Phenyl-substituted dihydronaphthyridines and their preparation and use

Abstract

The present invention discloses phenyl-substituted dihydronaphthyridine compounds and their preparation and use, which belong to the pharmaceutical technical field. The compound disclosed in the present invention is represented by Formula I and is used as a mineralocorticoid receptor antagonist for treating, preventing, or alleviating diseases such as hyperaldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, liver cirrhosis, renal failure, and stroke in patients. (I) TIFF2025526339000245.tif75158

Description

[Technical Field]

[0001] The present invention belongs to the technical field of medicine, and particularly relates to phenyl-substituted dihydronaphthyridine compounds and their preparation and use, which are used as mineralocorticoid receptor antagonists. [Background technology]

[0002] The mineralocorticoid receptor (MR) is an aldosterone-activated nuclear hormone receptor that regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular disease. Increased circulating aldosterone increases blood pressure through its effects on urinary sodium excretion, potentially affecting the brain, heart, and vasculature. Furthermore, aldosterone excess is associated with many pathophysiological processes leading to renal and cardiovascular disease. Hyperaldosteronism is typically caused by aldosterone-producing adenomas, but in patients with refractory hypertension, elevated aldosterone levels, often due to elevated serum potassium levels or residual AT1R activity, often referred to as "aldosterone escape." Aldosterone escape generally leads to increased MR activity, and MR antagonists act as potent antihypertensives and have been shown to be effective in treating heart failure and primary hyperaldosteronism. Furthermore, MR antagonists have been shown to be effective in preclinical models of kidney disease and can be used in combination with standard therapies to reduce proteinuria in patients with kidney diseases such as chronic kidney disease, including diabetic nephropathy.

[0003] Aldosterone is a steroid hormone produced by the adrenal cortex. Its production is highly dependent on and indirectly regulated by renal blood flow. Decreased renal blood flow triggers the release of renin into the circulation. This release activates the production of angiotensin II, which constricts the arterial vasculature and stimulates the production of aldosterone in the adrenal cortex. Consequently, the kidneys act as both a blood pressure sensor and, indirectly, a volume sensor. Acute volume reductions are counteracted by the renin-angiotensin-aldosterone system, which increases blood pressure (angiotensin II effect) and, on the other hand, rebalances the vascular filling state by increasing renal sodium and water reabsorption (aldosterone effect). This control system can be pathologically impaired in various ways. For example, chronically reduced renal blood flow (e.g., as a result of heart failure and associated venous blockage) leads to excessive aldosterone release. This increases blood volume and, therefore, the heart's blood supply, leading to impaired cardiac function. Pulmonary blood blockage, shortness of breath, edema of the extremities, ascites and pleural effusion may occur, and renal blood flow may be further reduced. Furthermore, the effects of excess aldosterone decrease potassium levels in the blood and extracellular fluid. Concentrations below a critical minimum can induce potentially fatal arrhythmias in otherwise previously damaged myocardium. This is thought to be one of the main causes of sudden cardiac death, which frequently occurs in patients with heart failure.

[0004] Furthermore, aldosterone is thought to be involved in many of the myocardial remodeling processes commonly observed in heart failure. Therefore, aldosterone excess plays a key role in the pathogenesis and prognosis of heart failure, which can be initially induced by various types of insults, including myocardial infarction, myocardial inflammation, and hypertension. This hypothesis is supported by the fact that extensive clinical studies of patients with chronic heart failure and acute myocardial infarction treated with aldosterone antagonists have shown a significant reduction in overall mortality (B. Pitt, F. Zannad, W. J. Remme et al., N. Engl. J. Med. ML 709-717 (1999); B. Pitt, W. Remme, F. Zannad et al., N. Engl. J. Med. 1309-1321 (2003)).

[0005] Furthermore, in visceral tissues such as the kidney and intestine, MR regulates sodium retention, potassium efflux, and water balance in response to aldosterone. MR expression in the brain also appears to be involved in the control of neuronal excitability, negative feedback regulation of the hypothalamic-pituitary-adrenal axis, and cognitive aspects of behavioral performance (Castren et al., J. of Neuroendocrinology, 3, 461-66 (1993)).

[0006] Elevated aldosterone levels or excessive stimulation of hydrocorticoid receptors are associated with numerous physiological disorders and pathological conditions, including Conn(s) syndrome, primary and secondary aldosterone excess, increased sodium retention, increased magnesium and potassium excretion (polyuria), increased water retention, hypertensive disorders (such as isolated systolic hypertension and combined systolic / diastolic hypertension), arrhythmias, myocardial fibrosis, myocardial infarction, Bart's syndrome, and conditions associated with excessive levels of catecholamines (Hadley, M.E., ENDOCRINOLOGY, 2nd Ed., pp. 366-81, (1988) and Brilla et al., Journal of Molecular and Cellular Cardiology, 25(5), pp. 563-75, (1993)). Compounds and / or pharmaceutical compositions with MR antagonism may be of therapeutic value for any of the aforementioned conditions.

[0007] Despite significant advances in the treatment of hypertensive disorders and heart failure with mineralocorticoid receptor antagonists, the current standard of care is only suboptimal, and there remains a significant unmet medical need for other therapeutic / pharmacological interventions. The present invention addresses these needs by providing compounds and compositions that can be used to treat or prevent diabetic nephropathy, hypertension, heart failure, other cardiovascular diseases, and other aldosteronism. Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention provides phenyl-substituted dihydronaphthyridine compounds having mineralocorticoid receptor (MR) antagonistic activity, compound crystals, and uses of the compounds in preparing drugs, which are used to treat, prevent, or alleviate diseases such as hyperaldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, liver cirrhosis, renal failure, and cerebral stroke in patients. [Means for solving the problem]

[0009] On the other hand, the present invention relates to a compound of formula (I) and its stereoisomers, geometric isomers, inverse isomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, [ka] (I) where: [ka] teeth, [ka] and R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, carboxyl, C 1~6 Alkanoyl, C 1~6 Alkyl sulfonyl, aminoacyl, aminosulfonyl, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R5 is [ka] and R6 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; [ka] teeth, [ka] and X is C or N; Y is O or S; R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, C 3~8 Cycloalkyl C 1~6 Alkyl, (heterocyclyl of 3 to 8 atoms)C 1~6 Alkyl, (heteroaryl consisting of 5-6 atoms)C 1~6 Alkyl, phenyl or phenylC 1~6alkyl, and R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz; Each Rz independently represents =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw; Each Rw independently represents =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, or C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 It is aryl.

[0010] [ka] teeth, [ka] and R8 and R9 are hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10It is an aryl, a heterocyclyl of 3 to 8 atoms, or a heteroaryl of 5 to 10 atoms.

[0011] On the other hand, the present invention relates to a compound of formula (I) and its stereoisomers, geometric isomers, inverse isomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, [ka] (I) where: [ka] teeth [ka] or [ka] and R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, carboxyl, C 1~6 Alkanoyl, C 1~6 Alkyl sulfonyl, aminoacyl, aminosulfonyl, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R5 is [ka] and R6 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; [ka] teeth, [ka] and X is C or N; Y is O or S; R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, C 3~8 Cycloalkyl C 1~6 Alkyl, (heterocyclyl of 3 to 8 atoms)C 1~6 Alkyl, (heteroaryl consisting of 5-6 atoms)C 1~6 Alkyl, phenyl or phenylC 1~6 alkyl, and R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz; Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw; Each Rw independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, or C 1~6 Alkyl, C 1~6Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 is aryl, [ka] teeth [ka] and R8 and R9 are hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R 10 and R 11 are each independently selected from -CH2- or O, at least one is O; R 12 is -CH2- or -CH2-CH2-, and R 12 is -CH2- and R 10 and R 11 are each independently selected from —CH— or O, at least one is O, and R 12 is -CH2-CH2- and R 10 and R 11 is simultaneously O or R 10 is -CH2- and R 11 is O.

[0012] In some embodiments, the compound of formula (I) according to the present invention is selected from the compounds of formula (Ia) or formula (Ib), more preferably the compound of formula (Ia), [ka] (Ia) [ka] (Ib).

[0013] In some embodiments, the compound of formula (I) according to the present invention is selected from the compounds of formula (Ia) or formula (Ib), more preferably the compound of formula (Ia), [ka] (Ia) [ka] (Ib).

[0014] where: [ka] , [ka] , [ka] , R1, R2, R3, R4, R5, R6, R7, R8, R9, X and Y have the meanings described in the present invention.

[0015] In some embodiments, each R, R, R, and R is independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4Alkylamino, carboxyl, C 1~4 Alkanoyl, C 1~4 Alkyl sulfonyl, aminoacyl, aminosulfonyl, C 3~6 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 6 atoms, or heteroaryl of 5 to 6 atoms; R6 is hydrogen, deuterium, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 3~6 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 6 atoms, or heteroaryl of 5 to 6 atoms; Each R8 and R9 is independently hydrogen, deuterium, halogen, cyano, or C 1~4 Alkoxyacyl, Carboxyl, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 1~4 Alkanoyl, C 1~4 alkylsulfonyl, aminoacyl or aminosulfonyl; In some embodiments, each R, R, R, and R is independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, carboxyl, methylacyl, ethylacyl, methylsulfonyl, aminoacyl, or aminosulfonyl; R6 is hydrogen, deuterium, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalenyl, cyclohexylethyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridinyl, pyrrolidinyl, thiazole, pyrazole or pyrimidinyl; R8 is hydrogen, deuterium, cyano, methyl acyl, ethyl acyl, propyl acyl, methoxyl acyl, ethoxyl acyl, propoxyacyl, carboxyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, or dimethylamino.

[0016] In some embodiments, the compounds according to the present invention are selected from compounds of formula (II): [ka] (II).

[0017] In some embodiments, the compounds according to the present invention are selected from compounds of formula (IIa) or formula (IIb). [ka] (IIa) [ka] (IIb)

[0018] In some embodiments, R7 is C 3~6Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, C 3~6 Cycloalkyl C 1~4 Alkyl, (heterocyclyl of 3-6 atoms)C 1~4 Alkyl or (heteroaryl consisting of 5-6 atoms)C 1~4 alkyl, where R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

[0019] In some embodiments, R7 is C 1~3 alkyl, where R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz, preferably R7 is methyl, ethyl, isopropyl, where R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

[0020] In some embodiments, R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetidinylmethyl, oxetidinylethyl, pyrrolidinylmethyl ... thiazolylmethyl, thiazolylethyl, pyrazolemethyl, pyrazoleethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz.

[0021] In some embodiments, each Rz is independently ═O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 It is aryl.

[0022] In some embodiments, each Rz is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethyla sil, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl, wherein each Rz is independently unsubstituted. or substituted with 1, 2, 3 or 4 Rw, each Rw independently being ═O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methyl ... and phenyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl.

[0023] In some embodiments, the compound is selected from a compound of formula (III): [ka] (III) where R5 is [ka] is selected from.

[0024] In some embodiments, R1, R2, R3, and R4 are independently hydrogen, deuterium, or C 1~6 is an alkoxy; R5 is [ka] and R6 is hydrogen, deuterium, C 1~6 alkyl.

[0025] In some embodiments, R1, R2, R3, and R4 are independently hydrogen, deuterium, or C 1~3 is an alkoxy; R5 is [ka] and R6 is hydrogen, deuterium, C 1~3 alkyl.

[0026] In some embodiments, R1, R2, R3, and R4 are independently hydrogen, deuterium, or methoxyl; R5 is [ka] and R6 is selected from hydrogen, deuterium, and methyl.

[0027] In some embodiments, the compound is selected from the group consisting of: [ka] (IV) where: [ka] teeth [ka] and R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1~6 is an alkoxy; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, Y is selected from O; X is selected from C.

[0028] In some embodiments, R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1~3 is an alkoxy; R6 is C 1~3 is alkyl, R7 is C 1~3 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~3 It is alkyl.

[0029] In some embodiments, the compound is selected from compounds of formula (V): [ka] (V) where: [ka] teeth [ka] and R3 and R4 are independently hydrogen or deuterium; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, where R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently halogen; R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, X is selected from C; Y is selected from O.

[0030] In some embodiments, R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, each Rz independently being fluorine, chlorine, bromine, or iodine; R8 and R9 are hydrogen, deuterium, and C 1~3 It is alkyl.

[0031] In some embodiments, R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently fluorine; R8 and R9 are hydrogen and methyl.

[0032] In some embodiments, the compound is selected from compounds of formula (V): [ka] (V) where: [ka] teeth [ka] and R3 and R4 are independently hydrogen or deuterium; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently halogen, C 1~6 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, X is selected from C; Y is selected from O.

[0033] In some embodiments, the compound is selected from a compound of Formula (Va) or Formula (Vb): [ka] (Va) (Vb) where: [ka] teeth [ka] and R3 and R4 are independently hydrogen or deuterium; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently halogen, C 1~6 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, X is selected from C; Y is selected from O.

[0034] In the above formula (V), formula (Va) and formula (Vb), R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently fluorine, chlorine, bromine, iodine, C 1~4 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~3 It is alkyl.

[0035] moreover, R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently fluorine, methyl; R8 and R9 are hydrogen and methyl.

[0036] In some embodiments, the compound is selected from a compound of Formula (VI), Formula (VIa), or Formula (VIb): [ka] (VI) [ka] (VIa) [ka] (VIb) R 10 and R 11 are each independently selected from —CH— or O, and at least one is O; R 12 is -CH2- or -CH2-CH2-, and R 12 is -CH2- and R 10 and R 11 are each independently selected from —CH— or O, at least one is O, and R 12 is -CH2-CH2- and R 10 and R 11 is simultaneously O or R 10 is -CH2- and R 11 is O, R7 is C 1~3 Alkyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, C 3~6 Cycloalkyl C 1~4 Alkyl, (heterocyclyl of 3-6 atoms)C 1~4 Alkyl or (heteroaryl consisting of 5-6 atoms)C 1~4alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz; Preferably, R7 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetidinylmethyl, oxetidinylethyl, pyrrolidinylmethyl. , pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl, pyrrolidinylmethyl, pyrrolidinylethyl, furanylmethyl, furanylethyl, thiophenemethyl, thiopheneethyl, thiazolemethyl, thiazoleethyl, pyrazolemethyl, pyrazoleethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 is aryl, Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl, wherein each Rz is independently unsubstituted. or substituted with 1, 2, 3 or 4 Rw, each Rw independently being O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl methyl acyl, ethyl acyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl or phenyl.

[0037] In some embodiments, the compound of formula (I) provided by the present invention is a compound of formula (I-10), (I-11), or (I-12), and a stereoisomer, geometric isomer, reverse isomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof: [ka] (I-10), [ka] (I-11), [ka] (I-12), where: [ka] teeth [ka] R and R are independently hydrogen or deuterium; R is hydrogen, deuterium, C 1~6 alkyl, and R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, or NH2, and R8 and R9 are hydrogen, deuterium, C 1~6 is alkyl, In the compound represented by (I-10), (I-11) or (I-12), R6 is C 1~4 alkyl, further selected from hydrogen, methyl, ethyl, propyl, In the compounds represented by (I-10), (I-11) or (I-12), each R8 and R9 independently represents hydrogen, deuterium, halogen, C 1~4 is alkyl, In the compound represented by (I-10), (I-11) or (I-12), R8 is independently hydrogen, methyl, ethyl, propyl or butyl, R9 is independently hydrogen or deuterium, In the compound represented by (I-10), (I-11) or (I-12), R7 is C 3~6 Cycloalkyl, C 3~8 Cycloalkyl, C 3~5 Cycloalkyl C 1~3 alkyl, and R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, each Rz independently being O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, or NH2; In the compounds represented by (I-10), (I-11) or (I-12), R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

[0038] In the compounds represented by (I'-10), (I'-11) or (I'-12), R7 is methyl or ethyl.

[0039] In the compounds represented by (I'-10), (I'-11) or (I'-12), R7 is substituted with 1 to 3 F atoms.

[0040] In some embodiments, the compound is selected from the following: [ka] [ka] [ka] [ka]

[0041] In the present invention, there are no compounds in which R1, R2, and R3 are hydrogen, R4 is methoxy, R5 is -CONH2, and R6 is hydrogen.

[0042] Meanwhile, the present invention provides a crystal of a compound, the structural formula of which is as follows: [ka] 36

[0043] Here, the crystal of Compound 36 has a monoclinic crystal structure, belongs to the C2 space group, and has cell parameters a = 23.1853(2) [Å], b = 8.74723(7) [Å], c = 10.94032(10) [Å], α = 90°, β = 112.7428(8)°, γ = 90°, and a cell volume V = 2046.27(3) [Å]. 3 , the minimum number of asymmetric units in a cell is Z=4.

[0044] Here, the crystal of compound 36 or its crystalline form has an XRPD pattern as shown in FIG. 4 or substantially as shown in FIG. 4, where "substantially" means that the difference in the number of peak shapes is within 85%.

[0045] The present invention further provides a crystal of another compound 62, the structural formula of which is as follows: [ka] 62

[0046] Here, the crystal of compound 62 has a monoclinic crystal structure, belongs to the C2 space group, and has cell parameters a = 24.92890(19) [Å], b = 8.89441(5) [Å], c = 21.18548(18) [Å], α = 90°, β = 121.6750(10)°, γ = 90°, and a cell volume V = 3997.68(6) [Å]. 3 , the minimum number of asymmetric units in a cell is Z=8.

[0047] Here, the crystal of Compound 62 or a crystalline form thereof has an XRPD pattern similar to or substantially similar to that shown in FIG. 8, where substantially means that the difference in the number of peak shapes is within 85%.

[0048] Specifically, the present invention provides a crystalline compound, Compound 36, whose structural formula is shown in the figure above. The crystalline Compound 36 has a monoclinic structure, belongs to the C2 space group, and has cell parameters a = 23.1853(2) [Å], b = 8.74723(7) [Å], c = 10.94032(10) [Å], α = 90°, β = 112.7428(8)°, γ = 90°, cell volume V = 2046.27(3) [Å]3, and a minimum number of asymmetric units in the cell Z = 4. The crystalline Compound 36 or its crystalline form has an XRPD pattern substantially as shown in Figure 4, where "substantially" means that the difference in the number of peak shapes is within 85%. The present invention further provides a crystal of another compound 62, whose structure is a monoclinic crystal, belonging to the C2 space group, with cell parameters a = 24.92890(19) [Å], b = 8.89441(5) [Å], c = 21.18548(18) [Å], α = 90°, β = 121.6750(10)°, γ = 90°, cell volume V = 3997.68(6) [Å]3, and a minimum number of asymmetric units in the cell Z = 8. The crystal of compound 62 or a crystalline form thereof has an XRPD pattern shown in Figure 8 or substantially shown in Figure 8, where "substantially" means that the difference in the number of peak shapes is within 85%. The present invention further provides a use of the crystals of the compound in preparing a drug, the drug being for treating or preventing a disease or condition related to mineralocorticoid, or for treating, preventing or alleviating a condition such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke in a patient, or the drug being used as a mineralocorticoid receptor antagonist.

[0049] On the other hand, it relates to the use of the compounds according to the present invention and their stereoisomers, geometric isomers, inverse isomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs in the preparation of a medicament, or to the use of the compounds according to the present invention and their stereoisomers, geometric isomers, inverse isomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs in the preparation of a medicament for treating or preventing a disease or condition related to mineralocorticoids.

[0050] Here, the drug is used to treat, prevent or alleviate diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke in patients.

[0051] Alternatively, wherein said drug is used as a mineralocorticoid receptor antagonist.

[0052] The mineralocorticoid-related disease or condition is selected from diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure, and cerebral apoplexy.

[0053] (Definitions and General Terms) Specific embodiments of the present invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications, and equivalent technical solutions falling within the scope of the present invention as defined by the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs or contradicts with this application (including, but not limited to, defined terms, application of terms, described techniques, etc.), this application shall control.

[0054] It should be further appreciated that certain features of the invention, which are, for clarity and legibility, described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0055] Unless otherwise specified, all technical terms and techniques used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications covered by this invention are incorporated herein by reference in their entirety.

[0056] As used herein, the following definitions apply unless otherwise specified: For purposes of the present invention, the chemical elements are defined in accordance with the Periodic Table, CAS Edition, and the Handbook of Chemistry and Physics, 75th Edition, 1994. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0057] Unless otherwise indicated or clearly contradicted by context, the articles "a," "an," "one," and "said," as used herein, are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more (i.e., at least one) objects. For example, a "component" refers to one or more components, i.e., there may be one or more components contemplated for employment or use in the described embodiments.

[0058] As used herein, the term "patient" refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0059] The term "comprises" is open-ended, that is, includes what is set forth in the present invention but does not exclude other embodiments.

[0060] "Stereoisomers" are compounds that have the same chemical constitution but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomeric isomers, diastereomeric isomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, blocking isomers, etc.

[0061] "Enantiomers" refer to two isomers of a compound that are non-superimposable but mirror images of one another.

[0062] "Diastereoisomers" refer to stereoisomers with two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers differ in physical properties such as melting points, boiling points, spectroscopic properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

[0063] The stereochemical definitions and rules used in the present invention generally follow those in S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0064] Any of the asymmetric atoms (e.g., carbon, etc.) of the compounds disclosed herein can be present in racemic or enantiomerically enriched form, such as the (R)-, (S)-, or (R,S)-configuration. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess with respect to the (R)- or (S)-configuration.

[0065] Any resulting mixture of stereoisomers can be separated, for example, by chromatography and / or stepwise crystallization, into pure or substantially pure geometric, enantiomeric, or diastereomeric isomers based on differences in the physicochemical properties of the components.

[0066] The term "reverse isomer" or "tautomeric form" refers to structural isomers with different energies that can be interconverted by a low energy barrier. If isomerization is possible (e.g., in solution), a chemical equilibrium of isomers can be achieved. For example, proton tautomers (prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via recombination of some bond electrons. A specific example of keto-enol isomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one isomers. Another example of tautomerism is phenol-keto interconversion isomers. A specific example of a phenol-ketone interconversion is the interconversion isomers of pyridin-4-ol and pyridin-4(1H)-one. Unless otherwise specified, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0067] As described herein, the compounds of the invention may be optionally substituted with one or more substituents, such as in the compounds of the general formula above, or in the specific examples, subclasses and classes of compounds encompassed by the invention within the Examples.

[0068] Furthermore, unless otherwise specified, in the present invention, "each independently" and "each independently" and "independently" are interchangeable and should be understood in a broad sense, meaning that specific options expressed between the same symbols in different groups do not affect each other, or that specific options expressed between the same symbols in the same group do not affect each other. Similarly, the term "independently" in the description "independently, optionally" should be understood in the broad sense described above.

[0069] The term "optional" or "optionally" means that the subsequently described event or circumstance may be present, but is not necessarily present; that is, the present specification covers not only situations in which the described event or circumstance is present, but also situations in which it is absent.

[0070] In various parts of this specification, substituents of the compounds disclosed herein are disclosed according to group types or ranges. In particular, it should be noted that the present invention encompasses the separate subcombinations of each member of these group types and ranges. For example, the terms "C1-C6 alkyl" or "C 1~6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl as individually disclosed; 1~4 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl (i.e., propyl, including n-propyl and isopropyl), and C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-propyl, and tert-propyl), each of which is disclosed independently.

[0071] In each section of the present invention, linking substituents are described. When a structure clearly requires a linking group, the Marksch variable recited for that group should be understood as the linking group. For example, if a structure requires a linking group and the Marksch group definition for that variable recites "alkyl" or "aryl," then "alkyl" or "aryl" represent the linked alkylidene or arylidene group, respectively.

[0072] As used herein, the term "alkyl" or "alkyl group" refers to a saturated, linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein said alkyl group may be substituted with one or more substituents described herein. In some embodiments, an alkyl group contains 1 to 12 carbon atoms, and in other embodiments, an alkyl group contains 1 to 6 carbon atoms, i.e., C 1~6 In yet another embodiment, the alkyl group contains 1 to 4 carbon atoms, i.e., C 1~4 In some embodiments, the alkyl group contains 1 to 3 carbon atoms, i.e., C 1~3 In some embodiments, the C 1~6 Alkyl is C 1~4 In some embodiments, the C 1~6 Alkyl is C 1~3 Contains alkyl.

[0073] Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), propyl (including n-butyl, isobutyl, sec-butyl, tert-propyl), n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like.

[0074] The term "alkoxy" indicates an alkyl group attached to the remainder of the molecule by an oxygen atom, where alkyl group has the meaning as described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy or 2-propoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), and the like.

[0075] The term "haloalkyl" or "haloalkoxy" indicates that an alkyl or alkoxy group is substituted with one or more halogen atoms, and examples include trifluoromethyl, trifluoromethoxy, chloroethyl (e.g., 2-chloroethyl), trifluoroethyl (including but not limited to 2,2,2-trifluoroethyl), 2,2-difluoroethyl, 2-chloro-1-methylethyl, and the like.

[0076] The term "amino" refers to the group -NH2. The term "carboxyl" refers to the group -COOH. The terms "hydroxyl," "cyano," "nitro," and "mercapto" refer to the groups -OH, -CN, -NO2, and -SH, respectively. The term "oxo" refers to the group =O.

[0077] The term "alkylamino" or "alkylamino" refers to the group -NH2 being substituted with one or two alkyl groups, i.e., said alkylamino or alkylamino includes monoalkylamino and dialkylamino, wherein said alkyl has the meaning described in the present invention. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, etc.

[0078] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring carbon atoms. In some embodiments, cycloalkyl refers to a ring containing 3 to 10 ring carbon atoms, such as C 3-10 In some other embodiments, cycloalkyl includes 3 to 8 ring carbon atoms, e.g., C3~8 In some further embodiments, cycloalkyl includes 3 to 6 ring carbon atoms, e.g., C 3~6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. As used herein, C 3~8 Cycloalkyl is C 3~6 including cycloalkyl, 3~6 Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Said cycloalkyl groups may be optionally substituted with one or more substituents as described herein.

[0079] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur, and oxygen atoms, and wherein the heterocyclyl is non-aromatic and does not contain an aromatic ring. Unless otherwise specified, a heterocyclyl may be carbon- or nitrogen-based, and a -CH2- group may optionally be replaced with -C(=O)-. A sulfur atom in the ring may optionally be oxidized to an S-oxide. A nitrogen atom in the ring may optionally be oxidized to an N-oxide. The term "heterocyclyl" may be used interchangeably with the term "heterocycle." Examples of heterocyclyl include, but are not limited to, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholino, etc. As described in the present invention, the heterocyclyl consists of 3 to 8 atoms or 3 to 6 atoms, the atoms being C, N, O, or S, and at least one atom being N, O, or S, where the heterocyclyl consisting of 3 to 8 atoms is a heterocyclyl consisting of 3 to 6 atoms, and the heterocyclyl consisting of 3 to 6 atoms is a heterocyclyl consisting of 3 to 5 atoms, and specifically, the heterocyclyl consisting of 3 to 6 atoms is ethylene oxide. [ka] Aziridine [ka] Azetidinyl [ka] Oxetidinil [ka] Pyrrolizini [ka] Tetrahydrofuranyl [ka] Tetrahydrothienyl [ka] Thiazolidinyl [ka] Pyrazolidinyl [ka] Pyrazolinyl [ka] Oxazolidinyl [ka] Imidazolidinyl [ka] Piperidinyl [ka] piperazinyl [ka] or morpholino [ka] Including, but not limited to, the following: Said heterocyclyl may be optionally substituted with one or more substituents described herein.

[0080] The term "halogen" means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0081] The term "aryl" refers to monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, where at least one is aromatic and there are one or more points of attachment to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aryl ring." Examples of aryl groups include phenyl, 2,3-dihydro-1H-indenyl, naphthalenyl, and anthracenyl. The aryl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, "C 6~10 An "aryl" group refers to an aryl group containing 6 to 10 ring carbon atoms.

[0082] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic rings containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, where at least one is aromatic and at least one is 1, 2, 3, or 4 cycloheteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl has one or more points of attachment to the remainder of the molecule. If a -CH- group is present in the heteroaryl group, the -CH- group may optionally be replaced with -C(=O)-. Unless otherwise specified, the heteroaryl group may be attached to the remainder of the molecule (e.g., the main structure in a general formula) through any reasonable position (e.g., C in CH or N in NH). The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or "heteroaryl compound." Examples of heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolidinyl, pyrazole, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophene, thiazole, triazolyl, tetrazolyl, etc. Said heteroaryl groups may be optionally substituted with one or more substituents described herein. In some embodiments, heteroaryl is a 5-10 atom heteroaryl, meaning that the heteroaryl contains 1-9 ring carbon atoms and 1, 2, 3, or 4 cycloheteroatoms selected from O, S, and N; in other embodiments, heteroaryl is a 5-6 atom heteroaryl, meaning that the heteroaryl contains 1-5 ring carbon atoms and 1, 2, 3, or 4 cycloheteroatoms selected from O, S, and N; examples of 5-6 atom heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolidinyl, pyrazole, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophene, thiazole, and the like.

[0083] The term "consisting of j to k atoms (j and k are each independently any non-zero natural number, k>j)" means that the cyclic group consists of j to k ring atoms, which are carbon atoms and / or heteroatoms such as O, N, S, and P, and the "j to k" includes j, k, and any natural numbers therebetween. For example, "consisting of 3 to 8 atoms," "consisting of 5 to 10 atoms," or "consisting of 5 to 6 atoms" means that the cyclic group consists of 3 to 8, 5 to 10, or 5 to 6 ring atoms, which are carbon atoms and / or heteroatoms such as O, N, S, and P.

[0084] As used herein, when a compound group is formed by linking two or more groups, the linking site follows the general principles of chemistry, i.e., the point of attachment refers to the last noun group in the name of the compound group. For example, "C 3~8 Cycloalkyl C 1~6 Alkyl, 3-8 heterocycloalkylC 1~6 Alkyl, Phenyl C 1~6 Alkyl, 5-6 heteroaryl C 1~6 When "alkyl" occurs, the main structural group or any point of attachment to another group must be "C 1~6 alkyl" and other types of groups are understood by reference to the sub-rule unless otherwise stated.

[0085] The "heterocyclyl having 3 to 8 ring atoms" and "heterocyclyl having 3 to 6 ring atoms" described in the present invention refer to a heterocyclyl having 3 to 8 ring atoms or a heterocyclyl having 3 to 6 ring atoms, wherein the heterocyclyl consists of 1, 2, 3, or 4 heteroatoms selected from N, O, and S, and CH2 in the heterocyclyl can be further oxidized to form C(=O), and similarly, S or N in the heterocycle can be further oxidized to form S(=O), S(=O)2, or N(=O).

[0086] The "heteroaryl having 5 to 10 ring atoms" and "heteroaryl having 5 to 6 ring atoms" described in the present invention refer to a heteroaryl having 5 to 10 ring atoms or a heteroaryl having 5 to 6 ring atoms, wherein the heteroaryl contains 1, 2, 3, or 4 heteroatoms selected from N, O, and S. In some embodiments, specific examples of the "heteroaryl having 5 to 10 ring atoms" or "heteroaryl having 5 to 6 ring atoms" described in the present invention include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, thiophene, thiazole, furanyl, pyrrolidinyl, pyrazole, imidazolyl, triazolyl, etc.

[0087] The term "alkanoyl" or "alkyl acyl" refers to a -C(=O)-alkyl group, wherein said alkyl has the meaning described herein, examples of which include, but are not limited to, methyl acyl (-C(=O)CH), ethyl acyl (-C(=O)CHCH), etc.

[0088] The term "alkoxyalkyl" refers to a -C(=O)-R group, where R is alkoxy, said alkoxy having the meaning described in the present invention, examples of which include, but are not limited to, methoxyl acyl (-C(=O)OCH), ethoxyl acyl (-C(=O)OCHCH), etc.

[0089] The term "alkylsulfonyl" refers to an -S(=O)2-alkyl group, wherein said alkyl has the meaning described in the present invention, and examples thereof include, but are not limited to, methylsulfonyl (-S(=O)2CH3), ethylsulfonyl (-S(=O)2CH2CH3), etc.

[0090] The term "aminosulfonyl" refers to the group -S(=O)2NH2 and the term "aminoacyl" refers to the group -C(=O)NH2.

[0091] The term "pharmaceutically acceptable" refers to molecular entities and compositions that, when administered to humans, are physiologically tolerable and generally do not produce allergic or similar untoward reactions, such as gastrointestinal discomfort, dizziness, etc. Preferably, as used herein, the term "pharmaceutically acceptable" refers to those approved by a federal regulatory agency or national government, or those listed in the United States Pharmacopoeia or other generally recognized pharmacopoeias, for use in animals, particularly humans.

[0092] The term "carrier" refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. These drug carriers may be sterile liquids, such as water and oils, including those derived from petroleum, animal, vegetable, or synthetic sources, including peanut oil, soybean oil, mineral oil, and sesame oil. Water and aqueous solutions (e.g., aqueous saline solutions, aqueous glucose solutions, and aqueous glycerol solutions) are preferred as carriers, particularly for injectable solutions. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

[0093] The term "prodrug" as used herein refers to the in vivo conversion of a compound to a compound of formula (I). Such conversion is effected by hydrolysis of the precursor drug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The precursor drug compounds of the present invention may be esters, and existing inventions have included esters that can be used as precursor drugs, such as phenyl esters, aliphatic (C 1~24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, one of the compounds of the present invention contains a hydroxyl group, which can be acylated to obtain a precursor drug form of the compound. Other precursor drug forms include phosphate esters, which can be obtained by phosphorylating the hydroxyl group on the parent. For a complete review of precursor drugs, see T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270; and S.J. Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0094] "Metabolite" refers to a product obtained by metabolism of a specific compound or its salt in the body. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods such as those described herein. Such products can be obtained by oxidation, reduction, hydrolysis, acylation, deacylation, esterification, delipidation, enzymatic cleavage, etc. of the administered compound. Thus, the present invention encompasses metabolites of a compound, including those resulting from sufficient exposure of a mammal to a compound of the present invention for a period of time.

[0095] As used herein, the term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art and are described in detail in, for example, S.M. Berge et al., "Describe pharmaceutically acceptable salts in detail" in J. Pharmaceutical Sciences, 1977, 66:1-19. Pharmaceutically acceptable salts formed from non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and perchlorate, organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, and malonate, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethylsulfonate, formate, transbutylenedioate, glucoheptanoate, glycerophosphate, gluconate, hemitosulfate, heptanoate, hexanoate, hydriodate, and the like. Salts obtained by reaction with an appropriate base include alkali metal, alkaline earth metal, ammonium, and N-isopropyl ethersulfates, such as 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pomalate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, sulfonate, undecanoate, pentanoate, and the like. + (C 1~4The present invention also contemplates quaternary ammonium salts formed from any compound containing an N group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali or alkaline earth metal salts which can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable non-toxic ammonium salts, quaternary ammonium salts, and amine cations which resist equilibrium ion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1~8 Includes sulfonates and aromatic sulfonates.

[0096] The term "solvate" in the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed with water as the solvent molecule.

[0097] The term "ester" as used herein refers to an ester formed from a compound containing hydroxyl or carboxyl and capable of being hydrolyzed in vivo. Such esters are pharmaceutically acceptable esters that are hydrolyzed in the human or animal body to produce the parent alcohol or acid. The compounds of formula (I) of the present invention contain an ester capable of being hydrolyzed in vivo with a suitable group, such as carboxyl, including, but not limited to, alkyl, arylalkyl, and the like.

[0098] "Nitrogen oxides" of the present invention refer to compounds containing multiple amine functional groups in which one or more nitrogen atoms have been oxidized to N - This means that oxides can be formed. - Specific examples of oxides include N-oxides of tertiary amines. - Oxides or nitrogen-containing heterocycles containing nitrogen atoms - The corresponding amines are treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to give N -It is possible to form oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th Edition, Jerry March, pages 1999). In particular, N - The oxides are prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0099] As used herein, the terms "compounds of the present invention," "compounds described in the present invention," "compounds described in the present invention," or similar expressions refer to any of the compounds represented by the general formula structures described in the present invention. For example, the compounds of the present invention can refer to compounds represented by Formula (I) or Formula (Ia) or Formula (Ib) or Formula (IIa) or Formula (IIb) or Formula (III) or Formula (IV) of the present invention. The compounds of the present invention include specific compounds of any of the Examples.

[0100] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., reducing, arresting, or alleviating the progression of the disease or at least one clinical symptom). In other embodiments, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be apparent to the patient. In other embodiments, "treatment" refers to modulating the disease or condition physically (e.g., stabilizing detectable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treatment" refers to preventing or delaying the onset, development, or worsening of the disease or condition.

[0101] The structural formulas provided herein are also intended to represent these compounds in isotopically unenriched and isotopically enriched forms.Isotopically enriched compounds have the structure described by the general formulas provided herein, except that one or more atoms are replaced with atoms having a selected atomic mass or mass number.Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, ion, fluorine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 31P, 32P, 35S, 36Cl and 125I.

[0102] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may offer certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life, reduced dosage, or improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound of formula (I). An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, particularly deuterium. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a designated isotope. When a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium doping at each designated deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping). Pharmaceutically usable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, such as DO, acetone-d, DMSO-d, and the like.

[0103] Unless otherwise specified, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Additionally, unless otherwise stated, the structural formulas of the compounds described in the present invention include enriched isotopes of one or more different atoms.

[0104] Abbreviations for any protecting groups, amino acids and other compounds used in the present invention are based on commonly used and accepted abbreviations unless otherwise stated, or may refer to the IUPAC-IUB Commission on Biochemical Nomenclature (Biochem. 1972, 11:942-944).

[0105] (Description of the Compounds of the Present Invention) The present invention provides phenyl-substituted dihydronaphthyridine compounds that competitively antagonize aldosterone receptors (MR), pharmaceutical compositions thereof, and uses of the compounds or pharmaceutical compositions in the preparation of drugs, which are used to treat, prevent, or alleviate diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, liver cirrhosis, renal failure, and stroke in patients.

[0106] On the other hand, the present invention relates to compounds of formula (I) or stereoisomers, geometric isomers, inverse isomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs of compounds of formula (I). [ka] (I)

[0107] Meanwhile, the present invention relates to the use of the compound or pharmaceutical composition according to the present invention in the preparation of a drug, wherein the drug is used to treat, prevent or alleviate diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure or cerebral stroke in patients.

[0108] On the other hand, the present invention further relates to the use of the compound or pharmaceutical composition according to the present invention in the preparation of a drug, wherein said drug is used as a mineralocorticoid receptor antagonist.

[0109] On the other hand, the compounds or pharmaceutical compositions described in the present invention are used to treat, prevent or alleviate diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke in patients.

[0110] On the other hand, the compounds or pharmaceutical compositions according to the present invention are used to antagonize mineralocorticoid receptors.

[0111] Meanwhile, the present invention relates to a method for treating, preventing or alleviating diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke in a patient using the compound or pharmaceutical composition described in the present invention, the method comprising treating the patient with a therapeutically effective amount of the compound or pharmaceutical composition described in the present invention.

[0112] On the other hand, the present invention further relates to a method for antagonizing mineralocorticoid receptors using a compound or pharmaceutical composition according to the present invention, said method comprising contacting an organism (in vivo or in vitro) with an effective amount of a compound or pharmaceutical composition according to the present invention.

[0113] The compounds or pharmaceutical compositions described in the present invention competitively antagonize the aldosterone receptor (MR) and therefore may be useful agents for treating and preventing diseases associated with elevated aldosterone levels.

[0114] The compounds or pharmaceutical compositions described in this invention are useful for treating or preventing aldosterone receptor-mediated diseases. The invention also includes a method for treating or alleviating an aldosterone receptor-mediated disease in a patient, or for reducing susceptibility to such a disease, comprising treating the patient with a therapeutically effective amount of a compound or pharmaceutical composition of this invention.

[0115] The present invention includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for the production of medicaments for treating the disorders described herein, disorders related to the mineralocorticoid receptor or aldosterone in patients. The present invention also includes pharmaceutical compositions comprising a compound of formula (I) in a therapeutically effective amount in association with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or mediator.

[0116] Unless otherwise specified, all hydrates, solvates and pharmaceutically acceptable salts of the compounds of the present invention are included within the scope of the present invention.

[0117] Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" means that the substance or composition must be chemically or toxicologically suitable in relation to the other ingredients that make up the formulation and the mammal for treatment.

[0118] Salts of the compounds of the present invention include salts for preparing or purifying intermediates of the compounds of formula (I) or formula (Ia) or formula (Ib) or formula (IIa) or formula (IIb) or formula (III) or formula (IV), or enantiomeric isomers separated from the compounds of formula (I) or formula (Ia) or formula (Ib) or formula (IIa) or formula (IIb) or formula (III) or formula (IV), but are not necessarily pharmaceutically acceptable salts.

[0119] Salts of the compounds of the present invention can be obtained by any suitable method provided in the literature, for example using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, hydroxyacetic acid and salicylic acid, pyranolic acids such as glucuronic acid and galacturonic acid, α-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid and ethylsulfonic acid, etc.

[0120] The biological activity of the compounds of the present invention can be evaluated using any conventional method. Suitable assays are well known in the art. For example, the compounds of the present invention can be assayed for MR antagonist activity, pharmacokinetic activity, and / or liver microsomal stability by suitable conventional methods. The assays provided herein are presented by way of example only and are not intended to limit the present invention. The compounds of the present invention are active in at least one of the assays provided herein. For example, the compounds of the present invention have good antagonist activity against MR, have better pharmacokinetic properties in the body, such as better absorption and exposure, higher bioavailability, and, for example, have fewer toxic side effects.

[0121] Administration and Use of the Compounds of the Invention A therapeutically effective amount of a compound of the present invention should be present in the above-described pharmaceutical formulation at a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight, of the total mixture. A therapeutically effective dose can be initially estimated using various methods known in the art. Initial doses for use in animal studies can be based on effective concentrations established in cell culture assays. A suitable dose range for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention can be prepared as pharmaceuticals for oral administration. Exemplary dosages of the compounds of the present invention in pharmaceuticals for oral administration are about 0.01 to about 100 mg / kg (where kg refers to the subject's body weight). In some embodiments, the pharmaceutical contains about 0.01 to about 20 mg / kg (where kg refers to the subject's body weight), or optionally about 0.01 to about 10 mg / kg (where kg refers to the subject's body weight), or optionally about 0.01 to about 5.0 mg / kg (where kg refers to the subject's body weight). In some embodiments, the compounds of the present invention are administered via the gastrointestinal route at an effective dose of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight.

[0122] Dosage regimens for drugs typically intended for oral administration are three times per week, twice per week, once per week, three times per day, twice per day, or once per day. In some embodiments, the compounds of the present invention are administered in a total amount of about 0.001 to about 50, preferably about 0.001 to about 10 mg / kg body weight of active ingredient per 24 hours, optionally in the form of multiple single doses to achieve the desired results. A single dose preferably contains about 0.001 to about 30, particularly 0.001 to 3 mg / kg body weight of the compounds of the present invention.

[0123] An effective amount or therapeutically effective amount or dose of a drug (e.g., a compound of the present invention) refers to the amount of drug or compound that causes an improvement in symptoms or a prolongation of survival in an individual. The toxicity and therapeutic effects of the molecule can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as LD50 / ED50. Drugs that exhibit a high therapeutic index are preferred.

[0124] An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that elicits a biological or medical response in a tissue, system, animal, or human being under investigation by a researcher, veterinarian, physician, or other clinician. The dosage is preferably within a range of circulating concentrations that includes the ED50 with minimal or no toxicity. The dosage may vary within this range depending on the dosage form and / or the route of administration used. The appropriate dosage form, route of administration, dosage, and administration interval should be selected according to methods known in the art, taking into account the specifics of each individual condition.

[0125] Dosage and administration intervals can be individually adjusted to achieve a plasma concentration of the active moiety sufficient to achieve the desired effect, i.e., the minimal effective concentration (MEC). The MEC varies depending on the compound but can be estimated, for example, from in vitro data or animal experiments. The dose required to achieve the MEC varies depending on individual characteristics and the route of administration. In cases of local administration or selective uptake, the effective local concentration of a drug may not depend on the plasma concentration.

[0126] The amount of agent or composition administered will depend on a variety of factors, including the sex, age, and weight of the individual being treated, the severity of the ailment, the manner of administration, and the judgment of the prescribing physician.

[0127] If necessary, the compositions of the present invention can be provided in a package or dispenser containing one or more unit dosage forms (including active ingredients). For example, the package or dispenser can be made of metal or plastic foil (e.g., styrofoam package) or glass and rubber stopper. The package or dispenser can be provided with instructions for administration. It is also possible to prepare compositions consisting of the compounds of the present invention formulated in a suitable pharmaceutical carrier, place them in an appropriate container, and attach a label for the treatment of the specified condition.

[0128] The compounds of the present invention have good safety, and the maximum tolerated dose after repeated administration for 14 days in mice indicates the high safety of compound 62. In particular, the maximum tolerated dose of compound 36 after repeated administration for 14 days is 2.7 times or more that of compound 62, and its safety window is 230 times or more the equivalent dose, providing high safety.

[0129] In addition, compound 36 of the present invention has a low CYP3A4 inhibitory effect, which reduces the contraindications of Finelenone, and also has a lower cardiac / renal AUC (tissue distribution) ratio than Finelenone, which greatly contributes to reducing the side effects of Finelenone.

[0130] The compounds of the present invention are suitable for the prevention and / or treatment of a wide range of pathological conditions and disease-related pathological conditions, in particular pathological conditions characterized by elevated plasma aldosterone levels or alterations in plasma aldosterone levels relative to plasma renin levels, or pathological conditions associated with these alterations. Examples that may be mentioned include, in particular, spontaneous primary hyperaldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenoma and / or adrenal carcinoma, hyperaldosteronism associated with liver cirrhosis, hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension.

[0131] Due to their mechanism of action, the compounds of the present invention are also suitable for preventing sudden cardiac death in patients at increased risk of dying from sudden cardiac death, in particular those suffering from any of the following conditions: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, refractory hypertension, acute and chronic heart failure, coronary artery disease, stable and unstable angina, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathies (e.g., Bmgada syndrome), cardiomyopathy due to Chagas disease, shock, atherosclerosis, atrial and ventricular arrhythmias, transient and ischemic episodes, stroke, inflammatory cardiovascular diseases, peripheral and cardiovascular diseases, peripheral blood flow disorders, occlusive arterial diseases such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, cardiac hypertrophic changes, pulmonary arterial hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic diseases, vasculitis, etc.

[0132] The compounds of the present invention may further be used in the prevention and / or treatment of edema formation, such as pulmonary edema, renal edema or pulmonary edema associated with heart failure, and in the prevention and / or treatment of restenosis after, for example, thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and coronary angioplasty (PTCA), heart transplantation and bypass surgery.

[0133] The compounds of the present invention are also suitable for use as potassium-sparing diuretics and in the treatment of electrolyte disorders such as hypercalcemia, hypernatremia or hypokalemia.

[0134] The compounds of the invention are also suitable for the treatment of renal diseases such as acute and chronic renal failure, hypertensive nephropathy, atherosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic nephropathy, for example, for the prevention of renal injury (e.g., renal injury induced by immune inhibitors (e.g., cyclosporin A) associated with organ transplantation), and for use in renal cancer.

[0135] The compounds of the present invention can further be used in the prevention and / or treatment of diabetes and diabetic sequelae such as neuropathy and nephropathy.

[0136] The compounds of the present invention can further be used in the prevention and / or treatment of microalbuminuria and proteinuria resulting from, for example, diabetes or hypertension.

[0137] The compounds of the present invention are also suitable for the prevention and / or treatment of conditions associated with elevated plasma glucocorticoid concentrations or elevated local glucocorticoid concentrations in tissues (e.g., the heart). Examples that may be mentioned are adrenal insufficiency (Cushing's syndrome) leading to excessive production of glucocorticoids, adrenocortical tumors leading to excessive production of glucocorticoids, and pituitary tumors that autonomously produce ACTH (adrenocorticotropic hormone), thereby leading to adrenal hyperplasia and Cushing's disease.

[0138] The compounds of the present invention can further be used in the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

[0139] The compounds of the invention may further be used in the prevention and / or treatment of inflammatory conditions caused by, for example, viruses, spirochetes, fungi, bacteria or mycobacteria, and inflammatory conditions of unknown cause such as polyarthritis, lupus erythematosus, periarthritis or polyarteritis nodosa, dermatomyositis, scleroderma, nodular disease, etc.

[0140] The compounds of the present invention can further be used to treat central nervous system disorders such as depression, anxiety, chronic pain, especially migraine, and neurodegenerative diseases such as Alzheimer's disease and Parkinsonism.

[0141] The compounds of the invention are also suitable for the prevention and / or treatment of vascular damage, for example after percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angiography, re-occlusion or restenosis after bypass surgery, and after endothelial dysfunction, Raynaud's disease, thromboembolic vasculitis (Buerger's syndrome) and tinnitus syndrome.

[0142] The compounds of the present invention can be used alone or, if desired, in combination with other active ingredients. The present invention further relates to pharmaceutical combinations (especially for the treatment and / or prevention of the aforementioned diseases) comprising at least one compound of the present invention and one or more other active ingredients, in particular pharmaceutical combinations for the treatment and / or prevention of the diseases described in the present invention. Suitable active ingredients for use in combination are active ingredients for lowering blood pressure, for example, preferably calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha blockers, beta blockers and Rho kinase inhibitors, diuretics, in particular tabular diuretics, and thiazide-type diuretics, drugs with antithrombotic action, for example, preferably platelet aggregation inhibitors, anticoagulants or fibrinolysis promoters, active ingredients which alter lipid metabolism, for example, preferably thyroid receptor agonists, cholesterol synthesis inhibitors, for example, preferably HMG-coenzyme A reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, bile acid reabsorption inhibitors and lipoprotein(a) antagonists, organic sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, morphine or SIN-1, organic nitrates and NO donors, such as inhaled NO, cardiac glycosides (digoxin), isoproterenol, epinephrine compounds with positive cardiotonic effects such as norepinephrine, dopamine, and dopabutylamine; compounds that inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 1, 2, 3, 4, and / or 5 inhibitors (e.g., sildenafil, vardenafil, tadalafil, amrinone, and milrinone); diuretic natriuretic peptides, such as atrial natriuretic peptide, B-type natriuretic peptide, tritiated or brain natriuretic peptides, C-type natriuretic peptide (CNP) and urinary dilating hormones, calcium sensitizers, such as, preferably, levosimendan, NO-independent but hematoxylin-dependent guanylate cyclase stimulators, in particular the compounds described in WO00 / 06568, WO00 / 06569, WO02 / 42301 and WO03 / 095451 (e.g. Riociguat), NO- and heme-independent guanylate cyclase activators,These include, but are not limited to, compounds described in particular in WO 01 / 19355, WO 01 / 19776, WO 01 / 19778, WO 02 / 070462 and WO 02 / 070510, human neutrophil elastase (HNE) inhibitors such as sevillastatone or DX-890 (Reltran), compounds that inhibit signal transduction cascades, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib, erlotinib, and / or compounds that affect cardiac energy metabolism, such as emoxetine, dichloroacetate, ranolazine, trimetazidine, etc.

[0143] The compounds of the present invention can also be administered in combination with other active ingredients. For example, in a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with a diuretic such as abscisic acid, bumetanide, torsemide, bendroflumethiazide, ketanserin, dihydrochlorothiazide, hydrofluoromethylthiazide, meclothiazide, porphyrin, triclothiazide, chlorthalidone, indapamide, metolazone, quinestrol, acetazolamide, dichlorobenzenesulfonamide, vinpocetine, glycerin, isosorbide, mannitol, amiloride, or aminopyralid. [Effects of the Invention]

[0144] The present invention has the following beneficial effects.

[0145] The present invention provides a novel compound that acts as a mineralocorticoid receptor inhibitor, has a favorable half-inhibitory concentration, and can be used to effectively treat and prevent diabetic nephropathy, hypertension, heart failure, other cardiovascular diseases, and other diseases related to aldosterone-related diseases. [Brief explanation of the drawings]

[0146] The advantages of these and / or other aspects of the present invention will become more apparent as the invention is more particularly described hereinafter in connection with the accompanying drawings and specific embodiments.

[0147] [Figure 1] 1 shows the asymmetric unit diagram of the crystal structure of compound 36. [Figure 2] A single-cell view of the crystal structure of compound 36 is shown. [Figure 3] A packing diagram of the crystal structure of compound 36 is shown. [Figure 4] Calculated and experimental comparison of the crystalline XRPD pattern of compound 36. [Figure 5] 1 shows the asymmetric unit diagram of the crystal structure of compound 62. [Figure 6] A single-cell view of the crystal structure of compound 62 is shown. [Figure 7] 6 shows the crystal structure packing diagram of compound 62. [Figure 8] Figure 1 shows a comparison of calculated and experimental crystalline XRPD patterns of compound 62. [Figure 9] A single crystal micrograph of compound 36 is shown. [Figure 10] A single crystal micrograph of compound 62 is shown. DETAILED DESCRIPTION OF THE INVENTION

[0148] In this specification, when a chemical name and a chemical structure differ, the structure prevails.

[0149] In general, the compounds of the present invention can be prepared by the methods described herein, unless further indicated, where the substituents are defined as shown in Formula (I). The following reaction schemes and examples are used to further illustrate the present invention.

[0150] Those skilled in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare other compounds of the invention, and other methods for preparing compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those compounds not exemplified by the invention can be successfully achieved by those skilled in the art by using modification methods such as appropriate protection of interfering groups, utilizing other known reagents in addition to those described in this invention, or making some routine changes to the reaction conditions. Furthermore, it will be recognized that the reactions disclosed in this invention or known reaction conditions can be applied to the preparation of other compounds of the invention.

[0151] For the examples described below, all temperatures are set in degrees Celsius unless otherwise specified. Unless otherwise specified, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification, and common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyan Chemical Factory.

[0152] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by reflux drying over metallic sodium. Anhydrous dichloromethane and chloroform were obtained by reflux drying over calcium hydride. Ethyl acetate, petroleum ether, hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0153] The following reactions are generally carried out under positive pressure of nitrogen or argon, or in anhydrous solvents in drying tubes (unless otherwise noted), reaction flasks are corked with suitable rubber stoppers, and substrates are syringed in. Glassware should be kept dry.

[0154] The chromatography column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Haihua Factory. Nuclear magnetic resonance spectral data were measured using a Bruker Avance 400 or Bruker Avance III HD 600 nuclear magnetic resonance spectrometer using CDCl3, DMSO-d6, CD3OD, or Acetone-d6 as solvents (units: ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets). Coupling constants are expressed in hertz (Hz).

[0155] Low-resolution mass spectrometry (MS) data were measured by a spectrometer of Agilent 6320 series LC-MS equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C), a G1329A autosampler and a G1315B DAD detector were applied to the analysis, and an ESI source was applied to the LC-MS spectrometer.

[0156] Low-resolution mass spectrometry (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quat pump and a G1316A TCC (column temperature was maintained at 30 °C), a G1329A autosampler and a G1315D DAD detector were applied for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0157] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, measuring 2.1 × 30 mm and 5 μm. The injection volume was determined based on the sample concentration, and the flow rate was 0.6 mL / min. HPLC peaks were recorded and read using UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were a 0.1% formic acid solution in acetonitrile (phase A) and a 0.1% formic acid solution in ultrapure water (phase B). The gradient elution conditions are shown in Table 1.

[0158] Table 1 (Gradient elution conditions for mobile phases for low-resolution mass spectrometry) [Table 1]

[0159] In the present invention, the following abbreviations are used:

[0160] DMSO-d6 deuterated dimethyl sulfoxide, g grams, mg milligrams, mol moles, mmol millimole, mL milliliter, μL microliter.

[0161] The following reaction schemes describe steps in the preparation of compounds disclosed in the present invention, where, unless otherwise specified, R1, R2, R3, R4, R6, R7, R8, and R9 each have the meanings described in the present invention. Unless otherwise specified, each reaction step in each reaction scheme described in the present invention is carried out in a solvent inert to the reaction, and the reaction-inert solvent includes, but is not limited to, the solvents involved in the embodiments of the present invention or their substitutes.

[0162] The method for preparing 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid described in the following examples is as follows. [ka]

[0163] Example 1 4-(5-ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile [ka]

[0164] Step 1) 4-(4-cyano-2-methoxylphenyl)-N-(2,2-dimethoxylethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, 0.395 mmol), 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (180 mg, 0.474 mmol), N,N-diisopropylethylamine (102 mg, 0.790 mmol), and N,N-dimethylcarboxamide (1.5 mL) were added to an 8 mL vial at room temperature. The reaction was allowed to proceed for 2 hours at room temperature. Aminoacetaldehyde dimethyl acetal (83 mg, 0.790 mmol) was added. The reaction was allowed to proceed overnight at room temperature. The reaction was quenched by adding water (15 mL). The mixture was extracted with ethyl acetate (10 ml x 3), and the combined organic phases were washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give a pale yellow solid (86 mg, yield 47.0%). MS (ESI) M / Z: 467.6 [M+H] +

[0165] Step 2) 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-N-(2-oxoethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2-methoxylphenyl)-N-(2,2-dimethoxylethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (65 mg, 0.139 mmol), acetone (6 mL), and 12.0 M 36% concentrated hydrochloric acid solution (42 mL) were added to a 25 mL single-neck bottle at room temperature. The mixture was allowed to react for 1 hour at room temperature. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate in an ice bath. Extraction was performed with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give a pale yellow solid (25 mg, 42.7% yield). MS(ESI) M / Z:421.5 [M+H] +

[0166] Step 3) 4-(5-ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-N-(2-oxoethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20 mg, 48.0 μmol), toluene (0.5 ml), and trichlormethrin (40.0 ml) were added to an 8 ml vial at room temperature. The mixture was heated to 120 °C and reacted for 1 hour. After cooling to room temperature, water (2 ml) was added, followed by extraction with ethyl acetate (2 ml x 3). The combined organic phase was washed with saturated brine (2 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography (purification conditions were as follows: chromatography column: XBridge Prep C18 OBD 30mm*150mm, 5μm; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 60ml / min; gradient: 7 minutes, acetonitrile increased from 37% to 52%; detection wavelength: 254 / 220nm) to obtain a white solid (1.7mg, yield 8.8%). MS(ESI) M / Z:403.50 [M+H] + 1 H NMR(400 MHz, Chloroform-d) δ 7.72(s, 1H), 7.50(s, 1H), 7.42(d, J =7.8 Hz, 1H), 7.21(d, J =7.8, 1H), 7.05(s, 1H), 6.99(s, 1H), 5.80(s, 1H), 5.70(s, 1H), 4.23-4.09(m, 2H), 3.78(s, 3H), 2.46(s, 3H), 2.17(s, 3H), 1.28-1.18(m, 3H).

[0167] Example 2 4-(5-ethoxy-2,8-dimethyl-3-(1,3,4-oxadiazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile [ka]

[0168] Step 1) 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (28 mg, 0.0740 mmol), dichloromethane (0.2 ml), and N,N-dimethylcarboxamide (0.05 ml) were added to an 8 ml vial at room temperature. After purging with nitrogen, oxalyl chloride (0.1 ml) was added dropwise in an ice-water bath. The mixture was then allowed to react at room temperature for 30 minutes. A solution of hydrazine hydrate (2 ml) and N,N-diisopropylethylamine (0.1 ml) in dichloromethane (0.5 ml) was added to the reaction mixture at room temperature, and the mixture was stirred for 1 hour. Water (10 ml) was added to the reaction mixture, which was then extracted with ethyl acetate (10 ml x 2). The combined organic phases were washed with saturated brine (10 ml) and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a dark yellow oil (50 mg, crude product), which was used directly in the next step reaction.

[0169] Step 2) 4-[5-ethoxy-2,8-dimethyl-3-(1,3,4-oxadiazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl]-3-methoxybenzonitrile 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide (35 mg, 0.0890 mmol), triethyl orthoformate (2 mL), and p-toluenesulfonic acid (40 mg, 0.232 mmol) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was stirred at 120°C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified using a separation dish (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a white solid (2.5 mg, 6.92%). MS(ESI) M / Z:403.95 [M+H] + 1H NMR(400 MHz, Chloroform-d) δ 8.24(s, 1H), 7.71(s, 1H), 7.42(d, J =7.8 Hz, 1H), 7.13(d, J =7.8 Hz, 1H), 7.01(s, 1H), 6.07(s, 1H), 5.64(s, 1H), 4.28-4.12(m, 2H), 3.77(s, 3H), 2.51(s, 3H), 2.19(s, 3H), 1.23(t, J =6.8 Hz, 3H).

[0170] Example 3 4-(5-ethoxy-2,8-dimethyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile [ka] 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide (20 mg, 0.0510 mmol), triethyl orthoacetate (2 mL), and p-toluenesulfonic acid (30 mg, 0.174 mmol) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was stirred at 120 °C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified using a separation dish (petroleum ether / ethyl acetate (v / v) = 2:1) to give a white solid (1.9 mg, 8.93%). MS(ESI) M / Z:418.45 [M+H] + 1H NMR(300 MHz, Chloroform-d) δ7.71(s, 1H), 7.39(d, J =7.5 Hz, 1H), 7.12(dd, J1=7.8 Hz, J2=1.5 Hz, 1H), 7.00(d, J =1.5 Hz, 1H), 6.05(s, 1H), 5.62(s, 1H), 4.28 - 4.16(m, 2H), 3.79(s, 3H), 2.47(s, 3H), 2.45(s, 3H), 2.18(s, 3H), 1.22(t, J =9.6 Hz, 3H).

[0171] Example 4 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane-1H-cyclopentanamide [ka]

[0172] Step 1) N-(2-cyanocyclopentan-1-en-1-yl)acetamide 1-Amino-2-cyano-1-cyclopentene (5.00 g, 46.2 mmol) and acetic anhydride (32 ml) were added to a 100 ml single-neck bottle at room temperature. The mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was pulped with petroleum ether (10 ml x 3) and filtered to obtain white needle-like crystals (4.80 g, 69.1% yield). MS(ESI) M / Z:151.10 [M+H] +

[0173] Step 2) 4-Amino-1,5,6,7-tetrahydro-2H-cyclopentylpyridin-2-one N-(2-cyanocyclopentan-1-en-1-yl)acetamide (2.40 g, 14.4 mmol) and tetrahydrofuran (50 ml) were added to a 250 ml three-neck bottle at room temperature. After purging with nitrogen, lithium diisopropylammonium (12 ml, 88.6 mmol) was slowly added dropwise at -78 °C. The reaction was allowed to proceed at -78 °C for 30 minutes, then heated to 80 °C and allowed to proceed overnight. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride (30 ml). The mixture was extracted with ethyl acetate (30 ml x 3), and the combined organic phase was washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 5 / 1) to give a pale yellow solid (1.25 g, 52.1% yield). MS(ESI) M / Z:151.10 [M+H] +

[0174] Step 3) 2-Cyanoethyl 4-(4-cyano-2-methoxylphenyl)-5-hydroxy-2-methyl-1H,4H,7H,8H,9H-cyclopenta[h]1,6-naphthyridine-3-carboxylate A 50 ml single-neck bottle was charged with 4-amino-1,5,6,7-tetrahydro-2H-cyclopentylpyridin-2-one (1.00 g, 6.66 mmol), 2-cyanoethyl-2-[(4-cyano-2-methoxylphenyl)methylidene]-3-oxobutyrate (2.18 g, 7.33 mmol), isopropanol (20 ml), and acetic acid (19 ml) at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was pulped with methyl tert-butyl ether (5 ml x 3) and filtered to give a yellow solid (1.70 g, 60.4%).

[0175] Step 4) 2-Cyanoethyl 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2-methyl-1H,4H,7H,8H,9H-cyclopenta[h]1,6-naphthyridine-3-carboxylate 2-Cyanoethyl 4-(4-cyano-2-methoxylphenyl)-5-hydroxy-2-methyl-1H,4H,7H,8H,9H-cyclopenta[h]1,6-naphthyridine-3-carboxylate (1.70 g, 4.02 mmol), methyl iodide (940 mg, 6.03 mmol), silver carbonate (1.11 g, 4.02 mmol), and 1,4-dioxane (15 mL) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 80 °C for 1 hour. The mixture was cooled to room temperature and quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: C18 silica gel column, mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 15 min, acetonitrile increasing from 30% to 50%, detection wavelength: 254 nm. A yellow solid was obtained (460 mg, yield 25.0%).

[0176] Step 5) 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane[h][1,6]naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2-methyl-1H,4H,7H,8H,9H-cyclopenta[h]1,6-naphthyridine-3-carboxylate (440 mg, 0.960 mmol), ethylene glycol dimethyl ether (4.5 mL), and an aqueous solution (1.5 mL) of sodium hydroxide (77 mg, 1.92 mmol) were added to a 50 mL single-neck bottle at room temperature. The reaction was allowed to proceed for 1 hour. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (15 mL x 3), and the combined organic phases were washed with saturated brine (15 mL x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: C18 silica gel column, mobile phase A: water (containing 0.04% aqueous ammonia) and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 20 min, acetonitrile increasing from 15% to 40%, detection wavelength: 254 nm. The product was collected and freeze-dried under reduced pressure.

[0177] A pale yellow solid was obtained (40 mg, 10.3% yield).

[0178] Step 6) 4-(4-cyano-2-methoxylphenyl)-5-hydroxy-2-methyl-1H,4H,7H,8H,9H-cyclopenta-1,6-naphthyridine-3-carbonitrile 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane[h][1,6]naphthyridine-3-carboxylic acid (40 mg, 0.100 mmol), N,N-diisopropylethylamine (38 mg, 0.297 mmol), N,N-dimethylcarboxamide (1.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.119 mmol) were added to an 8 mL vial at room temperature. The reaction was allowed to proceed for 1 hour at room temperature. A solution of ammonia in 1,4-dioxane (1.0 M, 0.5 mL) was added to the reaction mixture at room temperature. The reaction was allowed to proceed for 3 hours at 60 °C. The mixture was cooled to room temperature and quenched by adding water (15 mL). The mixture was extracted with ethyl acetate (15 ml x 3), and the combined organic phases were washed with saturated brine (15 ml x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography (HPLC). The purification conditions were as follows: Chromatography column: Sunfire prep C18, Mobile phase A: water (containing 0.1% formic acid) and Mobile phase B: acetonitrile, Flow rate: 60 ml / min, Gradient: 7 min, acetonitrile increasing from 20% to 42%, Detection wavelength: 254 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (9.0 mg, 22.6% yield). MS(ESI) M / Z:405.45 [M+H] + 1 H NMR(400 MHz,DMSO-d6) δ8.05(s,1H),7.36(s,1H),7.28(d,J=7.6 Hz,1H),7.15(d,J=7.6 Hz,1H),6.65(s,1H),5.33(s,1H),4.03 - 3.97(m,2H),3.83(s,3H),2.76(t,J=7.2 Hz,1H),2.68(t,J=7.2 Hz,1H),2.17(s,3H),2.08 - 1.90(m,2H),1.04(t,J=7.2 Hz,3H).

[0179] Example 5 4-(4-cyano-2-methoxyphenyl)-2-methyl-4,7,8,9-tetrahydrocyclopentane-3-carbonitrile [ka]

[0180] A solution of 2,3-dihydro-4-indenamine (12 mg, 0.0890 mmol), 4-cyano-2-methoxybenzaldehyde (24 mg, 0.150 mmol), sodium 1-cyanopropene-2-pentanoate (16 mg, 0.150 mmol), and glacial acetic acid (9 mL) in isopropanol (0.5 mL) was added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was heated to 90 °C and reacted overnight. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), increasing from 15% B to 50% B over 15 minutes, monitoring at 254 nm. A pale yellow solid (2.3 mg, 4.5% yield) was obtained. MS(ESI) M / Z: 340.25 [MH] - 1 H NMR(400 MHz,Chloroform-d) δ7.18 - 7.16(m,1H),7.14 - 7.09(m,2H),6.78(s,3H),5.90(s,1H),5.49(s,1H),3.93(s,3H),2.90 - 2.75(m,4H),2.24(s,3H),2.19 - 2.12(m,2H).

[0181] Example 6 4-(5-Cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka] [ka]

[0182] Step 1) Methyl 2-allyloxy-4-bromobenzoate Methyl 4-bromo-2-hydroxybenzoate (5.00 g, 21.6 mmol), potassium carbonate (5.98 g, 43.3 mmol), N,N-dimethylcarboxamide (50 mL), and 3-bromopropene (3.75 g, 43.3 mmol) were added to a 250 mL single-neck bottle at room temperature. The mixture was heated to 80 °C and reacted for 2 hours. The mixture was then cooled to room temperature. The reaction was quenched by adding water (300 mL). The mixture was extracted with ethyl acetate (500 mL x 3), and the combined organic phases were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give a yellow solid (4.32 g, 69.9% yield). LCMS(ESI,m / z): 271.0 [M+H] +

[0183] Step 2) Methyl 3-allyl-4-bromo-2-hydroxybenzoate Methyl 2-allyloxy-4-bromobenzoate (4.19 g, 15.5 mmol) and N-methylpyrrolidone (30 ml) were added to a 250 ml single-neck bottle at room temperature. The mixture was heated to 200 °C and reacted for 4 hours. The mixture was then cooled to room temperature. Water (300 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (500 ml x 3), and the combined organic phase was washed with saturated brine (500 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give a colorless oil (2.66 g, 63.4% yield). LCMS(ESI,m / z): 271.1 [M+H] +

[0184] Step 3) Methyl 4-bromo-2-hydroxy-3-(3-hydroxypropyl)benzoate Methyl 3-allyl-4-bromo-2-hydroxybenzoate (4.19 g, 15.5 mmol) and N-methylpyrrolidone (30 ml) were added to a 250 ml single-neck bottle at room temperature. The mixture was heated to 200 °C and reacted for 4 hours. The mixture was then cooled to room temperature. Water (300 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (500 ml x 3), and the combined organic phase was washed with saturated brine (500 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give a colorless oil (2.31 g, 83.3% yield). LCMS(ESI,m / z): 289.1 [M+H] +

[0185] Step 4) 5-Bromochromium-8-carboxylate methyl ester Methyl 4-bromo-2-hydroxy-3-(3-hydroxypropyl)benzoate (2.31 g, 7.99 mmol), triphenylphosphine (5.03 g, 19.2 mmol), and tetrahydrofuran (40 mL) were added to a 100 mL single-neck bottle at room temperature. After purging with nitrogen, diethyl azodicarboxylate (3.34 g, 19.2 mmol) was slowly added dropwise in an ice bath. The reaction was allowed to proceed overnight at room temperature. The mixture was then cooled to room temperature and quenched by adding water (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give a yellow oil (1.67 g, 77.1% yield). LCMS(ESI,m / z): 271.1 [M+H] +

[0186] Step 5) Methyl 5-cyanochromium-8-carboxylate Methyl 5-bromochromium-8-carboxylate (1.62 g, 5.96 mmol), zinc cyanide (3.51 g, 29.9 mmol), tris(dibenzylideneacetone)dipalladium (1.09 g, 1.20 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.32 g, 2.40 mmol), and N-methylpyrrolidone (30 mL) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 120 °C and reacted for 2 hours. The mixture was then cooled to room temperature. The reaction was quenched by adding aqueous solution (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3), and the combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give a white solid (952 mg, 73.3% yield). LCMS(ESI,m / z): 218.1 [M+H] +

[0187] Step 6) 8-Hydroxymethyl-5-chromonitrile Methyl 5-cyanochromium-8-carboxylate (860 mg, 3.96 mmol), tetrahydrofuran (10 mL), and a solution of lithium borohydride in tetrahydrofuran (3.96 mL, 2.0 mol / L, 7.92 mmol) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 60°C and reacted for 15 minutes. The mixture was then cooled to room temperature. The reaction was quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to give a yellow oil (450 mg, 60.1% yield). LCMS(ESI,m / z): 190.1 [M+H] +

[0188] Step 7) 8-Formylchroman-5-carbonitrile 8-Hydroxymethyl-5-chromonitrile (385 mg, 1.75 mmol), dichloromethane (5 mL), and Dess-Martin reagent (890 mg, 2.10 mmol) were added to a 25 mL single-neck bottle at room temperature. The mixture was allowed to react at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a yellow solid (280 mg, 72.9% yield). LCMS(ESI,m / z): 188.1 [M+H] +

[0189] Step 8) 2-Cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate) 8-Formylchroman-5-carbonitrile (200 mg, 1.07 mmol), 4-amino-5-methylpyridin-2-ol (200 mg, 1.61 mmol), 2-cyanoethyl 3-oxobutanoate (200 mg, 1.29 mmol), isopropanol (5 mL), and acetic acid (90 mL) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 120 g reverse-phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), increasing from 20% B to 50% B over 15 min, monitoring at 254 nm. A yellow solid (175 mg, 36.7% yield) was obtained. LCMS(ESI,m / z): 431.2 [M+H] +

[0190] Step 9) 2-Cyanoethyl 4-(5-cyano-8-cyano)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate) (175 mg, 0.407 mmol), silver carbonate (112 mg, 0.407 mmol), ethyl iodide (95 mg, 0.610 mmol), and 1,4-dioxane (2 mL) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was reacted at 90°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was collected and concentrated under reduced pressure, and the resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 120 g reverse-phase chromatography column, mobile phase A: (0.1% aqueous ammonium bicarbonate) and mobile phase B (acetonitrile), with a gradient of 15% B to 60% B over 10 minutes, to give a pale yellow oil (134 mg, 71.9% yield) as detected by UV 254 nm detection. LCMS(ESI,m / z):459.2 [M+H] +

[0191] Step 10) 4-(5-cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(5-cyano-8-cyano)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (134 mg, 0.292 mmol), ethylene glycol dimethyl ether (1 mL), and an aqueous solution (0.5 mL) of sodium hydroxide (24 mg, 0.600 mmol) were added to an 8 mL single-neck bottle at room temperature. The reaction was allowed to proceed for 1 hour. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath to adjust the pH to 5. The mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow solid (83 mg, 70.1%), which was used directly in the next step without further purification. LCMS(ESI,m / z): 406.2 [M+H] +

[0192] Step 11) 4-(5-cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(5-Cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (80 mg, 0.197 mmol), N,N-diisopropylethylamine (77 mg, 0.591 mmol), N,N-dimethylcarboxamide (2 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (225 mg, 0.591 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 1 hour at room temperature. A 1.0 M aqueous ammonia solution (0.7 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 2 hours at room temperature. The mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatographic column: YMC-Actus Triart C18, mobile phase A: water (containing 0.1% ammonium bicarbonate) and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 7 min, acetonitrile increasing from 25% to 45%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a yellow solid (59.0 mg, yield 73.9%). LCMS(ESI,m / z): 405.25 [M+H] + 1 H NMR(400 MHz,DMSO-d6) δ 7.70(s,1H),7.56(s,1H),7.18(d,J=8.0 Hz,1H),6.94(d,J=8.0 Hz,1H),6.68(s,2H),5.32(s,1H),4.28 - 4.20(m,2H),4.05(q,J=7.2 Hz,1H),2.87(t,J=6.4 Hz,2H),2.21(s,3H),2.12(s,3H),2.03 - 1.94(m,2H),1.10(t,J=7.2 Hz,3H).

[0193] Example 7 10-(4-cyano-2-methoxyphenyl)-6,8-dimethyl-7H,10H-pyrazolo[3,2-f]1,6-naphthyridine-9-carbonitrile [ka]

[0194] Step 1) tert-Butyl N-(2-bromo-5-methylpyridin-4-yl)aminoformate 2-Bromo-5-methylpyridin-4-amine (1.00 g, 5.35 mmol), N,N-dimethylpyridin-4-amine (66 mL, 0.540 mmol), di-tert-butyl dicarbonate (1.4 g, 6.42 mmol), and acetonitrile (12 mL) were added to a 50 mL single-neck bottle at room temperature. The mixture was allowed to react for 3 hours at room temperature. The mixture was then cooled to room temperature and quenched by adding water (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 3 / 1) to give a yellow solid (1.05 g, 28.3% yield). MS(ESI) M / Z:288 [MH] -

[0195] Step 2) tert-Butyl N-{5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridin-4-yl}aminoformate A 100 mL single-neck bottle was charged with tert-butyl N-(2-bromo-5-methylpyridin-4-yl)aminoformate (1.0 g, 3.48 mmol), bis(triphenylphosphine)palladium dichloride (733 mg, 1.05 mmol), cuprous iodide (3.99 g, 2.10 mmol), trimethylsilylacetylsilane (4.51 mL, 34.8 mmol), and tetrahydrofuran (30 mL) at room temperature. After purging with nitrogen, the mixture was heated to 110 °C and reacted for 2 hours. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a gray solid (640 mg, 56.1% yield). MS(ESI) M / Z:303.20 [MH] -

[0196] Step 3) 1-amino-4-[tert-butoxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridine-1-salt N-{5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridin-4-yl}amino tert-butyl formate (130 mg, 0.427 mmol), dichloromethane (2.5 mL), and amino 2,4,6-trimethylbenzenesulfonate (276 mg, 1.28 mmol) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was allowed to react at room temperature for 2 hours. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was converted to methyl tert-butyl ether (5 mL x 3) to give a gray solid (120 mg, 87.7% yield). MS(ESI) M / Z:319.90 [MH] -

[0197] Step 4) tert-Butyl N-{6-methylpyrazolo[1,5-a]pyridin-5-yl}aminoformate 1-Amino-4-[tert-butoxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridine-1-salt (400 mg, 1.25 mmol), potassium carbonate (345 mg, 2.45 mmol), and N,N-dimethylcarboxamide (4 mL) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was heated to 80 °C and reacted for 5 hours. The mixture was then cooled to room temperature. After filtration, the filtrate was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), 40% B to 90% B in 15 minutes, monitoring wavelength 254 nm. A gray solid (100 mg, 28.2% yield) was obtained. MS(ESI) M / Z:248.25 [M+H] +

[0198] Step 5) 6-Methylpyrazolo[1,5-a]pyridin-5-amine N-{6-methylpyrazolo[1,5-a]pyridin-5-yl}amino tert-butyl formate (200 mg, 0.81 mmol), dichloromethane (4 mL), and trifluoroacetic acid (1 mL) were added to a 25 mL single-neck bottle at room temperature. The mixture was allowed to react at room temperature for 2 hours. After concentration under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), washed sequentially with saturated aqueous sodium bicarbonate (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. After concentration under reduced pressure, a gray solid (100 mg, 84.1% yield) was obtained.

[0199] Step 6) 10-(4-cyano-2-methoxyphenyl)-6,8-dimethyl-7H,10H-pyrazolo[3,2-f]1,6-naphthyridine-9-carbonitrile A solution of 6-methylpyrazolo[1,5-a]pyridin-5-amine (85 mg, 0.578 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (145 mg, 0.639 mmol), and glacial acetic acid (36 mL) in isopropanol (2 mL) was added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was heated to 90 °C and reacted overnight. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), 15% B to 45% B in 15 minutes, monitoring wavelength 254 nm. A white solid (7 mg, 3.4% yield) was obtained. LCMS(ESI,m / z): 356.15 [M+H] + 1 H NMR(400 MHz,DMSO-d6) δ 8.70(s,1H), 8.41(s,1H), 7.68(s,1H), 7.52(s,1H), 7.33(d,J=8.0 Hz,1H), 7.26(d,J=8.0 Hz,1H), 5.92(s,1H), 5.46(s,1H), 3.95(s,3H), 2.30(s,3H), 2.20(s,3H).

[0200] Example 8 4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3-b]pyridine-3-carbonitrile [ka]

[0201] Step 1) Sodium 1-cyanopropen-2-enoate Sodium methylcellulose (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-neck bottle at room temperature. 5-Methylisoxazole (3.25 g, 60.0 mmol) was added dropwise in an ice-water bath. The reaction was allowed to proceed overnight at room temperature. A precipitate formed. The solid was filtered, pulped with methanol (15 ml), and filtered to give a yellow solid (3.10 g, 84.7% yield).

[0202] Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile Sodium 1-cyanopropen-2-enoate (3.00 g, 28.6 mmol), 4-formyl-3-methoxybenzonitrile (4.59 g, 28.6 mmol), dichloromethane (50 mL), piperidine (240 mg, 2.85 mmol), and glacial acetic acid (2.28 g, 57.1 mmol) were added to a 100 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 60 °C and reacted overnight. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was pulped with ethyl acetate (10 mL x 5) and filtered to give a yellow solid (2.50 g, 38.8% yield). MS(ESI) M / Z:227.95 [M+H] +

[0203] Step 3) 4-(4-cyano-2-methoxylphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3-b]pyridine-3-carbonitrile A solution of 1-benzothiophene-2-amine (50 mg, 0.335 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (76 mg, 0.335 mmol), and glacial acetic acid (9 mL) in isopropanol (0.5 mL) was added to an 8 mL vial at room temperature. After replacing the atmosphere with nitrogen, the mixture was heated to 80°C and reacted for 1 hour. The mixture was then cooled to room temperature. The residue was concentrated under reduced pressure and purified by preparative high-performance liquid chromatography (column model: Sunfire prep C18 silica gel column, 30*150 mm, 5 μm, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 48% B to 68% B in 8 min, 68% B, wavelength: 254 / 220 nm, peak time (min): 6.90), to give a white solid (22.3 mg, yield 18.1%). MS(ESI) M / Z:356.05 [MH] - 1 H NMR(400 MHz,DMSO-d6) δ 10.25(s,1H), 7.81 - 7.75(m,1H), 7.50(S,1H) 7.38 - 7.22(m,2H), 7.20 - 7.10(m,2H), 7.08 - 7.02(m,1H), 5.60(s,1H), 3.97(s,3H), 2.13(s,3H).

[0204] Example 9 4-(4-cyano-2-methoxyphenyl)-3-ethoxy-1,6-dimethyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile [ka]

[0205] Step 1) N-(2-cyanocyclopentan-1-en-1-yl)acetamide Methyl 3-hydroxy-1-methylpyrazole-5-carboxylate (2.30 g, 14.7 mmol), ethyl iodide (3.40 g, 22.1 mmol), potassium carbonate (2.00 g, 14.7 mmol), and N,N-dimethylcarboxamide (25 ml) were added to a 100 ml single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 60 °C and reacted for 5 hours. The mixture was cooled to room temperature and quenched by adding water (30 ml). The mixture was extracted with ethyl acetate (30 ml x 3), and the combined organic phase was washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow oil (2.30 g, 84.7% yield). LCMS(ESI,m / z):185.10 [M+H] +

[0206] Step 2) 3-ethoxy-1-methylpyrazole-5-carboxylic acid N-(2-cyanocyclopentan-1-en-1-yl)acetamide (2.30 g, 12.5 mmol), tetrahydrofuran (15 ml), and a saturated aqueous solution of lithium hydroxide (15 ml) were added to a 100 ml single-neck bottle at room temperature. The reaction was allowed to proceed for 3 hours at room temperature. The mixture was quenched with dilute hydrochloric acid (1.0 mol / l) and adjusted to pH 5. The mixture was extracted with ethyl acetate (30 ml x 3), and the combined organic phases were washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a white solid (2.00 g, 94.1% yield). LCMS(ESI,m / z):171.10 [M+H] +

[0207] Step 3) tert-butyl (3-ethoxy-1-methylpyrazol-5-yl)carbamate 3-Ethoxy-1-methylpyrazole-5-carboxylic acid (2.00 g, 11.7 mmol), triethylamine (3.57 g, 35.3 mmol), and tert-butyl alcohol (15 ml) were added to a 100 ml single-neck bottle at room temperature. After purging with nitrogen, diphenylphosphoryl azide (4.85 g, 17.6 mmol) was slowly added dropwise. The mixture was heated to 80 °C and reacted overnight. The mixture was cooled to room temperature. Water (20 ml) was added to quench the reaction. The mixture was extracted with ethyl acetate (30 ml x 3 times), and the combined organic phase was washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm), to give a white solid (1.60 g, yield 56.4%). LCMS(ESI,m / z):242.20 [M+H] +

[0208] Step 4) 3-ethoxy-1-methylpyrazol-5-amine tert-Butyl (3-ethoxy-1-methylpyrazol-5-yl)carbamate (800 mg, 3.32 mmol) and a 1,4-dioxane solution of hydrogen chloride (4.0 M, 5 ml) were added to a 25 ml single-neck bottle at room temperature. The mixture was stirred overnight at room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and adjusted to pH 7. The mixture was extracted with ethyl acetate (50 ml x 3), and the combined organic phases were washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid (405 mg, 86.5% yield). LCMS(ESI,m / z):142.10 [M+H] +

[0209] Step 5) 4-(4-cyano-2-methoxylphenyl)-3-ethoxy-1,6-dimethyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile A solution of 3-ethoxy-1-methylpyrazol-5-amine (50 mg, 0.344 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (78 mg, 0.344 mmol), and glacial acetic acid (18 mL) in isopropanol (1 mL) was added to an 8 mL vial at room temperature. Under nitrogen protection, the mixture was heated to 80°C and reacted for 2 hours. The mixture was cooled to room temperature and quenched by adding water (5 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (10 mmol / l aqueous ammonium bicarbonate solution) and mobile phase B (acetonitrile), 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm), to give a white solid (8.5 mg, yield 7.73%). MS(ESI)M / Z:350.20 [M+H] + . 1 H NMR(300 MHz,DMSO-d6)δ 9.74(s,1H), 7.47(s,1H), 7.38(d,J=7.9 Hz,1H), 7.17(d,J=7.9 Hz,1H), 5.16(s,1H), 3.99 - 3.78(m,5H), 3.80(s,3H), 2.13(s,3H), 1.03(t,J=7.0 Hz,3H).

[0210] Example 10 9-(4-cyano-2-methoxyphenyl)-5,7-dimethyl-6,9-dihydro[1,2,4]tricreoxazolo[4,3-a][1,5]naphthyridine-8-carbonitrile [ka]

[0211] Step 1) Sodium 1-cyanopropen-2-enoate Sodium dimethicone (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-neck bottle at room temperature. 5-Methylisoxazole (3.25 g, 60.0 mmol) was added dropwise in an ice-water bath. The reaction was allowed to proceed overnight at room temperature. A precipitate formed. The solid was filtered, pulped with methanol (15 ml), and filtered to give a yellow solid (3.10 g, 84.7% yield).

[0212] Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile Sodium 1-cyanopropen-2-enoate (3.00 g, 28.6 mmol), 4-formyl-3-methoxybenzonitrile (4.59 g, 28.6 mmol), dichloromethane (50 mL), piperidine (240 mg, 2.85 mmol), and glacial acetic acid (2.28 g, 57.1 mmol) were added to a 100 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 60 °C and reacted overnight. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was pulped with ethyl acetate (10 mL x 5) and filtered to give a yellow solid (2.50 g, 38.8% yield).

[0213] Step 3) 2-Hydrazino-4-methyl-5-nitropyridine 6-Chloro-2-methyl-3-nitropyridine (1.73 g, 10.0 mmol) and 1,4-dioxane (15 ml) were added to a 100 ml single-neck bottle at room temperature. Hydrazine hydrate (2.00 g, 40 mmol) was added under ice-water bath conditions. The reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was pulped with water (5 ml) and filtered to give a pale yellow solid (1.30 g, crude product). This was used directly in the next step without further purification.

[0214] Step 4) 7-Methyl-6-nitro[1,2,4]tricreoxazolo[4,3-a]pyridine 2-Hydrazino-4-methyl-5-nitropyridine (1.00 g, 5.95 mmol), triethyl orthoformate (2.52 g, 23.8 mmol), and dichloromethane (50 mL) were added to a 100 mL single-neck bottle at room temperature. Trifluoroacetic acid (140 mg, 1.19 mmol) was added in an ice-water bath. The reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure to give a pale yellow solid (900 mg, crude product).

[0215] Step 5) 7-Methyl-[1,2,4]tricreoxazolo[4,3-a]pyridin-6-amine 7-Methyl-6-nitro[1,2,4]tricreoxazolo[4,3-a]pyridine (900 mg, 5.01 mmol), iron powder (1.13 g, 20.2 mmol), ammonium chloride (1.07 g, 20.2 mmol), and tetrahydrofuran (50 mL) were added to a 100 mL single-neck bottle at room temperature. The mixture was heated to 50 °C and reacted overnight. The mixture was cooled to room temperature, filtered through diatomaceous earth, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a pale yellow solid (400 mg, 53.5% yield).

[0216] Step 6) 9-(4-cyano-2-methoxylphenyl)-5,7-dimethyl-6,9-dihydro[1,2,4]tricreoxazolo[4,3-a][1,5]naphthyridine-8-carbonitrile A solution of 7-methyl-[1,2,4]tricreoxazolo[4,3-a]pyridin-6-amine (50 mg, 0.337 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (76 mg, 0.337 mmol), and glacial acetic acid (54 mL) in isopropanol (3 mL) was added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was heated to 80 °C and reacted overnight. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), 30% B to 50% B over 10 min, monitoring wavelength 254 nm. A white solid (20.0 mg, 16.7% yield) was obtained. MS(ESI)M / Z:357.15[M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 8.80(s,1H), 8.18(s,1H), 7.82-7.52(m,2H), 7.28(s,1H), 7.04(s,1H), 5.89(s,1H), 3.88(s,3H), 2.19(s,3H).

[0217] Example 11 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0218] Step 1) Methyl 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate 4-Amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid (10.0 g, 46.9 mmol) and methanol (200 ml) were added to a 500 ml single-neck bottle at room temperature. Dichlorosulfoxide (8.35 g, 61.9 mmol) was slowly added dropwise in an ice-water bath. The mixture was heated to 70 °C and reacted for 1.5 hours. The mixture was cooled to room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate (300 ml). The mixture was extracted with ethyl acetate (500 ml x 3), and the combined organic phase was washed with saturated brine (500 ml) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid (10.5 g, 98.5% yield). LCMS(ESI,m / z):228.6 [M+H] +

[0219] Step 2) Methyl 4-amino-2,3-dihydro-1-benzofuran-7-carboxylate Methyl 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylate (10.5 g, 46.2 mmol), 10% palladium on carbon (5.35 g, 4.99 mmol), sodium hydroxide (3.15 g, 78.8 mmol), and methanol (200 ml) were added to a 500 ml sealed tube liner at room temperature. The mixture was heated to 30°C under 3 atmospheres of hydrogen pressure and reacted overnight. The mixture was then cooled to room temperature. The mixture was filtered through diatomaceous earth and the filter cake was washed with ethyl acetate (500 ml). The filtrate was combined, washed with saturated brine (500 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a yellow solid (4.80 g, 53.6% yield). LCMS(ESI,m / z):194.2 [M+H] +

[0220] Step 3) Methyl 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylate Methyl 4-amino-2,3-dihydro-1-benzofuran-7-carboxylate (4.20 g, 21.8 mmol), tert-butyl nitrite (3.15 g, 30.7 mmol), cuprous bromide (4.20 g, 29.4 mmol), and acetonitrile (20 mL) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 70 °C and reacted for 30 minutes. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give a yellow solid (3.50 g, 62.8% yield).

[0221] Step 4) Methyl 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylate Methyl 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylate (3.20 g, 12.5 mmol), zinc cyanide (9.54 g, 81.6 mmol), tris(dibenzylideneacetone)dipalladium (1.13 g, 1.25 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.37 g, 2.50 mmol), and N-methylpyrrolidone (20 ml) were added to a 50 ml single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 120 °C and reacted for 2 hours. The mixture was then cooled to room temperature. The reaction was quenched by adding 100 ml of aqueous solution. The mixture was extracted with ethyl acetate (100 ml x 3), and the combined organic phases were washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a white solid (2.20 g, yield 86.6%).

[0222] Step 5) 7-Hydroxymethyl-2,3-dihydro-1-benzofuran-4-carbonitrile Methyl 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylate (1.80 g, 8.86 mmol), tetrahydrofuran (20 mL), and a solution of lithium borohydride in tetrahydrofuran (6.54 mL, 2.0 mol / L, 13.3 mmol) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 60 °C and reacted for 20 minutes. The mixture was then cooled to room temperature. The reaction was quenched by adding water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to give a white solid (960 mg, 61.9% yield).

[0223] Step 6) 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile 7-Hydroxymethyl-2,3-dihydro-1-benzofuran-4-carbonitrile (920 mg, 6.58 mmol), dichloromethane (10 mL), and Dess-Martin reagent (3.24 g, 7.04 mmol) were added to a 25 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a yellow solid (800 mg, 70.2% yield).

[0224] Step 7) 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (100 mg, 0.577 mmol), 4-amino-5-methylpyridin-2-ol (100 mg, 0.806 mmol), 2-cyanoethyl 3-oxobutanoate (100 mg, 0.645 mmol), isopropanol (2.5 mL), and acetic acid (45 mL) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (10 mmol / L aqueous ammonium bicarbonate) and mobile phase B (acetonitrile), 30% B to 50% B in 15 min, monitored at 254 nm, to give a yellow solid (110 mg, 45.7% yield). LCMS(ESI,m / z):417.4 [M+H] +

[0225] Step 8) 2-Cyanoethyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (100 mg, 0.240 mmol), silver carbonate (73 mg, 0.264 mmol), ethyl iodide (75 mg, 0.480 mmol), and 1,4-dioxane (3 mL) were added to an 8 mL vial at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C for 1 hour. The mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50 mL). The filtrate was collected and concentrated under reduced pressure to give a yellow solid (110 mg, 45.7% yield), which was used directly in the next step without further purification. LCMS(ESI,m / z):445.20 [M+H] +

[0226] Step 9) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (100 mg, 0.225 mmol), ethylene glycol dimethyl ether (0.6 mL), and a solution of sodium hydroxide (18 mg, 0.450 mmol) in water (0.3 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was allowed to react for 1 hour at room temperature. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow solid (80 mg, 90.7%), which was used directly in the next step without further purification. LCMS(ESI,m / z):392.4 [M+H]+

[0227] Step 10) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (80 mg, 0.204 mmol), N,N-diisopropylethylamine (91 mg, 0.712 mmol), N,N-dimethylcarboxamide (1 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.245 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 1 hour at room temperature. An aqueous solution of ammonia (1.0 M, 0.5 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The mixture was filtered, and the resulting filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatographic column: YMC-Actus Triart C18, mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 7 min, acetonitrile increasing from 20% to 40%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a yellow solid (45.0 mg, yield 56.1%). LCMS(ESI,m / z):391.10 [M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 7.70(s,1H), 7.55(s,1H), 7.11(d,J=8.0 Hz,1H), 6.98(d,J=8.0 Hz,1H), 6.71(s,2H), 5.18(s,1H), 4.63(t,J=8.8 Hz,2H), 4.04(q,J=6.8 Hz,2H), 3.40(t,J=8.8 Hz,2H), 2.11(s,3H), 2.07(s,3H), 1.10(t,J=6.8 Hz,3H).

[0228] Example 12 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1H,4H-benzo[h]1,6-naphthyridine-3-carbonitrile [ka]

[0229] Step 1) 2-Ethoxyquinolin-4-amine 2-Chloroquinolin-4-amine (200 mg, 1.12 mmol), sodium ethanol (305 mg, 4.48 mmol), and ethanol (2.5 mL) were added to a 10 mL microwave tube at room temperature. The mixture was heated to 140 °C in a microwave oven for 1 hour. The mixture was then cooled to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography under the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous ammonia) and mobile phase B (acetonitrile), 25% B to 35% B in 10 minutes, monitoring wavelength 254 nm, to give a white solid (75 mg, 35.6% yield). MS(ESI)M / Z:189 [M+H] +

[0230] Step 2) 4-(4-cyano-2-methoxylphenyl)-5-ethoxy-2-methyl-1H,4H-benzo[h]1,6-naphthyridine-3-carbonitrile A solution of 2-ethoxyquinolin-4-amine (75 mg, 0.398 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (90 mg, 0.398 mmol), and glacial acetic acid (36 mL) in isopropanol (2 mL) was added to an 8 mL vial at room temperature. After replacing the atmosphere with nitrogen, the mixture was heated to 80°C and reacted overnight. The mixture was then cooled to room temperature. The residue was concentrated under reduced pressure and purified using a high-performance liquid chromatography column: column model YMC-Actus Triart C18, 30*150mm, 5μm, mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile, flow rate: 60ml / min, gradient: 55% B to 85% B in 7 min, wavelength: 254 / 220nm, peak time (min): 6.15, fractions were collected and freeze-dried under reduced pressure to obtain a white solid (48.8mg, yield 30.7%). MS(ESI)M / Z:397.15 [M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 9.60(s,1H), 8.36(d,J=8.4 Hz,1H), 7.63(d,J=3.9 Hz,2H), 7.52 - 7.41(m,2H), 7.29 -7.33(m,1H), 7.12(d,J=7.9 Hz,1H), 5.37(s,1H), 4.23-4.13(m,2H), 3.87(s,3H), 2.23(m,3H), 1.04(t,J=7.0 Hz,3H).

[0231] Example 13 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide [ka]

[0232] Step 1) N-(2-cyanothiophen-3-yl)acetamide 3-Amino-2-cyano-thiophene (1.00 g, 8.05 mmol) and acetic anhydride (10 ml) were added to a 50 ml single-neck bottle at room temperature. The mixture was allowed to react overnight at room temperature. After concentration under reduced pressure, the residue was pulped with petroleum ether (30 ml) and filtered to give a white solid (1.20 g, 89.6% yield). LCMS(ESI,m / z):167.0 [M+H] +

[0233] Step 2) 7-aminothieno[3,2-b]pyridin-5-ol N-(2-cyanothiophen-3-yl)acetamide (1.20 g, 7.22 mmol) and tetrahydrofuran (24 ml) were added to a 100 ml three-neck bottle at room temperature. After purging with nitrogen, lithium diisopropylammonium (6 ml, 44.3 mmol) was slowly added dropwise at -78 °C. The mixture was allowed to react at -78 °C for 30 minutes, then heated to 80 °C and reacted for 1 hour. The mixture was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride (10 ml). The mixture was extracted with ethyl acetate (15 ml x 3), and the combined organic phase was washed with saturated brine (15 ml) and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 5 / 1) to give a pale yellow solid (650 mg, 54.2% yield). LCMS(ESI,m / z):167.0 [M+H] +

[0234] Step 3) 2-Cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-hydroxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate 7-Aminothieno[3,2-b]pyridin-5-ol (907 mg, 5.42 mmol), 2-cyanoethyl-2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate (359 mg, 1.20 mmol), isopropanol (25 mL), and acetic acid (450 mL) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was pulped with ethyl acetate (15 mL x 3). The crude product obtained after filtration was purified by C18 reverse-phase column chromatography using a C18 BIOTAGE 330 g chromatography column with mobile phase A (0.1% FA in water) and mobile phase B (acetonitrile), with a gradient from 15% B to 50% B over 15 min, monitored at 254 nm. A pale yellow solid (1.09 g, 45.4% yield) was obtained. LCMS(ESI,m / z):447.1 [M+H] +

[0235] Step 4) 2-Cyanoethyl 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate 2-Cyanoethyl 6-(4-cyano-2-methoxylphenyl)-5-hydroxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate (195 mg, 0.437 mmol), methyl iodide (102 mg, 0.655 mmol), silver carbonate (120 mg, 0.437 mmol), and 1,4-dioxane (2 mL) were added to a 50 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C for 2 hours. The mixture was cooled to room temperature and quenched by adding saturated aqueous ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified using a C18 reverse-phase column. The purification conditions were as follows: chromatography column: BIOTAGE C18 reverse-phase column 120 g, mobile phase A: water (containing 0.1% aqueous ammonium bicarbonate solution) and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 15 min, acetonitrile increasing from 20% to 60%, detection wavelength: 254 nm. A white solid was obtained (120 mg, yield 57.9%). LCMS(ESI,m / z):475.1 [M+H] +

[0236] Step 5) 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylic acid 2-Cyanoethyl 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate (155 mg, 0.327 mmol), ethylene glycol dimethyl ether (1.5 mL), and an aqueous solution (0.5 mL) of sodium hydroxide (26 mg, 0.655 mmol) were added to a 50 mL single-neck bottle at room temperature. The reaction was allowed to proceed for 1 hour. The mixture was quenched in an ice bath with hydrochloric acid (1.0 mol / L) and adjusted to pH 5. Extraction was performed with ethyl acetate (5 mL x 3), and the combined organic phases were washed with saturated brine (15 mL x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: C18 silica gel column, mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 10 min, acetonitrile increased from 10% to 40%, detection wavelength: 254 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (111 mg, yield 80.6%). LCMS(ESI,m / z):422.1 [M+H] +

[0237] Step 6) 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylic acid (105 mg, 0.249 mmol), N,N-diisopropylethylamine (97 mg, 0.747 mmol), N,N-dimethylcarboxamide (2 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (284 mg, 0.747 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. Aqueous ammonia (0.8 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 3 hours at room temperature. The mixture was quenched by adding water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: Sunfire prep C18, mobile phase A: water (containing 0.1% aqueous ammonium bicarbonate), and mobile phase B: acetonitrile, flow rate: 60 ml / min, gradient: 7 min, acetonitrile increasing from 18% to 50%, detection wavelength: 254 nm. The product was collected and freeze-dried under reduced pressure to obtain a white solid (47.0 mg, yield 44.9%). LCMS(ESI,m / z):421.0 [M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 8.83(s,1H), 7.88(d,J=5.4 Hz,1H), 7.38(d,J=1.5 Hz,1H), 7.29 -7.22(m,2H), 7.18(d,J=7.9 Hz,1H), 6.88 -6.73(m,2H), 5.48(s,1H), 4.18 -4.04(m,2H), 3.82(s,3H), 2.19(s,3H), 1.10(t,J=7.0 Hz,3H).

[0238] Example 14 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0239] Step 1) Diethyl 2,3-dihydroxyterephthalate 2,3-Dihydroxyterephthalic acid (260 g, 1.31 mol) and ethanol (2.60 L) were added to a 10 L four-neck bottle at room temperature. Dichlorosulfoxide (908 g, 7.63 mol) was slowly added dropwise at 0°C, and the reaction mixture was then allowed to react overnight at 70°C. After cooling to room temperature, the reaction mixture was quenched by slowly adding dropwise to saturated aqueous sodium bicarbonate (5.20 L). The mixture was extracted with ethyl acetate (5.00 L x 3), and the combined organic phases were washed with saturated brine (3.00 L) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give an off-white solid (312 g, 93.5% yield). MS(ESI)M / Z:255.1 [M+H] +

[0240] Step 2) Benzo[d][1,3]dioxole-4,7-dicarboxylate diethyl ester Diethyl 2,3-dihydroxyterephthalate (312 g, 1.23 mol), bromochloromethane (175 g, 1.35 mol), potassium carbonate (340 g, 2.46 mol), and DMSO (1.90 L) were added to a 10 L four-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90°C overnight. The mixture was cooled to room temperature and quenched by adding saturated brine (19.0 L). The mixture was extracted with ethyl acetate (12.0 L x 3), and the combined organic phases were washed with saturated brine (12.0 L) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to give an off-white solid (289 g, 88.4% yield). MS(ESI)M / Z:267.1 [M+H] +

[0241] Step 3) Ethyl 7-hydroxymethylbenzo[d][1,3]dioxole-4-carboxylate Diethyl benzo[d][1,3]dioxole-4,7-dicarboxylate (289 g, 1.09 mol), tetrahydrofuran (2.90 L), and a solution of lithium borohydride in tetrahydrofuran (545 mL, 2.0 mol / L, 1.09 mol) were added to a 10 L four-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 60 °C for 2 hours. The reaction mixture was cooled to 0 °C and quenched by slowly adding saturated aqueous ammonium chloride (6.00 L). The mixture was extracted with ethyl acetate (4.50 L x 3), and the combined organic phases were washed with saturated brine (4.50 L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 7:3) to give a white solid (168 g, 69.0% yield). MS(ESI)M / Z:225.0 [M+H] +

[0242] Step 4) Ethyl 7-formylbenzo[d][1,3]dioxole-4-carboxylate Ethyl 7-hydroxymethylbenzo[d][1,3]dioxole-4-carboxylate (168 g, 750 mmol), dichloromethane (1.70 L), and Dess-Martin reagent (397 g, 937 mmol) were added to a 3-liter three-neck bottle at room temperature. After purging with nitrogen, the mixture was allowed to react overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to give a yellow solid (165 g, 99.1% yield). MS(ESI)M / Z:223.1 [M+H] +

[0243] Step 5) Ethyl 7-cyanobenzo[d][1,3]dioxole-4-carboxylate Ethyl 7-formylbenzo[d][1,3]dioxole-4-carboxylate (165 g, 757 mmol), hydroxylamine hydrochloride (158 g, 2.27 mol), and DMSO (1.00 L) were added to a 3-L three-neck bottle at room temperature. After purging with nitrogen, the mixture was heated to 90°C and reacted for 1 hour. After cooling to room temperature, the mixture was quenched by adding saturated brine (10.0 L). The mixture was extracted with ethyl acetate (6.00 L x 3), and the combined organic phases were washed with saturated brine (6.00 L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give a yellow solid (120 g, 73.7% yield).

[0244] Step 6) 7-Hydroxymethylbenzo[d][1,3]dioxole-4-carbonitrile Ethyl 7-cyanobenzo[d][1,3]dioxole-4-carboxylate (120 g, 548 mmol), tetrahydrofuran (1.20 L), and a solution of lithium borohydride in tetrahydrofuran (411 mL, 2.0 mol / L, 822 mmol) were placed in a 3-L three-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 60°C for 2 hours. The reaction mixture was cooled to 0°C and quenched by slowly adding saturated aqueous ammonium chloride (3.20 L). The mixture was extracted with ethyl acetate (2.50 L x 3), and the combined organic phases were washed with saturated brine (2.50 L) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to give a white solid (75.0 g, 77.3% yield).

[0245] Step 7) 7-Formylbenzo[1,3]dioxole-4-carbonitrile 7-Hydroxymethylbenzo[d][1,3]dioxole-4-carbonitrile (75.0 g, 424 mmol), dichloromethane (1.50 L), and Dess-Martin reagent (270 g, 636 mmol) were added to a 3-liter three-neck bottle at room temperature. After purging with nitrogen, the mixture was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to give a yellow solid (67.0 g, 90.4% yield).

[0246] Step 8) 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate A 3-L three-neck bottle was charged with 7-formylbenzo[1,3]dioxole-4-carbonitrile (65.0 g, 371 mmol), 2-cyanoethyl-3-oxobutyrate (63.3 g, 408 mmol), 4-amino-5-methylpyridin-2-ol (50.7 g, 408 mmol), isopropanol (1.30 L), and acetic acid (23.4 mL) at room temperature. After purging with nitrogen, the mixture was reacted at 90°C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was pulped with methyl tert-butyl ether (500 mL x 3) and filtered to give a pale yellow solid (88.0 g, 56.7%). MS(ESI)M / Z:419.2 [M+H] +

[0247] Step 9) 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (88.0 g, 210 mmol), ethyl iodide (49.3 g, 316 mmol), silver carbonate (58.1 g, 210 mmol), and 1,4-dioxane (880 mL) were added to a 2-L three-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to give a yellow solid (86.5 g, 92.1%). MS(ESI)M / Z:447.1 [M+H] +

[0248] Step 10) 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (85.0 g, 190 mmol), ethylene glycol dimethyl ether (1275 mL), water (425 mL), and an aqueous solution of sodium hydroxide (1.00 mol / L, 380 mL) were added to a 3-L three-neck bottle at room temperature. The mixture was allowed to react for 1 hour at room temperature. The mixture was diluted with water (1.50 L) and extracted with ethyl acetate (1.00 L x 1), and the aqueous phase was retained. The mixture was quenched with hydrochloric acid solution (1.00 mol / L) in an ice bath to adjust the pH to 5. After extraction with ethyl acetate (1.00 L x 3), the combined organic phases were washed with saturated brine (500 mL x 1) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a pale yellow solid (70.0 g, 91.8%), which was used directly in the next step reaction. MS(ESI)M / Z:394.2 [M+H] +

[0249] Step 11) 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (57.0 g, 145 mmol), N,N-diisopropylethylamine (37.4 g, 290 mmol), N,N-dimethylcarboxamide (570 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92.4 g, 218 mmol) were added to a 2-L three-neck bottle at room temperature. A 25% aqueous solution of ammonia (120 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react at room temperature for 1.5 hours. The reaction mixture was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: DAC prep C18, mobile phase A: water (containing 0.1% ammonium bicarbonate) and mobile phase B: acetonitrile, flow rate: 1 L / min, gradient: 30 min, acetonitrile increasing from 20% to 42%, detection wavelength: 254 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (38.0 g, 66.8%). MS(ESI)M / Z:393.3 [M+H] + 1 H NMR(400 MHz,Chloroform-d)δ 7.68(s,1H), 6.91(d,J=8.4 Hz,1H), 6.78(d,J=8.4 Hz,1H), 6.14 -6.12(m,2H), 5.79(s,1H), 5.43(s,2H), 5.16(s,1H), 4.26 -4.16(m,2H), 2.44(s,3H), 2.14(s,3H), 1.26(t,J=7.0 Hz,3H).

[0250] Example 15 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0251] Step 1) 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (100 mg, 0.240 mmol), cyclopentaiodide (71 mg, 0.360 mmol), silver carbonate (66 mg, 0.240 mmol), and 1,4-dioxane (3 mL) were added to an 8 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was collected and washed with ethyl acetate (3 x 10 mL), and the cake was filtered. The filtrate was concentrated under reduced pressure to give a yellow solid (110.0 mg, 94.5% yield). MS(ESI)M / Z:485.5 [M+H] +

[0252] Step 2) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (110 mg, 0.227 mmol), ethylene glycol dimethyl ether (3 mL), and a solution of sodium hydroxide (18 mg, 0.454 mmol) in water (1 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction was allowed to proceed for 1 hour. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath and adjusted to pH 5. Extraction was performed with ethyl acetate (5 mL x 3), and the combined organic phases were washed with saturated brine (5 mL x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow solid (100 mg, 93.6% yield), which was used directly in the next step. MS(ESI)M / Z:432.5 [M+H] +

[0253] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (90 mg, 0.209 mmol), N,N-diisopropylethylamine (54 mg, 0.418 mmol), N,N-dimethylcarboxamide (1.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (127 mg, 0.334 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. An aqueous solution of ammonia (25% content, 1.5 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 30 minutes at room temperature. The mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: Chromatography column: YMC-Actus Triart C18, 30*150mm, 5μm, Mobile phase A: water (containing 0.1% formic acid) and Mobile phase B: acetonitrile, Flow rate: 60ml / min, Gradient: 7min, acetonitrile increased from 38% to 55%, Detection wavelength: 254 / 220nm. The product was collected and freeze-dried under reduced pressure to give a white solid (50.0mg, yield 55.7%). LCMS(ESI,m / z):431.1 [M+H] + 1 H NMR(400 MHz,DMSO-d6)δ 7.67(s,1H), 7.56(s,1H), 7.12(d,J=8.0 Hz,1H), 6.95(d,J=8.0 Hz,1H), 6.72(s,2H), 5.17(s,1H), 5.12(s,1H), 4.62-4.52(m,2H), 3.50-3.36(m,2H), 2.17(s,3H), 2.11(s,3H), 1.80-1.18(m,8H).

[0254] Example 16 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(3,3-difluorocyclobutyl)methoxyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0255] Step 1) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (300 mg, 1.73 mmol), benzyl acetoacetate (333 mg, 1.73 mmol), 4-amino-5-methylpyridin-2-ol (215 mg, 1.73 mmol), isopropanol (8.5 mL), and acetic acid (0.15 mL) were added to an 8 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate) to give a white solid (185 mg, 23.6% yield). MS(ESI)M / Z:454.5 [M+H] +

[0256] Step 2) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (110 mg, 0.240 mmol), 3-bromomethyl-1,1-difluorocyclobutane (67 mg, 0.360 mmol), cesium carbonate (158 mg, 0.490 mmol), and N,N-dimethylcarboxamide (1 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was then heated at 60 °C for 2 hours. The mixture was cooled to room temperature and quenched by the addition of water (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate=5 / 1) to give a white solid (40 mg, yield 29.6%). MS(ESI)M / Z:558.6 [M+H] +

[0257] Step 3) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (100 mg, 0.180 mmol), palladium on carbon (10% content, 100 mg), and tetrahydrofuran (2 mL) were added to a 30 mL autoclave liner at room temperature. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres and the reaction was continued overnight at room temperature. The filtrate was filtered and concentrated under reduced pressure to give a pale yellow solid (30 mg, 35.8% yield), which was used directly in the next step. MS(ESI)M / Z:468.5 [M+H] +

[0258] Step 4) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(3,3-difluorocyclobutyl)methoxyl)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.064 mmol), N,N-diisopropylethylamine (17 mg, 0.130 mmol), N,N-dimethylcarboxamide (0.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 0.096 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.2 mL of 25% aqueous ammonia solution was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: column model XBridge Shield RP18 OBD Column, 30*150mm, 5μm; mobile phase A: water (containing 0.1% aqueous ammonia); mobile phase B: acetonitrile; flow rate: 60ml / min; gradient: from 25%B to 60%B, 7-minute rinse, 60%B; wavelength: 254 / 220nm; peak time (min): 6.58; fractions were collected and freeze-dried under reduced pressure to obtain a white solid (17.0mg, yield 56.8%). LCMS(ESI,m / z):467.5 [M+H] + 1 H NMR(400 MHz,CDCl3)δ 7.73(s,1H), 7.56(s,1H), 7.12(d,J=8.0 Hz,1H), 6.96(d,J=8.0 Hz,1H), 5.17(s,1H), 4.66 - 4.50(m,2H), 4.17 - 4.04(m,2H), 2.47 - 2.12(m,13H). 19 F NMR(376 MHz, CDCl3)δ -83.5,-94.4.

[0259] Example 17 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0260] Step 1) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (100 mg, 0.221 mmol), ethyl 2-bromo-2,2-difluoroacetate (67 mg, 0.332 mmol), cesium carbonate (144 mg, 0.442 mmol), and N,N-dimethylcarboxamide (2 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction was allowed to proceed at 60 °C for 2 hours. The mixture was cooled to room temperature and quenched by adding water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (petroleum ether / ethyl acetate = 5 / 1). A yellow solid was obtained (60 mg, 54.6% yield). MS(ESI)M / Z:504.6 [M+H] +

[0261] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid At room temperature, 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (60 mg, 0.119 mmol), palladium on carbon (10% content, 60 mg), and tetrahydrofuran (2 mL) were added to a 30 mL autoclave liner. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres and the reaction was carried out at 70 °C overnight. After cooling to room temperature, the reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a pale yellow solid (30 mg, 60.9% yield), which was used directly in the next step. MS(ESI)M / Z:414.4 [M+H] +

[0262] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (20 mg, 0.048 mmol), N,N-diisopropylethylamine (13 mg, 0.096 mmol), N,N-dimethylcarboxamide (0.3 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28 mg, 0.072 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.2 mL of 25% aqueous ammonia solution was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: column model XBridge Shield RP18 OBD Column, 30*150mm, 5μm; mobile phase A: water (containing 0.1% aqueous ammonia); mobile phase B: acetonitrile; flow rate: 60ml / min; gradient: from 30% B to 60% B, 7-minute rinse; wavelength: 254 / 220nm; fractions were collected and freeze-dried under reduced pressure to obtain a white solid (1.1mg, yield 5.51%). LCMS(ESI,m / z):413.05 [M+H] + 1 H NMR(300 MHz,CDCl3)δ 7.68(s,1H), 7.05 - 6.99(m,2H), 5.87(s,1H), 5.23(s,1H), 4.75(t,J=8.7 Hz,2H), 3.43(t,J=8.7 Hz,2H), 2.51(s,3H), 2.19(s,3H). 19 F NMR(282 MHz,CDCl3)δ -87.2,-90.2.

[0263] Example 18 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0264] Step 1) (Z)-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylidene)-3-hydroxybutyrate benzyl 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (566 mg, 3.27 mmol), piperidine (28 mg, 0.327 mmol), acetic acid (0.22 mL), benzyl acetoacetate (628 mg, 3.27 mmol), and dichloromethane (12.0 mL) were added to a 40 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 40 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to give a yellow oil (600 mg, 52.9% yield). LCMS(ESI,m / z):348.10 [M+H] +

[0265] Step 2) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide Benzyl (Z)-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylidene)-3-hydroxybutyrate (100 mg, 0.288 mmol), 4-amino-5-methylpyridin-2-ol (35.7 mg, 0.288 mmol), acetic acid (0.02 mL), and dichloromethane (2.0 mL) were added to a 40 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was pulped with isopropanol (2.0 mL x 3) and filtered to give a pale yellow solid (105 mg, 80.8% yield). LCMS(ESI,m / z):454.25 [M+H] +

[0266] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (200 mg, 0.441 mmol), cyclopropyl bromide (534 mg, 4.41 mmol), cesium carbonate (719 mg, 2.21 mmol), and N,N-dimethylcarboxamide (2 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was stirred overnight at 130 °C under nitrogen protection. After cooling to room temperature and filtration, the filtrate was purified on a carbon-18 column (mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; flow rate: 60 mL / min, increasing from 10% to 50% over 10 min; detection wavelength: 254 nm). The fractions were collected and freeze-dried in vacuo to give a yellow solid (35 mg, 16.1% yield). MS(ESI)M / Z:494.2 [M+H] +

[0267] Step 4) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (35 mg, 0.071 mmol), palladium on carbon (10% content, 35 mg), and tetrahydrofuran (2 mL) were added to a 30 mL autoclave liner at room temperature. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres, and the reaction was carried out at 50 °C for 3 hours. After cooling to room temperature, the reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a pale yellow solid (28 mg, 97.8% yield), which was used directly in the next step. MS(ESI)M / Z:404.2 [M+H] +

[0268] Step 5) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (28 mg, 0.069 mmol), N,N-diisopropylethylamine (27 mg, 0.207 mmol), N,N-dimethylcarboxamide (0.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.110 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.5 mL of 25% aqueous ammonia solution was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was filtered, and the resulting filtrate was purified on a carbon 18 column (mobile phase A: aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B: acetonitrile, flow rate: 60 ml / min, increasing from 20% to 50% over 10 min, detection wavelength: 254 nm). The fractions were collected and freeze-dried under reduced pressure to give a white solid (20.2 mg, yield 72.3%). LCMS(ESI,m / z):403.05 [M+H] + 1 H NMR(400 MHz,Chloroform-d)δ7.74(s,1H), 7.02 - 6.98(m,2H), 5.82(s,1H), 5.08(s,1H), 4.79 - 4.65(m,2H), 4.42 - 4.18(m,2H), 3.43(t,J=8.4 Hz,2H), 2.47(s,3H), 2.16(s,3H), 0.74 - 0.54(m,3H), 0.20 - 0.15(m,1H).

[0269] Example 19 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0270] Step 1) 2-Cyanoethyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (40 mg, 0.096 mmol), (iodomethyl)cyclopropane (71 mg, 0.360 mmol), silver carbonate (27 mg, 0.096 mmol), and 1,4-dioxane (1 mL) were added to an 8 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was incubated at 90 °C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified on a carbon-18 column (mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; flow rate: 60 mL / min; increasing from 10% B to 50% B over 10 min; detection wavelength: 254 nm). The fractions were collected and freeze-dried under vacuum to give a yellow solid (22.5 mg, 49.8% yield). MS(ESI)M / Z:471.2 [M+H] +

[0271] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (20 mg, 0.042 mmol), ethylene glycol dimethyl ether (0.6 mL), and a solution of sodium hydroxide (4 mg, 0.084 mmol) in water (0.2 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was allowed to react for 1 hour at room temperature. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (5 mL x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow solid (17 mg, 96.9% yield), which was used directly in the next step. MS(ESI)M / Z:418.5 [M+H] +

[0272] Step 3) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (16 mg, 0.038 mmol), N,N-diisopropylethylamine (15 mg, 0.115 mmol), N,N-dimethylcarboxamide (0.3 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.062 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.1 mL of an aqueous solution of ammonia (25% content) was added to the reaction mixture at room temperature. The mixture was allowed to react for 30 minutes at room temperature. The reaction mixture was filtered, and the filtrate was purified on a carbon-18 column (mobile phase A: 0.1% aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, flow rate: 60 ml / min, increasing from 20% B to 50% B over 10 min, detection wavelength: 254 nm). The fractions were collected and freeze-dried under reduced pressure. The product was recovered and freeze-dried under reduced pressure to give a white solid (2.2 mg, yield 12.9%). LCMS(ESI,m / z):417.0 [M+H] + 1 H NMR(400 MHz,CDCl3)δ 7.85(s,1H), 7.06 - 7.00(m,2H), 6.69(s,2H), 6.23(s,1H), 5.20(s,1H), 4.73(t,J=8.8 Hz,2H), 4.42 - 4.03(m,2H), 3.45(t,J=8.8 Hz,2H), 2.50(s,3H), 1.13 - 1.08(m,1H), 0.61 - 0.50(m,2H), 0.31 - 0.15(m,2H).

[0273] Example 20 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0274] Step 1) 2-Cyanoethyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (50 mg, 0.120 mmol), 2-iodopropane (33 mg, 0.192 mmol), silver carbonate (33 mg, 0.120 mmol), and 1,4-dioxane (1 mL) were added to an 8 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with ethyl acetate (3 × 5 mL). The filtrate was collected and concentrated to dryness under reduced pressure to give a white solid (40 mg, 72.7% yield). MS(ESI)M / Z:459.2 [MH] -

[0275] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (40 mg, 0.087 mmol), ethylene glycol dimethyl ether (0.9 mL), and an aqueous solution (0.3 mL) of sodium hydroxide (7 mg, 0.174 mmol) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was allowed to react for 1 hour at room temperature. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (3 mL x 3), and the combined organic phase was washed with saturated brine (3 mL x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow solid (30 mg, 84.6% yield), which was used directly in the next step. MS(ESI)M / Z:406.3 [M+H] +

[0276] Step 3) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.074 mmol), N,N-diisopropylethylamine (0.05 mL), N,N-dimethylcarboxamide (0.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.111 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.2 mL of an aqueous solution of ammonia (25% content) was added to the reaction mixture at room temperature. The mixture was allowed to react for 30 minutes at room temperature. The reaction mixture was filtered, and the filtrate was purified on a carbon-18 column (mobile phase A: aqueous solution containing 0.05% ammonia water, mobile phase B: acetonitrile, flow rate: 60 ml / min, increasing from 15% B to 40% B over 15 min, detection wavelength: 254 nm). The product was recovered and freeze-dried under reduced pressure to obtain a white solid (14.4 mg, yield 48.1%). LCMS(ESI,m / z):404.10 [M+H] + 1 H NMR(400 MHz,CDCl3)δ 7.68(s,1H), 7.13-6.83(m,2H), 6.20(s,1H), 5.78(s,1H), 5.33-5.03(m,3H), 4.92-4.53(m,2H), 3.43(t,J=9.2 Hz,2H), 2.49(s,3H), 2.15(s,3H), 1.25(d,J=6.1 Hz,3H), 0.94(d,J=6.1 Hz,3H).

[0277] Example 21 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0278] Step 1) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (50 mg, 0.110 mmol), iodocyclobutane (60 mg, 0.331 mmol), cesium carbonate (72 mg, 0.221 mmol), and N,N-dimethylcarboxamide (1 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was stirred overnight at 60 °C under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate=4 / 1) to give a white solid (40 mg, yield 71.4%). MS(ESI)M / Z:508.2 [M+H] +

[0279] Step 2) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (40 mg, 0.085 mmol), palladium on carbon (10% content, 40 mg), and tetrahydrofuran (2 mL) were added to a 30 mL autoclave liner at room temperature. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres, and the reaction was carried out at 50 °C for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a white solid (30 mg, 91.3% yield), which was used directly in the next step. MS(ESI)M / Z:418.2 [M+H] +

[0280] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.072 mmol), N,N-diisopropylethylamine (19 mg, 0.145 mmol), N,N-dimethylcarboxamide (1 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (41 mg, 0.109 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.5 mL of 25% aqueous ammonia was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was filtered, and the resulting filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: Xselect CSH C18 OBD, mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 50 ml / min, gradient: 7 min, acetonitrile increasing from 40% to 50%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (15.0 mg, yield 49.8%). LCMS(ESI,m / z):417.2 [M+H] + 1 H NMR(400 MHz,Chloroform-d)δ 7.66(s,1H), 7.10-6.96(m,2H), 6.28(s,1H), 5.77(s,1H), 5.20(s,1H), 5.12-5.00 (m,1H), 4.83-4.66(m,2H), 3.52-3.36(m,2H), 2.49(s,3H), 2.46-2.38(m,1H), 2.28 -2.18(m,1H), 2.14(s,3H), 2.06~1.95(m,1H), 1.76 -1.64(m,3H).

[0281] Example 22 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0282] Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (300 mg, 0.663 mmol), (iodomethyl)cyclobutane (194 mg, 0.996 mmol), cesium carbonate (431 mg, 1.27 mmol), and N,N-dimethylcarboxamide (3 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was stirred at 60 °C under nitrogen protection for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified on a carbon-18 reverse column (conditions: mobile phase A: water (containing 0.1% formic acid); mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 30% B increasing to 60% B with a 15-minute rinse; detection wavelength: 254 nm). The product was collected at a reference wavelength of 220 nm and concentrated under reduced pressure to give a white solid (47 mg, 13.7% yield). MS(ESI)M / Z:522.2 [M+H] +

[0283] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (47 mg, 0.090 mmol), palladium on carbon (10% content, 47 mg), and tetrahydrofuran (2 mL) were added to a 30 mL autoclave liner at room temperature. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres, and the reaction was carried out at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow solid (30 mg, 77.2% yield), which was used directly in the next step. MS(ESI)M / Z:432.2 [M+H] +

[0284] Step 3) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.070 mmol), N,N-diisopropylethylamine (19 mg, 0.145 mmol), N,N-dimethylcarboxamide (0.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.110 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. 0.2 mL of 25% ammonia solution was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was filtered, and the resulting filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatographic column: Xselect CSH C18 OBD, mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 50 ml / min, gradient: 7 min, acetonitrile increasing from 35% to 50%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (17.9 mg, yield 59.8%). LCMS(ESI,m / z):431.2 [M+H] + 1 H NMR(400 MHz,Chloroform-d3)δ 7.68(s,1H), 7.01(d,J=8.1 Hz,2H), 6.68(s,2H), 5.82(s,1H), 5.17(s,1H), 4.72(t,J=8.6 Hz,2H), 4.17-4.08(m,2H), 3.42(t,J=8.6 Hz,2H), 2.62-2.52(m,1H), 2.48(s,3H), 2.16(s,3H), 2.06~1.61(m,6H).

[0285] Example 23 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0286] Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (100 mg, 0.220 mmol), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodioxolane (218 mg, 0.663 mmol), and nitromethane (4 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was stirred at 100°C under nitrogen protection for 5 hours. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was washed with saturated brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate=1 / 1) to give a yellow solid (40 mg, yield 34.8%). MS(ESI)M / Z:522.2 [M+H] +

[0287] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20 mg, 0.038 mmol), palladium on carbon (10% content, 20 mg), and methanol (2 mL) were added to a 30 mL autoclave liner at room temperature. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres and the reaction was carried out at 70 °C for 4 hours. After cooling to room temperature, the reaction mixture was filtered to obtain a filtrate, which was then purified by preparative high-performance liquid chromatography (HPLC). The purification conditions were as follows: chromatographic column: carbon-18 reverse column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 40 mL / min; gradient: 30% B to 50% B over 15 min; detection wavelength: 254 nm. The product was collected, vacuumed, freeze-dried and concentrated in vacuo to give a white solid (12 mg, 72.5% yield) which was used directly in the next step reaction. MS(ESI)M / Z:432.2 [M+H] +

[0288] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (12 mg, 0.028 mmol), N,N-diisopropylethylamine (7 mg, 0.054 mmol), N,N-dimethylcarboxamide (0.3 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 0.042 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. A 25% aqueous solution of ammonia (0.1 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was filtered, and the resulting filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: Xselect CSH C18 OBD, mobile phase A: water (containing 0.1% trifluorocarboxylic acid), mobile phase B: acetonitrile, flow rate: 50 ml / min, gradient: 7 min, acetonitrile increasing from 20% to 50%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (2.9 mg, yield 24.2%). LCMS(ESI,m / z):431.2 [M+H] + 1 H NMR(400 MHz,CDCl3)δ 7.82(s,1H), 7.06-6.98(m,2H), 5.97(s,1H), 5.22(s,1H), 4.78(t,J=8.7 Hz,2H), 3.47(t,J=8.7 Hz,2H), 2.55(s,3H), 2.26(s,3H). 19 F NMR (377 MHz, CDCl3) δ -56.0.

[0289] Example 24 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0290] Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (100 mg, 0.221 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (92 mg, 0.354 mmol), cesium carbonate (144 mg, 0.442 mmol), and N,N-dimethylcarboxamide (2 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction was stirred at room temperature for 2 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative chromatographic plate (pre-TLC) (petroleum ether / ethyl acetate=2 / 1) to give a yellow solid (36 mg, yield 36.1%). MS(ESI)M / Z:536.2 [M+H] +

[0291] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxamide (36.0 mg, 0.067 mmol), palladium on carbon (10% content, 36 mg), and tetrahydrofuran (2 mL) were added to a 30 mL autoclave liner at room temperature. After purging with nitrogen, hydrogen was introduced at 3 standard atmospheres and the reaction was carried out at 70 °C for 3 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a white solid (24 mg, 80.1% yield), which was used directly in the next step. MS(ESI)M / Z:446.2 [M+H] +

[0292] Step 3) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (24 mg, 0.054 mmol), N,N-diisopropylethylamine (19 mg, 0.145 mmol), N,N-dimethylcarboxamide (0.5 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.081 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. A 25% aqueous solution of ammonia (0.2 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was filtered, and the resulting filtrate was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: Xselect CSH C18 OBD, mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile, flow rate: 50 ml / min, gradient: 7 min, acetonitrile increasing from 40% to 50%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (6.3 mg, yield 26.3%). MS(ESI)M / Z:445.15 [M+H] + 1 H NMR(400 MHz,CDCl3)δ 7.66(s,1H), 7.05-6.92(m,2H), 5.83(s,1H), 5.22(s,1H), 4.80-4.40(m,4H), 3.42(t,J=8.7 Hz,2H), 2.52(s,3H), 2.23(s,3H). 19 F NMR (282 MHz, CDCl3) δ -74.1.

[0293] Example 25 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide [ka]

[0294] Step 1) 8-Amino-2,3-dihydro-1,4-benzodioxazine-5-carboxamide 8-Amino-2,3-dihydro-1,4-benzodioxazine-5-carboxylic acid (1.00 g, 5.12 mmol), N,N-dimethylcarboxamide (25 ml), N,N-diisopropylethylamine (1.32 g, 10.2 mmol), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.92 g, 7.69 mmol) were added to a 100 ml single-neck bottle at room temperature. The mixture was allowed to react for 0.5 hours at room temperature. An aqueous solution of ammonia (1.0 M, 6 ml) was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. Water (250 ml) was added to dilute the mixture. The mixture was extracted with ethyl acetate (250 ml x 3), and the combined organic phase was washed with saturated brine (250 ml) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: pure ethyl acetate) to give an orange oil (800 mg, yield 80.4%). LCMS(ESI,m / z):195.1 [M+H] +

[0295] Step 2) 8-Amino-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile 8-Amino-2,3-dihydro-1,4-benzodioxazine-5-carboxamide (766 mg, 3.95 mmol) and trichlormethrin (15 mL) were added to a 50 mL single-neck bottle at room temperature. The mixture was heated to 80 °C and reacted for 1 hour. The mixture was then cooled to room temperature. The reaction was quenched by adding sodium hydroxide solution (1.0 mol / L) and the pH was adjusted to approximately 8. The mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to give a white solid (310 mg, 44.6% yield). LCMS(ESI,m / z):177.1 [M+H] +

[0296] Step 3) 8-Bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile 8-Amino-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (310 mg, 1.76 mmol), tert-butyl nitrite (181 mg, 1.76 mmol), cuprous bromide (366 mg, 2.55 mmol), and acetonitrile (8 mL) were added to a 40 mL sample bottle at room temperature. The mixture was allowed to react at 70 °C for 1.5 hours. The reaction mixture was cooled to room temperature, filtered, and rinsed three times with ethyl acetate (8 mL). The filtrate was concentrated under reduced pressure, and the residue was purified using a separatory dish (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a white solid (110 mg, 26.0% yield).

[0297] Step 4) 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile 8-Bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (110 mg, 0.458 mmol) and tetrahydrofuran (0.5 ml) were added to an 8 ml sample bottle at room temperature. After purging with nitrogen, the reaction mixture was cooled to -78 °C. A solution of n-butyllithium (0.2 ml, 2.5 mmol / ml, 0.50 mmol) in n-hexane was slowly added dropwise. The reaction mixture was allowed to react at -78 °C for 30 minutes. N,N-Dimethylcarboxamide (0.5 ml) was added, and the reaction mixture was allowed to react at -78 °C for 30 minutes. The mixture was quenched by adding saturated aqueous ammonium chloride (5 ml). The mixture was extracted with dichloromethane (5 ml x 3), and the combined organic phase was washed with saturated brine (5 ml) and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified using a separation dish (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a white solid (40 mg, yield 46.2%).

[0298] Step 5) 2-Cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (35 mg, 0.185 mmol), 2-cyanoethyl-3-oxobutyrate (29 mg, 0.185 mmol), 4-amino-5-methylpyridin-2-ol (23 mg, 0.185 mmol), isopropanol (0.6 mL), and acetic acid (12 mL) were added to an 8 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions: C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous ammonium bicarbonate) and mobile phase B (acetonitrile), gradient from 25% B to 30% B in 15 minutes, monitoring wavelength 254 nm. A pale yellow solid (15 mg, 18.8% yield) was obtained. MS(ESI)M / Z:433.2 [M+H] +

[0299] Step 6) 2-Cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate 2-Cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (15 mg, 0.035 mmol), ethyl iodide (8 mg, 0.053 mmol), silver carbonate (10 mg, 0.035 mmol), and 1,4-dioxane (0.3 mL) were added to an 8 mL single-neck bottle at room temperature. After purging with nitrogen, the mixture was reacted at 90 °C for 1 hour. The mixture was then cooled to room temperature. The mixture was filtered, rinsed with acetonitrile (3 mL), and the filtrate was concentrated under reduced pressure to give a yellow solid (15 mg, crude product), which was used directly in the next step without further purification. MS(ESI)M / Z:461.3 [M+H] +

[0300] Step 7) 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid 2-Cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (15 mg, 0.033 mmol), ethylene glycol dimethyl ether (0.45 mL), and a solution of sodium hydroxide (3 mg, 0.066 mmol) in water (0.15 mL) were added to an 8 mL single-neck bottle at room temperature. The reaction mixture was allowed to react for 1 hour at room temperature. The mixture was quenched with hydrochloric acid (1.0 mol / L) in an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (5 mL x 3) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give a pale yellow solid (10 mg, crude product), which was used directly in the next step without further purification. LCMS(ESI,m / z):408.1 [M+H] +

[0301] Step 8) 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (10 mg, 0.025 mmol), N,N-diisopropylethylamine (6 mg, 0.049 mmol), N,N-dimethylcarboxamide (0.3 mL), and 2-(7-azobenzotriazolyl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14 mg, 0.038 mmol) were added to an 8 mL vial at room temperature. The mixture was allowed to react for 30 minutes at room temperature. A 25% aqueous solution of ammonia (0.1 mL) was added to the reaction mixture at room temperature. The mixture was allowed to react for 1 hour at room temperature. The reaction mixture was purified by preparative high-performance liquid chromatography. The purification conditions were as follows: chromatography column: YMC-Actus Triart C18, mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile, flow rate: 50 ml / min, gradient: 10 min, acetonitrile increasing from 25% to 30%, detection wavelength: 254 / 220 nm. The product was collected and freeze-dried under reduced pressure to give a white solid (1.1 mg, yield 11.0%). MS(ESI)M / Z:407.30 [M+H] + 1 H NMR(300 MHz,DMSO-d6)δ 7.69(s,1H), 7.57(d,J=8.1 Hz,1H), 7.12(d,J=8.1 Hz,1H), 6.76 -6.62(m,3H), 5.34(s,1H), 4.44 -4.25(m,4H), 4.06(d,J=7.0 Hz,2H), 2.18(s,3H), 2.12(s,3H), 1.11(t,J=7.0 Hz,3H).

[0302] (Preparation of chiral compounds:) Examples 32 and 33 (S)-4-(5-cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 32 and (R)-4-(5-Cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 33 [ka] 4-(5-cyanochrom-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (56 mg, 0.138 mmol) (compound 6) was subjected to chiral separation under the following conditions: (chiral column: CHIRALPAK IG, 2*25 cm, 5 μm, Mobile phase A: n-hexane (10 mmol / L ammonia in methanol), Mobile phase B: ethanol, Flow rate: 20 ml / min, Gradient: 40% B for 15 min, Wavelength: 208 / 258 nm, 33 peak time: 8.80 min, 32 peak time: 12.0 min, Sample solution: ethanol, Injection volume: 0.8 ml, Number of injection needles: 5. Two enantiomeric isomers were obtained: 33 (20.3 mg, 36.2% yield) as a white solid and 32 (16.9 mg, 30.1% yield). 32 LCMS(ESI,m / z):405.25 [M+H] + 32 1 H NMR(400 MHz,DMSO-d6)δ 7.70(s,1H), 7.56(s,1H), 7.18(d,J=8.0 Hz,1H), 6.94(d,J=8.0 Hz,1H), 6.68(s,2H), 5.32(s,1H), 4.28 -4.20(m,2H), 4.08 -4.00(m,2H), 2.89(d,J=7.0 Hz,2H), 2.12(s,3H), 2.07(s,3H), 2.03 -1.94(m,2H), 1.10(t,J=7.0 Hz,3H). 33 LCMS(ESI,m / z):405.25 [M+H] + 33 1H NMR(400 MHz,DMSO-d6)δ 7.70(s,1H), 7.56(s,1H), 7.18(d,J=8.0 Hz,1H), 6.94(d,J=8.0 Hz,1H), 6.68(s,2H), 5.32(s,1H), 4.28 -4.20(m,2H), 4.08 -4.00(m,2H), 2.89(d,J=7.0 Hz,2H), 2.12(s,3H), 2.07(s,3H), 2.03 -1.94(m,2H), 1.10(t,J=7.0 Hz,3H).

[0303] Examples 36 and 37 (S)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 36 (R)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 37 [ka] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (40 mg, 0.102 mmol) (Compound 11) was subjected to chiral separation under the following conditions: (Chiral column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; Mobile phase A: n-hexane (10 mmol / L ammonia in methanol); Mobile phase B: ethanol; Flow rate: 20 ml / min; Gradient: 20% B to 20% B) , 15 min, wavelength: 218 / 270 nm, 36 peak time: 9.47 min, 37 peak time: 11.2 min, sample solution: ethanol, injection volume: 0.5 ml, number of injection needles: 9. Two enantiomeric isomers were obtained: 37 (white solid, 7.5 mg, 18.8% yield) and 36 (white solid, 9.3 mg, 23.3% yield). 36 LCMS(ESI,m / z):391.10 [M+H] + 36 1H NMR(400 MHz,DMSO-d6)δ 7.70(s,1H), 7.55(s,1H), 7.11(d,J=8.0 Hz,1H), 6.98(d,J=8.0 Hz,1H), 6.71(s,2H), 5.18(s,1H), 4.63(t,J=8.8 Hz,2H), 4.04(q,J=6.8 Hz,2H), 3.40(t,J=8.8 Hz,2H), 2.11(s,3H), 2.07(s,3H), 1.10(t,J=6.8 Hz,3H). 37 LCMS(ESI,m / z):391.10 [M+H] + 37 1 H NMR(400 MHz,DMSO-d6)δ 7.70(s,1H), 7.55(s,1H), 7.11(d,J=8.0 Hz,1H), 6.98(d,J=8.0 Hz,1H), 6.71(s,2H), 5.18(s,1H), 4.63(t,J=8.8 Hz,2H), 4.04(q,J=6.8 Hz,2H), 3.40(t,J=8.8 Hz,2H), 2.11(s,3H), 2.07(s,3H), 1.10(t,J=6.8 Hz,3H).

[0304] Examples 38 and 39 (S)-6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 38 (R)-6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 39 [ka] Chiral separation of 6-(4-cyano-2-methoxylphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide (60 mg, 0.148 mmol) was performed. IG, 2*25 cm, 5 μm, Mobile phase A: n-hexane (10 mmol / L ammonia in methanol), Mobile phase B: ethanol, Flow rate: 20 ml / min, Gradient: 10% B for 34.5 min, Wavelength: 210 / 220 nm, (39 peak time): 20.68 min, (38 peak time): 28.59 min, Sample solution: methanol:dichloromethane = 1:1, Injection volume: 0.35 ml, Number of injection needles: 12. Two enantiomeric isomers were obtained: Element 0A: white solid (13.8 mg, 33.6% yield) and Element 0B: white solid (14.0 mg, 34.1% yield). 38 MS(ESI)M / Z:421.00 [M+H] + 38 1 H NMR(400 MHz,DMSO-d6)δ 8.83(s,1H), 7.88(d,J=5.6 Hz,1H), 7.37(d,J=1.6 Hz,1H), 7.29 - 7.22(m,2H), 7.18(d,J=7.6 Hz,1H), 6.88 - 6.73(m,2H), 5.48(s,1H), 4.18 - 4.04(m,2H), 3.82(s,3H), 2.19(s,3H), 1.10(t,J=7.2 Hz,3H). 39 MS(ESI)M / Z:421.05 [M+H] + 39 1 H NMR(400 MHz,DMSO-d6)δ 8.83(s,1H), 7.88(d,J=5.6 Hz,1H), 7.37(d,J=1.6 Hz,1H), 7.29 - 7.22(m,2H), 7.18(d,J=7.6 Hz,1H), 6.88 - 6.73(m,2H), 5.48(s,1H), 4.18 - 4.04(m,2H), 3.82(s,3H), 2.19(s,3H), 1.10(t,J=7.2 Hz,3H).

[0305] Examples 40 and 41 (R)-4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 41 (S)-4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 40 [ka] 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (32.0 mg, 0.079 mmol) (compound 25) was subjected to chiral separation (separation conditions were as follows: chiral column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol ammonia in methanol); mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 15% B to 15% B, 20 min, wavelength: 218 / 260 nm, 41 peak time: 10.22 min, 40 peak time: 16.14 min, sample solution: ethanol:dichloromethane = 1:1, injection volume: 0.5 ml, number of injection needles: 3), enantiomer 41 (10.8 mg, white solid, yield 33.7%) and enantiomer 40 (9.8 mg, white solid, yield 30.6%) were obtained. 40: MS(ESI) M / Z: 407.30 [M+H] + 1 H NMR(300 MHz,DMSO-d6)δ 7.69(s,1H), 7.57(d,J=8.1 Hz,1H), 7.12(d,J=8.1 Hz,1H), 6.76 -6.62(m,3H), 5.34(s,1H), 4.44 -4.25(m,4H), 4.06(d,J=7.0 Hz,2H), 2.18(s,3H), 2.12(s,3H), 1.11(t,J=7.0 Hz,3H). 41: MS(ESI) M / Z: 407.30 [M+H] + 1 H NMR(300 MHz,DMSO-d6)δ 7.69(s,1H), 7.57(d,J=8.1 Hz,1H), 7.12(d,J=8.1 Hz,1H), 6.76 -6.62(m,3H), 5.34(s,1H), 4.44 -4.25(m,4H), 4.06(d,J=7.0 Hz,2H), 2.18(s,3H), 2.12(s,3H), 1.11(t,J=7.0 Hz,3H).

[0306] Examples 46 and 47 (S)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 46 (R)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 47 [ka] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (32.0 mg, 0.057 mmol) was subjected to chiral separation (separation conditions were as follows: chiral column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; mobile phase A: n-hexane (2 mmol ammonia in methanol); mobile phase B: ethanol; flow rate: 40 ml / min; gradient: 20% B). From 20% B, 23 min, wavelength: 207 / 236 nm, (47) peak time: 11.6 min, (46) peak time: 20.3 min, sample solution: methanol:dichloromethane = 1:1, injection volume: 0.2 ml, number of injection needles: 3), two enantiomeric isomers, simplex 0A (8.50 mg, white solid, yield 26.6%) and 0B (10.5 mg, white solid, yield 32.8%), were obtained. 46: MS(ESI) M / Z: 413.05 [M+H] + 46 1H NMR(300 MHz,CDCl3)δ 7.68(s,1H), 7.05 - 6.99(m,2H), 5.87(s,1H), 5.23(s,1H), 4.75(t,J=8.7 Hz,2H), 3.43(t,J=8.7 Hz,2H), 2.51(s,3H), 2.19(s,3H). 19F NMR(282 MHz,CDCl3)δ -87.2,-90.2. 47: MS(ESI) M / Z: 413.05 [M+H] + 47 1 H NMR(300 MHz,CDCl3)δ 7.68(s,1H), 7.05 - 6.99(m,2H), 5.87(s,1H), 5.23(s,1H), 4.75(t,J=8.7 Hz,2H), 3.43(t,J=8.7 Hz,2H), 2.51(s,3H), 2.19(s,3H). 19F NMR(282 MHz,CDCl3)δ -87.2,-90.2.

[0307] Examples 48 and 49 (S)4-(4-Cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 48 (R) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 49 [ka] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20.2 mg, 0.050 mmol) was subjected to chiral separation (separation conditions were as follows: chiral column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol ammonia in methanol); mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 30% B to 30% B, 22 min, wavelength: 200 / 220 nm, (49) peak time: 13.4 min, (48 peak time: 19.8 min, methanol:dichloromethane = 1:1, injection volume: 2 ml, number of injection needles: 3), gave two enantiomeric isomers, 49 (6.20 mg, white solid, yield 22.2%) and 48 (5.40 mg, white solid, yield 19.3%). 48:LCMS(ESI)M / Z:403.20 [M+H] + 48 1 H NMR(400 MHz,Chloroform-d)δ7.74(s,1H), 7.02 - 6.98(m,2H), 5.82(s,1H), 5.08(s,1H), 4.79 - 4.65(m,2H), 4.42 - 4.18(m,2H), 3.43(t,J=8.4 Hz,2H), 2.47(s,3H), 2.16(s,3H), 0.74 - 0.54(m,3H), 0.20 - 0.15(m,1H). 49:LCMS(ESI)M / Z:403.20 [M+H] + 49 1 H NMR(400 MHz,Chloroform-d)δ7.74(s,1H), 7.02 - 6.98(m,2H), 5.82(s,1H), 5.08(s,1H), 4.79 - 4.65(m,2H), 4.42 - 4.18(m,2H), 3.43(t,J=8.4 Hz,2H), 2.47(s,3H), 2.16(s,3H), 0.74 - 0.54(m,3H), 0.20 - 0.15(m,1H).

[0308] Examples 62 and 63 (R)-4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 63 (S)-4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 62 [ka] 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20 mg, 0.148 mmol) (compound 14) was subjected to chiral separation (separation conditions were as follows: chiral column CHIRAL ART Amylose-C NEO, 2*25 cm, 5 μm, mobile phase A: n-hexane (10 mmol ammonia in methanol), mobile phase B: ethanol, flow rate: 20 ml / min, gradient: 10% B to 10% B, 28 min, wavelength: 214 / 254 nm, (63) peak time: 10.7 min, (62 peak time: 15.6 min, n-hexane:ethanol = 85:15, injection volume: 0.4 ml, number of injection needles: 2), gave two enantiomeric isomers, 63 (5.7 mg, white solid, yield 28.5%) and 62 (3.7 mg, white solid, yield 18.5%). 62:LCMS(ESI)M / Z:393.1 [M+H] + 62 1 H NMR(400 MHz,Chloroform-d)δ δ 7.70(s,1H), 6.91(d,J=8.4 Hz,1H), 6.77(d,J=8.4 Hz,1H), 6.14(s,2H), 5.78(s,1H), 5.47(s,2H), 5.14(s,1H), 4.20(q,J=7.0 Hz,2H), 2.46(s,3H), 2.15(s,3H), 1.26(t,J=7.0 Hz,3H). 63:LCMS(ESI)M / Z:393.1 [M+H] + 63 1H NMR(400 MHz,Chloroform-d)δ δ 7.70(s,1H), 6.91(d,J=8.4 Hz,1H), 6.77(d,J=8.4 Hz,1H), 6.14(s,2H), 5.78(s,1H), 5.47(s,2H), 5.14(s,1H), 4.20(q,J=7.0 Hz,2H), 2.46(s,3H), 2.15(s,3H), 1.26(t,J=7.0 Hz,3H).

[0309] Other racemic examples of this application were resolved in a similar manner.

[0310] (Single crystal X-ray diffraction analysis) (Compound 36 single crystal X-ray diffraction analysis) Approximately 5 mg of compound 36 was dissolved in 0.6 mL of acetone at room temperature, followed by the slow addition of 1.4 mL of water. The filtrate was filtered into a clean vial, covered with a pinhole membrane, and allowed to slowly evaporate at room temperature. After one day, bulk single crystals were obtained. Single crystal X-ray diffraction analysis was performed on the resulting single crystals, as shown in Figure 9.

[0311] 36 crystallizes in the monoclinic system in the C2 space group and has the formula C 22 H 22 N4O3. There are 36 molecules in each asymmetric unit, and the cell contains four asymmetric units. As shown in Figure 1, the chiral carbon at C10 is determined to have the "S" configuration. The position of the terminal ethyl group is irregular.

[0312] The refined single crystal structure is shown in Figures 2 and 3 (for clarity, key conformations and hydrogen atoms have been omitted). The crystal structure data are summarized in Table 2, and detailed information on atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds, torsion angles, and atomic occupancies is given in Tables 3 to 10. The XRPD pattern calculated from the single crystal structure (top) was consistent with the experimental pattern (bottom) (Figure 4).

[0313] Table 2 (Crystal data and refined structure of compound 36) [Table 2]

[0314] Table 3 (fractional atomic coordinates of compound 36 (×10 4 ) and the equivalent isotropic displacement parameter (Å × 10 3 )) [Table 3]

[0315] U(eq) is defined as one-third of the orthogonalized Uij tensor locus.

[0316] Table 4. Anisotropic displacement parameters of compound 36 (Å) 2 x10 3 )) [Table 4-1] [Table 4-2]

[0317] The anisotropic displacement factor exponent is -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0318] Table 5 (Bond lengths of compound 36) [Table 5]

[0319] Table 6 (Bond angles of compound 36) [Table 6]

[0320] Table 7 (Hydrogen bonds of compound 36) [Table 7]

[0321] 1 1-x, 1+y, -z, 2 3 / 2-x,-1 / 2+y,-z

[0322] Table 8 (Torsion angles of compound 36) [Table 8-1] [Table 8-2]

[0323] Table 9 (Hydrogen atom coordinates of compound 36 (Å×10 4 ) and isotropic displacement parameters (Å × 10 3 )) [Table 9]

[0324] Table 10 (Atom occupancy of compound 36) [Table 10]

[0325] (Compound 62 single crystal X-ray diffraction analysis) Approximately 5 mg of compound 62 was dissolved in 0.1 mL of ethanol at room temperature, followed by the slow addition of 0.35 mL of n-heptane. The solution was filtered into a clean sample bottle, covered with a pinhole membrane, and allowed to evaporate slowly under ambient conditions. After one day, bulk single crystals were obtained. Single crystal X-ray diffraction analysis was performed on the resulting single crystals, as shown in Figure 10.

[0326] 62 crystallizes in the monoclinic form in the C2 space group and has the formula C 21 H 20 N4O4. There are two 62 molecules in each asymmetric unit, and the cell contains four asymmetric units. As shown in Figure 5, the chiral carbon at C9 (C30) is determined to have the "S" configuration.

[0327] The refined single crystal structure is shown in Figures 6 and 7 (hydrogen atoms have been omitted for clarity). The crystal structure data are summarized in Table 11, and detailed information on atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds, and torsion angles is given in Tables 12 to 18. The XRPD pattern calculated from the single crystal structure was consistent with the experimental pattern (Figure 8).

[0328] Table 11 (Crystal data and structure optimization of compound 62) [Table 11]

[0329] Table 12 (fractional atomic coordinates of compound 62 (×10 4 ) and the equivalent isotropic displacement parameter (Å × 10 3 )) [Table 12-1] [Table 12-2]

[0330] U(eq) is defined as one-third of the orthogonalized Uij tensor locus.

[0331] Table 13 (Anisotropic displacement parameters of compound 62 (Å × 10 3 )) [Table 13-1] [Table 13-2] [Table 13-3]

[0332] The exponent of the anisotropic displacement coefficient is of the form: -2π 2 [h 2 a* 2 U 11 +2hka*b*U12 +…].

[0333] Table 14 (Bond lengths of compound 62) [Table 14]

[0334] Table 15 (Bond angles of compound 62) [Table 15-1] [Table 15-2]

[0335] Table 16 (Hydrogen bonds of compound 62) [Table 16]

[0336] 1 1-x,-1+y,-z, 2 3 / 2-x,-1 / 2+y,-z, 3 2-x,-1+y,1-z

[0337] Table 17 (Torsion angle of compound 62) [Table 17-1] [Table 17-2] [Table 17-3]

[0338] Table 18 (Hydrogen atom coordinates of compound 62 (Å×10 4 ) and isotropic displacement parameters (Å × 10 3 )) [Table 18]

[0339] (Example) (In vitro activity test) 1. Experimental principle: Using the chemiluminescent reaction that occurs when luciferase binds to a substrate, human embryonic kidney cells (HEK293) were transfected with a plasmid containing the ligand-binding domain (LBD) of the mineralocorticoid receptor (MR) fused to the Gal4 DNA-binding domain (DBD) and a plasmid containing a firefly luciferase reporter gene under the control of the Gal4UAS (upstream activation sequence). Changes in mineralocorticoid receptor activity before and after stimulation, or the effects of different stimuli on mineralocorticoid receptor activity, were assessed by measuring the level of firefly luciferase activity.

[0340] 2. Experimental method: 1. Compound Preparation and Treatment 1.1 Preparation of compound DMSO stock solutions All compounds were dissolved in DMSO to prepare 25 mM stock solutions and stored in a -20°C refrigerator. 1.2 Preparation of working solution 1) The test compound was diluted 3-fold with DMSO to give a 10 concentration gradient, with the starting concentration being 10 mM. 2) The positive compound (Finelenone) was diluted 3-fold with DMSO to form a 10-point gradient, with a starting concentration of 1 mM. 3) A 1000x positive control (1 mM finerenone) and a 1000x negative control (100% DMSO) were prepared. 4) The compound plate was sealed and shaken for 5 min.

[0341] 2. Cell Suspension Preparation 1) All cells were cultured according to ATCC standard procedures, and HEK293T cells were cultured in the exponential growth phase. 2) Carefully discard the medium supernatant and wash the cells twice with PBS. 3) The cells were digested with trypsin digestion solution, the digestion was terminated with complete medium, and the cells were collected and counted. 4) 6x106 HEK293T cells were seeded into a 100mm cell culture dish. 5) The culture dish inoculated with the cells was cultured overnight at 37°C in a 5% CO2 incubator for 16 hours.

[0342] 3. Cell Transfection 1) Lipofectamine® 3000 & P3000 transfection reagent was left at room temperature. 2) Lipofectamine® 3000 reagent was added to the Opti-MEM™ medium, and simultaneously the P3000, plasmid and Opti-MEM™ medium were added to a separate tube, being careful not to touch the walls of the tube. 3) The mixture was mixed uniformly with a pipette gun and allowed to stand at room temperature for 5 minutes. 4) The plasmid was added to the diluted transfection reagent, mixed uniformly with a pipette gun, and allowed to stand at room temperature for 20 minutes. 5) The transfection reagent mixed with the plasmid was added to a 60 mm cell culture dish. 6) The culture dish was cultured in a 37°C, 5% CO2 incubator for 5 to 6 hours.

[0343] 4. Compound Treatment 1) 25 nL of the compound diluted with Echo655 was transferred to a cell culture plate. 2) Seed the cells (see step 1.3) into 384 cell culture plates at 17,000 cells per well with 25 µL of phenol red-free DMEM medium containing 5% CFBS and 0.8 nM Aldosteron. 3) The cell culture plate was cultured overnight in a 37°C, 5% CO2 incubator for 18 to 20 hours.

[0344] 5. Compound Detection 1) The Britelite plus detection reagent was left at room temperature. 2) The 384 cell plate was left at room temperature. 3) 25 μL of Britelite plus detection reagent was added per well to the cell culture plate. 4) Luminescence values were detected using Envision.

[0345] 6. Result processing: 1) Luminescence is read to determine the firefly luciferase signal and calculate the inhibition rate. 2) % inhibition rate = 100 - [(RLU compound - avgRLU positive control) / (RLU negative control - avgRLU positive control) × 100%, where avgRLU positive control is the average luminescence value of all positive control wells on the entire plate, avgRLU negative control is the average luminescence value of all negative control wells on the entire plate, and RLU compound is the luminescence value of the test compound at different concentrations. 3) Calculate the IC50 of the compound using Graphpad 8.0 graph software.

[0346] 7. Experimental results: Table 19 (In vitro activity data of compounds of the present invention) [Table 19]

[0347] Conclusion: As can be seen from the experimental results in Table 19, the compounds described in the present invention have good mineralocorticoid receptor (MR) antagonistic activity and can be used as effective mineralocorticoid receptor antagonists.

[0348] (Example) (Drug Metabolic Kinetics Study in Test Rats) The purpose of this experiment was to evaluate the pharmacokinetic behavior of the compounds of the examples after intravenous injection or oral administration in rats. Intravenous administration: The test compound was formulated as a 0.2 mg / ml clear solution in 10% ethanol, 40% polyethylene glycol 400, and 50% water. Plasma was collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. Oral administration: The test compound was formulated as a 1 mg / ml clear solution in 10% ethanol / 40% polyethylene glycol 400 / 50% water. Plasma was collected at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration.

[0349] The concentration of the test compound in plasma was measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention times of the compounds and internal standards, chromatogram collection, and chromatogram integration were processed by Analyst software (Applied Biosystems), and data statistics were also performed by Analyst software (Applied Biosystems).

[0350] Plasma concentrations were processed using the non-atrial model of WinNonlin™ Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear-logarithmic trapezoidal method.

[0351] The parameters for the drug metabolism kinetics in rats when the compound was administered by intravenous injection at 1 mg / kg and orally at 5 mg / kg are shown in Table 20 below.

[0352] Table 20 (SD rat pharmacokinetics (PK) data) [Table 20]

[0353] As can be seen from the experimental results in Table 20, the compounds described in the present invention have good in vivo drug metabolism kinetic properties.

[0354] (Example) (Drug Metabolic Kinetics Study in Test Mice) The purpose of this study was to evaluate the pharmacokinetic behavior of compounds after intravenous injection or oral administration to mice. Intravenous administration: The test compound was formulated as a 0.2 mg / ml clear solution in 10% ethanol / 40% polyethylene glycol 400 / 50% ultrapure water. Plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration.

[0355] The concentrations of test compounds in plasma were measured by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). Retention times of compounds and internal standards, chromatogram collection, and chromatogram integration were processed using Analyst software (Applied Biosystems), and data statistics were also performed using Analyst software (Applied Biosystems).

[0356] Plasma concentrations were processed using the non-atrial model of WinNonlin™ Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear-logarithmic trapezoidal method.

[0357] The parameters relating to the drug metabolism kinetics in mice when the compound was administered by intravenous injection at a dose of 1 mg / kg are shown in Table 21 below.

[0358] Table 21 (CD1 mouse pharmacokinetic (PK) data) [Table 21]

[0359] Example 70: Pharmacodynamic effects of compounds 36 and 62 on a mouse model of diabetic nephropathy 1. Research purpose The pharmacodynamic effects of compounds 36 and 62 on a mouse model of diabetic nephropathy will be evaluated.

[0360] 2. Drug Preparation The solvent and positive drug must be prepared on the same day, and the preparation method is shown in Table 70-1.

[0361] Table 70-1 (Drug Preparation) [Table 70-1]

[0362] 3. Laboratory animals and care 3.1 Experimental animals Lineage: C57BL / 6 mice, KK-Ay mice Age: Animals must be 6-8 weeks old and the experiment must start at 7-9 weeks old. Gender: Male Weight: C57BL / 6 mice 21-23g, KK-Ay mice 25-30g Number of experimental animals: 72

[0363] 3.2 Animal husbandry 3.2.1 Quarantine The quarantine and adaptation period lasted a total of 7 days, and routine health examinations were performed by a veterinarian. Animals exhibiting abnormal behavior were excluded prior to the experiment. 3.2.2 Animal housing conditions The experimental animals were housed in single cages in an SPF-class, constant-temperature, constant-humidity, laminar-flow clean room at the Animal Center (AAALAC-certified unit) of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. The room temperature was 22-25°C, the humidity was 40-80%, and the light was alternated every 12 hours. The cages were made of polycarbonate. Autoclaved, soft, clean corncob bedding was used and changed twice a week. Drinking water was autoclaved, and food was irradiated with cobalt-60. The animals had free access to sterile food and water. 3.2.3 Animal number Each cage was labeled with the number of animals, sex, lineage, time of reception, group, and start time of the experiment. Each animal was numbered on its tail.

[0364] 4. Grouping of Experimental Animals and Drug Administration On the day of administration, animals were randomly divided into 9 groups according to animal weight: model group (KK-Ay + solvent), fine lenone group (KK-Ay + fine lenone: 3mg / kg), low-dose compound 62 group (KK-Ay + compound 62: 1mg / kg), medium-dose compound 62 group (KK-Ay + compound 62: 3mg / kg), high-dose compound 62 group (KK-Ay + compound 62: 10mg / kg), low-dose compound 36 group (KK-Ay + compound 36: 1mg / kg), medium-dose compound 36 group (KK-Ay + compound 36: 3mg / kg), high-dose compound 36 group (KK-Ay + compound 36: 10mg / kg). The specific groupings and administration methods are shown in Table 70-2.

[0365] Table 70-2 (Groups of experimental animals and drug administration) [Table 70-2]

[0366] 7 Experimental methods and detection indicators 7.1 Urine collection Before modeling and at 2, 4, 6, and 8 weeks after modeling, urine samples were collected from the mice using metabolic cages for 24 hours. The urine was analyzed using a CANON TBA-120FR automated blood biochemistry detector to detect the contents of urinary microalbumin (MALB) and creatinine (CREA). The ratio (MALB / CREA) was calculated.

[0367] 7.2 Insulin content and serum ion detection After the experiment, the mice were euthanized, and blood was collected by cardiac puncture. The blood was placed in an EP tube without anticoagulant, left at room temperature for 0.5 hours, and then centrifuged at 6000g for 15 minutes at 4°C. The serum was collected, transferred to a new EP tube, and stored in a refrigerator at -80°C. The insulin content in the serum and serum ion assay were detected by ELISA.

[0368] 7.3 Tissue collection After the experiment, the kidneys of all animals were dissected, collected, fixed in formalin, embedded, and sectioned. The sections were then stained with PAS and Masson staining and quantitatively analyzed.

[0369] 8. Statistics The experimental results were expressed as "mean ± standard deviation." Data were analyzed using GraphPad 8.0 software, and p<0.05 was considered statistically significant.

[0370] 9.Results Both Compound 62 and Compound 36 significantly promoted urinary sodium excretion and significantly reduced the urinary protein / creatinine ratio, demonstrating the effects of improving diabetic nephropathy and hypertension.

[0371] Example 71 (In vitro CPY enzyme inhibition studies) According to the research results, the IC50 (μM) data for the main drug-metabolizing enzyme CYP3A4 in humans are as follows: CYP3A4-5M and CYP3A4-5T are finelenone (9.98, 8.02), compound 36 (22.86, 15.78), and compound 62 (13.66, 5.35), respectively.

[0372] Therefore, compounds 36 and 62 are safer than finerenone.Compound 36 has a higher half-inhibitory concentration than finerenone against CYP3A4-5M / CYP3A4-5T, which are two isoforms of the main human metabolic enzyme CYP3A4 (which metabolizes approximately 50% of drugs).

[0373] In the description herein, references to "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" mean that the specific features, structures, materials, or characteristics described with reference to the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, unless mutually inconsistent, those skilled in the art may combine and combine different embodiments or examples and features of different embodiments or examples described herein.

[0374] Although the embodiments of the present invention have been shown and described above, it should be understood that the above embodiments are merely illustrative and should not be construed as limiting the present invention, and that those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

[0375] (Addendum) (Appendix 1) A compound of formula (I) and its stereoisomers, geometric isomers, inverse isomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, [ka] (I) where: [ka] teeth, [ka] and R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6Haloalkoxy, C 1~6 Alkylamino, carboxyl, C 1~6 Alkanoyl, C 1~6 Alkyl sulfonyl, aminoacyl, aminosulfonyl, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R5 is [ka] and R6 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; [ka] teeth, [ka] and X is C or N, Y is O or S; R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, C 3~8 Cycloalkyl C 1~6 Alkyl, (heterocyclyl of 3 to 8 atoms)C 1~6 Alkyl, (heteroaryl consisting of 5-6 atoms)C 1~6 Alkyl, phenyl or phenylC 1~6 alkyl, and R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz; Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, where each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw; Each Rw independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, or C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 is aryl, [ka] teeth, [ka] and R8 and R9 are hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10 A compound characterized in that it is an aryl, a heterocyclyl having 3 to 8 atoms, or a heteroaryl having 5 to 10 atoms.

[0376] (Appendix 2) A compound of formula (I) and its stereoisomers, geometric isomers, inverse isomers, nitroxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, [ka] (I) where: [ka] teeth, [ka] or [ka] and R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, carboxyl, C 1~6 Alkanoyl, C 1~6 Alkyl sulfonyl, aminoacyl, aminosulfonyl, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R5 is [ka] and R6 is hydrogen, deuterium, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; [ka] teeth, [ka] and X is C or N, Y is O or S; R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, C 3~8 Cycloalkyl C 1~6 Alkyl, (heterocyclyl of 3 to 8 atoms)C 1~6 Alkyl, (heteroaryl consisting of 5-6 atoms)C 1~6 Alkyl, phenyl or phenylC 1~6 alkyl, R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz; Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 1~6 Haloalkyl, C 1~6 Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw; Each Rw independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, or C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6Alkylamino, C 1~6 Alkylsulfonyl, C 1~6 Alkyl acyl, C 3~8 Cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 is aryl, [ka] teeth, [ka] and R8 and R9 are hydrogen, deuterium, and C 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkylamino, C 3~8 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R 10 and R 11 are each independently selected from —CH— or O, and at least one is O; R 12 is -CH2- or -CH2-CH2-, R 12 is -CH2-, R 10 and R 11 are each independently selected from —CH— or O, at least one is O, and R 12 is -CH2-CH2-, R 10 and R 11 is simultaneously O or R 10 is -CH2- and R 11 is O.

[0377] (Appendix 3) The compound according to Appendix 1, which is selected from compounds represented by formula (Ia) or formula (Ib), more preferably a compound represented by formula (Ia). [ka] (Ia) [ka] (Ib)

[0378] (Appendix 4) Each R1, R2, R3 and R4 independently represents hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, carboxyl, C 1~4 Alkanoyl, C 1~4 Alkyl sulfonyl, aminoacyl, aminosulfonyl, C 3~6 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 6 atoms, or heteroaryl of 5 to 6 atoms; R6 is hydrogen, deuterium, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 3~6 Cycloalkyl, C 6~10 aryl, heterocyclyl of 3 to 6 atoms, or heteroaryl of 5 to 6 atoms; Each R8 and R9 is independently hydrogen, deuterium, halogen, cyano, or C 1~4 Alkoxyacyl, Carboxyl, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 1~4 Alkanoyl, C 1~4 The compound according to any one of appendices 1 to 3, which is alkylsulfonyl, aminoacyl, or aminosulfonyl.

[0379] (Appendix 5) each R1, R2, R3 and R4 is independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, carboxyl, methylacyl, ethylacyl, methylsulfonyl, aminoacyl or aminosulfonyl; R6 is hydrogen, deuterium, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalenyl, cyclohexylethyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridinyl, pyrrolidinyl, thiazole, pyrazole or pyrimidinyl; The compound according to any one of appendices 1 to 3, wherein R8 is hydrogen, deuterium, cyano, methyl acyl, ethyl acyl, propyl acyl, methoxyl acyl, ethoxyl acyl, propoxyacyl, carboxyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, or dimethylamino.

[0380] (Appendix 6) The compound according to any one of Appendices 1 to 3, which is selected from compounds represented by formula (II): [ka] (II)

[0381] (Appendix 7) The compound according to any one of appendices 1 to 3, which is a compound represented by formula (IIa) or formula (IIb). [ka] (IIa) [ka] (IIb)

[0382] (Appendix 8) R7 is C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, C 3~6 Cycloalkyl C 1~4 Alkyl, (heterocyclyl of 3-6 atoms)C 1~4 Alkyl or (heteroaryl consisting of 5-6 atoms)C 1~4 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz.

[0383] (Appendix 9) R7 is C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, preferably R7 is methyl, ethyl, or isopropyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz.

[0384] (Appendix 10) R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetidinylmethyl, oxetidinylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl , tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl, pyrrolidinylmethyl, pyrrolidinylethyl, furanylmethyl, furanylethyl, thiophenemethyl, thiopheneethyl, thiazolemethyl, thiazoleethyl, pyrazolemethyl, pyrazoleethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, or pyrimidinylethyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz.

[0385] (Appendix 11) Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 The compound according to any one of appendices 1 to 8, which is aryl.

[0386] (Appendix 12) Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, or cyclobutyl. , cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl, wherein each Rz is independently unsubstituted or 1, 2, 3, or 4 Rz and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl.

[0387] (Appendix 13) is selected from compounds of formula (III): [ka] (III) where R5 is [ka] 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

[0388] (Appendix 14) R1, R2, R3, and R4 are independently hydrogen, deuterium, or C 1~6 is an alkoxy; R5 is [ka] and R6 is hydrogen, deuterium, C 1~6 14. The compound of claim 13, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

[0389] (Appendix 15) R1, R2, R3, and R4 are independently hydrogen, deuterium, or C 1~3 is an alkoxy; R5 is [ka] and R6 is hydrogen, deuterium, C 1~3 14. The compound of claim 13, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

[0390] (Appendix 16) R1, R2, R3, and R4 are independently hydrogen, deuterium, or methoxyl; R5 is [ka] and 15. The compound of claim 14, wherein R6 is selected from hydrogen, deuterium, and methyl.

[0391] (Appendix 17) is selected from compounds of formula (IV): [ka] (IV) where: [ka] teeth [ka] and R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1~6 is an alkoxy; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, Y is selected from O; 2. The compound of claim 1, wherein X is selected from C.

[0392] (Appendix 18) R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1~3 is an alkoxy; R6 is C 1~3 is alkyl, R7 is C 1~3 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~3 18. The compound according to claim 17, wherein the aryl group is alkyl.

[0393] (Appendix 19) is selected from compounds of formula (V): [ka] (V) where: [ka] teeth [ka] and R3 and R4 are independently hydrogen or deuterium; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, where R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently halogen; R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, X is selected from C; 2. The compound of claim 1, wherein Y is selected from O.

[0394] (Appendix 20) R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, each Rz independently being fluorine, chlorine, bromine, or iodine; R8 and R9 are hydrogen, deuterium, and C 1~3 20. The compound of claim 19, wherein the aryl group is alkyl.

[0395] (Appendix 21) R6 is C 1~3 is alkyl, R7 is C1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently fluorine; The compound according to claim 19, wherein R8 and R9 are hydrogen and methyl.

[0396] (Appendix 22) is selected from compounds of formula (V): [ka] (V) where: [ka] teeth [ka] and R3 and R4 are independently hydrogen or deuterium; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently halogen, C 1~6 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, X is selected from C; The compound according to any one of claims 1 to 3, wherein Y is selected from O.

[0397] (Appendix 23) selected from compounds of formula (Va) or formula (Vb), [ka] (Va) (Vb) where: [ka] teeth [ka] and R3 and R4 are independently hydrogen or deuterium; R5 is [ka] is selected from R6 is C 1~6 is alkyl, R7 is C 1~6 Alkyl, C 3~8 Cycloalkyl, C 3~8 Cycloalkyl C 1~6 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently halogen, C 1~6 is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~6 is alkyl, X is selected from C; 23. The compound of claim 22, wherein Y is selected from O.

[0398] (Appendix 24) R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently fluorine, chlorine, bromine, iodine, C 1~4is alkyl, R8 and R9 are hydrogen, deuterium, and C 1~3 The compound according to any one of Appendices 22 to 23, which is alkyl.

[0399] (Appendix 25) R6 is C 1~3 is alkyl, R7 is C 1~3 Alkyl, C 3~5 Cycloalkyl, C 3-4 Cycloalkyl C 1~3 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3, or 4 Rz, and each Rz is independently fluorine, methyl; The compound according to any one of Appendices 22 to 23, wherein R8 and R9 are hydrogen and methyl.

[0400] (Appendix 26) selected from compounds of formula (VI), formula (VIa), or formula (VIb); [ka] (VI) [ka] (VIa) [ka] (VIb) R 10 and R 11 are each independently selected from —CH— or O, and at least one is O; R 12 is -CH2- or -CH2-CH2-, and R 12 is -CH2- and R 10 and R 11 are each independently selected from —CH— or O, at least one is O, and R 12 is -CH2-CH2- and R 10 and R 11 is simultaneously O or R10 is -CH2- and R 11 is O, R7 is C 1~3 Alkyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, C 3~6 Cycloalkyl C 1~4 Alkyl, (heterocyclyl of 3-6 atoms)C 1~4 Alkyl or (heteroaryl consisting of 5-6 atoms)C 1~4 alkyl, wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz; Preferably, R7 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetidinylmethyl, oxetidinylethyl, pyrrolidinylmethyl. , pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl, pyrrolidinylmethyl, pyrrolidinylethyl, furanylmethyl, furanylethyl, thiophenemethyl, thiopheneethyl, thiazolemethyl, thiazoleethyl, pyrazolemethyl, pyrazoleethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkoxy, C 1~4 Haloalkyl, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1~4 Alkyl, C 1~4 Alkoxy, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Alkylamino, C 1~4 Alkylsulfonyl, C 1~4 Alkyl acyl, C 3~6 Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C 6~10 is aryl, Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl ... cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl, wherein each Rz is independently unsubstituted or 1, 2, 3, or 4 each Rw independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl 4. The compound according to any one of claims 1 to 3, wherein the compound is pyryl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl.

[0401] (Appendix 27) 27. The compound according to any one of claims 1 to 26, selected from the following: [ka] [ka] [ka] [ka]

[0402] (Appendix 28) 28. Use of a compound according to any one of appendices 1 to 27 in the preparation of a medicament, preferably a medicament for treating, preventing or alleviating a disease such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke in a patient, or for treating or preventing a disease or condition related to mineralocorticoids.

[0403] (Appendix 29) 10. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for use as a mineralocorticoid receptor antagonist.

Claims

1. A compound of formula (I) and its stereoisomers, geometric isomers, inverse isomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, 【Chemical 1】 (I) where: 【Chemistry 2】 teeth, 【Chemistry 3】 and R １ , R ２ , R ３ and R ４ are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, carboxyl, C １～６ Alkanoyl, C １～６ Alkyl sulfonyl, aminoacyl, aminosulfonyl, C ３～８ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R ５ teeth, 【Chemistry 4】 and R ６ is hydrogen, deuterium, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, C ３～８ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; 【Chemistry 5】 teeth, 【Chemistry 6】 and X is C or N; Y is O or S; R ７ is C １～６ Alkyl, C ３～８ cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, C ３～８ Cycloalkyl C １～６ alkyl, (heterocyclyl of 3 to 8 atoms)C １～６ Alkyl, (heteroaryl consisting of 5 to 6 atoms)C １～６ Alkyl, phenyl or phenyl C １～６ alkyl, and R ７ is unsubstituted or substituted by 1, 2, 3 or 4 Rz; Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Haloalkyl, C １～６ Alkylamino, C １～６ Alkylsulfonyl, C １～６ Alkyl acyl, C ３～８ cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ aryl, where each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw; Each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, C １～６ Alkylsulfonyl, C １～６ Alkyl acyl, C ３～８ cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ is aryl, 【Chemistry 7】 teeth, 【Chemistry 8】 and R ８ , R ９ is hydrogen, deuterium, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, C ３～８ Cycloalkyl, C ６～１０ A compound characterized in that it is an aryl, a heterocyclyl of 3 to 8 atoms, or a heteroaryl of 5 to 10 atoms.

2. A compound of formula (I) and its stereoisomers, geometric isomers, inverse isomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs, 【Chemistry 9】 (I) where: 【Chemistry 10】 teeth, 【Chemistry 11】 or 【Chemistry 12】 and R １ , R ２ , R ３ and R ４ are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, carboxyl, C １～６ Alkanoyl, C １～６ Alkyl sulfonyl, aminoacyl, aminosulfonyl, C ３～８ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R ５ teeth, 【Chemistry 13】 and R ６ is hydrogen, deuterium, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, C ３～８ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; 【Chemistry 14】 teeth, 【Chemistry 15】 and X is C or N; Y is O or S; R ７ is C １～６ Alkyl, C ３～８ cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, C ３～８ Cycloalkyl C １～６ alkyl, (heterocyclyl of 3 to 8 atoms)C １～６ Alkyl, (heteroaryl consisting of 5 to 6 atoms)C １～６ Alkyl, phenyl or phenyl C １～６ Alkyl, R ７ is unsubstituted or substituted by 1, 2, 3 or 4 Rz; Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkoxy, C １～６ Haloalkyl, C １～６ Alkylamino, C １～６ Alkylsulfonyl, C １～６ Alkyl acyl, C ３～８ cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw; Each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, C １～６ Alkylsulfonyl, C １～６ Alkyl acyl, C ３～８ cycloalkyl, heterocyclyl of 3 to 8 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ is aryl, 【Chemistry 16】 teeth, 【Chemistry 17】 and R ８ , R ９ is hydrogen, deuterium, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl, C １～６ Haloalkoxy, C １～６ Alkylamino, C ３～８ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 8 atoms, or heteroaryl of 5 to 10 atoms; R １０ and R １１ are each independently -CH ２ - or O, at least one is O; R １２ Ha-CH ２ - or -CH ２ -CH ２ - and R １２ Ha-CH ２ -, then R １０ and R １１ are each independently -CH ２ - or O, at least one is O, and R １２ Ha-CH ２ -CH ２ -, then R １０ and R １１ are simultaneously O, or R １０ Ha-CH ２ - and R １１ is O.

3. 2. The compound according to claim 1, which is selected from compounds of formula (Ia) or (Ib), more preferably a compound of formula (Ia). 【Chemistry 18】 (Ia) 【Chemistry 19】 (Ib)

4. Each R １ , R ２ , R ３ and R ４ are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C １～４ Alkylamino, carboxyl, C １～４ Alkanoyl, C １～４ Alkyl sulfonyl, aminoacyl, aminosulfonyl, C ３～６ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 6 atoms, or heteroaryl of 5 to 6 atoms; R ６ is hydrogen, deuterium, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C １～４ Alkylamino, C ３～６ Cycloalkyl, C ６～１０ aryl, heterocyclyl of 3 to 6 atoms, or heteroaryl of 5 to 6 atoms; Each R ８ and R ９ are independently hydrogen, deuterium, halogen, cyano, C １～４ Alkoxyacyl, carboxyl, C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C １～４ Alkylamino, C １～４ Alkanoyl, C １～４ The compound according to any one of claims 1 to 3, which is alkylsulfonyl, aminoacyl or aminosulfonyl.

5. Each R １ , R ２ , R ３ and R ４ are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, carboxyl, methylacyl, ethylacyl, methylsulfonyl, aminoacyl, or aminosulfonyl; R ６ is hydrogen, deuterium, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthalenyl, cyclohexylethyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridinyl, pyrrolidinyl, thiazole, pyrazole or pyrimidinyl; R ８ is hydrogen, deuterium, cyano, methyl acyl, ethyl acyl, propyl acyl, methoxyl acyl, ethoxyl acyl, propoxy acyl, carboxyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, or dimethylamino.

6. The compound according to any one of claims 1 to 3, which is selected from the compounds of formula (II): 【Chemistry 20】 (II)

7. The compound according to any one of claims 1 to 3, which is a compound represented by formula (IIa) or (IIb). 【Chemical 21】 (IIa) 【Chemical 22】 (IIb)

8. R ７ is C ３～６ Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, C ３～６ Cycloalkyl C １～４ alkyl, (heterocyclyl of 3 to 6 atoms)C １～４ Alkyl or (heteroaryl consisting of 5 to 6 atoms)C １～４ alkyl, where R ７ The compound according to any one of claims 1 to 7, wherein is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

9. R ７ is C １～３ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, preferably R ７ is methyl, ethyl, isopropyl, where R ７ The compound according to any one of claims 1 to 7, wherein is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

10. R ７ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetidinylmethyl, oxetidinylethyl, pyrrolidinyl nylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl, pyrrolidinylmethyl, pyrrolidinylethyl, furanylmethyl, furanylethyl, thiophenemethyl, thiopheneethyl, thiazolemethyl, thiazoleethyl, pyrazolemethyl, pyrazoleethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl, wherein R ７ The compound according to any one of claims 1 to 7, wherein is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

11. Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, C １～４ Alkylamino, C １～４ Alkylsulfonyl, C １～４ Alkyl acyl, C ３～６ cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C １～４ Alkylamino, C １～４ Alkylsulfonyl, C １～４ Alkyl acyl, C ３～６ cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ The compound according to any one of claims 1 to 8, which is aryl.

12. Each Rz independently represents O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl nyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ 9. The compound according to claim 1, wherein the aryl group is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl.

13. is selected from compounds of formula (III): 【Chemical 23】 (III) Here, R ５ teeth 【Chemistry 24】 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

14. R １ , R ２ , R ３ , R ４ are independently hydrogen, deuterium, C １～６ is an alkoxy; R ５ teeth 【Chemistry 25】 and R ６ are hydrogen, deuterium, and C １～６ 14. The compound of claim 13, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

15. R １ , R ２ , R ３ , R ４ are independently hydrogen, deuterium, C １～３ is an alkoxy; R ５ teeth 【Chemical 26】 and R ６ are hydrogen, deuterium, and C １～３ 14. The compound of claim 13, wherein the alkyl is selected from the group consisting of aryl, arylsulfonyl ...

16. R １ , R ２ , R ３ , R ４ are independently hydrogen, deuterium, or methoxyl; R ５ teeth 【Chemical 27】 and R ６ 15. The compound of claim 14, wherein is selected from hydrogen, deuterium, and methyl.

17. is selected from compounds of formula (IV): 【Chemical 28】 (IV) where: 【Chemical Formula 29】 teeth 【Chemistry 30】 and R １ , R ２ , R ３ and R ４ are independently hydrogen, deuterium, C １～６ is an alkoxy; R ５ teeth 【Chemical 31】 is selected from R ６ is C １～６ is alkyl, R ７ is C １～６ is alkyl, R ８ , R ９ is hydrogen, deuterium, C １～６ is alkyl, Y is selected from O; 2. The compound of claim 1, wherein X is selected from C.

18. R １ , R ２ , R ３ and R ４ are independently hydrogen, deuterium, C １～３ is an alkoxy; R ６ is C １～３ is alkyl, R ７ is C １～３ is alkyl, R ８ , R ９ is hydrogen, deuterium, C １～３ 18. The compound of claim 17, wherein the compound is alkyl.

19. is selected from compounds of formula (V): 【Chemical 32】 (V) where: 【Chemical 33】 teeth 【Chemical 34】 and R ３ and R ４ are independently hydrogen and deuterium, R ５ teeth 【Chemistry 35】 is selected from R ６ is C １～６ is alkyl, R ７ is C １～６ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl C １～６ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being halogen; R ８ , R ９ is hydrogen, deuterium, C １～６ is alkyl, X is selected from C; 2. The compound of claim 1, wherein Y is selected from O.

20. R ６ is C １～３ is alkyl, R ７ is C １～３ Alkyl, C ３～５ Cycloalkyl, C ３－４ Cycloalkyl C １～３ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being fluorine, chlorine, bromine, or iodine; R ８ , R ９ is hydrogen, deuterium, C １～３ 20. The compound of claim 19, wherein said compound is alkyl.

21. R ６ is C １～３ is alkyl, R ７ is C １～３ Alkyl, C ３～５ Cycloalkyl, C ３－４ Cycloalkyl C １～３ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being fluorine; R ８ , R ９ 20. The compound of claim 19, wherein is hydrogen, methyl.

22. is selected from compounds of formula (V): 【Chemical 36】 (V) where: 【Chemical 37】 teeth 【Chemical Formula 38】 and R ３ and R ４ are independently hydrogen and deuterium, R ５ teeth 【Chemical 39】 is selected from R ６ is C １～６ is alkyl, R ７ is C １～６ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl C １～６ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being halogen, C １～６ is alkyl, R ８ , R ９ is hydrogen, deuterium, C １～６ is alkyl, X is selected from C; 4. The compound according to claim 1, wherein Y is selected from O.

23. selected from compounds of formula (Va) or (Vb), 【Chemistry 40】 (Va) (Vb) where: 【Chemistry 41】 teeth 【Chemistry 42】 and R ３ and R ４ are independently hydrogen and deuterium, R ５ teeth 【Chemistry 43】 is selected from R ６ is C １～６ is alkyl, R ７ is C １～６ Alkyl, C ３～８ Cycloalkyl, C ３～８ Cycloalkyl C １～６ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being halogen, C １～６ is alkyl, R ８ , R ９ is hydrogen, deuterium, C １～６ is alkyl, X is selected from C; 23. The compound of claim 22, wherein Y is selected from O.

24. R ６ is C １～３ is alkyl, R ７ is C １～３ Alkyl, C ３～５ Cycloalkyl, C ３－４ Cycloalkyl C １～３ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being fluorine, chlorine, bromine, iodine, C １～４ is alkyl, R ８ , R ９ is hydrogen, deuterium, C １～３ The compound according to any one of claims 22 to 23, characterized in that it is alkyl.

25. R ６ is C １～３ is alkyl, R ７ is C １～３ Alkyl, C ３～５ Cycloalkyl, C ３－４ Cycloalkyl C １～３ alkyl, where R ７ is unsubstituted or substituted with 1, 2, 3 or 4 Rz, each Rz independently being fluorine, methyl; R ８ , R ９ The compound according to any one of claims 22 to 23, wherein is hydrogen or methyl.

26. selected from compounds of formula (VI), formula (VIa), or formula (VIb); 【Chemical 44】 (VI) 【Chemistry 45】 (VIa) 【Chemistry 46】 (VIb) R １０ and R １１ are each independently -CH ２ - or O, at least one is O; R １２ Ha-CH ２ - or -CH ２ -CH ２ - and R １２ Ha-CH ２ - and R １０ and R １１ are each independently -CH ２ - or O, at least one is O, and R １２ Ha-CH ２ -CH ２ - and R １０ and R １１ are simultaneously O, or R １０ Ha-CH ２ - and R １１ is O, R ７ is C １～３ Alkyl, C ３～６ Cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, C ３～６ Cycloalkyl C １～４ alkyl, (heterocyclyl of 3 to 6 atoms)C １～４ Alkyl or (heteroaryl consisting of 5 to 6 atoms)C １～４ alkyl, where R ７ is unsubstituted or substituted by 1, 2, 3 or 4 Rz; Preferably, R ７ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetidinylmethyl, oxetidinylethyl methyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinomethyl, morpholinoethyl, pyrrolidinylmethyl, pyrrolidinylethyl, furanylmethyl, furanylethyl, thiophenemethyl, thiophenethyl, thiazolemethyl, thiazoleethyl, pyrazolemethyl, pyrazoleethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl, wherein R ７ is unsubstituted or substituted by 1, 2, 3 or 4 Rz; Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkoxy, C １～４ Haloalkyl, C １～４ Alkylamino, C １～４ Alkylsulfonyl, C １～４ Alkyl acyl, C ３～６ cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ aryl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , C １～４ Alkyl, C １～４ Alkoxy, C １～４ Haloalkyl, C １～４ Haloalkoxy, C １～４ Alkylamino, C １～４ Alkylsulfonyl, C １～４ Alkyl acyl, C ３～６ cycloalkyl, heterocyclyl of 3 to 6 atoms, heteroaryl of 5 to 6 atoms, or C ６～１０ is aryl, Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ , methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl nyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl, wherein each Rz is independently unsubstituted or substituted with 1, 2, 3, or 4 Rw, and each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH ２ 4. The compound according to claim 1, wherein the aryl group is methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethylene oxide, azetidinyl, oxetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholino, pyrrolidinyl, furanyl, thiophene, thiazole, pyrazole, pyridinyl, pyrimidinyl, or phenyl.

27. 27. A compound according to any one of claims 1 to 26, selected from: 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 【Chemistry 50】

28. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament, preferably a medicament for treating, preventing or alleviating diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke in a patient, or for treating or preventing a disease or condition related to mineralocorticoids.

29. Use of a compound according to any one of claims 1 to 27 in the preparation of a medicament for use as a mineralocorticoid receptor antagonist.

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