Pharmaceutical preparation containing phenyl-substituted dihydronaphthyridine compound, and use thereof

Abstract

Disclosed in the present invention are a pharmaceutical preparation containing a phenyl-substituted dihydronaphthyridine compound and the use thereof, which belong to the technical field of medicine. The pharmaceutical preparation and a compound crystal disclosed in the present invention can be used as a mineralocorticoid receptor antagonist for treating, preventing or alleviating diseases, such as hyperaldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure and stroke, in patients.

Description

Pharmaceutical preparations and uses of dihydronaphthyridine compounds containing phenyl groups Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to pharmaceutical preparations and uses of dihydronaphthyridine compounds containing phenyl substitution. Background Art

[0002] The mineralocorticoid receptor (MR) is an aldosterone-activated nuclear hormone receptor that regulates the expression of numerous genes involved in electrolyte homeostasis and cardiovascular disease. Increased circulating aldosterone elevates blood pressure through its effects on urinary sodium excretion, potentially impacting the brain, heart, and vascular system. Furthermore, hyperaldosteronism is associated with numerous pathological processes leading to renal and cardiovascular disease. Although hyperaldosteronism is typically caused by aldosterone-producing adenomas, patients with refractory hypertension often have elevated aldosterone levels, often referred to as "aldosterone escape," due to elevated serum potassium or residual AT1R activity. Hyperaldosteronism and aldosterone escape typically result in elevated MR activity, and MR antagonists have been shown to be effective antihypertensive agents and are also effective in treating heart failure and primary aldosteronism. Furthermore, MR antagonists have been shown to be effective in preclinical models of renal disease and can be used in combination with standard therapies to reduce proteinuria in patients with renal diseases, such as chronic kidney disease, including diabetic nephropathy.

[0003] Aldosterone is a steroid hormone formed in the adrenal cortex. Its production depends greatly on renal blood flow and is indirectly regulated. Any reduction in renal blood flow leads to the release of renin in the kidney and its entry into the circulating blood. This in turn activates the formation of angiotensin II, which has a contractile effect on arterial blood vessels on the one hand, but also stimulates the formation of aldosterone in the adrenal cortex on the other hand. Thus, the kidney serves as a blood pressure sensor in the blood circulation and indirectly as a volume sensor, and the renin-angiotensin-aldosterone system offsets the severe loss of volume, on the one hand by increasing blood pressure (angiotensin II effect) and on the other hand by increasing the reabsorption of sodium and water in the kidney to rebalance the filling state of the vascular system (aldosterone effect). This control system may be pathologically damaged in various ways. For example, a chronic reduction in renal blood flow (e.g., due to heart failure and the resulting blood obstruction in the venous system) leads to excessive release of aldosterone. This is followed by an expansion of blood volume and thus weakening the heart by increasing the supply of blood volume to the heart. This can lead to congestion of blood in the lungs, shortness of breath, edema of the extremities, ascites, and pleural effusions; renal blood flow is further reduced. Furthermore, the effects of excessive aldosterone lead to a decrease in potassium concentrations in the blood and extracellular fluid. In previously damaged myocardium, if levels fall below a critical minimum, arrhythmias with potentially fatal consequences can occur. This is likely one of the main causes of sudden cardiac death, which frequently occurs in patients with heart failure.

[0004] In addition, aldosterone is also considered to be the cause of many myocardial remodeling processes commonly observed in heart failure. Therefore, hyperaldosteronism is the key to the pathogenesis and prognosis of heart failure (which is initially induced by various types of damage 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 rate 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)).

[0005] In addition, 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)).

[0006] Elevated aldosterone levels or excessive stimulation of the mineralocorticoid receptor 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 excessive catecholamine levels (Hadley, ME, ENDOCRINOLOGY, 2nd Ed., pp366-81, (1988); and Brilla et al., Journal of Molecular and Cellular Cardiology, 25(5), pp563-75 (1993)). Compounds and / or pharmaceutical compositions having MR antagonistic activity have therapeutic value for any of the above conditions.

[0007] While mineralocorticoid receptor antagonists have made significant progress in treating hypertension and heart failure, 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.

[0008] Summary of the Invention

[0009] The present invention provides a phenyl-substituted dihydronaphthyridine compound having a mineralocorticoid receptor (MR) antagonistic effect, a compound crystal, and use of the compound in preparing a medicament. The medicament is used to treat, prevent or alleviate diseases such as hyperaldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, cirrhosis, renal failure and stroke in patients.

[0010] 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,

[0011] in, for

[0012] R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, 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;

[0013] R5 is

[0014] R6 is 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, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0015] for

[0016] X is C or N;

[0017] Y is O or S;

[0018] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, heteroaryl composed of 5-6 atoms, C 3-8 Cycloalkyl C 1-6 Alkyl, (heterocyclic group consisting of 3-8 atoms) C 1-6 Alkyl, (heteroaryl composed of 5-6 atoms) C 1-6 Alkyl, phenyl or phenyl C 1-6 Alkyl; R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0019] Each Rz is independently =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; wherein each Rz is independently unsubstituted or substituted with 1, 2, 3 or 4 Rw;

[0020] 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 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl.

[0021] for

[0022] R8, R9 are hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 haloalkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3 to 8 atoms or heteroaryl group consisting of 5 to 10 atoms.

[0023] 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,

[0024] in, for

[0025] R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, 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;

[0026] R5 is

[0027] R6 is hydrogen, deuterium, C 1-6Alkyl, 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, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0028] for

[0029] X is C or N;

[0030] Y is O or S;

[0031] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, heteroaryl composed of 5-6 atoms, C 3-8 Cycloalkyl C 1-6 Alkyl, (heterocyclic group consisting of 3-8 atoms) C 1-6 Alkyl, (heteroaryl composed of 5-6 atoms) C 1-6 Alkyl, phenyl or phenyl C 1-6 Alkyl; R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0032] Each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; wherein each Rz is independently unsubstituted or substituted with 1, 2, 3 or 4 Rw;

[0033] 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 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C6-10 aryl;

[0034] for

[0035] R8, R9 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, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0036] R 10 and R 11 are independently selected from -CH2- or O, and at least one is O;

[0037] R 12 is -CH2- or -CH2-CH2-; when R 12 -CH2-, R 10 and R 11 are independently selected from -CH2- or O, and at least one of them is O; when R 12 -CH2-CH2-, R 10 and R 11 O or R at the same time 10 -CH2-, R 11 It is O.

[0038] In some embodiments, the compound represented by formula (I) of the present invention is selected from the compound represented by formula (Ia) or formula (Ib); further preferably, the compound represented by formula (Ia);

[0039] In some embodiments, the compound represented by formula (I) of the present invention is selected from the compound represented by formula (Ia) or formula (Ib); more preferably, the compound represented by formula (Ia);

[0040] in, R1, R2, R3, R4, R5, R6, R7, R8, R9, X and Y have the meanings described in the present invention.

[0041] In some embodiments, each of R1, R2, R3 and R4 is independently hydrogen, deuterium, amino, hydroxyl, thiol, cyano, nitro, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4Halogenated alkoxy, C 1-4 Alkylamino, carboxyl, C 1-4 Alkanoyl, C 1-4 Alkylsulfonyl, aminoacyl, aminosulfonyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-6 atoms or heteroaryl group consisting of 5-6 atoms;

[0042] R6 is hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-6 atoms or heteroaryl group consisting of 5-6 atoms;

[0043] Each R8 and R9 is independently hydrogen, deuterium, halogen, cyano, C 1-4 Alkoxy acyl, 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 Alkanoyl, C 1-4 alkylsulfonyl, aminoacyl or aminosulfonyl;

[0044] In some embodiments, each of R1, R2, R3 and R4 is independently hydrogen, deuterium, amino, hydroxyl, thiol, 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;

[0045] R6 is hydrogen, deuterium, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxiranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrrolyl, thiazolyl, pyrazolyl or pyrimidinyl;

[0046] R8 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.

[0047] In some embodiments, the compound of the present invention is selected from the compound represented by formula (II):

[0048] In some embodiments, the compound of the present invention is selected from the compound represented by formula (IIa) or formula (IIb):

[0049] In some embodiments, R7 is C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, heteroaryl composed of 5-6 atoms, C 3-6 Cycloalkyl C 1-4 Alkyl, (heterocyclic group consisting of 3-6 atoms) C 1-4 Alkyl or (heteroaryl consisting of 5-6 atoms) C 1-4 Alkyl; wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

[0050] In some embodiments, R7 is C 1-3 Alkyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; preferably, R7 is methyl, ethyl, isopropyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz.

[0051] In some embodiments, R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl ...ethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl, pyrim pyridinylmethyl, imidazolylethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl; wherein R is unsubstituted or substituted with 1, 2, 3 or 4 Rs.

[0052] In some embodiments, each Rz is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; 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, 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 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl.

[0053] 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, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or phenyl; wherein each Rz is independently is unsubstituted or substituted with 1, 2, 3 or 4 Rw; each Rw is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, 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, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl.

[0054] In some embodiments, the compound is selected from the group consisting of:

[0055] Wherein, R5 is selected from

[0056] In some embodiments,

[0057] R1, R2, R3, and R4 are independently hydrogen, deuterium, C 1-6 alkoxy;

[0058] R5 is

[0059] R6 is selected from hydrogen, deuterium, C 1-6 alkyl.

[0060] In some embodiments,

[0061] R1, R2, R3, and R4 are independently hydrogen, deuterium, C 1-3 alkoxy;

[0062] R5 is

[0063] R6 is selected from hydrogen, deuterium, C 1-3 alkyl.

[0064] In some embodiments,

[0065] R1, R2, R3, and R4 are independently hydrogen, deuterium, or methoxy;

[0066] R5 is

[0067] R6 is selected from hydrogen, deuterium, and methyl.

[0068] In some embodiments, the compound is selected from the group consisting of:

[0069] in, for

[0070] R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1-6 alkoxy;

[0071] R5 is selected from

[0072] R6 is C 1-6 alkyl;

[0073] R7 is C 1-6 alkyl;

[0074] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0075] Y is selected from O;

[0076] X is selected from C.

[0077] In some embodiments,

[0078] R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1-3 alkoxy;

[0079] R6 is C 1-3 alkyl;

[0080] R7 is C 1-3 alkyl;

[0081] R8, R9 are hydrogen, deuterium, C 1-3 alkyl.

[0082] In some embodiments, the compound is selected from the group consisting of:

[0083] in, for

[0084] R3 and R4 are independently hydrogen or deuterium;

[0085] R5 is selected from

[0086] R6 is C 1-6 alkyl;

[0087] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: halogen;

[0088] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0089] X is selected from C;

[0090] Y is selected from O.

[0091] In some embodiments,

[0092] R6 is C 1-3 alkyl;

[0093] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: fluorine, chlorine, bromine, iodine;

[0094] R8, R9 are hydrogen, deuterium, C 1-3 alkyl.

[0095] In some embodiments,

[0096] R6 is C 1-3 alkyl;

[0097] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently fluorine;

[0098] R8 and R9 are hydrogen or methyl.

[0099] In some embodiments, the compound is selected from the group consisting of:

[0100] in, for

[0101] R3 and R4 are independently hydrogen or deuterium;

[0102] R5 is selected from

[0103] R6 is C 1-6 alkyl;

[0104] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: halogen, C 1-6 alkyl;

[0105] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0106] X is selected from C;

[0107] Y is selected from O.

[0108] In some embodiments, the compound is selected from the group consisting of:

[0109] in, for

[0110] R3 and R4 are independently hydrogen or deuterium;

[0111] R5 is selected from

[0112] R6 is C 1-6 alkyl;

[0113] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: halogen, C 1-6 alkyl;

[0114] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0115] X is selected from C;

[0116] Y is selected from O.

[0117] In the above formula (V), formula (Va) and formula (Vb),

[0118] R6 is C 1-3 alkyl;

[0119] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: fluorine, chlorine, bromine, iodine, C 1-4 alkyl;

[0120] R8, R9 are hydrogen, deuterium, C 1-3 alkyl.

[0121] Furthermore,

[0122] R6 is C 1-3 alkyl;

[0123] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently fluoro or methyl;

[0124] R8 and R9 are hydrogen or methyl.

[0125] In some embodiments, the compound is selected from the compounds represented by Formula (VI), Formula (VIa), or Formula (VIb);

[0126] R 10 and R 11 are independently selected from -CH2- or O, and at least one is O;

[0127] R 12 is -CH2- or -CH2-CH2-; when R 12 -CH2-, R 10 and R 11 are independently selected from -CH2- or O, and at least one of them is O; when R 12 -CH2-CH2-, R 10 and R 11 At the same time, O or R 10 -CH2-, R 11 is O;

[0128] R7 is C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, heteroaryl composed of 5-6 atoms, C 3-6Cycloalkyl C 1-4 Alkyl, (heterocyclic group consisting of 3-6 atoms) C 1-4 Alkyl or (heteroaryl consisting of 5-6 atoms) C 1-4 Alkyl; wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0129] Preferably, R7 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl , cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, Morpholinylethyl, pyrrolylmethyl, pyrrolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, thiazolylmethyl, thiazolylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl; wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0130] Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; 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, 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 Alkylsulfonyl, C1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 aryl;

[0131] Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl; wherein each Rz is independently substituted. wherein R is independently substituted or substituted with 1, 2, 3 or 4 R; each R is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, cyano, NH, 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, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl.

[0132] 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;

[0133] in, Choose from and R4 are independently hydrogen or deuterium; R6 is hydrogen, deuterium, C 1-6 Alkyl; R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C3-8 cycloalkylC1-6 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, NH 2、; R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0134] In the compound represented by (I-10), (I-11) or (I-12), R6 is C 1-4 Alkyl is further selected from hydrogen, methyl, ethyl, propyl, and butyl;

[0135] In the compound represented by (I-10), (I-11) or (I-12), each R8 and R9 are independently hydrogen, deuterium, halogen, C 1-4 alkyl;

[0136] In the compound represented by (I-10), (I-11) or (I-12), R8 is independently hydrogen, methyl, ethyl, propyl or butyl, and R9 is independently hydrogen or deuterium;

[0137] 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;

[0138] In the compound represented by (I-10), (I-11) or (I-12), R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

[0139] In the compound represented by (I'-10), (I'-11) or (I'-12), R7 is a methyl group or an ethyl group.

[0140] In the compound represented by (I'-10), (I'-11) or (I'-12), R7 is substituted by 1-3 Fs.

[0141] In some embodiments, the compound is selected from:

[0142] In the present invention, the compound does not have the situation where R1, R2, and R3 are hydrogen, R4 is methoxy, R5 is -CONH2, and R6 is hydrogen.

[0143] In one aspect, the present invention relates to a pharmaceutical preparation comprising (i) any one or more of a first component and a second component, and (ii) a pharmaceutically acceptable excipient.

[0144] wherein the first component is selected from the compound represented by formula (I) and its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs;

[0145] Wherein, the second component is selected from any one or more of the crystal forms of the compound represented by formula (I) or one or more of the crystal forms of the salt of the compound represented by formula (I);

[0146] in, for

[0147] R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, 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;

[0148] R5 is

[0149] R6 is 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, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0150] for

[0151] X is C or N;

[0152] Y is O or S;

[0153] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, heteroaryl composed of 5-6 atoms, C 3-8 Cycloalkyl C 1-6 Alkyl, (heterocyclic group consisting of 3-8 atoms) C 1-6Alkyl, (heteroaryl composed of 5-6 atoms) C 1-6 Alkyl, phenyl or phenyl C 1-6 Alkyl; R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0154] Each Rz is independently =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; wherein each Rz is independently unsubstituted or substituted with 1, 2, 3 or 4 Rw;

[0155] 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 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl.

[0156] for

[0157] R8, R9 are hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 halogenated alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 aryl, heterocyclic group consisting of 3 to 8 atoms or heteroaryl group consisting of 5 to 10 atoms.

[0158] In one aspect, the present invention relates to a pharmaceutical preparation comprising (i) any one or more of a first component and a second component, and (ii) a pharmaceutically acceptable excipient.

[0159] wherein the first component is selected from the compound represented by formula (I) and its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs;

[0160] Wherein, the second component is selected from any one or more of the crystal forms of the compound represented by formula (I) or one or more of the crystal forms of the salt of the compound represented by formula (I);

[0161] in, for

[0162] R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, 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;

[0163] R5 is

[0164] R6 is 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, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0165] for

[0166] X is C or N;

[0167] Y is O or S;

[0168] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group composed of 3-8 atoms, heteroaryl composed of 5-6 atoms, C 3-8 Cycloalkyl C 1-6 Alkyl, (heterocyclic group consisting of 3-8 atoms) C 1-6Alkyl, (heteroaryl composed of 5-6 atoms) C 1-6 Alkyl, phenyl or phenyl C 1-6 Alkyl; R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0169] Each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Halogenated alkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; wherein each Rz is independently unsubstituted or substituted with 1, 2, 3 or 4 Rw;

[0170] 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 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 aryl;

[0171] for

[0172] R8, R9 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, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0173] R 10 and R 11 are independently selected from -CH2- or O, and at least one is O;

[0174] R 12 is -CH2- or -CH2-CH2-; when R 12-CH2-, R 10 and R 11 are independently selected from -CH2- or O, and at least one of them is O; when R 12 -CH2-CH2-, R 10 and R 11 O or R at the same time 10 -CH2-, R 11 It is O.

[0175] In some embodiments, the compound represented by formula (I) of the present invention is selected from the compound represented by formula (Ia) or formula (Ib); more preferably, the compound represented by formula (Ia);

[0176] In some embodiments, the compound represented by formula (I) of the present invention is selected from the compound represented by formula (Ia) or formula (Ib); more preferably, the compound represented by formula (Ia);

[0177] in, R1, R2, R3, R4, R5, R6, R7, R8, R9, X and Y have the meanings described in the present invention.

[0178] In some embodiments, each of R1, R2, R3 and R4 is independently hydrogen, deuterium, amino, hydroxyl, thiol, 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 Alkanoyl, C 1-4 Alkylsulfonyl, aminoacyl, aminosulfonyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-6 atoms or heteroaryl group consisting of 5-6 atoms;

[0179] R6 is hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkylamino, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-6 atoms or heteroaryl group consisting of 5-6 atoms;

[0180] Each R8 and R9 is independently hydrogen, deuterium, halogen, cyano, C 1-4 Alkoxy acyl, carboxyl, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C 1-4 Alkylamino, C 1-4 Alkanoyl, C 1-4 alkylsulfonyl, aminoacyl or aminosulfonyl;

[0181] In some embodiments, each of R1, R2, R3 and R4 is independently hydrogen, deuterium, amino, hydroxyl, thiol, 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;

[0182] R6 is hydrogen, deuterium, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxiranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl, pyrrolyl, thiazolyl, pyrazolyl or pyrimidinyl;

[0183] R8 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.

[0184] In some embodiments, the compound of the present invention is selected from the compound represented by formula (II):

[0185] In some embodiments, the compound of the present invention is selected from the compound represented by formula (IIa) or formula (IIb):

[0186] In some embodiments, R7 is C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, heteroaryl composed of 5-6 atoms, C 3-6 Cycloalkyl C 1-4 Alkyl, (heterocyclic group consisting of 3-6 atoms) C 1-4 Alkyl or (heteroaryl consisting of 5-6 atoms) C 1-4Alkyl; wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz.

[0187] In some embodiments, R7 is C 1-3 Alkyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; preferably, R7 is methyl, ethyl, isopropyl, wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz.

[0188] In some embodiments, R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl ...ethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl, pyrim pyridinylmethyl, imidazolylethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl; wherein R is unsubstituted or substituted with 1, 2, 3 or 4 Rs.

[0189] In some embodiments, each Rz is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; 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, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl, C 1-4 Halogenated alkoxy, C1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl.

[0190] 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, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thiophenyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or phenyl; wherein each Rz is independently is unsubstituted or substituted with 1, 2, 3 or 4 Rw; each Rw is independently =0, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, 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, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl.

[0191] In some embodiments, the compound is selected from the group consisting of:

[0192] Wherein, R5 is selected from

[0193] In some embodiments,

[0194] R1, R2, R3, and R4 are independently hydrogen, deuterium, C 1-6 alkoxy;

[0195] R5 is

[0196] R6 is selected from hydrogen, deuterium, C 1-6 alkyl.

[0197] In some embodiments,

[0198] R1, R2, R3, and R4 are independently hydrogen, deuterium, C 1-3 alkoxy;

[0199] R5 is

[0200] R6 is selected from hydrogen, deuterium, C 1-3 alkyl.

[0201] In some embodiments,

[0202] R1, R2, R3, and R4 are independently hydrogen, deuterium, or methoxy;

[0203] R5 is

[0204] R6 is selected from hydrogen, deuterium, and methyl.

[0205] In some embodiments, the compound is selected from the group consisting of:

[0206] in, for

[0207] R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1-6 alkoxy;

[0208] R5 is selected from

[0209] R6 is C 1-6 alkyl;

[0210] R7 is C 1-6 alkyl;

[0211] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0212] Y is selected from O;

[0213] X is selected from C.

[0214] In some embodiments,

[0215] R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1-3 alkoxy;

[0216] R6 is C 1-3 alkyl;

[0217] R7 is C 1-3 alkyl;

[0218] R8, R9 are hydrogen, deuterium, C 1-3 alkyl.

[0219] In some embodiments, the compound is selected from the group consisting of:

[0220] in, for

[0221] R3 and R4 are independently hydrogen or deuterium;

[0222] R5 is selected from

[0223] R6 is C 1-6 alkyl;

[0224] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: halogen;

[0225] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0226] X is selected from C;

[0227] Y is selected from O.

[0228] In some embodiments,

[0229] R6 is C 1-3 alkyl;

[0230] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: fluorine, chlorine, bromine, iodine;

[0231] R8, R9 are hydrogen, deuterium, C 1-3 alkyl.

[0232] In some embodiments,

[0233] R6 is C 1-3 alkyl;

[0234] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently fluorine;

[0235] R8 and R9 are hydrogen or methyl.

[0236] In some embodiments, the compound is selected from the group consisting of:

[0237] in, for

[0238] R3 and R4 are independently hydrogen or deuterium;

[0239] R5 is selected from

[0240] R6 is C 1-6 alkyl;

[0241] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: halogen, C 1-6 alkyl;

[0242] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0243] X is selected from C;

[0244] Y is selected from O.

[0245] In some embodiments, the compound is selected from the group consisting of:

[0246] in, for

[0247] R3 and R4 are independently hydrogen or deuterium;

[0248] R5 is selected from

[0249] R6 is C 1-6 alkyl;

[0250] R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkyl C 1-6 wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: halogen, C 1-6 alkyl;

[0251] R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0252] X is selected from C;

[0253] Y is selected from O.

[0254] In the above formula (V), formula (Va) and formula (Vb),

[0255] R6 is C 1-3 alkyl;

[0256] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently: fluorine, chlorine, bromine, iodine, C 1-4 alkyl;

[0257] R8, R9 are hydrogen, deuterium, C 1-3 alkyl.

[0258] Furthermore,

[0259] R6 is C 1-3 alkyl;

[0260] R7 is C 1-3 Alkyl, C 3-5 Cycloalkyl, C 3-4 Cycloalkyl C 1-3 Alkyl; wherein R7 is unsubstituted or substituted by 1, 2, 3 or 4 Rz; each Rz is independently fluoro or methyl;

[0261] R8 and R9 are hydrogen or methyl.

[0262] In some embodiments, the compound is selected from the compounds represented by Formula (VI), Formula (VIa), or Formula (VIb);

[0263] R 10 and R 11 are independently selected from -CH2- or O, and at least one is O;

[0264] R 12 is -CH2- or -CH2-CH2-; when R 12 -CH2-, R 10 and R 11 are independently selected from -CH2- or O, and at least one of them is O; when R 12 -CH2-CH2-, R 10 and R11 At the same time, O or R 10 -CH2-, R 11 is O;

[0265] R7 is C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group composed of 3-6 atoms, heteroaryl composed of 5-6 atoms, C 3-6 Cycloalkyl C 1-4 Alkyl, (heterocyclic group consisting of 3-6 atoms) C 1-4 Alkyl or (heteroaryl consisting of 5-6 atoms) C 1-4 Alkyl; wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0266] Preferably, R7 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, azetidinylmethyl, azetidinylethyl, oxetanylmethyl, oxetanylethyl, pyrrolidinylmethyl , pyrrolidinylethyl, tetrahydrofuranylmethyl, tetrahydrofuranylethyl, tetrahydrothienylmethyl, tetrahydrothienylethyl, piperidinylmethyl, piperidinylethyl, piperazinylmethyl, piperazinylethyl, morpholinylmethyl, morpholinylethyl, pyrrolylmethyl, pyrrolylethyl, furanylmethyl, furanylethyl, thienylmethyl, thienylethyl, thiazolylmethyl, thiazolylethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl or pyrimidinylethyl; wherein R7 is unsubstituted or substituted with 1, 2, 3 or 4 Rz;

[0267] Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Halogenated alkyl, C 1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10Aryl; 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, 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 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 aryl;

[0268] Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, 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

[0269] O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, trifluoromethoxy, monofluoromethoxy, difluoromethoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, methylamino, ethylamino, dimethylamino, methylethylamino, diethylamino, methylsulfonyl, ethylsulfonyl, methylacyl, ethylacyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or phenyl.

[0270] 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;

[0271] in, Choose from and R4 are independently hydrogen or deuterium; R6 is hydrogen, deuterium, C 1-6 Alkyl; R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C3-8 cycloalkylC1-6 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, NH 2、 ; R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0272] In the compound represented by (I-10), (I-11) or (I-12), R6 is C 1-4 Alkyl is further selected from hydrogen, methyl, ethyl, propyl, and butyl;

[0273] In the compound represented by (I-10), (I-11) or (I-12), each R8 and R9 are independently hydrogen, deuterium, halogen, C 1-4 alkyl;

[0274] In the compound represented by (I-10), (I-11) or (I-12), R8 is independently hydrogen, methyl, ethyl, propyl or butyl, and R9 is independently hydrogen or deuterium;

[0275] 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;

[0276] In the compound represented by (I-10), (I-11) or (I-12), R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

[0277] In the compound represented by (I'-10), (I'-11) or (I'-12), R7 is a methyl group or an ethyl group.

[0278] In the compound represented by (I'-10), (I'-11) or (I'-12), R7 is substituted by 1-3 Fs.

[0279] In some embodiments, the compound is selected from:

[0280] In the present invention, the compound does not have the situation where R1, R2, and R3 are hydrogen, R4 is methoxy, R5 is -CONH2, and R6 is hydrogen.

[0281] In some embodiments, in the pharmaceutical preparation of the present invention, component (i) is used as the active ingredient, and the mass content of component (i) in the preparation is greater than 0.1% and less than 0.5%, greater than 0.5% and less than 95%, greater than 95% and less than 99.5%, or greater than 99.5% and less than 100%, preferably 0.2%-0.4%, 0.6%-94%, 96%-99.4%, or 99.6%-99.9%, such as 0.3%, 1%, 2%, 93%, 94%, 96%, 98%, and 99%.

[0282] In some embodiments, the pharmaceutical preparation is a solid preparation; in some embodiments, the pharmaceutical preparation is an oral preparation, including a capsule or a tablet.

[0283] In some embodiments, the pharmaceutically acceptable excipients include solvents and fillers.

[0284] In one aspect, the present invention provides a crystal of a compound and a salt thereof, selected from the compound shown in Formula VII:

[0285] in,

[0286] for

[0287] R3 and R4 are independently selected from hydrogen and deuterium;

[0288] R5 is selected from

[0289] R6-R8 are independently selected from C 1-3 alkyl;

[0290] R9 is hydrogen or deuterium;

[0291] X is selected from C;

[0292] Y is selected from O.

[0293] In some embodiments, the compound in the crystals of the compound and its salt is compound 36, with the following structural formula:

[0294] The crystal structure of compound 36 belongs to the monoclinic system, C2 space group, and the unit cell parameters are α=90°,β=112.7428(8)°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z = 4.

[0295] The crystal of compound 36 or its crystalline form has an XRPD pattern as shown in FIG4 or substantially as shown in FIG4 , where “substantially” means that the difference in the number of peaks is within 85%.

[0296] In some embodiments, the crystalline form of compound 36 is a free base crystalline form; preferably, the free base crystalline form is free base crystalline form I; preferably, the X-ray diffraction patterns of the free base crystalline form and the free base crystalline form I include a diffraction peak located at 9.35±0.2°, 2θ, preferably include diffraction peaks located at 8.16±0.2°, 9.35±0.2°, 12.80±0.2°, 21.92±0.2°, 22.10±0.2°, and 24.38±0.2°, 2θ; preferably, the X-ray diffraction pattern of the free base crystalline form is shown in Figure 37.

[0297] In some embodiments, the crystals of the compound and its salt are acid salts of compound 36;

[0298] The acid in the acid salt is selected from hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, malic acid, and succinic acid, preferably hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, and phosphoric acid, and more preferably benzenesulfonic acid.

[0299] The number of acids in the acid salt is 0.2-3, preferably 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0.5, 1, 2 or 3, and further preferably 1.

[0300] Wherein, the acid salt is a non-solvate or a solvate; the solvent is selected from one or more of water, methanol, ethanol, ethylene glycol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, glacial acetic acid, acetone, butanone, 3-pentanone, n-hexane, cyclohexane, n-heptane, isopropyl ether, methyl tert-butyl ether, petroleum ether, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, dichloromethane, chloroform, 1,2-dichloroethane, ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dioxane, benzene or toluene.

[0301] The number of the solvents is 0-3, preferably 0, 0.2, 0.5, 1, 1.5, 2, 2.5 or 3, more preferably 0, 0.5, 1, 2 or 3, and further preferably 1.

[0302] Wherein, the acid salt is a crystalline form or an amorphous form; preferably, the acid salt is a benzenesulfonate crystalline form; preferably, the benzenesulfonate crystalline form is benzenesulfonate crystalline form I; preferably, the X-ray diffraction pattern of the benzenesulfonate crystalline form and the benzenesulfonate crystalline form I includes a diffraction peak at 2θ of 17.31±0.2°, preferably including diffraction peaks at 2θ of 4.28±0.2°, 17.31±0.2°, and 26.12±0.2°; preferably, the X-ray diffraction pattern of the benzenesulfonate crystalline form I is shown in Figure 30.

[0303] In the present invention, the salt of compound 36 includes other crystalline forms in addition to the free base crystalline form and the benzenesulfonate crystalline form I, such as:

[0304] Hydrochloride Form I, the X-ray diffraction pattern comprises diffraction peaks located at 2θ of 8.88±0.2°, 11.15±0.2°, 24.16±0.2°, and 27.07±0.2°. Preferably, the X-ray diffraction pattern of the hydrochloride Form I is shown in Figure 11;

[0305] Hydrochloride Form II, the X-ray diffraction pattern comprises diffraction peaks at 2θ of 7.80±0.2°, 12.15±0.2°, 18.95±0.2°, 21.44±0.2°, 21.80±0.2°, 23.67±0.2°, 24.55±0.2°, 27.15±0.2°, and 31.77±0.2°. Preferably, the X-ray diffraction pattern of the hydrochloride Form II is shown in Figure 14;

[0306] Sulfate salt crystalline form I, the X-ray diffraction pattern comprises diffraction peaks at 2θ of 6.90±0.2°, 11.33±0.2°, 17.47±0.2°, 22.37±0.2°, and 22.89±0.2°. Preferably, the X-ray diffraction pattern of the sulfate salt crystalline form I is shown in FIG17 ;

[0307] The p-toluenesulfonate salt form I has an X-ray diffraction pattern comprising diffraction peaks at 2θ of 16.26±0.2° and 25.23±0.2°. Preferably, the X-ray diffraction pattern of the toluenesulfonate salt form I is shown in FIG20 ;

[0308] Tosylate salt Form II, the X-ray diffraction pattern comprises diffraction peaks at 2θ of 10.13±0.2°, 15.27±0.2°, 21.96±0.2°, 23.07±0.2°, and 26.22±0.2°. Preferably, the X-ray diffraction pattern of the tosylate salt Form II is shown in FIG23 ;

[0309] The mesylate salt crystalline form I has an X-ray diffraction pattern comprising diffraction peaks at 2θ of 8.89±0.2° and 17.94±0.2°. Preferably, the X-ray diffraction pattern of the mesylate salt crystalline form I is shown in FIG27 ;

[0310] Phosphate crystal form I, the X-ray diffraction pattern comprises diffraction peaks at 2θ of 5.96±0.2° and 12.30±0.2°. Preferably, the X-ray diffraction pattern of the phosphate crystal form I is shown in FIG34 ;

[0311] Form II, the X-ray diffraction pattern includes diffraction peaks at 2θ of 19.21±0.2°, 22.48±0.2°, 23.89±0.2°, and 24.85±0.2°. Preferably, the X-ray diffraction pattern of Form II is shown in Figure 41.

[0312] The present invention also provides another crystal of compound 62, the structural formula of compound 62 is as follows:

[0313] The crystal structure of compound 62 belongs to the monoclinic system, C2 space group, and the unit cell parameters are α=90°,β=121.6750(10)°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z = 8.

[0314] The crystal of compound 62 or its crystalline form has an XRPD pattern as shown in FIG8 or substantially as shown in FIG8 , where “substantially” means that the difference in the number of peaks is within 85%.

[0315] Regarding 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 the compound 36 belongs to the monoclinic system, the C2 space group, and the unit cell parameters are α=90°,β=112.7428(8)°,γ=90°,unit cell volume The minimum number of asymmetric units Z in the unit cell is 4; further, the crystal of compound 36 or its crystalline form has an XRPD pattern as shown in Figure 4 or substantially as shown in Figure 4, wherein the substantially refers to that the difference in the number of peaks is within 85%. The present invention also provides a crystal of compound 62, which belongs to the monoclinic system, the C2 space group, and the unit cell parameters α=90°,β=121.6750(10)°,γ=90°,unit cell volume The minimum number of asymmetric units Z in the unit cell is 8. Furthermore, the crystal of compound 62 or a crystalline form thereof has an XRPD pattern as shown in Figure 8 or substantially as shown in Figure 8, wherein substantially means that the number of peaks differs by 85% or more. The present invention also provides the use of the crystal of the compound in the preparation of a medicament, wherein the medicament is a medicament for treating or preventing a disease or condition associated with mineralocorticoids, or a medicament for treating, preventing, or alleviating the following diseases in a patient: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis, renal failure, or stroke; or, the medicament is used as a mineralocorticoid receptor antagonist.

[0316] The invention also discloses the use of the crystals of the compound and its salt in preparing medicines.

[0317] The drug is a drug for treating or preventing diseases or conditions related to mineralocorticoids, 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.

[0318] The invention also discloses the use of the crystals of the compound and its salt in preparing medicines.

[0319] wherein the drug is used as a mineralocorticoid receptor antagonist.

[0320] The present invention also discloses a high performance liquid chromatography method for resolving crystals of the above compound, wherein the chromatographic conditions are:

[0321] Chromatographic column: using cellulose-tris(3,5-dimethylphenylcarbamate) or amylose-tris(3,5-dimethylphenylcarbamate) as the stationary phase; preferably, cellulose-tris(3,5-dimethylphenylcarbamate) is used as the stationary phase when resolving the crystals of compound 36; preferably, amylose-tris(3,5-dimethylphenylcarbamate) is used as the stationary phase when resolving the crystals of compound 62;

[0322] Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol;

[0323] Liquidity B: alcohol;

[0324] Elution was performed using an isocratic elution procedure;

[0325] Preferably, compound 11 is dissolved in alcohol, and the obtained sample is resolved by high performance liquid chromatography to obtain compound 36; preferably, compound 14 is dissolved in alcohol and n-hexane, and the obtained sample is resolved by high performance liquid chromatography to obtain compound 62; the volume ratio of the alcohol and n-hexane is 15:75-95, preferably 15:80-90, preferably 15:85.

[0326] The concentration of compound 11 in the sample is 6.9-10.9 mg / mL, preferably 7.9-9.9 mg / mL, preferably 8.9 mg / mL; the concentration of compound 14 in the sample compound is 15-35 mg / mL, preferably 20-30 mg / mL, preferably 25 mg / mL.

[0327] Wherein, the diameter of the chromatographic column is 1-3 cm, preferably 1.5-2.5 cm, preferably 2 cm; preferably, the column length of the chromatographic column is 19-31 cm, preferably 22-28 cm, preferably 25 cm; preferably, the particle size of the stationary phase is 4-6 μm, preferably 4.5-5.5 μm, preferably 5 μm; preferably, when the compound is compound 36, the chromatographic column is CHIRAL ART Cellulose-SB; preferably, when the compound is compound 62, the chromatographic column is CHIRAL ART Amylose-C NEO.

[0328] Wherein, the alcohol is a C1-C6 alcohol, preferably a C1-C3 alcohol, preferably methanol and / or ethanol; preferably, the concentration of ammonia in the mixed solution of n-hexane, ammonia and alcohol is 5-15 mmol / L, preferably 8-12 mmol / L, preferably 10 mmol / L; preferably, when splitting the crystals of compound 36, the volume ratio of alcohol to n-hexane in the mixed solution of n-hexane, ammonia and alcohol is 1:2-6, preferably 1:3-5, preferably 1:4; preferably, when splitting the crystals of compound 36, the amount ratio of alcohol to n-hexane in the mixed solution of n-hexane, ammonia and alcohol is 1:7-11, preferably 1:8-10, preferably 1:9.

[0329] Wherein, the volume percentage of fluidity B in the isocratic elution procedure is 4%-30%, preferably 7%-25%, preferably 10%-20%; preferably, when the compound is compound 36, the volume percentage of fluidity B in the isocratic elution procedure is 10%-30%, preferably 15%-25%, preferably 20%; preferably, when the compound is compound 62, the volume percentage of fluidity B in the isocratic elution procedure is 4%-16%, preferably 7%-13%, preferably 10%.

[0330] Wherein, the flow rate is 16-24 mL / min, preferably 18-22 mL / min, preferably 20 mL / min.

[0331] Wherein, an ultraviolet detector is used for detection; preferably, dual-wavelength detection is used; preferably, when splitting the crystals of compound 36, the first wavelength is 212-226 nm, preferably 216-222 nm, preferably 218 nm, and the second wavelength is 262-278 nm, preferably 266-274 nm, preferably 270 nm; preferably, when splitting the crystals of compound 62, the first wavelength is 208-222 nm, preferably 212-218 nm, preferably 214 nm, and the second wavelength is 246-262 nm, preferably 250-258 nm, preferably 254 nm.

[0332] Wherein, when the compound is compound 36, the chromatographic conditions are:

[0333] Chromatographic column: Chiral column CHIRAL ART Cellulose-SB, 2*25cm, 5μm;

[0334] Mobile phase A: a mixed solution of n-hexane, ammonia, and alcohol, with an ammonia concentration of 10 mmol / L n-hexane and a volume ratio of alcohol to n-hexane of 1:4;

[0335] Mobile phase B: ethanol;

[0336] Flow rate: 20 mL / min;

[0337] Isocratic elution: 20vt% mobile phase B and 80vt% mobile phase A;

[0338] Elution time: 15 min;

[0339] Wavelength: 218 / 270nm;

[0340] Wherein, when the compound is compound 62, the chromatographic conditions are:

[0341] Chromatographic column: Chiral column CHIRAL ART Amylose-C NEO;

[0342] Mobile phase A: a mixed solution of n-hexane, ammonia, and alcohol, with an ammonia concentration of 10 mmol / L n-hexane and a volume ratio of alcohol to n-hexane of 1:9;

[0343] Mobile phase B: ethanol;

[0344] Flow rate: 20 mL / min;

[0345] Isocratic elution: 10vt% mobile phase B and 90vt% mobile phase A;

[0346] Elution time: 28 min;

[0347] Wavelength: 214 / 254nm.

[0348] Furthermore, the present invention discloses a pharmaceutical preparation containing compound 36 and / or compound 62, and pharmaceutically acceptable excipients.

[0349] 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 mineralocorticoids.

[0350] 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.

[0351] Or, wherein the medicament is used as a mineralocorticoid receptor antagonist.

[0352] The mineralocorticoid-related disease or disorder is selected from the group consisting of diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke.

[0353] The tris(3,5-dimethylphenylcarbamate) structural formula of the present invention is as follows:

[0354] Definitions and General Terms

[0355] Certain embodiments of the present invention are now described in detail, examples of which are illustrated by the accompanying structural formulas and chemical formulae. The present invention is intended to encompass all substitutions, modifications, and equivalent technical solutions, which are all included within the scope of the invention as defined in the claims. Those skilled in the art will 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 combined documents, patents, and similar materials differ from or contradict the present application (including but not limited to defined terms, term applications, described technologies, etc.), the present application shall prevail.

[0356] It will be further appreciated that certain features of the invention, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which, for brevity, are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0357] Unless otherwise specified, all technical terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.

[0358] Unless otherwise indicated, the following definitions as used herein shall apply. For purposes of the present invention, the chemical elements are referred to in accordance with the Periodic Table of the Elements, CAS version, and Handbook of Chemistry and Physics, 75th edition, 1994. In addition, general principles of organic chemistry may 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.

[0359] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more than one (i.e., at least one) of the objects. For example, "a component" refers to one or more components, i.e., more than one component may be contemplated for use or use in implementing the described embodiments.

[0360] 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.

[0361] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0362] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0363] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0364] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0365] Stereochemical definitions and conventions used herein generally follow SP 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.

[0366] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can 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 terms of the (R)- or (S)-configuration.

[0367] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, and diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0368] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be converted into each other through 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 known as prototropic tautomers) include interconversions performed by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions performed by the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-ene-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0369] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as described in the specific examples, subclasses, and classes of compounds encompassed by the present invention.

[0370] In addition, it should be noted that, unless otherwise expressly stated, the descriptions used in the present invention such as "each ... independently is" and "... each independently is" are interchangeable and should be understood in a broad sense. They can mean that specific options expressed by the same symbols in different groups do not affect each other, or that specific options expressed by the same symbols in the same group do not affect each other. Similarly, the word "independent" in the description "... independently optionally" should also be understood in the above broad sense.

[0371] The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, ie, the description includes instances where said event or circumstance occurs and instances where it does not.

[0372] In various parts of this specification, substituents of compounds disclosed herein are disclosed in terms of group types or ranges. It is specifically noted that the present invention includes every independent subcombination of the individual members of these group types and ranges. For example, the term "C1-C6 alkyl" or "C 1-6 "Alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl disclosed independently; "C 1-4The term "alkyl" specifically refers to methyl, ethyl, C3 alkyl (i.e., propyl, including n-propyl and isopropyl) and C4 alkyl (i.e., butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl) disclosed independently.

[0373] In various parts of the present 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 a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0374] The term "alkyl" or "alkyl group" as used herein refers to a saturated, linear or branched, monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein. 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 some embodiments, the alkyl group contains 1-3 carbon atoms, i.e., C 1-3 In some embodiments, the C 1-6 Alkyl groups include C 1-4 In other embodiments, the C 1-6 Alkyl groups include C 1-3 alkyl.

[0375] 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.

[0376] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy and 2-propoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy), and the like.

[0377] The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which 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, and the like.

[0378] The term "amino" refers to the group -NH2. The term "carboxyl" refers to the group -COOH. The terms "hydroxy," "cyano," "nitro," and "mercapto" refer to the groups -OH, -CN, -NO2, and -SH, respectively. The term "oxo" refers to the group =O.

[0379] The term "alkylamino" or "alkylamino" refers to a group -NH2 substituted with one or two alkyl groups, i.e., the alkylamino or alkylamino group includes monoalkylamino and dialkylamino groups; wherein the alkyl group has the meaning as defined herein. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, and the like.

[0380] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group contains 3 to 10 ring carbon atoms, for example, C 3-10 In other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3-8 In yet other embodiments, the cycloalkyl group contains 3-6 ring carbon atoms, such as C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. 3-8 Cycloalkyl groups include C 3-6 Cycloalkyl; the C 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl groups may be optionally substituted with one or more substituents described herein.

[0381] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen; wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings. Unless otherwise specified, a heterocyclyl group can be carbonyl or nitrogenyl, and a -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to an S-oxide. The nitrogen atom of the ring can be optionally oxidized to an N-oxide. The term "heterocyclyl" can be used interchangeably with the term "heterocycle." Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, or morpholinyl, among others. 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 Aziridine Azetidinyl Oxetanyl Pyrrolidin Tetrahydrofuranyl Tetrahydrothienyl Thiazolidine Pyrazolidinyl Pyrazolyl Oxazolidinyl Imidazolidinyl Piperidinyl Piperazinyl or morpholinyl The heterocyclyl group may be optionally substituted with one or more substituents described herein.

[0382] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0383] 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 herein. Unless otherwise specified, the group "C 6-10 "Aryl" means an aromatic group containing 6 to 10 ring carbon atoms.

[0384] The term "heteroaryl" refers to monocyclic, bicyclic, and tricyclic ring 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 wherein the heteroaryl group has one or more points of attachment to the rest of the molecule. When a -CH2- group is present in a heteroaryl group, the -CH2- group may optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) at any reasonable site (which may be C in CH or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, etc. The heteroaryl group can be optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a 5-10 atom heteroaryl group, 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 5-6 atom heteroaryl group, 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 5-6 atom heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl and the like.

[0385] The term "jk atoms (j and k are each independently any non-zero natural number, and k>j)" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; the "jk" includes j, k, and any natural number between them. For example, "3-8 atoms", "5-10 atoms", or "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.

[0386] In this article, when there are two or more groups connected to the compound group, the connection point is in accordance with the general principles of chemistry, that is, the connection point is the last noun group in the name of the compound group. 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 When the alkyl group is "alkyl", the connection site with the main structure group or other groups is "C 1-6 "Alkyl"; other similar groups, unless otherwise specified, shall be understood in accordance with this principle.

[0387] The “heterocyclic group consisting of 3-8 atoms” and “heterocyclic group consisting of 3-6 atoms” described 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). Similarly, the S or N in the heterocycle can also be further oxidized to form S(=O), S(=O)2 or N(=O).

[0388] 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" and "heteroaryl group consisting of 5-6 atoms" described in the present invention include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and the like.

[0389] The term "alkanoyl" or "alkylacyl" refers to the group -C(=O)-alkyl, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, methylacyl (-C(=O)CH3), ethylacyl (-C(=O)CH2CH3), and the like.

[0390] The term "alkoxyacyl" refers to the group -C(=O)-R, wherein R is an alkoxy group having the meaning as described herein, examples of which include, but are not limited to, methoxyacyl (-C(=O)OCH3), ethoxyacyl (-C(=O)OCH2CH3), and the like.

[0391] 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)2CH3), ethylsulfonyl (-S(=O)2CH2CH3), and the like.

[0392] The term "aminosulfonyl" refers to the group -S(=O)2NH2; the term "aminoacyl" refers to the group -C(=O)NH2.

[0393] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and do not typically produce allergic or similar untoward reactions, such as gastrointestinal upset, dizziness, etc., when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein means approved by federal regulatory agencies or state governments or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0394] 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, and the like. Water and aqueous solutions (e.g., saline solutions, aqueous dextrose solutions, aqueous glycerol solutions) are preferably used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0395] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound represented by formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by enzyme conversion to the parent structure in the blood or tissue. The prodrug compound of the present invention can be an ester. In the existing invention, 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 of the present invention containing a hydroxyl group can be acylated to produce a prodrug form of the compound. Other prodrug forms include phosphate esters, such as these phosphate ester compounds, which are obtained by phosphorylating a hydroxyl group on the parent compound. For a complete discussion of prodrugs, see 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.

[0396] "Metabolite" refers to a product resulting from the in vivo metabolism of a specific compound or salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized using assays such as those described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention encompasses metabolites of the compound, including metabolites produced by contacting a compound of the invention with a mammal for a sufficient period of time.

[0397] As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed with non-toxic acids 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, tartrates, citrates, succinates, and malonates; or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, 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 alkali metal, alkaline earth metal, ammonium and N + (C 1-4 The present invention also contemplates quaternary ammonium salts formed by any compound containing a N group. Water-soluble or oil-soluble or dispersible products can be obtained by quaternization. Alkali 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 formed by counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulfonates and aromatic sulfonates.

[0398] "Polymorph" or "polymorph" refers to a crystalline form having the same chemical composition but with different spatial arrangements of the molecules, atoms, and / or ions that make up the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties, such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution rate, and the like. Depending on their temperature-stability relationship, the relative stability of the two solid phases switches. This phenomenon of a compound existing in different crystal lattice structures is known as pharmaceutical polymorphism.

[0399] The crystal structures equivalent to the crystal structures disclosed or claimed in the present invention may show similar but not identical analytical characteristics within a reasonable error range according to experimental conditions, purity, equipment and other common variables known to those skilled in the art. Accordingly, it will be apparent to those skilled in the art that various modifications and variations can be made within the present invention without departing from the scope and spirit of the present invention. On the basis of considering the description and practice of the present invention disclosed herein, other embodiments of the present invention will be apparent to those skilled in the art. Applicants expect that these descriptions and examples are considered exemplary, rather than limiting their scope.

[0400] "X-ray powder diffraction pattern or XRPD" means the powder diffraction pattern of a substance according to the Bragg formula 2d sinθ = nλ (where λ is the wavelength of the X-rays, The diffraction order n is any positive integer, generally taking the first order diffraction peak as n=1. The "2θ or 2θ angle" mentioned herein refers to the diffraction angle, with θ being the Bragg angle, measured in degrees. When X-rays strike an atomic plane with a lattice spacing of d in a crystal or a portion of a crystalline sample at a grazing angle θ (the complementary angle to the incident angle, also known as the Bragg angle), the Bragg equation is satisfied, resulting in the measured X-ray powder diffraction pattern.

[0401] It is well known to those skilled in the art that XRPD may produce certain displacement and intensity deviations due to reasons such as sample tiling thickness, detection method, conditions, and instrumentation. Identical samples of the same crystal form typically have the same primary XRPD characteristic peaks, but there may be certain operational errors. When a person skilled in the art uses the same instrument and detection method to detect isomorphous samples obtained using the corresponding method, the characteristic peak error is typically within ±0.2°. However, different technicians using different instruments may occasionally have errors in a few characteristic peaks that exceed this range. For example, errors within ±0.5° or ±0.3° should all be considered to belong to the same crystal form. Therefore, as a specific example of the crystal form of the present invention, its XRPD is shown in Figure X. However, those skilled in the art understand that when the 2θ deviation of the key characteristic peak shift is within ±0.5°, ±0.3°, or ±0.2°, especially around ±0.2°, it can be identified as the same crystal form and can be interpreted as being within the scope of protection of the present invention.

[0402] Furthermore, the absolute and relative intensities of the peaks shown in the aforementioned tables and figures may vary due to various factors, such as the effects of the selective orientation of the crystalline solid on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed, or the crystallinity of the sample. Furthermore, peak positions may shift due to variations in sample height. Furthermore, when measurements are performed using different wavelengths, different shift values ​​are obtained according to the Bragg formula (nλ = 2dsinθ). Such different XRPD patterns obtained using different wavelengths are also within the scope of the present invention.

[0403] "Interplanar spacing or interplanar spacing (d value)" refers to the selection of three non-parallel unit vectors a, b, and c connecting two adjacent lattice points in the space lattice. They divide the lattice into juxtaposed parallelepiped units, which are called interplanar spacing. The space lattice is divided according to the lines connecting the parallelepiped units to obtain a set of straight line grids, which are called space grids or lattices. The lattice and lattice respectively use geometric points and lines to reflect the periodicity of the crystal structure. Different crystal planes have different interplanar spacings (that is, the distance between two adjacent parallel crystal planes); the unit is Or angstrom.

[0404] “Relative intensity (I%)” refers to the ratio of the intensity of other peaks to the intensity of the first strongest peak among all diffraction peaks in an X-ray powder diffraction pattern (XRPD) when the intensity of the first strongest peak is 100%.

[0405] Differential Scanning Calorimetry (DSC) measures the transition temperatures of a crystal when heat is absorbed or released due to changes in its crystal structure or melting. For the same crystalline form of the same compound, the thermal transition temperatures and melting points can be within about 5°C, and typically within about 3°C, in consecutive analyses. When a compound is described as having a given DSC peak or melting point, this is referred to as ±5°C relative to that peak or melting point, essentially taking this temperature variation into account. DSC provides an auxiliary method for distinguishing between different crystalline forms. Different crystalline forms can be identified by their distinct transition temperature signatures. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. Furthermore, because decomposition occurs during melting, the melting temperature is related to the heating rate.

[0406] Thermogravimetric analysis (TGA) is a common method for determining the thermal stability of compounds. In the present invention, TGA can also be used to determine the hydration state of a compound. The heating rate during the test will have a certain impact on the spectrum. The error of TGA can be within approximately ±0.5% by mass.

[0407] "Amorphous," "amorphous form," or "amorphous form" refers to a substance whose particles (molecules, atoms, ions) are arranged in a three-dimensional space without periodicity. This is characterized by a diffuse, non-peaked X-ray powder diffraction pattern. Amorphous is a specialized physical form of solid matter, and its locally ordered structure suggests a close relationship to crystalline forms.

[0408] As used herein, a "solvate" refers to an association formed between one or more solvent molecules and a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed when the solvent molecule is water.

[0409] "Esters" herein refer to in vivo hydrolyzable esters formed from compounds containing hydroxyl or carboxyl groups. Such esters are, for example, pharmaceutically acceptable esters that hydrolyze in the human or animal body to produce the parent alcohol or acid. The compounds of formula (I) herein contain a carboxyl group and can form in vivo hydrolyzable esters with suitable groups, including, but not limited to, alkyl groups, arylalkyl groups, and the like.

[0410] The term "nitrogen oxide" in the present invention refers to a compound containing several amine functional groups, which can oxidize one or more nitrogen atoms to form N - Oxide. N - A special example of an oxide is the N - Oxide or nitrogen-containing heterocyclic nitrogen atom N -Oxides. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form N - Oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N - The oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514) wherein, for example, the amine compound is reacted with m-chloroperbenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0411] As used herein, "compounds of the present invention," "compounds described herein," "compounds of the present invention," or similar expressions refer to compounds represented by any one of the general structures of the present invention. For example, the compounds of the present invention may refer to compounds represented by Formula (I), (Ia), (Ib), (IIa), (IIb), (III), or (IV) of the present invention. The compounds of the present invention also include the specific compounds of any one of the Examples.

[0412] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). 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 a perceptible symptom) or physiologically (e.g., stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0413] Any structural formula provided herein is also intended to represent non-isotopically enriched forms of these compounds as well as isotopically enriched forms. Isotopically enriched compounds have the structure depicted by the general formula provided herein, except that one or more atoms are replaced by atoms having a selected atomic weight 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.

[0414] In addition, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D), can provide certain therapeutic advantages resulting from greater metabolic stability. For example, this can result in an increased half-life in vivo, a reduced dosage requirement, or an improved therapeutic index. It should be understood that deuterium in the present invention is considered a substituent of a compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined using 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 given isotope. Where 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 according to the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, acetone-d6, DMSO-d6.

[0415] Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein may include enriched isotopes of one or more different atoms.

[0416] Unless otherwise indicated, the abbreviations of any protecting groups, amino acids and other compounds used in the present invention are based on their commonly used and recognized abbreviations or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

[0417] Description of the compounds of the present invention

[0418] The present invention provides a phenyl-substituted dihydronaphthyridine compound and a pharmaceutical composition thereof that can competitively antagonize aldosterone receptors (MR), as well as use of the compound or the pharmaceutical composition in preparing a medicament. The medicament is used to treat, prevent or alleviate diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, cirrhosis, renal failure and stroke in patients.

[0419] 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),

[0420] In one aspect, the present invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament 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.

[0421] On the other hand, the present invention also relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used as a mineralocorticoid receptor antagonist.

[0422] In one aspect, the compounds or pharmaceutical compositions of 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.

[0423] In another aspect, the compound or pharmaceutical composition of the present invention can be used to antagonize mineralocorticoid receptors.

[0424] On the one hand, the present invention relates to a method for treating, preventing or alleviating the following diseases in patients using the compound or pharmaceutical composition of the present invention: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke, wherein the method comprises treating the patient with a therapeutically effective dose of the compound or pharmaceutical composition of the present invention.

[0425] On the other hand, the present invention also relates to a method of antagonizing mineralocorticoid receptors using the compound or pharmaceutical composition of the present invention, which comprises contacting an effective dose of the compound or pharmaceutical composition of the present invention with an organism (including in vivo or in vitro).

[0426] 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.

[0427] The compounds or pharmaceutical 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 disease in a patient, or a patient susceptible to such disease, comprising treating the patient with a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

[0428] The present invention comprises the use of the compounds of the present invention and pharmaceutically acceptable salts thereof for producing pharmaceutical products for treating diseases associated with the mineralocorticoid receptor or aldosterone, including those described herein. The present invention also comprises pharmaceutical compositions comprising a therapeutically effective amount of a compound represented by formula (I) in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, or vehicle.

[0429] Unless otherwise indicated, all hydrates, solvates and pharmaceutically acceptable salts of the compounds of the present invention are within the scope of the present invention.

[0430] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically in relation to the other ingredients making up the formulation and the mammal to be treated.

[0431] The salts of the compounds of the present invention also include intermediates used in the preparation or purification of compounds represented by formula (I) or formula (Ia) or formula (Ib) or formula (IIa) or formula (IIb) or formula (III) or formula (IV), or salts of separated enantiomers of compounds represented by formula (I) or formula (Ia) or formula (Ib) or formula (IIa) or formula (IIb) or formula (III) or formula (IV), but are not necessarily pharmaceutically acceptable salts.

[0432] 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, glycolic 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 and ethanesulfonic acid, etc.

[0433] The biological activity of the compounds of the present invention can be assessed using any conventionally 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.

[0434] Administration and use of the compounds of the present invention.

[0435] The therapeutically effective amount of the compound of the present invention should be present in the above-mentioned pharmaceutical preparation 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 for animal studies can be based on the effective concentration established in cell culture assays. The dosage range suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compound of the present invention can be prepared as a medicament for oral administration. An exemplary dosage of the compound of the present invention in a medicament for oral administration is from about 0.01 to about 100 mg / kg (wherein kg represents the body weight of the subject). In some embodiments, the medicament includes from about 0.01 to about 20 mg / kg (wherein kg represents the body weight of the subject), or optionally from about 0.01 to about 10 mg / kg (wherein kg represents the body weight of the subject), or optionally from about 0.01 to about 5.0 mg / kg (wherein kg represents the body weight of the subject). In certain embodiments, the compounds of the present invention are administered parenterally, and an effective dosage thereof is about 0.001-1 mg / kg, preferably about 0.01-0.5 mg / kg body weight.

[0436] Typically, the dosage regimen for orally administered medicaments is 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 the 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, optionally in the form of multiple single doses to achieve the desired results. A single dose preferably contains a compound of the present invention in an amount of about 0.001 to about 30, particularly 0.001 to 3 mg / kg body weight.

[0437] An effective amount or therapeutically effective amount or dose of an agent (e.g., a compound of the invention) refers to that amount of the agent or compound that results in amelioration of symptoms or prolongation of survival in a subject. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as LD50 / ED50. Agents that exhibit high therapeutic indices are preferred.

[0438] Effective dose or therapeutically effective dose is the amount of a compound or pharmaceutical composition that will induce the biological or medical response of the tissue, system, animal or human being that the researcher, veterinarian, doctor or other clinician is seeking. The dosage is preferably within the range of a circulating concentration that includes minimal toxicity or avirulent ED50. The dosage can vary within this range, depending on the dosage form used and / or the route of administration used. The particularity of the individual condition should be considered to select the correct preparation, route of administration, dosage and dosing interval according to methods known in the art.

[0439] Dosage amount and interval can be adjusted individually to provide plasma levels of the active moiety that are 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 studies. 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.

[0440] The amount of 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 manner of administration, and the judgment of the prescribing physician.

[0441] If desired, the compositions of the present invention can 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 can also be prepared, placed in an appropriate container, and labeled for use in treating a designated condition.

[0442] The compounds of the present invention have good safety. The maximum tolerated dose of compound 62 after repeated administration to mice for 14 days showed that the compound was highly safe. In particular, the maximum tolerated dose of compound 36 after repeated administration for 14 days 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, showing high safety.

[0443] In addition, 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 significantly helps to reduce the side effects of Finerenone.

[0444] The compounds according to the invention are suitable for the prevention and / or treatment of various disorders and disease-related conditions, in particular disorders which are characterized by an increase in the plasma aldosterone concentration or by changes in the plasma aldosterone concentration relative to the plasma renin concentration, or disorders which are associated with these changes. Examples which may be mentioned are: spontaneous primary aldosteronism, aldosteronism associated with adrenal hyperplasia, adrenal adenoma and / or adrenal carcinoma, aldosteronism associated with cirrhosis of the liver, aldosteronism associated with heart failure, and (relative) aldosteronism associated with essential hypertension, etc.

[0445] 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 sudden cardiac death. These patients are, in particular, those 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), cardiomyopathy caused by Chagas disease, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and heart vascular disorders, peripheral blood flow disturbances, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, cardiac hypertrophic changes, pulmonary hypertension, coronary and peripheral artery spasm, thrombosis, thromboembolic disorders and vasculitis.

[0446] The compounds of the invention can furthermore be used for the prevention and / or treatment of edema formation, for example pulmonary edema, nephrogenic 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.

[0447] The compounds of the invention are also suitable for use as potassium-sparing diuretics and for the treatment of electrolyte disturbances such as hypercalcemia, hypernatremia or hypokalemia.

[0448] The compounds of the present invention are also useful in the treatment of renal diseases such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic kidney disease, for the prevention of renal damage (e.g., caused by immunosuppressants (e.g., cyclosporin A) associated with organ transplantation) and for renal cancer.

[0449] The compounds of the present invention may further be used for the prevention and / or treatment of diabetes and diabetic sequelae, such as neuropathy and nephropathy.

[0450] The compounds of the present invention may further be used for the prevention and / or treatment of microalbuminuria, for example caused by diabetes or hypertension, and proteinuria.

[0451] 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 dysfunction (Cushing's syndrome) which leads to an overproduction of glucocorticoids, adrenocortical tumors which lead to an overproduction of glucocorticoids, and pituitary tumors which autonomously produce ACTH (adrenocorticotropic hormone) leading to adrenal hyperplasia and Cushing's disease.

[0452] The compounds of the present invention may further be used for the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

[0453] The compounds of the present invention can further be used for the prevention and / or treatment of inflammatory disorders caused, for example, by viruses, spirochetes, fungi, bacteria or mycobacteria, and inflammatory disorders of unknown etiology, such as polyarthritis, lupus erythematosus, periarthritis or polyarteritis, dermatomyositis, scleroderma and sarcoidosis.

[0454] The compounds of the present invention may further be used to treat central nervous system disorders, such as depression, anxiety and chronic pain, in particular migraine, and neurodegenerative disorders, such as Alzheimer's disease and Parkinson's syndrome.

[0455] The compounds of the invention are also suitable for the prevention and / or treatment of vascular damage, for example after reocclusion or restenosis following procedures such as percutaneous transluminal coronary angioplasty (PTCA), stent implantation, coronary angioscopy, bypass surgery, and endothelial dysfunction, Raynaud's disease, thromboangiitis obliterans (Buerger's syndrome) and tinnitus syndrome.

[0456] 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 medicaments 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), in particular for the combined use of medicaments for the treatment and / or prevention of the diseases described herein. 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, alpha-receptor blockers, beta-receptor blockers and Rho kinase inhibitors; diuretics, in particular loop diuretics, and thiazides and diuretics of the thiazide class; agents with an antithrombotic effect, for example and preferably selected from platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; active ingredients that modify lipid metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably HMG-CoA 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, molsidomide or SIN-1, and Inhaled nitric oxide; 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); natriuretic peptides, such as atrial natriuretic peptide, type B Natriuretic peptides or brain natriuretic peptides, C-type natriuretic peptide (CNP) and urodilidine; 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 sivelepristone 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.

[0457] 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 a diuretic such as chloramphenicol, bumetanide, torsemide, bendroflumethiazide, clomiphene, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlorothiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorbenzenesulfonamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0458] The beneficial effects of the present invention are:

[0459] A new compound is proposed, which can act as a mineralocorticoid receptor inhibitor with a good half-inhibitory concentration, and can effectively treat and prevent diabetic nephropathy, hypertension, heart failure, other cardiovascular diseases and other aldosterone-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0460] The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more apparent.

[0461] Figure 1 is a diagram of the asymmetric unit of the crystal structure of compound 36.

[0462] Figure 2 is a single unit cell diagram of the crystal structure of compound 36.

[0463] Figure 3 is a filling diagram of the crystal structure of compound 36.

[0464] FIG4 is a comparison of the calculated and experimental XRPD patterns of the crystal of compound 36.

[0465] FIG5 is an asymmetric unit diagram of the crystal structure of compound 62.

[0466] FIG6 is a single unit cell diagram of the crystal structure of compound 62.

[0467] Figure 7 is a filling diagram of the crystal structure of compound 62.

[0468] FIG8 is a comparison of the calculated and experimental XRPD patterns of the crystal of compound 62.

[0469] Figure 9 Single crystal micrograph of compound 36.

[0470] FIG10 is a single crystal micrograph of compound 62.

[0471] FIG11 is an XRPD pattern of hydrochloride salt form I.

[0472] FIG12 is a DSC diagram of hydrochloride salt form I.

[0473] FIG13 is a TGA diagram of hydrochloride salt form I.

[0474] FIG14 is an XRPD pattern of hydrochloride Form II.

[0475] FIG15 is a DSC diagram of hydrochloride crystal form II.

[0476] FIG16 is a TGA diagram of hydrochloride crystal form II.

[0477] FIG17 is an XRPD pattern of sulfate salt Form I.

[0478] FIG18 is a DSC graph of sulfate salt form I.

[0479] FIG19 is a TGA diagram of sulfate salt form I.

[0480] FIG20 is an XRPD pattern of p-toluenesulfonate Form I.

[0481] FIG21 is a DSC diagram of p-toluenesulfonate Form I.

[0482] FIG22 is a TGA chart of p-toluenesulfonate Form I.

[0483] FIG23 is an XRPD pattern of p-toluenesulfonate Form II.

[0484] FIG24 is a DSC chart of p-toluenesulfonate Form II.

[0485] FIG25 is a TGA chart of p-toluenesulfonate Form II.

[0486] FIG26 is a DVS diagram of p-toluenesulfonate Form II.

[0487] FIG27 is an XRPD pattern of mesylate salt Form I.

[0488] FIG28 is a DSC graph of mesylate salt Form I.

[0489] FIG29 is a TGA chart of mesylate salt Form I.

[0490] FIG30 is an XRPD pattern of benzenesulfonate salt Form I.

[0491] FIG31 is a DSC diagram of benzenesulfonate Form I.

[0492] FIG32 is a TGA diagram of benzenesulfonate Form I.

[0493] FIG33 is a DVS diagram of benzenesulfonate salt Form I.

[0494] FIG34 is an XRPD pattern of phosphate crystal form I.

[0495] FIG35 is a DSC graph of phosphate crystal form I.

[0496] FIG36 is a TGA diagram of phosphate crystal form I.

[0497] Figure 37 is an XRPD pattern of the free base Form I.

[0498] FIG38 is a DSC graph of the free base Form I.

[0499] Figure 39 is a TGA chart of the free base Form I.

[0500] Figure 40 is a DVS diagram of the free base Form I.

[0501] Figure 41 is an XRPD pattern of Form II.

[0502] Figure 42 is a DSC graph of Form II.

[0503] Figure 43 is a TGA chart of Form II.

[0504] Figure 44 is the NMR image of benzenesulfonate salt form I.

[0505] Figure 45 is the NMR image of p-toluenesulfonate Form I.

[0506] Figure 46 is the NMR image of p-toluenesulfonate Form II.

[0507] Figure 47 is the NMR image of the mesylate salt form I. DETAILED DESCRIPTION

[0508] In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure prevails.

[0509] Generally, the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are defined as shown in formula (I). The following reaction schemes and examples are provided to further illustrate the present invention.

[0510] 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 the 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 modifications, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also generally applicable to the preparation of other compounds of the present invention.

[0511] In the examples described below, all temperatures are set forth 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. Typical reagents were purchased from Shantou Xilong Chemical Plant, Guangdong Guanghua Chemical Reagent Plant, Guangzhou Chemical Reagent Plant, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Plant.

[0512] Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were dried over sodium reflux. Anhydrous dichloromethane and chloroform were dried over calcium hydride reflux. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0513] The following reactions were generally carried out under a positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction flasks were plugged with suitable rubber stoppers, and substrates were introduced via syringe. All glassware was dried.

[0514] Silica gel columns were used for chromatography. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. Nuclear magnetic resonance spectroscopy data were measured on a Bruker Avance 400 NMR spectrometer or a Bruker Avance III HD 600 NMR spectrometer using CDCl₃, DMSO-d₆, CD₃OD, or Acetone-d₆ as solvents (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as reference standards. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets). Coupling constants are expressed in Hertz (Hz).

[0515] 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 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.

[0516] 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 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.

[0517] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column, 2.1 × 30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; HPLC peaks were recorded at UV-Vis wavelengths of 210 nm and 254 nm. The mobile phases consisted of 0.1% formic acid in acetonitrile (Phase A) and 0.1% formic acid in ultrapure water (Phase B). Gradient elution conditions are shown in Table 1:

[0518] Table 1 Gradient elution conditions of low-resolution mass spectrometry mobile phase

[0519] The following abbreviations are used throughout this invention:

[0520] DMSO-d6 deuterated dimethyl sulfoxide; g gram; mg milligram; mol mole; mmol millimole; mL milliliter; μL microliter.

[0521] The following reaction schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise indicated, R1, R2, R3, R4, R6, R7, R8, and R9 have the meanings herein. Unless otherwise indicated, each reaction step in each reaction scheme described herein is performed in a solvent inert to the reaction, including, but not limited to, the solvents described in the Examples or their substitutes.

[0522] 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:

[0523] Example 1 4-(5-Ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile

[0524] Step 1) 4-(4-cyano-2-methoxyphenyl)-N-(2,2-dimethoxyethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0525] To an 8 mL vial at room temperature, add 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). Allow to react at room temperature for 2 hours. Add aminoacetaldehyde dimethyl acetal (83 mg, 0.790 mmol). Allow to react at room temperature overnight. Quench with water (15 mL). Extract with ethyl acetate (10 mL x 3). 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 give a pale yellow solid (86 mg, yield 47.0%).

[0526] MS (ESI) M / Z: 467.6 [M+H] +

[0527] Step 2) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-N-(2-oxoethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0528] In a 25 ml single-necked flask, 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 12.0 M 36% concentrated hydrochloric acid solution (42 μL) were added at room temperature. The reaction was allowed to react at room temperature for 1 hour. Under an ice bath, the pH was adjusted to 7 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (10 ml x 3). The combined organic phases were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain a light yellow solid (25 mg, 42.7% yield).

[0529] MS (ESI) M / Z: 421.5 [M+H] +

[0530] Step 3) 4-(5-ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile

[0531] To an 8 mL vial at room temperature, 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). Heat to 120°C and react for 1 hour. Cool to room temperature, add water (2 mL), and extract with ethyl acetate (2 mL x 3). Combine the organic phases, wash with saturated brine (2 mL), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography (purification conditions were as follows: column: XBridge Prep C18OBD 30 mm * 150 mm, 5 μm; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 37% to 52% over 7 minutes; detection wavelength: 254 / 220 nm) to give a white solid (1.7 mg, 8.8% yield).

[0532] MS (ESI) M / Z: 403.50 [M+H] +

[0533] 1 H NMR(400MHz,Chloroform-d)δ7.72(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).

[0534] 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

[0535] Step 1) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide

[0536] To an 8 ml vial at room temperature, add 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). After nitrogen replacement, oxalyl chloride (0.1 ml) was added dropwise under an ice-water bath. After the addition, the mixture 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 mixture at room temperature and stirred for 1 hour. Water (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 ml x 2). The organic phases were combined, washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to give a dark yellow oil (50 mg, crude product), which was used directly in the next reaction.

[0537] 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

[0538] To an 8 ml vial at room temperature were added 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). 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 on a preparative plate (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a white solid (2.5 mg, 6.92%).

[0539] MS (ESI) M / Z: 403.95 [M+H] +

[0540] 1 H NMR(400MHz,Chloroform-d)δ8.24(s,1H),7.71(s,1H),7.42(d,J=7.8Hz,1H),7.13(d,J=7.8Hz,1H),7.01(s,1 H),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).

[0541] 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

[0542] To an 8 mL vial at room temperature were added 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). 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 resulting residue was purified on a preparative plate (petroleum ether / ethyl acetate (v / v) = 2:1) to yield a white solid (1.9 mg, 8.93%).

[0543] MS (ESI) M / Z: 418.45 [M+H] +

[0544] 1 H NMR(300MHz,Chloroform-d)δ7.71(s,1H),7.39(d,J=7.5Hz,1H),7.12(dd,J1=7.8Hz,J2=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).

[0545] Example 4 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane-1H-cyclopentanamide

[0546] Step 1) N-(2-cyanocyclopent-1-en-1-yl)acetamide

[0547] 1-Amino-2-cyano-1-cyclopentene (5.00 g, 46.2 mmol) and acetic anhydride (32 ml) were added to a 100 ml single-necked flask at room temperature. The reaction was allowed to proceed overnight. The mixture was concentrated under reduced pressure, and the residue was slurried with petroleum ether (10 ml x 3) and filtered to obtain white needle-like crystals (4.80 g, 69.1% yield).

[0548] MS (ESI) M / Z: 151.10 [M+H] +

[0549] Step 2) 4-amino-1,5,6,7-tetrahydro-2H-cyclopentylpyridin-2-one

[0550] N-(2-cyanocyclopent-1-en-1-yl)acetamide (2.40 g, 14.4 mmol) and tetrahydrofuran (50 mL) were added to a 250 mL three-necked flask at room temperature. After nitrogen replacement, lithium diisopropylamide (12 mL, 88.6 mmol) was slowly added dropwise at -78°C. The reaction was allowed to proceed for half an hour at -78°C, then the temperature was raised to 80°C and allowed to react overnight. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride (30 mL). The mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 5 / 1) to obtain a light yellow solid (1.25 g, 52.1% yield).

[0551] MS (ESI) M / Z: 151.10 [M+H] +

[0552] 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

[0553] To a 50 mL single-necked flask at room temperature were added 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). After nitrogen substitution, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was slurried with methyl tert-butyl ether (5 mL x 3) and filtered to afford a yellow solid (1.70 g, 60.4%).

[0554] 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

[0555] To a 50 mL single-necked flask at room temperature was added 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). After nitrogen replacement, the reaction was allowed to proceed at 80°C for 1 hour. The mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC. Purification conditions were as follows: chromatographic column: C18 silica gel; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 30% to 50% acetonitrile over 15 minutes; detection wavelength: 254 nm. A yellow solid (460 mg, 25.0% yield) was obtained.

[0556] Step 5) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane[h][1,6]naphthyridine-3-carboxylic acid

[0557] To a 50 ml single-necked flask at room temperature was added 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 a 1.5 ml aqueous solution of sodium hydroxide (77 mg, 1.92 mmol). The reaction was allowed to react at room temperature for 1 hour. The mixture was quenched with hydrochloric acid solution (1.0 mol / L) under an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (15 ml x 3 times), and the combined organic phases were washed with saturated brine (15 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. Purification conditions were as follows: chromatographic column: C18 silica gel; mobile phase A: water (containing 0.04% ammonia) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 15% to 40% over 20 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure.

[0558] Obtained a light yellow solid (40 mg, yield 10.3%)

[0559] Step 6) 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl-1H,4H,7H,8H,9H-cyclopentane-1,6-naphthyridine-3-carbonitrile

[0560] To an 8 mL vial, add 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopenta[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) at room temperature. The reaction mixture was allowed to react for 1 hour. A solution of ammonia in 1,4-dioxane (1.0 M, 0.5 mL) was added to the reaction mixture at room temperature. The reaction mixture was allowed to react at 60°C for 3 hours. The mixture was cooled to room temperature and quenched with water (15 mL). Extract with ethyl acetate (15 ml x 3 times), combine the organic phases, wash with saturated brine (15 ml x 3 times), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting residue was purified by preparative HPLC. Purification conditions were as follows: 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 from 20% to 42% over 7 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (9.0 mg, 22.6% yield).

[0561] MS (ESI) M / Z: 405.45 [M+H] +

[0562] 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).

[0563] Example 5 4-(4-cyano-2-methoxyphenyl)-2-methyl-4,7,8,9-tetrahydrocyclopentane-3-carbonitrile

[0564] To an 8 mL vial at room temperature was added a solution of 2,3-dihydro-4-indanamine (12 mg, 0.0890 mmol), 4-cyano-2-methoxybenzaldehyde (24 mg, 0.150 mmol), sodium 1-cyanopropylene-2-pentanoate (16 mg, 0.150 mmol), and glacial acetic acid (9 μL) in isopropanol (0.5 mL). After nitrogen replacement, the mixture was heated to 90°C and allowed to react overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous formic acid) and mobile phase B (acetonitrile), from 15% B to 50% B over 15 minutes, monitoring at 254 nm), yielding a light yellow solid (2.3 mg, 4.5% yield).

[0565] MS (ESI) M / Z: 340.25 [MH] -

[0566] 1 H 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).

[0567] Example 6 4-(5-cyanocyanin-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0568] Step 1) Methyl 2-allyloxy-4-bromobenzoate

[0569] To a 250 mL single-necked flask, 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-bromopropene (3.75 g, 43.3 mmol) at room temperature. Heat to 80°C and react for 2 hours. Cool to room temperature. Quench with water (300 mL). Extract with ethyl acetate (500 mL x 3). The combined organic phases are washed with saturated brine (500 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to afford a yellow solid (4.32 g, 69.9% yield).

[0570] LCMS (ESI, m / z): 271.0 [M+H] +

[0571] Step 2) methyl 3-allyl-4-bromo-2-hydroxybenzoate

[0572] Methyl 2-allyloxy-4-bromobenzoate (4.19 g, 15.5 mmol) and N-methylpyrrolidone (30 mL) were added to a 250 mL single-necked flask at room temperature. The mixture was heated to 200°C and allowed to react for 4 hours. The mixture was cooled to room temperature and quenched with water (300 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain a colorless oil (2.66 g, 63.4% yield).

[0573] LCMS (ESI, m / z): 271.1 [M+H] +

[0574] Step 3) Methyl 4-bromo-2-hydroxy-3-(3-hydroxypropyl)benzoate

[0575] Methyl 3-allyl-4-bromo-2-hydroxybenzoate (4.19 g, 15.5 mmol) and N-methylpyrrolidone (30 mL) were added to a 250 mL single-necked flask at room temperature. The mixture was heated to 200°C and allowed to react for 4 hours. The mixture was cooled to room temperature and quenched with water (300 mL). The mixture was extracted with ethyl acetate (500 mL x 3). The combined organic phases were washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to afford a colorless oil (2.31 g, 83.3% yield).

[0576] LCMS (ESI, m / z): 289.1 [M+H] +

[0577] Step 4) 5-bromochrome-8-methylcarboxylate

[0578] To a 100 mL single-necked flask at room temperature, 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). After nitrogen replacement, diethyl azodicarboxylate (3.34 g, 19.2 mmol) was slowly added dropwise under an ice bath. The reaction was allowed to react overnight at room temperature. Cool to room temperature and quench with water (100 mL). Extract with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain a yellow oil (1.67 g, 77.1% yield).

[0579] LCMS (ESI, m / z): 271.1 [M+H] +

[0580] Step 5) Methyl 5-cyanochromium-8-carboxylate

[0581] Methyl 5-bromochrome-8-carboxylate (1.62 g, 5.96 mmol), zinc cyanide (3.51 g, 29.9 mmol), tris(dibenzylideneacetone)dipalladium (1.09 g, 1.20 mmol), 1,1'-bis(diphenylphosphino)ferrocene (1.32 g, 2.40 mmol), and N-methylpyrrolidone (30 mL) were added to a 50 mL single-necked flask at room temperature. The atmosphere was replaced with nitrogen and the mixture was heated to 120°C for 2 hours. The mixture was cooled to room temperature and quenched with aqueous solution (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to afford a white solid (952 mg, 73.3% yield).

[0582] LCMS (ESI, m / z): 218.1 [M+H] +

[0583] Step 6) 8-Hydroxymethyl-5-chromonitrile

[0584] To a 50 mL single-necked flask at room temperature, add methyl 5-cyanochromium-8-carboxylate (860 mg, 3.96 mmol), tetrahydrofuran (10 mL), and a solution of lithium borohydride in tetrahydrofuran (3.96 mL, 2.0 mol / L, 7.92 mmol). Replace the atmosphere with nitrogen and heat to 60°C for 15 minutes. Cool to room temperature and quench with water (30 mL). Extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to afford a yellow oil (450 mg, 60.1% yield).

[0585] LCMS (ESI, m / z): 190.1 [M+H] +

[0586] Step 7) 8-Formylchromane-5-carbonitrile

[0587] 8-Hydroxymethyl-5-chromonitrile (385 mg, 1.75 mmol), dichloromethane (5 mL), and Dess-Martin reagent (890 mg, 2.10 mmol) were added to a 25 mL single-necked flask at room temperature. The mixture was allowed to react 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 afford a yellow solid (280 mg, 72.9% yield).

[0588] LCMS (ESI, m / z): 188.1 [M+H] +

[0589] Step 8) 2-cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate)

[0590] To an 8 ml vial at room temperature were added 8-formylchromane-5-carbonitrile (200 mg, 1.07 mmol), 4-amino-5-methylpyridin-2-ol (200 mg, 1.61 mmol), 2-cyanoethyl 3-oxobutanoate (200 mg, 1.29 mmol), isopropyl alcohol (5 ml), and acetic acid (90 μl). After nitrogen replacement, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 120 g reverse-phase column, mobile phase A (0.1% aqueous formic acid) and mobile phase B (acetonitrile), 20% B to 50% B over 15 minutes, monitoring wavelength at 254 nm) to yield a yellow solid (175 mg, 36.7% yield).

[0591] LCMS (ESI, m / z): 431.2 [M+H] +

[0592] Step 9) 2-cyanoethyl 4-(5-cyano-8-cyano)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0593] To an 8 mL vial at room temperature was added 2-cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate) (175 mg, 0.407 mmol), silver carbonate (112 mg, 0.407 mmol), ethyl iodide (95 mg, 0.610 mmol), and 1,4-dioxane (2 mL). After nitrogen substitution, the reaction was continued 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 and concentrated under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography under the following conditions: C18 BIOTAGE 120 g reverse phase chromatography column, mobile phase A: (0.1% aqueous ammonium bicarbonate solution) and mobile phase B (acetonitrile), 15% B to 60% B gradient over 10 minutes, UV 254 nm detector to give a light yellow oil (134 mg, 71.9% yield).

[0594] LCMS (ESI, m / z): 459.2 [M+H] +

[0595] Step 10) 4-(5-cyanocyanin-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0596] 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 the reaction and the pH was adjusted to 5. The mixture was extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a light yellow solid (83 mg, 70.1%), which was used directly in the next reaction without further purification.

[0597] LCMS (ESI, m / z): 406.2 [M+H] +

[0598] Step 11) 4-(5-cyanocyanin-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0599] To an 8 mL vial at room temperature were added 4-(5-cyanocyanin-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). The reaction was allowed to react at room temperature for 1 hour. A 1.0 M aqueous ammonia solution (0.7 mL) was added to the reaction mixture at room temperature. The reaction was allowed to react at room temperature for 2 hours. The mixture was filtered, and the resulting filtrate was 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 from 25% to 45% over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a yellow solid (59.0 mg, 73.9% yield).

[0600] LCMS (ESI, m / z): 405.25 [M+H] +

[0601] 1 H NMR (400MHz, DMSO-d6) δ7.70(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).

[0602] Example 7 10-(4-cyano-2-methoxyphenyl)-6,8-dimethyl-7H,10H-pyrazolo[3,2-f]1,6-naphthyridine-9-carbonitrile

[0603] Step 1) tert-Butyl N-(2-bromo-5-methylpyridin-4-yl)carbamate

[0604] 2-Bromo-5-methylpyridin-4-amine (1.00 g, 5.35 mmol), N,N-dimethylpyridin-4-amine (66 ml, 0.540 mmol), di-tert-butyl dicarbonate (1.4 g, 6.42 mmol), and acetonitrile (12 ml) were added to a 50 ml single-necked flask at room temperature. The reaction was allowed to react at room temperature for 3 hours. The mixture was cooled to room temperature and quenched by adding water (30 ml). The mixture was extracted with ethyl acetate (30 ml x 3). The combined organic phases were washed with saturated brine (30 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. 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, 28.3% yield).

[0605] MS (ESI) M / Z: 288 [MH] -

[0606] Step 2) tert-Butyl N-{5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridin-4-yl}carbamate

[0607] To a 100 ml single-necked flask at room temperature were added tert-butyl N-(2-bromo-5-methylpyridin-4-yl)carbamate (1.0 g, 3.48 mmol), bistriphenylphosphine palladium dichloride (733 mg, 1.05 mmol), cuprous iodide (3.99 g, 2.10 mmol), trimethylethynylsilane (4.51 ml, 34.8 mmol), and tetrahydrofuran (30 ml). After nitrogen substitution, the mixture was heated to 110°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to afford a gray solid (640 mg, 56.1% yield).

[0608] MS (ESI) M / Z: 303.20 [MH] -

[0609] Step 3) 1-amino-4-[tert-butoxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridinium-1-salt

[0610] To an 8 mL vial at room temperature were added 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). After nitrogen replacement, the reaction was allowed to proceed at room temperature for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with methyl tert-butyl ether (5 mL x 3) to afford a gray solid (120 mg, 87.7% yield).

[0611] MS (ESI) M / Z: 319.90 [MH]-

[0612] Step 4) tert-Butyl N-{6-methylpyrazolo[1,5-a]pyridin-5-yl}carbamate

[0613] To an 8 mL vial at room temperature were added 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). After nitrogen displacement, the mixture was heated to 80°C and reacted for 5 hours. The mixture was cooled to room temperature and filtered. The filtrate was then purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), from 40% B to 90% B over 15 minutes, monitoring at 254 nm). This afforded a gray solid (100 mg, 28.2% yield).

[0614] MS (ESI) M / Z: 248.25 [M+H] +

[0615] Step 5) 6-methylpyrazolo[1,5-a]pyridin-5-amine

[0616] To a 25 ml single-necked flask, 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) were added at room temperature. The reaction was allowed to proceed for 2 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (10 ml), washed sequentially with saturated aqueous sodium bicarbonate (10 ml) and saturated brine (10 ml), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain a gray solid (100 mg, 84.1% yield).

[0617] Step 6) 10-(4-cyano-2-methoxyphenyl)-6,8-dimethyl-7H,10H-pyrazolo[3,2-f]1,6-naphthyridine-9-carbonitrile

[0618] To an 8 mL vial at room temperature was added 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). After nitrogen replacement, the mixture was heated to 90°C and allowed to react overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous formic acid) and mobile phase B (acetonitrile), from 15% B to 45% B over 15 minutes, monitoring at 254 nm) to yield a white solid (7 mg, 3.4% yield).

[0619] LCMS (ESI, m / z): 356.15 [M+H] +

[0620] 1 H NMR (400MHz, DMSO-d6) δ8.70(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).

[0621] Example 8 4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3-b]pyridine-3-carbonitrile

[0622] Step 1) Sodium 1-cyanopropene-2-olate

[0623] Sodium methoxide (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-necked flask at room temperature. 5-Methylisoxazole (3.25 g, 60.0 mmol) was added dropwise under an ice-water bath. The mixture was allowed to react overnight at room temperature. A precipitate formed. The solid was filtered and slurried with methanol (15 ml). The resulting solid was filtered to give a yellow solid (3.10 g, 84.7% yield).

[0624] Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile

[0625] To a 100 mL single-necked flask at room temperature were added sodium 1-cyanoacrylate (3.00 g, 28.6 mmol), 4-formyl-3-methoxybenzonitrile (4.59 g, 28.6 mmol), dichloromethane (50 mL), piperidine (240 mg, 2.85 mmol), and glacial acetic acid (2.28 g, 57.1 mmol). After nitrogen replacement, the mixture was heated to 60°C and allowed to react overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with ethyl acetate (10 mL x 5) and filtered to afford a yellow solid (2.50 g, 38.8% yield).

[0626] MS (ESI) M / Z: 227.95 [M+H] +

[0627] Step 3) 4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3-b]pyridine-3-carbonitrile

[0628] To an 8 mL vial at room temperature, add a solution of 1-benzothiophene-2-amine (50 mg, 0.335 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (76 mg, 0.335 mmol), and glacial acetic acid (9 μL) in isopropanol (0.5 mL). After nitrogen purge, heat to 80°C for 1 hour. Cool to room temperature. The product was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column model: Sunfire prep C18 silica gel column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 48% B to 68% B over 8 minutes, 68% B; wavelength: 254 / 220 nm; elution time (min): 6.90) to give a white solid (22.3 mg, yield 18.1%).

[0629] MS (ESI) M / Z: 356.05 [MH] -

[0630] 1 H NMR(400MHz,DMSO-d6)δ10.25(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).

[0631] Example 9 4-(4-cyano-2-methoxyphenyl)-3-ethoxy-1,6-dimethyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile

[0632] Step 1) N-(2-cyanocyclopent-1-en-1-yl)acetamide

[0633] To a 100 mL single-necked flask at room temperature, add methyl 3-hydroxy-1-methylpyrazole-5-carboxylate (2.30 g, 14.7 mmol), ethyl iodide (3.40 g, 22.1 mmol), potassium carbonate (2.00 g, 14.7 mmol), and N,N-dimethylformamide (25 mL). After nitrogen displacement, heat to 60°C and react for 5 hours. Cool to room temperature. Quench with water (30 mL). Extract with ethyl acetate (30 mL x 3). The combined organic phases are washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a light yellow oil (2.30 g, 84.7% yield).

[0634] LCMS (ESI, m / z): 185.10 [M+H] +

[0635] Step 2) 3-Ethoxy-1-methylpyrazole-5-carboxylic acid

[0636] In a 100 ml single-necked flask, 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) at room temperature. Allow to react at room temperature for 3 hours. Quench with dilute hydrochloric acid (1.0 mol / L) and adjust the pH to 5. Extract with ethyl acetate (30 ml x 3). The combined organic phases are washed with saturated brine (30 ml), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a white solid (2.00 g, 94.1% yield).

[0637] LCMS (ESI, m / z): 171.10 [M+H] +

[0638] Step 3) tert-Butyl (3-ethoxy-1-methylpyrazol-5-yl)carbamate

[0639] To a 100 mL single-necked flask at room temperature, 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). After nitrogen purge, slowly add diphenylphosphoryl azide (4.85 g, 17.6 mmol) dropwise. Heat to 80°C and react overnight. Cool to room temperature. Quench with water (20 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 and concentrate under reduced pressure. The resulting residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (0.1% formic acid in water) and mobile phase B (acetonitrile), 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm) to give a white solid (1.60 g, 56.4% yield).

[0640] LCMS (ESI, m / z): 242.20 [M+H] +

[0641] Step 4) 3-ethoxy-1-methylpyrazol-5-amine

[0642] To a 25 mL single-necked flask, add tert-butyl (3-ethoxy-1-methylpyrazol-5-yl)carbamate (800 mg, 3.32 mmol) and a solution of hydrogen chloride in 1,4-dioxane (4.0 M, 5 mL) at room temperature. Stir overnight at room temperature. Quench with saturated aqueous sodium bicarbonate and adjust the pH to 7. Extract with ethyl acetate (50 mL x 3). The combined organic phases are washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (405 mg, 86.5% yield).

[0643] LCMS (ESI, m / z): 142.10 [M+H] +

[0644] Step 5) 4-(4-cyano-2-methoxyphenyl)-3-ethoxy-1,6-dimethyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile

[0645] To an 8 mL vial at room temperature, add a solution of 3-ethoxy-1-methylpyrazol-5-amine (50 mg, 0.344 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (78 mg, 0.344 mmol), and glacial acetic acid (18 μL) in isopropanol (1 mL). Under nitrogen, heat to 80°C for 2 hours. Cool to room temperature and quench with water (5 mL). Extract with ethyl acetate (10 mL x 3). 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 C18 reverse-phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (10 mmol / L aqueous ammonium bicarbonate solution) and mobile phase B (acetonitrile), 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm) to give a white solid (8.5 mg, 7.73% yield).

[0646] MS (ESI) M / Z: 350.20 [M+H] + .

[0647] 1 H NMR (300MHz, DMSO-d6) δ9.74(s,1H),7.47(s,1H),7.38(d,J=7.9Hz,1H),7.17(d,J=7.9H z,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).

[0648] 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

[0649] Step 1) Sodium 1-cyanopropene-2-olate

[0650] Sodium methoxide (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-necked flask at room temperature. 5-Methylisoxazole (3.25 g, 60.0 mmol) was added dropwise under an ice-water bath. The mixture was allowed to react overnight at room temperature. A precipitate formed. The solid was filtered and slurried with methanol (15 ml). The resulting solid was filtered to give a yellow solid (3.10 g, 84.7% yield).

[0651] Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile

[0652] Sodium 1-cyanoacrylate (3.00 g, 28.6 mmol), 4-formyl-3-methoxybenzonitrile (4.59 g, 28.6 mmol), dichloromethane (50 ml), piperidine (240 mg, 2.85 mmol), and glacial acetic acid (2.28 g, 57.1 mmol) were added to a 100 ml single-necked flask at room temperature. After nitrogen replacement, the mixture was heated to 60°C and allowed to react overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was slurried with ethyl acetate (10 ml x 5) and filtered to afford a yellow solid (2.50 g, 38.8% yield).

[0653] Step 3) 2-Hydrazino-4-methyl-5-nitropyridine

[0654] 6-Chloro-2-methyl-3-nitropyridine (1.73 g, 10.0 mmol) and 1,4-dioxane (15 ml) were added to a 100 ml single-necked flask at room temperature. Hydrazine hydrate (2.00 g, 40 mmol) was added under an ice-water bath. The reaction was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was slurried with water (5 ml) and filtered to obtain a pale yellow solid (1.30 g, crude product). This was used directly in the next reaction without further purification.

[0655] Step 4) 7-Methyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine

[0656] To a 100 ml single-necked flask at room temperature were added 2-hydrazino-4-methyl-5-nitropyridine (1.00 g, 5.95 mmol), triethyl orthoformate (2.52 g, 23.8 mmol), and dichloromethane (50 ml). Trifluoroacetic acid (140 mg, 1.19 mmol) was added under an ice-water bath. The reaction was allowed to react at room temperature overnight. The mixture was concentrated under reduced pressure to yield a pale yellow solid (900 mg, crude product).

[0657] Step 5) 7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine

[0658] 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) were added to a 100 ml single-necked flask at room temperature. The mixture was heated to 50°C and allowed to react overnight. The mixture was cooled to room temperature, filtered through celite, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to afford a light yellow solid (400 mg, 53.5% yield).

[0659] 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

[0660] To an 8 mL vial at room temperature was added a solution of 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). After nitrogen replacement, the reaction was heated to 80°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous formic acid) and mobile phase B (acetonitrile), 30% B to 50% B over 10 minutes, monitoring at 254 nm) to yield a white solid (20.0 mg, 16.7% yield).

[0661] MS (ESI) M / Z: 357.15 [M+H] +

[0662] 1 H NMR (400MHz, DMSO-d6) δ8.80(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).

[0663] Example 11 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0664] Step 1) 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0665] To a 500 mL single-necked flask at room temperature, add 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid (10.0 g, 46.9 mmol) and methanol (200 mL). Add thionyl chloride (8.35 g, 61.9 mmol) slowly dropwise under an ice-water bath. Heat to 70°C and react for 1.5 hours. Cool to room temperature. Quench with saturated aqueous sodium bicarbonate (300 mL). 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, 98.5% yield).

[0666] LCMS (ESI, m / z): 228.6 [M+H] +

[0667] Step 2) 4-amino-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0668] At room temperature, 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. Heat to 30°C under 3 atmospheres of hydrogen pressure and react overnight. Cool to room temperature. Filter through celite and rinse the filter cake with ethyl acetate (500 ml). Combine the filtrates, 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, 53.6% yield).

[0669] LCMS (ESI, m / z): 194.2 [M+H] +

[0670] Step 3) 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0671] To a 50 mL single-necked flask at room temperature was added methyl 4-amino-2,3-dihydro-1-benzofuran-7-carboxylate (4.20 g, 21.8 mmol), tert-butyl nitrite (3.15 g, 30.7 mmol), cuprous bromide (4.20 g, 29.4 mmol), and acetonitrile (20 mL). The atmosphere was replaced with nitrogen and the mixture was heated to 70°C for half an hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to afford a yellow solid (3.50 g, 62.8% yield).

[0672] Step 4) 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0673] To a 50 mL single-necked flask 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(diphenylphosphino)ferrocene (1.37 g, 2.50 mmol), and N-methylpyrrolidone (20 mL). The atmosphere was replaced with nitrogen and heated to 120°C for 2 hours. The mixture was cooled to room temperature and quenched with aqueous solution (100 mL). The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a white solid (2.20 g, yield 86.6%).

[0674] Step 5) 7-hydroxymethyl-2,3-dihydro-1-benzofuran-4-carbonitrile

[0675] To a 50 mL single-necked flask at room temperature were added methyl 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylate (1.80 g, 8.86 mmol), tetrahydrofuran (20 mL), and a solution of lithium borohydride in tetrahydrofuran (6.54 mL, 2.0 mol / L, 13.3 mmol). The atmosphere was replaced with nitrogen and the reaction mixture was heated to 60°C for 20 minutes. The mixture was cooled to room temperature and quenched with water (50 mL). The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to afford a white solid (960 mg, 61.9% yield).

[0676] Step 6) 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile

[0677] 7-Hydroxymethyl-2,3-dihydro-1-benzofuran-4-carbonitrile (920 mg, 6.58 mmol), dichloromethane (10 mL), and Dess-Martin reagent (3.24 g, 7.04 mmol) were added to a 25 mL single-necked flask at room temperature. The atmosphere was replaced with nitrogen and 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 afford a yellow solid (800 mg, 70.2% yield).

[0678] 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

[0679] To an 8 ml vial at room temperature were added 7-formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (100 mg, 0.577 mmol), 4-amino-5-methylpyridin-2-ol (100 mg, 0.806 mmol), 2-cyanoethyl 3-oxobutanoate (100 mg, 0.645 mmol), isopropyl alcohol (2.5 ml), and acetic acid (45 μl). After nitrogen replacement, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (10 mmol / L aqueous ammonium bicarbonate) and mobile phase B (acetonitrile), 30% B to 50% B over 15 minutes, monitoring wavelength at 254 nm) to yield a yellow solid (110 mg, 45.7% yield).

[0680] LCMS (ESI, m / z): 417.4 [M+H]+

[0681] 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

[0682] To an 8 mL vial at room temperature were added 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). After nitrogen substitution, the reaction was continued 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, 45.7% yield), which was used in the next step without further purification.

[0683] LCMS (ESI, m / z): 445.20 [M+H] +

[0684] Step 9) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0685] 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 an ice bath, the mixture was quenched by the addition of hydrochloric acid solution (1.0 mol / L) and adjusted to pH = 5. The mixture was extracted with ethyl acetate (20 ml x 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a light yellow solid (80 mg, 90.7%), which was used directly in the next reaction without further purification.

[0686] LCMS (ESI, m / z): 392.4 [M+H]+

[0687] Step 10) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0688] To an 8 mL vial at room temperature were added 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). The reaction was allowed to react at room temperature for 1 hour. A 1.0 M aqueous ammonia solution (0.5 mL) was added to the reaction mixture at room temperature. The reaction was allowed to react at room temperature for 1 hour. The mixture was filtered, and the resulting filtrate was 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 from 20% to 40% over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a yellow solid (45.0 mg, 56.1% yield).

[0689] LCMS (ESI, m / z): 391.10 [M+H] +

[0690] 1 H NMR (400MHz, DMSO-d6) δ7.70(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).

[0691] Example 12 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1H,4H-benzo[h]1,6-naphthyridine-3-carbonitrile

[0692] Step 1) 2-ethoxyquinolin-4-amine

[0693] 2-Chloroquinolin-4-amine (200 mg, 1.12 mmol), sodium ethoxide (305 mg, 4.48 mmol), and ethanol (2.5 mL) were added to a 10 mL microwave tube at room temperature. The mixture was heated in a microwave oven at 140°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous ammonia) and mobile phase B (acetonitrile), 25% B to 35% B over 10 minutes, monitoring wavelength at 254 nm) to yield a white solid (75 mg, 35.6% yield).

[0694] MS (ESI) M / Z: 189 [M+H] +

[0695] Step 2) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1H,4H-benzo[h]1,6-naphthyridine-3-carbonitrile

[0696] To an 8 mL vial at room temperature was added a solution of 2-ethoxyquinolin-4-amine (75 mg, 0.398 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (90 mg, 0.398 mmol), and glacial acetic acid (36 μL) in isopropanol (2 mL). After nitrogen substitution, the reaction was heated to 80°C overnight. The mixture was then cooled to room temperature. The product was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC 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 over 7 min; wavelength: 254 / 220 nm; peak elution time (min): 6.15. Fractions were collected and lyophilized under reduced pressure to obtain a white solid (48.8 mg, 30.7% yield).

[0697] MS (ESI) M / Z: 397.15 [M+H] +

[0698] 1H NMR(400MHz, DMSO-d6)δ9.60(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).

[0699] Example 13 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide

[0700] Step 1) N-(2-cyanothiophene-3-yl)acetamide

[0701] 3-Amino-2-cyano-thiophene (1.00 g, 8.05 mmol) and acetic anhydride (10 ml) were added to a 50 ml single-necked flask at room temperature. The reaction was allowed to proceed overnight. The mixture was concentrated under reduced pressure, and the residue was slurried with petroleum ether (30 ml) and filtered to obtain a white solid (1.20 g, 89.6% yield).

[0702] LCMS (ESI, m / z): 167.0 [M+H] +

[0703] Step 2) 7-aminothieno[3,2-b]pyridin-5-ol

[0704] N-(2-cyanothiophene-3-yl)acetamide (1.20 g, 7.22 mmol) and tetrahydrofuran (24 mL) were added to a 100 mL three-necked flask at room temperature. After nitrogen replacement, lithium diisopropylamide (6 mL, 44.3 mmol) was slowly added dropwise at -78°C. The reaction was allowed to proceed for half an hour at -78°C, then the temperature was raised to 80°C and the reaction was continued for 1 hour. The reaction was cooled to room temperature and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 5 / 1) to obtain a light yellow solid (650 mg, 54.2% yield).

[0705] LCMS (ESI, m / z): 167.0 [M+H] +

[0706] Step 3) 2-cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-hydroxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate

[0707] 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 flask at room temperature. After nitrogen replacement, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was slurried with ethyl acetate (15 ml x 3) and filtered to obtain the crude product, which was then purified by C18 reverse-phase column chromatography using the following conditions: a C18 BIOTAGE 330 g column, mobile phase A (0.1% aqueous FA) and mobile phase B (acetonitrile), with a gradient from 15% B to 50% B over 15 minutes, and monitoring at 254 nm. This afforded a light yellow solid (1.09 g, 45.4% yield).

[0708] LCMS (ESI, m / z): 447.1 [M+H] +

[0709] Step 4) 2-cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate

[0710] To a 50 mL single-necked flask at room temperature were added 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). After nitrogen replacement, the reaction was allowed to proceed at 90°C for 2 hours. The reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride (5 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified using a C18 reverse-phase column. Purification conditions were as follows: 120 g BIOTAGE C18 reverse-phase column; mobile phase A: water (containing 0.1% aqueous ammonium bicarbonate) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 20% to 60% acetonitrile over 15 minutes; detection wavelength: 254 nm. A white solid (120 mg, 57.9% yield) was obtained.

[0711] LCMS (ESI, m / z): 475.1 [M+H] +

[0712] Step 5) 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylic acid

[0713] To a 50 ml single-necked flask at room temperature were added 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 a 0.5 ml aqueous solution of sodium hydroxide (26 mg, 0.655 mmol). The reaction was allowed to react at room temperature for 1 hour. The mixture was quenched with hydrochloric acid solution (1.0 mol / L) under an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (5 ml x 3 times), and the combined organic phases were washed with saturated brine (15 ml x 3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative high-performance liquid chromatography. Purification conditions were as follows: chromatographic column: C18 silica gel; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 10% to 40% over 10 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (111 mg, 80.6% yield).

[0714] LCMS (ESI, m / z): 422.1 [M+H] +

[0715] Step 6) 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide

[0716] To an 8 ml vial at room temperature, add 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). Allow to react at room temperature for half an hour. Add ammonia (0.8 ml) to the reaction mixture at room temperature. Allow to react at room temperature for 3 hours. Quench with water (10 ml). Extract with ethyl acetate (10 ml x 3). 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 preparative HPLC. Purification conditions were as follows: Sunfire prep C18 column; mobile phase A: water (containing 0.1% aqueous ammonium bicarbonate) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 18% to 50% acetonitrile over 7 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (47.0 mg, 44.9% yield).

[0717] LCMS (ESI, m / z): 421.0 [M+H] +

[0718] 1 H NMR (400MHz, DMSO-d6) δ8.83(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).

[0719] Example 14 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0720] Step 1) Diethyl 2,3-dihydroxyterephthalate

[0721] 2,3-Dihydroxyterephthalic acid (260 g, 1.31 mol) and ethanol (2.60 L) were added to a 10-liter four-necked flask at room temperature. Thionyl chloride (908 g, 7.63 mol) was slowly added dropwise at 0°C, and the mixture was allowed to react overnight at 70°C. After cooling to room temperature, the reaction mixture was slowly quenched by adding saturated aqueous sodium bicarbonate (5.20 L) dropwise. The mixture was extracted with ethyl acetate (5.00 L x 3), and the combined organic phases were washed with saturated brine (3.00 L), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to yield an off-white solid (312 g, 93.5% yield).

[0722] MS (ESI) M / Z: 255.1 [M+H] +

[0723] Step 2) Diethyl benzo[d][1,3]dioxole-4,7-dicarboxylate

[0724] To a 10-L four-necked flask at room temperature, 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 L). After nitrogen replacement, react at 90°C overnight. Cool to room temperature and quench with saturated brine (19.0 L). Extract with ethyl acetate (12.0 L x 3). The combined organic phases are washed with saturated brine (12.0 L), and dried over anhydrous sodium sulfate. Filter with suction, and the filtrate is concentrated under reduced pressure to obtain an off-white solid (289 g, 88.4% yield).

[0725] MS (ESI) M / Z: 267.1 [M+H] +

[0726] Step 3) Ethyl 7-hydroxymethylbenzo[d][1,3]dioxole-4-carboxylate

[0727] Benzo[d][1,3]dioxole-4,7-dicarboxylic acid diethyl ester (289 g, 1.09 mol), tetrahydrofuran (2.90 L), and a 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 replacement, the reaction was allowed to proceed at 60°C for 2 hours. After cooling to 0°C, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (6.00 L) to quench the mixture. The mixture was extracted with ethyl acetate (4.50 L x 3). The combined organic phases were washed with saturated brine (4.50 L), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 7:3) to afford a white solid (168 g, 69.0% yield).

[0728] MS (ESI) M / Z: 225.0 [M+H]+

[0729] Step 4) Ethyl 7-formylbenzo[d][1,3]dioxole-4-carboxylate

[0730] To a 3-L three-necked flask at room temperature were added ethyl 7-hydroxymethylbenzo[d][1,3]dioxole-4-carboxylate (168 g, 750 mmol), dichloromethane (1.70 L), and Dess-Martin reagent (397 g, 937 mmol). The atmosphere was replaced with nitrogen and the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1) to afford a yellow solid (165 g, 99.1% yield).

[0731] MS (ESI) M / Z: 223.1 [M+H] +

[0732] Step 5) Ethyl 7-cyanobenzo[d][1,3]dioxole-4-carboxylate

[0733] At room temperature, ethyl 7-formylbenzo[d][1,3]dioxole-4-carboxylate (165 g, 757 mmol), hydroxylamine hydrochloride (158 g, 2.27 mol), and DMSO (1.00 L) were added to a 3-liter three-necked flask. The atmosphere was replaced with nitrogen and heated to 90 degrees Celsius for 1 hour. After cooling to room temperature, the reaction was quenched by adding saturated brine (10.0 L). The mixture was extracted with ethyl acetate (6.00 L x 3), and the organic phases were combined, washed with saturated brine (6.00 L), and dried over anhydrous sodium sulfate. The mixture 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 give a yellow solid (120 g, 73.7% yield).

[0734] Step 6) 7-Hydroxymethylbenzo[d][1,3]dioxole-4-carbonitrile

[0735] To a 3-L three-necked flask at room temperature were added ethyl 7-cyanobenzo[d][1,3]dioxole-4-carboxylate (120 g, 548 mmol), tetrahydrofuran (1.20 L), and a solution of lithium borohydride in tetrahydrofuran (411 mL, 2.0 mol / L, 822 mmol). After nitrogen displacement, the reaction was allowed to proceed at 60°C for 2 hours. After cooling to 0°C, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (3.20 L) to quench the reaction. The mixture was extracted with ethyl acetate (2.50 L x 3). The combined organic phases were washed with saturated brine (2.50 L), and dried over anhydrous sodium sulfate. The filtrate was filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to afford a white solid (75.0 g, 77.3% yield).

[0736] Step 7) 7-Formylbenzo[1,3]dioxole-4-carbonitrile

[0737] 7-Hydroxymethylbenzo[d][1,3]dioxole-4-carbonitrile (75.0 g, 424 mmol), dichloromethane (1.50 L), and Dess-Martin reagent (270 g, 636 mmol) were added to a 3-L three-necked flask at room temperature. After nitrogen replacement, the reaction was allowed to proceed overnight at room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to afford a yellow solid (67.0 g, 90.4% yield).

[0738] Step 8) 2-cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0739] To a 3-L three-necked flask at room temperature were added 7-formylbenzo[1,3]dioxole-4-carbonitrile (65.0 g, 371 mmol), 2-cyanoethyl-3-oxobutanoate (63.3 g, 408 mmol), 4-amino-5-methylpyridin-2-ol (50.7 g, 408 mmol), isopropyl alcohol (1.30 L), and acetic acid (23.4 mL). After nitrogen substitution, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was slurried with methyl tert-butyl ether (500 mL x 3) and filtered to yield a pale yellow solid (88.0 g, 56.7%).

[0740] MS (ESI) M / Z: 419.2 [M+H] +

[0741] Step 9) 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0742] To a 2-L three-necked flask at room temperature were added 2-cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (88.0 g, 210 mmol), ethyl iodide (49.3 g, 316 mmol), silver carbonate (58.1 g, 210 mmol), and 1,4-dioxane (880 ml). After nitrogen substitution, the reaction was continued at 90°C for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to yield a yellow solid (86.5 g, 92.1%).

[0743] MS (ESI) M / Z: 447.1 [M+H] +

[0744] Step 10) 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0745] To a 3-liter three-necked flask at room temperature were added 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 sodium hydroxide solution (1.00 mol, 380 ml). The mixture was allowed to react at room temperature for 1 hour. The mixture was diluted with water (1.50 L) and extracted with ethyl acetate (1.00 L x 1). The aqueous phase was retained. Under an ice bath, the mixture was quenched with hydrochloric acid solution (1.00 mol) and adjusted to pH 5. The mixture was extracted with ethyl acetate (1.00 L x 3). The organic phases were combined, washed with saturated brine (500 ml x 1), and dried over anhydrous sodium sulfate. The residue was filtered and the filtrate was concentrated under reduced pressure to obtain a light yellow solid (70.0 g, 91.8%), which was used directly in the next reaction.

[0746] MS (ESI) M / Z: 394.2 [M+H] +

[0747] Step 11) 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0748] In a 2-liter three-necked flask at room temperature were added 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). A 25% aqueous ammonia solution (120 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1.5 hours. The reaction mixture was purified by preparative high-performance liquid chromatography. Purification conditions were as follows: DAC prep C18 column; mobile phase A: water (containing 0.1% ammonium bicarbonate) and mobile phase B: acetonitrile; flow rate: 1 L / min; gradient: 20% to 42% acetonitrile over 30 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure to yield a white solid (38.0 g, 66.8%).

[0749] MS (ESI) M / Z: 393.3 [M+H] +

[0750] 1 H NMR(400MHz,Chloroform-d)δ7.68(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).

[0751] Example 15 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0752] 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

[0753] 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 degrees Celsius for 2 hours. The reaction mixture was cooled to room temperature, 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%).

[0754] MS (ESI) M / Z: 485.5 [M+H] +

[0755] 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

[0756] To an 8 ml single-necked flask at room temperature were added 2-cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (110 mg, 0.227 mmol), ethylene glycol dimethyl ether (3 ml), and a 1 ml aqueous solution of sodium hydroxide (18 mg, 0.454 mmol). The reaction was allowed to react at room temperature for 1 hour. Under an ice bath, the mixture was quenched by the addition of hydrochloric acid solution (1.0 mol / L) and adjusted to pH 5. The mixture was extracted with ethyl acetate (5 ml x 3 times), and the combined organic phases were washed with saturated brine (5 ml x 3 times), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to obtain a light yellow solid (100 mg, 93.6% yield), which was used directly in the next reaction.

[0757] MS (ESI) M / Z: 432.5 [M+H] +

[0758] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0759] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous ammonia solution (1.5 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for half an hour. The mixture was filtered, and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: YMC-Actus Triart C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 38% to 55% acetonitrile over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (50.0 mg, 55.7% yield).

[0760] LCMS (ESI, m / z): 431.1 [M+H] +

[0761] 1H NMR (400MHz, DMSO-d6) δ7.67(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).

[0762] 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

[0763] Step 1) Benzyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0764] To an 8 ml single-necked flask at room temperature were added 7-formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (300 mg, 1.73 mmol), benzyl acetoacetate (333 mg, 1.73 mmol), 4-amino-5-methylpyridin-2-ol (215 mg, 1.73 mmol), isopropyl alcohol (8.5 ml), and acetic acid (0.15 ml). After nitrogen substitution, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a white solid (185 mg, 23.6% yield).

[0765] MS (ESI) M / Z: 454.5 [M+H] +

[0766] Step 2) Benzyl 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-carboxylate

[0767] To an 8 ml single-necked vial at room temperature was added 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). The reaction was allowed to react at 60°C for 2 hours. The mixture was cooled to room temperature and quenched with water (10 ml). The mixture was extracted with ethyl acetate (10 ml x 3). The combined organic phases were washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 5 / 1). A white solid (40 mg, yield 29.6%) was obtained.

[0768] MS (ESI) M / Z: 558.6 [M+H] +

[0769] 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

[0770] To a 30 mL autoclave at room temperature was added benzyl 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-carboxylate (100 mg, 0.180 mmol), palladium on carbon (10% content, 100 mg), and tetrahydrofuran (2 mL). After nitrogen purging, the atmosphere was purged with hydrogen at 3 atmospheres and the reaction was allowed to proceed overnight at room temperature. The filtrate was filtered and concentrated under reduced pressure to yield a pale yellow solid (30 mg, 35.8% yield), which was used directly in the next reaction.

[0771] MS (ESI) M / Z: 468.5 [M+H] +

[0772] 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

[0773] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.2 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The mixture was filtered, and the resulting filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: XBridge Shield RP18OBD Column, 30 x 150 mm, 5 μm; mobile phase A: water (containing 0.1% ammonia), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 25% B to 60% B over 7 minutes, then 60% B; wavelength: 254 / 220 nm; peak elution time (min): 6.58 min; fractions were collected and lyophilized under reduced pressure. A white solid (17.0 mg, 56.8% yield) was obtained.

[0774] LCMS (ESI, m / z): 467.5 [M+H] +

[0775] 1 H NMR (400MHz, CDCl3) δ7.73(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).

[0776] 19 F NMR (376MHz, CDCl3) δ-83.5,-94.4.

[0777] Example 17 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0778] Step 1) Benzyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0779] To an 8 mL single-necked vial at room temperature was added 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). The reaction was allowed to react at 60°C for 2 hours. The mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 5 / 1). A yellow solid (60 mg, yield 54.6%) was obtained.

[0780] MS (ESI) M / Z: 504.6 [M+H] +

[0781] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0782] To a 30 mL autoclave at room temperature was added benzyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (60 mg, 0.119 mmol), palladium on carbon (10% content, 60 mg), and tetrahydrofuran (2 mL). After nitrogen purging, hydrogen was introduced at 3 atmospheres and the reaction was allowed to proceed overnight at 70°C. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield a pale yellow solid (30 mg, 60.9% yield), which was used directly in the next reaction.

[0783] MS (ESI) M / Z: 414.4 [M+H] +

[0784] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0785] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous ammonia solution (0.2 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The mixture was filtered, and the resulting filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: XBridge Shield RP18OBD Column, 30 x 150 mm, 5 μm; mobile phase A: water (containing 0.1% ammonia), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 30% B to 60% B over 7 minutes; wavelength: 254 / 220 nm; fractions were collected and lyophilized under reduced pressure. A white solid (1.1 mg, 5.51% yield) was obtained.

[0786] LCMS (ESI, m / z): 413.05 [M+H] +

[0787] 1 H NMR(300MHz, CDCl3)δ7.68(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).

[0788] 19 F NMR(282MHz, CDCl3)δ-87.2,-90.2.

[0789] Example 18 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0790] Step 1) Benzyl (Z)-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylene)-3-hydroxybutanoate

[0791] To a 40 ml single-necked flask at room temperature were added 7-formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (566 mg, 3.27 mmol), piperidine (28 mg, 0.327 mmol), acetic acid (0.22 ml), benzyl acetoacetate (628 mg, 3.27 mmol), and dichloromethane (12.0 ml). After nitrogen replacement, the reaction was allowed to proceed overnight at 40°C. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to afford a yellow oil (600 mg, 52.9% yield).

[0792] LCMS (ESI, m / z): 348.10 [M+H] +

[0793] Step 2) Benzyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0794] To a 40 ml single-necked flask at room temperature was added benzyl (Z)-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylene)-3-hydroxybutanoate (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). After nitrogen substitution, the reaction was allowed to proceed at 90°C overnight. The mixture was cooled to room temperature and filtered. The resulting solid was slurried with isopropanol (2.0 ml x 3) and filtered to afford a pale yellow solid (105 mg, 80.8% yield).

[0795] LCMS (ESI, m / z): 454.25 [M+H] +

[0796] Step 3) Benzyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0797] Benzyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (200 mg, 0.441 mmol), cyclopropane bromide (534 mg, 4.41 mmol), cesium carbonate (719 mg, 2.21 mmol), and N,N-dimethylformamide (2 mL) were added to an 8 mL single-necked vial at room temperature. The reaction was stirred overnight at 130°C under nitrogen. The mixture was cooled to room temperature, filtered, and the filtrate was purified on a C18 column (mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile; flow rate: 60 mL / min; 10% to 50% over 10 minutes; detection wavelength: 254 nm). Fractions were collected and lyophilized under reduced pressure to yield a yellow solid (35 mg, 16.1% yield).

[0798] MS (ESI) M / Z: 494.2 [M+H] +

[0799] Step 4) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0800] To a 30 mL autoclave at room temperature was added benzyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (35 mg, 0.071 mmol), palladium on carbon (10% content, 35 mg), and tetrahydrofuran (2 mL). After nitrogen purging, hydrogen was introduced at 3 atmospheres of pressure and the reaction was allowed to proceed at 50°C for 3 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield a pale yellow solid (28 mg, 97.8% yield), which was used directly in the next reaction.

[0801] MS (ESI) M / Z: 404.2 [M+H] +

[0802] Step 5) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0803] To an 8 ml vial were added 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-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) at room temperature. The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.5 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was filtered, and the resulting filtrate was purified on a C18 column (mobile phase A: aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 60 ml / min, increasing from 20% to 50% within 10 minutes; detection wavelength: 254 nm). The fractions were collected and lyophilized under reduced pressure to obtain a white solid (20.2 mg, yield 72.3%).

[0804] LCMS (ESI, m / z): 403.05 [M+H] +

[0805] 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).

[0806] Example 19 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0807] 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

[0808] 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 vial at room temperature. After nitrogen purge, the reaction was continued at 90°C for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified using a C18 column (mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile; flow rate: 60 mL / min, increasing from 10% B to 50% B over 10 minutes; detection wavelength: 254 nm). The fractions were collected and lyophilized under reduced pressure to obtain a yellow solid (22.5 mg, yield 49.8%)

[0809] MS (ESI) M / Z: 471.2 [M+H] +

[0810] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0811] To an 8 ml single-necked flask at room temperature were added 2-cyanoethyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (20 mg, 0.042 mmol), ethylene glycol dimethyl ether (0.6 ml), and a 0.2 ml aqueous solution of sodium hydroxide (4 mg, 0.084 mmol). The reaction was allowed to react at room temperature for 1 hour. The mixture was quenched by the addition of hydrochloric acid solution (1.0 mol / L) under an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (5 ml x 3 times), and the combined organic phases were washed with saturated brine (5 ml x 3 times), and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain a light yellow solid (17 mg, 96.9% yield), which was used directly in the next reaction.

[0812] MS (ESI) M / Z: 418.5 [M+H] +

[0813] Step 3) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0814] To an 8 ml vial at room temperature were added 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). The mixture was allowed to react at room temperature for half an hour. A 25% aqueous ammonia solution (0.1 ml) was added to the reaction mixture at room temperature. The reaction was allowed to react at room temperature for half an hour. The reaction solution was filtered, and the filtrate was purified via a C18 column (mobile phase A: 0.1% aqueous ammonium bicarbonate; mobile phase B: acetonitrile; flow rate: 60 ml / min, increasing from 20% B to 50% B over 10 minutes; detection wavelength: 254 nm). Fractions were collected and lyophilized under reduced pressure. The product was collected and lyophilized under reduced pressure to obtain a white solid (2.2 mg, 12.9% yield).

[0815] LCMS (ESI, m / z): 417.0 [M+H] +

[0816] 1 H NMR (400MHz, CDCl3) δ7.85(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).

[0817] 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

[0818] 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

[0819] To an 8 ml single-necked vial at room temperature were added 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). After nitrogen purge, the reaction was continued at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filter cake was rinsed with ethyl acetate (3 x 5 ml). The filtrate was collected and concentrated to dryness under reduced pressure to obtain a white solid (40 mg, 72.7% yield).

[0820] MS (ESI) M / Z: 459.2 [MH] -

[0821] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0822] To an 8 ml single-necked flask at room temperature were added 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 a 0.3 ml aqueous solution of sodium hydroxide (7 mg, 0.174 mmol). The reaction was allowed to react at room temperature for 1 hour. The mixture was quenched by the addition of hydrochloric acid solution (1.0 mol / L) under an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (3 ml x 3 times), and the combined organic phases were washed with saturated brine (3 ml x 3 times), then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to afford a pale yellow solid (30 mg, 84.6% yield), which was used directly in the next reaction.

[0823] MS (ESI) M / Z: 406.3 [M+H] +

[0824] 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

[0825] To an 8 ml vial at room temperature were added 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). The mixture was allowed to react at room temperature for half an hour. A 25% aqueous ammonia solution (0.2 ml) was added to the reaction mixture at room temperature. The mixture was allowed to react at room temperature for half an hour. The reaction mixture was filtered, and the filtrate was purified via a C18 column (mobile phase A: aqueous solution containing 0.05% ammonia; mobile phase B: acetonitrile; flow rate: 60 ml / min, increasing from 15% B to 40% B over 15 minutes; detection wavelength: 254 nm). The product was collected and lyophilized under reduced pressure to obtain a white solid (14.4 mg, 48.1% yield).

[0826] LCMS (ESI, m / z): 404.10 [M+H] +

[0827] 1 H NMR(400MHz, CDCl3)δ7.68(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).

[0828] Example 21 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0829] Step 1) Benzyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0830] To an 8 ml single-necked vial at room temperature, benzyl 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, 0.110 mmol), iodocyclobutane (60 mg, 0.331 mmol), cesium carbonate (72 mg, 0.221 mmol), and N,N-dimethylformamide (1 ml) were added. Under nitrogen, the reaction was stirred at 60°C overnight. The reaction mixture was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate (3 x 10 ml). The organic phases were combined, washed with saturated brine (3 x 10 ml), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated to dryness under reduced pressure. The resulting residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 4 / 1) to give a white solid (40 mg, yield 71.4%).

[0831] MS (ESI) M / Z: 508.2 [M+H] +

[0832] Step 2) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0833] To a 30 mL autoclave at room temperature was added benzyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (40 mg, 0.085 mmol), palladium on carbon (10% content, 40 mg), and tetrahydrofuran (2 mL). After nitrogen purging, hydrogen was introduced at 3 atmospheres of pressure and the reaction was allowed to proceed at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield a white solid (30 mg, 91.3% yield), which was used directly in the next reaction.

[0834] MS (ESI) M / Z: 418.2 [M+H] +

[0835] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0836] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.5 ml) was added to the reaction solution at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was filtered, and the resulting filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: Xselect CSH C18OBD column; mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: 40% to 50% acetonitrile over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (15.0 mg, 49.8% yield).

[0837] LCMS (ESI, m / z): 417.2 [M+H] +

[0838] 1 H NMR(400MHz,Chloroform-d)δ7.66(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),4.83-4.6 6(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).

[0839] Example 22 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0840] Step 1) Benzyl 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0841] To an 8 mL single-necked vial at room temperature were added benzyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (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). The reaction was stirred at 60°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was purified by carbon-18 reverse phase column (conditions 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, rinse over 15 minutes; detection wavelength: 254 nm, reference wavelength: 220 nm). The product was collected and concentrated under reduced pressure to give a white solid (47 mg, yield 13.7%).

[0842] MS (ESI) M / Z: 522.2 [M+H] +

[0843] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0844] To a 30 mL autoclave at room temperature was added benzyl 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (47 mg, 0.090 mmol), palladium on carbon (10% content, 47 mg), and tetrahydrofuran (2 mL). After nitrogen purging, hydrogen was introduced at 3 atmospheres of pressure and the reaction was allowed to proceed at 50°C for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield a pale yellow solid (30 mg, 77.2% yield), which was used directly in the next reaction.

[0845] MS (ESI) M / Z: 432.2 [M+H] +

[0846] Step 3) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0847] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.2 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was filtered, and the resulting filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: Xselect CSH C18 OBD column; mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: 35% to 50% acetonitrile over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (17.9 mg, 59.8% yield).

[0848] LCMS (ESI, m / z): 431.2 [M+H] +

[0849] 1 H NMR(400MHz,Chloroform-d3)δ7.68(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).

[0850] Example 23 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0851] Step 1) Benzyl 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0852] To an 8 ml single-necked vial at room temperature, 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, 0.220 mmol), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodooxolane (218 mg, 0.663 mmol), and nitromethane (4 ml) were added. Under nitrogen, the reaction was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate (3 x 10 ml). The combined organic phases were washed with saturated brine (3 x 10 ml), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated to dryness under reduced pressure. The resulting residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid (40 mg, yield 34.8%).

[0853] MS (ESI) M / Z: 522.2 [M+H] +

[0854] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0855] Benzyl 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylate (20 mg, 0.038 mmol), palladium on carbon (10% content, 20 mg), and methanol (2 mL) were added to a 30 mL autoclave at room temperature. After nitrogen replacement, hydrogen was introduced at 3 atmospheres and the reaction was incubated at 70°C for 4 hours. After cooling to room temperature, the reaction solution was filtered and the filtrate was purified by preparative HPLC. Purification conditions were as follows: column: C-18 reverse phase column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 40 mL / min; gradient: 30% B to 50% B over 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 used directly in the next reaction.

[0856] MS (ESI) M / Z: 432.2 [M+H] +

[0857] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0858] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.1 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was filtered, and the resulting filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: Xselect CSH C18OBD column; mobile phase A: water (containing 0.1% trifluoroformic acid), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: 20% to 50% acetonitrile over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (2.9 mg, 24.2% yield).

[0859] LCMS (ESI, m / z): 431.2 [M+H] +

[0860] 1 H NMR(400MHz, CDCl3)δ7.82(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).

[0861] 19 F NMR (377 MHz, CDCl3) δ-56.0.

[0862] 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

[0863] Step 1) Benzyl 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0864] To an 8 ml single-necked vial at room temperature was added 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), 2,2,2-trifluoroethyl trifluoromethanesulfonate (92 mg, 0.354 mmol), cesium carbonate (144 mg, 0.442 mmol), and N,N-dimethylformamide (2 ml). The reaction was stirred at room temperature for 2 hours. The mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic phases were washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and filtered to obtain the filtrate, which was concentrated to dryness under reduced pressure. The resulting residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 2 / 1) to give a yellow solid (36 mg, yield 36.1%).

[0865] MS (ESI) M / Z: 536.2 [M+H] +

[0866] 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

[0867] To a 30 mL autoclave at room temperature was added benzyl 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylate (36.0 mg, 0.067 mmol), palladium on carbon (10% content, 36 mg), and tetrahydrofuran (2 mL). After nitrogen purging, hydrogen was introduced at 3 atmospheres of pressure and the reaction was incubated at 70°C for 3 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to yield a white solid (24 mg, 80.1% yield), which was used directly in the next reaction.

[0868] MS (ESI) M / Z: 446.2 [M+H] +

[0869] 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

[0870] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.2 ml) was added to the reaction solution at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was filtered, and the resulting filtrate was purified by preparative high performance liquid chromatography. Purification conditions were as follows: Xselect CSH C18OBD column; mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: 40% to 50% acetonitrile over 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (6.3 mg, 26.3% yield).

[0871] MS (ESI) M / Z: 445.15 [M+H] +

[0872] 1 H NMR (400MHz, CDCl3) δ7.66(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).

[0873] 19 F NMR (282 MHz, CDCl3) δ-74.1.

[0874] 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

[0875] Step 1) 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carboxamide

[0876] To a 100 ml single-necked flask, add 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) at room temperature. Allow to react at room temperature for 0.5 hour. Add an aqueous ammonia solution (1.0 M, 6 ml) at room temperature. Allow to react at room temperature for 1 hour. Dilute with water (250 ml). Extract with ethyl acetate (250 ml x 3). Combine the organic phases, wash with saturated brine (250 ml), and dry over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: pure ethyl acetate) to obtain an orange oil (800 mg, yield 80.4%).

[0877] LCMS (ESI, m / z): 195.1 [M+H] +

[0878] Step 2) 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

[0879] 8-Amino-2,3-dihydro-1,4-benzodioxazine-5-carboxamide (766 mg, 3.95 mmol) and phosphorus oxychloride (15 mL) were added to a 50 mL single-necked flask at room temperature. The mixture was heated to 80°C and reacted for 1 hour. Cooled to room temperature. The mixture was quenched with sodium hydroxide solution (1.0 mol / L) and the pH was adjusted to approximately 8. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to afford a white solid (310 mg, 44.6% yield).

[0880] LCMS (ESI, m / z): 177.1 [M+H] +

[0881] Step 3) 8-bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

[0882] To a 40 mL vial was added 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) at room temperature. The mixture was allowed to react at 70°C for 1.5 hours. The reaction mixture was cooled to room temperature, filtered, and rinsed three times with ethyl acetate (8 mL). The filtrate was concentrated under reduced pressure, and the residue was purified on a preparative plate (petroleum ether / ethyl acetate (v / v) = 5 / 1) to afford a white solid (110 mg, 26.0% yield).

[0883] Step 4) 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

[0884] 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 vial at room temperature. After nitrogen replacement, cool the reaction mixture to -78°C. Slowly add a solution of n-butyllithium (0.2 ml, 2.5 mmol / ml, 0.50 mmol) in n-hexane dropwise. Incubate at -78°C for 30 minutes. Add N,N-dimethylformamide (0.5 ml) and incubate at -78°C for 30 minutes. Quench the mixture with saturated aqueous ammonium chloride (5 ml). 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 was purified by preparative plate (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a white solid (40 mg, yield 46.2%).

[0885] 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

[0886] 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (35 mg, 0.185 mmol), 2-cyanoethyl-3-oxobutanoate (29 mg, 0.185 mmol), 4-amino-5-methylpyridin-2-ol (23 mg, 0.185 mmol), isopropyl alcohol (0.6 ml), and acetic acid (12 μl) were added to an 8 ml single-necked vial at room temperature. After nitrogen replacement, the reaction was carried out at 90°C for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by C18 reverse-phase column chromatography using the following conditions (C18 BIOTAGE 40 g reverse-phase column, mobile phase A (0.1% aqueous ammonium bicarbonate) and mobile phase B (acetonitrile), gradient from 25% B to 30% B over 15 minutes, monitoring wavelength at 254 nm) to obtain a light yellow solid (15 mg, 18.8% yield).

[0887] MS (ESI) M / Z: 433.2 [M+H] +

[0888] 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

[0889] To an 8 mL single-necked vial at room temperature was added 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). After nitrogen substitution, the reaction was continued at 90°C for 1 hour. The mixture was cooled to room temperature. The filtrate was filtered and rinsed with acetonitrile (3 mL). The filtrate was concentrated under reduced pressure to yield a yellow solid (15 mg, crude product), which was used in the next step without further purification.

[0890] MS (ESI) M / Z: 461.3 [M+H] +

[0891] 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

[0892] To an 8 ml single-necked flask at room temperature were added 2-cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (15 mg, 0.033 mmol), ethylene glycol dimethyl ether (0.45 ml), and a 0.15 ml aqueous solution of sodium hydroxide (3 mg, 0.066 mmol). The reaction was allowed to react at room temperature for 1 hour. The mixture was quenched with hydrochloric acid solution (1.0 mol / L) under an ice bath and adjusted to pH 5. The mixture was extracted with ethyl acetate (5 ml x 3 times), and the combined organic phases were washed with saturated brine (5 ml x 3 times), then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to yield a pale yellow solid (10 mg, crude product), which was used in the next reaction without further purification.

[0893] LCMS (ESI, m / z): 408.1 [M+H] +

[0894] 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

[0895] To an 8 ml vial at room temperature were added 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). The reaction was allowed to proceed at room temperature for half an hour. A 25% aqueous solution of ammonia (0.1 ml) was added to the reaction mixture at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. The reaction mixture was 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: 50 ml / min; gradient: acetonitrile from 25% to 30% over 10 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (1.1 mg, 11.0% yield).

[0896] MS (ESI) M / Z: 407.30 [M+H] +

[0897] 1 H NMR(300MHz,DMSO-d6)δ7.69(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).

[0898] Preparation of chiral compounds:

[0899] Examples 32 & 33

[0900] (S)-4-(5-cyanocyanin-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 32 and

[0901] (R)-4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 33

[0902] 4-(5-Cyanine-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 solution), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 40% B over 15 minutes; wavelength: 208 / 258 nm; elution time of 33: 8.80 minutes; elution time of 32: 12.0 minutes; sample solution: ethanol; injection volume: 0.8 ml; number of injections: 5. Two enantiomers, monomer 33: white solid (20.3 mg, yield 36.2%) and monomer 32: white solid (16.9 mg, yield 30.1%), were obtained.

[0903] 32LCMS (ESI, m / z): 405.25 [M+H] +

[0904] 32 1 H NMR (400MHz, DMSO-d6) δ7.70(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),4.2 8-4.20(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).

[0905] 33LCMS (ESI, m / z): 405.25 [M+H] +

[0906] 33 1 H NMR (400MHz, DMSO-d6) δ7.70(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),4.2 8-4.20(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).

[0907] Examples 36 & 37

[0908] (S)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 36

[0909] (R)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 37

[0910] 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) (i.e., a mixed solution of n-hexane, ammonia and alcohol, the ammonia concentration is 10 mmol / L n-hexane, and the volume ratio of alcohol to n-hexane is 1:4), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 20% B to The reaction was carried out using 20% ​​B for 15 minutes; detection was performed using a UV detector at wavelengths of 218 / 270 nm; peak elution time of 36 was 9.47 minutes; peak elution time of 37 was 11.2 minutes; sample solution was an ethanol solution of compound 11, with a concentration of 8.9 mg / mL; injection volume was 0.5 mL; and number of injections was 9. Two enantiomers, monomer 37 (7.5 mg, 18.8% yield) and monomer 36 (9.3 mg, 23.3% yield), were obtained as white solids.

[0911] 36 LCMS (ESI, m / z): 391.10 [M+H] +

[0912] 36 1 H NMR (400MHz, DMSO-d6) δ7.70(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).

[0913] 37 LCMS (ESI, m / z): 391.10 [M+H] +

[0914] 37 1 H NMR (400MHz, DMSO-d6) δ7.70(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).

[0915] Examples 38 & 39

[0916] (S)-6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 38

[0917] (R)-6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 39

[0918] 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 over 34.5 minutes; wavelength: 210 / 220 nm; (39 peak time): 20.68 minutes; (38 peak time): 28.59 minutes; sample solution: methanol: dichloromethane = 1:1; injection volume: 0.35 ml; number of injection needles: 12) to obtain two enantiomers, monomer 0A: white solid (13.8 mg, yield 33.6%) and monomer 0B: white solid (14.0 mg, white solid, yield 34.1%).

[0919] 38 MS (ESI) M / Z: 421.00 [M+H] +

[0920] 38 1H NMR (400MHz, DMSO-d6) δ8.83(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).

[0921] 39 MS (ESI) M / Z: 421.05 [M+H] +

[0922] 39 1 H NMR (400MHz, DMSO-d6) δ8.83(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).

[0923] Examples 40 & 41

[0924] (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

[0925] (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

[0926] 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (32.0 mg, 0.079 mmol) (Compound 25) was subjected to chiral separation (separation conditions were as follows: (chiral column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol ammonia in methanol), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 15% B to 15% B for 20 minutes; wavelength: 218 / 260 nm; peak elution time of 41: 10.22 minutes; peak elution 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, 33.7% yield) and enantiomeric monomer 40 (9.8 mg, white solid, 30.6% yield) were obtained.

[0927] 40: MS (ESI) M / Z: 407.30 [M+H] +

[0928] 1 H NMR(300MHz,DMSO-d6)δ7.69(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).

[0929] 41: MS (ESI) M / Z: 407.30 [M+H] +

[0930] 1 H NMR(300MHz,DMSO-d6)δ7.69(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).

[0931] Examples 46 & 47

[0932] (S)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 46

[0933] (R)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 47

[0934] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (32.0 mg, 0.057 mmol) was subjected to chiral separation (separation conditions were as follows: Chiral column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; mobile phase A: n-hexane (2 mmol ammonia in methanol), mobile phase B: ethanol; flow rate: 40 ml / min; gradient: 20% B to 20% B over 23 min; wavelength: 207 / 236 nm; (47) peak elution time: 11.6 min; (46) peak elution time: 20.3 min; sample solution: methanol: dichloromethane = 1:1; injection volume: 0.2 ml; number of injections: 3) to obtain two enantiomer monomers 0A (8.50 mg, white solid, yield 26.6%) and 0B (10.5 mg, white solid, yield 32.8%)

[0935] 46: MS (ESI) M / Z: 413.05 [M+H] +

[0936] 46 1 H NMR(300MHz, CDCl3)δ7.68(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).

[0937] 19F NMR (282MHz, CDCl3) δ-87.2,-90.2.

[0938] 47: MS (ESI) M / Z: 413.05 [M+H] +

[0939] 47 1H NMR(300MHz, CDCl3)δ7.68(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).

[0940] 19F NMR (282MHz, CDCl3) δ-87.2,-90.2.

[0941] Examples 48 & 49

[0942] (S) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 48

[0943] (R) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 49

[0944] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20.2 mg, 0.050 mmol) was subjected to chiral separation (separation conditions were as follows: chiral column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol ammonia in methanol), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 30% B to 30% B for 22 minutes; wavelength: 200 / 220 nm; (49) peak time: 13.4 minutes; (48) peak time: 19.8 minutes; methanol: dichloromethane = 1:1; injection volume: 2 ml; number of injections: 3) to obtain two enantiomer monomers 49 (6.20 mg, white solid, yield 22.2%) and 48 (5.40 mg, white solid, yield 19.3%)

[0945] 48:LCMS(ESI)M / Z:403.20[M+H] +

[0946] 48 1H 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).

[0947] 49:LCMS(ESI)M / Z:403.20[M+H] +

[0948] 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).

[0949] Example 62 & 63

[0950] (R)-4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 63

[0951] (S)-4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 62

[0952] 4-(7-Cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20 mg, 0.148 mmol) (Compound 14) was subjected to chiral separation (separation conditions are as follows: chiral column CHIRAL ART Amylose-C NEO, 2*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol ammonia in methanol solution) (i.e., a mixed solution of n-hexane, ammonia and alcohol, the concentration of ammonia is 10 mmol / L n-hexane, the ratio of alcohol to n-hexane is 1:9), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 10% B to 10% B for 28 minutes; detection was performed using a UV detector, wavelength: 214 / 254 nm; (63) peak time: 10.7 minutes; (62 peak time): 15.6 minutes; sample solution: solution of compound 14, the concentration of compound 14 was 25 mg / mL, the solvent was n-hexane:ethanol = 85:15; injection volume: 0.4 ml; number of injection needles: 2) to obtain two enantiomer monomers 63 (5.7 mg, white solid, yield 28.5%) and 62 (3.7 mg, white solid, yield 18.5%).

[0953] 62:LCMS(ESI)M / Z:393.1[M+H] +

[0954] 62 1 H NMR(400MHz,Chloroform-d)δδ7.70(s,1H),6.91(d,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.14(s,2H),5.7 8(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).

[0955] 63:LCMS(ESI)M / Z:393.1[M+H] +

[0956] 63 1 H NMR(400MHz,Chloroform-d)δδ7.70(s,1H),6.91(d,J=8.4Hz,1H),6.77(d,J=8.4Hz,1H),6.14(s,2H),5.7 8(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).

[0957] Other racemic examples in this application were resolved by similar means.

[0958] Single crystal X-ray diffraction analysis

[0959] Single crystal X-ray diffraction analysis of compound 36

[0960] Approximately 5 mg of compound 36 was dissolved in 0.6 mL of acetone at room temperature, followed by the gradual addition of 1.4 mL of water. The filtrate was filtered into a clean vial, covered with a pinhole film, and allowed to evaporate slowly at room temperature. Bulk single crystals formed after one day, which were used for single crystal X-ray diffraction analysis, as shown in Figure 9.

[0961] 36 crystallizes in the monoclinic system in the C2 space group with the chemical formula C 22 H 22 N₄O₃. Each asymmetric unit contains one 36 molecule, 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.

[0962] The refined single crystal structure is shown in Figures 2 and 3 (for clarity, major conformers and hydrogen atoms have been omitted). The crystal structure data are summarized in Table 2, and detailed information on atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds, torsion angles, and atomic occupancies is shown in Tables 3 to 10. The XRPD pattern calculated from the single crystal structure (top) is consistent with the experimental pattern (bottom) (Figure 4).

[0963] Table 2 Crystal data and structure refinement of compound 36

[0964] Table 3 Fractional atomic coordinates of compound 36 (×10 4 ) and equivalent isotropic displacement parameters

[0965] U(eq) is defined as one-third of the orthogonalized Uij tensor trajectory.

[0966] Table 4 Anisotropic displacement parameters of compound 36

[0967] The anisotropic displacement factor exponent is -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0968] Table 5 Bond lengths of compound 36

[0969] Table 6 Bond angles of compound 36

[0970] Table 7 Hydrogen bonds of compound 36

[0971] 1 1-x,1+y,-z; 2 3 / 2-x,-1 / 2+y,-z

[0972] Table 8 Torsion angle of compound 36

[0973] Table 9 Hydrogen atom coordinates of compound 36 and isotropic displacement parameters

[0974] Table 10 Atomic occupancy of compound 36

[0975] Single crystal X-ray diffraction analysis of compound 62

[0976] Approximately 5 mg of compound 62 was dissolved in 0.1 mL of ethanol at room temperature, followed by the gradual addition of 0.35 mL of n-heptane. The solution was filtered into a clean sample vial, covered with a pinhole film, and allowed to evaporate slowly under ambient conditions. After one day, a bulk single crystal formed, which was used for single crystal X-ray diffraction analysis, as shown in Figure 10.

[0977] 62 crystallizes in the monoclinic system in the C2 space group with the chemical formula C 21 H 20 N4O4. 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 at C9 (C30) is determined to be in the "S" configuration.

[0978] The refined single crystal structure is shown in Figures 6 and 7 (hydrogen atoms are omitted for clarity). The crystal structure data is summarized in Table 11, and detailed information on atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds, and torsion angles is shown in Tables 12 to 18. The XRPD pattern calculated from the single crystal structure is consistent with the experimental pattern (Figure 8).

[0979] Table 11 Crystal data and structure optimization of compound 62

[0980] Table 12 Fractional atomic coordinates of compound 62 (×10 4 ) and equivalent isotropic displacement parameters

[0981] U(eq)is defined as one third of the trace of the orthogonalized U ij tensor.

[0982] Table 13 Anisotropic displacement parameters of compound 62

[0983] The anisotropic displacement factor exponent takes the form: -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…] .

[0984] Table 14 Bond lengths of compound 62

[0985] Table 15 Bond angles of compound 62

[0986] Table 16 Hydrogen bonds of compound 62

[0987] 1 1-x,-1+y,-z; 2 3 / 2-x,-1 / 2+y,-z; 3 2-x,-1+y,1-z

[0988] Table 17 Torsion angle of compound 62

[0989] Table 18 Hydrogen atom coordinates of compound 62 and isotropic displacement parameters

[0990] Example In vitro activity test

[0991] 1. Experimental principle:

[0992] Taking advantage of the chemiluminescent reaction produced by luciferase binding to substrates, a plasmid containing the Gal4 DNA binding domain (DBD) fused to the mineralocorticoid receptor (MR) ligand binding domain (LBD) and a firefly luciferase reporter gene plasmid under the control of a Gal4 UAS (upstream activating sequence) was transfected into human embryonic kidney (HEK293) cells. The level of firefly luciferase activity was used to determine changes in MR activity before and after stimulation, or the effects of different stimuli on MR activity.

[0993] 2. Experimental methods:

[0994] 1. Preparation and Handling of Compounds

[0995] 1.1 Preparation of compound DMSO stock solution

[0996] All compounds were dissolved in DMSO to prepare 25 mM stock solutions, which were stored in a -20°C refrigerator.

[0997] 1.2 Preparation of working solution

[0998] 1) The test compound was diluted 3-fold with DMSO, with 10 concentration gradients, starting at 10 mM.

[0999] 2) The positive compound (Finerenone) was diluted 3-fold with DMSO, with a 10-point concentration gradient and a starting concentration of 1 mM.

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

[1001] 4) Block the compound plate and shake for 5 minutes.

[1002] 2. Cell Suspension Preparation

[1003] 1) All cells were cultured according to ATCC standards, and HEK293T cells were used in the exponential growth phase.

[1004] 2) Gently discard the culture supernatant and wash the cells twice with PBS.

[1005] 3) Digest the cells with trypsin solution, stop the digestion with complete culture medium, collect the cells and count them.

[1006] 4) Seed 6 × 106 HEK293T cells into a 100 mm cell culture dish.

[1007] 5) Place the culture dish seeded with cells in a 37°C, 5% CO2 incubator and culture overnight for 16 hours.

[1008] 3. Cell Transfection

[1009] 1) 3000&P3000 transfection reagent placed at room temperature

[1010] 2) Add 3000 reagents to Opti-MEM TM In the culture medium, P3000, plasmid and Opti-MEM TM Add the culture medium to another tube, taking care not to touch the tube wall.

[1011] 3) Mix well with a pipette and let stand at room temperature for 5 minutes.

[1012] 4) Add the plasmid to the diluted transfection reagent, mix well with a pipette, and let stand at room temperature for 20 minutes.

[1013] 5) Add the mixed plasmid and transfection reagent to a 60 mm cell culture dish.

[1014] 6) Place the culture dish in a 37°C, 5% CO2 incubator for 5-6 hours.

[1015] 4. Compound Treatment

[1016] 1) Transfer 25 nL of the diluted compound to the cell culture plate using Echo655.

[1017] 2) Seed the cells (see step 1.3) into a 384-well cell culture plate at 17,000 cells per well in 25 μL of phenol red-free DMEM medium containing 5% CFBS and 0.8 nM Aldosteron.

[1018] 3) The cell culture plate was cultured in a 37°C, 5% CO2 incubator overnight for 18-20 hours.

[1019] 5. Compound Detection

[1020] 1) Place the Britelite plus detection reagent at room temperature.

[1021] 2) Place the 384-cell plate at room temperature.

[1022] 3) Add 25 μL of Britelite plus detection reagent to each well of the cell culture plate.

[1023] 4) Detect the luminescence value using Envision.

[1024] 6. Result processing:

[1025] 1) Obtain firefly luciferase signal by reading luminescence and calculate inhibition rate;

[1026] 2) % Inhibition = 100 - [(RLU compound - avgRLU positive control) / (RLU negative control - avgRLU positive control) × 100%, where avgRLU positive control is the average luminescence value of all positive control wells on the plate; avgRLU negative control is the average luminescence value of all negative control wells on the plate; RLU compound is the luminescence value of the test compound at different concentrations;

[1027] 3) Calculate the IC50 of the compound using Graphpad 8.0 software;

[1028] 7. Experimental results:

[1029] Table 19 In vitro activity data of the compounds of the present invention

[1030] in conclusion:

[1031] It can be seen from the experimental results in Table 19 that the compounds of the present invention have good mineralocorticoid receptor (MR) antagonist activity and can be used as effective mineralocorticoid receptor antagonists.

[1032] Example Test Mouse Pharmacokinetics Study

[1033] This study evaluated the pharmacokinetic behavior of the test compound in rats following intravenous or oral administration. For intravenous administration, the test compound was prepared as a 0.2 mg / mL clear solution in a vehicle consisting of 10% ethanol, 40% polyethylene glycol 400, and 50% water, and plasma was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. For oral administration, the test compound was prepared as a 1 mg / mL clear solution in a vehicle consisting of 10% ethanol / 40% polyethylene glycol 400 / 50% water, and plasma was collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration.

[1034] 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 performed using the software Analyst (Applied

[1035] Biosystems) and the data were processed using Analyst (Applied Biosystems) software.

[1036] Plasma concentrations were treated using a non-compartmental model using WinNonlin™ Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[1037] 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.

[1038] Table 20 SD rat pharmacokinetic (PK) data

[1039] The experimental results in Table 20 show that the compounds of the present invention have good in vivo pharmacokinetic properties.

[1040] Example Test Pharmacokinetic Study in Mice

[1041] This study aims to evaluate the pharmacokinetic behavior of compounds in mice following intravenous or oral administration. For intravenous administration, the test compound was prepared as a 0.2 mg / mL clear solution in a vehicle of 10% ethanol / 40% polyethylene glycol 400 / 50% ultrapure water. Plasma was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 hours after administration.

[1042] The concentrations of the test compounds in plasma were determined by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention times of the compounds and internal standards, chromatogram acquisition, and chromatogram integration were processed using the Analyst software (Applied Biosystems). Data statistics were also processed using the Analyst software (Applied Biosystems).

[1043] Plasma concentrations were treated using a non-compartmental model using WinNonlin™ Version 6.1 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[1044] The pharmacokinetic parameters of the compound in mice at a dose of 1 mg / kg after intravenous injection are shown in Table 21 below.

[1045] Table 21 Pharmacokinetic (PK) data of CD1 mice

[1046] Example 70 Pharmacological effects of compounds 36 and 62 on diabetic nephropathy mouse model

[1047] 1. Research Objectives

[1048] The pharmacodynamic effects of compounds 36 and 62 on diabetic nephropathy mouse model were evaluated.

[1049] 2. Drug preparation

[1050] The solvent and positive drug need to be prepared on the same day as shown in Table 22.

[1051] Table 22 Drug preparation

[1052] 3. Experimental Animals and Feeding Management

[1053] 3.1 Experimental animals

[1054] Strain: C57BL / 6 mice, KK-Ay mice

[1055] Age: Animals are 6-8 weeks old, experiments start at 7-9 weeks old

[1056] Gender: Male

[1057] Body weight: C57BL / 6 mice 21-23g, KK-Ay mice 25-30g

[1058] Number: 72 experimental animals

[1059] 3.2 Animal husbandry

[1060] 3.2.1 Quarantine

[1061] The quarantine and acclimatization period lasted for 7 days. Routine health examinations were performed by a veterinarian, and animals with abnormal performance were culled before the experiment.

[1062] 3.2.2 Animal rearing conditions

[1063] Experimental animals were housed in individual cages in an SPF-rated, laminar flow cleanroom with constant temperature and humidity at the Animal Center of Kanglong Chemical (Beijing) Pharmaceutical Technology Co., Ltd. (AAALAC-accredited). The room temperature was 22-25°C, the humidity was 40-80%, and the lighting was alternating between light and dark on a 12-hour cycle. Cages were made of polycarbonate. The bedding was autoclaved soft corn cob and changed twice weekly. The drinking water was autoclaved, and the food was irradiated with cobalt-60 radiation. Animals had free access to sterile food and water.

[1064] 3.2.3 Animal number

[1065] Each cage was labeled with the number of animals, sex, strain, date of receipt, group, and start time of the experiment. Each animal was individually numbered on its tail.

[1066] 4. Experimental Animal Grouping and Dosing

[1067] On the day of administration, 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), and high-dose compound 36 group (KK-Ay + compound 36: 10 mg / kg). The specific groups and dosing schedules are shown in Table 23.

[1068] Table 23 Experimental animal grouping and drug administration

[1069] 7 Experimental methods and test indicators

[1070] 7.1 Urine Collection

[1071] Before the start of the experiment and at weeks 2, 4, 6, and 8 after modeling, urine was collected from mice using metabolic cages for 24 hours. Urine microalbumin (MALB) and creatinine (CREA) levels were measured using a CANON TBA-120FR automated blood biochemistry instrument. The ratio (MALB / CREA) was calculated.

[1072] 7.2 Insulin Content and Serum Ion Detection

[1073] 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 h, the blood was centrifuged at 6000 g for 15 min at 4°C. 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.

[1074] 7.3 Tissue Collection

[1075] After the experiment, the kidneys of all animals were collected by dissection, fixed in formalin, embedded and made into sections for PAS staining and Masson staining, and quantitative analysis was performed.

[1076] 8. Statistics

[1077] The experimental results are expressed as "mean ± standard deviation". The data of each group were statistically analyzed using GraphPad 8.0 software, and p < 0.05 was considered statistically significant.

[1078] 9. Results

[1079] Both compound 62 and compound 36 significantly promoted urinary sodium excretion, could significantly reduce the urine protein / creatinine ratio, and had the effect of improving diabetic nephropathy and hypertension.

[1080] Example 71 Study of CPY enzyme inhibition in vitro

[1081] 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), respectively.

[1082] Therefore, compounds 36 and 62 have higher safety than finerenone.Compound 36 and finerenone have higher half-maximal inhibition concentrations for the two isoforms of CYP3A4-5M / CYP3A4-5T, the main metabolizing enzyme in humans (this metabolizing enzyme metabolizes about 50% of drugs).

[1083] Example 72 Preparation of Formulation

[1084] 500 g of compound 36 and 40 g of talc were added to a granulator for granulation, dried, sized, and 5 g of sodium lauryl sulfate was added. The mixture was mixed well and tableted.

[1085] Example 73 Preparation of Preparation

[1086] 500 g of compound 22 was mixed with 10 g of hydroxypropyl methylcellulose, 10 g of talc, and 3 g of calcium sulfate, and the mixture was passed through a 100-mesh sieve. An appropriate amount of anhydrous ethanol was added to prepare a soft material, and then granulated with a 20-mesh sieve. The mixture was dried, sized, and encapsulated.

[1087] Screening of crystal forms of salts of example compounds

[1088] It is well known to those skilled in the art that the compounds of the above embodiments have been shown to have pharmacological effects, and their pharmaceutically acceptable salts often have the same pharmacological and pharmacodynamic activities. On this basis, the inventors further studied the physicochemical properties of the salt forms and crystal forms of the corresponding compounds. However, the preparation and characterization of the following specific salt forms or crystal forms do not limit the scope of protection of the present invention. Those skilled in the art can, based on the present invention, obtain more salt forms and crystals of the compounds of the present invention through conventional salt formation or crystallization methods. These salt forms and crystals are all solutions protected by the present invention. Specifically as follows:

[1089] 1 Experimental Purpose

[1090] The purpose of this experiment is to select a suitable crystallization method and screen the above salt crystal form based on the above-mentioned research results on the crystal form of compound 36 salt.

[1091] 2 Preparation method

[1092] 2.1 Preparation of twelve acid solutions

[1093] The twelve acids are hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, malic acid, and succinic acid. Appropriate amounts of the twelve acids are dissolved in methanol to prepare an acid solution with a concentration of 0.1 M. Solutions of other concentrations and other solvents can also be prepared according to experimental requirements, or the solutions can be used directly.

[1094] 2.3 Preparation of Compound 36 Salt Crystalline Form

[1095] The following methods were used to prepare various salts on a 25 mg scale. The general experimental steps are as follows.

[1096] An appropriate amount of compound 36 free base was added to a desired amount of solvent at room temperature. Subsequently, 1.1 or 0.55 eq. of acid was added to initiate salt formation. If no precipitation occurred, alternative crystallization methods were attempted, such as slurrying, evaporation, or antisolvent precipitation. The resulting solid sample was filtered, dried, and then characterized.

[1097] 2.3.1 Preparation of Hydrochloride Form I

[1098] 25.86 mg of compound 36 free base was added to 0.5 mL of acetonitrile at room temperature. Subsequently, 1.1 eq. of 6 M aqueous hydrochloric acid was added to initiate a salt formation reaction. A viscous substance was initially obtained, to which 0.2 mL of acetonitrile was added. After stirring overnight, the solid was collected and dried under vacuum at 50°C overnight to obtain hydrochloride Form I. Analysis revealed the XRPD pattern shown in Figure 11, the DSC pattern shown in Figure 12, and the TGA pattern shown in Figure 13.

[1099] 2.3.2 Preparation of Hydrochloride Form II

[1100] 25.94 mg of compound 36 free base was added to 0.5 mL of ethyl acetate at room temperature. Subsequently, 1.1 eq. of 6 M aqueous hydrochloric acid was added and stirred at room temperature overnight, resulting in a viscous product. After stirring at room temperature for 6 days, the resulting solid was collected by filtration and dried under vacuum at 50°C for 6 h to obtain hydrochloride Form II. Analysis revealed the XRPD pattern shown in Figure 14 , the DSC pattern shown in Figure 15 , and the TGA pattern shown in Figure 16 .

[1101] 2.3.3 Preparation of Sulfate Form I

[1102] 24.6 mg of compound 36 free base was added to 0.5 mL of acetone at room temperature. Subsequently, 0.55 eq. of 6 M methanolic sulfuric acid was added. After the addition of the acid, the reaction solution clarified. 40 volumes of n-heptane were added, and the mixture was stirred at room temperature for 5 h. The resulting solid was filtered and dried under vacuum at 50°C overnight to obtain the sulfate salt Form I. The XRPD pattern is shown in Figure 17 , the DSC pattern is shown in Figure 18 , and the TGA pattern is shown in Figure 19 .

[1103] 2.3.4 Preparation of p-toluenesulfonate Form I

[1104] To 26.83 mg of compound 36 free base, 0.5 mL of acetonitrile was added at room temperature. Subsequently, 1.1 eq. of p-toluenesulfonic acid (100 mg / mL p-toluenesulfonic acid in ethanol) was added. The reaction solution remained clear 2 hours after the addition of the acid at room temperature. Subsequently, 600 μL of ethyl acetate was added. After stirring overnight, the solid was filtered and dried under vacuum at 50°C overnight. This afforded Form I of the p-toluenesulfonic acid salt.

[1105] Alternatively, 26.83 mg of compound 36 free base was added to 0.5 mL of ethanol at room temperature, followed by the addition of 1.1 eq. of p-toluenesulfonic acid (100 mg / mL p-toluenesulfonic acid ethanol solution). Two hours after the addition of the acid at room temperature, a precipitate formed. Subsequently, 200 μL of ethanol was added. After stirring overnight, the solid sample was collected by filtration and dried under vacuum at 50°C overnight. Form I of the p-toluenesulfonate salt was obtained, and its NMR is shown in Figure 45. It has an XRPD pattern as shown in Figure 20, a DSC pattern as shown in Figure 21, and a TGA pattern as shown in Figure 22.

[1106] 2.3.5 Preparation of p-toluenesulfonate Form II

[1107] To 24.83 mg of compound 36 free base was added 0.5 mL of methyl tert-butyl ether at room temperature; subsequently, 1.1 eq. of p-toluenesulfonic acid (100 mg / mL p-toluenesulfonic acid ethanol solution) was added. The addition of the acid at room temperature yielded a viscous product. The product was stirred overnight at room temperature, collected by filtration, and dried under vacuum at 50°C for 5 h to obtain p-toluenesulfonate salt Form II. Its NMR spectra are shown in Figure 46. The product exhibits an XRPD pattern as shown in Figure 23, a DSC pattern as shown in Figure 24, and a TGA pattern as shown in Figure 25.

[1108] The p-toluenesulfonate salt form II has a high degree of crystallinity, and a DVS test was performed on it.

[1109] DVS testing of Form II p-toluenesulfonate was performed using a two-cycle method, starting from the current ambient humidity. The results showed that the sample dehydrated when the relative humidity was <30% RH; however, the XRPD pattern of the sample remained unchanged after the DVS test, likely due to the sample absorbing water again. The DVS pattern is shown in Figure 26.

[1110] 2.3.6 Preparation of Methanesulfonate Form I

[1111] To 26.9 mg of compound 36 free base, 0.5 mL of ethanol was added at room temperature; subsequently, 1.1 eq. of methanesulfonic acid was added. If the reaction solution remained clear 2 hours after the addition of the acid, 1 mL of methyl tert-butyl ether was added and stirred at room temperature overnight. The solid was collected by filtration and dried under vacuum at 50°C for 7 hours to obtain the mesylate salt Form I. Its NMR is shown in Figure 47. It has an XRPD pattern as shown in Figure 27, a DSC pattern as shown in Figure 28, and a TGA pattern as shown in Figure 29.

[1112] 2.3.7 Preparation of Benzenesulfonate Form I

[1113] To 20.39 mg of compound 36 free base, 0.5 mL of butanone was added at room temperature; subsequently, 1.1 eq. of benzenesulfonic acid was added. A clear solution was obtained after the addition of the acid; after stirring for 1 hour, a precipitate formed. The resulting solid was stirred at room temperature overnight, collected by filtration, and dried under vacuum at 50°C for 5 hours to obtain benzenesulfonate salt Form I. The NMR spectrum is shown in Figure 44. It has an XRPD pattern as shown in Figure 30, a DSC pattern as shown in Figure 31, and a TGA pattern as shown in Figure 32. DVS analysis was performed on the product, yielding the DVS pattern shown in Figure 33.

[1114] 2.3.8 Preparation of Phosphate Form I

[1115] 22.95 mg of compound 36 free base was added to 0.5 mL of acetonitrile at room temperature. Subsequently, 1.1 eq. of 4.9 M phosphoric acid in dry methanol was added. Addition of the acid at room temperature yielded a viscous substance. After stirring for 2 days, the solid was collected by filtration and dried under vacuum at 50°C to yield Form I, a phosphate salt. This product has an XRPD pattern as shown in Figure 34 , a DSC pattern as shown in Figure 35 , and a TGA pattern as shown in Figure 36 .

[1116] 2.4 Preparation of Compound 36 Free Base and Solvate Crystalline Forms

[1117] 2.4.1 Preparation of Free Base Form I

[1118] At room temperature, 177.42 mg of compound 36 was dissolved in 4 mL of methanol and filtered. 300 μL of the sample solution was transferred to an 8 mL vial and added dropwise to 0.9 mL of water with stirring. After stirring overnight, the solid was collected by filtration and dried under vacuum at 50°C overnight to obtain the free base Form I. This form has an XRPD pattern as shown in Figure 37 , a DSC pattern as shown in Figure 38 , and a TGA pattern as shown in Figure 39 . A DSV analysis was performed on this form, yielding the DVS pattern shown in Figure 40 .

[1119] 2.4.2 Preparation of Compound 36 Form II

[1120] 24.49 mg of compound 36 was weighed into 0.42 mL of dichloromethane, and 1.1 eq of maleic acid (100 mg / mL dissolved in ethanol) was added. After the addition of the acid, the reaction solution became clear, and 1 mL of methyl tert-butyl ether was added. After stirring for 2 days, the solid was collected by filtration and dried under vacuum at 50°C overnight. The XRPD pattern of the product is shown in Figure 41 , the DSC pattern is shown in Figure 42 , and the TGA pattern is shown in Figure 43 .

[1121] 2.5 Crystallinity and dehydration temperature test of compound 36 salt crystal form

[1122] The experiment yielded crystalline hydrochloride, sulfate, p-toluenesulfonate, methanesulfonate, benzenesulfonate, and phosphate salts, but the resulting salt samples were hydrates or solvates. Crystalline free base Form I, which is an anhydrous form, and free base Form II, which is a dichloromethane solvate, were also obtained. Characterization results for the free base and crystalline salts are summarized in the table below.

[1123] The degree of crystallinity was determined by comparing different XRPD patterns, and the dehydration temperature was determined by combining DSC, TGA, and DVS. Form I of the benzenesulfonate salt was selected as the dominant salt due to its relatively superior solid-state properties, high crystallinity, and high dehydration temperature.

[1124] Table 24 Summary data

[1125] Note: The stoichiometric ratios of hydrochloride, sulfate, and phosphate are not determined; 1 / 1 represents the molar ratio of base and acid in salt formation, which is determined by NMR integration.

[1126] 2.6 Solubility experiment of compound 36 salt crystal form

[1127] 15 mg of each of the free base Form I and the benzenesulfonate Form I were weighed and added to 3 mL of biological medium (artificial gastric fluid SGF, fasting artificial gastric fluid FaSSIF, and fed artificial gastric fluid FeSSIF). The samples were shaken at 200 rpm on a shaker at 37°C. Samples were taken and filtered after 0.5 h, 2 h, and 24 h. The filtrates were tested for HPLC and pH, and the solids were tested for XRPD. The results are shown in the table below.

[1128] The free base form I and the benzenesulfonate salt form I both have high solubility in SGF, >5 mg / mL; their solubility in FeSSIF and FaSSIF is lower, ranging from 0.0002 to 0.13 mg / mL.

[1129] During the solubility test, the free base form I did not change its crystal form in FeSSIF and FaSSIF within 24 hours, but the benzenesulfonate salt form I converted to the free base form I within 0.5 hours in FeSSIF and FaSSIF.

[1130] In summary, compared with the free base form I, the benzenesulfonate salt form I dissociated rapidly in FeSSIF and FaSSIF, and the solubility was not significantly improved.

[1131] Table 25 Solubility and pH of free base crystal form I and benzenesulfonate crystal form I in biological media

[1132] 2.7 Stability test of compound 36 salt crystal form

[1133] The stability of the free base Form I and benzenesulfonate Form I of Compound 36 was determined at 60°C (closed), 40°C / 75% RH (open), and RT / 92.5% RH (open) for seven days. The results are shown in Table 26.

[1134] The free base, Form I, remained physically and chemically stable over 7 days at 60°C, 40°C / 75% RH, and RT / 92.5% RH. The benzenesulfonate, Form I, showed no change in crystalline form under all three test conditions, but exhibited a 0.16% increase in impurities with an RRT of 1.78 over 7 days at RT / 92.5% RH.

[1135] Table 26 Stability results of free base crystal form I and benzenesulfonate crystal form I

[1136] In the description of this specification, the reference terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" mean 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 representations of the above terms do 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 a suitable manner. In addition, those skilled in the art can combine and combine different embodiments or examples described in this specification and features of different embodiments or examples without contradiction.

[1137] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A pharmaceutical preparation, characterized in that comprising (i) any one or more of the first component and / or the second component, and (ii) a pharmaceutically acceptable excipient; Wherein, the first component is selected from the compound represented by formula (I) and its stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs; Wherein, the second component is selected from any one or more of the crystal forms of the compound represented by formula (I) or one or more of the crystal forms of the salt of the compound represented by formula (I); in, for R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, 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; R5 is R6 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms; for X is C or N; Y is O or S; R7 is C 1-6 Alkyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl group consisting of 5-6 atoms, C 3-8 Cycloalkyl C 1-6 Alkyl, (3-8 atoms composed of heterocyclic) C 1-6 Alkyl, (heteroaryl composed of 5-6 atoms) C 1-6 Alkyl, phenyl or phenyl C 1-6 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, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; wherein each Rz is independently unsubstituted or substituted with 1, 2, 3 or 4 Rw; Each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl; for R8 and R9 are hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms; R 10 and R 11 Each is independently selected from -CH2- or O, and at least one of them is O; R 12 is -CH2- or -CH2-CH2-; When R 12 -CH2-, R 10 and R 11 are independently selected from -CH2- or O, and at least one of them is O; when R 12 is -CH2-CH2-, R 10 and R 11 O or R at the same time 10 -CH2-, R 11 is O.

2. The pharmaceutical preparation according to claim 1, characterized in that The compound is selected from the compounds represented by formula (Ia), formula (Ib), formula (II), formula (IIa), and formula (IIb); 3. The pharmaceutical preparation according to any one of claim 1, characterized in that The compound is selected from:

4. The pharmaceutical preparation according to claim 1, characterized in that Component (i) is used as an active ingredient, and the mass content of component (i) in the preparation is greater than 0.1% and less than 0.5%, greater than 0.5% and less than 95%, greater than 95% and less than 99.5%, or greater than 99.5% and less than 100%, preferably 0.2%-0.4%, 0.6%-94%, 96%-99.4%, or 99.6%-99.9%.

5. The pharmaceutical preparation according to any one of claim 1, characterized in that The pharmaceutically acceptable excipients include any one or any two of a solvent and a filler; further, the pharmaceutical preparation is a solid preparation, further a capsule or a tablet.

6. The use of a pharmaceutical preparation according to any one of claims 1 to 5 in the preparation of a medicament or in the preparation of a medicament for treating or preventing a disease or condition associated with a mineralocorticoid; preferably, the medicament is used to treat, prevent or alleviate the following diseases in a patient: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, cirrhosis of the liver, renal failure or stroke, preferably, the medicament is used as a mineralocorticoid receptor antagonist.

7. A crystal of a compound and a salt thereof, characterized in that: Selected from compounds shown in formula VII: in, for R3 and R4 are independently selected from hydrogen and deuterium; R5 is selected from R6-R8 are independently selected from C 1-3 alkyl; R9 is hydrogen or deuterium; X is selected from C; Y is selected from O.

8. The crystal of the compound and its salt according to claim 7, characterized in that: The compound is compound 36 or its acid salt, and the structural formula of compound 36 is as follows:

9. The crystal of the compound and its salt according to claim 8, characterized in that: The crystal of compound 36 has a structure belonging to the monoclinic system, a C2 space group, and a unit cell parameter. α=90°,β=112.7428(8)°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z = 4.

10. The crystal of the compound and its salt according to claim 8, characterized in that: The crystals or crystalline forms of the compound 36 have an XRPD spectrum as shown in FIG4 or substantially as shown in FIG4 , wherein substantially means that the difference in the number of peaks is within 85%.

11. The crystal of the compound and its salt according to claim 8, characterized in that: The crystal form of compound 36 is a free base crystal form; preferably, the free base crystal form is a free base crystal form I; preferably, the X-ray diffraction pattern of the free base crystal form and the free base crystal form I comprises a diffraction peak at 2θ of 9.35±0.2°, preferably comprises diffraction peaks at 2θ of 8.16±0.2°, 9.35±0.2°, 12.80±0.2°, 21.92±0.2°, 22.10±0.2°, and 24.38±0.2°; preferably, the X-ray diffraction pattern of the free base crystal form is shown in Figure 37.

12. The crystal of the compound and its salt according to claim 8, characterized in that: The acid salt is crystalline or amorphous; preferably, the acid salt is a benzenesulfonate crystalline form; preferably, the benzenesulfonate crystalline form is benzenesulfonate crystalline form I; preferably, the X-ray diffraction pattern of the benzenesulfonate crystalline form and the benzenesulfonate crystalline form I comprises a diffraction peak at 2θ of 17.31±0.2°, preferably comprising diffraction peaks at 2θ of 4.28±0.2°, 17.31±0.2°, and 26.12±0.2°; preferably, the X-ray diffraction pattern of the benzenesulfonate crystalline form I is shown in Figure 30.

13. The crystal of the compound and its salt according to claim 7, characterized in that: The compound is compound 62, and its structural formula is as follows:

14. The crystal of the compound and its salt according to claim 13, characterized in that: The crystal of compound 62 has a structure belonging to the monoclinic system, a C2 space group, and a unit cell parameter. α=90°,β=121.6750(10)°,γ=90°,unit cell volume The minimum number of asymmetric units Z in the unit cell is 8. The crystal of compound 62 or a crystalline form thereof has an XRPD spectrum as shown in FIG8 or substantially as shown in FIG8 , wherein substantially means that the difference in the number of peak shapes is within 85%.

15. A high performance liquid chromatography method for resolving crystals of the compound according to any one of claims 8 to 14, characterized in that: The chromatographic conditions are: Chromatographic column: using cellulose-tris(3,5-dimethylphenylcarbamate) or amylose-tris(3,5-dimethylphenylcarbamate) as the stationary phase; preferably, when resolving the crystals of compound 36, cellulose-tris(3,5-dimethylphenylcarbamate) is used as the stationary phase; preferably, when resolving the crystals of compound 62, amylose-tris(3,5-dimethylphenylcarbamate) is used as the stationary phase; Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol; Liquidity B: alcohol; The elution was performed using an isocratic elution procedure; Preferably, compound 11 is dissolved in alcohol, and the obtained sample is separated by high performance liquid chromatography to obtain compound 36; Preferably, compound 14 is dissolved in alcohol and n-hexane, and the obtained sample is separated by high performance liquid chromatography to obtain compound 62; the volume ratio of the alcohol to n-hexane is 15:75-95, preferably 15:80-90, preferably 15:85;

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