IG (3 mm × 50 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Gradient elution was performed, with a mobile phase B content of 10% to 40% and a time of 5 min. Isocratic elution was performed, with a mobile phase B content of 40% and a flow rate of 1.5 ml / min.

[0274] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 36-1 (39 mg) and compound 36-2 (35 mg).

[0275] Compound 36-1: Retention time under analytical conditions was 3.3 min, and LCMS m / z = 609.2 [M + H]. + That was the case.

[0276] Compound 36-2: Retention time under analytical conditions was 5.4 min, and LCMS m / z = 609.2 [M + H].+ That was the case.

[0277] Example 37: [ka] Step 1: Manufacturing 37A 10 mL of THF was placed in a three-necked flask, high-purity zinc powder (0.74 g, 11.31 mmol) was added, the mixture was purged three times with nitrogen gas, and 1,2-dibromoethane (0.11 g, 0.56 mmol) was added. After adding the zinc, the mixture was heated to 70°C and stirred for 10 minutes. After cooling to room temperature, trimethylchlorosilane (0.061 g, 0.56 mmol) was slowly added. After adding the trimethylchlorosilane, the mixture was stirred vigorously at room temperature for 10 minutes. 5 mL of a THF solution of 1,1,1,2,2-pentafluoro-4-iodobutane (1.55 g, 5.66 mmol) was slowly added dropwise. After adding the trimethylchlorosilane, the mixture was stirred at room temperature for 2 hours to prepare the resulting reagent for use. In a separate reaction flask, 3,5-difluoropyridinyl chloride (CAS: 1048340-35-7, synthesis referred to WO2011158149) (0.5 g, 2.82 mmol) was dissolved in THF (10 mL), bistriphenylphosphine dichloride palladium (0.20 g, 0.28 mmol) was added, the mixture was purged three times with nitrogen gas, and the reagents prepared for use were slowly added dropwise at room temperature. After all additions were made, the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 20 mL of saturated ammonium chloride, extracted with 20 mL of ethyl acetate and 10 mL of water, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 20) to obtain compound 37A (0.22 g, yield: 27%). LCMS m / z = 290.1[M+H] +

[0278] Step 2: Manufacturing of 37B Compound 37A (0.22 g, 0.76 mmol) was dissolved in ethylene glycol (3 mL), hydrazine hydrate (0.38 g, 7.59 mmol, wt%=80%) was added, the temperature was raised to 100°C and stirred for 30 minutes, then the temperature was raised to 120°C and stirred for 2 hours. The mixture was cooled to room temperature, stirred, and 6 mL of water was slowly added dropwise to precipitate the solid. The mixture was filtered, and the filtered cake was dried under reduced pressure to obtain compound 37B (0.1 g, yield: 46%). LCMS m / z=284.2[M+H] +

[0279] Step 3: Manufacturing of 37C Compound 37B (0.1 g, 0.35 mmol), 2F (0.18 g), and potassium carbonate (0.097 g, 0.70 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 80°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 37C (0.15 g, yield: 66%). LCMS m / z = 643.1[M+H] +

[0280] Step 4: Preparation of Compound 37 Compound 37C (0.15 g, 0.23 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL), lithium hydroxide (0.056 g, 2.33 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 silica gel column chromatography (dichloromethane / methanol (V / V) = 100 / 0-97 / 3) to obtain compound 37 (90 mg, yield: 62%). LCMS m / z = 629.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ12.19(s,1H),11.55(s,1H),9.06(dd,1H),8.72(dd,1H),7 .56-6.90(m,3H),3.40-3.32(m,2H),2.97-2.81(m,4H),1.82(s,3H),1.11(s,6H).

[0281] Preparation of Compound 37-1 and Compound 37-2: Compound 37 (80 mg) was taken and used for chiral separation and purification. Preparative chromatography conditions: Instrument: SFC Prep 150 AP, Chromatography column: IG (19 mm × 250 mm). The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Isocratic elution was performed, with a mobile phase B content of 15% and a flow rate of 42 ml / min.

[0282] Analytical conditions: Instrument: UPC2, chromatographic column: IG (3 mm × 50 mm). The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. Preparative chromatography conditions: Mobile phase A: CO2, Mobile phase B: Methanol (containing 0.5% aqueous ammonia). Gradient elution was performed, with a mobile phase B content of 10% to 40% and a time of 5 min. Isocratic elution was performed, with a mobile phase B content of 40% and a flow rate of 1.5 ml / min.

[0283] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 37-1 (38 mg) and compound 37-2 (35 mg).

[0284] Compound 37-1: Retention time under analytical conditions was 1.9 min, and LCMS m / z = 629.2 [M + H]. + That was the case.

[0285] Compound 37-2: Retention time under analytical conditions was 2.7 min, and LCMS m / z = 629.2 [M + H]. +That was the case.

[0286] Example 38: [ka] Step 1: Manufacturing 38A Compounds 2,4-difluoronitrobenzene (1 g, 6.29 mmol) and 2-fluorobenzylamine (0.86 g, 6.88 mmol) were dissolved in DMSO (5 mL), diisopropylethylamine (1.22 g, 9.44 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Extraction was performed by adding 30 mL of methyl tert-butyl ether and 30 mL of water. The organic layer was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was beaten with 20 mL of methyl tert-butyl ether / petroleum ether (V / V=1 / 5) to obtain compound 38A (1.1 g, yield: 66%).

[0287] Step 2: Manufacturing of 38B Compound 38A (1.1 g, 4.16 mmol) was dissolved in a mixed solvent of ethanol (10 mL) and water (3 mL). Ammonium chloride (2.22 g, 41.49 mmol) and iron powder (2.32 g, 41.56 mmol) were added in sequence. After adding the compounds, the temperature was raised to 75°C and the mixture was stirred for 1.5 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with 20 mL of dichloromethane. The filtrates were combined, and 20 mL of saturated saline solution was added to wash the filtrate. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was beaten with 20 mL of methyl tert-butyl ether / petroleum ether (V / V=1 / 4) to obtain compound 38B (0.8 g, yield 82%).

[0288] Step 3: Manufacturing of 38C Compound 38B (0.8 g, 3.42 mmol) was dissolved in THF (10 mL), and N,N'-carbonyldiimidazole (0.83 g, 5.13 mmol) was added. After the addition, the mixture was stirred at room temperature for 16 hours. 20 mL of dichloromethane was added, and the organic layer was washed with 20 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was beaten with 20 mL of methyl tert-butyl ether / petroleum ether (V / V=1 / 1) to obtain compound 38C (0.45 g, yield: 50%). LCMS m / z=261.1[M+H] +

[0289] Step 4: Manufacturing of 38D Compound 38C (0.10 g, 0.40 mmol), 2F (0.20 g), and potassium carbonate (0.11 g, 0.80 mmol) were mixed and dissolved in DMF (5 mL). The mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, 20 mL of ethyl acetate and 20 mL of water were added for extraction. The organic layer was washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 1 / 5 to 1 / 1) to obtain compound 38D (70 mg, yield: 28%). LCMS m / z = 620.3[M+H] +

[0290] Step 5: Preparation of Compound 38 Compound 38D (0.07 g, 0.11 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (2 mL), lithium hydroxide (0.026 g, 1.1 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-50 / 50) to obtain the trifluoroacetate salt of compound 38 (30 mg). LCMS m / z = 606.0[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),7.84(dd,1H),7.41-7.32(m,1H),7.31-6.98( m,7H),6.94-6.87(m,1H),5.15(s,2H),2.93(s,2H),1.81(s,3H),1.15-1.01(m,6H).

[0291] Preparation of Compound 38-1 and Compound 38-2: [ka] Compound 38 (300 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm). 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. The mobile phase consists of systems A and B: mobile phase A: CO2, mobile phase B: methanol (0.05% aqueous ammonia), b. Isocratic elution, with mobile phase B content at 40%, c. Flow rate: 40 mL / min.

[0292] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 38-1 (110 mg) and compound 38-2 (120 mg).

[0293] Compound 38-1: Retention time under fractional separation conditions was 7.78 min, and LCMS m / z = 606.0 [M+1]. + That was the case.

[0294] Compound 38-2: Retention time under fractional separation conditions was 12.85 min, and LCMS m / z = 606.2 [M+1]. + That was the case.

[0295] Example 39: [ka] Referring to the synthesis in Example 38, trifluoroacetate (25 mg) of compound 39 was obtained. LCMS m / z = 578.2[M+H] +

[0296] Example 40: [ka] Step 1: Manufacturing 40B Compounds 2-bromo-6-fluorobenzoate methyl (2 g, 8.58 mmol) and 2-fluorophenylacetic acid (1.45 g, 90.48 mmol) were dissolved in THF (40 mL), and sodium bis(trimethylsilyl)amide (12 mL, 2 M, 24.06 mmol) was added at -78 °C. After addition, the mixture was stirred at the same temperature for 15 min and reacted, then the temperature was raised to 0 °C and the reaction was continued for 2 hours. 1N hydrochloric acid (60 mL) was added to quench the reaction, and the mixture was stirred overnight at room temperature. Ethyl acetate was added for extraction, the organic phase was washed twice with saturated sodium bicarbonate solution, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 20) to obtain compound 40B (1.8 g, yield: 67%).

[0297] Step 2: Manufacturing 40C Compound 40B (1.6 g, 5.14 mmol) was dissolved in methanol (10 mL), and aminoguanidine hydrochloride (0.57 g, 7.71 mmol) and boron trifluoride diethyl ether (1.1 mL, 8.91 mmol) were added. The mixture was heated to 100°C in a sealed tube and reacted for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain compound 40C, which was used directly in the next step. LCMS m / z=367.0[M+H] +

[0298] Step 3: Manufacturing of 40D Compounds 40C (0.1 g, 0.27 mmol), 21D (0.094 g, 0.27 mmol), and potassium tert-butoxide (0.03 g, 0.27 mmol) were mixed and dissolved in tert-butanol (15 mL). The mixture was heated to 130°C in a sealed tube and stirred for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form a layer. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 40D (90 mg, yield: 50%).

[0299] Step 4: Manufacturing of 40E Compound 40D (90 mg, 0.13 mmol) was dissolved in DMF (3 mL), N,N-dimethylethylenediamine (17 mg, 0.19 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added, the mixture was purged three times with nitrogen gas, and the reaction was carried out for 2 hours under nitrogen gas protection. Ethyl acetate and water were added, the mixture was stirred, and then layered. The organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 40E (30 mg, yield: 39%).

[0300] Step 5: Preparation of Compound 40 Compound 40E (0.03 g, 0.051 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL), lithium hydroxide (0.012 g, 0.51 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 40 (10 mg, yield: 34%). LCMS m / z = 572.5 [MH] - 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.67(d,1H),7.75(s,1H),7.56-7.46(m,1H),7.33-7.25(m,1H),7.24-7.16(m ,2H),7.14-7.00(m,2H),6.96-6.74(m,2H),4.43(s,2H),2.71-2.61(m,2H),1.81(s,3H),1.11(s,3H),1.08(s,3H).

[0301] Example 41: [ka] Step 1: Manufacturing of 41B Compound 40C (0.1 g, 0.27 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxypropyl)thiazole-2-yl)-2-methylpropionate (CAS: 2101649-65-2, synthesis route referred to patent US20170174693) (98 mg, 0.27 mmol), and potassium tert-butoxide (0.03 g, 0.27 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 130°C in a sealed tube and stirred for 3 hours. The mixture was cooled to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 41B (90 mg, yield: 49%).

[0302] Step 2: Manufacturing of 41C Compound 41B (90 mg, 0.90 mmol) was dissolved in DMF (3 mL), N,N-dimethylethylenediamine (11 mg, 0.13 mmol) and cuprous iodide (25 mg, 0.13 mmol) were added, the mixture was purged three times with nitrogen gas, and the reaction was carried out for 2 hours under nitrogen gas protection. Ethyl acetate and water were added, the mixture was stirred, and then layered. The organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 41C (28 mg, yield: 36%).

[0303] Step 5: Preparation of Compound 41 Compound 41C (0.028 g, 0.046 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL), lithium hydroxide (0.011 g, 0.46 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain compound 41 (10 mg, yield: 37%). LCMS m / z = 588.5 [MH] - 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.68(d,1H),7.56-7.48(m,1H),7.33-7.02(m,8H),4.43(s,2H),2.93(s,2H),1.81(s,3H),1.10(s,6H).

[0304] Preparation of Compound 41-1 and Compound 41-2: [ka] Compound 41 (90 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia), b. Isocratic elution occurred, and the content of mobile phase B was 45%, c. The flow rate was 44 ml / min.

[0305] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 41-1 (40 mg) and compound 41-2 (40 mg).

[0306] Compound 41-1: Retention time under fractional separation conditions was 4.53 min, and LCMS m / z = 590.5 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.52(s,1H),8.68(d,1H),7.57-7.43(m,1H),7.35-6.98(m,8H),4.43(s,2H),2.93(s,2H),1.81(s,3H),1.10(s,6H).

[0307] Compound 41-2: Retention time under fractional separation conditions was 23.08 min, and LCMS m / z = 590.5 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),8.68(d,1H),7.59-7.43(m,1H),7.36-6.93(m,8H),4.43(s,2H),2.93(s,2H),1.81(s,3H),1.10(s,6H).

[0308] Example 42: [ka] Compound 42 (10 mg) was obtained by referring to the synthesis of Example 40. LCMS m / z = 592.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.50(s,1H),8.67(d,1H),7.75(s,1H),7.57-7.48(m,1H),7.37-7.25(m,1H),7.1 6-6.99(m,3H),6.99-6.68(m,2H),4.48(s,2H),2.71-2.61(m,2H),1.82(s,3H),1.11(s,3H),1.09(s,3H).

[0309] Example 43: [ka] Step 1: Manufacturing of 43B Compound 40A (2 g, 8.58 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (3.3 g, 17 mmol) were dissolved in THF (100 mL). Sodium bis(trimethylsilyl)amide (18 mL, 2 M, 36 mmol) was added at -78 °C, and the mixture was stirred at the same temperature for 15 minutes to allow the reaction to proceed. The temperature was then raised to 0 °C and the reaction was continued for 2 hours. 1N hydrochloric acid (160 mL) was added to quench the reaction, and the mixture was stirred overnight at room temperature. Ethyl acetate was added for extraction, the organic phase was washed twice with saturated sodium bicarbonate aqueous solution, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 to 1 / 20) to obtain compound 43B (0.6 g, yield: 20%).

[0310] Step 2: Manufacturing of 43C Compound 43B (0.6 g, 1.72 mmol) was dissolved in methanol (20 mL), and aminoguanidine hydrochloride (0.38 g, 3.44 mmol) and boron trifluoride diethyl ether (0.49 g, 3.44 mmol) were added. The mixture was heated to 100°C in a sealed tube and reacted for 3 hours. After cooling to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form a layer. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 43C (0.3 g, yield: 43%).

[0311] Step 3: Manufacturing of 43D Compound 43C (0.34 g, 0.83 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxypropyl)thiazole-2-yl)-2-methylpropionate (CAS: 2101649-65-2, synthesis route referred to patent US20170174693) (300 mg, 0.83 mmol), and potassium bicarbonate (83 mg, 0.83 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 130°C in a sealed tube and stirred for 3 hours. The mixture was cooled to room temperature, 1N sodium hydroxide aqueous solution and ethyl acetate were added, and the mixture was stirred to form layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (mobile phase: dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 43D (200 mg, yield: 34%). LCMS m / z = 722.1[M+H] +

[0312] Step 4: Manufacturing of 43E Compound 43D (200 mg, 0.28 mmol) was dissolved in DMF (5 mL), N,N-dimethylethylenediamine (37 mg, 0.42 mmol) and cuprous iodide (53 mg, 0.28 mmol) were added, the mixture was purged three times with nitrogen gas, and the reaction was carried out for 2 hours under nitrogen gas protection. Ethyl acetate and water were added, the mixture was stirred, and then layered. The organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 to 10 / 1) to obtain compound 43E (120 mg, yield: 68%). LCMS m / z = 642.2[M+H] +

[0313] Step 5: Preparation of Compound 43 Compound 43E (0.12 g, 0.19 mmol) was dissolved in a mixed solvent of 1,4-dioxane (3 mL) and water (1 mL), lithium hydroxide (0.011 g, 0.46 mmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was adjusted to pH 3-4 with 1 N aqueous HCl solution, 20 mL of ethyl acetate was added, 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 (acetonitrile / water (containing 0.1% trifluoroacetic acid) (V / V) = 0 / 100-60 / 40) to obtain the trifluoroacetate salt of compound 43 (40 mg). LCMS m / z = 628.2[M+H] + 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.68(d,1H),7.61-7.46(m,1H),7.25(s,1H),7.22- 6.96(m,3H),3.42-3.28(m,2H),2.93(s,2H),2.85-2.69(m,2H),1.82(s,3H),1.11(s,6H).

[0314] A racemic mixture of compound 43 (130 mg) was taken and subjected to chiral resolution. The chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: Methanol (0.05% aqueous ammonia), b. Isocratic elution occurred, with a mobile phase B content of 22%, and c. The flow rate was 43 ml / min.

[0315] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 43-1 (60 mg) and compound 43-2 (60 mg). [ka]

[0316] Compound 43-1: Retention time under fractional separation conditions was 4.05 min, and LCMS m / z = 628.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.53(s,1H),8.68(d,1H),7.58-7.49(m,1H),7.25(s,1H),7.22- 6.98(m,3H),3.39-3.32(m,2H),2.94(s,2H),2.88-2.64(m,2H),1.82(s,3H),1.11(s,6H).

[0317] Compound 43-2: Retention time under fractional separation conditions was 9.87 min, and LCMS m / z = 628.2 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.68(d,1H),7.58-7.48(m,1H),7.25(s,1H),7.22- 6.95(m,3H),3.40-3.32(m,2H),2.94(s,2H),2.86-2.67(m,2H),1.82(s,3H),1.11(s,6H).

[0318] Example 44: [ka] Compound 44 (50 mg) was obtained by referring to the synthesis of Example 35. LCMS m / z = 579.3[M+H] +

[0319] Example 45: [ka] Step 1: Manufacturing 45A In the reaction flask, 6-fluoro-3-(3,3,4,4-pentafluorobutyl)imidazo[1,5-a]pyridine-1-formamide (CAS: 1407815-26-2, 0.2g, 0.62 mmol), 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxypropyl)thiazole-2-yl)-2-methylpropionate ethyl (CAS: 2101649-65-2, 0.23 g, 0.62 mmol) of sodium bicarbonate (0.21 g, 2.48 mmol) and tert-butanol (10 mL) were added, and the mixture was heated overnight in an oil bath at 85°C to allow the reaction to proceed. An appropriate amount of silica gel was added to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain 45A (0.23 g, yield: 58%).

[0320] Step 2: Preparation of Compound 45 45A (0.23 g, 0.36 mmol), lithium hydroxide monohydrate (0.15 g, 3.60 mmol), 1,4-dioxane (5 mL), and water (3 mL) were added to a reaction flask and stirred overnight at room temperature. Ethyl acetate and water were added, and the pH was adjusted to 2-3 with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure and dried. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to obtain compound 45 (0.19 g, yield: 84%). LCMS m / z = 628.0[M+H] +

[0321] Compound 45 (180 mg) was subjected to chiral resorption, and the chiral resorption method was as follows. 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: methanol / isopropanol = 8 / 2 (0.05% aqueous ammonia), b. Isocratic elution occurred, and the content of mobile phase B was 25%, c. The flow rate was 40 ml / min.

[0322] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 45-1 (72 mg) and compound 45-2 (70 mg). [ka]

[0323] Compound 45-1: Retention time under fractional separation conditions was 8.1 min, and LCMS m / z = 628.3 [M + H]. + That was the case. 1 H NMR(400MHz,CDCl3 / CD3OD(v / v)=1 / 1)δ8.68(dd,1H),8.16-8.05(m,1H),7.14-6.91(m,2H),3. 33-3.28(m,2H),3.13-2.98(m,2H),2.94-2.76(m,2H),1.88(s,3H),1.24(s,3H),1.21(s,3H).

[0324] Compound 45-2: Retention time under fractional separation conditions was 27.1 min, and LCMS m / z = 628.3 [M + H]. + That was the case. 1H NMR(400MHz,CDCl3 / CD3OD(v / v)=1 / 1)δ8.68(dd,1H),8.09-7.93(m,1H),7.12-6.90(m,2H),3. 34-3.25(m,2H),3.14-2.98(m,2H),2.94-2.74(m,2H),1.88(s,3H),1.24(s,3H),1.22(s,3H).

[0325] Example 46: [ka] Step 1: Manufacturing of 46A 6-fluoro-3-(3,3,4,4-pentafluorobutyl)imidazo[1,5-a]pyridine-1-formamide (CAS: 1407815-26-2, 0.16 g, 0.49 mmol), 21D (0.17 g, 0.49 mmol), sodium bicarbonate (0.16 g, 1.96 mmol), and tert-butanol (10 mL) were added to a reaction flask and heated overnight in an oil bath at 85°C to allow the reaction to proceed. An appropriate amount of silica gel was added to the reaction solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE-EA = 100-0 to 40-60) to obtain 46A (0.23 g, yield: 75%).

[0326] Step 2: Preparation of Compound 46 46A (0.21 g, 0.34 mmol), lithium hydroxide monohydrate (0.14 g, 3.40 mmol), 1,4-dioxane (5 mL), and water (3 mL) were added to a reaction flask. The mixture was stirred overnight at room temperature and reacted. Ethyl acetate and water were then added, and the pH was adjusted to 2-3 with 1N hydrochloric acid. The organic layer was concentrated under reduced pressure and dried. The residue was purified by silica gel column chromatography (eluent: DCM-CH3OH = 100-0 to 90-10) to obtain compound 46 (0.18 g, yield: 88%). LCMS m / z = 612.2[M+H] +

[0327] Example 47: [ka] Step 1: Manufacturing of 47A Compounds 2-(aminomethyl)-5-chloropyridine hydrochloride (1.00 g, 5.59 mmol) and 4,4,5,5,5-pentafluoropentanoic acid (1.61 g, 8.38 mmol) were dissolved in DMF (20 mL), HATU (4.25 g, 11.18 mmol) was added, and the mixture was stirred at room temperature for 30 min. DIPEA (3.61 g, 27.95 mmol) was added, and the mixture was reacted at room temperature for 1 hour. Water and ethyl acetate were added for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (V / V) = 100 / 0 to 100 / 30) to obtain compound 47A (1.7 g, yield: 96%).

[0328] Step 2: Manufacturing of 47B Compound 47A (1.7 g, 5.37 mmol) was dissolved in phosphorus oxychloride (20 mL), the mixture was heated to reflux, and the reaction was allowed to proceed overnight. The mixture was cooled to room temperature, concentrated under reduced pressure, water was carefully and slowly added to the residue, the mixture was stirred for 5 minutes, ethyl acetate was added, and the mixture was stirred to form a layer. The aqueous layer was treated with saturated sodium bicarbonate aqueous solution, then extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by high-performance silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100~20 / 100) to obtain compound 47B (1.6 g). LCMS m / z=299.1[M+H] +

[0329] Step 3: Manufacturing of 47C Compound 47B (1.7 g, 5.69 mmol) was dissolved in DCM (20 mL), NBS (1.14 g, 6.26 mmol) was added, and the mixture was reacted at room temperature for 30 minutes. Water was added, the mixture was stirred to form layers, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was rapidly separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 100~10 / 100) to obtain compound 47C (2.1 g).

[0330] Step 4: Manufacturing of 47D Compound 47C (2 g, 5.30 mmol) and zinc cyanide (1.24 g, 10.6 mmol) were added to a 50 mL pouring flask. Then, zinc powder (693.35 mg, 10.6 mmol), 1,1'-bis(diphenylphosphin)ferrocene (1.76 g, 3.18 mmol), tris(dibenzylidene-BASE acetone)dipalladium (1.46 g, 1.59 mmol), and N,N-dimethylacetamide (30 mL) were added. The mixture was then protected with nitrogen gas, heated to 120 °C, and stirred for 2 hours. The reaction mixture was diluted with 100 mL of ethyl acetate, washed three times with water, washed once with saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by high-performance silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 10 / 1) to obtain compound 47D (400 mg, yield: 23%). LCMS m / z=324.0[M+H] +

[0331] Step 5: Manufacturing of 47E Under ice bath conditions, ammonium chloride (190 mg, 3.55 mmol) was added to a 50 mL single-mouthed flask, toluene (10 mL) was added, and then trimethylaluminum (1.77 mL, 2 M, toluene solution) was slowly added dropwise. The mixture was heated to room temperature and stirred for 3 hours to allow the reaction to proceed. Compound 47D (230 mg, 0.71 mmol) was dissolved in toluene and added dropwise to the reaction mixture. The mixture was heated to 110°C and stirred overnight. The mixture was cooled to room temperature, silica gel and 20 mL of methanol were added under ice bath conditions, and stirring continued for 30 minutes. The mixture was filtered by suction, the filter cake was washed three times with methanol, the organic phases were combined, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 8 / 1) to obtain compound 47E (145 mg, yield: 60%).

[0332] Step 6: Manufacturing of 47F Compound 47E (140 mg, 0.41 mmol), ethyl 3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxypropyl)thiazole-2-yl)-2-methylpropionate (CAS: 2101649-65-2, synthesis route referred to patent US20170174693) (149 mg, 0.41 mmol), and sodium bicarbonate (137.78 mg, 1.64 mmol) were mixed and dissolved in tert-butanol (5 mL). The mixture was heated to 80°C and stirred overnight. After cooling to room temperature, it was concentrated under direct reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 20 / 1) to obtain compound 47F (120 mg, yield: 44%). LCMS m / z = 658.2[M+H] +

[0333] Step 7: Preparation of Compound 47 Compound 47F (120 mg, 0.18 mmol) was dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (2 mL), lithium hydroxide hydrate (76 mg, 1.8 mmol) was added, and the mixture was heated to 60°C and stirred for 3 hours. After cooling to room temperature, dilute hydrochloric acid was added under an ice bath to adjust the acidity, and the mixture was extracted three times with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified using a reversed-phase column (mobile phase: acetonitrile / 0.1% TFA water (V / V) = 5 / 95~50 / 50) to obtain compound 47 (68 mg, yield: 58%). LCMS m / z = 644.1[M+H] +

[0334] Compounds 47-1 and 47-2 [ka] A racemic mixture of compound 47 (68 mg) was taken and subjected to chiral resolution. The chiral resolution method was as follows: 1. Instrument: SFC Prep 150 AP, Chromatography column: IG (19mm x 250mm) 2. The sample was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. 3. Preparative chromatography conditions: a. Composition of mobile phases A and B: Mobile phase A: CO2, Mobile phase B: Methanol / Isopropanol = 8 / 2 (0.05% aqueous ammonia), b. Isocratic elution occurred, and the content of mobile phase B was 40%, c. The flow rate was 41 ml / min.

[0335] After separation by preparative extraction, components with the same retention time were combined and concentrated under reduced pressure to obtain compound 47-1 (30 mg) and compound 47-2 (30 mg).

[0336] Compound 47-1: Retention time under fractional separation conditions was 4.85 min, and LCMS m / z = 644.5 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ12.30-11.96(m,1H),11.31(s,1H),8.72-8.62(m,2H),7.23(s,1H),7.12 -7.02(m,1H),6.83-6.67(m,2H),3.39-3.32(m,2H),2.99-2.78(m,4H),1.78(s,3H),1.11(s,6H).

[0337] Compound 47-2: Retention time under fractional separation conditions was 19.15 min, and LCMS m / z = 644.5 [M + H]. + That was the case. 1 H NMR(400MHz,DMSO-d6)δ12.36-12.01(m,1H),11.31(s,1H),8.78-8.58(m,2H),7.23(s,1H),7.11 -7.01(m,1H),6.82-6.66(m,2H),3.41-3.31(m,2H),3.00-2.76(m,4H),1.79(s,3H),1.11(s,6H).

[0338] [Table 2]

[0339] Examples of biological tests 1. CHO-KI / sGC cell cGMP detection experiment Stable transfected CHO-K1 cells that stably express sGC α1 / β1 heterodimers were constructed and named CHO-KI / sGC. CHO-KI / sGC cells were cultured in complete medium (FK12 + 10% FBS + 1% biantibody + 0.5 mg / mL hygromycin + 0.25 mg / mLG418). On the day of detection, cells were re-selected from EAB detection buffer (EBSS assay buffer + 5 mL MgCl2 + 10 mM HEPES + 0.05% BSA) and the cell concentration was reduced to 2.25 * 10 5 The concentration was set to / mL. 0.5 mM IBMX was added to prevent cGMP degradation.

[0340] Cells were pre-incubated with 1 pM diethylenetriamine / nitric oxide (EDTA-NO) at room temperature for 30 minutes, then different concentrations of the compound were added, followed by incubation at 37°C for 1 hour. After incubation, the reaction was stopped, and the intracellular cGMP content was detected according to the instructions for the Cisbio kit (CisBio, 62GM2PEC). The maximum cGMP production for the positive compound was calculated according to formula (1-1), where RLU compound This is the reading of the detected compound, RLU reference This was the highest reading for the positive compound. Activation %=RLU compound / RUL reference *100% formula (1-1) Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good stimulating effect on the production of cGMP in CHO-KI / sGC cells.

[0341] 2. Experiment to detect the enzyme activity of in vitro guanylate cyclase (sGC) First, 100 nL of compounds of different concentrations were transferred to a 384 reaction plate (Greiner, Cat. No. 784075) using an Echo655 (LABCYTE, Cat. No. 655). The DMSO content was 1% at the final reaction concentration. 2 μL of sGC (ICE, Cat. No. S2304F-H07SH2) was added to the 384 reaction plate, and the mixture was centrifuged at 1000 rpm for 1 minute. Then, 1 μL of DETA NONOate was added, and the mixture was incubated at 37°C for 10 minutes. After incubation, 2 μL of GTP was added, the mixture was centrifuged at 1000 rpm for 1 minute, and the reaction was allowed to proceed at 37°C for 60 minutes. In the reaction system, the final concentrations of sGC, GTP, and DETA NONOate were 1.5 nM, 5 μM, and 100 μM, respectively. After the reaction was complete, 5 μL of the detection mixture (PerkinElmer, Cat. No. 62GM2PEG) was added and incubated at room temperature for 60 minutes. The TR-FRET signal (Ratio: 665 / 620 nm) was read using a microplate reader (BMG, Cat. No. PHERAstar FSX), and nonlinear regression curve fitting was performed using GraphPad Prism software. 50 The values ​​were calculated. Compound A (Example 1 in WO2010065275) was used as the positive reference compound, and the activation rate was calculated using Equation 2-1, where Low control was the TR-FRET signal value of 1 μM compound A, and High control was the TR-FRET signal value of the DMSO well. stimulation%=(ave High control-cpd well) / (ave High control-ave Low control)*100% formula 2-1

[0342] [Table 3] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good agonist and / or activating activity of guanylate cyclase (sGC).

[0343] 3. cGMP detection experiment in LNCap cells LNCap cells are a human prostate cancer cell line capable of expressing the sGC protein. LNCap cells were purchased from ATCC and cultured in complete medium (RPMI-1640 + 10% FBS + 1% PS). On the day of detection, cells were re-selected from the detection buffer (EBSS assay buffer + 5 mL MgCl2 + 10 mM HEPES + 0.05% BSA) and the cell concentration was reduced to 2 × 10⁻⁶. 5 The concentration was set to / mL. 0.5 mM IBMX was added to prevent cGMP degradation.

[0344] Cells were pre-incubated with 20 μM diethylenetriamine / nitric oxide (DETA-NO) at 37°C for 30 minutes, then different concentrations of the compound were added, followed by incubation at room temperature for 1 hour. After incubation, the reaction was stopped, and the intracellular cGMP content was detected according to the instructions for the Cisbio kit (CisBio, 62GM2PEC). The amount of cGMP produced relative to compound A (Example 1 in WO2010065275) was calculated according to formula (3-1), and EC 50 The values ​​were calculated. Here, Sample cGMP was the reading for the detected compound, Low control GMP was the 1% DMSO control, and High control cGMP was the maximum cGMP reading for compound A. %Activity=(Sample cGMP-Low control GMP) / (High control cGMP-Low control cGMP)*100% formula (3-1)

[0345] [Table 4] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a beneficial stimulating effect on the cGMP production of LNCap cells.

[0346] 4. Pharmacokinetic studies in rats (inhalation administration) Experimental Objective: This experiment involved administering a test substance to SD rats via single-dose inhalation, measuring the concentration of the test substance in rat plasma and lungs, and evaluating the pharmacokinetic properties and bioavailability of the test substance in rats.

[0347] Test animals: Male SD rats, 180-200g. Purchased from Chengdu Dashuo Laboratory Animals Co., Ltd.

[0348] Test Method: On the day of the test, SD rats (for each compound) were randomly divided into six groups based on body weight, with two rats in each group. One day prior to administration, the rats were fasted for 12-16 hours without water restriction, and feeding was resumed 4 hours after administration.

[0349] [Table 5] * The dosage is based on the free base, (DMA: dimethylacetamide, HS-15 (Solutol): polyethylene glycol-15-hydroxyhydroxystearate, Saline: physiological saline)

[0350] Plasma sampling: Blood was collected from the orbit under isoflurane anesthesia before and after administration and placed in an EDTAK2 centrifuge tube. Plasma was collected by centrifugation at 6000 rpm and 4°C for 10 minutes. Plasma collection times: 0, 0.0833, 0.25, 0.5, 1, 2, 4, 7, 24h.

[0351] Lung tissue sampling: Each group of test animals was euthanized by CO2 inhalation at 0.25, 0.5, 1, 4, 7, and 24 hours after administration. The animals were then dissected, lung tissue was collected, washed with saline solution, wiped with filter paper and dried, weighed using a balance, placed on moist ice, homogenized within 2 hours, and then homogenized with 6 times the volume of homogenate solution (50% methanol-water) (i.e., 6 mL of homogenate solution was added to 1 g of tissue).

[0352] Prior to analysis and detection, all samples were stored at -60°C. Quantitative analysis was performed on the samples by LC-MS / MS.

[0353] [Table 6] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good exposure levels and / or ventilation-perfusion ratios in the rat lungs after inhalation administration.

[0354] 5. hERG potassium ion channel action test Experimental platform: Electrophysiological manual patch clamp system

[0355] Cell line: Chinese hamster ovary (CHO) cell line that stably expresses hERG potassium ion channels

[0356] Experimental Method: hERG potassium channel current was recorded in CHO (Chinese Hamster Ovary) cells that stably express hERG potassium channels using whole-cell patch-clamp technique at room temperature. A glass microelectrode was formed by pulling out a glass electrode blank (BF150-86-10, Sutter) with a puller. After filling the electrode internal fluid, the tip resistance was approximately 2-5 MΩ. The glass microelectrode was then connected to a patch-clamp amplifier by inserting it into an amplifier probe. Limiting voltage and data recording were controlled by a computer using pClamp 10 software. The sampling frequency was 10 kHz, and the filtering frequency was 2 kHz. After acquiring whole-cell recordings, the cells were limited to -80 mV, and the hERG potassium current (I) was measured. hERG The step voltage to induce ) was applied from -80mV to +20mV by applying a depolarizing voltage for 2s, then repolarized to -50mV, held for 1s, and then returned to -80mV. The cells were stimulated by applying voltage in this manner every 10s seconds, and the administration process was started only after it was confirmed that the hERG potassium current was stable (for at least 1 minute). The compound was applied for at least 1 minute for each test concentration, and at least 2 cells were tested at each concentration (n≧2).

[0357] Data Processing: Data analysis and processing were performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (hERG tail current peak induced at -50mV) at different compound concentrations was calculated using the following formula. Inhibition%=[1-(I / Io)]×100% Here, Inhibition% represents the percentage of inhibition of the compound against the hERG potassium current, and I and Io represent the amplitudes of the hERG potassium current before and after administration, respectively.

[0358] Compound IC 50 This was calculated by fitting the following equation using GraphPad Prism 5 software. Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*HillSlope)) Here, X is the logarithm of the sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively. Conclusion: The compounds of the present invention do not exhibit any significant inhibitory effect on hERG potassium ion channels.

[0359] 6. CYP450 enzyme inhibition test The purpose of this study is to evaluate the effects of a test substance on the activity of five isozymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) of cytochrome P450 (CYP) in human liver microsomes using an in vitro test system. Specific probe substrates for each CYP450 isozyme were incubated with human liver microsomes and different concentrations of the test substance. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction was complete, the metabolites generated by the specific substrate were processed and quantitatively measured using liquid chromatography-tandem mass spectrometry (LC-MS / MS) to measure the change in CYP enzyme activity and IC50. 50The values ​​were calculated to evaluate the potential inhibitory capacity of the test substance against each CYP enzyme subtype.

[0360] Conclusion: The compounds of the present invention have no apparent inhibitory effect on CYP450 enzymes, or only a weak inhibitory effect.

[0361] 7. Pharmacodynamic studies of dilation of the thoracic aortic ring in SD rats SPF grade 8-week-old male SD rats were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. After arriving at the animal facility, they were allowed to acclimate for at least one week. Before the experiment, the rats were weighed and randomly divided into groups according to their weight. On the day of the experiment, the rats were deeply anesthetized with Terazol 50 (20 mg / kg, ip) + Xylazine (8 mg / kg, ip). Then, the thoracic cavity was quickly opened, the aorta was carefully isolated, the descending aorta was excised and placed in a culture dish containing saturated oxygen (95% O2 + 5% CO2) KH solution, and the connective tissue on the vascular surface was removed to create a vascular ring approximately 3-5 mm in length. The vascular ring was suspended using a custom-made hook in an ex vivo tissue perfusion bath containing 37°C constant temperature KH solution, saturated oxygen was supplied, and it was connected to a tension sensor (Chengdu Instrument Factory, JZ101H). A tension sensor was connected to a multi-channel electrophysiological signal recording device (Chengdu Instruments Factory, RM6240E). The vascular ring was washed with KH solution, and equilibrated for 90 minutes under a basic tensile force of 3g, after which it was placed in a bathtub for 10 minutes. -6 The vascular ring was pre-constricted by adding norepinephrine (M) until it reached a stable tension value. Then, the test compounds were added to the bathtub in order of increasing concentration to dilate the vascular ring, with a 5-minute interval between each compound addition, and the changes in tension of the thoracic aortic vascular ring were observed. The dilation percentage at different concentrations was calculated.

[0362] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant dilating effect on the rat thoracic aortic ring.

[0363] 8. Remote monitoring of blood pressure in SHR rats Remote monitoring blood pressure implant implantation: The day before surgery, the DSI implant was disinfected (immersed in 2% glutaraldehyde solution for 8-10 hours), the animal's weight was weighed, anesthesia was administered with xylazine (8 mg / kg, ip.) + Terazol 50 (20 mg / kg, ip.), the animal was fasted the day before surgery, and the implant implantation was performed on the first day of the experiment. The procedure was as follows: The abdominal skin of the rats was aseptically disinfected, a longitudinal incision was made, the abdominal organs were separated, the abdominal aorta was exposed, an implantable blood pressure-sensitive probe catheter was inserted into the abdominal aorta, hemostasis was achieved with biogel, the implant was then fixed to the abdominal wall, the muscles and skin were sutured, disinfected, and meloxicam was administered subcutaneously for analgesia. Postoperatively, the animals were placed in a constant temperature (37°C) incubator, and after they were fully awake (returned to spontaneous movement), they were returned to their cages and kept individually in the cages. To prevent infection, 4-8 mg / kg of gentamicin sulfate was subcutaneously injected within 3 days postoperatively, and meloxicam was subcutaneously injected for analgesia.

[0364] Blood pressure monitoring: Basal blood pressure was measured for 24 hours approximately 10 days after postoperative recovery. Rats were divided into groups according to their basal blood pressure, administered (oral or intravenous), and blood pressure was monitored for 24 hours after a single dose. Changes in systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate within 24 hours were recorded. Mean systolic blood pressure, mean diastolic blood pressure, mean arterial pressure, and mean heart rate were calculated from the raw data over a set period (usually 30 minutes). A p-value of less than 0.05 was considered statistically significant.

[0365] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a significant reducing effect on rat blood pressure, but do not have a significant reducing effect on abdominal aortic pressure after IT administration.

Claims

1. A compound or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, wherein the compound is selected from the compounds shown in general formula (I). 【Chemistry 1】 Here, R is 【Chemistry 2】 Selected from, Z is selected from CH or N. Z １ or Z ２ Each is independently selected from CH or N, and Z １ and Z ２ At least one of them is selected from N, X １ or X ２ Each is independently selected from O or S. A is C ３－１２ Selected from a carbocyclic group or a 4- to 12-membered heterocyclic group, R １ is selected from -M-(CR １ａ R １ｂ ), ｒ -(CR １ｃ R １ｄ ), ｓ -COOH, M is bond, C ３－１２ A carbocyclic group or a 4- to 12-membered heterocyclic group is selected, and the carbocyclic group or heterocyclic group may optionally have 1 to 4 R ｍ Replaced by, R ２ C １－６ Alkyl alkyl group or -C １－６ Selected from alkylene-Q, the alkyl group or alkylene group optionally comprises 1 to 10 R groups. ｋ Replaced by, Q is C ３－１２ A carbocyclic group or a 4- to 12-membered heterocyclic group is selected, and the carbocyclic group or heterocyclic group may optionally have 1 to 4 R ｑ Replaced by, R ａ , R ｃ , R ｍ , R ｑ , R ｂ３ , R １ａ , R １ｂ , R １ｃ , R １ｄ These are H, deuterium, halogen, OH, CN, and NH, respectively, independently. ２ , C １－６ Alkyl alkyl groups, OC １－６ Alkyl, SC １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, NHC １－６ alkyl group, N(C) １－６ Alkyl) ２ , -O-C ３－６ Carbon ring group, -O-3 to 7-membered heterocyclic group, -NH-C ３－６ Carbon ring group, -NH-3 to 7-membered heterocyclic group, -C ０－４ Alkylene-C ３－６ Carbocyclic group, -C ０－４ The alkylene group is selected from a 3- to 7-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally have 1 to 4 R groups. ｋ Replaced by, or R １ａ and R １ｂ or R １ｃ and R １ｄ Each of these, along with the carbon atoms linked to them, is C ３－１２ A carbon ring group or a 4- to 12-membered heterocyclic group is formed, and the carbon ring group or heterocyclic group optionally has 1 to 4 R ｋ Replaced by, R ｂ１ , R ｂ２ , R ｂ４ These are H, deuterium, OH, CN, and NH, respectively, independently. ２ , C １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, NHC １－６ alkyl group, N(C) １－６ Alkyl) ２ , -NH-C ３－６ Carbon ring group, -NH-3 to 7-membered heterocyclic group, -C ０－４ Alkylene-C ３－６ Carbocyclic group, -C ０－４ The alkylene group is selected from a 3- to 7-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally have 1 to 4 R groups. ｋ Replaced by, R ｋ These are H, deuterium, halogen, OH, =O, CN, and NH, respectively, independently. ２ , COOH, CONH ２ , C １－６ Alkyl alkyl groups, OC １－６ Alkyl, SC １－６ alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, NHC １－６ alkyl group, N(C) １－６ Alkyl) ２ , -O-C ３－６ Carbon ring group, -O-3 to 7-membered heterocyclic group, -NH-C ３－６ Carbon ring group, -NH-3 to 7-membered heterocyclic group, -C ０－４ Alkylene-C ３－６ Carbocyclic group, -C ０－４ The alkylene group is selected from a 3- to 7-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally be deuterium, halogen, =O, CN, OH, or NH. ２ , C １－６ alkyl group, C １－６ Substituted with 1 to 4 substituents selected from alkoxy groups, a, c, r, and s are each independently selected from 0, 1, 2, 3, and 4, and are compounds or their stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

2. A is C ３－１１ Cycloalkyl groups, 4-11 member heterocycloalkyl groups, C ６－１０ Selected from an aryl group or a 5- to 10-membered heteroaryl group, M is bond, C ３－１１ selected from a cycloalkyl group, a 4- to 11-member heterocycloalkyl group, C ６－１０ an aryl group or a 5- to 10-member heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group are optionally substituted with 1 to 4 R ｍ and R ２ C １－５ Alkyl alkyl group or -C １－４ Selected from alkylene-Q, the alkyl group or alkylene group optionally comprises 1 to 8 R groups. ｋ Replaced by, Q is C ３－１１ a cycloalkyl group, a 4- to 11-member heterocycloalkyl group, C ６－１０ an aryl group or a 5- to 10-member heteroaryl group, and the cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group are optionally substituted with 1 to 4 R ｑ and R ａ , R ｃ , R ｍ , R ｑ , R ｂ３ , R １ａ , R １ｂ , R １ｃ , R １ｄ These are H, deuterium, halogen, OH, CN, and NH, respectively, independently. ２ , C １－４ Alkyl alkyl groups, OC １－４ Alkyl, SC １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, NHC １－４ alkyl group, N(C) １－４ Alkyl) ２ , -O-C ３－６ Carbon ring group, -O-3 to 6-membered heterocyclic group, -NH-C ３－６ Carbon ring group, -NH-3 to 6-membered heterocyclic group, -C ０－２ Alkylene-C ３－６ Carbocyclic group, -C ０－２ The alkylene group is selected from a 3- to 6-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally have 1 to 4 R groups. ｋ Replaced by, or R １ａ and R １ｂ or R １ｃ and R １ｄ Each of these, along with the carbon atoms linked to them, is C ３－１１ A cycloalkyl group or a 4- to 11-membered heterocycloalkyl group is formed, and the cycloalkyl group or heterocycloalkyl group optionally has 1 to 4 R ｋ Replaced by, R ｂ１ , R ｂ２ , R ｂ４ These are H, deuterium, OH, CN, and NH, respectively, independently. ２ , C １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, NHC １－４ alkyl group, N(C) １－４ Alkyl) ２ , -NH-C ３－６ Carbon ring group, -NH-3 to 6-membered heterocyclic group, -C ０－２ Alkylene-C ３－６ Carbocyclic group, -C ０－２ The alkylene group is selected from a 3- to 6-membered heterocyclic group, and the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group may optionally have 1 to 4 R groups. ｋ Replaced by, R ｋ These are H, deuterium, halogen, OH, =O, CN, and NH, respectively, independently. ２ , COOH, CONH ２ , C １－４ Alkyl alkyl groups, OC １－４ Alkyl, SC １－４ alkyl group, C ２－４ Alkenyl group, C ２－４ Alkynyl group, NHC １－４ alkyl group, N(C) １－４ Alkyl) ２ , -O-C ３－６ Carbon ring group, -O-3 to 6-membered heterocyclic group, -NH-C ３－６ Selected from a carbocyclic group, a -NH-3 to 6-membered heterocyclic group, a -C0-2 alkylene-C3-6 carbocyclic group, and a -C0-2 alkylene-3 to 6-membered heterocyclic group, wherein the alkyl group, alkylene group, alkenyl group, alkynyl group, carbocyclic group, or heterocyclic group can be optionally deuterium, halogen, =O, CN, OH, or NH ２ , C １－４ alkyl group, C １－４ The compound according to claim 1, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, substituted with one to four substituents selected from alkoxy groups.

3. A is C ３－６ Cycloalkyl groups, 4-6 member heterocycloalkyl groups, C ６－１０ Selected from an aryl group or a 5- to 10-membered heteroaryl group, M is bond, C ３－６ Cycloalkyl groups, 4-6 member heterocycloalkyl groups, C ６－１０ Selected from aryl groups or 5-10 membered heteroaryl groups, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group optionally have 1 to 4 R ｍ Replaced by, R ２ C １－４ Alkyl alkyl group or -C １－３ Selected from alkylene-Q, the alkyl group or alkylene group optionally comprises 1 to 6 R groups. ｋ Replaced by, Q is C ３－６ Cycloalkyl groups, 4-6 member heterocycloalkyl groups, C ６－１０ Selected from aryl groups or 5-10 membered heteroaryl groups, the cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group optionally have 1 to 4 R ｑ Replaced by, R ａ , R ｃ , R ｍ , R ｑ , R ｂ３ , R １ａ , R １ｂ , R １ｃ , R １ｄ These are H, deuterium, F, Cl, Br, I, OH, CN, and NH, respectively, independently. ２ , NHCH ３ , N (CH ３ ) ２ , or optionally 1 to 4 R ｋ The group substituted with is selected from the following groups: methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, isopropoxy group, vinyl group, ethinyl group, methylthio group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, and phenyl group. or R １ａ and R １ｂ or R １ｃ and R １ｄ Each of these, along with the carbon atoms linked to them, is C ３－７ A cycloalkyl group or a 4- to 7-membered heterocycloalkyl group is formed, and the cycloalkyl group or heterocycloalkyl group optionally has 1 to 4 R ｋ Replaced by, R ｂ１ , R ｂ２ , R ｂ４ These are H, deuterium, OH, CN, and NH, respectively, independently. ２ , or optionally 1 to 4 R ｋ The group selected from the following substituted groups is a methyl group, ethyl group, propyl group, isopropyl group, vinyl group, ethynyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, and phenyl group. R ｋ These are, independently, deuterium, F, Cl, Br, I, OH, =O, CN, and NH. ２ , COOH, CONH ２ , NHCH ３ , N (CH ３ ) ２ The group is selected from methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, methylthio group, vinyl group, ethynyl group, propynyl group, propargyl group, cyclopropyl group, cyclobutyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, pyrazolyl group, pyrrolyl group, morpholinyl group, and phenyl group, and the group is optionally replaced with deuterium, F, Cl, Br, I, =O, CN, OH, NH ２ , C １－４ alkyl group, C １－４ The compound according to claim 2, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, substituted with one to four substituents selected from alkoxy groups.

4. A can choose 1 to 4 R ａ The group selected from the following substituted groups is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, phenyl group, pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. M is bonded, or optionally 1 to 4 R ｍ The group selected from the following substituted groups is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, phenyl group, pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. R ２ The group is selected from methyl, ethyl, propyl, butyl, -methylene-Q, -ethylene-Q, and -propylene-Q, and the methyl, ethyl, propyl, butyl, methylene, ethylene, and propylene groups can optionally have 1 to 6 R groups. ｋ Replaced by, Q is an optional set of 1 to 4 R's. ｑ The group selected from the following substituted groups is a cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, tetrahydrofuranyl group, tetrahydropyranyl group, phenyl group, pyrrolyl group, thienyl group, furyl group, pyrazolyl group, imidazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. R ａ , R ｃ , R ｍ , R ｑ , R ｂ３ , R １ａ , R １ｂ , R １ｃ , R １ｄ These are H, deuterium, F, Cl, Br, I, OH, CN, and NH, respectively, independently. ２ , NHCH ３ , N (CH ３ ) ２ , or optionally 1 to 4 R ｋ Selected from substituted methyl, ethyl, methoxy, and cyclopropyl groups, or R １ａ and R １ｂ or R １ｃ and R １ｄ Each of these, along with the carbon atoms linked to them, optionally contains 1 to 4 R atoms. ｋ Substituted with the following groups, they form the following groups: cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, oxetanyl group, azetidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, tetrahydrofuranyl group, and tetrahydropyranyl group. R ｂ１ , R ｂ２ , R ｂ４ These are H, deuterium, OH, CN, and NH, respectively, independently. ２ , or optionally 1 to 4 R ｋ Selected from substituted methyl, ethyl, methoxy, and cyclopropyl groups, R ｋ These are, independently, deuterium, F, Cl, Br, I, OH, =O, CN, and NH. ２ , COOH, CONH ２ , NHCH ３ , N (CH ３ ) ２ The group is selected from methyl group, ethyl group, propyl group, isopropyl group, methoxy group, ethoxy group, methylthio group, vinyl group, ethynyl group, propynyl group, propargyl group, cyclopropyl group, cyclobutyl group, azetidinyl group, oxetanyl group, pyrrolidinyl group, piperidinyl group, pyrazolyl group, pyrrolyl group, morpholinyl group, and phenyl group, and the group is optionally replaced with deuterium, F, Cl, Br, I, =O, CN, OH, NH ２ The compound according to claim 3, or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, which are substituted with one to four substituents selected from methyl, ethyl, methoxy, and ethoxy groups.

5. A can choose 1 to 4 R ａ The group substituted is selected from the following groups: phenyl group, thiazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, and pyridadinyl group. R １ teeth, 【Transformation 3】 Selected from, R is, 【Chemistry 4】 Selected from, R ２ teeth, 【Transformation 5】 Selected from, R ａ , R ｃ , R ｂ３ These are H, deuterium, F, Cl, Br, I, OH, CN, and NH, respectively, independently. ２ , NHCH ３ , N (CH ３ ) ２ CF ３ CHF ２ ,CH ２ F is selected from methyl group, ethyl group, methoxy group, and cyclopropyl group. R ｂ１ , R ｂ２ , R ｂ４ These are H, deuterium, OH, CN, and NH, respectively, independently. ２ Selected from methyl group, ethyl group, methoxy group, and cyclopropyl group, c is selected from 0, 1, or 2 to be the compound according to claim 4 or its stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

6. The compound is selected from one of the structures in Table E-1, and is either a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier, preferably the pharmaceutical composition comprising 0.01 to 1500 mg of a compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

8. Application of a compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 7, in the manufacture of a pharmaceutical for treating diseases related to sGC.

9. The application according to claim 8, wherein the disease is selected from cardiovascular disease, kidney disease, or respiratory disease, and is preferably pulmonary arterial hypertension, pulmonary hypertension, or chronic obstructive pulmonary disease.

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 its stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition according to claim 7, wherein the therapeutically effective amount is preferably 0.01 to 1500 mg, and the disease is preferably a cardiovascular disease, a kidney disease or a respiratory disease.

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