TWI888920B - Phenyl substituted dihydronaphthalidines and preparation and use thereof - Google Patents

Abstract

The present invention discloses Phenyl substituted dihydronaphthalidines and preparation and use thereof, belonging to the field of pharmaceutical technology. The compound disclosed by the invention is shown in Formula I, which can be used as a mineralocorticoid receptor antagonist to treat, prevent or alleviate aldosterone excess, diabetes nephropathy, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver sclerosis, renal failure, stroke and other diseases.

Description

Phenyl substituted dihydronaphthyridine compounds and their preparation and use

The present invention belongs to the field of medical technology, and specifically relates to phenyl-substituted dihydronaphthyridine compounds and their preparation and use. The compounds can be used as halocorticoid receptor antagonists.

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, with potential effects on the brain, heart, and vascular system. In addition, aldosteronism has been implicated in many of the disease processes that lead to renal and cardiovascular disease. Although aldosteronism is usually caused by an aldosterone-producing adenoma, patients with persistent hypertension often have elevated aldosterone levels, often referred to as "aldosterone escape," due to elevated serum potassium or residual AT1R activity. Aldosteronism and aldosterone escape typically result in increased MR activity, and MR antagonists have been shown to be effective antihypertensive agents and are also effective in the treatment of heart failure and primary aldosteronism. In addition, MR antagonists have also been shown to be effective in preclinical models of renal disease and can be used in combination with standard therapy to reduce proteinuria in patients with renal disease, such as chronic renal disease, including diabetic nephropathy.

Aldosterone is a steroid hormone formed in the adrenal cortex. Its production is regulated indirectly, depending largely on renal blood flow. Any reduction in renal blood flow leads to the release of renin in the kidneys into the circulating blood. This in turn activates the formation of angiotensin II, which on the one hand has a constrictive effect on the arterial vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex. Thus, the kidneys act as blood pressure sensors in the blood circuit and indirectly as volume sensors, and compensate severe losses of volume via the renin-angiotensin-aldosterone system, on the one hand by increasing blood pressure (angiotensin II effect) and on the other hand by rebalancing the filling state of the vascular system by increasing the reabsorption of sodium and water in the kidneys (aldosterone effect). This control system can be pathologically impaired in various ways. For example, a chronic reduction in renal blood flow (e.g., due to heart failure and the resulting blood blockage in the venous system) leads to an excessive release of aldosterone. This is followed by an expansion of the blood volume and thus a weakening of the heart by an increased supply of blood volume to the heart. Obstruction of blood in the lungs, shortness of breath, edema of the extremities and ascites and pleural effusions may result; renal blood flow is further reduced. In addition, the excess aldosterone effect leads to a decrease in potassium concentrations in the blood and extracellular fluid. In previously damaged myocardium, the presence of subcritical minimum levels may induce arrhythmias with fatal consequences. This is probably one of the main causes of sudden cardiac death that often occurs in patients with heart failure.

In addition, aldosterone is also believed to be responsible for many of the myocardial remodeling processes commonly observed in heart failure. Therefore, hyperaldosteronism is key to the pathogenesis and prognosis of heart failure, which is initially induced by various types of injury such as myocardial infarction, myocardial inflammation or hypertension. This hypothesis is supported by the fact that in extensive clinical studies of patients with chronic heart failure and acute myocardial infarction treated with aldosterone antagonists, the overall mortality of patients was significantly reduced (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)).

Additionally, in visceral tissues, such as the kidney and intestine, MR regulates sodium retention, potassium excretion, and water balance in response to aldosterone. MR expression in the brain also appears to play a role in controlling 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)).

Elevated aldosterone levels or overstimulation of alkaloid receptors are associated with a number of physiological disorders or pathological disease states, including Conn's syndrome, primary and secondary aldosteronism, increased sodium retention, increased magnesium and potassium excretion (polyuria), increased water retention, hypertension (isolated systolic hypertension and combined systolic/diastolic hypertension), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's syndrome, and conditions associated with excess catecholamine levels (Hadley, M.E., ENDOCRINOLOGY, 2nd Ed., pp366-81, (1988); and Brilla et al., Journal of Molecular and Cellular Cardiology, 25(5), pp563-75 (1993)). Compounds and/or drug compositions having MR antagonistic effects have therapeutic value for any of the above-mentioned diseases.

Despite the significant advances in the treatment of hypertension and heart failure with alkaloid receptor antagonists, the current standard of care is only suboptimal and significant unmet medical needs exist for additional therapeutic/pharmacological interventions. The present invention addresses those needs by providing compounds and compositions that can be used to treat or prevent diabetic nephropathy, hypertension, heart failure, other cardiovascular disorders, and other aldosterone disorders.

The present invention provides a phenyl-substituted dihydronaphthyridine compound with halocorticoid receptor (MR) antagonism, a compound crystal, and the use of the compound in the preparation of a drug, which is used to treat, prevent or alleviate aldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure and stroke in patients.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) and its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,

為

in,

for

R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen, deuterium, amino, hydroxyl, alkyl, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, C _1-6 alkylamino, carboxyl, C _1-6 alkylyl, C _1-6 alkylsulfonyl, aminoacyl, aminosulfonyl, C _3-8 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms; R ₅ is

為

_R6 is hydrogen, deuterium, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-8 atoms, or a heteroaryl group consisting of 5-10 atoms;

for

X is C or N; Y is O or S; _R7 is _C1-6 alkyl, _C3-8 cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of _5-6 atoms, a C3-8 cycloalkylC1-6 alkyl, (heterocyclic group consisting of _{3-8 atoms)C1-6 alkyl} , (heteroaryl group consisting of 5-6 atoms) _C1-6 alkyl, phenyl or _phenylC1-6 alkyl; _R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2 _{, C1-6} alkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, _C1-6 halogenated alkyl, _C1-6 alkylamino, C1-6 C _1-6 alkylsulfonyl, C _1-6 alkylacyl, C _3-8 cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of 5-6 atoms, or a C _6-10 aryl group; wherein each Rz is independently unsubstituted or substituted by 1, 2, 3 or 4 Rw; each Rw is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonyl, C _1-6 alkylacyl, C _3-8 cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of 5-6 atoms, or a C 6-10 aryl group _{. 6-10} Aryl.

為

for

R ₈ and R ₉ are hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, C 1-6 alkylamino, C _3-8 cycloalkyl, C _6-10 aryl, a heterocyclic group consisting of 3-8 atoms, or a heteroaryl group consisting of 5-10 atoms.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) and its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,

為

或

；R₁、R₂、R₃和R₄獨立地為氫、氘、氨基、羥基、巰基、氰基、硝基、C_1-6烷基、C_1-6烷氧基、C_1-6鹵代烷基、C_1-6鹵代烷氧基、C_1-6烷氨基、羧基、C_1-6烷醯基、C_1-6烷基磺醯基、氨基醯基、氨基磺醯基、C_3-8環烷基、C_6-10芳基、3-8個原子組成的雜環基或5-10個原子組成的雜芳基；R₅為

in,

for

or

_R1 , _R2 , _R3 and _R4 are independently hydrogen, deuterium, amino, hydroxyl, alkyl, cyano, nitro, _C1-6 alkyl, _C1-6 alkoxy, C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, carboxyl, _C1-6 alkylacyl, _C1-6 alkylsulfonyl, aminoacyl, aminosulfonyl, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of _3-8 atoms or a heteroaryl group consisting of 5-10 atoms; _R5 is

為

_R6 is hydrogen, deuterium, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 halogenated alkyl, _C1-6 halogenated alkoxy, _C1-6 alkylamino, _C3-8 cycloalkyl, _C6-10 aryl, a heterocyclic group consisting of 3-8 atoms, or a heteroaryl group consisting of 5-10 atoms;

for

為

；R₈、R₉為氫、氘、C_1-6烷基、C_1-6烷氧基、C_1-6鹵代烷基、C_1-6鹵代烷氧基、C_1-6烷氨基、C_3-8環烷基、C_6-10芳基、3-8個原子組成的雜環基或5-10個原子組成的雜芳基；R₁₀和R₁₁分別獨立地選自-CH₂-或O，且至少有一個為O；R₁₂為-CH₂-或-CH₂-CH₂-；當R₁₂為-CH₂-，R₁₀和R₁₁分別獨立地選自-CH₂-或O，且至少有一個為O；當R₁₂為-CH₂-CH₂-，R₁₀和R₁₁同時為O，或R₁₀為-CH₂-，R₁₁為O。 X is C or N; Y is O or S; _R7 is _C1-6 alkyl, _C3-8 cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of _5-6 atoms, a C3-8 cycloalkylC1-6 alkyl, (heterocyclic group consisting of _{3-8 atoms)C1-6 alkyl} , (heteroaryl group consisting of 5-6 atoms) _C1-6 alkyl, phenyl or _phenylC1-6 alkyl; _R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, _C1-6 alkyl, _C1-6 alkoxy, _C1-6 halogenated alkoxy, _C1-6 halogenated alkyl, _C1-6 alkylamino, _C1-6 C _1-6 alkylsulfonyl, C _1-6 alkylacyl, C _3-8 cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of 5-6 atoms, or a C _6-10 aryl group; wherein each Rz is independently unsubstituted or substituted by 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 halogenated alkyl, C _1-6 halogenated alkoxy, C _1-6 alkylamino, C _1-6 alkylsulfonyl, C _1-6 alkylacyl, C _3-8 cycloalkyl, a heterocyclic group consisting of 3-8 atoms, a heteroaryl group consisting of 5-6 atoms, or a C _6-10 aryl group;

for

; R ₈ and R ₉ are hydrogen, deuterium, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 halogenated alkyl, C _1-6 halogenated alkoxy, C _1-6 alkylamino, C _3-8 cycloalkyl, C _6-10 aryl, a heterocyclic group consisting of 3-8 atoms, or a heteroaryl group consisting of 5-10 atoms; R ₁₀ and R ₁₁ are independently selected from -CH ₂ - or O, and at least one of them is O; R ₁₂ is -CH ₂ - or -CH ₂ -CH ₂ -; when R ₁₂ is -CH ₂ -, R ₁₀ and R ₁₁ are independently selected from -CH ₂ - or O, and at least one of them is O; when R ₁₂ is -CH ₂ -CH ₂ -, R ₁₀ and R ₁₁ are both O, or R _R10 is _-CH2- , and _R11 is O.

In some embodiments, the compound represented by formula (I) of the present invention is selected from the compounds represented by formula (Ia) or formula (Ib); more preferably, the compound represented by formula (Ia);

In some embodiments, the compound represented by formula (I) of the present invention is selected from the compounds represented by formula (Ia) or formula (Ib); more preferably, the compound represented by formula (Ia);

、

、

、R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈、 R₉、X和Y具有本發明所描述的含義。 in,

,

,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , X and Y have the same meanings as described in the present invention.

In some embodiments, each of R ₁ , R ₂ , R ₃ and R ₄ is independently hydrogen, deuterium, amino, hydroxyl, alkyl, cyano, nitro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 halogenated alkyl, C _1-4 halogenated alkoxy, C _1-4 alkylamino, carboxyl, C _1-4 alkylyl, C _1-4 alkylsulfonyl, aminoacyl, aminosulfonyl, C _3-6 cycloalkyl, C _6-10 aryl, a heterocyclic group consisting of 3-6 atoms, or a heteroaryl group consisting of 5-6 atoms; R ₆ is hydrogen, deuterium, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 halogenated alkyl, C _1-4 halogenated alkoxy, C 1-4 In some embodiments, each of R 1, R _2, R 3 and R ₉ is independently hydrogen, deuterium, halogen, cyano, C _1-4 alkoxyacyl, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 halogenated alkyl, C _1-4 halogenated alkoxy, C _1-4 alkylamino, C 1-4 alkylacyl, C _1-4 alkylsulfonyl, aminoacyl or aminosulfonyl; in some embodiments, each of R 1, R ₂ , R 3 and R ₉ is independently hydrogen, deuterium, halogen, cyano, C _1-4 alkoxyacyl, carboxyl, C _1-4 alkyl, C _1-4 alkoxy, C 1-4 halogenated alkyl, C _1-4 halogenated alkoxy, C 1-4 alkylamino, C _{1-4 alkylacyl} , C 1-4 alkylsulfonyl, aminoacyl or aminosulfonyl. _R is independently hydrogen, deuterium, amino, hydroxyl, hydroxyl, 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 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, naphthyl, oxadiazole, pyrrolidinyl, piperidinyl, piperazinyl, fluorenyl, pyridinyl, pyrrolyl, thiazolyl, pyrazolyl or pyrimidinyl; ₈ is hydrogen, deuterium, cyano, methylacyl, ethylacyl, propylacyl, methoxyacyl, ethoxyacyl, 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.

In some embodiments, the compound of the present invention is selected from the compound represented by formula (II):

In some embodiments, the compound of the present invention is selected from the compounds represented by formula (IIa) or formula (IIb):

In some embodiments, _R7 is _C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 atoms, a heteroaryl group consisting of 5-6 atoms, a _C3-6 cycloalkylC1-4 alkyl, (heterocyclic group consisting of _3-6 atoms) _C1-4 alkyl or (heteroaryl group consisting of 5-6 atoms) _C1-4 alkyl; wherein _R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz.

In some embodiments, R ₇ is C _1-3 alkyl, wherein R ₇ is unsubstituted or substituted with 1, 2, 3 or 4 R z ; preferably, R ₇ is methyl, ethyl, isopropyl, wherein R ₇ is unsubstituted or substituted with 1, 2, 3 or 4 R z .

In some embodiments, R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxathiolanyl, azocyclobutyl, oxathiocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, furanyl, thiophene, yl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azacyclobutylmethyl, azacyclobutylethyl, oxacyclobutylmethyl, oxacyclobutylethyl, pyrrolidine wherein R is substituted with 1, 2, 3 or 4 Rs; wherein R is substituted with 1, 2, 3 or ₄ Rs.

In some embodiments, each Rz is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, _C1-4 alkyl, _C1-4 alkoxy, _C1-4 halogenated alkoxy, _C1-4 halogenated alkyl, _C1-4 alkylamino, _C1-4 alkylsulfonyl, _C1-4 alkylacyl, C3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl group consisting of 5-6 atoms, or C6-10 aryl; wherein each Rz is independently unsubstituted or substituted with 1, 2, ₃ or 4 Rw; each Rw is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, _C1-4 alkyl, C1-4 alkoxy, C1-4 halogenated alkoxy, C1-4 halogenated alkyl, C1-4 alkylamino, C1-4 alkylsulfonyl, _C1-4 alkylacyl, _C3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl group consisting of _5-6 atoms, or _C6-10 aryl. C _1-4 halogenated alkyl, C _1-4 halogenated alkoxy, C _1-4 alkylamino, C _1-4 alkylsulfonyl, C _1-4 alkylacyl, C _3-6 cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl group consisting of 5-6 atoms or C _6-10 aryl group.

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, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, oxazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl; wherein each Rz is independently unsubstituted or substituted with 1, 2, 3 or 4 Rw; each Rw is independently =0, 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, oxathiolanyl, azocyclobutyl, oxathiocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl.

In some embodiments, the compound is selected from the compound shown in formula (III):

。 Among them, R ₅ is selected from

.

R₆選自氫、氘、C_1-6烷基。 In some embodiments, R ₁ , R ₂ , R ₃ , and R ₄ are independently hydrogen, deuterium, or C _1-6 alkoxy; R ₅ is

_R6 is selected from hydrogen, deuterium, and _C1-6 alkyl.

；R₆選自氫、氘、C_1-3烷基。 In some embodiments, R ₁ , R ₂ , R ₃ , and R ₄ are independently hydrogen, deuterium, or C _1-3 alkoxy; R ₅ is

; R ₆ is selected from hydrogen, deuterium, C _1-3 alkyl.

；R₆選自氫、氘、甲基。 In some embodiments, R ₁ , R ₂ , R ₃ , and R ₄ are independently hydrogen, deuterium, or methoxy; R ₅ is

; R ₆ is selected from hydrogen, deuterium, and methyl.

In some embodiments, the compound is selected from the compound shown in formula (IV):

為

；R₁、R₂、R₃和R₄獨立地為氫、氘、C_1-6烷氧基；R₅選自

；R₆為C_1-6烷基；R₇為C_1-6烷基；R₈、R₉為氫、氘、C_1-6烷基；Y選自O；X選自C。 in

for

; R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen, deuterium, C _1-6 alkoxy; R ₅ is selected from

; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl; R ₈ and R ₉ are hydrogen, deuterium, or C _1-6 alkyl; Y is selected from O; and X is selected from C.

In some embodiments, R ₁ , R ₂ , R ₃ and R ₄ are independently hydrogen, deuterium, or C _1-3 alkoxy; R ₆ is C _1-3 alkyl; R ₇ is C _1-3 alkyl; R ₈ and R ₉ are hydrogen, deuterium, or C _1-3 alkyl.

In some embodiments, the compound is selected from the compound shown in formula (V):

為

；R₃和R₄獨立地為氫、氘；R₅選自

；R₆為C_1-6烷基；R₇為C_1-6烷基、C_3-8環烷基、C_3-8環烷基C_1-6烷基；其中，R₇未被取代或被1、2、3或4個Rz取代；各Rz獨立地為：鹵素；R₈、R₉為氫、氘、C_1-6烷基；X選自C；Y選自O。 in,

for

; R ₃ and R ₄ are independently hydrogen or deuterium; R ₅ is selected from

; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkylC _1-6 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2, 3 or 4 R z; each R z is independently: halogen; R ₈ and R ₉ are hydrogen, deuterium, C _1-6 alkyl; X is selected from C; Y is selected from O.

In some embodiments, R ₆ is C _1-3 alkyl; R ₇ is C _1-3 alkyl, C _3-5 cycloalkyl, C _3-4 cycloalkyl, C _1-3 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2, 3 or 4 R z; each R z is independently: fluorine, chlorine, bromine, iodine; R ₈ and R ₉ are hydrogen, deuterium, C _1-3 alkyl.

In some embodiments, R ₆ is C _1-3 alkyl; R ₇ is C _1-3 alkyl, C _3-5 cycloalkyl, C _3-4 cycloalkyl, C _1-3 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2, 3 or 4 R z; each R z is independently fluorine; R ₈ and R ₉ are hydrogen or methyl.

In some embodiments, the compound is selected from the compound shown in formula (V):

為

；R₃和R₄獨立地為氫、氘；R₅選自

；R₆為C_1-6烷基；R₇為C_1-6烷基、C_3-8環烷基、C_3-8環烷基C_1-6烷基；其中，R₇未被取代或被1、2、3或4個Rz取代；各Rz獨立地為：鹵素、C_1-6烷基；R₈、R₉為氫、氘、C_1-6烷基；X選自C；Y選自O。 in,

for

; R ₃ and R ₄ are independently hydrogen or deuterium; R ₅ is selected from

; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkylC _1-6 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2, 3 or 4 R z; each R z is independently: halogen, C _1-6 alkyl; R ₈ and R ₉ are hydrogen, deuterium, C _1-6 alkyl; X is selected from C; Y is selected from O.

In some embodiments, the compound is selected from the compounds represented by formula (Va) or formula (Vb);

為

；R₃和R₄獨立地為氫、氘；R₅選自

；R₆為C_1-6烷基；R₇為C_1-6烷基、C_3-8環烷基、C_3-8環烷基C_1-6烷基；其中，R₇未被取代或被1、2、3或4個Rz取代；各Rz獨立地為：鹵素、C_1-6烷基；R₈、R₉為氫、氘、C_1-6烷基；X選自C；Y選自O。 in,

for

; R ₃ and R ₄ are independently hydrogen or deuterium; R ₅ is selected from

; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl, C _3-8 cycloalkylC _1-6 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2, 3 or 4 R z; each R z is independently: halogen, C _1-6 alkyl; R ₈ and R ₉ are hydrogen, deuterium, C _1-6 alkyl; X is selected from C; Y is selected from O.

In the above formula (V), formula (Va) and formula (Vb), _R6 is _C1-3 alkyl; _R7 is _C1-3 alkyl, _C3-5 cycloalkyl, _{C3-4 cycloalkylC1-3} alkyl; wherein _R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: fluorine, chlorine, bromine, iodine, _C1-4 alkyl; _R8 and _R6 are hydrogen, deuterium, _C1-3 alkyl.

Further, _R6 is _C1-3 alkyl; _R7 is _C1-3 alkyl, _C3-5 cycloalkyl, _C3-4 cycloalkyl, _C1-3 alkyl; wherein _R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently fluorine or methyl; _R8 and _R9 are hydrogen or methyl.

In some embodiments, the compound is selected from the compounds represented by formula (VI), formula (VIa), or formula (VIb);

_R10 and _R11 are independently selected from _-CH2- or O, and at least one of them is O; _R12 is _-CH2- or _{-CH2- CH2-} ; when _R12 is _-CH2- , _R10 and _R11 are independently selected from _-CH2- or O, and at least one of them is O; when _R12 is _{-CH2- CH2-} , _R10 and _R11 are both O, or _R10 is _-CH2- , _R11 is O; _R7 is _C1-3 alkyl, _C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 atoms, a heteroaryl group consisting of _5-6 atoms, a C3-6 _{cycloalkylC1-4} alkyl, (a heterocyclic group consisting of 3-6 atoms)C wherein R ₇ is unsubstituted or substituted by ₁ , 2, ₃ or 4 R z; preferably, R ₇ is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, azocyclobutyl, oxazolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azocyclobutylmethyl, azocyclobutylethyl, oxocyclobutylmethyl, oxocyclobutylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinyl wherein R is 1, 2, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 123, 133, 144, 157, 169, 110, 111, 124, 135, 146, 158, 171 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, _NH2 , _C1-4 alkyl, C1-4 alkoxy, _C1-4 halogenated alkoxy, _C1-4 halogenated alkyl, _C1-4 alkylamino, C1-4 alkylsulfonyl, _C1-4 alkylacyl, _C3-6 cycloalkyl, a heterocyclic group consisting of _3-6 atoms, a heteroaryl group consisting of 5-6 atoms or a _C6-10 aryl group; wherein each Rz is independently unsubstituted or substituted by 1, ₂ , 3 or 4 Rw; each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C1-4 alkyl, C1-4 alkoxy, C1-4 halogenated alkoxy, _C1-4 halogenated alkyl, C1-4 alkylamino, C1-4 alkylsulfonyl, C1-4 alkylacyl, C3-6 cycloalkyl, a heterocyclic group consisting of 3-6 atoms, a heteroaryl group consisting of 5-6 atoms or a _C6-10 aryl group. _{C 1-4} alkoxy, C _1-4 halogenated alkyl, C _1-4 halogenated alkoxy, C _1-4 alkylamino, C _1-4 alkylsulfonyl, C _1-4 alkylacyl, C _3-6 cycloalkyl, a heterocyclic group consisting of 3-6 atoms, a heteroaryl group consisting of 5-6 atoms, or a C _6-10 aryl group; 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, oxathinyl, cyclobutylazine, cyclobutylazine, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl; 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, 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, oxathiolanyl, azocyclobutyl, oxathiocyclobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, oxolinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl.

In some embodiments, the compound represented by (I) provided by the present invention is specifically a compound represented by formula (I-10), (I-11) or (I-12) and its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs;

任選自

；R₃和R₄獨立地為氫或氘；R₆為氫、氘、C_1-6烷基；R₇為C_1-6烷基、C_3-8環烷基、C3-8環烷基C1-6烷基；R₇未被取代或被1、2、3或4個Rz取代；各Rz獨立地為O、氘、氟、氯、溴、碘、羥基、氰基、NH_2、；R₈、R₉為氫、氘、C_1-6烷基；所述(I-10)、(I-11)或(I-12)所示的化合物，R₆為C_1-4烷基，進一步地選自氫、甲基、乙基、丙基、丁基；所述(I-10)、(I-11)或(I-12)所示的化合物，各R₈和R₉獨立地為氫、氘、鹵素、C_1-4烷基；所述(I-10)、(I-11)或(I-12)所示的化合物，R₈獨立地為氫、基、乙基、丙基或丁基，R₉獨立地為氫、氘；所述(I-10)、(I-11)或(I-12)所示的化合物，R7為C3-6環烷基、C3-8環烷基、C3-5環烷基C1-3烷基；R7未被取代或被1、2、3或4個Rz取代；各Rz獨立地為O、氘、氟、氯、溴、碘、羥基、氰基、NH2；所述(I-10)、(I-11)或(I-12)所示的化合物，R₇為環丙基、環丁基、環戊基、環己基、環丙基甲基、環丙基乙基、環丁基甲基、環 丁基乙基、環戊基甲基、環戊基乙基、環己基甲基、環己基乙基。 in

Choose from

; R ₃ and R ₄ are independently hydrogen or deuterium; R ₆ is hydrogen, deuterium, C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl, C3-8 cycloalkylC1-6 alkyl; R ₇ is unsubstituted or substituted by 1, 2, 3 or 4 R z; each R z is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH _2, ; R ₈ and R ₉ are hydrogen, deuterium, C _1-6 alkyl; the compound shown in (I-10), (I-11) or (I-12), R ₆ is C _1-4 alkyl, further selected from hydrogen, methyl, ethyl, propyl, butyl; the compound shown in (I-10), (I-11) or (I-12), each R ₈ and R _{R 9} is independently hydrogen, deuterium, halogen, C _1-4 alkyl; in the compound represented by (I-10), (I-11) or (I-12), R ₈ is independently hydrogen, methyl, ethyl, propyl or butyl, R ₉ is independently hydrogen or deuterium; in the compound represented by (I-10), (I-11) or (I-12), R7 is C3-6 cycloalkyl, C3-8 cycloalkyl, C3-5 cycloalkyl or C1-3 alkyl; R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano or NH2; in the compound represented by (I-10), (I-11) or (I-12), R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

In the compound represented by (I'-10), (I'-11) or (I'-12), R ₇ is methyl or ethyl.

In the compound represented by (I'-10), (I'-11) or (I'-12), _R7 is substituted by 1 to 3 Fs.

In some embodiments, the compound is selected from:

In the present invention, the compound does not contain the situation where R ₁ , R ₂ , and R ₃ are hydrogen, R ₄ is methoxy, R ₅ is -CONH ₂ , and R ₆ is hydrogen.

In one aspect, the present invention provides a crystal of a compound, wherein the structural formula of the compound 36 is as follows:

The crystal structure of compound 36 belongs to the monoclinic system, C2 space group, unit 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°, unit cell volume V=2046.27(3)[Å] ³ , and the minimum number of asymmetric units in the unit cell Z=4.

Wherein, the crystal or its crystalline form of the compound 36 has an XRPD spectrum as shown in Figure 4 or substantially as shown in Figure 4, wherein substantially means that the difference in the number of peak shapes is within 85%.

The present invention also provides another crystal of compound 62, the structural formula of compound 62 is as follows:

The crystal structure of compound 62 belongs to the monoclinic system, C2 space group, unit 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°, unit cell volume V=3997.68(6)[Å] ³ , and the minimum asymmetric unit number Z=8 in the unit cell.

Wherein, the crystal or its crystalline form of the compound 62 has an XRPD spectrum as shown in Figure 8 or substantially as shown in Figure 8, wherein substantially means that the difference in the number of peak shapes is within 85%.

For the crystal form, specifically: the present invention provides a crystal of a compound, the compound is compound 36, and its structural formula is shown in the above figure; the crystal of compound 36, its structure belongs to the monoclinic system, C2 space group, unit 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°, unit cell volume V=2046.27(3)[Å]3, the minimum number of asymmetric units in the unit cell Z=4; further, the crystal of compound 36 or its crystal form has an XRPD spectrum as shown in Figure 4 or substantially as shown in Figure 4, wherein substantially means that the difference in the number of peak shapes is within 85%. The present invention further provides a crystal of compound 62, whose structure belongs to the monoclinic system, C2 space group, unit 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°, unit cell volume V=3997.68(6)[Å]3, and the minimum number of asymmetric units in the unit cell Z=8. Furthermore, the crystal of compound 62 or its crystalline form has an XRPD spectrum as shown in Figure 8 or substantially as shown in Figure 8, wherein substantially means that the difference in the number of peak shapes is more than 85%. The present invention also provides the use of the crystal of the compound in the preparation of a drug, wherein the drug is a drug for treating or preventing a disease or condition related to salvocorticoids, or a drug for treating, preventing or alleviating the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke; or, the drug is used as a salvocorticoid receptor antagonist.

On the other hand, it relates to the use of the compounds described in the present invention and their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs in the preparation of drugs; or it relates to the use of the compounds described in the present invention and their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs or in the preparation of drugs for treating or preventing diseases or conditions related to salvocorticoids.

The drug is used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

Or, wherein the drug is used as a nasocorticoid receptor antagonist.

The salvocorticoid-related disease or condition is selected from the following diseases: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

Definitions and General Terms

Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural and chemical formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included in 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 to practice 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 from or contradicts this application (including but not limited to defined terms, term applications, described technologies, etc.), this application shall prevail.

It should be further appreciated that certain features of the present invention, which for clarity are described in separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present invention, which for brevity are described in a single embodiment, may also be provided individually or in any suitable subcombination.

Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by technical personnel in the field to which the present invention belongs. All patents and publications related to the present invention are incorporated into the present invention as a whole by reference.

Unless otherwise stated, the following definitions used herein shall apply. For the purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry can be found 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.

Unless otherwise specified or there is a clear conflict in the context, the articles "a", "an", and "the" used herein are intended to include "at least one" or "one or more". Therefore, these articles used herein refer to one or more than one (i.e., at least one) object article. For example, "a component" refers to one or more components, i.e., there may be more than one component considered to be adopted or used in the implementation of the embodiment.

The term "patient" used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to humans.

The term "comprising" is an open expression, which includes the contents specified in the present invention but does not exclude other contents.

"Stereoisomers" refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis/trans) isomers, atropisomers, etc.

"Enantiomers" refer to two isomers of a compound that are non-superimposable but mirror images of each other.

"Diastereoisomers" are stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

The stereochemical definitions and rules used in the present invention generally follow 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.

Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed in the present invention may exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain 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 in the (R)- or (S)-configuration.

Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible across a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerizations and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the tautomerism of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is phenol-keto tautomerism. Phenol-keto A specific example of tautomerism is the tautomerism of pyridine-4-ol and pyridine-4(1H)-one. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

As described in the present invention, the compounds of the present invention may be optionally substituted with one or more substituents, such as the general formula compounds above, or as the specific examples, subclasses, and classes of compounds included in the embodiments.

In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used in the present invention "each...independently" and "...each independently" and "...independently" can be interchanged and should be broadly understood, which can mean that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other. Similarly, the "independent" in the description "...independently optional" should also be understood in the above broad sense.

The term "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, i.e., the description includes instances where the event or circumstance occurs and instances where it does not occur.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the group types or ranges. It is particularly pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the term "C ₁ -C ₆ alkyl" or "C _1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl; "C _1-4 alkyl" specifically refers to the independently disclosed methyl, ethyl, C ₃ alkyl (i.e., propyl, including n-propyl and isopropyl) and C ₄ alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

In various parts of this invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for the variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent alkyl group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, i.e., C _1-6 alkyl; in yet other embodiments, the alkyl group contains 1-4 carbon atoms, i.e., C _1-4 alkyl; in still other embodiments, the alkyl group contains 1-3 carbon atoms, i.e., C _1-3 alkyl. In some embodiments, the C _1-6 alkyl described in the present invention includes C _1-4 alkyl; in other embodiments, the C _1-6 alkyl described in the present invention includes C _1-3 alkyl.

Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl), 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.

The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the 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, iso-butoxy, sec-butoxy, tert-butoxy), and the like.

The term "halogenated alkyl" or "halogenated alkoxy" means that the alkyl or alkoxy group is substituted by one or more halogen atoms, such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, chloroethyl (e.g., 2-chloroethyl), trifluoroethyl (including but not limited to, 2,2,2-trifluoroethyl), 2,2-difluoroethyl, 2-chloro-1-methylethyl, etc.

The term "amino" refers to the group -NH ₂ . The term "carboxy" refers to the group -COOH. The terms "hydroxy", "cyano", "nitro" and "hydroxyl" refer to the groups -OH, -CN, -NO ₂ , and -SH, respectively. The term "oxo" represents the group =O.

The term "alkylamino" or "alkylamino" means that the group _-NH2 is substituted by one or two alkyl groups, i.e., the alkylamino or alkylamino group includes monoalkylamino and dialkylamino; wherein the alkyl group has the meaning as described in the present invention. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, and the like.

The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic system containing 3-12 ring carbon atoms. In some embodiments, the cycloalkyl contains 3-10 ring carbon atoms, such as _C3-10 cycloalkyl; in other embodiments, the cycloalkyl contains 3-8 ring carbon atoms, such as _C3-8 cycloalkyl; in yet other embodiments, the cycloalkyl contains 3-6 ring carbon atoms, such as _C3-6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Wherein, as described in the present invention, C _3-8 cycloalkyl includes C _3-6 cycloalkyl; the C _3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be optionally substituted by one or more substituents described in the present invention.

)氮雜環丙烷基(

)氮雜環丁基(

)氧雜環丁基(

)吡咯烷基(

)四氫呋喃基(

)四氫噻吩基(

)噻唑烷基(

)吡唑烷基(

)吡唑啉基(

)惡唑烷基(

)咪唑烷基(

)呱啶基(

)呱嗪基(

)或嗎啉基(

)等。所述雜環基基團可以任選地被一個或多個本發明描述的取代基所取代。 The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the heterocyclic group is non-aromatic and does not contain any aromatic ring. Unless otherwise specified, the heterocyclic group can be carbon-based or nitrogen-based, and the _-CH2- group can be optionally replaced by -C(=O)-. The sulfur atoms of the ring can be optionally oxidized to S-oxides. The nitrogen atoms of the ring can be optionally oxidized to N-oxides. The term "heterocyclic group" can be used interchangeably with the term "heterocycle". Examples of heterocyclic groups include, but are not limited to, oxirane, azocyclobutyl, oxazolobutyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and the like. As described in the present invention, the heterocyclic group may be composed of 3-8 atoms or 3-6 atoms, wherein the atoms are C, N, O or S and at least one atom is N, O or S; wherein the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms; specifically, the heterocyclic group composed of 3-6 atoms includes but is not limited to, ethylene oxide (

) Cyclopropane aziridine (

)Azocyclobutyl(

)Oxycyclobutyl(

)Pyrrolidinyl(

)Tetrahydrofuranyl(

)Tetrahydrothienyl(

)Thiazolidinyl(

)Pyrazolidine(

)pyrazolyl(

)Oxazolidinyl (

)Imidazolidinyl(

)piperidinyl(

)piperazine

) or morpholinyl (

) etc. The heterocyclic group may be optionally substituted with one or more substituents described in the present invention.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbon ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic and has one or more points of attachment to the rest of the molecule. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, 2,3-dihydro-1H-indenyl, naphthyl and anthracenyl. The aryl group can be optionally substituted with one or more substituents described in the present invention. Unless otherwise specified, the group "C _6-10 aryl" refers to an aryl group containing 6-10 ring carbon atoms.

The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen and sulfur, and at the same time, the heteroaryl has one or more points of attachment to the rest of the molecule. When a -CH ₂ - group is present in the heteroaryl group, the -CH ₂ - group can be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which can be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or "heteroaromatic compound". Examples of heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms, which means that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms selected from O, S and N; in other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms, which means that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms selected from O, S and N. Examples of heteroaryl groups consisting of 5-6 atoms include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, oxazinyl, pyrazinyl, thienyl, thiazolyl and the like.

The term "composed of j-k atoms (j and k are each independently any non-zero natural number, and k>j)" means that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, and P; the "j-k" includes j, k, and any natural number between the two. For example, "composed of 3-8 atoms", "composed of 5-10 atoms" or "composed of 5-6 atoms" means that the cyclic group is composed of 3-8, 5-10 or 5-6 ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, and P.

In this article, when there are two or more complex groups connected, the connection point is referred to the general chemical principle, that is, the connection point is the last noun group in the name of the complex group. For example, when "C _3-8 cycloalkyl C _1-6 alkyl, 3-8 membered heterocycloalkyl C _1-6 alkyl, phenyl C _1-6 alkyl, 5-6 membered heteroaryl C _1-6 alkyl" appears, the connection point with the main structure group or other groups is "C _1-6 alkyl"; other similar groups, unless otherwise specified, are understood in accordance with this principle.

The “heterocyclic group consisting of 3-8 atoms” and “heterocyclic group consisting of 3-6 atoms” mentioned in the present invention refer to a heterocyclic group consisting of 3-8 ring atoms or a heterocyclic group consisting of 3-6 ring atoms, wherein the heterocyclic group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S, and the _CH2 in the heterocyclic group can be further oxidized to form C(=O), and similarly, the S or N in the heterocycle can be further oxidized to form S(=O), S(=O) ₂ or N(=O).

The "heteroaryl group consisting of 5-10 atoms" and "heteroaryl group consisting of 5-6 atoms" described in the present invention refer to heteroaryl groups containing 5-10 ring atoms and heteroaryl groups containing 5-6 ring atoms, wherein the heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S. In some embodiments, specific examples of the "heteroaryl group consisting of 5-10 atoms" or "heteroaryl group consisting of 5-6 atoms" described in the present invention include but are not limited to pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, etc.

The term "alkanoyl" or "alkylacyl" refers to the group -C(=O)-alkyl, wherein the alkyl has the meaning as described herein, examples of which include, but are not limited to, methylacyl (-C(=O)CH ₃ ), ethylacyl (-C(=O)CH ₂ CH ₃ ), and the like.

The term "alkoxyacyl" refers to the group -C(=O)-R, wherein R is alkoxy, which has the meaning as described herein, and examples include, but are not limited to, methoxyacyl (-C(=O)OCH ₃ ), ethoxyacyl (-C(=O)OCH ₂ CH ₃ ), and the like.

The term "alkylsulfonyl" refers to the group -S(=O) ₂ -alkyl, wherein the alkyl has the meaning as described herein, examples of which include, but are not limited to, methylsulfonyl (-S(=O) ₂ CH ₃ ), ethylsulfonyl (-S(=O) ₂ CH ₂ CH ₃ ), and the like.

The term "aminosulfonyl" refers to the group -S(=O) ₂ NH ₂ ; the term "aminoacyl" refers to the group -C(=O)NH ₂ .

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic or similar untoward reactions, such as gastrointestinal discomfort, dizziness, etc., when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by federal regulatory agencies or state governments or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, especially in humans.

The term "carrier" refers to a diluent, adjuvant, excipient or matrix with which the compound is administered. These pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water and aqueous solutions (e.g., saline solutions, aqueous glucose solutions, aqueous glycerol solutions) are preferably used as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in "Remington 's Pharmaceutical Sciences" by EW Martin.

The term "prodrug" used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion of the prodrug into the parent structure in the blood or tissues. The prodrug compound of the present invention can be an ester. In the existing invention, the esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters, such as these phosphate ester compounds that are obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, see the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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 SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

"Metabolites" refer to products 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 assays as described in the present invention. Such products can be obtained by administering compounds through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, degreasing, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.

The term "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid-formed salts include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, and perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartarates, citrates, succinates, and malonates; or these salts can be obtained by other methods described in the literature, such as ion exchange methods. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate. , hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, appletate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, sulfonate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by reaction with an appropriate base include salts of alkali metals, alkali earth metals, ammonium and N ⁺ (C _1-4 alkyl) 4. The present invention also contemplates quaternary ammonium salts formed from any compound containing a nitrogen-containing group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkaline metals or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and aromatic sulfonates.

The "solvate" of the present invention refers to a compound formed by one or more solvent molecules and the compound of the present invention. Solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to a compound formed by the solvent molecule being water.

The "ester" of the present invention refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce a parent alcohol or acid. The compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolyzable ester with an appropriate group, such as, but not limited to, an alkyl group, an arylalkyl group, etc.

The "nitrogen oxide" of the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N ^- oxides. Specific examples of N ^- oxides are N ^- oxides of tertiary amines or N ^- oxides of nitrogen atoms of nitrogen-containing heterocyclic rings. The corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (e.g. peroxycarboxylic acids) to form N ^- oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N ^- oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), wherein, for example, in an inert solvent such as dichloromethane, the amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA).

The "compound of the present invention", "compound described in the present invention", "compound described in the present invention" or similar expressions used in the present invention refer to the compound represented by any general structure described in the present invention. For example, the compound of the present invention may refer to the compound represented by formula (I) or formula (Ia) or formula (Ib) or formula (IIa) or formula (IIb) or formula (III) or formula (IV) in the present invention. The compound of the present invention also includes the specific compound in any embodiment.

As used herein, the term "treating" any disease or condition refers to ameliorating the disease or condition (i.e., slowing down or stopping or reducing the development of the disease or at least one of its clinical symptoms) in some embodiments. In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

Any structural formula given herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have structures depicted by the general formula given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 31P, 32P, 35S, 36Cl, and 125I.

In addition, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, may be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If 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 incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the crystallization solvent may be isotopically substituted, such as _D2O , acetone- _d6 , DMSO- _d6 .

Unless otherwise indicated, all tautomeric isomeric forms of the compounds of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.

Unless otherwise specified, any abbreviations of protective groups, amino acids and other compounds used in the present invention shall be based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

Description of the compounds of the present invention

The present invention provides a phenyl-substituted dihydronaphthyridine compound and a drug composition thereof that can competitively antagonize aldosterone receptor (MR), as well as the use of the compound or the drug composition in preparing a drug, wherein the drug is used to treat, prevent or alleviate diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, cirrhosis, renal failure and stroke in patients.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),

On the one hand, the present invention relates to the use of the compound or drug composition described in the present invention in the preparation of a drug, wherein the drug is used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

On the other hand, the present invention also relates to the use of the compound or drug composition described in the present invention in the preparation of a drug, wherein the drug is used as a halocorticoid receptor antagonist.

On the one hand, the compounds or drug compositions described in the present invention are used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

On the other hand, the compounds or drug compositions described in the present invention can be used to antagonize alkaloid receptors.

On the one hand, the present invention relates to a method for treating, preventing or alleviating the following diseases in patients using the compounds or drug compositions described in the present invention: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke, and the method comprises treating the patient with a therapeutically effective dose of the compounds or drug compositions described in the present invention.

On the other hand, the present invention also relates to a method for antagonizing alkaloid receptors using the compound or drug composition described in the present invention, the method comprising contacting an effective dose of the compound or drug composition described in the present invention with an organism (including in vivo or in vitro).

The compounds or pharmaceutical compositions of the present invention competitively antagonize the aldosterone receptor (MR), and therefore they may be useful agents for the treatment and prevention of conditions associated with elevated aldosterone levels.

The compounds or drug compositions of the present invention can be used to treat or prevent aldosterone receptor-mediated diseases. The present invention also includes a method for treating or alleviating aldosterone receptor-mediated diseases in patients, or patients sensitive to these conditions, which comprises treating the patient with a therapeutically effective amount of the compounds or drug compositions of the present invention.

The present invention includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for producing pharmaceutical products for treating patients with diseases associated with alkaloid receptors or aldosterone, including those described in the present invention. The present invention includes a pharmaceutical composition comprising a compound represented by formula (I) in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle in an effective therapeutic amount.

Unless otherwise indicated, all hydrates, solvates and pharmaceutically acceptable salts of the compounds of the present invention belong to the scope of the present invention.

Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically and toxicologically suitable in relation to the other ingredients of the formulation and the mammal to be treated.

The salts of the compounds of the present invention also include intermediates used to prepare or purify compounds of formula (I) or (Ia) or (Ib) or (IIa) or (IIb) or (III) or (IV) or salts of separated enantiomers of compounds of formula (I) or (Ia) or (Ib) or (IIa) or (IIb) or (III) or (IV), but they are not necessarily pharmaceutically acceptable salts.

The salts of the compounds of the present invention can be prepared 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, etc. Or using 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; pyranose 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, ethanesulfonic acid, etc.

The biological activity of the compounds of the present invention can be assessed by using any conventional known method. Appropriate detection methods are well known in the art. For example, the MR antagonist activity, pharmacokinetic activity and/or liver microsomal stability of the compounds of the present invention can be detected by appropriate conventional methods. The detection methods provided by the present invention are presented only as examples and do not limit the present invention. The compounds of the present invention are active in at least one of the detection methods provided by the present invention. For example, the compounds of the present invention have good antagonist activity against aldosterone receptors and have good in vivo pharmacokinetic properties, such as good absorption and exposure, and high bioavailability; for example, the compounds of the present invention have low toxic side effects.

Administration and use of the compounds of the present invention.

The therapeutically effective amount of the compounds of the present invention should be present in the above-mentioned pharmaceutical preparations at a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight of the entire mixture. The therapeutically effective dose can first be estimated using various methods well known in the art. The initial dose used for animal studies can be based on the effective concentration established in cell culture assays. The dosage range suitable for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as a medicament for oral administration. An exemplary dose of the compounds of the present invention in a medicament for oral administration is from about 0.01 to about 100 mg/kg (wherein kg represents the weight of the subject). In some embodiments, the dosage comprises from about 0.01 to about 20 mg/kg (wherein kg represents the subject's weight), or optionally from about 0.01 to about 10 mg/kg (wherein kg represents the subject's weight), or optionally from about 0.01 to about 5.0 mg/kg (wherein kg represents the subject's weight). In certain embodiments, the compounds of the present invention are administered enterally, and the effective dosage is about 0.001-1 mg/kg, preferably about 0.01-0.5 mg/kg body weight.

The dosage regimen for oral administration is usually three times a week, twice a week, once a week, three times a day, twice a day or once a day. In certain embodiments, the compound of the present invention is administered as an active ingredient in a total amount of about 0.001 to about 50, preferably 0.001 to 10 mg/kg body weight per 24 hours, and in order to obtain the desired result, it can be administered in the form of multiple single doses. A single dose can preferably contain a compound of the present invention in an amount of about 0.001 to about 30, especially 0.001 to 3 mg/kg body weight.

An effective amount or therapeutically effective amount or dose of an agent (e.g., a compound of the present invention) refers to the amount of the agent or compound that causes an improvement in symptoms or a prolongation of survival in an individual. The toxicity and therapeutic efficacy of the molecule can be determined by standard pharmaceutical procedures in cell culture or experimental animals, such as by determining the LD50 (the dose that kills 50% of the population) and the ED50 (the dose that is therapeutically effective for 50% of the population). The dose ratio of toxic effects to therapeutic effects is the therapeutic index, which can be expressed as LD50/ED50. Agents that show a high therapeutic index are preferred.

An effective dose or therapeutically effective dose is the amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human being that is being sought by a researcher, veterinarian, physician or other clinician. The dose is preferably within a range of circulating concentrations that include the ED50 with minimal or no toxicity. The dose may vary within this range, depending on the dosage form used and/or the route of administration used. The correct formulation, route of administration, dose and dosing interval should be selected according to methods known in the art, taking into account the particularities of the individual condition.

Dosage and interval may be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect; the minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated, for example, from in vitro data and animal experiments. The dose necessary to achieve the MEC will depend on individual characteristics and route of administration. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

The amount of the agent or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the affliction, the route of administration and the judgment of the prescribing physician.

When desired, the compositions of the present invention may be provided in a package or dispensing device containing one or more unit dosage forms (containing the active ingredient). For example, the package or device may comprise metal or plastic foil (such as a blister pack) or glass and a rubber stopper. The package or dispensing device may be accompanied by instructions for use. Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

The compounds of the present invention have good safety. The maximum tolerated dose of repeated administration in mice for 14 days showed that compound 62 is highly safe. In particular, the maximum tolerated dose of compound 36 for repeated administration for 14 days showed that it was more than 2.7 times that of compound 62. In particular, its safety window was more than 230 times that of the equivalent dose, which is highly safe.

In addition, the compound 36 of the present invention has a smaller CYP3A4 inhibitory effect, which can reduce the contraindications of Finerenone. It also has a lower heart/kidney AUC (tissue distribution) ratio than Finerenone, which is significantly helpful in reducing the side effects of Finerenone.

The compounds of the invention are suitable for the prevention and/or treatment of various disorders and disease-related conditions, in particular disorders characterized by an increased plasma aldosterone concentration or a change in the plasma aldosterone concentration relative to the plasma renin concentration, or disorders associated with these changes. Examples that may be mentioned are: spontaneous primary aldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenomas and/or adrenal carcinomas, hyperaldosteronism associated with cirrhosis of the liver, hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with primary hypertension, etc.

Due to their mechanism of action, the compounds of the invention are also suitable for preventing sudden cardiac death in patients at increased risk of death from sudden cardiac death. These patients are in particular patients suffering from one 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 heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathy (such as Bmgada syndrome), heart disease caused by Chagas disease, Myopathy, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disturbances, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, hypertrophic changes of the heart, pulmonary hypertension, coronary and peripheral artery spasms, thrombosis, thromboembolic disorders and vasculitis.

The compounds of the invention can furthermore be used for the prevention and/or treatment of edema formation, for example pulmonary edema, renal edema or floating lung associated with heart failure, and restenosis, for example after thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and coronary angioplasty (PTCA), heart transplantation and bypass surgery.

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

The compounds of the present invention are also suitable for the treatment of kidney diseases such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic nephropathy, for the prevention of kidney damage (e.g., kidney damage caused by immunosuppressants (e.g., cyclosporin A) associated with organ transplantation) and for kidney cancer.

The compounds of the present invention may additionally be used for the prevention and/or treatment of diabetes and diabetic sequelae, such as neuropathy and nephropathy.

The compounds of the present invention may further be used for the prevention and/or treatment of microalbuminuria, e.g. caused by diabetes or hypertension, and proteinuria.

The compounds according to the invention are also suitable for the prevention and/or treatment of disorders which are associated with an increased plasma glucocorticoid concentration or with a local increase in the glucocorticoid concentration in tissues (e.g. the heart). Examples which may be mentioned are: adrenal gland disorders leading to an overproduction of glucocorticoids (Cushing's syndrome), adrenocortical tumors leading to an overproduction of glucocorticoids, and pituitary tumors which autonomously produce ACTH (adrenotrophic hormone) leading to adrenal hyperplasia and Cushing's disease.

The compounds of the present invention may additionally be used for the prevention and/or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

The compounds of the present invention can further be used for the prevention and/or treatment of inflammatory diseases caused, for example, by viruses, spirochetes, fungi, bacteria or mycobacteria, and inflammatory diseases of unknown etiology, such as polyarthritis, lupus erythematosus, periarthritis or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.

The compounds of the present invention may further be used to treat central nervous system disorders, such as depression, anxiety and chronic pain, especially migraine, and neurodegenerative disorders, such as Alzheimer's disease and Parkinson's syndrome.

The compounds of the present invention are also suitable for the prevention and/or treatment of vascular damage, for example, vascular damage after reocclusion or restenosis after percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angioscopy, bypass surgery, and endothelial dysfunction, Raynaud's disease, thromboangiitis (Buerger's syndrome) and tinnitus syndrome.

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 a medicament comprising at least one compound of the present invention and one or more other active ingredients (particularly for the treatment and/or prevention of the above-mentioned conditions), particularly for the combined use of a medicament for the treatment and/or prevention of the diseases described in the present invention. Suitable active ingredients for combination include, but are not limited to: active ingredients that lower blood pressure, for example and preferably selected from calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers and Rho kinase inhibitors; diuretics, especially loop diuretics, and thiazides and thiazide diuretics; agents with antithrombotic effects, for example and preferably selected from platelet aggregation inhibitors, anticoagulants or or fibroblasts; active ingredients that alter lipid metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors such as and preferably HMG-coenzyme A reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, bile acid reabsorption inhibitors and lipoprotein (a) antagonists; organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, morphine or SIN-1, and adsorbents. NO that is released by the mitochondria; compounds with positive inotropic effects, such as cardiac glycosides (digoxin), isoproterenol, epinephrine, norepinephrine, dopamine and dobutamine; compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 1, 2, 3, 4 and/or 5 inhibitors (such as sildenafil, vardenafil, tadalafil, amrinone and milrinone); diuretic peptides, such as atrial natriuretic peptide, type B Natriuretic peptide or brain natriuretic peptide, C-type natriuretic peptide (CNP) and urotensin; calcium sensitizers, for example and preferably levosimendan; NO-independent but heme-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, in particular WO 01/19355, WO 01/19776, WO 01/19778, WO 02/070462 and WO 02/070510; human neutrophil elastase (HNE) inhibitors, such as cilicestone or DX-890 (Reltran); compounds that inhibit signal transduction cascades, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and/or compounds that affect cardiac energy metabolism, such as etomoxir, dichloroacetate, ranolazine or trimetazidine.

The compounds of the present invention can also be administered in combination with other active ingredients other than the above-mentioned active ingredients. For example, in a preferred embodiment of the present invention, the compounds of the present invention are administered in combination with diuretics such as chloranil, bumetanide, torsemide, bendroflumethiazide, chlordiazepoxide, dihydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlorothiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorobenzenesulfonamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

The beneficial effects of the present invention are: a new compound is proposed, which can be used as a halocorticoid receptor inhibitor, has a good half-inhibitory concentration, and can effectively treat and prevent diabetic nephropathy, hypertension, heart failure, other cardiovascular diseases and other aldosterone-related diseases.

The present invention will be further described below in conjunction with the attached drawings and specific implementation methods, and the above and/or other advantages of the present invention will become clearer.

Figure 1 is an asymmetric unit diagram of the crystal structure of compound 36.

Figure 2 is a single cell diagram of the crystal structure of compound 36.

Figure 3 is the crystal structure filling diagram of compound 36.

Figure 4 is a comparison of the calculated and experimental XRPD patterns of the crystal of compound 36.

Figure 5 is an asymmetric unit cell diagram of the crystal structure of compound 62.

Figure 6 is a single cell diagram of the crystal structure of compound 62.

Figure 7 is a filling diagram of the crystal structure of compound 62.

Figure 8 is a comparison of the calculated and experimental XRPD patterns of the crystal of compound 62.

Figure 9 Single crystal micrograph of compound 36.

Figure 10 is a single crystal micrograph of compound 62.

In this specification, if there is any difference between the chemical name and the chemical structure, the structure prevails.

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are used to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the present invention, and that other methods for preparing compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some routine modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the present invention.

In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification; general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

Anhydrous tetrahydrofuran, dioxane, toluene, and ether are obtained by reflux drying over metallic sodium. Anhydrous dichloromethane and chloroform are obtained by reflux drying over calcium hydroxide. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide are used after being dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or in a drying tube over anhydrous solvent (unless otherwise indicated), reaction bottles are plugged with appropriate rubber stoppers, and substrates are injected via syringe. All glassware is dried.

The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The NMR spectroscopic data were measured by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer, using CDCl3, DMSO-d6, CD3OD or Acetone-d6 as solvent (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. 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).

Low-resolution mass spectrometry (MS) data were measured by an Agilent 6320 series LC-MS spectrometer 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 used for analysis, and an ESI source was applied to the LC-MS spectrometer.

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

Both spectrometers were equipped with Agilent Zorbax SB-C18 columns with specifications of 2.1×30mm, 5μm. The injection volume was determined by the sample concentration; the flow rate was 0.6mL/min; the HPLC peak was recorded and read by UV-Vis wavelengths at 210nm and 254nm. The mobile phase was 0.1% formic acid acetonitrile solution (phase A) and 0.1% formic acid ultrapure water solution (phase B). The gradient elution conditions are shown in Table 1:

The following abbreviations are used throughout the present invention: DMSO- _d6 -deuterated dimethyl sulfoxide; g gram; mg milligram; mol mole; mmol millimole; mL milliliter; μL microliter.

The following reaction schemes describe the steps for preparing the compounds disclosed in the present invention. Unless otherwise specified, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ , and R ₉ all have the meanings as 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 solvent inert to the reaction includes but is not limited to the solvents involved in the embodiments of the present invention or their substitutes.

The preparation method of 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid described in the following examples is as follows:

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

Step 1) 4-(4-cyano-2-methoxyphenyl) -N- (2,2-dimethoxyethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (150 mg, 0.395 mmol), 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (180 mg, 0.474 mmol), N , N -diisopropylethylamine (102 mg, 0.790 mmol) and N,N -dimethylformamide (1.5 ml) were added to an 8 ml vial at room temperature. The reaction was allowed to proceed at room temperature for 2 hours. Aminoacetaldehyde dimethanol (83 mg, 0.790 mmol) was added. The reaction was allowed to proceed at room temperature overnight. The reaction was quenched by adding water (15 ml). The mixture was extracted with ethyl acetate (10 ml x 3 times), the organic phases were combined, 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 obtain a light yellow solid (86 mg, yield 47.0%).

MS (ESI) M/Z: 467.6 [M+H] ⁺

Step 2) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl- N- (2-oxoethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Add 4-(4-cyano-2-methoxyphenyl) -N- (2,2-dimethoxyethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (65 mg, 0.139 mmol), acetone (6 ml) and 12.0M 36% concentrated hydrochloric acid solution (42 μl) to a 25 ml single-necked bottle at room temperature. React at room temperature for 1 hour. Add saturated sodium bicarbonate aqueous solution to adjust pH to 7 under ice bath. Extract with ethyl acetate (10 ml × 3 times), combine the organic phases, wash with saturated brine (10 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol (v/v) = 10/1) to obtain a light yellow solid (25 mg, yield 42.7%).

MS (ESI) M/Z: 421.5 [M+H] ⁺

Step 3) 4-(5-ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile

Add 4-(4-cyano-2-methoxyphenyl)-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 phosphorus oxychloride (40.0 μl) to an 8 ml vial at room temperature. Heat to 120 degrees Celsius for 1 hour. Cool to room temperature, add water (2 ml), extract with ethyl acetate (2 ml x 3 times), combine the organic phases, wash with saturated brine (2 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by preparative HPLC (purification conditions were as follows: chromatographic column: XBridge Prep C18 OBD 30 mm * 150 mm, 5 μm; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 60 ml/min; gradient: acetonitrile increased from 37% to 52% in 7 minutes; detection wavelength: 254/220 nm) to obtain a white solid (1.7 mg, yield 8.8%).

MS (ESI) M/Z: 403.50 [M+H] ⁺

¹ H NMR(400MHz,Chloroform- d )δ 7.72(s,1H),7.50(s,1H),7.42(d, J =7.8Hz,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).

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

Step 1) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide

4-(4-cyano-2-methoxyphenyl)-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 -dimethylformamide (0.05 ml) were added to an 8 ml vial at room temperature. After nitrogen substitution, oxalyl chloride (0.1 ml) was added dropwise under ice-water bath. After addition, the reaction was 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 solution at room temperature and stirred for 1 hour. Water (10 ml) was added to the reaction solution, extracted with ethyl acetate (10 ml x 2), the organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain a dark yellow oil (50 mg, crude product), which was directly used in the next reaction.

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-methoxyphenyl)-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 nitrogen substitution, the mixture was stirred at 120 degrees Celsius for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative plate (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain a white solid (2.5 mg, 6.92%)

MS (ESI) M/Z: 403.95 [M+H] ⁺

¹ H NMR(400MHz,Chloroform- d )δ 8.24(s,1H),7.71(s,1H),7.42(d, J =7.8Hz,1H),7.13(d, J =7.8Hz,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 =6.8Hz,3H).

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

4-(4-cyano-2-methoxyphenyl)-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 nitrogen substitution, 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 by preparative plate (petroleum ether/ethyl acetate (v/v) = 2:1) to obtain a white solid (1.9 mg, 8.93%).

MS (ESI) M/Z: 418.45 [M+H] ⁺

¹ H NMR (300MHz, Chloroform- d ) δ7.71 (s, 1H), 7.39 (d, J =7.5Hz, 1H), 7.12 (dd, J ₁ =7.8Hz, J ₂ =1.5Hz, 1H), 7.00 (d, J =1.5Hz,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 =9.6Hz,3H).

Example 4 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane- 1H -cyclopentylamide S

Step 1) N- (2-cyanocyclopent-1-en-1-yl)acetamide

Add 1-amino-2-cyano-1-cyclopentene (5.00 g, 46.2 mmol) and acetic anhydride (32 ml) to a 100 ml single-mouth bottle at room temperature. React at room temperature overnight. Reduce pressure and concentrate, slurry the residue with petroleum ether (10 ml x 3), and filter to obtain white needle-like crystals (4.80 g, yield 69.1%)

MS (ESI) M/Z: 151.10 [M+H] ⁺

Step 2) 4-amino-1,5,6,7-tetrahydro- 2H -cyclopentylpyridin-2-one

Add N- (2-cyanocyclopent-1-en-1-yl)acetamide (2.40 g, 14.4 mmol) and tetrahydrofuran (50 ml) to a 250 ml three-necked flask at room temperature. After nitrogen replacement, slowly add lithium diisopropylamide (12 ml, 88.6 mmol) at -78 degrees Celsius. React at -78 degrees Celsius for half an hour, then raise the temperature to 80 degrees Celsius and react overnight. Cool to room temperature and quench with saturated aqueous ammonium chloride solution (30 ml). Extract with ethyl acetate (30 ml x 3), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter by suction, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 5/1) to give a light yellow solid (1.25 g, yield 52.1%).

MS (ESI) M/Z: 151.10 [M+H] ⁺

Step 3) 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl- 1H , 4H , 7H , 8H , 9H -cyclopentane[ h ]1,6-naphthyridine-3-carboxylate

4-Amino-1,5,6,7-tetrahydro- 2H -cyclopentylpyridin-2-one (1.00 g, 6.66 mmol), 2-cyanoethyl-2-[(4-cyano-2-methoxyphenyl)methylene]-3-oxobutanoate (2.18 g, 7.33 mmol), isopropanol (20 ml) and acetic acid (19 μl) were added to a 50 ml single-necked bottle at room temperature. After nitrogen substitution, the reaction was carried out at 90 degrees Celsius overnight. The mixture was cooled to room temperature and filtered. The obtained solid was slurried with methyl tert-butyl ether (5 ml × 3) and filtered to obtain a yellow solid (1.70 g, 60.4%).

Step 4) 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl- 1H , 4H , 7H , 8H , 9H -cyclopentane[ h ]1,6-naphthyridine-3-carboxylate

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl- 1H , 4H , 7H , 8H , 9H -cyclopentane[ h ]1,6-naphthyridine-3-carboxylate (1.70 g, 4.02 mmol), iodomethane (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 one-mouth bottle at room temperature. After nitrogen substitution, the reaction was carried out 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 × 3 times), and the organic phases were combined, washed with saturated brine (50 ml), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by preparative HPLC. The purification conditions were as follows: chromatographic 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: acetonitrile increased from 30% to 50% in 15 minutes; detection wavelength: 254 nm. A yellow solid (460 mg, yield 25.0%) was obtained.

Step 5) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane[ h ][1,6]naphthyridine-3-carboxylic acid

2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl- 1H , 4H , 7H , 8H , 9H -cyclopentane[ 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-necked bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust the pH to 5. The mixture was extracted with ethyl acetate (15 ml × 3 times), the organic phases were combined, washed with saturated brine (15 ml × 3 times), and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure. The obtained residue is purified by preparative HPLC. The purification conditions are as follows: chromatographic column: C18 silica gel column; mobile phase A: water (containing 0.04% ammonia water) and mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: acetonitrile increased from 15% to 40% in 20 minutes; detection wavelength: 254 nm. Collect the product and freeze-dry under reduced pressure.

Obtained light yellow solid (40 mg, yield 10.3%)

Step 6) 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl- 1H , 4H , 7H , 8H , 9H -cyclopentane-1,6-naphthyridine-3-carbonitrile

4-(4-cyano-2-methoxyphenyl)-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 -dimethylformamide (1.5 ml) and 2-(7-azobenzotriazole)-N ,N,N',N'- tetramethyluronium hexafluorophosphate (19 mg, 0.119 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out at room temperature for 1 hour. Ammonia in 1,4-dioxane (1.0 M, 0.5 ml) solution was added to the reaction solution at room temperature. The reaction was carried out at 60 degrees Celsius for 3 hours. Cool to room temperature and add water (15 ml) to quench. Extract with ethyl acetate (15 ml × 3 times), combine the organic phases, wash with saturated brine (15 ml × 3 times), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting residue is purified by preparative HPLC. The purification conditions are as follows: chromatographic column: Sunfire prep C18; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: acetonitrile increased from 20% to 42% in 7 minutes; detection wavelength: 254 nm. Collect the product and freeze-dry under reduced pressure. A white solid (9.0 mg, yield 22.6%) is obtained.

MS (ESI) M/Z: 405.45 [M+H] ⁺

¹ H NMR (400MHz, DMSO- d6 ) δ8.05(s,1H),7.36(s,1H),7.28(d, J =7.6Hz,1H),7.15(d, J =7.6Hz,1H),6.65(s,1H),5.33(s,1H),4.03-3.97(m,2H),3.83(s,3H),2.76(t, J =7.2Hz,1H),2.68(t, J =7.2Hz,1H),2.17(s,3H),2.08-1.90(m,2H),1.04(t, J =7.2Hz,3H).

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

In an 8 ml vial, add 2,3-dihydro-4-indanamine (12 mg, 0.0890 mmol), 4-cyano-2-methoxybenzaldehyde (24 mg, 0.150 mmol), sodium 1-cyanopropene-2-valerate (16 mg, 0.150 mmol) and glacial acetic acid (9 μl) in isopropanol (0.5 ml) at room temperature. After nitrogen substitution, heat to 90 degrees Celsius and react overnight. Cool to room temperature. The residue was concentrated under reduced pressure and 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, 15% B to 50% B in 15 minutes, monitoring wavelength 254 nm), to obtain a light yellow solid (2.3 mg, yield 4.5%).

MS (ESI) M/Z: 340.25 [MH] ^-

^1H NMR(400MHz,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).

Example 6 4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Step 1) 2-allyloxy-4-bromobenzoic acid methyl ester

Add methyl 4-bromo-2-hydroxybenzoate (5.00 g, 21.6 mmol), potassium carbonate (5.98 g, 43.3 mmol), N,N-dimethylformamide (50 ml) and 3-bromopropylene (3.75 g, 43.3 mmol) to a 250 ml one-mouth bottle at room temperature. Heat to 80 degrees Celsius and react for 2 hours. Cool to room temperature. Add water (300 ml) to quench. Extract with ethyl acetate (500 ml x 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain a yellow solid (4.32 g, yield 69.9%).

LCMS (ESI, m/z): 271.0 [M+H] ⁺

Step 2) 3-allyl-4-bromo-2-hydroxybenzoic acid methyl ester

Add methyl 2-allyloxy-4-bromobenzoate (4.19 g, 15.5 mmol) and N -methylpyrrolidone (30 ml) to a 250 ml single-mouth bottle at room temperature. Heat to 200 degrees Celsius for 4 hours. Cool to room temperature. Quench with water (300 ml). Extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain a colorless oil (2.66 g, yield 63.4%).

LCMS (ESI, m/z): 271.1 [M+H] ⁺

Step 3) 4-bromo-2-hydroxy-3-(3-hydroxypropyl)benzoic acid methyl ester

Add methyl 3-allyl-4-bromo-2-hydroxybenzoate (4.19 g, 15.5 mmol) and N -methylpyrrolidone (30 ml) to a 250 ml single-mouth bottle at room temperature. Heat to 200 degrees Celsius for 4 hours. Cool to room temperature. Quench with water (300 ml). Extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain a colorless oil (2.31 g, yield 83.3%).

LCMS (ESI, m/z): 289.1 [M+H] ⁺

Step 4) 5-bromochrome-8-carboxylic acid methyl ester

Add 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) to a 100 ml single-necked bottle at room temperature. After nitrogen replacement, diethyl azodicarboxylate (3.34 g, 19.2 mmol) was slowly added dropwise under ice bath. The reaction was allowed to proceed overnight at room temperature. Cooled to room temperature. Quenched by adding water (100 ml). Extracted with ethyl acetate (100 ml x 3), the organic phases were combined, washed with saturated brine (100 ml), and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain a yellow oil (1.67 g, yield 77.1%).

LCMS (ESI, m/z ): 271.1[M+H] ⁺

Step 5) 5-cyanochromium-8-carboxylic acid methyl ester

Add 5-bromochrome-8-carboxylic acid methyl ester (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) in a 50 ml one-mouth bottle at room temperature. Replace with nitrogen, heat to 120 degrees Celsius and react for 2 hours. Cool to room temperature. Add aqueous solution (100 ml) to quench. Extract with ethyl acetate (100 ml x 3), combine the organic phases, wash with saturated brine (100 ml), and dry over anhydrous sodium sulfate. The product 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, yield 73.3%).

LCMS (ESI, m/z): 218.1 [M+H] ⁺

Step 6) 8-Hydroxymethyl-5-chromium nitrile

Add methyl 5-cyanochromium-8-carboxylate (860 mg, 3.96 mmol), tetrahydrofuran (10 ml) and tetrahydrofuran solution of lithium borohydride (3.96 ml, 2.0 mol/L, 7.92 mmol) to a 50 ml single-necked bottle at room temperature. Replace with nitrogen, heat to 60 degrees Celsius and react for 15 minutes. Cool to room temperature. Add water (30 ml) to quench. Extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a yellow oil (450 mg, yield 60.1%).

LCMS (ESI, m/z): 190.1 [M+H] ⁺

Step 7) 8-Formylchromane-5-carbonitrile

8-Hydroxymethyl-5-chromium nitrile (385 mg, 1.75 mmol), dichloromethane (5 ml) and Desmartin reagent (890 mg, 2.10 mmol) were added to a 25 ml single-necked bottle at room temperature. The reaction was allowed to proceed 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 obtain a yellow solid (280 mg, yield 72.9%).

LCMS (ESI, m/z): 188.1 [M+H] ⁺

Step 8) 2-cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate)

8-Methylchromane-5-carbonitrile (200 mg, 1.07 mmol), 4-amino-5-methylpyridin-2-ol (200 mg, 1.61 mmol), 2-cyanoethyl 3-oxobutyrate (200 mg, 1.29 mmol), isopropanol (5 ml) and acetic acid (90 μl) were added to an 8 ml vial at room temperature. After nitrogen replacement, the reaction was carried out at 90 °C overnight. Cool to room temperature, reduce pressure and concentrate, and purify the residue by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 120g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile, 20% B to 50% B in 15 minutes, monitoring wavelength 254 nm), to obtain a yellow solid (175 mg, yield 36.7%).

LCMS (ESI, m/z): 431.2 [M+H] ⁺

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), iodoethane (95 mg, 0.610 mmol) and 1,4-dioxane (2 ml) were added to an 8 ml vial at room temperature. After nitrogen substitution, the reaction was carried out at 90 °C for 2 hours. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (50 ml). The filtrate was collected, concentrated under reduced pressure, and the residue was purified by C18 reverse phase column chromatography under the following conditions: C18 BIOTAGE 120g reverse phase column, mobile phase A: (0.1% ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile), 15% B to 60% B gradient in 10 minutes, UV 254 nanometer detector, to obtain a light yellow oil (134 mg, yield 71.9%).

LCMS (ESI, m/z): 459.2 [M+H] ⁺

Step 10) 4-(5-cyanocyanine-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-necked bottle at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust the pH to 5. The mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. Filter, reduce pressure and concentrate to obtain a light yellow solid (83 mg, 70.1%), which was used directly in the next reaction without further purification.

LCMS (ESI, m/z): 406.2 [M+H] ⁺

Step 11) 4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

4-(5-cyanocyanine-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 -dimethylformamide (2 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (225 mg, 0.591 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for 1 hour at room temperature. Ammonia aqueous solution (1.0 M, 0.7 ml) was added to the reaction solution at room temperature. The reaction was carried out for 2 hours at room temperature. The filtrate was filtered and purified by preparative high performance liquid chromatography. 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: acetonitrile increased from 25% to 45% in 7 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure. A yellow solid (59.0 mg, yield 73.9%) was obtained.

LCMS (ESI, m/z): 405.25 [M+H] ⁺

¹ H NMR (400MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.56 (s, 1H), 7.18 (d, J =8.0Hz, 1H), 6.94 (d, J =8.0Hz,1H),6.68(s,2H),5.32(s,1H),4.28-4.20(m,2H),4.05(q, J =7.2Hz,1H),2.87(t, J =6.4Hz,2H),2.21(s,3H),2.12(s,3H),2.03-1.94(m,2H),1.10(t, J =7.2Hz,3H).

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

Step 1) tert-Butyl N- (2-bromo-5-methylpyridin-4-yl)carbamate

Add 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) to a 50 ml single-necked bottle at room temperature. React at room temperature for 3 hours. Cool to room temperature. Quench with water (30 ml). Extract with ethyl acetate (30 ml x 3), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. The product was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate (v/v) = 3/1) to obtain a yellow solid (1.05 g, yield 28.3%).

MS (ESI) M/Z: 288 [MH] ^-

Step 2) tert-Butyl N- {5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridin-4-yl}carbamate

At room temperature, tert-butyl N- (2-bromo-5-methylpyridin-4-yl)carbamate (1.0 g, 3.48 mmol), bistriphenylphosphine dichloropalladium (733 mg, 1.05 mmol), cuprous iodide (3.99 g, 2.10 mmol), trimethylethynylsilane (4.51 ml, 34.8 mmol) and tetrahydrofuran (30 ml) were added to a 100 ml single-mouth bottle. After nitrogen substitution, the mixture was heated to 110 degrees Celsius for 2 hours. The mixture was 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 obtain a gray solid (640 mg, yield 56.1%).

MS (ESI) M/Z: 303.20 [MH] ^-

Step 3) 1-amino-4-[tert-butoxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridine-1-salt

Add tert-butyl N-{5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridin-4-yl}carbamate (130 mg, 0427 mmol), dichloromethane (2.5 ml) and amino 2,4,6-trimethylbenzenesulfonate (276 mg, 1.28 mmol) to an 8 ml vial at room temperature. After nitrogen substitution, react at room temperature for 2 hours. Cool to room temperature. Concentrate under reduced pressure, and use methyl tert-butyl ether (5 ml x 3) to obtain a gray solid (120 mg, yield 87.7%).

MS (ESI) M/Z: 319.90 [MH] ^-

Step 4) tert-butyl N- {6-methylpyrazolo[1,5-a]pyridin-5-yl}carbamate

1-Amino-4-[tert-butoxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridinium-1-salt (400 mg, 1.25 mmol), potassium carbonate (345 mg, 2.45 mmol) and N,N-dimethylformamide (4 ml) were added to an 8 ml vial at room temperature. After nitrogen substitution, the mixture was heated to 80 °C for 5 hours and cooled to room temperature. Filter, and purify the filtrate by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 40% B to 90% B in 15 minutes, monitoring wavelength 254 nm, to obtain a gray solid (100 mg, yield 28.2%).

MS (ESI) M/Z: 248.25 [M+H] ⁺

Step 5) 6-methylpyrazolo[1,5- a ]pyridin-5-amine

At room temperature, add tert-butyl N- {6-methylpyrazolo[1,5- a ]pyridin-5-yl}carbamate (200 mg, 0.81 mmol), dichloromethane (4 ml) and trifluoroacetic acid (1 ml) in a 25 ml single-necked bottle. React at room temperature for 2 hours. Concentrate under reduced pressure, dissolve the residue in ethyl acetate (10 ml), wash with saturated aqueous sodium bicarbonate solution (10 ml) and saturated brine (10 ml) in sequence, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a gray solid (100 mg, yield 84.1%).

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

In an 8 ml vial, add 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 μl) in isopropanol (2 ml) at room temperature. After replacing the atmosphere with nitrogen, heat to 90 degrees Celsius and react overnight. Cool to room temperature. The product was concentrated under reduced pressure, and the 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), 15% B to 45% B in 15 minutes, monitoring wavelength 254 nm, to obtain a white solid (7 mg, yield 3.4%).

LCMS (ESI, m/z): 356.15 [M+H] ⁺

¹ H NMR (400MHz, DMSO- d 6) δ 8.70 (s, 1H), 8.41 (s, 1H), 7.68 (s, 1H), 7.52 (s, 1H), 7.33 (d, J =8.0Hz, 1H), 7.26 (d, J =8.0Hz,1H),5.92(s,1H),5.46(s,1H),3.95(s,3H),2.30(s,3H),2.20(s,3H).

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

Step 1) Sodium 1-cyanoacrylate-2-carboxylate

Sodium methanol (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-necked 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 was formed. The solid was filtered and slurried with methanol (15 ml). A yellow solid (3.10 g, yield 84.7%) was obtained by filtration.

Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile

Add sodium 1-cyanopropene-2-acid (3.00 g, 28.6 mmol), 4-methyl-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) to a 100 ml single-necked bottle at room temperature. After nitrogen replacement, heat to 60 degrees Celsius and react overnight. Cool to room temperature. Concentrate under reduced pressure, slurry the residue with ethyl acetate (10 ml x 5), and filter to obtain a yellow solid (2.50 g, yield 38.8%).

MS (ESI) M/Z: 227.95 [M+H] ⁺

Step 3) 4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3- b ]pyridine-3-carbonitrile

Add 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 μL) in isopropanol (0.5 mL) to an 8 mL vial at room temperature. After replacing the atmosphere with nitrogen, heat to 80 °C for 1 hour and cool to room temperature. The residue was concentrated under reduced pressure and purified by preparative HPLC (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 minutes, 68% B; wavelength: 254/220 nm; peak time (min): 6.90;) to obtain a white solid (22.3 mg, yield 18.1%).

MS (ESI) M/Z: 356.05 [MH] ^-

^1H NMR(400MHz,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).

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

Step 1) N- (2-cyanocyclopent-1-en-1-yl)acetamide

Add 3-hydroxy-1-methylpyrazole-5-carboxylic acid methyl ester (2.30 g, 14.7 mmol), iodoethane (3.40 g, 22.1 mmol), potassium carbonate (2.00 g, 14.7 mmol) and N,N -dimethylformamide (25 ml) to a 100 ml single-mouth bottle at room temperature. After nitrogen replacement, heat to 60 degrees Celsius for 5 hours. Cool to room temperature. Add water (30 ml) to quench. Extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a light yellow oil (2.30 g, yield 84.7%).

LCMS (ESI, m/z): 185.10 [M+H] ⁺

Step 2) 3-ethoxy-1-methylpyrazole-5-carboxylic acid

Add N- (2-cyanocyclopent-1-en-1-yl)acetamide (2.30 g, 12.5 mmol), tetrahydrofuran (15 ml) and a saturated aqueous solution of lithium hydroxide (15 ml) to a 100 ml single-necked bottle at room temperature. React at room temperature for 3 hours. Add dilute hydrochloric acid solution (1.0 mol/L) to quench and adjust to pH = 5. Extract with ethyl acetate (30 ml × 3 times), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a white solid (2.00 g, yield 94.1%).

LCMS (ESI, m/z): 171.10 [M+H] ⁺

Step 3) tert-Butyl (3-ethoxy-1-methylpyrazol-5-yl)carbamate

Add 3-ethoxy-1-methylpyrazole-5-carboxylic acid (2.00 g, 11.7 mmol), triethylamine (3.57 g, 35.3 mmol) and tert-butanol (15 ml) to a 100 ml single-necked bottle at room temperature. After nitrogen substitution, slowly add diphenyl azidophosphate (4.85 g, 17.6 mmol). Heat to 80 degrees Celsius and react overnight. Cool to room temperature. Add water (20 ml) to quench. Extract with ethyl acetate (30 ml × 3 times), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40g 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, and a white solid (1.60g, yield 56.4%) was obtained.

LCMS (ESI, m/z): 242.20 [M+H] ⁺

Step 4) 3-ethoxy-1-methylpyrazol-5-amine

Add tert-butyl (3-ethoxy-1-methylpyrazol-5-yl) carbamate (800 mg, 3.32 mmol) and hydrogen chloride in 1,4-dioxane (4.0 M, 5 ml) to a 25 ml single-necked bottle at room temperature. Stir overnight at room temperature. Quench with saturated sodium bicarbonate aqueous solution and adjust to pH = 7. Extract with ethyl acetate (50 ml × 3 times), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (405 mg, yield 86.5%).

LCMS (ESI, m/z): 142.10 [M+H] ⁺

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

Add 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 μL) in isopropanol (1 mL) to an 8 mL vial at room temperature. Heat to 80 °C for 2 hours under nitrogen protection. Cool to room temperature and add water (5 mL) to quench. Extract with ethyl acetate (10 mL × 3 times), combine the organic phases, wash with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The 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 ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile), 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm), to obtain a white solid (8.5 mg, yield 7.73%).

MS(ESI)M/Z: 350.20[M+H] ⁺ .

¹ H NMR (300MHz, DMSO- d 6) δ 9.74 (s, 1H), 7.47 (s, 1H), 7.38 (d, J =7.9Hz, 1H), 7.17 (d, J =7.9Hz,1H),5.16(s,1H),3.99-3.78(m,5H),3.80(s,3H),2.13(s,3H),1.03(t, J =7.0Hz,3H).

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

Step 1) Sodium 1-cyanoacrylate-2-carboxylate

Sodium methanol (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-necked 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 was formed. The solid was filtered and slurried with methanol (15 ml). A yellow solid (3.10 g, yield 84.7%) was obtained by filtration.

Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile

Add sodium 1-cyanopropene-2-acid (3.00 g, 28.6 mmol), 4-methyl-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) to a 100 ml single-necked bottle at room temperature. After nitrogen replacement, heat to 60 degrees Celsius and react overnight. Cool to room temperature. Concentrate under reduced pressure, slurry the residue with ethyl acetate (10 ml x 5), and filter to obtain a yellow solid (2.50 g, yield 38.8%).

Step 3) 2-Hydrazino-4-methyl-5-nitropyridine

Add 6-chloro-2-methyl-3-nitropyridine (1.73 g, 10.0 mmol) and 1,4-dioxane (15 ml) to a 100 ml single-necked bottle at room temperature. Add hydrazine hydrate (2.00 g, 40 mmol) under ice-water bath. React at room temperature overnight. Concentrate under reduced pressure. Slurry the residue with water (5 ml) and filter to obtain a light yellow solid (1.30 g, crude product). Use it directly in the next reaction without further purification.

Step 4) 7-methyl-6-nitro[1,2,4]triazolo[4,3- a ]pyridine

Add 2-hydrazino-4-methyl-5-nitropyridine (1.00 g, 5.95 mmol), triethyl orthoformate (2.52 g, 23.8 mmol) and dichloromethane (50 ml) to a 100 ml single-necked bottle at room temperature. Add trifluoroacetic acid (140 mg, 1.19 mmol) under ice-water bath. React at room temperature overnight. Concentrate under reduced pressure to obtain a light yellow solid (900 mg, crude product).

Step 5) 7-methyl-[1,2,4]triazolo[4,3- a ]pyridin-6-amine

Add 7-methyl-6-nitro[1,2,4]triazolo[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) to a 100 ml single-necked bottle at room temperature. Heat to 50 degrees Celsius and react overnight. Cool to room temperature, filter through diatomaceous earth, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether/ethyl acetate (v/v) = 2/1) to obtain a light yellow solid (400 mg, yield 53.5%).

Step 6) 9-(4-cyano-2-methoxyphenyl)-5,7-dimethyl-6,9-dihydro[1,2,4]triazolo[4,3- a ][1,5]naphthyridine-8-carbonitrile

In an 8 ml vial, add 7-methyl-[1,2,4]triazolo[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 μl) in isopropanol (3 ml) at room temperature. After nitrogen substitution, heat to 80 degrees Celsius and react overnight. Cool to room temperature. The product was concentrated under reduced pressure and the 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 obtain a white solid (20.0 mg, yield 16.7%).

MS (ESI) M/Z: 357.15 [M+H] ⁺

¹ H NMR (400MHz, DMSO- d 6) 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).

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

Step 1) 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

Add 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid (10.0 g, 46.9 mmol) and methanol (200 ml) to a 500 ml single-mouth bottle at room temperature. Slowly add dichlorosulfoxide (8.35 g, 61.9 mmol) under ice-water bath. Heat to 70 degrees Celsius and react for 1.5 hours. Cool to room temperature. Add saturated sodium bicarbonate aqueous solution (300 ml) to quench. Extract with ethyl acetate (500 ml x 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (10.5 g, yield 98.5%).

LCMS (ESI, m/z): 228.6 [M+H] ⁺

Step 2) 4-amino-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

Add 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) to a 500 ml sealed tube at room temperature. Heat to 30 degrees Celsius under 3 atmospheres of hydrogen pressure and react overnight. Cool to room temperature. Filter through diatomaceous earth and rinse the filter cake with ethyl acetate (500 ml). Combine the filtrate, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (4.80 g, yield 53.6%).

LCMS (ESI, m/z): 194.2 [M+H] ⁺

Step 3) 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

Add 4-amino-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester (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) to a 50 ml single-necked bottle at room temperature. Replace with nitrogen, heat to 70 degrees Celsius and react for half an hour. Cool to room temperature. Reduce pressure and concentrate, and the residue is purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain a yellow solid (3.50 g, yield 62.8%).

Step 4) 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

In a 50 ml one-necked bottle at room temperature, add 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(di-phenylphosphino)ferrocene (1.37 g, 2.50 mmol) and N -methylpyrrolidone (20 ml). Replace with nitrogen, heat to 120 degrees Celsius and react for 2 hours. Cool to room temperature. Add aqueous solution (100 ml) to quench. Extract with ethyl acetate (100 ml x 3), combine the organic phases, wash with saturated brine (100 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether/ethyl acetate (v/v) = 6:1) to obtain a white solid (2.20 g, yield 86.6%).

Step 5) 7-Hydroxymethyl-2,3-dihydro-1-benzofuran-4-carbonitrile

Add methyl 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylate (1.80 g, 8.86 mmol), tetrahydrofuran (20 ml) and tetrahydrofuran solution of lithium borohydride (6.54 ml, 2.0 mol/L, 13.3 mmol) to a 50 ml single-necked bottle at room temperature. Replace with nitrogen, heat to 60 degrees Celsius and react for 20 minutes. Cool to room temperature. Add water (50 ml) to quench. Extract with ethyl acetate (50 ml x 3), combine the organic phases, wash with saturated brine (50 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a white solid (960 mg, yield 61.9%).

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 Dessmartin reagent (3.24 g, 7.04 mmol) were added to a 25 ml single-necked bottle at room temperature. Nitrogen was replaced and the reaction was carried out 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 obtain a yellow solid (800 mg, yield 70.2%).

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-Methylyl-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-oxobutyrate (100 mg, 0.645 mmol), isopropanol (2.5 ml) and acetic acid (45 μl) were added to an 8 ml vial at room temperature. After nitrogen substitution, the reaction was carried out at 90 °C overnight. Cool to room temperature, reduce pressure and concentrate, and purify the residue by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (10 mmol/L ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile, 30% B to 50% B in 15 minutes, monitoring wavelength 254 nm), to obtain a yellow solid (110 mg, yield 45.7%).

LCMS (ESI, m/z): 417.4 [M+H] ⁺

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), iodoethane (75 mg, 0.480 mmol) and 1,4-dioxane (3 ml) were added to an 8 ml vial at room temperature. After nitrogen substitution, the reaction was carried out at 90 °C for 1 hour. The mixture was cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (50 ml). The filtrate was collected and concentrated under reduced pressure to obtain a yellow solid (110 mg, yield 45.7%), which was directly used in the next reaction without further purification.

LCMS (ESI, m/z): 445.20 [M+H] ⁺

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 an aqueous solution (0.3 ml) of sodium hydroxide (18 mg, 0.450 mmol) were added to an 8 ml single-necked bottle at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust the pH to 5. The mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. Filter, reduce pressure and concentrate to obtain a light yellow solid (80 mg, 90.7%), which was used directly in the next reaction without further purification.

LCMS (ESI, m/z): 392.4 [M+H] +

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 -dimethylformamide (1 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.245 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for 1 hour at room temperature. Ammonia aqueous solution (1.0 M, 0.5 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The filtrate was filtered and purified by preparative high performance liquid chromatography. 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: acetonitrile increased from 20% to 40% in 7 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure. A yellow solid (45.0 mg, yield 56.1%) was obtained.

LCMS (ESI, m/z): 391.10 [M+H] ⁺

¹ H NMR(400MHz, DMSO- d 6)δ 7.70(s,1H),7.55(s,1H),7.11(d, J =8.0Hz,1H),6.98(d, J =8.0Hz,1H),6.71(s,2H),5.18(s,1H),4.63(t, J =8.8Hz,2H),4.04(q, J =6.8Hz,2H),3.40(t, J =8.8Hz,2H),2.11(s,3H),2.07(s,3H),1.10(t, J =6.8Hz,3H).

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

Step 1) 2-ethoxyquinolin-4-amine

Add 2-chloroquinolin-4-amine (200 mg, 1.12 mmol), sodium ethoxide (305 mg, 4.48 mmol) and ethanol (2.5 ml) to a 10 ml microwave tube at room temperature. Heat the mixture to 140 °C for 1 hour. Cool to room temperature. Concentrate under reduced pressure, dissolve the residue in ethyl acetate (100 ml), wash with saturated brine (100 ml), and dry over anhydrous sodium sulfate. Filter under vacuum and concentrate under reduced pressure. The residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40g reverse phase column, mobile phase A (0.1% ammonia water) and mobile phase B (acetonitrile), 25% B to 35% B in 10 minutes, monitoring wavelength 254 nm), to obtain a white solid (75 mg, yield 35.6%).

MS (ESI) M/Z: 189 [M+H] ⁺

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

Add 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 μl) in isopropanol (2 ml) to an 8 ml vial at room temperature. After nitrogen substitution, heat to 80 degrees Celsius and react overnight. Cool to room temperature. The residue was concentrated under reduced pressure and purified by HPLC preparative column: column model YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 55% B to 85% B in 7 minutes; wavelength: 254/220 nm: peak time (min): 6.15, fractions were collected and lyophilized under reduced pressure to obtain a white solid (48.8 mg, yield 30.7%).

MS (ESI) M/Z: 397.15 [M+H] ⁺

¹ H NMR (400MHz, DMSO- d 6)δ 9.60 (s, 1H), 8.36 (d, J =8.4Hz, 1H), 7.63 (d, J = 3.9Hz, 2H), 7.52-7.41 (m, 2H), 7.29-7.33 (m, 1H), 7.12 (d, J =7.9Hz,1H),5.37(s,1H),4.23-4.13(m,2H),3.87(s,3H),2.23(m,3H),1.04(t, J =7.0Hz,3H).

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

Step 1) N- (2-cyanothiophene-3-yl)acetamide

Add 3-amino-2-cyano-thiophene (1.00 g, 8.05 mmol) and acetic anhydride (10 ml) to a 50 ml single-necked bottle at room temperature. React at room temperature overnight. Reduce pressure and concentrate, slurry the residue with petroleum ether (30 ml), filter, and obtain a white solid (1.20 g, yield 89.6%)

LCMS (ESI, m/z): 167.0 [M+H] ⁺

Step 2) 7-aminothieno[3,2- b ]pyridin-5-ol

Add N- (2-cyanothiophene-3-yl)acetamide (1.20 g, 7.22 mmol) and tetrahydrofuran (24 ml) to a 100 ml three-necked flask at room temperature. After nitrogen replacement, slowly add lithium diisopropylamide (6 ml, 44.3 mmol) at -78 degrees Celsius. React at -78 degrees Celsius for half an hour, then heat to 80 degrees Celsius for 1 hour. Cool to room temperature and quench with saturated aqueous ammonium chloride solution (10 ml). Extract with ethyl acetate (15 ml x 3), combine the organic phases, wash with saturated brine (15 ml), and dry over anhydrous sodium sulfate. Filter by suction, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 5/1) to obtain a light yellow solid (650 mg, yield 54.2%).

LCMS (ESI, m/z): 167.0 [M+H] ⁺

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-oxobutanoic acid (359 mg, 1.20 mmol), isopropanol (25 ml) and acetic acid (450 μl) were added to a 50 ml single-necked bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. The mixture was cooled to room temperature and filtered. The obtained solid was slurried with ethyl acetate (15 ml x 3), filtered to obtain a crude product, and purified by C18 reverse phase column chromatography under the following conditions: C18 BIOTAGE 330 g chromatography column, mobile phase A (0.1% FA aqueous solution) and mobile phase B (acetonitrile), 15% B to 50% B gradient for 15 minutes, monitoring wavelength 254 nm, and obtaining a light yellow solid (1.09 g, yield 45.4%).

LCMS (ESI, m/z): 447.1 [M+H] ⁺

Step 4) 2-cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2- h ][1,6]naphthyridine-7-carboxylate

2-Cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-hydroxy-8-methyl-6,9-dihydrothieno[3,2 -h ][1,6]naphthyridine-7-carboxylate (195 mg, 0.437 mmol), iodomethane (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-necked bottle at room temperature. After nitrogen substitution, the reaction was carried out at 90 °C for 2 hours. The mixture was cooled to room temperature and quenched by adding a saturated aqueous ammonium chloride solution (5 ml). The mixture was extracted with ethyl acetate (10 ml × 3 times), and the organic phases were combined, washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Filter, concentrate under reduced pressure. The residue was purified by C18 reverse phase column. Purification conditions were as follows: chromatographic column: BIOTAGE C18 reverse phase column 120 g; mobile phase A: water (containing 0.1% ammonium bicarbonate aqueous solution) and mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: acetonitrile increased from 20% to 60% in 15 minutes; detection wavelength: 254 nm. A white solid (120 mg, yield 57.9%) was obtained.

LCMS (ESI, m/z): 475.1 [M+H] ⁺

Step 5) 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2- h ][1,6]naphthyridine-7-carboxylic acid

2-Cyanoethyl 6-(4-cyano-2-methoxyphenyl)-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-necked bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust the pH to 5. Extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (15 ml × 3 times), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC. The purification conditions were as follows: chromatographic 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: acetonitrile increased from 10% to 40% in 10 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. A white solid (111 mg, yield 80.6%) was obtained.

LCMS (ESI, m/z): 422.1 [M+H] ⁺

Step 6) 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2- h ][1,6]naphthyridine-7-carboxamide

6-(4-cyano-2-methoxyphenyl)-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-dimethylformamide (2 ml) and 2-(7-azobenzotriazole)-N, N , N' ,N' -tetramethyluronium hexafluorophosphate (284 mg, 0.747 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia (0.8 ml) solution was added to the reaction solution at room temperature. The reaction was carried out for 3 hours at room temperature. Water (10 ml) was added to quench the reaction. Extract with ethyl acetate (10 ml x 3 times), combine the organic phases, wash with saturated brine (10 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained residue is purified by preparative HPLC. The purification conditions are as follows: chromatographic column: Sunfire prep C18; mobile phase A: water (containing 0.1% ammonium bicarbonate aqueous solution) and mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: acetonitrile increased from 18% to 50% in 7 minutes; detection wavelength: 254 nm. Collect the product and freeze-dry under reduced pressure. A white solid (47.0 mg, yield 44.9%) was obtained.

LCMS (ESI, m/z): 421.0 [M+H] ⁺

¹ H NMR(400MHz, DMSO-d6)δ 8.83(s,1H),7.88(d, J =5.4Hz,1H),7.38(d, J =1.5Hz,1H),7.29-7.22(m,2H),7.18(d, J =7.9Hz,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=7.0Hz,3H).

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

Step 1) Diethyl 2,3-dihydroxyterephthalate

Add 2,3-dihydroxyterephthalic acid (260 g, 1.31 mol) and ethanol (2.60 liters) to a 10-liter four-necked flask at room temperature. Slowly add dichlorosulfoxide (908 g, 7.63 mol) at 0 degrees Celsius, and react at 70 degrees Celsius overnight. Cool to room temperature, slowly add the reaction solution to a saturated sodium bicarbonate aqueous solution (5.20 liters) to quench. Extract with ethyl acetate (5.00 liters × 3), combine the organic phases, wash with saturated brine (3.00 liters), and dry over anhydrous sodium sulfate. Filter, reduce pressure and concentrate to obtain an off-white solid (312 g, yield 93.5%).

MS (ESI) M/Z: 255.1 [M+H] ⁺

Step 2) Diethyl benzo[ d ][1,3]dioxacyclopentene-4,7-dicarboxylate

Add 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 liters) to a 10-liter four-necked flask at room temperature. After nitrogen replacement, react at 90 degrees Celsius overnight. Cool to room temperature and add saturated brine (19.0 liters) to quench. Extract with ethyl acetate (12.0 liters × 3), combine the organic phases, wash with saturated brine (12.0 liters), and dry over anhydrous sodium sulfate. Filter by suction, and concentrate the filtrate under reduced pressure to obtain an off-white solid (289 g, yield 88.4%).

MS (ESI) M/Z: 267.1 [M+H] ⁺

Step 3) 7-Hydroxymethylbenzo[ d ][1,3]dioxacyclopentene-4-carboxylic acid ethyl ester

Benzo[ d ][1,3]dioxacyclopentene-4,7-dicarboxylic acid diethyl ester (289 g, 1.09 mol), tetrahydrofuran (2.90 L) and tetrahydrofuran solution of lithium borohydride (545 mL, 2.0 mol/L, 1.09 mol) were added to a 10 L four-necked flask at room temperature. After nitrogen substitution, the reaction was carried out at 60 °C for 2 hours. The reaction mixture was cooled to 0 °C and slowly added to a saturated aqueous ammonium chloride solution (6.00 L) to quench. The mixture was extracted with ethyl acetate (4.50 L × 3), the organic phases were combined, washed with saturated brine (4.50 L), and dried over anhydrous sodium sulfate. The product was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 7:3) to obtain a white solid (168 g, yield 69.0%).

MS (ESI) M/Z: 225.0 [M+H] ⁺

Step 4) 7-methylbenzo[ d ][1,3]dioxacyclopentene-4-carboxylic acid ethyl ester

Ethyl 7-hydroxymethylbenzo[ d ][1,3]dioxolane-4-carboxylate (168 g, 750 mmol), dichloromethane (1.70 L) and Dessmartin reagent (397 g, 937 mmol) were added to a 3-liter three-necked flask at room temperature. The atmosphere was replaced with nitrogen and the reaction was carried out 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) = 1:1) to obtain a yellow solid (165 g, yield 99.1%).

MS (ESI) M/Z: 223.1 [M+H] ⁺

Step 5) 7-cyanobenzo[ d ][1,3]dioxacyclopentene-4-carboxylic acid ethyl ester

Add ethyl 7-methylbenzo[ d ][1,3]dioxolane-4-carboxylate (165 g, 757 mmol), hydroxylamine hydrochloride (158 g, 2.27 mol) and DMSO (1.00 L) to a 3 L three-necked flask at room temperature. Replace with nitrogen, heat to 90 °C and react for 1 hour. After cooling to room temperature, add saturated brine (10.0 L) to quench. Extract with ethyl acetate (6.00 L × 3), combine the organic phases, wash with saturated brine (6.00 L), and dry over anhydrous sodium sulfate. The product was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 4:1) to obtain a yellow solid (120 g, yield 73.7%).

Step 6) 7-Hydroxymethylbenzo[ d ][1,3]dioxacyclopentene-4-carbonitrile

Ethyl 7-cyanobenzo[ d ][1,3]dioxolane-4-carboxylate (120 g, 548 mmol), tetrahydrofuran (1.20 L) and tetrahydrofuran solution of lithium borohydride (411 mL, 2.0 mol/L, 822 mmol) were added to a 3 L three-necked flask at room temperature. After nitrogen substitution, the reaction was carried out at 60 °C for 2 hours. The reaction mixture was cooled to 0 °C and slowly added to a saturated aqueous ammonium chloride solution (3.20 L) to quench. The mixture was extracted with ethyl acetate (2.50 L × 3), the organic phases were combined, washed with saturated brine (2.50 L), and dried over anhydrous sodium sulfate. The product was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate (v/v) = 5:1) to obtain a white solid (75.0 g, yield 77.3%).

Step 7) 7-Formylbenzo[1,3]dioxacyclopentene-4-carbonitrile

7-Hydroxymethylbenzo[ d ][1,3]dioxolane-4-carbonitrile (75.0 g, 424 mmol), dichloromethane (1.50 L) and Dessmartin reagent (270 g, 636 mmol) were added to a 3-liter three-necked flask at room temperature. After nitrogen substitution, the reaction was carried out 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 obtain a yellow solid (67.0 g, yield 90.4%).

Step 8) 2-Cyanoethyl 4-(7-cyanobenzo[ d ][1,3]dioxacyclopenten-4-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

7-Methylbenzo[1,3]dioxolanecyclopentene-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) were added to a 3-liter three-necked flask at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. Cool to room temperature and filter. The obtained solid was slurried with methyl tert-butyl ether (500 mL × 3) and filtered to obtain a light yellow solid (88.0 g, 56.7%).

MS (ESI) M/Z: 419.2 [M+H] ⁺

Step 9) 2-Cyanoethyl 4-(7-cyanobenzo[ d ][1,3]dioxacyclopenten-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), iodoethane (49.3 g, 316 mmol), silver carbonate (58.1 g, 210 mmol) and 1,4-dioxane (880 ml) were added to a 2-liter three-necked flask at room temperature. After nitrogen substitution, the reaction was carried out at 90°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid (86.5 g, 92.1%).

MS (ESI) M/Z: 447.1 [M+H] ⁺

Step 10) 4-(7-cyanobenzo[ d ][1,3]dioxacyclopent-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, 380 ml) were added to a 3-liter three-necked flask at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. Water (1.50 L) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (1.00 L x 1 time), and the aqueous phase was retained. Under ice bath, hydrochloric acid solution (1.00 mol) was added to quench the mixture and the pH was adjusted to 5. Extract with ethyl acetate (1.00 L × 3 times), combine the organic phases, wash with saturated brine (500 mL × 1 time), and dry over anhydrous sodium sulfate. Filter and concentrate the filtrate under reduced pressure to obtain a light yellow solid (70.0 g, 91.8%), which is directly used in the next reaction.

MS (ESI) M/Z: 394.2 [M+H] ⁺

Step 11) 4-(7-cyanobenzo[d][1,3]dioxolylcyclopentene-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-dimethylformamide (570 ml) and 2-(7-azobenzotriazole)-N, N , N ',N'-tetramethyluronium hexafluorophosphate (92.4 g, 218 mmol) were added to a 2-liter three-necked flask at room temperature. Ammonia aqueous solution (25%) (120 ml) was added to the reaction solution at room temperature. The reaction was carried out at room temperature for 1.5 hours. The reaction solution was purified by preparative high performance liquid chromatography. Purification conditions were as follows: chromatographic column: DAC prep C18; mobile phase A: water (containing 0.1% ammonium bicarbonate) and mobile phase B: acetonitrile; flow rate: 1 L/min; gradient: acetonitrile from 20% to 42% in 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. A white solid (38.0 g, 66.8%) was obtained.

MS (ESI) M/Z: 393.3 [M+H] ⁺

¹ H NMR(400MHz,Chloroform- d )δ 7.68(s,1H),6.91(d, J =8.4Hz,1H),6.78(d, J =8.4Hz,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 =7.0Hz,3H).

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

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), iodocyclopentane (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-necked bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90°C for 2 hours. The reaction mixture was cooled to room temperature, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate (3×10 ml). The filtrate was concentrated under reduced pressure to obtain a yellow solid (110.0 mg, yield 94.5%). MS (ESI) M/Z: 485.5 [M+H] ⁺

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 an aqueous solution (1 ml) of sodium hydroxide (18 mg, 0.454 mmol) were added to an 8 ml single-necked bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust the pH to 5. The mixture was extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (5 ml × 3 times), and dried over anhydrous sodium sulfate. Filter and reduce pressure to concentrate to obtain a light yellow solid (100 mg, yield 93.6%), which is directly used in the next reaction.

MS (ESI) M/Z: 432.5 [M+H] ⁺

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 -dimethylformamide (1.5 ml) and 2-(7-azobenzotriazole) -N,N,N',N' -tetramethyluronium hexafluorophosphate (127 mg, 0.334 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (content 25%) (1.5 ml) was added to the reaction solution at room temperature. The mixture was reacted for half an hour at room temperature. Filter, and purify the filtrate by preparative HPLC. The purification conditions are as follows: chromatographic column: YMC-Actus Triart C18; 30*150 mm, 5 μm; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: acetonitrile from 38% to 55% in 7 minutes; detection wavelength: 254/220 nm. Collect the product and freeze-dry under reduced pressure. A white solid (50.0 mg, yield 55.7%) was obtained.

LCMS (ESI, m/z): 431.1 [M+H] ⁺

¹ H NMR (400MHz, DMSO- d ₆ ) δ 7.67 (s, 1H), 7.56 (s, 1H), 7.12 (d, J =8.0Hz, 1H), 6.95 (d, J =8.0Hz,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).

Example 16 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(3,3-difluorocyclobutyl)methoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

Step 1) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

7-Methyl-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-mouth bottle at room temperature. After nitrogen substitution, the reaction was carried out at 90 degrees Celsius overnight. Cool to room temperature, reduce pressure and concentrate. The residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a white solid (185 mg, yield 23.6%).

MS (ESI) M/Z: 454.5 [M+H] ⁺

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-carboxylic acid benzyl ester

Benzyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (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 -dimethylformamide (1 ml) were added to an 8 ml single-necked bottle at room temperature. The mixture was reacted at 60°C for 2 hours. The mixture was cooled to room temperature and quenched by adding water (10 ml). The mixture was extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. The residue was purified by preparative chromatography (petroleum ether/ethyl acetate = 5/1) to obtain a white solid (40 mg, yield 29.6%).

MS (ESI) M/Z: 558.6 [M+H] ⁺

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-carboxylic acid benzyl ester (100 mg, 0.180 mmol), palladium carbon (10% content, 100 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at room temperature overnight. The filtrate was filtered and concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 35.8%), which was directly used in the next reaction.

MS (ESI) M/Z: 468.5 [M+H] ⁺

Step 4) 4-(4-cyano-2,3-dihydrobenzofuran-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-[(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 -dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N ,N,N',N'- tetramethyluronium hexafluorophosphate (37 mg, 0.096 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. Filter, and the obtained filtrate is purified by preparative HPLC. The purification conditions are as follows: column model XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (containing 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 25% B to 60% B for 7 minutes, 60% B; wavelength: 254/220 nm; peak time (min): 6.58; collect the distillate, reduce pressure and freeze-dry. A white solid (17.0 mg, yield 56.8%) is obtained.

LCMS (ESI, m/z): 467.5 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ 7.73 (s, 1H), 7.56 (s, 1H), 7.12 (d, J =8.0Hz, 1H), 6.96 (d, J =8.0Hz,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 (376MHz, CDCl3) δ -83.5, -94.4.

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

Step 1) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

Benzyl 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, 0.221 mmol), ethyl 2-bromo-2,2-difluoroacetate (67 mg, 0.332 mmol), cesium carbonate (144 mg, 0.442 mmol) and N,N -dimethylformamide (2 ml) were added to an 8 ml single-necked bottle at room temperature. The mixture was reacted 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 × 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The residue was purified by preparative chromatography (petroleum ether/ethyl acetate = 5/1) to obtain a yellow solid (60 mg, yield 54.6%).

MS (ESI) M/Z: 504.6 [M+H] ⁺

Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (60 mg, 0.119 mmol), palladium carbon (10% content, 60 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 70 degrees Celsius overnight. After cooling to room temperature, the reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 60.9%), which was directly used in the next reaction.

MS (ESI) M/Z: 414.4 [M+H] ⁺

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 -dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N ,N,N',N'- tetramethyluronium hexafluorophosphate (28 mg, 0.072 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The filtrate was filtered and purified by preparative high performance liquid chromatography. The purification conditions were as follows: column model XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (containing 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 60 ml/min; gradient: 30% B to 60% B for 7 minutes; wavelength: 254/220 nm; fractions were collected and lyophilized under reduced pressure. A white solid (1.1 mg, yield 5.51%) was obtained.

LCMS (ESI, m/z): 413.05 [M+H] ⁺

¹ H NMR (300MHz, CDCl ₃ ) δ 7.68 (s, 1H), 7.05-6.99 (m, 2H), 5.87 (s, 1H), 5.23 (s, 1H), 4.75 (t, J =8.7Hz, 2H), 3.43 (t, J =8.7Hz,2H),2.51(s,3H),2.19(s,3H).

¹⁹ F NMR (282MHz, CDCl ₃ ) δ -87.2, -90.2.

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

Step 1) ( Z )-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylene)-3-hydroxybutyric acid benzyl ester

7-Methyl-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-necked bottle at room temperature. After nitrogen substitution, the reaction was carried out at 40 degrees Celsius overnight. Cooled to room temperature, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v) = 3:1) to obtain a yellow oil (600 mg, yield 52.9%).

LCMS (ESI, m/z): 348.10 [M+H] ⁺

Step 2) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

Add ( Z )-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylene)-3-hydroxybutyric acid benzyl ester (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) to a 40 ml single-necked bottle at room temperature. After nitrogen substitution, react at 90 degrees Celsius overnight. Cool to room temperature and filter. The obtained solid is slurried with isopropanol (2.0 ml × 3) and filtered to obtain a light yellow solid (105 mg, yield 80.8%).

LCMS (ESI, m/z): 454.25 [M+H] ⁺

Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (200 mg, 0.441 mmol), cyclopropane bromide (534 mg, 4.41 mmol), cesium carbonate (719 mg, 2.21 mmol) and NN -dimethylformamide (2 ml) were added to an 8 ml single-necked bottle at room temperature. The reaction was stirred at 130 °C overnight under nitrogen protection. The mixture was cooled to room temperature and filtered. The filtrate was purified by a carbon 18 column (mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: acetonitrile; flow rate: 60 ml/min; 10% to 50% within 10 minutes; detection wavelength: 254 nm). The distillate fractions were collected and lyophilized under reduced pressure to obtain a yellow solid (35 mg, yield 16.1%).

MS (ESI) M/Z: 494.2 [M+H] ⁺

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-carboxylic acid benzyl ester (35 mg, 0.071 mmol), palladium carbon (10% content, 35 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 50 degrees Celsius for 3 hours. After cooling to room temperature, the reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a light yellow solid (28 mg, yield 97.8%), which was directly used in the next reaction.

MS (ESI) M/Z: 404.2 [M+H] ⁺

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 -dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (42 mg, 0.110 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.5 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The reaction solution was filtered, and the filtrate was purified by a carbon 18 column (mobile phase A: aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 60 ml/min, 20% to 50% within 10 minutes; detection wavelength was 254 nm). The distillate fractions were collected and lyophilized under reduced pressure to obtain a white solid (20.2 mg, yield 72.3%).

LCMS (ESI, m/z): 403.05 [M+H] ⁺

¹ H NMR(400MHz,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 =8.4Hz,2H),2.47(s,3H),2.16(s,3H),0.74-0.54(m,3H),0.20-0.15(m,1H).

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

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-necked bottle at room temperature. After replacing the atmosphere with nitrogen, the reaction was carried out at 90°C for 2 hours. Cool to room temperature, reduce pressure and concentrate, and purify the residue with a carbon 18 column (mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; flow rate: 60 ml/min, from 10% B to 50% B in 10 minutes; detection wavelength is 254 nm). Collect the distillate, reduce pressure and freeze-dry to obtain a yellow solid (22.5 mg, yield 49.8%)

MS (ESI) M/Z: 471.2 [M+H] ⁺

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 an aqueous solution (0.2 ml) of sodium hydroxide (4 mg, 0.084 mmol) were added to an 8 ml single-necked bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust to pH = 5. Extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (5 ml × 3 times), and dried over anhydrous sodium sulfate. Filter, reduce pressure and concentrate to obtain a light yellow solid (17 mg, yield 96.9%), which is directly used in the next reaction.

MS (ESI) M/Z: 418.5 [M+H] ⁺

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 -dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N ,N,N',N'- tetramethyluronium hexafluorophosphate (23 mg, 0.062 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (content 25%) (0.1 ml) was added to the reaction solution at room temperature. The mixture was reacted for half an hour at room temperature. The reaction solution was filtered and purified by a carbon 18 column (mobile phase A: 0.1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 60 ml/min, from 20% B to 50% B in 10 minutes; detection wavelength was 254 nm). The distillate fractions were collected and lyophilized under reduced pressure, and the product was collected and lyophilized under reduced pressure. A white solid (2.2 mg, yield 12.9%) was obtained.

LCMS (ESI, m/z): 417.0 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) 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 =8.8Hz,2H),4.42-4.03(m,2H),3.45(t, J =8.8Hz,2H),2.50(s,3H),1.13-1.08(m,1H),0.61-0.50(m,2H),0.31-0.15(m,2H).

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

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

Add 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) to an 8 ml single-necked bottle at room temperature. After nitrogen replacement, react at 90 degrees Celsius for 2 hours. Cool to room temperature, filter the reaction solution, rinse the filter cake with ethyl acetate (3 x 5 ml), collect the filtrate, reduce pressure and concentrate to obtain a white solid (40 mg, yield 72.7%)

MS (ESI) M/Z: 459.2 [MH] ^-

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-necked bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust to pH = 5. Extracted with ethyl acetate (3 ml × 3 times), the organic phases were combined, washed with saturated brine (3 ml × 3 times), and dried over anhydrous sodium sulfate. Filter, reduce pressure and concentrate to obtain a light yellow solid (30 mg, yield 84.6%), which is directly used in the next reaction.

MS (ESI) M/Z: 406.3 [M+H] ⁺

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 -dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (42 mg, 0.111 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (content 25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for half an hour at room temperature. The reaction solution was filtered and purified by a carbon 18 column (mobile phase A: aqueous solution containing 0.05% ammonia; mobile phase B: acetonitrile; flow rate: 60 ml/min, from 15% B to 40% B in 15 minutes; detection wavelength: 254 nm). The product was collected and lyophilized 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 (400MHz, CDCl ₃ )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 =9.2Hz,2H),2.49(s,3H),2.15(s,3H),1.25(d, J =6.1Hz,3H),0.94(d, J =6.1Hz,3H).

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

Step 1) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (50 mg, 0.110 mmol), iodocyclobutane (60 mg, 0.331 mmol), cesium carbonate (72 mg, 0.221 mmol) and N,N -dimethylformamide (1 ml) were added to an 8 ml single-necked bottle at room temperature. The reaction was stirred at 60 degrees Celsius overnight under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate (3×10 ml). The organic phases were combined, washed with saturated brine (3×10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography (pre-TLC) (petroleum ether/ethyl acetate = 4/1) to obtain a white solid (40 mg, yield 71.4%).

MS (ESI) M/Z: 508.2 [M+H] ⁺

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-carboxylic acid benzyl ester (40 mg, 0.085 mmol), palladium carbon (10% content, 40 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and reacted at 50 degrees Celsius for 2 hours. After cooling to room temperature, the reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (30 mg, yield 91.3%), which was directly used in the next reaction.

MS (ESI) M/Z: 418.2 [M+H] ⁺

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 -dimethylformamide (1 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (41 mg, 0.109 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.5 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative HPLC. 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: acetonitrile increased from 40% to 50% in 7 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (15.0 mg, yield 49.8%).

LCMS (ESI, m/z): 417.2 [M+H] ⁺

^1H NMR(400MHz,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).

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

Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (300 mg, 0.663 mmol), (iodomethyl)cyclobutane (194 mg, 0.996 mmol), cesium carbonate (431 mg, 1.27 mmol) and N,N -dimethylformamide (3 ml) were added to an 8 ml single-necked bottle at room temperature. The reaction was stirred at 60 °C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and purified by a carbon 18 reverse column (conditions were as follows: mobile phase A: water (containing 0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml/min, gradient: 30% B to 60% B, washing for 15 minutes; detection wavelength 254 nm, reference wavelength 220 nm). The product was collected and concentrated under reduced pressure to obtain a white solid (47 mg, yield 13.7%).

MS (ESI) M/Z: 522.2 [M+H] ⁺

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-carboxylic acid benzyl ester (47 mg, 0.090 mmol), palladium carbon (10% content, 47 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and reacted at 50 degrees Celsius for 2 hours. After cooling to room temperature, the reaction liquid was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 77.2%), which was directly used in the next reaction.

MS (ESI) M/Z: 432.2 [M+H] ⁺

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 -dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (42 mg, 0.110 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative HPLC. 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: acetonitrile increased from 35% to 50% in 7 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (17.9 mg, yield 59.8%).

LCMS (ESI, m/z): 431.2 [M+H] ⁺

¹ H NMR (400MHz, Chloroform- d ₃ ) δ 7.68 (s, 1H), 7.01 (d, J =8.1Hz, 2H), 6.68 (s, 2H), 5.82 (s, 1H), 5.17 (s, 1H), 4.72 (t, J =8.6Hz,2H),4.17-4.08(m,2H),3.42(t, J =8.6Hz,2H),2.62-2.52(m,1H),2.48(s,3H),2.16(s,3H),2.06-1.61(m,6H).

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

Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (100 mg, 0.220 mmol), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodine (218 mg, 0.663 mmol) and nitromethane (4 ml) were added to an 8 ml single-necked bottle at room temperature. The reaction was stirred at 100 degrees Celsius for 5 hours under nitrogen protection. The reaction solution was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate (3×10 ml). Combine the organic phases, wash with saturated brine (3×10 ml), dry with anhydrous sodium sulfate, filter, obtain the filtrate, and concentrate under reduced pressure. The residue was purified by preparative chromatography (pre-TLC) (petroleum ether/ethyl acetate = 1/1) to obtain a yellow solid (40 mg, yield 34.8%).

MS (ESI) M/Z: 522.2 [M+H] ⁺

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-carboxylic acid benzyl ester (20 mg, 0.038 mmol), palladium carbon (10% content, 20 mg) and methanol (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen substitution, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 70 degrees Celsius for 4 hours. After cooling to room temperature, the reaction solution was filtered to obtain a filtrate, which was purified by preparative high performance liquid chromatography. The purification conditions are as follows: chromatographic column: carbon 18 reverse phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 40 ml/min; gradient: from 30% B to 50% B in 15 minutes; detection wavelength: 254 nm. The product was collected, lyophilized and concentrated under reduced pressure to obtain a white solid (12 mg, yield 72.5%), which was directly used in the next reaction.

MS (ESI) M/Z: 432.2 [M+H] ⁺

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 -dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (16 mg, 0.042 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.1 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: chromatographic column: Xselect CSH C18 OBD; mobile phase A: water (containing 0.1% trifluoroformic acid), mobile phase B: acetonitrile; flow rate: 50 ml/min; gradient: acetonitrile increased from 20% to 50% in 7 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (2.9 mg, yield 24.2%).

LCMS (ESI, m/z): 431.2 [M+H] ⁺

¹ H NMR (400MHz, CDCl ₃ ) δ 7.82 (s, 1H), 7.06-6.98 (m, 2H), 5.97 (s, 1H), 5.22 (s, 1H), 4.78 (t, J =8.7Hz, 2H), 3.47 (t, J =8.7Hz,2H),2.55(s,3H),2.26(s,3H).

¹⁹ F NMR (377MHz, CDCl ₃ )δ -56.0.

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

Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (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 -dimethylformamide (2 ml) were added to an 8 ml single-necked bottle at room temperature. The reaction was stirred at room temperature for 2 hours. Water (20 ml) was added to dilute the mixture and the mixture was extracted with ethyl acetate (3×20 ml). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative chromatography (pre-TLC) (petroleum ether/ethyl acetate = 2/1) to obtain a yellow solid (36 mg, yield 36.1%).

MS (ESI) M/Z: 536.2 [M+H] ⁺

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-carboxylic acid benzyl ester (36.0 mg, 0.067 mmol), palladium carbon (10% content, 36 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 70 degrees Celsius for 3 hours. After cooling to room temperature, the reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (24 mg, yield 80.1%), which was directly used in the next reaction.

MS (ESI) M/Z: 446.2 [M+H] ⁺

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 -dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (30 mg, 0.081 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative HPLC. 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: acetonitrile increased from 40% to 50% in 7 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (6.3 mg, yield 26.3%).

MS (ESI) M/Z: 445.15 [M+H] ⁺

¹ H NMR(400MHz, CDCl ₃ )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 =8.7Hz,2H),2.52(s,3H),2.23(s,3H).

¹⁹ F NMR (282MHz, CDCl ₃ )δ -74.1.

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

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 -dimethylformamide (25 ml), N,N -diisopropylethylamine (1.32 g, 10.2 mmol) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (2.92 g, 7.69 mmol) were added to a 100 ml single-necked bottle at room temperature. The reaction was carried out at room temperature for 0.5 hours. Ammonia aqueous solution (1.0 M, 6 ml) was added to the reaction solution at room temperature. The reaction was carried out at room temperature for 1 hour. Water (250 ml) was added to dilute. Extract with ethyl acetate (250 ml x 3), combine the organic phases, wash with saturated brine (250 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: pure ethyl acetate) to obtain an orange oil (800 mg, yield 80.4%).

LCMS (ESI, m/z): 195.1 [M+H] ⁺

Step 2) 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

Add 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carboxamide (766 mg, 3.95 mmol) and phosphorus oxychloride (15 ml) to a 50 ml single-necked bottle at room temperature. Heat to 80 degrees Celsius for 1 hour. Cool to room temperature. Quench with sodium hydroxide solution (1.0 mol/L) and adjust the pH to about 8. Extract with ethyl acetate (50 ml × 3), combine the organic phases, wash with saturated brine (50 ml), and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure, and purify the residue by column chromatography (dichloromethane/methanol (v/v) = 20/1) to obtain a white solid (310 mg, yield 44.6%).

LCMS (ESI, m/z): 177.1 [M+H] ⁺

Step 3) 8-bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

At room temperature, add 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) to a 40 ml sample bottle. React at 70 degrees Celsius for 1.5 hours. The reaction solution was cooled to room temperature, filtered, and rinsed with ethyl acetate (8 ml) 3 times. The filtrate was concentrated under reduced pressure, and the residue was purified on a preparative plate (petroleum ether/ethyl acetate (v/v) = 5/1) to obtain a white solid (110 mg, yield 26.0%).

Step 4) 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

Add 8-bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (110 mg, 0.458 mmol) and tetrahydrofuran (0.5 ml) to an 8 ml sample bottle at room temperature. After nitrogen substitution, cool the reaction solution to -78 degrees Celsius. Slowly add n-butyl lithium (0.2 ml, 2.5 mmol/ml, 0.50 mmol) in n-hexane solution. React at -78 degrees Celsius for half an hour. Add N,N -dimethylformamide (0.5 ml) and react at -78 degrees Celsius for half an hour. Add saturated aqueous ammonium chloride solution (5 ml) to quench. Extract with dichloromethane (5 ml x 3), combine the organic phases, wash with saturated brine (5 ml), and dry over anhydrous sodium sulfate. Filter the filtrate and concentrate under reduced pressure. The residue is purified on a preparative plate (petroleum ether/ethyl acetate (v/v) = 5/1) to obtain a white solid (40 mg, yield 46.2%).

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-Methylyl-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 μl) were added to an 8 ml single-necked bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90°C for 4 hours. Cool to room temperature, reduce pressure and concentrate, and purify the residue by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40g reverse phase column, mobile phase A (0.1% ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile, gradient 25% B to 30% B in 15 minutes, monitoring wavelength 254 nm), to obtain a light yellow solid (15 mg, yield 18.8%).

MS (ESI) M/Z: 433.2 [M+H] ⁺

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), iodoethane (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-necked bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 °C for 1 hour. The mixture was cooled to room temperature. The mixture was filtered and washed with acetonitrile (3 ml). The filtrate was concentrated under reduced pressure to obtain a yellow solid (15 mg, crude product), which was used directly in the next reaction without further purification.

MS (ESI) M/Z: 461.3 [M+H] ⁺

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 an aqueous solution (0.15 ml) of sodium hydroxide (3 mg, 0.066 mmol) were added to an 8 ml single-necked bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol/L) was added to quench and adjust to pH = 5. The mixture was extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (5 ml × 3 times), and dried over anhydrous sodium sulfate. The product was filtered and concentrated under reduced pressure to obtain a light yellow solid (10 mg, crude product), which was used directly in the next reaction without further purification.

LCMS (ESI, m/z): 408.1 [M+H] ⁺

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 -dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N ,N,N',N' -tetramethyluronium hexafluorophosphate (14 mg, 0.038 mmol) were added to an 8 ml vial at room temperature. The reaction was carried out for half an hour at room temperature. Ammonia aqueous solution (25%) (0.1 ml) was added to the reaction solution at room temperature. The reaction was carried out for 1 hour at room temperature. The reaction solution was purified by preparative HPLC. 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: 50 ml/min; gradient: acetonitrile increased from 25% to 30% in 10 minutes; detection wavelength: 254/220 nm. The product was collected and lyophilized under reduced pressure. A white solid (1.1 mg, yield 11.0%) was obtained.

MS (ESI) M/Z: 407.30 [M+H] ⁺

¹ H NMR (300MHz, DMSO- d ₆ ) δ 7.69 (s, 1H), 7.57 (d, J =8.1Hz, 1H), 7.12 (d, J =8.1Hz,1H),6.76-6.62(m,3H),5.34(s,1H),4.44-4.25(m,4H),4.06(d, J =7.0Hz,2H),2.18(s,3H),2.12(s,3H),1.11(t, J =7.0Hz,3H).

Preparation of Chiral Compounds:

Embodiment 32 & 33

( S )-4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 32 and

( R )-4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 33

4-(5-cyanocyanine-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 elution time: 8.80 min; 32 elution time: 12.0 min; sample solution: ethanol; injection volume: 0.8 ml; number of injections: 5. Two enantiomeric monomers 33 were obtained. : white solid (20.3 mg, yield 36.2%) and monomer 32 : white solid (16.9 mg, yield 30.1%).

32 LCMS(ESI,m/z)：405.25[M+H] ⁺

32 ¹ H NMR (400MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.56 (s, 1H), 7.18 (d, J =8.0Hz, 1H), 6.94 (d, J =8.0Hz,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 =7.0Hz,3H).

33 LCMS(ESI,m/z)：405.25[M+H] ⁺

33 ¹ H NMR (400MHz, DMSO- d 6) δ 7.70 (s, 1H), 7.56 (s, 1H), 7.18 (d, J =8.0Hz, 1H), 6.94 (d, J =8.0Hz,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 =7.0Hz,2H),2.12(s,3H),2.07(s,3H),2.03-1.94(m,2H),1.10(t, J =7.0Hz,3H).

Embodiment 36 & 37

( S )-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

( R )-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 37

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 for 15 min; wavelength: 218/270 nm; 36 peak time: 9.47 min; 37 peak time: 11.2 minutes; sample solution: ethanol; injection volume: 0.5 ml; number of injections: 9. Two enantiomers were obtained: monomer 37 : white solid (7.5 mg, yield 18.8%) and monomer 36 : white solid (9.3 mg, yield 23.3%).

36 LCMS(ESI,m/z)：391.10[M+H] ⁺

36 ¹ H NMR(400MHz, DMSO- d 6)δ 7.70(s,1H),7.55(s,1H),7.11(d, J =8.0Hz,1H),6.98(d, J =8.0Hz,1H),6.71(s,2H),5.18(s,1H),4.63(t, J =8.8Hz,2H),4.04(q, J =6.8Hz,2H),3.40(t, J =8.8Hz,2H),2.11(s,3H),2.07(s,3H),1.10(t, J =6.8Hz,3H).

37 LCMS(ESI,m/z)：391.10[M+H] ⁺

37 ¹ H NMR(400MHz, DMSO- d 6)δ 7.70(s,1H),7.55(s,1H),7.11(d, J =8.0Hz,1H),6.98(d, J =8.0Hz,1H),6.71(s,2H),5.18(s,1H),4.63(t, J =8.8Hz,2H),4.04(q, J =6.8Hz,2H),3.40(t, J =8.8Hz,2H),2.11(s,3H),2.07(s,3H),1.10(t, J =6.8Hz,3H).

Embodiment 38 & 39

(S)-6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 38

(R)-6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 39

6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide (60 mg, 0.148 mmol) 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: 10% B for 34.5 min; wavelength: 210/220 nm; ( 39 peak time): 20.68 min; ( 38 peak time): 28.59 minutes; sample solution: methanol: dichloromethane = 1:1; injection volume: 0.35 ml; number of injections: 12) to obtain two enantiomeric monomers 0A: white solid (13.8 mg, yield 33.6%) and monomer 0B: white solid (14.0 mg, white solid, yield 34.1%).

38 MS (ESI) M/Z: 421.00 [M+H] ⁺

38 ¹ H NMR (400MHz, DMSO- d 6) δ 8.83 (s, 1H), 7.88 (d, J =5.6Hz, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.29-7.22 (m, 2H), 7.18 (d, J =7.6Hz,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=7.2Hz,3H).

39 MS (ESI) M/Z: 421.05 [M+H] ⁺

39 ¹ H NMR (400MHz, DMSO- d 6) δ 8.83 (s, 1H), 7.88 (d, J =5.6Hz, 1H), 7.37 (d, J = 1.6Hz, 1H), 7.29-7.22 (m, 2H), 7.18 (d, J =7.6Hz,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=7.2Hz,3H).

Embodiment 40 & 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

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 separated by chiral separation (separation conditions are as follows: (chiral column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol ammonia in methanol solution), mobile phase B: ethanol; flow rate: 20 ml/min; gradient: 15% B to 15% B for 20 min; wavelength: 218/260 nm; 41 peak time: 10.22 min; Peak time of 40 : 16.14 minutes; sample solution: ethanol: dichloromethane = 1:1; injection volume: 0.5 ml; number of injections: 3. Enantiomeric monomer 41 (10.8 mg, white solid, yield 33.7%) and enantiomeric monomer 40 (9.8 mg, white solid, yield 30.6%) were obtained.

40 : MS(ESI)M/Z: 407.30[M+H] ⁺

¹ H NMR (300MHz, DMSO- d ₆ ) δ 7.69 (s, 1H), 7.57 (d, J =8.1Hz, 1H), 7.12 (d, J =8.1Hz,1H),6.76-6.62(m,3H),5.34(s,1H),4.44-4.25(m,4H),4.06(d, J =7.0Hz,2H),2.18(s,3H),2.12(s,3H),1.11(t, J =7.0Hz,3H).

41 : MS(ESI)M/Z: 407.30[M+H] ⁺

¹ H NMR (300MHz, DMSO- d ₆ ) δ 7.69 (s, 1H), 7.57 (d, J =8.1Hz, 1H), 7.12 (d, J =8.1Hz,1H),6.76-6.62(m,3H),5.34(s,1H),4.44-4.25(m,4H),4.06(d, J =7.0Hz,2H),2.18(s,3H),2.12(s,3H),1.11(t, J =7.0Hz,3H).

Embodiment 46 & 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

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 separated by 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 to 20% B in 23 min; wavelength: 207/236 nm; ( 47 ) peak time: 11.6 min; ( 46 peak time): 20.3 minutes; sample solution: methanol: dichloromethane = 1:1; injection volume: 0.2 ml; number of injections: 3) to obtain two enantiomeric monomers 0A (8.50 mg, white solid, yield 26.6%) and 0B (10.5 mg, white solid, yield 32.8%)

46 : MS(ESI)M/Z: 413.05[M+H] ⁺

46 ¹ H NMR (300MHz, CDCl ₃ )δ 7.68 (s, 1H), 7.05-6.99 (m, 2H), 5.87 (s, 1H), 5.23 (s, 1H), 4.75 (t, J =8.7Hz, 2H), 3.43 (t, J =8.7Hz,2H),2.51(s,3H),2.19(s,3H).

19F NMR (282MHz, CDCl3) δ -87.2, -90.2.

47 : MS(ESI)M/Z: 413.05[M+H] ⁺

47 ¹ H NMR (300MHz, CDCl ₃ )δ 7.68 (s, 1H), 7.05-6.99 (m, 2H), 5.87 (s, 1H), 5.23 (s, 1H), 4.75 (t, J =8.7Hz, 2H), 3.43 (t, J =8.7Hz,2H),2.51(s,3H),2.19(s,3H).

19F NMR (282MHz, CDCl3) δ -87.2, -90.2.

Embodiment 48 & 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

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 separated by 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 for 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 injections: 3) to obtain two enantiomeric monomers 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(400MHz,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 =8.4Hz,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 (400MHz, 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 =8.4Hz,2H),2.47(s,3H),2.16(s,3H),0.74-0.54(m,3H),0.20-0.15(m,1H).

Embodiment 62 & 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

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 separated by chiral separation (separation conditions were as follows: chiral column CHIRAL ART Amylose-C NEO, 2*25 cm, 5 um; 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 for 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 injections: 2) to obtain two enantiomeric monomers 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 (400MHz, Chloroform- d )δ δ 7.70 (s, 1H), 6.91 (d, J =8.4Hz, 1H), 6.77 (d, J =8.4Hz,1H),6.14(s,2H),5.78(s,1H),5.47(s,2H),5.14(s,1H),4.20(q, J =7.0Hz,2H),2.46(s,3H),2.15(s,3H),1.26(t, J =7.0Hz,3H).

63： LCMS(ESI)M/Z：393.1[M+H] ⁺

63 ¹ H NMR (400MHz, Chloroform- d )δ δ 7.70 (s, 1H), 6.91 (d, J =8.4Hz, 1H), 6.77 (d, J =8.4Hz,1H),6.14(s,2H),5.78(s,1H),5.47(s,2H),5.14(s,1H),4.20(q, J =7.0Hz,2H),2.46(s,3H),2.15(s,3H),1.26(t, J =7.0Hz,3H).

Other racemic embodiments in this application are separated by similar means.

Single crystal X-ray diffraction analysis

Single crystal X-ray diffraction analysis of compound 36

About 5 mg of compound 36 was dissolved in 0.6 mL of acetone at room temperature, and then 1.4 mL of water was gradually added. After the filtrate was filtered into a clean vial, it was covered with a pinhole membrane and slowly evaporated at room temperature. After 1 day, a block single crystal was generated, and the obtained single crystal was used for single crystal x-ray diffraction, as shown in Figure 9.

36 crystallizes in the monoclinic form in the C2 space group with the chemical formula C ₂₂ H ₂₂ N ₄ O ₃ . There is one 36 molecule in each asymmetric unit, and the unit cell contains four asymmetric units. As shown in Figure 1, the chiral carbon at C10 is determined to be in the "S" configuration. The terminal ethyl group is in a disordered position.

The refined single crystal structure is shown in Figures 2 and 3 (for clarity, the main conformations and hydrogen atoms are omitted). The crystal structure data are summarized in Table 2, and the detailed information of atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds, torsion angles, and atomic occupancy are shown in Tables 3 to 10. The XRPD pattern calculated from the single crystal structure (above) is consistent with the experimental pattern (below) (Figure 4).

U(eq)被定義為正交化Uij張量軌跡的三分之一。

U(eq) is defined as one third of the trajectory of the orthogonalized Uij tensor.

各向異性位移因數指數為-2π²[h²a*²U₁₁+2hka*b*U₁₂+...].

The anisotropic displacement factor has the value -2π ² [h ² a* ² U ₁₁ +2hka*b*U ₁₂ +...].

¹1-x,1+y,-z；²3/2-x,-1/2+y,-z

¹ 1- x ,1+ y ,- z ; ² 3/2- x ,-1/2+ y ,- z

Single crystal X-ray diffraction analysis of compound 62

About 5 mg of compound 62 was dissolved in 0.1 mL of ethanol at room temperature, and then 0.35 mL of n-heptane was gradually added. After filtering, it was placed in a clean sample bottle, the filtrate was covered with a pinhole membrane, and slowly evaporated under ambient conditions. After 1 day, a block single crystal was generated, and the obtained single crystal was used for single crystal x-ray diffraction, as shown in Figure 10.

62 crystallizes in the monoclinic system in the C2 space group with the chemical formula C ₂₁ H ₂₀ N ₄ O ₄ . There are two 62 molecules in each asymmetric unit, and the unit cell contains four asymmetric units. As shown in Figure 5, the chiral carbon of C9 (C30) is determined to be in the "S" configuration.

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

U(eq)is defined as one third of the trace of the orthogonalized U_ij tensor.

U(eq)is defined as one third of the trace of the orthogonalized U _ij tensor.

The anisotropic displacement factor exponent takes the form：-2π²[h²a*²U₁₁+2hka*b*U₁₂+...].

The anisotropic displacement factor exponent takes the form: -2π ² [h ² a* ² U ₁₁ +2hka*b*U ₁₂ +...].

¹1-x,-1+y,-z；²3/2-x,-1/2+y,-z；³2-x,-1+y,1-z

¹ 1- x ,-1+ y ,- z ; ² 3/2- x ,-1/2+ y ,- z ; ³ 2- x ,-1+ y ,1- z

Examples In vitro activity test

1. Experimental principle:

Taking advantage of the characteristic of luminescence reaction of luciferase binding to substrate, the plasmid containing Gal4DNA binding domain (DBD) fused with halocorticoid receptor (MR) ligand binding domain (LBD) and the firefly luciferase reporter gene plasmid under the control of Gal4UAS (upstream start sequence) was transfected into human embryonic kidney cells (HEK293). The change of halocorticoid receptor activity before and after stimulation or the effect of different stimulation on halocorticoid receptor activity was judged by the level of firefly luciferase activity.

2. Experimental methods:

1. Preparation and processing of compounds

1.1 Preparation of compound DMSO stock solution

All compounds were dissolved in DMSO, prepared into 25mM stock solutions, and stored in a -20℃ refrigerator.

1.2 Preparation of working solution

1) The test compound was diluted 3-fold with DMSO, with 10 concentration gradients and a starting concentration of 10mM.

2) The positive compound (Finerenone) was diluted 3-fold with DMSO, with 10 concentration gradients and a starting concentration of 1mM.

3) Prepare 1000× positive control (1mM, Finerenone) and 1000× negative control (100% DMSO).

4) Seal the compound plate and shake for 5 minutes.

2. Preparation of cell suspension

1) All cells were cultured according to ATCC standard procedures, and HEK293T cells were used for experiments in the exponential growth phase.

2) Gently discard the culture medium supernatant. Wash the cells twice with PBS.

3) Digest the cells with trypsin digestion solution, terminate the digestion with complete culture medium, collect the cells and count them.

4) Inoculate 6 X106 HEK293T cells into a 100mm cell culture dish.

5) Place the culture dish with cells in a 37°C, 5% CO2 incubator and culture overnight for 16 hours.

3. Cell transfection

1) Place Lipofectamine® 3000&P3000 transfection reagent at room temperature

2) Add Lipofectamine® 3000 reagent to Opti-MEM ^TM medium. Add P3000, plasmid and Opti-MEM ^TM medium to another tube, being careful not to touch the tube wall.

3) Mix well with a pipette and let stand at room temperature for 5 minutes.

4) Add the plasmid to the diluted transfection reagent, mix well with a pipette and let stand at room temperature for 20 minutes.

5) Add the transfection reagent mixed with plasmid into a 60mm cell culture dish.

6) Place the culture dish in a 37°C, 5% CO2 incubator for 5-6 hours.

4. Compound treatment

1) Use Echo655 to transfer 25nL of the diluted compound to the cell culture plate.

2) Seed the cells (see step 1.3) into 384 cell culture plates, 17,000 cells per well, 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 18-20 hours.

5. Compound detection

1) Place the Britelite plus test reagent at room temperature.

2) Place the 384-cell plate at room temperature.

3) Add 25μL of Britelite plus detection reagent to each well of the cell culture plate.

4) Use Envision to detect the luminescence value.

6. Result processing:

1) Obtain the firefly luciferase signal by reading Luminescence 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 of all positive control wells on the whole plate; avgRLU negative control is the average Luminescence of all negative control wells on the whole plate; RLU compound is the Luminescence value of the test compound at different concentrations; 3) Calculate the IC50 of the compound using Graphpad8.0 graphics software;

7. Experimental results:

Conclusion:

From the experimental results in Table 19, it can be seen that the compound of the present invention has good halocorticoid receptor (MR) antagonist activity and can be used as an effective halocorticoid receptor antagonist.

Example Test rat drug metabolism kinetics study

This experiment aims to evaluate the pharmacokinetic behavior of the compound after intravenous injection or oral administration in rats. Intravenous injection: the test compound was prepared into a 0.2 mg/ml clear solution, the solvent was 10% ethanol, 40% polyethylene glycol 400 and 50% water, and plasma was collected at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration; oral administration: the test compound was prepared into a 1 mg/ml clear solution, the solvent was 10% ethanol/40% polyethylene glycol 400/50% water, and plasma was collected at 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.

The concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The retention time of the compound and internal standard, chromatogram acquisition and chromatogram integration were processed by Analyst (Applied Biosystems), and the data statistics were processed by Analyst (Applied Biosystems).

The non-compartmental model of WinNonlinTM Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process plasma concentration, and the linear logarithmic trapezoidal method was used to calculate pharmacokinetic parameters.

The pharmacokinetic parameters of the compound in rats at a dose of 1 mg/kg by intravenous injection and 5 mg/kg by oral gavage are shown in Table 20 below.

From the experimental results in Table 20, it can be seen that the compound described in the present invention has good in vivo pharmacokinetic properties.

Example Testing of drug metabolism kinetics in mice

This experiment aims to evaluate the pharmacokinetic behavior of compounds in mice after intravenous injection or oral gavage. Intravenous injection: The test compound was prepared into a 0.2 mg /ml clear solution, the solvent was 10% ethanol/40% polyethylene glycol 400/50% ultrapure water, and plasma was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 hours after administration.

The concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The retention time of the compound and internal standard, chromatogram acquisition and chromatogram integration were processed by Analyst (Applied Biosystems), and the data statistics were processed by Analyst (Applied Biosystems).

The non-compartmental model of WinNonlinTM Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process plasma concentration, and the linear logarithmic trapezoidal method was used to calculate pharmacokinetic parameters.

The pharmacokinetic parameters of the compound in mice at a dose of 1 mg/kg by intravenous injection are shown in Table 21 below.

Example 70 Pharmacodynamic effects of compounds 36 and 62 on diabetic nephropathy mouse model

1. Research purpose

Evaluate the pharmacological effects of compounds 36 and 62 on diabetic nephropathy mouse models.

2. Drug preparation

The solvent and positive drug need to be prepared on the same day as shown in Table 70-1.

Table 70-1 Drug Preparation

3. Experimental animals and breeding management

3.1 Experimental animals

Strain: C57BL/6 mice, KK-Ay mice

Age: Animals reach 6-8 weeks, experiments start at 7-9 weeks

Gender: Male

Weight: C57BL/6 mice 21-23g, KK-Ay mice 25-30g

Number: 72 experimental animals

3.2 Animal husbandry

3.2.1 Quarantine

The quarantine and adaptation period lasts for 7 days in total. Routine health checks are performed by veterinarians, and animals with abnormal performance are eliminated before the experiment.

3.2.2 Animal breeding conditions

The experimental animals were raised in single cages in an SPF-grade constant temperature and humidity laminar flow clean room at the Animal Center of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. (AAALAC accredited unit). The temperature in the breeding room was 22-25℃, the humidity was 40-80%, and the lighting was alternating between light and dark for 12 hours. The cages were made of polycarbonate. Soft corn cob autoclaved clean bedding was used and replaced twice a week. The drinking water was autoclaved and the food was irradiated with cobalt 60 radiation. The animals could freely take sterile food and drinking water.

3.2.3 Animal number

Each cage has a cage label indicating the number of animals, sex, strain, receipt time, group, and start time of the experiment. Each animal is marked with an individual animal number at the tail.

4. Experimental animal grouping and drug administration

On the day of dosing, the animals were randomly divided into 9 groups according to their body weight; model group (KK-Ay + solvent), Finerenone group (KK-Ay + Finerenone: 3 mg/kg), low-dose compound 62 group (KK-Ay + compound 62: 1 mg/kg), medium-dose compound 62 group (KK-Ay + compound 62: 3 mg/kg), high-dose compound 62 group (KK-Ay + compound 62: 10 mg/kg), low-dose compound 36 group (KK-Ay + compound 36: 1 mg/kg), medium-dose compound 36 group (KK-Ay + compound 36: 3 mg/kg), high-dose compound 36 group (KK-Ay + compound 36: 10 mg/kg). The specific groups and dosing schedules are shown in Table 70-2.

7 Experimental methods and test indicators

7.1 Urine collection

Before the start of the experiment and at 2, 4, 6, and 8 weeks after modeling, the urine of mice was collected in a metabolic cage for 24 hours. The urine was tested for the content of urine microalbumin (MALB) and creatinine (CREA) by CANON TBA-120FR automatic blood biochemistry. Calculation (MALB/CREA).

7.2 Insulin content and serum ion detection

At the end of the experiment, mice were euthanized, and blood was collected by cardiac puncture and placed in an EP tube without anticoagulant. After standing at room temperature for 0.5 hours, the blood was centrifuged at 4°C and 6000g for 15 minutes. The serum was collected and transferred to a new EP tube and stored in a -80°C refrigerator. The ELISA method was used to detect the insulin content in the serum and serum ion detection.

7.3 Tissue Collection

After the experiment, all animal kidneys were collected by dissection, fixed in formalin, embedded and sliced for PAS staining and Masson staining, and quantitative analysis was performed.

8. Statistics

The experimental results are expressed as "mean ± standard deviation". GraphPad 8.0 software was used to analyze the data of each group, and p < 0.05 was considered statistically significant.

9. Results

Compound 62 and compound 36 both significantly promote urinary sodium excretion, can significantly reduce the urine protein/creatinine ratio, and have the effect of improving diabetic nephropathy and hypertension.

Example 71 Study on in vitro CPY enzyme inhibition

The research results show that the IC50 (μM) data of the main drug metabolizing enzyme CYP3A4 in the human body are as follows: CYP3A4-5M and CYP3A4-5T are Finerenone (9.98, 8.02), compound 36 (22.86, 15.78), and compound 62 (13.66, 5.35).

Therefore, compounds 36 and 62 have higher safety than finerenone. Compound 36 and finerenone have higher half-maximal inhibition concentrations for the two subtypes of CYP3A4-5M/CYP3A4-5T, the main metabolizer CYP3A4 in the human body (the metabolizer metabolizes about 50% of the drugs).

In the description of this specification, the description of the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in an appropriate manner. In addition, the technical personnel in this field can combine and combine different embodiments or examples described in this specification and the features of different embodiments or examples without contradiction.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations of the present invention. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims (24)

A compound characterized in that it is a compound represented by formula (I) and its stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts;

in,

for

_R3 and _R4 are independently hydrogen; _R5 is

_R6 is _C1-6 alkyl;

for

X is C; Y is O; _R7 is _C1-6 alkyl, _C3-8 cycloalkyl or _C3-8 cycloalkylC1-6 alkyl; _R7 is unsubstituted or substituted by ₁ , 2 or 3 Rz; each Rz is independently fluorine, chlorine, bromine, iodine or _C1-6 alkyl;

for

R ₈ and R ₉ are hydrogen or C _1-6 alkyl. A compound characterized in that it is a compound represented by formula (I) and its stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts;

in,

for

_R3 and _R4 are independently hydrogen; _R5 is

_R6 is _C1-6 alkyl;

for

X is C; Y is O; _R7 is _C1-6 alkyl, _C3-8 cycloalkyl or _C3-8 cycloalkylC1-6 alkyl; _R7 is unsubstituted or substituted by ₁ , 2 or 3 Rz; each Rz is independently fluorine, chlorine, bromine, iodine or _C1-6 alkyl;

for

R ₈ and R ₉ are hydrogen or C _1-6 alkyl; R ₁₀ and R ₁₁ are independently selected from -CH ₂ - or O, and at least one of them is O; R ₁₂ is -CH ₂ - or -CH ₂ -CH ₂ -; when R ₁₂ is -CH ₂ -, R ₁₀ and R ₁₁ are independently selected from -CH ₂ - or O, and at least one of them is O; when R ₁₂ is -CH ₂ -CH ₂ -, R ₁₀ and R ₁₁ are both O, or R ₁₀ is -CH ₂ - and R ₁₁ is O. The compound as claimed in claim 1, characterized in that it is selected from the compound represented by formula (Ia) or formula (Ib) and stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts thereof;

The compound as described in any one of claims 1 to 3, characterized in that each R ₃ and R ₄ is independently hydrogen; R ₆ is C _1-4 alkyl; and each R ₈ and R ₉ is independently hydrogen or C _1-4 alkyl. The compound as described in any one of claims 1 to 3, characterized in that each of R ₃ and R ₄ is independently hydrogen; R ₆ is methyl; and R ₈ is methyl. The compound as described in any one of claims 1 to 3, characterized in that it is selected from the compound represented by formula (II) and its stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts;

The compound as described in any one of claims 1 to 3, characterized in that it is selected from the compounds represented by formula (IIa), formula (IIb) and stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts thereof;

The compound as described in any one of claims 1 to 3, characterized in that R ₇ is C _3-6 cycloalkyl or C _3-6 cycloalkylC _1-4 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z. The compound according to any one of claims 1 to 3, characterized in that R ₇ is C _1-3 alkyl, wherein R ₇ is unsubstituted or substituted with 1, 2 or 3 R z . The compound of any one of claims 1 to 3, characterized in that R ₇ is cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl or cyclobutylmethyl; wherein R ₇ is unsubstituted or substituted with 1, 2 or 3 R z . The compound according to any one of claims 1 to 3, wherein each Rz is independently fluorine, chlorine, bromine, iodine or C _1-4 alkyl. The compound as described in any one of claims 1 to 3, characterized in that each Rz is independently fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl or butyl. The compound as claimed in claim 1 is selected from the compound represented by formula (V) and its stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts:

in,

for

; R ₃ and R ₄ are independently hydrogen; R ₅ is selected from

; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl or C _3-8 cycloalkylC _1-6 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z; each R z is independently: fluorine, chlorine, bromine or iodine; R ₈ and R ₉ are hydrogen or C _1-6 alkyl; X is selected from C; Y is selected from O. The compound as described in claim 13 is characterized in that: _R6 is _C1-3 alkyl; _R7 is _C1-3 alkyl, _C3-5 cycloalkyl or _{C3-4 cycloalkylC1-3} alkyl; wherein _R7 is unsubstituted or substituted by 1, 2 or 3 Rz; each Rz is independently: fluorine, chlorine, bromine or iodine; _R8 and _R9 are hydrogen or _C1-3 alkyl. The compound of claim 13, characterized in that: R ₆ is C _1-3 alkyl; R ₇ is C _1-3 alkyl, C _3-5 cycloalkyl or C _3-4 cycloalkyl C _1-3 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z; each R z is independently fluorine; R ₈ and R ₉ are hydrogen or methyl. The compound as described in any one of claims 1 to 3 is characterized in that it is selected from the compound represented by formula (V) and its stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts:

in,

for

; R ₃ and R ₄ are independently hydrogen; R ₅ is selected from

; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl or C _3-8 cycloalkylC _1-6 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z; each R z is independently: fluorine, chlorine, bromine, iodine or C _1-6 alkyl; R ₈ and R ₉ are hydrogen or C _1-6 alkyl; X is selected from C; Y is selected from O. The compound of claim 16, characterized in that it is selected from the compound represented by formula (Va) or formula (Vb) and stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts thereof;

in,

for

; R ₃ and R ₄ are independently hydrogen; R ₆ is C _1-6 alkyl; R ₇ is C _1-6 alkyl, C _3-8 cycloalkyl or C _3-8 cycloalkylC _1-6 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z; each R z is independently: fluorine, chlorine, bromine, iodine or C _1-6 alkyl; R ₈ and R ₉ are hydrogen or C _1-6 alkyl. The compound as described in claim 17 is characterized in that: _R6 is _C1-3 alkyl; _R7 is _C1-3 alkyl, _C3-5 cycloalkyl or _{C3-4 cycloalkylC1-3} alkyl; wherein _R7 is unsubstituted or substituted by 1, 2 or 3 Rz; each Rz is independently: fluorine, chlorine, bromine, iodine or _C1-4 alkyl; _R8 and _R9 are hydrogen or _C1-3 alkyl. The compound of claim 17, characterized in that: R ₆ is C _1-3 alkyl; R ₇ is C _1-3 alkyl, C _3-5 cycloalkyl or C _3-4 cycloalkyl C _1-3 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z; each R z is independently fluorine or methyl; R ₈ and R ₉ are hydrogen or methyl. The compound as described in any one of claims 1 to 3, characterized in that it is selected from the compound represented by formula (VI), formula (VIa), or formula (VIb), and stereoisomers, tautomers, hydrates, esters, or pharmaceutically acceptable salts thereof;

R ₁₀ and R ₁₁ are independently selected from -CH ₂ - or O, and at least one of them is O; R ₁₂ is -CH ₂ - or -CH ₂ -CH ₂ -; when R ₁₂ is -CH ₂ -, R ₁₀ and R ₁₁ are independently selected from -CH ₂ - or O, and at least one of them is O; when R ₁₂ is -CH ₂ -CH ₂ -, R ₁₀ and R ₁₁ are both O, or R ₁₀ is -CH ₂ -, R ₁₁ is O; R ₇ is C _1-3 alkyl, C _3-6 cycloalkyl or C _3-6 cycloalkylC _1-4 alkyl; wherein R ₇ is unsubstituted or substituted by 1, 2 or 3 R z. The compound as claimed in claim 1 is characterized in that it is selected from the following compounds and their stereoisomers, tautomers, hydrates, esters or pharmaceutically acceptable salts:

A use of a compound as described in claim 1 in the preparation of a drug for treating a disease or condition associated with saliva corticosteroids. The use as described in claim 22 is characterized in that the drug is used to treat or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure or stroke. A use of a compound as described in claim 1 in the preparation of a drug, characterized in that the drug is used as a halocorticoid receptor antagonist.