Crystal of phenyl-substituted dihydronaphthyridine compound and application thereof

Abstract

The invention discloses a crystal of a phenyl-substituted dihydronaphthyridine compound and application thereof, and belongs to the technical field of medicines. The crystal of the compound disclosed by the invention is a compound 36 or a compound 62, can be used as a mineralocorticoid receptor antagonist, and is used for treating, preventing or relieving diseases such as aldosterone excess, diabetic nephropathy, hypertension, heart failure (including chronic heart failure and the like), sequelae of myocardial infarction, liver cirrhosis, renal failure, stroke and the like of patients. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to crystals of phenyl-substituted dihydronaphthyridine compounds and uses thereof. Background Art

[0002] The mineralocorticoid receptor (MR) is an aldosterone-activated nuclear hormone receptor that regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular disease. Increases in circulating aldosterone increase blood pressure through its effects on urinary sodium excretion, while potentially affecting the brain, heart and vascular system. In addition, hyperaldosteronism is associated with many disease physiological processes that lead to renal and cardiovascular disease. Although hyperaldosteronism is usually caused by adenoma that produces aldosterone, patients with refractory hypertension often have elevated aldosterone levels, commonly referred to as "aldosterone escape," due to increased serum potassium levels or residual AT1R activity. Hyperaldosteronism and aldosterone escape typically lead to increased MR activity, and MR antagonists have been shown to be effective antihypertensive agents and can also be effective in treating heart failure and primary hyperaldosteronism. In addition, MR antagonists have also been shown to be effective in preclinical models of renal disease and can be used in combination with standard therapy to reduce proteinuria in patients with renal disease, such as chronic 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 enters the circulating blood. This in turn activates the formation of angiotensin II, which has a contraction 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 is used as a blood pressure sensor in the blood circulation, and indirectly as a volume sensor, and the severe loss of volume is offset through the renin-angiotensin-aldosterone system, which is achieved 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, the chronic reduction of renal blood flow (for example, due to heart failure and blood obstruction in the venous system caused thereby) leads to excessive release of aldosterone. Followed by the expansion of blood volume and thus by increasing the supply of blood volume to the heart to make the heart weak. Obstruction of blood in the lungs, shortness of breath, edema of the extremities and ascites and pleural effusions may result; renal blood flow is further reduced. In addition, the excess aldosterone effect leads to a decrease in the potassium concentration in the blood and extracellular fluid. In a myocardium that has previously been damaged in other ways, the presence of levels below a critical minimum may induce arrhythmias with fatal consequences. This is probably one of the main causes of sudden cardiac death that often occurs in patients with heart failure.

[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, etc., N. Engl. J. Med. ML 709-717 (1999); B. Pitt, W. Remme, F. Zannad, etc., 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] Increased aldosterone levels or excessive stimulation of mineralocorticoid receptors are associated with a number of physiological disorders or pathological disease states, including Conn's syndrome, primary and secondary aldosteronism, increased sodium retention, increased magnesium and potassium excretion (polyuria), increased water retention, hypertension (isolated systolic hypertension and combined systolic / diastolic hypertension, etc.), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's syndrome and disorders 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 antagonism have therapeutic value for any of the above-mentioned disorders.

[0007] Although mineralocorticoid receptor antagonists have made significant progress in the treatment of hypertension and heart failure, the current standard of care is only near optimal, and there is a significant unmet medical need for other 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. Summary of the invention

[0008] 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 drug. The drug is used to treat, prevent or alleviate diseases such as aldosteronism, diabetic nephropathy, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, liver cirrhosis, renal failure and stroke in patients.

[0009] 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,

[0010]

[0011] in, for

[0012]

[0013] R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, C 1-6 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;

[0014] R5 is

[0015]

[0016] R6 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0017] for

[0018]

[0019] X is C or N;

[0020] Y is O or S;

[0021] 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;

[0022] Each Rz is independently =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, 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;

[0023] Each Rw is independently =O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl.

[0024] for

[0025]

[0026] R8 and R9 are hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C1-6 halogenated alkoxy, C1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms.

[0027] 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,

[0028]

[0029] in, for

[0030] R1, R2, R3 and R4 are independently hydrogen, deuterium, amino, hydroxyl, mercapto, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, carboxyl, C 1-6 Alkanoyl, C 1-6 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;

[0031] R5 is

[0032]

[0033] R6 is hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0034] for

[0035]

[0036] X is C or N;

[0037] Y is O or S;

[0038] R7 is C 1-6 Alkyl, C 3-8Cycloalkyl, 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;

[0039] Each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Haloalkyl, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, 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;

[0040] Each Rw is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 1-6 Alkylsulfonyl, C 1-6 Alkyl acyl, C 3-8 Cycloalkyl, heterocyclic group consisting of 3-8 atoms, heteroaryl consisting of 5-6 atoms or C 6-10 Aryl;

[0041] for

[0042] R8 and R9 are hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkylamino, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 5-10 atoms;

[0043] R 10 and R 11Each is independently selected from -CH2- or O, and at least one of them is O;

[0044] 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.

[0045] 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);

[0046]

[0047] 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);

[0048]

[0049] in, R1, R2, R3, R4, R5, R6, R7, R8, R9, X and Y have the meanings described herein.

[0050] 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 Haloalkyl, C 1-4 Haloalkoxy, 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;

[0051] R6 is hydrogen, deuterium, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkylamino, C3-6 Cycloalkyl, C 6-10 Aryl, heterocyclic group consisting of 3-6 atoms or heteroaryl group consisting of 5-6 atoms;

[0052] 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 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkylamino, C 1-4 Alkanoyl, C 1-4 Alkylsulfonyl, aminoacyl or aminosulfonyl;

[0053] 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;

[0054] 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, pyridinyl, pyrrolyl, thiazolyl, pyrazolyl or pyrimidinyl;

[0055] 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.

[0056] In some embodiments, the compound of the present invention is selected from the compound represented by formula (II):

[0057]

[0058] In some embodiments, the compound of the present invention is selected from the compound represented by formula (IIa) or formula (IIb):

[0059]

[0060] In some embodiments, R7 is C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl group consisting of 5-6 atoms, C 3-6 Cycloalkyl C 1-4 Alkyl, (3-6 atoms composed of heterocyclic) 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.

[0061] 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.

[0062] 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, pyrimidinyl pyridinylmethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylmethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylethyl, pyrimidinylethyl, pyrimidinylmethyl, pyrimid ...ethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrimidinylethyl, pyrimidinylethyl, pyrimidinylethyl, pyrimidinylethyl, pyrimidinylmethyl, pyrimidinylethyl,

[0063] 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 Haloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4Alkyl 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 Haloalkyl, C 1-4 Haloalkoxy, 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.

[0064] 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, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or phenyl; wherein each Rz is independently R is unsubstituted or substituted with 1, 2, 3 or 4 R; each R 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.

[0065] In some embodiments, the compound is selected from the group consisting of:

[0066]

[0067] Wherein R5 is selected from

[0068] In some embodiments,

[0069] R1, R2, R3, and R4 are independently hydrogen, deuterium, C 1-6 Alkoxy;

[0070] R5 is

[0071] R6 is selected from hydrogen, deuterium, C 1-6 alkyl.

[0072] In some embodiments,

[0073] R1, R2, R3, and R4 are independently hydrogen, deuterium, C 1-3 Alkoxy;

[0074] R5 is

[0075] R6 is selected from hydrogen, deuterium, C 1-3 alkyl.

[0076] In some embodiments,

[0077] R1, R2, R3, and R4 are independently hydrogen, deuterium, or methoxy;

[0078] R5 is

[0079] R6 is selected from hydrogen, deuterium, and methyl.

[0080] In some embodiments, the compound is selected from the group consisting of:

[0081]

[0082] in, for

[0083] R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1-6 Alkoxy;

[0084] R5 is selected from

[0085] R6 is C 1-6 alkyl;

[0086] R7 is C 1-6 alkyl;

[0087] R8 and R9 are hydrogen, deuterium, C 1-6 alkyl;

[0088] Y is selected from O;

[0089] X is selected from C.

[0090] In some embodiments,

[0091] R1, R2, R3 and R4 are independently hydrogen, deuterium, C 1-3 Alkoxy;

[0092] R6 is C 1-3 alkyl;

[0093] R7 is C 1-3 alkyl;

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

[0095] In some embodiments, the compound is selected from the group consisting of:

[0096]

[0097] in, for

[0098] R3 and R4 are independently hydrogen or deuterium;

[0099] R5 is selected from

[0100] R6 is C 1-6 alkyl;

[0101] 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;

[0102] R8 and R9 are hydrogen, deuterium, C 1-6 alkyl;

[0103] X is selected from C;

[0104] Y is selected from O.

[0105] In some embodiments,

[0106] R6 is C 1-3 alkyl;

[0107] 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, chlorine, bromine, iodine;

[0108] R8 and R9 are hydrogen, deuterium, C 1-3 alkyl.

[0109] In some embodiments,

[0110] R6 is C 1-3 alkyl;

[0111] 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;

[0112] R8 and R9 are hydrogen or methyl.

[0113] In some embodiments, the compound is selected from the group consisting of:

[0114]

[0115] in, for

[0116] R3 and R4 are independently hydrogen or deuterium;

[0117] R5 is selected from

[0118] R6 is C 1-6 alkyl;

[0119] 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,

[0120] 3 or 4 Rz substituted; each Rz is independently: halogen, C 1-6 alkyl;

[0121] R8 and R9 are hydrogen, deuterium, C 1-6 alkyl;

[0122] X is selected from C;

[0123] Y is selected from O.

[0124] In some embodiments, the compound is selected from the group consisting of compounds represented by formula (Va) or formula (Vb);

[0125]

[0126] in, for R3 and R4 are independently hydrogen or deuterium;

[0127] R5 is selected from

[0128] R6 is C 1-6 alkyl;

[0129] 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;

[0130] R8 and R9 are hydrogen, deuterium, C 1-6 alkyl;

[0131] X is selected from C;

[0132] Y is selected from O.

[0133] In the above formula (V), formula (Va) and formula (Vb),

[0134] R6 is C 1-3 alkyl;

[0135] 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;

[0136] R8 and R9 are hydrogen, deuterium, C 1-3 alkyl.

[0137] Further,

[0138] R6 is C 1-3 alkyl;

[0139] 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 or methyl;

[0140] R8 and R9 are hydrogen or methyl.

[0141] In some embodiments, the compound is selected from the compounds represented by formula (VI), formula (VIa), or formula (VIb);

[0142]

[0143] R 10 and R 11 Each is independently selected from -CH2- or O, and at least one of them is O;

[0144] 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;

[0145] R7 is C 1-3 Alkyl, C 3-6 Cycloalkyl, heterocyclic group consisting of 3-6 atoms, heteroaryl group consisting of 5-6 atoms, C 3-6 Cycloalkyl C 1-4 Alkyl, (3-6 atoms composed of heterocyclic) 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;

[0146] 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;

[0147] Preferably, each Rz is independently O, deuterium, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, NH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Haloalkyl, C 1-4 Alkylamino, C 1-4 Alkylsulfonyl, C 1-4 Alkyl acyl, C 3-6 Cycloalkyl, 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 Haloalkyl, C 1-4 Haloalkoxy, 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;

[0148] 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, oxirane, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl or phenyl; wherein each Rz is independently substituted. R is substituted or substituted with 1, 2, 3 or 4 R; each R is independently O, 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.

[0149] In some embodiments, the compound shown in (I) provided by the present invention is specifically a compound shown in 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;

[0150]

[0151] in, Choose from R3 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, C3-8cycloalkylC1-6alkyl; 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,; R8, R9 are hydrogen, deuterium, C 1-6 alkyl;

[0152] The compound represented by (I-10), (I-11) or (I-12), R6 is C1-4 Alkyl is further selected from hydrogen, methyl, ethyl, propyl, butyl;

[0153] 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;

[0154] 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;

[0155] In the compound represented by (I-10), (I-11) or (I-12), R7 is C3-6 cycloalkyl, C3-8 cycloalkyl, C3-5 cycloalkylC1-3 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, NH2;

[0156] In the compounds represented by (I-10), (I-11) or (I-12), R7 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

[0157] In the compound represented by (I'-10), (I'-11) or (I'-12), R7 is methyl or ethyl.

[0158] In the compound represented by (I'-10), (I'-11) or (I'-12), R7 is substituted by 1 to 3 Fs.

[0159] In some embodiments, the compound is selected from:

[0160]

[0161]

[0162]

[0163]

[0164] In the present invention, the compound does not have the situation where R1, R2, R3 are hydrogen, R4 is methoxy, R5 is -CONH2, and R6 is hydrogen.

[0165] In one aspect, the present invention provides a crystal of a compound and a salt thereof, selected from the compound shown in Formula I:

[0166]

[0167] in,

[0168] for

[0169] R3 and R4 are independently selected from hydrogen and deuterium;

[0170] R5 is selected from

[0171] R6-R8 are independently selected from C 1-3 alkyl;

[0172] R9 is hydrogen or deuterium;

[0173] X is selected from C;

[0174] Y is selected from O.

[0175] In some embodiments, the compound in the crystal of the compound and its salt is compound 36, and the structural formula is as follows:

[0176]

[0177] 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.

[0178] Wherein, the crystal or its crystalline form of compound 36 has the following Figure 4 Or basically as attached Figure 4 For the XRPD patterns shown, “substantially” means that the difference in the number of peaks is within 85%.

[0179] In some embodiments, the crystalline form of compound 36 is a free base crystalline form; preferably, the free base crystalline form is a free base crystalline form I; preferably, the X-ray diffraction pattern of the free base crystalline form and the free base crystalline form I comprises a diffraction peak at 2θ of 9.35±0.2°, preferably comprises a diffraction peak at 2θ of 8.16±0.2°, 9.35±0.2°, 12.80±0.2°, 21.92±0.2°, 22.10±0.2°, 24.38±0.2°; preferably, the X-ray diffraction pattern of the free base crystalline form is as follows Fig.37 shown.

[0180] In some embodiments, the crystals of the compound and its salt are the acid salt of compound 36;

[0181]

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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 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 as follows Fig.30 shown.

[0187] 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:

[0188] The hydrochloride salt form I has an X-ray diffraction pattern comprising diffraction peaks 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 salt form I is as follows: Fig.11 As shown;

[0189] The hydrochloride salt form II has an X-ray diffraction pattern comprising 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 salt form II is as follows Fig.14 As shown;

[0190] The sulfate crystal form I has an X-ray diffraction pattern comprising 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 crystal form I is as follows: Fig.17 As shown;

[0191] 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 p-toluenesulfonate salt form I is as follows: Fig. 20 As shown;

[0192] 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 as follows: Fig.23 As shown;

[0193] The mesylate salt 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 mesylate salt form I has an X-ray diffraction pattern as shown in Fig. 27 As shown;

[0194] Phosphate crystal form I, the X-ray diffraction spectrum comprises diffraction peaks at 2θ of 5.96±0.2° and 12.30±0.2°. Preferably, the X-ray diffraction spectrum of the phosphate crystal form I is as follows Fig.34 As shown;

[0195] Form II, the X-ray diffraction pattern comprises 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 as follows Fig.41 shown.

[0196] The present invention also provides another crystal of compound 62, the structural formula of compound 62 is as follows:

[0197]

[0198] 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.

[0199] Wherein, the crystal or its crystalline form of compound 62 has the following Figure 8 Or basically as attached Figure 8 For the XRPD patterns shown, “substantially” means that the difference in the number of peaks is within 85%.

[0200] As for the crystal form, specifically: the present invention provides a crystal of a compound, the compound is compound 36, and its structural formula is shown in the above figure; the crystal of compound 36, its structure belongs to the monoclinic system, C2 space group, unit cell parameters α=90°,β=112.7428(8)°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z=4; further, the crystal of compound 36 or its crystalline form has the following Figure 4 Or basically as attached Figure 4 The XRPD spectrum shown in the figure, "basic" means that the difference in the number of peaks is within 85%. The present invention also provides a crystal of compound 62, whose structure belongs to the monoclinic system, C2 space group, and unit cell parameters α=90°,β=121.6750(10)°,γ=90°,unit cell volume The minimum number of asymmetric units in the unit cell is Z=8. Further, the crystal of compound 62 or its crystalline form has the following Figure 8 Or basically as attached Figure 8 The XRPD spectrum shown in the figure, the "basic" means that the difference in the number of peaks is more than 85%. The present invention also provides the use of the crystal of the compound in the preparation of a drug, the drug is a drug for treating or preventing a disease or condition 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; or, the drug is used as a mineralocorticoid receptor antagonist.

[0201] The invention also discloses the use of the crystals of the compound and its salt in preparing medicines.

[0202] 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.

[0203] The invention also discloses the use of the crystals of the compound and its salt in preparing medicines.

[0204] Therein, the drug is used as a mineralocorticoid receptor antagonist.

[0205] The present invention also discloses a high performance liquid chromatography method for resolving the crystals of the above compound, wherein the chromatographic conditions are:

[0206] 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;

[0207] Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol;

[0208] Liquidity B: alcohol;

[0209] The elution was performed using an isocratic elution procedure;

[0210] 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 and n-hexane is 15:75-95, preferably 15:80-90, preferably 15:85.

[0211]

[0212] Wherein, 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.

[0213] 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 CHIRALART Amylose-C NEO.

[0214] 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 5-15mmol / L, preferably 8-12mmol / L, preferably 10mmol / 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.

[0215] 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%.

[0216] Wherein, the flow rate is 16-24 mL / min, preferably 18-22 mL / min, preferably 20 mL / min.

[0217] 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 212-226nm, preferably 216-222nm, preferably 218nm, and the second wavelength is 262-278nm, preferably 266-274nm, preferably 270nm; preferably, when splitting the crystals of compound 62, the first wavelength is 208-222nm, preferably 212-218nm, preferably 214nm, and the second wavelength is 246-262nm, preferably 250-258nm, preferably 254nm.

[0218] Wherein, when the compound is compound 36, the chromatographic conditions are:

[0219] Chromatographic column: Chiral column CHIRAL ART Cellulose-SB, 2*25cm, 5μm;

[0220] Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol, the concentration of ammonia is 10mmol / L n-hexane, and the volume ratio of alcohol to n-hexane is 1:4;

[0221] Mobile phase B: ethanol;

[0222] Flow rate: 20 mL / min;

[0223] Isocratic elution: 20 vt% mobile phase B and 80 vt% mobile phase A;

[0224] Elution time: 15min;

[0225] Wavelength: 218 / 270nm;

[0226] Wherein, when the compound is compound 62, the chromatographic conditions are:

[0227] Chromatographic column: Chiral column CHIRAL ART Amylose-C NEO;

[0228] Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol, the concentration of ammonia is 10mmol / L n-hexane, and the volume ratio of alcohol to n-hexane is 1:9;

[0229] Mobile phase B: ethanol;

[0230] Flow rate: 20 mL / min;

[0231] Isocratic elution: 10 vt% mobile phase B and 90 vt% mobile phase A;

[0232] Elution time: 28min;

[0233] Wavelength: 214 / 254nm.

[0234] Furthermore, the present invention discloses a pharmaceutical preparation, which contains compound 36 and / or compound 62 or their salts, crystals thereof, and pharmaceutically acceptable excipients.

[0235] 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.

[0236] 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.

[0237] Or, wherein the medicament is used as a mineralocorticoid receptor antagonist.

[0238] The mineralocorticoid-related disease or disorder is selected from the following diseases: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure or stroke.

[0239] The tris(3,5-dimethylphenylcarbamate) structural formula of the present invention is as follows:

[0240]

[0241] Definitions and general terms

[0242] 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 present invention as defined in the claims. It should be appreciated by those skilled in the art 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.

[0243] It should be further appreciated that certain features of the invention, which for clarity are described in the context of multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0244] 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.

[0245] Unless otherwise indicated, the following definitions used herein shall apply. For purposes of the present invention, chemical elements are consistent 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 can be found in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0246] Unless otherwise specified or there is a clear conflict in context, the articles "a", "an", and "the" as used herein are intended to include "at least one" or "one or more". Therefore, these articles as used herein refer to articles that 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., there may be more than one component contemplated for use or use in the implementation of the described embodiment.

[0247] 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.

[0248] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0249] "Stereoisomers" refer to compounds that have the same chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0250] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0251] "Diastereoisomers" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, for example HPLC.

[0252] The 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.

[0253] 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.

[0254] Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and / or fractional crystallization.

[0255] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that can be mutually converted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (protontautomers) (also known as prototropic tautomers) include mutual conversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include mutual conversions 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 stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0256] As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the above general formula compounds, or as the specific examples, subclasses, and classes of compounds included in the embodiments.

[0257] In addition, it should be noted that, unless otherwise explicitly stated, the descriptions used in the present invention "each ... independently is" and "... each independently is" and "... independently is" can be interchanged and should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other. Similarly, the "independent" in the description "... independently and optionally" should also be understood in the above broad sense.

[0258] 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.

[0259] In various parts of this specification, substituents of compounds disclosed in the present invention are disclosed according to group types or ranges. It is particularly noted that the present invention includes each 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) which are disclosed independently.

[0260] 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 as 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 an alkylene group or an arylene group, respectively, that is linked.

[0261] The term "alkyl" or "alkyl group" as used herein refers to a saturated, straight-chain 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 In some 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.

[0262] 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.

[0263] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy or 2-propoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy) and the like.

[0264] The term "haloalkyl" or "haloalkoxy" means that an alkyl or alkoxy group is substituted with one or more halogen atoms, such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, chloroethyl (e.g., 2-chloroethyl), trifluoroethyl (including but not limited to, 2,2,2-trifluoroethyl), 2,2-difluoroethyl, 2-chloro-1-methylethyl, and the like.

[0265] 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.

[0266] The term "alkylamino" or "alkylamino" means that the group -NH2 is substituted by one or two alkyl groups, i.e., the alkylamino or alkylamino group includes monoalkylamino and dialkylamino groups; wherein the alkyl group has the meaning as described in the present invention. Examples of alkylamino groups include, but are not limited to, methylamino, ethylamino, methylethylamino, dimethylamino, etc.

[0267] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 ring carbon atoms. In some embodiments, the cycloalkyl group contains 3-10 ring carbon atoms, such as C 3-10 In other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C 3-8 In some 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.

[0268] 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 atoms; wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings. Unless otherwise specified, the heterocyclyl may be a carbonyl or nitrogenyl group, and the -CH2- group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to an S-oxide. The nitrogen atom of the ring may be optionally oxidized to an N-oxide. The term "heterocyclyl" may be used interchangeably with the term "heterocycle". Examples of heterocyclyl groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiazolidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl or morpholinyl, and the like. As described in the present invention, the heterocyclic group may be composed of 3-8 atoms or 3-6 atoms, wherein the atoms are C, N, O or S and at least one atom is N, O or S; wherein the heterocyclic group composed of 3-8 atoms includes a heterocyclic group composed of 3-6 atoms; the heterocyclic group composed of 3-6 atoms includes a heterocyclic group composed of 3-5 atoms; specifically, the heterocyclic group composed of 3-6 atoms includes, but is not limited to, ethylene oxide Aziridine Azetidinyl Oxetane Pyrrolidin Tetrahydrofuranyl Tetrahydrothienyl Thiazolidine Pyrazolidinyl Pyrazolyl Oxazolidinyl Imidazolidinyl Piperidinyl Piperazine Morpholinyl The heterocyclyl group may be optionally substituted with one or more substituents described herein.

[0269] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0270] 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 radical containing 6 to 10 ring carbon atoms.

[0271] 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 at the same time, the heteroaryl group has one or more attachment points to the rest of the molecule. When a -CH2- group is present in the heteroaryl group, the -CH2- group can be optionally replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which can be C in CH, or N in NH). The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, etc. The heteroaryl group may be optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms, which means that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms selected from O, S and N; in other embodiments, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms, which means that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3 or 4 ring heteroatoms selected from O, S and N. Examples of heteroaryl groups consisting of 5-6 atoms include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl and the like.

[0272] 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, P, etc.; the "jk" includes j, k and any natural number in between. 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, P, etc.

[0273] In this article, when there are two or more groups connected to a compound group, the connection point is based on 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 C1-6 Alkyl, 5-6 membered heteroaryl C 1-6 When the alkyl group is "alkyl", the connection point between it and 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.

[0274] 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).

[0275] The "heteroaryl group consisting of 5-10 atoms" and "heteroaryl group consisting of 5-6 atoms" described in the present invention refer to heteroaryl groups containing 5-10 ring atoms and heteroaryl groups containing 5-6 ring atoms, wherein the heteroaryl group contains 1, 2, 3 or 4 heteroatoms selected from N, O and S. In some embodiments, specific examples of the "heteroaryl group consisting of 5-10 atoms" or "heteroaryl group consisting of 5-6 atoms" described in the present invention include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, thienyl, thiazolyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl and the like.

[0276] The term "alkanoyl" or "alkylacyl" refers to the group -C(=O)-alkyl, wherein the alkyl has the meaning as described herein, examples of which include, but are not limited to, methylacyl (-C(=O)CH3), ethylacyl (-C(=O)CH2CH3), and the like.

[0277] 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.

[0278] 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.

[0279] The term "aminosulfonyl" refers to the group -S(=O)2NH2; the term "aminoacyl" refers to the group -C(=O)NH2.

[0280] The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce allergic or similar untoward reactions, such as gastrointestinal discomfort, dizziness, etc. when administered to humans. Preferably, the term "pharmaceutically acceptable" as used herein refers to those approved by federal regulatory agencies or state governments or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly in humans.

[0281] 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, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water and aqueous solutions (e.g., saline solutions, aqueous dextrose, aqueous glycerol) are preferably used as carriers, particularly injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0282] The term "prodrug" as used in the present invention refers to a compound that is converted into a compound of formula (I) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or by the conversion of the prodrug into the parent structure by enzymes in the blood or tissues. The prodrug compounds of the present invention may be esters. In the prior 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 contains a hydroxyl group, which can be acylated to obtain a prodrug form of the compound. Other prodrug forms include phosphates, such as these phosphate compounds obtained by phosphorylation of the hydroxyl group on the parent. For a complete discussion of prodrugs, please refer to the following literature: 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.

[0283] "Metabolite" refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo. The metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time.

[0284] The "pharmaceutically acceptable salt" used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable salts formed by non-toxic acids include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates; organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates; or other methods described in books and literature, such as ion exchange methods, to obtain these salts. 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-hydroxy-ethanesulfonate, 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.

[0285] "Polymorph" or "polymorphs" refers to crystalline forms having the same chemical composition but 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 is swapped. This phenomenon of a compound existing in different lattice structures is called pharmaceutical polymorphism.

[0286] 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 changes can be made within the present invention without departing from the scope and spirit of the present invention. On the basis of considering the specification and practice of the present invention disclosed herein, other embodiments of the present invention are apparent to those skilled in the art. Applicants expect that the specification and embodiments are considered exemplary, rather than limiting their scope.

[0287] "X-ray powder diffraction pattern or XRPD" means the powder diffraction pattern 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 the first diffraction peak is taken, n=1), and the "2θ or 2θ angle" refers to the diffraction angle, θ is the Bragg angle, and the unit is ° or degree. When X-rays are incident on a certain atomic plane with d lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle θ (the complementary angle of the incident angle, also called the Bragg angle), the Bragg equation can be satisfied, thereby measuring this set of X-ray powder diffraction patterns.

[0288] It is well known to those skilled in the art that XRPD may produce certain displacement and intensity deviations due to sample tiling thickness, detection methods, conditions and instruments. The same sample of the same crystal form usually has the same main XRPD characteristic peak, but there may be certain operating errors. When the same crystal form sample obtained by the same method is detected by the same instrument and detection method by the ordinary technicians in the art, the characteristic peak error is usually within ±0.2°. However, different technicians using different instruments may occasionally have a few characteristic peaks with errors exceeding this range. For example, the error within ±0.5° or ±0.3° should be considered to belong to the XRPD characteristic peak of the same crystal form. Therefore, as a specific example of the crystal form of the present invention, its XRPD is shown in spectrum X, but the ordinary technicians understand that when the 2θ deviation of the key characteristic peak displacement 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 within the scope of protection of the present invention.

[0289] In addition, the absolute intensity and relative intensity of the peaks shown in the above tables and figures may vary due to various factors, such as the effect 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. In addition, the peak position may also shift according to the change in the sample height. Furthermore, if different wavelengths are used for measurement, different displacement values ​​are obtained according to the Bragg formula (nλ=2dsinθ), and such different XRPD patterns obtained by using different wavelengths are also included in the scope of the present invention.

[0290] "Interplanar spacing or interplanar spacing (d value)" refers to the selection of three non-parallel unit vectors a, b, 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 determined parallelepiped unit connection lines to obtain a set of straight line grids, called space grids or lattices. The lattice and lattice 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.

[0291] “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%.

[0292] "Differential Scanning Calorimetry or DSC" measures the transition temperatures of a crystal when heat is absorbed or released as a result of changes in its crystal structure or melting of the crystal. For the same crystalline form of the same compound, the thermal transition temperatures and melting points can be within about 5°C, usually within about 3°C, in consecutive analyses. When a compound is described as having a given DSC peak or melting point, it is referred to as the DSC peak or melting point ±5°C, and this temperature variation is generally taken into account. DSC provides an auxiliary method for distinguishing different crystalline forms. Different crystal forms can be identified by their different transition temperature characteristics. It should be noted that for mixtures, the DSC peak or melting point may vary over a wider range. In addition, since decomposition is associated with the melting of a substance, the melting temperature is related to the heating rate.

[0293] "Thermogravimetric analysis (TGA)" is a common method for determining the thermal stability of a compound. In the present invention, TGA can also be used to determine the hydration state of the compound, and the heating rate during the test will have a certain impact on the spectrum. The error of TGA can be within about ±0.5 mass%.

[0294] "Amorphous", "amorphous" or "amorphous form" refers to the material formed when the particles (molecules, atoms, ions) of the material are arranged in three-dimensional space without periodicity, characterized by a diffuse X-ray powder diffraction pattern without peaks. Amorphous / form is a special physical form of solid matter, and its locally ordered structural characteristics suggest that it is inextricably linked to crystalline substances.

[0295] The "solvate" of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association formed by the solvent molecule being water.

[0296] The "ester" of the present invention refers to an in vivo hydrolyzable ester formed by a compound containing a hydroxyl or carboxyl group. Such an ester is, for example, a pharmaceutically acceptable ester that is hydrolyzed in the human or animal body to produce a parent alcohol or acid. The compound of formula (I) of the present invention contains a carboxyl group and can form an in vivo hydrolyzable ester with an appropriate group, such as, but not limited to, an alkyl group, an arylalkyl group, etc.

[0297] 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. - A special example of an oxide is N - Oxide or nitrogen-containing heterocyclic nitrogen atom N -The corresponding amine 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 may 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.

[0298] The "compound of the present invention", "compound described in the present invention", "compound described in the present invention" or similar expressions used in the present invention refer to the compound represented by any general structure described in the present invention. For example, the compound of the present invention may refer to the compound represented by formula (I) or formula (Ia) or formula (Ib) or formula (IIa) or formula (IIb) or formula (III) or formula (IV) in the present invention. The compound of the present invention also includes the specific compound in any one of the embodiments.

[0299] As used herein, the term "treating" any disease or condition, in some embodiments, refers to ameliorating the disease or condition (i.e., slowing or preventing 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 perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.

[0300] Any structural formula given by the present invention is also intended to represent the isotopically unenriched form of these compounds and the isotopically enriched form. Isotopically enriched compounds have the structure described by the general formula given by the present invention, except that one or more atoms are replaced by atoms with selected atomic weights or mass numbers. 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.

[0301] In addition, the substitution of heavier isotopes, especially deuterium (i.e., 2H or D) can provide certain therapeutic advantages, which are brought about by higher metabolic stability. For example, an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index. It should be understood that deuterium in the present invention is regarded as a substituent of the compound of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a specified 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, for example D2O, acetone-d6, DMSO-d6.

[0302] 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 in the present invention include enriched isotopes of one or more different atoms.

[0303] Any abbreviations for protecting groups, amino acids and other compounds used in the present invention, unless otherwise specified, are based on their commonly used and recognized abbreviations, or refer to IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

[0304] Description of the compounds of the present invention

[0305] The present invention provides a phenyl-substituted dihydronaphthyridine compound and a pharmaceutical composition thereof which can competitively antagonize aldosterone receptor (MR), as well as use of the compound or the pharmaceutical composition in preparing a drug. The drug is used to treat, prevent or alleviate diseases such as diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure), sequelae of myocardial infarction, liver cirrhosis, renal failure and stroke in patients.

[0306] 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),

[0307]

[0308] On the one hand, the present invention relates to the use of the compound or pharmaceutical composition of the present invention in the preparation of a drug, wherein the drug is used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

[0309] 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 drug, wherein the drug is used as a mineralocorticoid receptor antagonist.

[0310] On the one hand, the compounds or pharmaceutical compositions described in the present invention are used to treat, prevent or alleviate the following diseases in patients: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke.

[0311] In another aspect, the compound or pharmaceutical composition of the present invention can be used to antagonize mineralocorticoid receptors.

[0312] On the one hand, the present invention relates to a method for treating, preventing or alleviating the following diseases in patients using the compounds or pharmaceutical compositions described in the present invention: diabetic nephropathy, hyperaldosteronism, hypertension, heart failure (including chronic heart failure, etc.), sequelae of myocardial infarction, cirrhosis, renal failure or stroke, wherein the method comprises treating the patient with a therapeutically effective dose of the compounds or pharmaceutical compositions described in the present invention.

[0313] On the other hand, the present invention also relates to a method for 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).

[0314] 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.

[0315] 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 diseases in a patient, or a patient susceptible to these conditions, comprising treating the patient with a therapeutically effective amount of a compound or pharmaceutical composition of the present invention.

[0316] The present invention includes the use of the compounds of the present invention and their pharmaceutically acceptable salts for producing pharmaceutical products for treating patients with diseases associated with mineralocorticoid receptors or aldosterone, including those described herein. The present invention includes 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.

[0317] Unless otherwise indicated, all hydrates, solvates and pharmaceutically acceptable salts of the compounds of the present invention belong to the scope of the present invention.

[0318] In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and the mammal to be treated.

[0319] The salts of the compounds of the present invention also include intermediates used in the preparation or purification of compounds represented by formula (I), (Ia), (Ib), (IIa), (IIb), (III), or (IV), or salts of separated enantiomers of compounds represented by formula (I), (Ia), (Ib), (IIa), (IIb), (III), or (IV), but are not necessarily pharmaceutically acceptable salts.

[0320] 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, ethanesulfonic acid, etc.

[0321] The biological activity of the compounds of the present invention can be assessed by using any conventional known method. Appropriate detection methods are well known in the art. For example, the MR antagonist activity, pharmacokinetic activity and / or liver microsomal stability of the compounds of the present invention can be detected by appropriate conventional methods. The detection methods provided by the present invention are presented only as examples and do not limit the present invention. The compounds of the present invention are active in at least one of the detection methods provided by the present invention. For example, the compounds of the present invention have good antagonist activity against aldosterone receptors and have good in vivo pharmacokinetic properties, such as good absorption and exposure, and high bioavailability; for example, the compounds of the present invention have lower toxic side effects.

[0322] Administration and use of the compounds of the present invention.

[0323] 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 be estimated first using various methods well known in the art. The initial dose for animal studies can be based on the effective concentration established in the cell culture assay. The dosage range suitable for human individuals can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compound of the present invention can be prepared as a medicament for oral administration. An exemplary dose 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 the effective dosage is about 0.001-1 mg / kg, preferably about 0.01-0.5 mg / kg body weight.

[0324] The dosage regimen for oral administration is usually three times a week, twice a week, once a week, three times a day, twice a day or once a day. In certain embodiments, the compound of the present invention is administered as an active ingredient in a total amount of about 0.001 to about 50, preferably 0.001 to 10 mg / kg body weight per 24 hours, and in order to obtain the desired results, it is optionally administered in the form of multiple single doses. A single dose preferably can contain 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.

[0325] An effective amount or therapeutically effective amount or dose of an agent (e.g., a compound of the invention) refers to the amount of the agent or compound that causes an improvement in symptoms or a prolongation of survival in a subject. The toxicity and therapeutic efficacy of the molecules can be determined by standard medical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose that is lethal to 50% of the population) and the ED50 (the dose that is therapeutically effective to 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.

[0326] The effective amount or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will induce a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, doctor or other clinician. The dosage is preferably within the range of a circulating concentration of an ED50 that includes minimal toxicity or avirulence. The dosage can vary within this range, depending on the dosage form used and / or the route of administration used. The correct preparation, route of administration, dosage and dosing interval should be selected according to methods known in the art, taking into account the particularity of the individual condition.

[0327] 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. Dosages 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.

[0328] 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.

[0329] When desired, the composition 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 containing compounds of the present invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of a specified condition.

[0330] The compounds of the present invention have good safety. The maximum tolerated dose of repeated administration to mice for 14 days showed that compound 62 is highly safe. In particular, the maximum tolerated dose of repeated administration to compound 36 for 14 days was shown to be more than 2.7 times that of compound 62. In particular, its safety window is more than 230 times that of the equivalent dose, which is highly safe.

[0331] 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.

[0332] 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 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.

[0333] Due to their mechanism of action, the compounds according to the invention are also suitable for preventing sudden cardiac death in patients with an increased risk of death from sudden cardiac death. These patients are especially 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 cardiovascular 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.

[0334] 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 such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and coronary angioplasty (PTCA), heart transplantation and bypass surgery.

[0335] The compounds of the invention are also suitable for use as potassium-sparing diuretics and for the treatment of electrolyte disorders such as hypercalcemia, hypernatremia or hypokalemia.

[0336] The compounds of the 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.

[0337] 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.

[0338] The compounds of the invention may further be used for the prevention and / or treatment of microalbuminuria, for example caused by diabetes or hypertension, and proteinuria.

[0339] 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 leading to an overproduction of glucocorticoids (Cushing's syndrome), adrenocortical tumors leading to an overproduction of glucocorticoids, and pituitary tumors which autonomously produce ACTH (adrenocorticotropic hormone) leading to adrenal hyperplasia and Cushing's disease.

[0340] The compounds of the invention may further be used for the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

[0341] The compounds of the 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.

[0342] 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.

[0343] 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.

[0344] The compounds of the present invention can be used alone or, if desired, in combination with other active ingredients. The present invention further relates to a medicament comprising at least one compound of the present invention and one or more other active ingredients (particularly for the treatment and / or prevention of the above-mentioned conditions), in particular for the combined use of a medicament 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 alter 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 NO; 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 urodilator; 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 cyvilicestone 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.

[0345] 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 chloranil, bumetanide, torsemide, bendroflumethiazide, chloranil, hydrochlorothiazide, hydroflumethiazide, methylchlorothiazide, polythiazide, trichlorothiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorobenzenesulfonamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0346] The beneficial effects of the present invention are:

[0347] A new compound is proposed, which can be used 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

[0348] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0349] Figure 1 Figure 3 is the asymmetric unit diagram of the crystal structure of compound 36.

[0350] Figure 2 This is a single unit cell diagram of the crystal structure of compound 36.

[0351] Figure 3 This is the filled diagram of the crystal structure of compound 36.

[0352] Figure 4 The calculated and experimental comparison diagram of the crystal XRPD pattern of compound 36.

[0353] Figure 5 This is the asymmetric unit diagram of the crystal structure of compound 62.

[0354] Figure 6 This is a single unit cell diagram of the crystal structure of compound 62.

[0355] Figure 7 This is the filled diagram of the crystal structure of compound 62.

[0356] Figure 8 This is a comparison diagram of the calculated and experimental crystalline XRPD patterns of compound 62.

[0357] Fig. 9 Single crystal micrograph of compound 36.

[0358] Fig.10 This is a single crystal micrograph of compound 62.

[0359] Fig.11 It is the XRPD pattern of hydrochloride form I.

[0360] Fig.12 It is the DSC diagram of hydrochloride form I.

[0361] Fig.13 This is the TGA diagram of hydrochloride form I.

[0362] Fig.14 It is the XRPD pattern of hydrochloride form II.

[0363] Fig.15 It is the DSC diagram of hydrochloride form II.

[0364] Fig.16 It is the TGA diagram of hydrochloride form II.

[0365] Fig.17 This is the XRPD pattern of sulfate form I.

[0366] Fig.18 This is the DSC diagram of sulfate crystal form I.

[0367] Fig.19 This is the TGA diagram of sulfate crystal form I.

[0368] Fig. 20 This is the XRPD pattern of p-toluenesulfonate Form I.

[0369] Fig.21 It is the DSC diagram of p-toluenesulfonate crystal form I.

[0370] Fig. 22 This is the TGA diagram of p-toluenesulfonate crystalline form I.

[0371] Fig.23 This is the XRPD pattern of p-toluenesulfonate Form II.

[0372] Fig.24 It is the DSC diagram of p-toluenesulfonate crystal form II.

[0373] Fig.25 This is the TGA diagram of p-toluenesulfonate Form II.

[0374] Fig.26 It is the DVS diagram of p-toluenesulfonate form II.

[0375] Fig. 27 This is the XRPD pattern of mesylate Form I.

[0376] Fig.28 This is the DSC diagram of mesylate form I.

[0377] Fig.29 This is the TGA diagram of mesylate form I.

[0378] Fig.30 This is the XRPD pattern of benzenesulfonate form I.

[0379] Fig.31 This is the DSC diagram of benzenesulfonate form I.

[0380] Fig.32 This is the TGA diagram of benzenesulfonate form I.

[0381] Fig.33 It is the DVS diagram of benzenesulfonate form I.

[0382] Fig.34 This is the XRPD pattern of phosphate form I.

[0383] Fig.35 This is the DSC diagram of phosphate crystal form I.

[0384] Fig.36 This is the TGA diagram of phosphate crystal form I.

[0385] Fig.37 This is the XRPD pattern of the free base Form I.

[0386] Fig.38 This is the DSC diagram of free base form I.

[0387] Fig.39 This is the TGA diagram of the free base form I.

[0388] Fig.40 This is the DVS diagram of the free base form I.

[0389] Fig.41 This is the XRPD pattern of Form II.

[0390] Fig.42 This is the DSC diagram of Form II.

[0391] Fig.43 This is the TGA diagram of Form II.

[0392] Fig.44 This is the NMR image of benzenesulfonate salt form I.

[0393] Fig.45 It is the NMR image of p-toluenesulfonate crystalline form I.

[0394] Fig.46 It is the NMR image of p-toluenesulfonate crystal form II.

[0395] Fig.47 This is the NMR image of the mesylate salt form I. DETAILED DESCRIPTION

[0396] In this specification, if there is any discrepancy between a chemical name and a chemical structure, the structure prevails.

[0397] 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.

[0398] Those skilled in the art will recognize that the chemical reactions described herein can be used to appropriately prepare other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by utilizing other known reagents in addition to those described herein, or by making some conventional modifications to the reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of the invention.

[0399] In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification; general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.

[0400] Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal. Anhydrous dichloromethane and chloroform were obtained by drying under reflux with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0401] The following reactions were generally carried out under positive pressure of nitrogen or argon or with a drying tube over anhydrous solvents (unless otherwise indicated), reaction bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringes. All glassware was dried.

[0402] The chromatographic column used was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant. The nuclear magnetic resonance spectral data were measured by Bruker Avance 400 nuclear magnetic resonance spectrometer or Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, using CDCl3, DMSO-d6, CD3OD or Acetone-d6 as solvent (reported in ppm), and TMS (0 ppm) or chloroform (7.25 ppm) as reference standard. When multiple peaks are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet ofdoublet of doublet of doublets). Coupling constants are expressed in Hertz (Hz).

[0403] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315B DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0404] Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C). A G1329A autosampler and a G1315D DAD detector were used for analysis, and an ESI source was applied to the LC-MS spectrometer.

[0405] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1×30 mm, 5 μm. The injection volume was determined by the sample concentration; the flow rate was 0.6 mL / min; the HPLC peak was recorded and read at UV-Vis wavelengths at 210 nm and 254 nm. The mobile phase was 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1:

[0406] Table 1 Gradient elution conditions of low resolution mass spectrometry mobile phase

[0407] Time (min) A(CH3CN,0.1%HCOOH) B(H2O,0.1%HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

[0408] The following abbreviations are used throughout this invention:

[0409] DMSO-d6 deuterated dimethyl sulfoxide; g gram; mg milligram; mol mole; mmol millimole; mL milliliter; μL microliter.

[0410] The following reaction schemes describe the steps for preparing the compounds disclosed in the present invention. Unless otherwise specified, R1, R2, R3, R4, R6, R7, R8, and R9 all have the meanings as described in the present invention. Unless otherwise specified, each reaction step in each reaction scheme described in the present invention is carried out in a solvent inert to the reaction, and the solvent inert to the reaction includes but is not limited to the solvents involved in the embodiments of the present invention or their substitutes.

[0411] 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:

[0412]

[0413] Example 1 4-(5-ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile

[0414]

[0415] Step 1) 4-(4-cyano-2-methoxyphenyl)-N-(2,2-dimethoxyethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0416] 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) to an 8 ml vial at room temperature. React at room temperature for 2 hours. Add aminoacetaldehyde dimethyl acetal (83 mg, 0.790 mmol). React at room temperature overnight. Add water (15 ml) to quench. Extract with ethyl acetate (10 ml × 3 times), combine the organic phases, wash with saturated brine (10 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to give a light yellow solid (86 mg, yield 47.0%).

[0417] MS (ESI) M / Z: 467.6 [M+H] +

[0418] Step 2) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-N-(2-oxoethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0419] 4-(4-cyano-2-methoxyphenyl)-N-(2,2-dimethoxyethyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (65 mg, 0.139 mmol), acetone (6 ml) and 12.0M 36% concentrated hydrochloric acid solution (42 μl) were added to a 25 ml single-mouth bottle at room temperature. The reaction was allowed to react for 1 hour at room temperature. Under ice bath, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 7. Ethyl acetate (10 ml × 3 times) was added for extraction, and the organic phases were combined, washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol (v / v) = 10 / 1) to obtain a light yellow solid (25 mg, yield 42.7%).

[0420] MS (ESI) M / Z: 421.5 [M+H] +

[0421] Step 3) 4-(5-ethoxy-2,8-dimethyl-3-oxazol-2-yl)-1,4-dihydro-1,6-naphthyridin-4-yl)-3-methoxybenzonitrile

[0422] Add 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-N-(2-oxoethyl)-1,4-dihydro-1,6-naphthyridine-3-carboxamide (20 mg, 48.0 μmol), toluene (0.5 ml) and phosphorus oxychloride (40.0 μl) to an 8 ml vial at room temperature. Heat to 120 degrees Celsius for 1 hour. Cool to room temperature, add water (2 ml), extract with ethyl acetate (2 ml x 3 times), combine the organic phases, wash with saturated brine (2 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained residue was purified by preparative HPLC (purification conditions were as follows: chromatographic 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 increased from 37% to 52% in 7 minutes; detection wavelength: 254 / 220 nm) to give a white solid (1.7 mg, yield 8.8%).

[0423] MS (ESI) M / Z: 403.50 [M+H] +

[0424] 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).

[0425] 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

[0426]

[0427] Step 1) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide

[0428] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (28 mg, 0.0740 mmol), dichloromethane (0.2 ml) and N,N-dimethylformamide (0.05 ml) were added to an 8 ml vial at room temperature. After nitrogen replacement, oxalyl chloride (0.1 ml) was added dropwise under ice-water bath. After the addition, the reaction was allowed to react at room temperature for 30 minutes. A solution of hydrazine hydrate (2 ml) and N,N-diisopropylethylamine (0.1 ml) in dichloromethane (0.5 ml) was added to the reaction solution at room temperature and stirred for 1 hour. Water (10 ml) was added to the reaction solution, extracted with ethyl acetate (10 ml x 2), the organic phases were combined, washed with saturated brine (10 ml), 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 step.

[0429] 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

[0430] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide (35 mg, 0.0890 mmol), triethyl orthoformate (2 ml) and p-toluenesulfonic acid (40 mg, 0.232 mmol) were added to an 8 ml vial at room temperature. After nitrogen replacement, the mixture was stirred at 120 degrees Celsius for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative plate (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a white solid (2.5 mg, 6.92%).

[0431] MS (ESI) M / Z: 403.95 [M+H] +

[0432] 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).

[0433] 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

[0434]

[0435] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carbohydrazide (20 mg, 0.0510 mmol), triethyl orthoacetate (2 ml) and p-toluenesulfonic acid (30 mg, 0.174 mmol) were added to an 8 ml vial at room temperature. After nitrogen replacement, the mixture was stirred at 120 degrees Celsius for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative plate (petroleum ether / ethyl acetate (v / v) = 2:1) to obtain a white solid (1.9 mg, 8.93%).

[0436] MS (ESI) M / Z: 418.45 [M+H] +

[0437] 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).

[0438] Example 4 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane-1H-cyclopentanamide

[0439]

[0440] Step 1) N-(2-cyanocyclopent-1-en-1-yl)acetamide

[0441] Add 1-amino-2-cyano-1-cyclopentene (5.00 g, 46.2 mmol) and acetic anhydride (32 ml) to a 100 ml single-mouth bottle at room temperature. Allow to react overnight at room temperature. Concentrate under reduced pressure, slurry the residue with petroleum ether (10 ml x 3), and filter to obtain white needle-like crystals (4.80 g, yield 69.1%).

[0442] MS (ESI) M / Z: 151.10 [M+H] +

[0443] Step 2) 4-amino-1,5,6,7-tetrahydro-2H-cyclopentylpyridin-2-one

[0444] 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 degrees Celsius. The reaction was carried out for half an hour at -78 degrees Celsius, and then the temperature was raised to 80 degrees Celsius to react overnight. Cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (30 ml). Extracted with ethyl acetate (30 ml × 3), the organic phases were combined, washed with saturated brine (30 ml), and dried over anhydrous sodium sulfate. Filtered with suction, 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, yield 52.1%).

[0445] MS (ESI) M / Z: 151.10 [M+H] +

[0446] 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

[0447] 4-Amino-1,5,6,7-tetrahydro-2H-cyclopentylpyridin-2-one (1.00 g, 6.66 mmol), 2-cyanoethyl-2-[(4-cyano-2-methoxyphenyl)methylene]-3-oxobutanoate (2.18 g, 7.33 mmol), isopropanol (20 ml) and acetic acid (19 μl) were added to a 50 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. Cooled to room temperature and filtered. The obtained solid was slurried with methyl tert-butyl ether (5 ml × 3) and filtered to obtain a yellow solid (1.70 g, 60.4%).

[0448] 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

[0449] 2-Cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl-1H,4H,7H,8H,9H-cyclopentane[h]1,6-naphthyridine-3-carboxylate (1.70 g, 4.02 mmol), iodomethane (940 mg, 6.03 mmol), silver carbonate (1.11 g, 4.02 mmol) and 1,4-dioxane (15 ml) were added to a 50 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 80 degrees Celsius for 1 hour. Cooled to room temperature, quenched by adding water (50 ml). Extracted with ethyl acetate (50 ml × 3 times), the organic phases were combined, washed with saturated brine (50 ml), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: C18 silica gel column; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile increased from 30% to 50% in 15 minutes; detection wavelength: 254 nm. A yellow solid (460 mg, yield 25.0%) was obtained.

[0450] Step 5) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane[h][1,6]naphthyridine-3-carboxylic acid

[0451] Add 2-cyanoethyl 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1H,4H,7H,8H,9H-cyclopentane[h]1,6-naphthyridine-3-carboxylate (440 mg, 0.960 mmol), ethylene glycol dimethyl ether (4.5 ml) and an aqueous solution (1.5 ml) of sodium hydroxide (77 mg, 1.92 mmol) to a 50 ml single-mouth bottle at room temperature. React at room temperature for 1 hour. Under ice bath, add hydrochloric acid solution (1.0 mol / L) to quench and adjust to pH = 5. Extract with ethyl acetate (15 ml × 3 times), combine the organic phases, wash with saturated brine (15 ml × 3 times), and dry over anhydrous sodium sulfate. Filter with suction and concentrate under reduced pressure. The obtained residue is purified by preparative high performance liquid chromatography. The purification conditions are as follows: chromatographic column: C18 silica gel column; mobile phase A: water (containing 0.04% ammonia water) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile increased from 15% to 40% in 20 minutes; detection wavelength: 254 nm. The product was collected and freeze-dried under reduced pressure.

[0452] Obtained a light yellow solid (40 mg, yield 10.3%)

[0453] Step 6) 4-(4-cyano-2-methoxyphenyl)-5-hydroxy-2-methyl-1H,4H,7H,8H,9H-cyclopentane-1,6-naphthyridine-3-carbonitrile

[0454] 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-4,7,8,9-tetrahydrocyclopentane[h][1,6]naphthyridine-3-carboxylic acid (40 mg, 0.100 mmol), N,N-diisopropylethylamine (38 mg, 0.297 mmol), N,N-dimethylformamide (1.5 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (19 mg, 0.119 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for 1 hour at room temperature. Ammonia in 1,4-dioxane (1.0 M, 0.5 ml) was added to the reaction mixture at room temperature. The mixture was reacted at 60 degrees Celsius for 3 hours. The mixture was cooled to room temperature and quenched by adding 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 obtained residue is purified by preparative high performance liquid chromatography. The purification conditions are as follows: chromatographic column: Sunfire prep C18; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile increased from 20% to 42% in 7 minutes; detection wavelength: 254 nm. Collect the product and lyophilize under reduced pressure. A white solid (9.0 mg, yield 22.6%) was obtained.

[0455] MS (ESI) M / Z: 405.45 [M+H] +

[0456] 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).

[0457] Example 5 4-(4-cyano-2-methoxyphenyl)-2-methyl-4,7,8,9-tetrahydrocyclopentane-3-carbonitrile

[0458]

[0459] 2,3-dihydro-4-indanamine (12 mg, 0.0890 mmol), 4-cyano-2-methoxybenzaldehyde (24 mg, 0.150 mmol), sodium 1-cyanopropene-2-pentanoate (16 mg, 0.150 mmol) and glacial acetic acid (9 μl) in isopropanol (0.5 ml) were added to an 8 ml vial at room temperature. After nitrogen replacement, the reaction was heated to 90 degrees Celsius overnight. Cooled to room temperature. Concentrated under reduced pressure, the residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 15% B to 50% B in 15 minutes, monitoring wavelength 254 nm), to obtain a light yellow solid (2.3 mg, yield 4.5%).

[0460] MS (ESI) M / Z: 340.25 [MH] -

[0461] 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).

[0462] Example 6 4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0463]

[0464] Step 1) Methyl 2-allyloxy-4-bromobenzoate

[0465] Add methyl 4-bromo-2-hydroxybenzoate (5.00 g, 21.6 mmol), potassium carbonate (5.98 g, 43.3 mmol), N,N-dimethylformamide (50 ml) and 3-bromopropylene (3.75 g, 43.3 mmol) to a 250 ml single-mouth bottle at room temperature. Heat to 80 degrees Celsius for 2 hours. Cool to room temperature. Add water (300 ml) to quench. Extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain a yellow solid (4.32 g, yield 69.9%).

[0466] LCMS (ESI, m / z): 271.0 [M+H] +

[0467] Step 2) 3-allyl-4-bromo-2-hydroxybenzoic acid methyl ester

[0468] Add methyl 2-allyloxy-4-bromobenzoate (4.19 g, 15.5 mmol) and N-methylpyrrolidone (30 ml) to a 250 ml single-mouth bottle at room temperature. Heat to 200 degrees Celsius for 4 hours. Cool to room temperature. Add water (300 ml) to quench. Extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain a colorless oil (2.66 g, yield 63.4%).

[0469] LCMS (ESI, m / z): 271.1 [M+H] +

[0470] Step 3) Methyl 4-bromo-2-hydroxy-3-(3-hydroxypropyl)benzoate

[0471] Add methyl 3-allyl-4-bromo-2-hydroxybenzoate (4.19 g, 15.5 mmol) and N-methylpyrrolidone (30 ml) to a 250 ml single-mouth bottle at room temperature. Heat to 200 degrees Celsius for 4 hours. Cool to room temperature. Add water (300 ml) to quench. Extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain a colorless oil (2.31 g, yield 83.3%).

[0472] LCMS (ESI, m / z): 289.1 [M+H] +

[0473] Step 4) 5-bromochrome-8-carboxylic acid methyl ester

[0474] 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) to a 100 ml single-mouth bottle. After nitrogen replacement, diethyl azodicarboxylate (3.34 g, 19.2 mmol) was slowly added dropwise under ice bath. React at room temperature overnight. Cool to room temperature. Add water (100 ml) to quench. Extract with ethyl acetate (100 ml × 3), combine the organic phases, wash with saturated brine (100 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain a yellow oil (1.67 g, yield 77.1%).

[0475] LCMS (ESI, m / z): 271.1 [M+H] +

[0476] Step 5) Methyl 5-cyanochromium-8-carboxylate

[0477] At room temperature, 5-bromochrome-8-carboxylic acid methyl ester (1.62 g, 5.96 mmol), zinc cyanide (3.51 g, 29.9 mmol), tris(dibenzylideneacetone)dipalladium (1.09 g, 1.20 mmol), 1,1'-bis(di-phenylphosphino)ferrocene (1.32 g, 2.40 mmol) and N-methylpyrrolidone (30 ml) were added to a 50 ml single-mouth bottle. Nitrogen was replaced and heated to 120 degrees Celsius for 2 hours. Cool to room temperature. Add aqueous solution (100 ml) to quench. Extract with ethyl acetate (100 ml × 3), combine the organic phases, wash with saturated brine (100 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to obtain a white solid (952 mg, yield 73.3%).

[0478] LCMS (ESI, m / z): 218.1 [M+H] +

[0479] Step 6) 8-Hydroxymethyl-5-chromonitrile

[0480] At room temperature, add methyl 5-cyanochromium-8-carboxylate (860 mg, 3.96 mmol), tetrahydrofuran (10 ml) and tetrahydrofuran solution of lithium borohydride (3.96 ml, 2.0 mol / L, 7.92 mmol) to a 50 ml single-mouth bottle. Replace with nitrogen and heat to 60 degrees Celsius for 15 minutes. Cool to room temperature. Add water (30 ml) to quench. Extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain a yellow oil (450 mg, yield 60.1%).

[0481] LCMS (ESI, m / z): 190.1 [M+H] +

[0482] Step 7) 8-Formylchromane-5-carbonitrile

[0483] 8-Hydroxymethyl-5-chromenitrile (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 bottle at room temperature. The mixture was reacted for 2 hours at room temperature. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to obtain a yellow solid (280 mg, yield 72.9%).

[0484] LCMS (ESI, m / z): 188.1 [M+H] +

[0485] Step 8) 2-cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate)

[0486] 8-Formylchromane-5-carbonitrile (200 mg, 1.07 mmol), 4-amino-5-methylpyridin-2-ol (200 mg, 1.61 mmol), 2-cyanoethyl 3-oxobutyrate (200 mg, 1.29 mmol), isopropanol (5 ml) and acetic acid (90 μl) were added to an 8 ml vial at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 120 g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 20% B to 50% B in 15 minutes, monitoring wavelength 254 nm), to obtain a yellow solid (175 mg, yield 36.7%).

[0487] LCMS (ESI, m / z): 431.2 [M+H] +

[0488] Step 9) 2-Cyanoethyl 4-(5-cyano-8-cyano)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate

[0489] 2-Cyanoethyl 4-(5-cyano-8-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate) (175 mg, 0.407 mmol), silver carbonate (112 mg, 0.407 mmol), iodoethane (95 mg, 0.610 mmol) and 1,4-dioxane (2 ml) were added to an 8 ml vial at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 2 hours. Cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (50 ml). The filtrate was collected and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography under the following conditions: C18 BIOTAGE 120 g reverse phase column, mobile phase A: (0.1% ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile), 15% B to 60% B gradient in 10 minutes, UV 254 nm detector to obtain a light yellow oil (134 mg, yield 71.9%).

[0490] LCMS (ESI, m / z): 459.2 [M+H] +

[0491] Step 10) 4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0492] At room temperature, add 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) to an 8 ml single-mouth bottle. React at room temperature for 1 hour. Under ice bath, add hydrochloric acid solution (1.0 mol / L) to quench and adjust to pH = 5. Extract with ethyl acetate (20 ml × 3 times), combine the organic phases, wash with saturated brine (20 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a light yellow solid (83 mg, 70.1%), which is directly used in the next reaction without further purification.

[0493] LCMS (ESI, m / z): 406.2 [M+H] +

[0494] Step 11) 4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0495] 4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (80 mg, 0.197 mmol), N,N-diisopropylethylamine (77 mg, 0.591 mmol), N,N-dimethylformamide (2 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (225 mg, 0.591 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for 1 hour at room temperature. Ammonia aqueous solution (1.0 M, 0.7 ml) was added to the reaction solution at room temperature. The mixture was reacted for 2 hours at room temperature. The filtrate was filtered and purified by preparative high performance liquid chromatography. Purification conditions are 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% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a yellow solid (59.0 mg, yield 73.9%).

[0496] LCMS (ESI, m / z): 405.25 [M+H] +

[0497] 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).

[0498] Example 7 10-(4-cyano-2-methoxyphenyl)-6,8-dimethyl-7H,10H-pyrazolo[3,2-f]1,6-naphthyridine-9-carbonitrile

[0499]

[0500] Step 1) tert-Butyl N-(2-bromo-5-methylpyridin-4-yl)carbamate

[0501] 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-mouth bottle at room temperature. The reaction was allowed to react for 3 hours at room temperature. The mixture was cooled to room temperature. The mixture was quenched by adding water (30 ml). The mixture was extracted with ethyl acetate (30 ml × 3), the organic phases were combined, 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, yield 28.3%).

[0502] MS (ESI) M / Z: 288 [MH] -

[0503] Step 2) tert-Butyl N-{5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridin-4-yl}carbamate

[0504] At room temperature, 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) were added to a 100 ml single-mouth bottle. After nitrogen replacement, the mixture was heated to 110 degrees Celsius for 2 hours. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a gray solid (640 mg, yield 56.1%).

[0505] MS (ESI) M / Z: 303.20 [MH] -

[0506] Step 3) 1-amino-4-[tert-butoxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridinium-1-salt

[0507] At room temperature, 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) were added to an 8 ml vial. After nitrogen replacement, the reaction was carried out at room temperature for 2 hours. Cooled to room temperature. Concentrated under reduced pressure, the residue was treated with methyl tert-butyl ether (5 ml × 3) to obtain a gray solid (120 mg, yield 87.7%).

[0508] MS (ESI) M / Z: 319.90 [MH]-

[0509] Step 4) tert-Butyl N-{6-methylpyrazolo[1,5-a]pyridin-5-yl}carbamate

[0510] 1-Amino-4-[tert-butyloxycarbonylamino]-5-methyl-2-[2-(trimethylsilyl)ethynyl]pyridine-1-salt (400 mg, 1.25 mmol), potassium carbonate (345 mg, 2.45 mmol) and N,N-dimethylformamide (4 ml) were added to an 8 ml vial at room temperature. After nitrogen replacement, the mixture was heated to 80 degrees Celsius for 5 hours. The mixture was cooled to room temperature. The mixture was filtered and the filtrate was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 40% B to 90% B in 15 minutes, monitoring wavelength 254 nm, and a gray solid (100 mg, yield 28.2%) was obtained.

[0511] MS (ESI) M / Z: 248.25 [M+H] +

[0512] Step 5) 6-methylpyrazolo[1,5-a]pyridin-5-amine

[0513] At room temperature, add tert-butyl N-{6-methylpyrazolo[1,5-a]pyridin-5-yl}carbamate (200 mg, 0.81 mmol), dichloromethane (4 ml) and trifluoroacetic acid (1 ml) in a 25 ml single-mouth bottle. React at room temperature for 2 hours. Concentrate under reduced pressure, dissolve the residue in ethyl acetate (10 ml), wash with saturated sodium bicarbonate aqueous solution (10 ml) and saturated brine (10 ml) in turn, and dry over anhydrous sodium sulfate. Concentrate under reduced pressure to obtain a gray solid (100 mg, yield 84.1%).

[0514] Step 6) 10-(4-cyano-2-methoxyphenyl)-6,8-dimethyl-7H,10H-pyrazolo[3,2-f]1,6-naphthyridine-9-carbonitrile

[0515] At room temperature, add 6-methylpyrazolo[1,5-a]pyridine-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 substitution, heat to 90 degrees Celsius to react overnight. Cool to room temperature. Concentrate under reduced pressure, and the residue is purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 15% B to 45% B in 15 minutes, monitoring wavelength 254 nm, to obtain a white solid (7 mg, yield 3.4%).

[0516] LCMS (ESI, m / z): 356.15 [M+H] +

[0517] 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).

[0518] Example 8 4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3-b]pyridine-3-carbonitrile

[0519]

[0520] Step 1) Sodium 1-cyanoacrylate-2-carboxylate

[0521] Sodium methoxide (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-mouth bottle at room temperature. 5-methylisoxazole (3.25 g, 60.0 mmol) was added dropwise under an ice-water bath. The reaction was allowed to proceed overnight at room temperature. A precipitate was generated. The solid was filtered and slurried with methanol (15 ml). A yellow solid (3.10 g, yield 84.7%) was obtained by filtration.

[0522] Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile

[0523] Sodium 1-cyanopropene-2-acid (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-mouth bottle at room temperature. After nitrogen replacement, the mixture was heated to 60 degrees Celsius to react overnight. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (10 ml × 5). The mixture was filtered to obtain a yellow solid (2.50 g, yield 38.8%).

[0524] MS (ESI) M / Z: 227.95 [M+H] +

[0525] Step 3) 4-(4-cyano-2-methoxyphenyl)-2-methyl-1,4-dihydrobenzo[4,5]thieno[2,3-b]pyridine-3-carbonitrile

[0526] Add 1-benzothiophene-2-amine (50 mg, 0.335 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (76 mg, 0.335 mmol) and glacial acetic acid (9 μl) in isopropanol (0.5 ml) to an 8 ml vial at room temperature. After nitrogen substitution, heat to 80 degrees Celsius for 1 hour. Cool to room temperature. The product was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column model: Sunfire prep C18 silica gel column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 48% B to 68% B in 8 minutes, 68% B; wavelength: 254 / 220 nm; elution time (min): 6.90) to give a white solid (22.3 mg, yield 18.1%).

[0527] MS (ESI) M / Z: 356.05 [MH] -

[0528] 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).

[0529] Example 9 4-(4-cyano-2-methoxyphenyl)-3-ethoxy-1,6-dimethyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile

[0530]

[0531] Step 1) N-(2-cyanocyclopent-1-en-1-yl)acetamide

[0532] Add 3-hydroxy-1-methylpyrazole-5-carboxylic acid methyl ester (2.30 g, 14.7 mmol), iodoethane (3.40 g, 22.1 mmol), potassium carbonate (2.00 g, 14.7 mmol) and N,N-dimethylformamide (25 ml) to a 100 ml single-mouth bottle at room temperature. After nitrogen replacement, heat to 60 degrees Celsius for 5 hours. Cool to room temperature. Add water (30 ml) to quench. Extract with ethyl acetate (30 ml × 3), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a light yellow oil (2.30 g, yield 84.7%).

[0533] LCMS (ESI, m / z): 185.10 [M+H] +

[0534] Step 2) 3-ethoxy-1-methylpyrazole-5-carboxylic acid

[0535] Add N-(2-cyanocyclopent-1-en-1-yl)acetamide (2.30 g, 12.5 mmol), tetrahydrofuran (15 ml) and saturated aqueous solution of lithium hydroxide (15 ml) to a 100 ml single-mouth bottle at room temperature. React at room temperature for 3 hours. Add dilute hydrochloric acid solution (1.0 mol / L) to quench and adjust to pH = 5. Extract with ethyl acetate (30 ml × 3 times), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a white solid (2.00 g, yield 94.1%).

[0536] LCMS (ESI, m / z): 171.10 [M+H] +

[0537] Step 3) tert-Butyl (3-ethoxy-1-methylpyrazol-5-yl)carbamate

[0538] Add 3-ethoxy-1-methylpyrazole-5-carboxylic acid (2.00 g, 11.7 mmol), triethylamine (3.57 g, 35.3 mmol) and tert-butanol (15 ml) to a 100 ml single-mouth bottle at room temperature. After nitrogen replacement, slowly add diphenylphosphoryl azide (4.85 g, 17.6 mmol). Heat to 80 degrees Celsius and react overnight. Cool to room temperature. Add water (20 ml) to quench. Extract with ethyl acetate (30 ml × 3 times), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 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, yield 56.4%).

[0539] LCMS (ESI, m / z): 242.20 [M+H] +

[0540] Step 4) 3-ethoxy-1-methylpyrazole-5-amine

[0541] 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) to a 25 ml single-mouth bottle at room temperature. Stir overnight at room temperature. Add saturated sodium bicarbonate aqueous solution to quench and adjust to pH = 7. Extract with ethyl acetate (50 ml × 3 times), combine the organic phases, wash with saturated brine (30 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (405 mg, yield 86.5%).

[0542] LCMS (ESI, m / z): 142.10 [M+H] +

[0543] Step 5) 4-(4-cyano-2-methoxyphenyl)-3-ethoxy-1,6-dimethyl-4,7-dihydropyrazolo[3,4-b]pyridine-5-carbonitrile

[0544] Add 3-ethoxy-1-methylpyrazole-5-amine (50 mg, 0.344 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (78 mg, 0.344 mmol) and glacial acetic acid (18 μL) in isopropanol (1 mL) to an 8 mL vial at room temperature. Heat to 80 °C for 2 hours under nitrogen protection. Cool to room temperature and quench with water (5 mL). Extract with ethyl acetate (10 mL × 3 times), combine the organic phases, wash with saturated brine (10 mL), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (10 mmol / L ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile, 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm) to give a white solid (8.5 mg, yield 7.73%).

[0545] MS (ESI) M / Z: 350.20 [M+H] + .

[0546] 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).

[0547] 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

[0548]

[0549] Step 1) Sodium 1-cyanoacrylate-2-carboxylate

[0550] Sodium methoxide (5.00 g, 60.0 mmol) and anhydrous methanol (30 ml) were added to a 100 ml single-mouth bottle at room temperature. 5-methylisoxazole (3.25 g, 60.0 mmol) was added dropwise under an ice-water bath. The reaction was allowed to proceed overnight at room temperature. A precipitate was generated. The solid was filtered and slurried with methanol (15 ml). A yellow solid (3.10 g, yield 84.7%) was obtained by filtration.

[0551] Step 2) 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile

[0552] Sodium 1-cyanopropene-2-acid (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-mouth bottle at room temperature. After nitrogen replacement, the mixture was heated to 60 degrees Celsius and reacted overnight. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was slurried with ethyl acetate (10 ml × 5). The mixture was filtered to obtain a yellow solid (2.50 g, yield 38.8%).

[0553] Step 3) 2-Hydrazino-4-methyl-5-nitropyridine

[0554] Add 6-chloro-2-methyl-3-nitropyridine (1.73 g, 10.0 mmol) and 1,4-dioxane (15 ml) to a 100 ml single-mouth bottle at room temperature. Add hydrazine hydrate (2.00 g, 40 mmol) under ice-water bath. React at room temperature overnight. Concentrate under reduced pressure. The residue is slurried with water (5 ml) and filtered to obtain a light yellow solid (1.30 g, crude product). It is used directly in the next step without further purification.

[0555] Step 4) 7-methyl-6-nitro[1,2,4]triazolo[4,3-a]pyridine

[0556] 2-Hydrazino-4-methyl-5-nitropyridine (1.00 g, 5.95 mmol), triethyl orthoformate (2.52 g, 23.8 mmol) and dichloromethane (50 ml) were added to a 100 ml single-mouth bottle at room temperature. Trifluoroacetic acid (140 mg, 1.19 mmol) was added under ice-water bath. The reaction was allowed to react overnight at room temperature. The solution was concentrated under reduced pressure to obtain a light yellow solid (900 mg, crude product).

[0557] Step 5) 7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine

[0558] 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-mouth bottle at room temperature. The mixture was heated to 50 degrees Celsius and reacted overnight. The mixture was cooled to room temperature, filtered through diatomaceous earth, concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to give a light yellow solid (400 mg, yield 53.5%).

[0559] 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

[0560] At room temperature, add 7-methyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (50 mg, 0.337 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (76 mg, 0.337 mmol) and glacial acetic acid (54 μl) in isopropanol (3 ml). After nitrogen replacement, heat to 80 degrees Celsius to react overnight. Cool to room temperature. Concentrate under reduced pressure, and the residue is purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40g reverse phase column, mobile phase A (0.1% formic acid aqueous solution) and mobile phase B (acetonitrile), 30% B to 50% B in 10 minutes, monitoring wavelength 254 nm) to obtain a white solid (20.0 mg, yield 16.7%).

[0561] MS (ESI) M / Z: 357.15 [M+H] +

[0562] 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).

[0563] Example 11 4-(4-Cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0564]

[0565] Step 1) 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0566] Add 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid (10.0 g, 46.9 mmol) and methanol (200 ml) to a 500 ml single-mouth bottle at room temperature. Slowly add dichlorothionyl (8.35 g, 61.9 mmol) dropwise under an ice-water bath. Heat to 70 degrees Celsius and react for 1.5 hours. Cool to room temperature. Add saturated sodium bicarbonate aqueous solution (300 ml) to quench. Extract with ethyl acetate (500 ml × 3), combine the organic phases, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (10.5 g, yield 98.5%).

[0567] LCMS (ESI, m / z): 228.6 [M+H] +

[0568] Step 2) 4-amino-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0569] Add 4-amino-5-chloro-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester (10.5 g, 46.2 mmol), 10% palladium carbon (5.35 g, 4.99 mmol), sodium hydroxide (3.15 g, 78.8 mmol) and methanol (200 ml) to a 500 ml sealed tube at room temperature. Heat to 30 degrees Celsius under 3 atmospheres of hydrogen pressure and react overnight. Cool to room temperature. Filter through diatomaceous earth and rinse the filter cake with ethyl acetate (500 ml). Combine the filtrate, wash with saturated brine (500 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a yellow solid (4.80 g, yield 53.6%).

[0570] LCMS (ESI, m / z): 194.2 [M+H] +

[0571] Step 3) 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0572] At room temperature, add 4-amino-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester (4.20 g, 21.8 mmol), tert-butyl nitrite (3.15 g, 30.7 mmol), cuprous bromide (4.20 g, 29.4 mmol) and acetonitrile (20 ml) in a 50 ml single-mouth bottle. Replace with nitrogen, heat to 70 degrees Celsius and react for half an hour. Cool to room temperature. Concentrate under reduced pressure, and the residue is purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain a yellow solid (3.50 g, yield 62.8%).

[0573] Step 4) 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester

[0574] Add 4-bromo-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester (3.20 g, 12.5 mmol), zinc cyanide (9.54 g, 81.6 mmol), tris(dibenzylideneacetone)dipalladium (1.13 g, 1.25 mmol), 1,1'-bis(di-phenylphosphino)ferrocene (1.37 g, 2.50 mmol) and N-methylpyrrolidone (20 ml) to a 50 ml single-mouth bottle at room temperature. Replace with nitrogen, heat to 120 degrees Celsius and react for 2 hours. Cool to room temperature. Add aqueous solution (100 ml) to quench. Extract with ethyl acetate (100 ml × 3), combine the organic phases, wash with saturated brine (100 ml), and dry over anhydrous sodium sulfate. The residue was filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to give a white solid (2.20 g, yield 86.6%).

[0575] Step 5) 7-Hydroxymethyl-2,3-dihydro-1-benzofuran-4-carbonitrile

[0576] At room temperature, add 4-cyano-2,3-dihydro-1-benzofuran-7-carboxylic acid methyl ester (1.80 g, 8.86 mmol), tetrahydrofuran (20 ml) and tetrahydrofuran solution of lithium borohydride (6.54 ml, 2.0 mol / L, 13.3 mmol) to a 50 ml single-mouth bottle. Replace with nitrogen and heat to 60 degrees Celsius for 20 minutes. Cool to room temperature. Add water (50 ml) to quench. Extract with ethyl acetate (50 ml × 3), combine the organic phases, wash with saturated brine (50 ml), and dry 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 obtain a white solid (960 mg, yield 61.9%).

[0577] Step 6) 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile

[0578] 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-mouth bottle at room temperature. The atmosphere was replaced with nitrogen and reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 6:1) to obtain a yellow solid (800 mg, yield 70.2%).

[0579] 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

[0580] 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-oxobutyrate (100 mg, 0.645 mmol), isopropanol (2.5 ml) and acetic acid (45 μl) were added to an 8 ml vial at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (10 mmol per liter ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile), 30% B to 50% B in 15 minutes, monitoring wavelength 254 nm), to obtain a yellow solid (110 mg, yield 45.7%).

[0581] LCMS (ESI, m / z): 417.4 [M+H] +

[0582] 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

[0583] 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (100 mg, 0.240 mmol), silver carbonate (73 mg, 0.264 mmol), iodoethane (75 mg, 0.480 mmol) and 1,4-dioxane (3 ml) were added to an 8 ml vial at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 1 hour. Cooled to room temperature, filtered, and the filter cake was rinsed with ethyl acetate (50 ml). The filtrate was collected and concentrated under reduced pressure to obtain a yellow solid (110 mg, yield 45.7%), which was directly used in the next step without further purification.

[0584] LCMS (ESI, m / z): 445.20 [M+H] +

[0585] Step 9) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0586] 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-mouth bottle at room temperature. The reaction was allowed to proceed at room temperature for 1 hour. Under an ice bath, hydrochloric acid solution (1.0 mol / L) was added to quench the reaction and the pH was adjusted to 5. The reaction mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The 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.

[0587] LCMS (ESI, m / z): 392.4 [M+H]+

[0588] Step 10) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0589] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (80 mg, 0.204 mmol), N,N-diisopropylethylamine (91 mg, 0.712 mmol), N,N-dimethylformamide (1 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (39 mg, 0.245 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted at room temperature for 1 hour. Ammonia aqueous solution (1.0 M, 0.5 ml) was added to the reaction solution at room temperature. The mixture was reacted at room temperature for 1 hour. The mixture was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are 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% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a yellow solid (45.0 mg, yield 56.1%).

[0590] LCMS (ESI, m / z): 391.10 [M+H] +

[0591] 1H 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).

[0592] Example 12 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1H,4H-benzo[h]1,6-naphthyridine-3-carbonitrile

[0593]

[0594] Step 1) 2-ethoxyquinolin-4-amine

[0595] 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 to 140 degrees Celsius in a microwave oven for 1 hour. The mixture was cooled to room temperature. The mixture was concentrated under reduced pressure, and the 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 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% ammonia water) and mobile phase B (acetonitrile), 25% B to 35% B in 10 minutes, monitoring wavelength 254 nm), and a white solid (75 mg, yield 35.6%) was obtained.

[0596] MS (ESI) M / Z: 189 [M+H] +

[0597] Step 2) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2-methyl-1H,4H-benzo[h]1,6-naphthyridine-3-carbonitrile

[0598] Add 2-ethoxyquinolin-4-amine (75 mg, 0.398 mmol), 4-(2-cyano-3-oxobut-1-en-1-yl)-3-methoxybenzonitrile (90 mg, 0.398 mmol) and glacial acetic acid (36 μl) in isopropanol (2 ml) to an 8 ml vial at room temperature. After nitrogen substitution, heat to 80 degrees Celsius to react overnight. Cool to room temperature. The product was concentrated under reduced pressure and the residue was purified by HPLC preparative column: column model YMC-Actus Triart C18, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml per minute; gradient: 55% B to 85% B for 7 minutes; wavelength: 254 / 220 nm: elution time (minutes): 6.15. The fractions were collected and lyophilized under reduced pressure to obtain a white solid (48.8 mg, yield 30.7%).

[0599] MS (ESI) M / Z: 397.15 [M+H] +

[0600] 1 H 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).

[0601] Example 13 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide

[0602]

[0603] Step 1) N-(2-cyanothiophene-3-yl)acetamide

[0604] 3-Amino-2-cyano-thiophene (1.00 g, 8.05 mmol) and acetic anhydride (10 ml) were added to a 50 ml single-mouth bottle at room temperature. The reaction was allowed to proceed overnight at room temperature. 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, yield 89.6%).

[0605] LCMS (ESI, m / z): 167.0 [M+H] +

[0606] Step 2) 7-aminothieno[3,2-b]pyridin-5-ol

[0607] 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 degrees Celsius. The mixture was reacted for half an hour at -78 degrees Celsius, and then the temperature was raised to 80 degrees Celsius for reaction for 1 hour. The mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride solution (10 ml). The mixture was extracted with ethyl acetate (15 ml × 3), the organic phases were combined, 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, yield 54.2%).

[0608] LCMS (ESI, m / z): 167.0 [M+H] +

[0609] Step 3) 2-Cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-hydroxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate

[0610] 7-aminothieno[3,2-b]pyridine-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-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out overnight at 90 degrees Celsius. Cooled to room temperature and filtered. The obtained solid was slurried with ethyl acetate (15 ml × 3), filtered to obtain a crude product, and purified by C18 reverse phase column chromatography under the following conditions: C18 BIOTAGE 330 g chromatography column, mobile phase A (0.1% FA aqueous solution) and mobile phase B (acetonitrile), 15% B to 50% B gradient 15 minutes, monitoring wavelength 254 nm, to obtain a light yellow solid (1.09 g, yield 45.4%).

[0611] LCMS (ESI, m / z): 447.1 [M+H] +

[0612] Step 4) 2-Cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate

[0613] 2-Cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-hydroxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate (195 mg, 0.437 mmol), iodomethane (102 mg, 0.655 mmol), silver carbonate (120 mg, 0.437 mmol) and 1,4-dioxane (2 ml) were added to a 50 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 2 hours. Cooled to room temperature, quenched by adding saturated aqueous ammonium chloride solution (5 ml). Extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure. The obtained residue was purified by C18 reverse phase column. Purification conditions are as follows: chromatographic column: BIOTAGE C18 reverse phase column 120 g; mobile phase A: water (containing 0.1% ammonium bicarbonate aqueous solution) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile increased from 20% to 60% in 15 minutes; detection wavelength: 254 nm. A white solid (120 mg, yield 57.9%) was obtained.

[0614] LCMS (ESI, m / z): 475.1 [M+H] +

[0615] Step 5) 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylic acid

[0616] Add 2-cyanoethyl 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxylate (155 mg, 0.327 mmol), ethylene glycol dimethyl ether (1.5 ml) and an aqueous solution (0.5 ml) of sodium hydroxide (26 mg, 0.655 mmol) to a 50 ml single-mouth bottle at room temperature. React at room temperature for 1 hour. Under ice bath, add hydrochloric acid solution (1.0 mol / L) to quench and adjust to pH = 5. Extract with ethyl acetate (5 ml × 3 times), combine the organic phases, wash with saturated brine (15 ml × 3 times), and dry over anhydrous sodium sulfate. Filter with suction and concentrate under reduced pressure. The obtained residue is purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: C18 silica gel column; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile increased from 10% to 40% in 10 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. A white solid (111 mg, yield 80.6%) was obtained.

[0617] LCMS (ESI, m / z): 422.1 [M+H] +

[0618] Step 6) 6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide

[0619] 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) to an 8 ml vial at room temperature. React at room temperature for half an hour. Add ammonia (0.8 ml) solution to the reaction solution at room temperature. React at room temperature for 3 hours. Add water (10 ml) to quench. Extract with ethyl acetate (10 ml × 3 times), combine the organic phases, wash with saturated brine (10 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography. The purification conditions were as follows: chromatographic column: Sunfire prep C18; mobile phase A: water (containing 0.1% aqueous ammonium bicarbonate solution) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile increased from 18% to 50% in 7 minutes; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. A white solid (47.0 mg, yield 44.9%) was obtained.

[0620] LCMS (ESI, m / z): 421.0 [M+H] +

[0621] 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).

[0622] Example 14 4-(7-Cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0623]

[0624] Step 1) Diethyl 2,3-dihydroxyterephthalate

[0625] Add 2,3-dihydroxyterephthalic acid (260 g, 1.31 mol) and ethanol (2.60 liters) to a 10-liter four-necked flask at room temperature. Slowly add dichlorothionyl (908 g, 7.63 mol) at 0 degrees Celsius, and react overnight at 70 degrees Celsius. Cool to room temperature, slowly add saturated sodium bicarbonate aqueous solution (5.20 liters) to quench the reaction solution. Extract with ethyl acetate (5.00 liters × 3), combine the organic phases, wash with saturated brine (3.00 liters), and dry over anhydrous sodium sulfate. Filter with suction and concentrate under reduced pressure to obtain an off-white solid (312 g, yield 93.5%).

[0626] MS (ESI) M / Z: 255.1 [M+H] +

[0627] Step 2) Diethyl benzo[d][1,3]dioxole-4,7-dicarboxylate

[0628] Add diethyl 2,3-dihydroxyterephthalate (312 g, 1.23 mol), bromochloromethane (175 g, 1.35 mol), potassium carbonate (340 g, 2.46 mol) and DMSO (1.90 liters) to a 10-liter four-necked flask at room temperature. After nitrogen replacement, react at 90 degrees Celsius overnight. Cool to room temperature and quench with saturated brine (19.0 liters). Extract with ethyl acetate (12.0 liters × 3), combine the organic phases, wash with saturated brine (12.0 liters), and dry over anhydrous sodium sulfate. Filter with suction, and concentrate the filtrate under reduced pressure to obtain an off-white solid (289 g, yield 88.4%).

[0629] MS (ESI) M / Z: 267.1 [M+H] +

[0630] Step 3) Ethyl 7-hydroxymethylbenzo[d][1,3]dioxole-4-carboxylate

[0631] Benzo[d][1,3]dioxole-4,7-dicarboxylic acid diethyl ester (289 g, 1.09 mol), tetrahydrofuran (2.90 L) and lithium borohydride tetrahydrofuran solution (545 ml, 2.0 mol per liter, 1.09 mol) were added to a 10-liter four-necked flask at room temperature. After nitrogen replacement, the reaction was carried out at 60 degrees Celsius for 2 hours. After cooling to 0 degrees Celsius, the reaction solution was slowly added to a saturated aqueous ammonium chloride solution (6.00 L) to quench. It was extracted with ethyl acetate (4.50 L × 3), the organic phases were combined, washed with saturated brine (4.50 L), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 7:3) to obtain a white solid (168 g, yield 69.0%).

[0632] MS (ESI) M / Z: 225.0 [M+H] +

[0633] Step 4) Ethyl 7-formylbenzo[d][1,3]dioxole-4-carboxylate

[0634] Ethyl 7-hydroxymethylbenzo[d][1,3]dioxole-4-carboxylate (168 g, 750 mmol), dichloromethane (1.70 L) and Dess-Martin reagent (397 g, 937 mmol) were added to a 3-liter three-necked flask at room temperature. 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 give a yellow solid (165 g, yield 99.1%).

[0635] MS (ESI) M / Z: 223.1 [M+H] +

[0636] Step 5) Ethyl 7-cyanobenzo[d][1,3]dioxole-4-carboxylate

[0637] At room temperature, 7-formylbenzo[d][1,3]dioxole-4-carboxylic acid ethyl ester (165 g, 757 mmol), hydroxylamine hydrochloride (158 g, 2.27 mol) and DMSO (1.00 liter) were added to a 3-liter three-necked flask. Nitrogen was replaced and heated to 90 degrees Celsius for 1 hour. After cooling to room temperature, saturated brine (10.0 liters) was added to quench. It was extracted with ethyl acetate (6.00 liters × 3), the organic phases were combined, washed with saturated brine (6.00 liters), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 4:1) to give a yellow solid (120 g, yield 73.7%).

[0638] Step 6) 7-Hydroxymethylbenzo[d][1,3]dioxole-4-carbonitrile

[0639] At room temperature, add ethyl 7-cyanobenzo[d][1,3]dioxole-4-carboxylate (120 g, 548 mmol), tetrahydrofuran (1.20 L) and tetrahydrofuran solution of lithium borohydride (411 ml, 2.0 mol / L, 822 mmol) to a 3-liter three-necked flask. After nitrogen replacement, react at 60 degrees Celsius for 2 hours. Cool to 0 degrees Celsius, and slowly add saturated aqueous ammonium chloride solution (3.20 L) to quench. Extract with ethyl acetate (2.50 L × 3), combine the organic phases, wash with saturated brine (2.50 L), and dry over anhydrous sodium sulfate. Filter with suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain a white solid (75.0 g, yield 77.3%).

[0640] Step 7) 7-Formylbenzo[1,3]dioxole-4-carbonitrile

[0641] 7-Hydroxymethylbenzo[d][1,3]dioxole-4-carbonitrile (75.0 g, 424 mmol), dichloromethane (1.50 L) and Dess-Martin reagent (270 g, 636 mmol) were added to a 3-liter three-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 obtain a yellow solid (67.0 g, yield 90.4%).

[0642] 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

[0643] 7-Formylbenzo[1,3]dioxole-4-carbonitrile (65.0 g, 371 mmol), 2-cyanoethyl-3-oxobutyrate (63.3 g, 408 mmol), 4-amino-5-methylpyridin-2-ol (50.7 g, 408 mmol), isopropanol (1.30 L) and acetic acid (23.4 mL) were added to a 3-liter three-necked flask at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. Cooled to room temperature and filtered. The obtained solid was slurried with methyl tert-butyl ether (500 mL × 3) and filtered to obtain a light yellow solid (88.0 g, 56.7%).

[0644] MS (ESI) M / Z: 419.2 [M+H] +

[0645] 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

[0646] 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (88.0 g, 210 mmol), iodoethane (49.3 g, 316 mmol), silver carbonate (58.1 g, 210 mmol) and 1,4-dioxane (880 ml) were added to a 2-liter three-necked flask at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 2 hours. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellow solid (86.5 g, 92.1%).

[0647] MS (ESI) M / Z: 447.1 [M+H] +

[0648] 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

[0649] 2-Cyanoethyl 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (85.0 g, 190 mmol), ethylene glycol dimethyl ether (1275 ml), water (425 ml) and an aqueous solution of sodium hydroxide (1.00 mol / L, 380 ml) were added to a 3-liter three-necked flask at room temperature. The mixture was reacted for 1 hour at room temperature. Water (1.50 liters) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (1.00 liters x 1 time), and the aqueous phase was retained. Under ice bath, hydrochloric acid solution (1.00 mol / L) was added to quench the mixture and the pH was adjusted to 5. The mixture was extracted with ethyl acetate (1.00 liters x 3 times), the organic phases were combined, washed with saturated brine (500 ml x 1 time), and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure to obtain a light yellow solid (70.0 g, 91.8%), which was directly used in the next reaction.

[0650] MS (ESI) M / Z: 394.2 [M+H] +

[0651] Step 11) 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0652] 4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (57.0 g, 145 mmol), N,N-diisopropylethylamine (37.4 g, 290 mmol), N,N-dimethylformamide (570 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (92.4 g, 218 mmol) were added to a 2-liter three-necked flask at room temperature. A 25% aqueous solution of ammonia (120 ml) was added to the reaction solution at room temperature. The reaction was allowed to react for 1.5 hours at room temperature. The reaction solution was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: DAC prep C18; mobile phase A: water (containing 0.1% ammonium bicarbonate) and mobile phase B: acetonitrile; flow rate: 1 liter / minute; gradient: acetonitrile from 20% to 42% in 30 minutes; detection wavelength: 254 nanometers. The product was collected and lyophilized under reduced pressure. A white solid (38.0 g, 66.8%) was obtained.

[0653] MS (ESI) M / Z: 393.3 [M+H] +

[0654] 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).

[0655] Example 15 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0656]

[0657] 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

[0658] 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-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was collected, and the filter cake was washed with ethyl acetate (3×10 ml). The filtrate was concentrated under reduced pressure to obtain a yellow solid (110.0 mg, yield 94.5%)

[0659] MS (ESI) M / Z: 485.5 [M+H] +

[0660] 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

[0661] At room temperature, add 2-cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (110 mg, 0.227 mmol), ethylene glycol dimethyl ether (3 ml) and an aqueous solution (1 ml) of sodium hydroxide (18 mg, 0.454 mmol) in an 8 ml single-mouth bottle. React at room temperature for 1 hour. Under ice bath, add hydrochloric acid solution (1.0 mol / L) to quench and adjust to pH = 5. Extract with ethyl acetate (5 ml × 3 times), combine the organic phases, wash with saturated brine (5 ml × 3 times), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain a light yellow solid (100 mg, yield 93.6%), which is directly used in the next reaction.

[0662] MS (ESI) M / Z: 432.5 [M+H] +

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

[0664] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-cyclopentyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (90 mg, 0.209 mmol), N,N-diisopropylethylamine (54 mg, 0.418 mmol), N,N-dimethylformamide (1.5 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (127 mg, 0.334 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (content 25%) (1.5 ml) was added to the reaction solution at room temperature. The mixture was reacted for half an hour at room temperature. The mixture was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: YMC-Actus Triart C18; 30*150 mm, 5 μm; mobile phase A: water (containing 0.1% formic acid) and mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: acetonitrile from 38% to 55% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure. A white solid (50.0 mg, yield 55.7%) was obtained.

[0665] LCMS (ESI, m / z): 431.1 [M+H] +

[0666] 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).

[0667] 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

[0668]

[0669] Step 1) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0670] 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (300 mg, 1.73 mmol), benzyl acetoacetate (333 mg, 1.73 mmol), 4-amino-5-methylpyridin-2-ol (215 mg, 1.73 mmol), isopropanol (8.5 ml) and acetic acid (0.15 ml) were added to an 8 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius overnight. Cooled to room temperature and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (100% ethyl acetate) to obtain a white solid (185 mg, yield 23.6%).

[0671] MS (ESI) M / Z: 454.5 [M+H] +

[0672] Step 2) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0673] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (110 mg, 0.240 mmol), 3-bromomethyl-1,1-difluorocyclobutane (67 mg, 0.360 mmol), cesium carbonate (158 mg, 0.490 mmol) and N,N-dimethylformamide (1 ml) were added to an 8 ml single-mouth bottle at room temperature. The reaction was carried out at 60 degrees Celsius for 2 hours. The mixture was cooled to room temperature and quenched by adding water (10 ml). The mixture was extracted with ethyl acetate (10 ml × 3 times), the organic phases were combined, washed with saturated brine (10 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 5 / 1). A white solid (40 mg, yield 29.6%) was obtained.

[0674] MS (ESI) M / Z: 558.6 [M+H] +

[0675] 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

[0676] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (100 mg, 0.180 mmol), palladium carbon (10% content, 100 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was allowed to proceed overnight at room temperature. The filtrate was filtered and concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 35.8%), which was directly used for the next step.

[0677] MS (ESI) M / Z: 468.5 [M+H] +

[0678] 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

[0679] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-[(3,3-difluorocyclobutyl)methoxy]-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.064 mmol), N,N-diisopropylethylamine (17 mg, 0.130 mmol), N,N-dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (37 mg, 0.096 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The filtrate was filtered and purified by preparative high performance liquid chromatography. Purification conditions were as follows: column model XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (containing 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 25% B to 60% B for 7 minutes, 60% B; wavelength: 254 / 220 nm; peak time (min): 6.58; fractions were collected and lyophilized under reduced pressure to obtain a white solid (17.0 mg, yield 56.8%).

[0680] LCMS (ESI, m / z): 467.5 [M+H] +

[0681] 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).

[0682] 19 F NMR (376MHz, CDCl3) δ-83.5,-94.4.

[0683] Example 17 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0684]

[0685] Step 1) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0686] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (100 mg, 0.221 mmol), ethyl 2-bromo-2,2-difluoroacetate (67 mg, 0.332 mmol), cesium carbonate (144 mg, 0.442 mmol) and N,N-dimethylformamide (2 ml) were added to an 8 ml single-mouth bottle at room temperature. The reaction was carried out at 60 degrees Celsius for 2 hours. The mixture was cooled to room temperature and quenched by adding water (20 ml). The mixture was extracted with ethyl acetate (20 ml × 3 times), the organic phases were combined, washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate = 5 / 1). A yellow solid (60 mg, yield 54.6%) was obtained.

[0687] MS (ESI) M / Z: 504.6 [M+H] +

[0688] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0689] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (60 mg, 0.119 mmol), palladium carbon (10% content, 60 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 70 degrees Celsius overnight. After cooling to room temperature, the reaction solution was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 60.9%), which was directly used for the next step reaction.

[0690] MS (ESI) M / Z: 414.4 [M+H] +

[0691] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0692] 4-cyano-2,3-dihydrobenzofuran-7-yl-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (20 mg, 0.048 mmol), N,N-diisopropylethylamine (13 mg, 0.096 mmol), N,N-dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28 mg, 0.072 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The filtrate was filtered and purified by preparative high performance liquid chromatography. Purification conditions were as follows: column model XBridge Shield RP18 OBD Column, 30*150 mm, 5 μm; mobile phase A: water (containing 0.1% ammonia water), mobile phase B: acetonitrile; flow rate: 60 ml / min; gradient: 30% B to 60% B for 7 minutes; wavelength: 254 / 220 nm; fractions were collected and freeze-dried under reduced pressure to obtain a white solid (1.1 mg, yield 5.51%).

[0693] LCMS (ESI, m / z): 413.05 [M+H] +

[0694] 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).

[0695] 19 F NMR(282MHz, CDCl3)δ-87.2,-90.2.

[0696] Example 18 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0697]

[0698] Step 1) (Z)-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylene)-3-hydroxybutyric acid benzyl ester

[0699] 7-Formyl-2,3-dihydro-1-benzofuran-4-carbonitrile (566 mg, 3.27 mmol), piperidine (28 mg, 0.327 mmol), acetic acid (0.22 ml), benzyl acetoacetate (628 mg, 3.27 mmol) and dichloromethane (12.0 ml) were added to a 40 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 40 degrees Celsius overnight. Cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain a yellow oil (600 mg, yield 52.9%).

[0700] LCMS (ESI, m / z): 348.10 [M+H] +

[0701] Step 2) 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0702] At room temperature, add (Z)-2-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)methylene)-3-hydroxybutyric acid benzyl ester (100 mg, 0.288 mmol), 4-amino-5-methylpyridin-2-ol (35.7 mg, 0.288 mmol), acetic acid (0.02 ml) and dichloromethane (2.0 ml) in a 40 ml single-mouth bottle. After nitrogen replacement, react at 90 degrees Celsius overnight. Cool to room temperature and filter. The obtained solid is slurried with isopropanol (2.0 ml × 3) and filtered to obtain a light yellow solid (105 mg, yield 80.8%).

[0703] LCMS (ESI, m / z): 454.25 [M+H] +

[0704] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0705] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (200 mg, 0.441 mmol), cyclopropane bromide (534 mg, 4.41 mmol), cesium carbonate (719 mg, 2.21 mmol) and N,N-dimethylformamide (2 ml) were added to an 8 ml single-mouth bottle at room temperature. Under nitrogen protection, the reaction was stirred at 130 degrees Celsius overnight. Cooled to room temperature, filtered, and the filtrate was purified by carbon 18 column (mobile phase A: 0.1% formic acid aqueous solution, mobile phase B is acetonitrile; flow rate: 60 ml / min; 10% to 50% within 10 minutes; detection wavelength is 254 nm. The fractions were collected and lyophilized under reduced pressure to obtain a yellow solid (35 mg, yield 16.1%).

[0706] MS (ESI) M / Z: 494.2 [M+H] +

[0707] Step 4) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0708] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (35 mg, 0.071 mmol), palladium carbon (10% content, 35 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 50 degrees Celsius for 3 hours. After cooling to room temperature, the reaction liquid was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a light yellow solid (28 mg, yield 97.8%), which was directly used for the next step.

[0709] MS (ESI) M / Z: 404.2 [M+H] +

[0710] Step 5) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0711] 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) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.5 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by carbon 18 column (mobile phase A: aqueous solution containing 0.1% ammonium bicarbonate, mobile phase B: acetonitrile; flow rate: 60 ml / min, 20% to 50% within 10 minutes; detection wavelength was 254 nm. The fractions were collected and freeze-dried under reduced pressure to obtain a white solid (20.2 mg, yield 72.3%).

[0712] LCMS (ESI, m / z): 403.05 [M+H] +

[0713] 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).

[0714] Example 19 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0715]

[0716] 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

[0717] 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-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was then purified by carbon 18 column (mobile phase A: 0.1% formic acid aqueous solution; mobile phase B: acetonitrile; flow rate: 60 ml / min, from 10% B to 50% B in 10 minutes; detection wavelength was 254 nm). The fractions were collected and freeze-dried under reduced pressure to obtain a yellow solid (22.5 mg, yield 49.8%)

[0718] MS (ESI) M / Z: 471.2 [M+H] +

[0719] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0720] 2-Cyanoethyl 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (20 mg, 0.042 mmol), ethylene glycol dimethyl ether (0.6 ml) and an aqueous solution (0.2 ml) of sodium hydroxide (4 mg, 0.084 mmol) were added to an 8 ml single-mouth bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol / L) was added to quench and adjust to pH = 5. Extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (5 ml × 3 times), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a light yellow solid (17 mg, yield 96.9%), which was directly used in the next reaction.

[0721] MS (ESI) M / Z: 418.5 [M+H] +

[0722] Step 3) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0723] 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclopropylmethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (16 mg, 0.038 mmol), N,N-diisopropylethylamine (15 mg, 0.115 mmol), N,N-dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23 mg, 0.062 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (content 25%) (0.1 ml) was added to the reaction solution at room temperature. The mixture was reacted for half an hour at room temperature. The reaction solution was filtered, and the filtrate was purified by carbon 18 column (mobile phase A: 0.1% ammonium bicarbonate aqueous solution; mobile phase B: acetonitrile; flow rate: 60 ml / min, from 20% B to 50% B within 10 minutes; detection wavelength was 254 nm). The fractions were collected and lyophilized under reduced pressure, and the product was collected and lyophilized under reduced pressure. A white solid (2.2 mg, yield 12.9%) was obtained.

[0724] LCMS (ESI, m / z): 417.0 [M+H] +

[0725] 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).

[0726] 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

[0727]

[0728] 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

[0729] 2-Cyanoethyl-4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (50 mg, 0.120 mmol), 2-iodopropane (33 mg, 0.192 mmol), silver carbonate (33 mg, 0.120 mmol) and 1,4-dioxane (1 ml) were added to an 8 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 2 hours. After cooling to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (3X 5 ml), the filtrate was collected, and concentrated under reduced pressure to obtain a white solid (40 mg, yield 72.7%)

[0730] MS (ESI) M / Z: 459.2 [MH] -

[0731] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0732] 2-Cyanoethyl 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (40 mg, 0.087 mmol), ethylene glycol dimethyl ether (0.9 ml) and an aqueous solution (0.3 ml) of sodium hydroxide (7 mg, 0.174 mmol) were added to an 8 ml single-mouth bottle at room temperature. The reaction was carried out at room temperature for 1 hour. Under ice bath, hydrochloric acid solution (1.0 mol / L) was added to quench and adjust to pH = 5. Extracted with ethyl acetate (3 ml × 3 times), the organic phases were combined, washed with saturated brine (3 ml × 3 times), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 84.6%), which was directly used in the next step.

[0733] MS (ESI) M / Z: 406.3 [M+H] +

[0734] 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

[0735] 4-cyano-2,3-dihydrobenzofuran-7-yl-5-isopropoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.074 mmol), N,N-diisopropylethylamine (0.05 ml), N,N-dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.111 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (content 25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for half an hour at room temperature. The reaction solution was filtered, and the filtrate was purified by carbon 18 column (mobile phase A: aqueous solution containing 0.05% ammonia water; mobile phase B: acetonitrile; flow rate: 60 ml / min, from 15% B to 40% B in 15 minutes; detection wavelength was 254 nm). The product was collected and freeze-dried under reduced pressure to obtain a white solid (14.4 mg, yield 48.1%).

[0736] LCMS (ESI, m / z): 404.10 [M+H] +

[0737] 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).

[0738] Example 21 4-(4-Cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0739]

[0740] Step 1) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0741] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (50 mg, 0.110 mmol), iodocyclobutane (60 mg, 0.331 mmol), cesium carbonate (72 mg, 0.221 mmol) and N,N-dimethylformamide (1 ml) were added to an 8 ml single-mouth bottle at room temperature. Under nitrogen protection, the reaction was stirred at 60 degrees Celsius overnight. The reaction solution was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate (3×10 ml). The organic phases were combined, washed with saturated brine (3×10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate=4 / 1) to give a white solid (40 mg, yield 71.4%).

[0742] MS (ESI) M / Z: 508.2 [M+H] +

[0743] Step 2) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0744] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (40 mg, 0.085 mmol), palladium carbon (10% content, 40 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and reacted at 50 degrees Celsius for 2 hours. After cooling to room temperature, the reaction liquid was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (30 mg, yield 91.3%), which was directly used for the next step.

[0745] MS (ESI) M / Z: 418.2 [M+H] +

[0746] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0747] 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.072 mmol), N,N-diisopropylethylamine (19 mg, 0.145 mmol), N,N-dimethylformamide (1 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (41 mg, 0.109 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.5 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: Xselect CSH C18 OBD; mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: acetonitrile from 40% to 50% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (15.0 mg, yield 49.8%).

[0748] LCMS (ESI, m / z): 417.2 [M+H] +

[0749] 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).

[0750] Example 22 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0751]

[0752] Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0753] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (300 mg, 0.663 mmol), (iodomethyl)cyclobutane (194 mg, 0.996 mmol), cesium carbonate (431 mg, 1.27 mmol) and N,N-dimethylformamide (3 ml) were added to an 8 ml single-mouth bottle at room temperature. The reaction was stirred at 60 degrees Celsius for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was purified by carbon 18 reverse column (conditions are as follows: mobile phase A: water (containing 0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 ml / min, gradient: 30% B to 60% B, washing for 15 minutes; detection wavelength 254 nm, reference wavelength 220 nm). The product was collected and concentrated under reduced pressure to give a white solid (47 mg, yield 13.7%).

[0754] MS (ESI) M / Z: 522.2 [M+H] +

[0755] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0756] 4-Cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (47 mg, 0.090 mmol), palladium carbon (10% content, 47 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and reacted at 50 degrees Celsius for 2 hours. After cooling to room temperature, the reaction liquid was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a light yellow solid (30 mg, yield 77.2%), which was directly used for the next step reaction.

[0757] MS (ESI) M / Z: 432.2 [M+H] +

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

[0759] 4-cyano-2,3-dihydrobenzofuran-7-yl-5-cyclobutyl-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (30 mg, 0.070 mmol), N,N-diisopropylethylamine (19 mg, 0.145 mmol), N,N-dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (42 mg, 0.110 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: Xselect CSH C18 OBD; mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: acetonitrile from 35% to 50% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (17.9 mg, yield 59.8%).

[0760] LCMS (ESI, m / z): 431.2 [M+H] +

[0761] 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).

[0762] Example 23 4-Cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0763]

[0764] Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0765] 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (100 mg, 0.220 mmol), 3,3-dimethyl-1-(trifluoromethyl)-1,2-benzoiodooxolane (218 mg, 0.663 mmol) and nitromethane (4 ml) were added to an 8 ml single-mouth bottle at room temperature. Under nitrogen protection, the reaction was stirred at 100 degrees Celsius for 5 hours. The reaction solution was cooled to room temperature, diluted with water (10 ml), and extracted with ethyl acetate (3×10 ml). The organic phases were combined, washed with saturated brine (3×10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The obtained residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate=1 / 1) to give a yellow solid (40 mg, yield 34.8%).

[0766] MS (ESI) M / Z: 522.2 [M+H] +

[0767] Step 2) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid

[0768] 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (20 mg, 0.038 mmol), palladium carbon (10% content, 20 mg) and methanol (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 70 degrees Celsius for 4 hours. After cooling to room temperature, the reaction liquid was filtered to obtain a filtrate, which was purified by preparative high performance liquid chromatography. The purification conditions are as follows: chromatographic column: carbon 18 reverse column; mobile phase: water (containing 0.1% formic acid) and acetonitrile; flow rate: 40 ml / min; gradient: from 30% B to 50% B in 15 minutes; detection wavelength: 254 nm. The product was collected, freeze-dried and concentrated under reduced pressure to obtain a white solid (12 mg, yield 72.5%), which was directly used in the next reaction.

[0769] MS (ESI) M / Z: 432.2 [M+H] +

[0770] Step 3) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclobutoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

[0771] 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-trifluoromethoxy-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (12 mg, 0.028 mmol), N,N-diisopropylethylamine (7 mg, 0.054 mmol), N,N-dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 0.042 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.1 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: Xselect CSH C18 OBD; mobile phase A: water (containing 0.1% trifluoroformic acid), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: acetonitrile from 20% to 50% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (2.9 mg, yield 24.2%).

[0772] LCMS (ESI, m / z): 431.2 [M+H] +

[0773] 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).

[0774] 19 F NMR (377 MHz, CDCl3) δ-56.0.

[0775] 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

[0776]

[0777] Step 1) 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester

[0778] Add 4-(4-cyano-2,3-dihydro-1-benzofuran-7-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (100 mg, 0.221 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (92 mg, 0.354 mmol), cesium carbonate (144 mg, 0.442 mmol) and N,N-dimethylformamide (2 ml) to an 8 ml single-mouth bottle at room temperature. Stir the reaction at room temperature for 2 hours. Dilute with water (20 ml) and extract with ethyl acetate (3×20 ml). Combine the organic phases, wash with saturated brine (20 ml), dry with anhydrous sodium sulfate, filter with suction to obtain the filtrate, and concentrate under reduced pressure. The obtained residue was purified by preparative chromatography (pre-TLC) (petroleum ether / ethyl acetate=2 / 1) to give a yellow solid (36 mg, yield 36.1%).

[0779] MS (ESI) M / Z: 536.2 [M+H] +

[0780] 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

[0781] 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid benzyl ester (36.0 mg, 0.067 mmol), palladium carbon (10% content, 36 mg) and tetrahydrofuran (2 ml) were added to a 30 ml autoclave at room temperature. After nitrogen replacement, 3 standard atmospheric pressures of hydrogen were introduced and the reaction was carried out at 70 degrees Celsius for 3 hours. After cooling to room temperature, the reaction solution was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a white solid (24 mg, yield 80.1%), which was directly used for the next step.

[0782] MS (ESI) M / Z: 446.2 [M+H] +

[0783] 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

[0784] 4-cyano-2,3-dihydrobenzofuran-7-yl-2,8-dimethyl-5-(2,2,2-trifluoroethoxy)-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (24 mg, 0.054 mmol), N,N-diisopropylethylamine (19 mg, 0.145 mmol), N,N-dimethylformamide (0.5 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (30 mg, 0.081 mmol) were added to an 8 ml vial at room temperature. The mixture was reacted for half an hour at room temperature. Ammonia aqueous solution (25%) (0.2 ml) was added to the reaction solution at room temperature. The mixture was reacted for 1 hour at room temperature. The reaction solution was filtered and the filtrate was purified by preparative high performance liquid chromatography. Purification conditions are as follows: chromatographic column: Xselect CSH C18OBD; mobile phase A: water (containing 5 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 50 ml / min; gradient: acetonitrile from 40% to 50% in 7 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (6.3 mg, yield 26.3%).

[0785] MS (ESI) M / Z: 445.15 [M+H] +

[0786] 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).

[0787] 19 F NMR (282MHz,CDCl3)δ-74.1.

[0788] 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

[0789]

[0790] Step 1) 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carboxamide

[0791] 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carboxylic acid (1.00 g, 5.12 mmol), N,N-dimethylformamide (25 ml), N,N-diisopropylethylamine (1.32 g, 10.2 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.92 g, 7.69 mmol) were added to a 100 ml single-mouth bottle at room temperature. The reaction was allowed to proceed for 0.5 hours at room temperature. Ammonia aqueous solution (1.0 M, 6 ml) was added to the reaction solution at room temperature. The reaction was allowed to proceed for 1 hour at room temperature. Water (250 ml) was added to dilute the mixture. The mixture was extracted with ethyl acetate (250 ml x 3), the organic phases were combined, washed with saturated brine (250 ml), and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: pure ethyl acetate) to obtain an orange oil (800 mg, yield 80.4%).

[0792] LCMS (ESI, m / z): 195.1 [M+H] +

[0793] Step 2) 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

[0794] 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-mouth bottle at room temperature. Heat to 80 degrees Celsius for 1 hour. Cool to room temperature. Add sodium hydroxide solution (1.0 mol / L) to quench and adjust the pH to about 8. Extract with ethyl acetate (50 ml × 3), combine the organic phases, wash with saturated brine (50 ml), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure. The residue is purified by column chromatography (dichloromethane / methanol (v / v) = 20 / 1) to obtain a white solid (310 mg, yield 44.6%).

[0795] LCMS (ESI, m / z): 177.1 [M+H] +

[0796] Step 3) 8-bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

[0797] At room temperature, 8-amino-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (310 mg, 1.76 mmol), tert-butyl nitrite (181 mg, 1.76 mmol), cuprous bromide (366 mg, 2.55 mmol) and acetonitrile (8 ml) were added to a 40 ml sample bottle. The mixture was reacted at 70 degrees Celsius for 1.5 hours. The reaction solution was cooled to room temperature, filtered, and rinsed with ethyl acetate (8 ml) 3 times. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative plate (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a white solid (110 mg, yield 26.0%).

[0798] Step 4) 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile

[0799] Add 8-bromo-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (110 mg, 0.458 mmol) and tetrahydrofuran (0.5 ml) to an 8 ml sample bottle at room temperature. After nitrogen replacement, cool the reaction solution to -78 degrees Celsius. Slowly drop n-butyl lithium (0.2 ml, 2.5 mmol / ml, 0.50 mmol) in n-hexane. React at -78 degrees Celsius for half an hour. Add N,N-dimethylformamide (0.5 ml) and react at -78 degrees Celsius for half an hour. Quench with saturated aqueous ammonium chloride solution (5 ml). Extract with dichloromethane (5 ml × 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%).

[0800] 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

[0801] 8-Formyl-2,3-dihydro-1,4-benzodioxazine-5-carbonitrile (35 mg, 0.185 mmol), 2-cyanoethyl-3-oxobutyrate (29 mg, 0.185 mmol), 4-amino-5-methylpyridin-2-ol (23 mg, 0.185 mmol), isopropanol (0.6 ml) and acetic acid (12 μl) were added to an 8 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 4 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by C18 reverse phase column chromatography under the following conditions (C18 BIOTAGE 40 g reverse phase column, mobile phase A (0.1% ammonium bicarbonate aqueous solution) and mobile phase B (acetonitrile), gradient 25% B to 30% B in 15 minutes, monitoring wavelength 254 nm), and a light yellow solid (15 mg, yield 18.8%) was obtained.

[0802] MS (ESI) M / Z: 433.2 [M+H] +

[0803] 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

[0804] 2-Cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-hydroxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (15 mg, 0.035 mmol), iodoethane (8 mg, 0.053 mmol), silver carbonate (10 mg, 0.035 mmol) and 1,4-dioxane (0.3 ml) were added to an 8 ml single-mouth bottle at room temperature. After nitrogen replacement, the reaction was carried out at 90 degrees Celsius for 1 hour. Cool to room temperature. Filter by suction, rinse with acetonitrile (3 ml), obtain the filtrate, and concentrate under reduced pressure to obtain a yellow solid (15 mg, crude product), which was directly used in the next step without further purification.

[0805] MS (ESI) M / Z: 461.3 [M+H] +

[0806] 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

[0807] 2-Cyanoethyl 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylate (15 mg, 0.033 mmol), ethylene glycol dimethyl ether (0.45 ml) and an aqueous solution (0.15 ml) of sodium hydroxide (3 mg, 0.066 mmol) were added to an 8 ml single-mouth bottle at room temperature. The reaction was allowed to proceed for 1 hour at room temperature. Under ice bath, hydrochloric acid solution (1.0 mol / L) was added to quench and adjust to pH = 5. Extracted with ethyl acetate (5 ml × 3 times), the organic phases were combined, washed with saturated brine (5 ml × 3 times), and dried over anhydrous sodium sulfate. Filtered and concentrated under reduced pressure to obtain a light yellow solid (10 mg, crude product), which was used directly in the next reaction without further purification.

[0808] LCMS (ESI, m / z): 408.1 [M+H] +

[0809] 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

[0810] 4-(8-cyano-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxylic acid (10 mg, 0.025 mmol), N,N-diisopropylethylamine (6 mg, 0.049 mmol), N,N-dimethylformamide (0.3 ml) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14 mg, 0.038 mmol) were added to an 8 ml vial at room temperature. The reaction was allowed to proceed for half an hour at room temperature. Ammonia aqueous solution (25%) (0.1 ml) was added to the reaction solution at room temperature. The reaction was allowed to proceed for 1 hour at room temperature. The reaction solution was purified by preparative high performance liquid chromatography. Purification conditions are 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% in 10 minutes; detection wavelength: 254 / 220 nm. The product was collected and lyophilized under reduced pressure to obtain a white solid (1.1 mg, yield 11.0%).

[0811] MS (ESI) M / Z: 407.30 [M+H] +

[0812] 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).

[0813] Preparation of chiral compounds:

[0814] Example 32 & 33

[0815] (S)-4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 32 and

[0816] (R)-4-(5-cyanocyanine-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 33

[0817]

[0818] 4-(5-Cyanine red-8-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide (56 mg, 0.138 mmol) (Compound 6) was separated by chiral separation, and the separation conditions were as follows: (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 for 15 minutes; wavelength: 208 / 258 nm; 33 elution time: 8.80 minutes; 32 elution time: 12.0 minutes; sample solution: ethanol; injection volume: 0.8 ml; number of injection needles: 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.

[0819] 32LCMS (ESI, m / z): 405.25 [M+H] +

[0820] 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).

[0821] 33LCMS (ESI, m / z): 405.25 [M+H] +

[0822] 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).

[0823] Example 36 & 37

[0824] (S)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 36

[0825] (R)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 37

[0826]

[0827] 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: CHIRALART 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 concentration of ammonia 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 20% B for 15 minutes; UV detector for detection, wavelength: 218 / 270 nm; 36 peak time: 9.47 minutes; 37 peak time: 11.2 minutes; sample solution: ethanol solution of compound 11, compound 11 concentration is 8.9 mg / mL; injection volume: 0.5 ml; injection needle number: 9. Two enantiomers monomer 37: white solid (7.5 mg, yield 18.8%) and monomer 36: white solid (9.3 mg, yield 23.3%) were obtained.

[0828] 36LCMS (ESI, m / z): 391.10 [M+H] +

[0829] 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).

[0830] 37LCMS (ESI, m / z): 391.10 [M+H] +

[0831] 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).

[0832] Example 38 & 39

[0833] (S)-6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 38

[0834] (R)-6-(4-cyano-2-methoxyphenyl)-5-ethoxy-8-methyl-6,9-dihydrothieno[3,2-h][1,6]naphthyridine-7-carboxamide 39

[0835]

[0836] 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. Separation conditions: (chiral column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: n-hexane (10 mmol / L ammonia in methanol), mobile phase B: ethanol; flow rate: 20 ml / min; gradient: 10% B for 34.5 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%).

[0837] 38MS (ESI) M / Z: 421.00 [M+H] +

[0838] 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).

[0839] 39MS (ESI) M / Z: 421.05 [M+H] +

[0840] 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).

[0841] Embodiment 40 & 41

[0842] (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

[0843] (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

[0844]

[0845] 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 are 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; 41 peak time: 10.22 minutes; 40 peak time: 16.14 minutes; sample solution: ethanol: dichloromethane = 1:1; injection volume: 0.5 ml; injection needle number: 3. Enantiomer monomer 41 (10.8 mg, white solid, yield 33.7%) and enantiomer monomer 40 (9.8 mg, white solid, yield 30.6%) were obtained.

[0846] 40: MS (ESI) M / Z: 407.30 [M+H] +

[0847] 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).

[0848] 41: MS (ESI) M / Z: 407.30 [M+H] +

[0849] 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).

[0850] Example 46 & 47

[0851] (S)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 46

[0852] (R)-4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-(difluoromethoxy)-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 47

[0853]

[0854] 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 chiral resolved (resolution conditions were as follows: Chiral column: CHIRAL ART Cellulose-SZ, 3*25 cm, 5 μm; mobile phase A: n-hexane (2 mmol ammonia in methanol), mobile phase B: ethanol; flow rate: 40 ml / min; gradient: 20% B to 20% B in 23 min; wavelength: 207 / 236 nm; (47) peak time: 11.6 min; (46) peak time: 20.3 min; sample solution: methanol: dichloromethane = 1:1; injection volume: 0.2 ml; injection needle number: 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%)

[0855] 46: MS (ESI) M / Z: 413.05 [M+H] +

[0856] 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).

[0857] 19F NMR (282MHz, CDCl3) δ-87.2,-90.2.

[0858] 47: MS (ESI) M / Z: 413.05 [M+H] +

[0859] 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).

[0860] 19F NMR (282MHz, CDCl3) δ-87.2,-90.2.

[0861] Example 48 & 49

[0862] (S) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 48

[0863] (R) 4-(4-cyano-2,3-dihydrobenzofuran-7-yl)-5-cyclopropyloxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 49

[0864]

[0865] 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 chiral separated (separation conditions were as follows: chiral column: CHIRALART 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; injection needle number: 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%)

[0866] 48:LCMS(ESI)M / Z:403.20[M+H] +

[0867] 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).

[0868] 49:LCMS(ESI)M / Z:403.20[M+H] +

[0869] 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).

[0870] Example 62 & 63

[0871] (R)-4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 63

[0872] (S)-4-(7-cyanobenzo[d][1,3]dioxol-4-yl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide 62

[0873]

[0874] 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 um; 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, and 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 by 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%).

[0875] 62:LCMS(ESI)M / Z:393.1[M+H] +

[0876] 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).

[0877] 63:LCMS(ESI)M / Z:393.1[M+H] +

[0878] 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).

[0879] Other racemic examples in this application are resolved by similar means.

[0880] Single crystal X-ray diffraction analysis

[0881] Single crystal X-ray diffraction analysis of compound 36

[0882] About 5 mg of compound 36 was dissolved in 0.6 mL of acetone at room temperature, and then 1.4 mL of water was gradually added. The filtrate was filtered into a clean vial, covered with a pinhole film, and slowly evaporated at room temperature. After 1 day, a block single crystal was generated. The obtained single crystal was used for single crystal X-ray diffraction, such as Fig. 9 shown.

[0883] 36 crystallizes in the monoclinic form in the C2 space group with the chemical formula C 22 H 22 N4O3. There is one 36 molecule in each asymmetric unit, and the unit cell contains four asymmetric units. Figure 1 As shown, the chiral carbon of C10 is determined to be in "S" configuration. The position of the terminal ethyl group is disordered.

[0884] The single crystal structure after refinement is as follows Figure 2 and Figure 3 (For clarity, the main conformation and hydrogen atoms are omitted). The crystal structure data are summarized in Table 2, and the detailed information of atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds, torsion angles and atomic occupancies are shown in Tables 3 to 10. The XRPD pattern calculated from the single crystal structure (above) is consistent with the experimental pattern (below) ( Figure 4 ).

[0885] Table 2 Crystal data and structural refinement of compound 36

[0886]

[0887] Table 3 Fractional atomic coordinates of compound 36 (×10 4 ) and equivalent isotropic displacement parameter

[0888] Atom x y z U(eq) O1 5598.3(7) 7323.4(16) 2415.6(16) 40.3(4) O2 6551.3(8) 8603(2) -853.4(16) 52.5(5) O3 7008.4(7) 6525(2) 5083.5(15) 45.4(4) N1 4786.8(13) 1056(3) 1548(3) 69.4(7) N2 6078.2(10) 8909(3) 550.6(19) 47.1(5) N3 8006.3(8) 6131(2) 2080.7(17) 39.1(4) N4 8025.3(8) 5611(2) 5878.4(16) 38.5(4) C1 6408.3(8) 5702(2) 2201.2(17) 27.8(4) C2 6546.6(9) 4203(2) 1959.5(19) 32.9(4) C3 6127.8(10) 3011(2) 1753(2) 38.8(5) C4 5538.3(10) 3304(2) 1772(2) 37.4(5) C5 5379.3(9) 4780(2) 1978(2) 36.3(5) C6 4787.7(11) 5459(3) 2001(3) 53.1(6) C7 5004.1(10) 7049(3) 2550(3) 52.4(6) C8 5814.0(9) 5932(2) 2197.9(18) 31.3(4) C9 5112.1(11) 2057(3) 1637(2) 48.0(5) C10 6904.6(8) 6949(2) 2508.4(17) 27.0(4) C11 7021.4(9) 7387(2) 1268.1(18) 30.2(4) C12 6544.6(9) 8333(2) 244.2(19) 35.0(4) C13 7535.8(9) 6892(3) 1091.8(19) 35.9(4) C14 7688.9(13) 7122(4) -112(2) 57.9(7) C15 8018.1(9) 5964(2) 3345.7(18) 31.1(4) C16 7500.8(8) 6389(2) 3597.2(18) 27.6(4) C17 7533.9(9) 6162(2) 4892.2(19) 32.0(4) C18 8523.3(10) 5251(3) 5591(2) 39.8(5) C19 8556.0(9) 5384(2) 4372(2) 36.4(4) C20 9134.7(11) 4958(4) 4141(3) 58.6(7) C21A 6947(9) 6260(30) 6319(17) 61(2) C21B 7011(12) 6080(40) 6340(20) 61(2) C22A 6454(6) 5055(14) 6100(12) 97(3) C22B 6345(8) 5840(20) 6176(18) 97(3)

[0889] U(eq) is defined as one third of the orthogonalized Uij tensor trajectory.

[0890] Table 4 Anisotropic displacement parameters of compound 36

[0891]

[0892]

[0893] The anisotropic displacement factor exponent is -2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0894] Table 5 Bond lengths of compound 36

[0895]

[0896]

[0897] Table 6 Bond angles of compound 36

[0898] Atom Atom Atom Angle / ° Atom Atom Atom Angle / ° C8 O1 C7 107.03(16) C12 C11 C10 118.21(16) C17 O3 C21A 122.2(8) C13 C11 C10 120.99(16) C17 O3 C21B 114.7(12) C13 C11 C12 120.78(17) C13 N3 C15 122.79(16) O2 C12 N2 119.03(19) C17 N4 C18 116.20(17) O2 C12 C11 123.9(2) C2 C1 C10 120.22(16) N2 C12 C11 117.11(17) C8 C1 C2 115.76(17) N3 C13 C14 111.69(18) C8 C1 C10 123.96(17) C11 C13 N3 121.22(16) C3 C2 C1 122.67(18) C11 C13 C14 127.05(19) C2 C3 C4 119.21(19) N3 C15 C19 120.27(17) C3 C4 C9 119.7(2) C16 C15 N3 119.28(17) C5 C4 C3 119.74(18) C16 C15 C19 120.45(17) C5 C4 C9 120.5(2) C15 C16 C10 121.92(16) C4 C5 C6 132.24(19) C15 C16 C17 116.79(17) C8 C5 C4 119.16(18) C17 C16 C10 121.10(16) C8 C5 C6 108.59(19) O3 C17 C16 115.01(17) C5 C6 C7 101.74(17) N4 C17 O3 120.25(17) O1 C7 C6 106.91(19) N4 C17 C16 124.72(18) O1 C8 C1 123.76(17) N4 C18 C19 125.65(19) O1 C8 C5 112.81(17) C15 C19 C20 121.79(19) C5 C8 C1 123.43(18) C18 C19 C15 116.15(18) N1 C9 C4 178.5(3) C18 C19 C20 122.05(19) C1 C10 C11 111.11(14) O3 C21A C22A 108.1(13) C16 C10 C1 108.82(15) O3 C21B C22B 107.4(17) C16 C10 C11 110.94(15)

[0899] Table 7 Hydrogen bonds of compound 36

[0900]

[0901] 1 1-x,1+y,-z; 2 3 / 2-x,-1 / 2+y,-z

[0902] Table 8 Torsion angle of compound 36

[0903] A B C D Angle / ° A B C D Angle / ° N3 C15 C16 C10 3.5(3) C10 C1 C8 O1 2.9(3) N3 C15 C16 C17 178.62(17) C10 C1 C8 C5 -176.97(17) N3 C15 C19 C18 -179.62(19) C10 C11 C12 O2 -171.2(2) N3 C15 C19 C20 1.2(3) C10 C11 C12 N2 8.3(3) N4 C18 C19 C15 0.6(3) C10 C11 C13 N3 -7.6(3) N4 C18 C19 C20 179.7(2) C10 C11 C13 C14 174.9(2) C1 C2 C3 C4 0.6(3) C10 C16 C17 O3 -1.9(3) C1 C10 C11 C12 74.8(2) C10 C16 C17 N4 176.72(18) C1 C10 C11 C13 -103.5(2) C11 C10 C16 C15 -15.7(2) C1 C10 C16 C15 106.82(19) C11 C10 C16 C17 169.41(17) C1 C10 C16 C17 -68.1(2) C12 C11 C13 N3 174.2(2) C2 C1 C8 O1 -179.97(18) C12 C11 C13 C14 -3.3(4) C2 C1 C8 C5 0.2(3) C13 N3 C15 C16 9.1(3) C2 C1 C10 C11 72.2(2) C13 N3 C15 C19 -170.2(2) C2 C1 C10 C16 -50.2(2) C13 C11 C12 O2 7.1(3) C2 C3 C4 C5 0.9(3) C13 C11 C12 N2 -173.5(2) C2 C3 C4 C9 -176.32(19) C15 N3 C13 C11 -7.0(3) C3 C4 C5 C6 177.4(2) C15 N3 C13 C14 170.9(2) C3 C4 C5 C8 -1.8(3) C15 C16 C17 O3 -177.07(17) C4 C5 C6 C7 169.2(2) C15 C16 C17 N4 1.6(3) C4 C5 C8 O1 -178.57(18) C16 C10 C11 C12 -164.03(16) C4 C5 C8 C1 1.3(3) C16 C10 C11 C13 17.7(3) C5 C6 C7 O1 16.5(3) C16 C15 C19 C18 1.1(3) C6 C5 C8 O1 2.0(2) C16 C15 C19 C20 -178.0(2) C6 C5 C8 C1 -178.09(19) C17 O3 C21A C22A -113.5(12) C7 O1 C8 C1 -170.83(19) C17 O3 C21B C22B -152.9(16) C7 O1 C8 C5 9.0(2) C17 N4 C18 C19 -1.2(3) C8 O1 C7 C6 -16.2(3) C18 N4 C17 O3 178.60(19) C8 C1 C2 C3 -1.1(3) C18 N4 C17 C16 0.0(3) C8 C1 C10 C11 -110.78(18) C19 C15 C16 C10 -177.20(18) C8 C1 C10 C16 126.79(18) C19 C15 C16 C17 -2.1(3) C8 C5 C6 C7 -11.5(3) C21A O3 C17 N4 -3.4(11) C9 C4 C5 C6 -5.4(4) C21A O3 C17 C16 175.3(11) C9 C4 C5 C8 175.38(18) C21B O3 C17 N4 -7.5(15) C10 C1 C2 C3 176.12(17) C21B O3 C17 C16 171.2(15)

[0904] Table 9 Hydrogen atom coordinates of compound 36 and isotropic displacement parameters

[0905]

[0906]

[0907] Table 10 Atomic occupancy of compound 36

[0908] Atom Occupancy Atom Occupancy Atom Occupancy C21A 0.584(14) H21A 0.584(14) H21B 0.584(14) C21B 0.416(14) H21C 0.416(14) H21D 0.416(14) C22A 0.584(14) H22A 0.584(14) H22B 0.584(14) H22C 0.584(14) C22B 0.416(14) H22D 0.416(14) H22E 0.416(14) H22F 0.416(14)

[0909] Single crystal X-ray diffraction analysis of compound 62

[0910] About 5 mg of compound 62 was dissolved in 0.1 mL of ethanol at room temperature, and then 0.35 mL of n-heptane was gradually added. After filtering, it was put into a clean sample bottle, and the filtrate was covered with a pinhole membrane and slowly evaporated under ambient conditions. After 1 day, a block single crystal was generated, and the obtained single crystal was used for single crystal X-ray diffraction, such as Fig.10 shown.

[0911] 62 crystallizes in the monoclinic form in the C2 space group with the chemical formula C21 H 20 N4O4. There are two 62 molecules in each asymmetric unit, and the unit cell contains four asymmetric units. Figure 5 As shown, the chiral carbon of C9 (C30) was determined to be in the "S" configuration.

[0912] The single crystal structure after refinement is as follows Figure 6 and Figure 7 (for clarity, hydrogen atoms are omitted). The crystal structure data are summarized in Table 11, and the detailed information of atomic coordinates, anisotropic displacement parameters, bond lengths and angles, hydrogen bonds and torsion angles are shown in Tables 12 to 18. The XRPD pattern calculated from the single crystal structure is consistent with the experimental pattern ( Figure 8 ).

[0913] Table 11 Crystal data and structure optimization of compound 62

[0914]

[0915] Table 12 Fractional atomic coordinates of compound 62 (×10 4 ) and equivalent isotropic displacement parameter

[0916]

[0917]

[0918]

[0919] U(eq)is defined as one third of the trace of the orthogonalized U ij tensor.

[0920] Table 13 Anisotropic displacement parameters of compound 62

[0921]

[0922]

[0923] The anisotropic displacement factor exponent takes the form:-2π 2 [h 2 a* 2 U 11 +2hka*b*U 12 +…].

[0924] Table 14 Bond length of compound 62

[0925]

[0926]

[0927] Table 15 Bond angles of compound 62

[0928]

[0929]

[0930] Table 16 Hydrogen bonds of compound 62

[0931]

[0932] 1 1-x,-1+y,-z; 2 3 / 2-x,-1 / 2+y,-z; 3 2-x,-1+y,1-z

[0933] Table 17 Torsion angle of compound 62

[0934]

[0935]

[0936] Table 18 Hydrogen atom coordinates of compound 62 and isotropic displacement parameters

[0937]

[0938]

[0939] Example In vitro activity test

[0940] 1. Experimental principle:

[0941] Taking advantage of the chemiluminescent reaction of luciferase binding to substrate, the plasmid containing the Gal4DNA binding domain (DBD) fused with the mineralocorticoid receptor (MR) ligand binding domain (LBD) and the firefly luciferase reporter gene plasmid under the control of Gal4UAS (upstream activation sequence) was transfected into human embryonic kidney cells (HEK293). The change of mineralocorticoid receptor activity before and after stimulation or the effect of different stimulations on mineralocorticoid receptor activity was judged by the level of firefly luciferase activity.

[0942] 2. Experimental methods:

[0943] 1. Preparation and handling of compounds

[0944] 1.1 Preparation of DMSO stock solutions of compounds

[0945] All compounds were dissolved in DMSO to prepare 25 mM stock solutions, which were stored in a -20°C refrigerator.

[0946] 1.2 Preparation of working solution

[0947] 1) The test compound was diluted 3-fold with DMSO, with 10 concentration gradients, starting at 10 mM.

[0948] 2) The positive compound (Finerenone) was diluted 3-fold with DMSO, with 10 concentration gradients and a starting concentration of 1 mM.

[0949] 3) Prepare 1000× positive control (1 mM, Finerenone) and 1000× negative control (100% DMSO).

[0950] 4) Block the compound plate and shake for 5 minutes.

[0951] 2. Preparation of Cell Suspension

[0952] 1) All cells were cultured according to ATCC standard operations, and HEK293T cells were used for experiments in the exponential growth phase.

[0953] 2) Gently discard the culture supernatant and wash the cells twice with PBS.

[0954] 3) Digest the cells with trypsin solution, terminate the digestion with complete medium, collect the cells and count them.

[0955] 4) Seed 6X106 HEK293T cells into a 100 mm cell culture dish.

[0956] 5) Place the culture dish seeded with cells in a 37°C, 5% CO2 incubator and culture overnight for 16 hours.

[0957] 3. Cell Transfection

[0958] 1) 3000&P3000 transfection reagent placed at room temperature

[0959] 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, being careful not to touch the tube wall.

[0960] 3) Mix well with a pipette and let stand at room temperature for 5 minutes.

[0961] 4) Add the plasmid to the diluted transfection reagent, mix well with a pipette and let stand at room temperature for 20 minutes.

[0962] 5) Add the transfection reagent mixed with the plasmid into a 60 mm cell culture dish.

[0963] 6) Place the culture dish in a 37°C, 5% CO2 incubator for 5-6 hours.

[0964] 4. Compound treatment

[0965] 1) Use Echo655 to transfer 25 nL of the diluted compound to the cell culture plate.

[0966] 2) Seed the cells (see step 1.3) into a 384 cell culture plate, with 17,000 cells per well, and 25 μL of phenol red-free DMEM medium containing 5% CFBS and 0.8 nM Aldosteron.

[0967] 3) The cell culture plate was cultured overnight in a 37°C, 5% CO2 incubator for 18-20 hours.

[0968] 5. Compound Detection

[0969] 1) Place the Britelite plus detection reagent at room temperature.

[0970] 2) Place the 384-cell plate at room temperature.

[0971] 3) Add 25 μL of Britelite plus detection reagent to each well of the cell culture plate.

[0972] 4) Detect the luminescence value using Envision.

[0973] 6. Result processing:

[0974] 1) Obtain firefly luciferase signal by reading Luminescence and calculate inhibition rate;

[0975] 2) % inhibition rate = 100-[(RLU compound-avgRLU positive control) / (RLU negative control-avgRLU positive control) × 100%, where avgRLU positive control is the average Luminescence value of all positive control wells on the whole plate; avgRLU negative control is the average Luminescence value of all negative control wells on the whole plate; RLU compound is the Luminescence value of the test compound at different concentrations;

[0976] 3) Calculate the IC50 of the compound using Graphpad8.0 software;

[0977] 7. Experimental results:

[0978] Table 19 In vitro activity data of the compounds of the present invention

[0979]

[0980]

[0981] in conclusion:

[0982] 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.

[0983] Example Test rat drug metabolism kinetics study

[0984] This experiment is designed to evaluate the pharmacokinetic behavior of the test compound after intravenous injection or oral administration in rats. Intravenous administration: the test compound is prepared into a 0.2 mg / ml clear solution, the solvent is 10% ethanol, 40% polyethylene glycol 400 and 50% water, and plasma is collected at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration; oral administration: the test compound is prepared into a 1 mg / ml clear solution, the solvent is 10% ethanol / 40% polyethylene glycol 400 / 50% water, and plasma is collected at 0.25h, 0.5h, 1h, 2h, 4h, 8h and 24h after administration.

[0985] The concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention time of the compound and internal standard, chromatogram acquisition and chromatogram integration were processed by software Analyst (Applied Biosystems), and the statistics of the data were processed by software Analyst (Applied Biosystems).

[0986] Plasma concentrations were treated with 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.

[0987] 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.

[0988] Table 20 SD rat pharmacokinetic (PK) data

[0989]

[0990] It can be seen from the experimental results in Table 20 that the compounds of the present invention have good in vivo pharmacokinetic properties.

[0991] Example Test Mouse Pharmacokinetic Study

[0992] This experiment aims to evaluate the pharmacokinetic behavior of the compound after intravenous or oral administration in mice. Intravenous administration: The test compound was prepared into a 0.2 mg / ml clear solution in a solvent of 10% ethanol / 40% polyethylene glycol 400 / 50% ultrapure water, and plasma was collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h after administration.

[0993] The concentration of the test compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). The retention time of the compound and internal standard, chromatogram acquisition and chromatogram integration were processed by software Analyst (Applied Biosystems), and the statistics of the data were processed by software Analyst (Applied Biosystems).

[0994] Plasma concentrations were treated with 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.

[0995] The pharmacokinetic parameters of the compound in mice at a dose of 1 mg / kg after intravenous injection are shown in Table 21 below.

[0996] Table 21CD1 mouse pharmacokinetic (PK) data

[0997]

[0998] Pharmacodynamic effects of Example compounds 36 and 62 on diabetic nephropathy mouse model

[0999] 1. Research objectives

[1000] The pharmacodynamic effects of compounds 36 and 62 on the diabetic nephropathy mouse model were evaluated.

[1001] 2. Drug preparation

[1002] The solvent and positive drug need to be prepared on the same day as shown in Table 22.

[1003] Table 22 Drug preparation

[1004]

[1005]

[1006] 3. Experimental animals and feeding management

[1007] 3.1 Experimental animals

[1008] Strain: C57BL / 6 mice, KK-Ay mice

[1009] Age: Animals are 6-8 weeks old, experiments start at 7-9 weeks old

[1010] Gender: Male

[1011] Body weight: C57BL / 6 mice 21-23g, KK-Ay mice 25-30g

[1012] Number: 72 experimental animals

[1013] 3.2 Animal husbandry

[1014] 3.2.1 Quarantine

[1015] The quarantine and acclimatization period lasted for 7 days, routine health examinations were performed by a veterinarian, and animals showing abnormal performance were culled before the experiment.

[1016] 3.2.2 Animal rearing conditions

[1017] The experimental animals were kept in a SPF-level constant temperature and humidity laminar clean room at the Animal Center of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. (AAALAC certified unit) and kept in single cages. The temperature in the breeding room was 22-25℃, the humidity was 40-80%, and the light was alternated between light and dark for 12 hours. The cages were made of polycarbonate. The soft corn cob was sterilized and cleaned by high pressure and changed twice a week. The drinking water was sterilized by high pressure and the food was irradiated with cobalt 60 rays. The animals could freely take sterile food and drinking water.

[1018] 3.2.3 Animal number

[1019] Each cage has a cage label indicating the number of animals, sex, strain, receipt time, group, and start time of the experiment. Each animal is marked with an individual animal number at the tail.

[1020] 4. Experimental Animal Grouping and Drug Administration

[1021] 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.

[1022] Table 23 Experimental animal grouping and drug administration

[1023]

[1024]

[1025] 7 Experimental methods and test indicators

[1026] 7.1 Urine Collection

[1027] Before the start of the experiment and at 2, 4, 6, and 8 weeks after modeling, the urine of mice was collected in metabolic cages for 24 hours, and the urine was tested for the contents of urine microalbumin (MALB) and creatinine (CREA) by CANON TBA-120FR automatic blood biochemistry. (MALB / CREA) was calculated.

[1028] 7.2 Insulin content and serum ion detection

[1029] 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 4°C and 6000g for 15 min. 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.

[1030] 7.3 Tissue Collection

[1031] After the experiment, 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.

[1032] 8. Statistics

[1033] 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.

[1034] 9. Results

[1035] 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.

[1036] Example In vitro CPY enzyme inhibition studies

[1037] 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.

[1038] Therefore, compared with finerenone, compounds 36 and 62 have higher safety.Compound 36 and finerenone have higher half-maximal inhibition concentrations for two subtypes of enzymes CYP3A4-5M / CYP3A4-5T, the main metabolizing enzyme CYP3A4 in the human body (the metabolizing enzyme metabolizes about 50% of the drug).

[1039] Screening of Crystalline Forms of Example Compound Salts

[1040] It is well known to those skilled in the art that the above-mentioned example compounds 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 physical and chemical properties of the salt forms and crystal forms of the corresponding compounds, but the preparation and characterization of the following specific salt forms or crystal forms do not represent a limitation on the scope of protection of the present invention. Those skilled in the art can obtain more salt forms and crystals of the compounds of the present invention based on the present invention through conventional salt formation or crystallization methods, and these salt forms and crystals are all solutions protected by the present invention. Specifically as follows:

[1041] 1 Experimental Purpose

[1042] The purpose of this experiment is to select a suitable crystallization method and screen the above-mentioned salt crystal form based on the above-mentioned crystal form research results of the salt of compound 36.

[1043] 2 Preparation method

[1044] 2.1 Preparation of twelve acid solutions

[1045] 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 acid solutions with a concentration of 0.1 M. Solutions of other concentrations and other solvents can also be prepared according to experimental requirements, or can be used directly.

[1046] 2.3 Preparation of Compound 36 Salt Crystalline Form

[1047] The following methods were used to prepare various salts on a scale of approximately 25 mg. The general experimental steps are as follows.

[1048] An appropriate amount of compound 36 free base is added to a certain amount of solvent at room temperature; then, 1.1 or 0.55 eq. of acid is added to form a salt. If no precipitation occurs, other crystallization methods are tried to prepare crystalline salts, such as pulping, volatilization or anti-solvent precipitation crystallization. The obtained solid sample is filtered, dried and then characterized accordingly.

[1049] 2.3.1 Preparation of Hydrochloride Form I

[1050] 25.86 mg of compound 36 free base was added with 0.5 mL of acetonitrile at room temperature; then, 1.1 eq. of 6M hydrochloric acid aqueous solution was added to carry out salt formation reaction. A viscous substance was obtained at the beginning of the reaction, and 0.2 mL of acetonitrile was added. After stirring overnight, the solid was collected and vacuum dried at 50°C overnight to obtain hydrochloride crystal form I. After detection and analysis, it has the following characteristics: Fig.11 The XRPD pattern shown; Fig.12 The DSC diagram shown and Fig.13 TGA graph shown.

[1051] 2.3.2 Preparation of Hydrochloride Form II

[1052] 25.94 mg of compound 36 free base was added with 0.5 mL of ethyl acetate at room temperature; then, 1.1 eq. of 6M hydrochloric acid aqueous solution was added and stirred at room temperature overnight to obtain a viscous substance. After stirring at room temperature for 6 days, the obtained solid was collected by filtration and dried under vacuum at 50°C for 6 hours to obtain hydrochloride crystal form II. After detection and analysis, it has the following characteristics: Fig.14 The XRPD pattern shown; Fig.15 The DSC diagram shown and Fig.16 TGA graph shown.

[1053] 2.3.3 Preparation of Sulfate Form I

[1054] 24.6 mg of compound 36 free base was added with 0.5 mL of acetone at room temperature; then, 0.55 eq. of 6M sulfuric acid methanol solution was added. After the addition of acid, the reaction solution became clear. 40 times the volume of n-heptane was added and stirred at room temperature for 5 h. The obtained solid was filtered and dried under vacuum at 50°C overnight to obtain sulfate salt form I. It has the following characteristics: Fig.17 The XRPD pattern shown; Fig.18 The DSC diagram shown and Fig.19 TGA graph shown.

[1055] 2.3.4 Preparation of p-toluenesulfonate Form I

[1056] 26.83 mg of compound 36 free base was added with 0.5 mL of acetonitrile at room temperature; then, 1.1 eq. of p-toluenesulfonic acid (100 mg / mL p-toluenesulfonic acid ethanol solution) was added. 2 hours after the addition of acid at room temperature, the reaction solution was still clear. Then, 600 μL of ethyl acetate was added. After stirring overnight, the solid was filtered and dried under vacuum at 50°C overnight. The p-toluenesulfonate salt Form I was obtained.

[1057] Alternatively, 26.83 mg of compound 36 free base was added with 0.5 mL of ethanol at room temperature, followed by 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 was formed. Subsequently, 200 μL of ethanol was added. After stirring overnight, the solid sample was collected by filtration and dried in vacuum at 50°C overnight. The p-toluenesulfonate salt form I was obtained, and the NMR was as follows: Fig.45 As shown. It has Fig. 20 The XRPD pattern shown; Fig.21 The DSC diagram shown and Fig. 22 TGA graph shown.

[1058] 2.3.5 Preparation of p-toluenesulfonate Form II

[1059] 24.83 mg of compound 36 free base was added with 0.5 mL of methyl tert-butyl ether at room temperature; then, 1.1 eq. of p-toluenesulfonic acid (100 mg / mL p-toluenesulfonic acid ethanol solution) was added. After adding the acid at room temperature, a viscous substance was obtained. The obtained viscous substance was stirred at room temperature overnight, filtered, and dried under vacuum at 50°C for 5 h to obtain p-toluenesulfonate salt Form II. The NMR was as follows: Fig.46 As shown. It has Fig.23 The XRPD pattern shown; Fig.24 The DSC diagram shown and Fig.25 TGA graph shown.

[1060] The p-toluenesulfonate salt form II has a high degree of crystallinity, and a DVS test was performed on it.

[1061] The DVS test of p-toluenesulfonate Form II was conducted using a two-cycle method starting from the current ambient humidity. The results showed that when the relative humidity was <30% RH, the sample would dehydrate; however, the XRPD pattern of the sample did not change after the DVS test, which may be due to the sample absorbing water again. Fig.26 The DVS diagram shown.

[1062] 2.3.6 Preparation of Methanesulfonate Form I

[1063] 26.9 mg of compound 36 free base was added with 0.5 mL of ethanol at room temperature; then, 1.1 eq. of methanesulfonic acid was added. The reaction solution was still clear 2 hours after the addition of the acid, and 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 mesylate salt form I. The NMR was as follows: Fig.47 As shown. It has Fig. 27 The XRPD pattern shown; Fig.28 The DSC diagram shown and Fig.29 TGA graph shown.

[1064] 2.3.7 Preparation of benzenesulfonate salt form I

[1065] 20.39 mg of compound 36 free base was added with 0.5 mL of butanone at room temperature; then, 1.1 eq. of benzenesulfonic acid was added. After the addition of the acid, a clear solution was obtained; after stirring for 1 hour, a precipitate was precipitated. The obtained solid was stirred at room temperature overnight, collected by filtration, and dried in vacuo at 50°C for 5 hours to obtain benzenesulfonate salt form I. The NMR was as follows: Fig.44 As shown. It has Fig.30 The XRPD pattern shown; Fig.31 The DSC diagram shown and Fig.32 The TGA graph is shown in Figure 2. The DVS test is performed on it and the following results are obtained: Fig.33 The DVS diagram shown.

[1066] 2.3.8 Preparation of Phosphate Form I

[1067] 22.95 mg of compound 36 free base was added with 0.5 mL of acetonitrile at room temperature; then, 1.1 eq. 4.9 M phosphoric acid in dry methanol was added. After adding the acid at room temperature, a viscous substance was obtained. After stirring for 2 days, the solid was collected by filtration, and the solid was dried and filtered at 50° C. to obtain phosphate crystal form I. It has the following characteristics: Fig.34 The XRPD pattern shown; Fig.35 The DSC diagram shown and Fig.36 TGA graph shown.

[1068] 2.4 Preparation of free base and solvate crystalline forms of compound 36

[1069] 2.4.1 Preparation of Free Base Form I

[1070] At room temperature, 177.42 mg of compound 36 was dissolved in 4 mL of methanol, filtered, and 300 μL of the sample solution was taken into an 8 mL vial. The sample solution was added dropwise to 0.9 mL of water while stirring. After stirring overnight, the solid was collected by filtration and dried under vacuum at 50° C. overnight to obtain free base crystal form I. It has the following characteristics: Fig.37 The XRPD pattern shown; Fig.38The DSC diagram shown and Fig.39 The TGA graph is shown in Figure 2. The DVS test is performed on it and the following results are obtained: Fig.40 The DVS diagram shown.

[1071] 2.4.2 Preparation method of compound 36 crystal form II

[1072] Weigh 24.49 mg of compound 36 into 0.42 mL of dichloromethane, add 1.1 eq of maleic acid (100 mg / mL dissolved in ethanol), add the acid until the reaction solution is clear, add 1 mL of methyl tert-butyl ether, stir for 2 days, collect the solid by filtration, and dry overnight at 50°C in vacuum. Fig.41 The XRPD pattern shown; Fig.42 The DSC diagram shown and Fig.43 TGA graph shown.

[1073] 2.5 Crystallinity and dehydration temperature test of compound 36 salt

[1074] The experiment obtained crystalline hydrochloride, sulfate, p-toluenesulfonate, methanesulfonate, benzenesulfonate and phosphate, but the obtained salt samples were hydrates or solvates; the experiment also obtained crystalline free base crystal form I, which is an anhydrous crystal form; and free base crystal form II, which is a dichloromethane solvate. The characterization results of the free base and crystalline salts are summarized in the table below.

[1075] The crystallinity was determined by comparing different XRPD patterns, and the dehydration temperature was determined by combining DSC, TGA and DVS. Benzenesulfonate Form I had relatively good solid state properties, high crystallinity and dehydration temperature, and was selected as the dominant salt form.

[1076] Table 24 Summary data

[1077]

[1078]

[1079] Note: The stoichiometric ratios of hydrochloride, sulfate and phosphate have not been determined; 1 / 1 represents the molar ratio of base and acid in salt formation, which is determined by NMR integration.

[1080] 2.6 Solubility experiment of compound 36 salt crystal

[1081] 15 mg of free base crystal form I and benzenesulfonate crystal form I were weighed separately and added to 3 mL of biological medium (artificial gastric juice SGF, artificial gastric juice FaSSIF under fasting, artificial gastric juice FeSSIF under feeding). The sample was shaken at 200 rpm in a shaker at 37 ° C. Samples were taken and filtered at 0.5 h, 2 h, and 24 h. The filtrate was tested for HPLC and pH, and the solid was tested for XRPD. The results are shown in the table below.

[1082] The free base form I and the benzenesulfonate salt form I both have high solubility in SGF, >5 mg / mL; and the solubility in FeSSIF and FaSSIF is lower, at 0.0002-0.13 mg / mL.

[1083] During the solubility test, the free base form I did not change its form in FeSSIF and FaSSIF within 24 hours, but the benzenesulfonate salt form I was converted into the free base form I within 0.5 hours in FeSSIF and FaSSIF.

[1084] In summary, compared with the free base form I, the benzenesulfonate salt form I dissociates rapidly in FeSSIF and FaSSIF, and the solubility is not significantly improved.

[1085] Table 25 Solubility and pH value of free base crystal form I and benzenesulfonate crystal form I in biological media

[1086]

[1087]

[1088] 2.7 Stability test of the crystal form of compound 36 salt

[1089] The stability of the free base form I and benzenesulfonate salt form I of compound 36 was determined under the conditions of 60°C (closed), 40°C / 75%RH (open) and RT / 92.5%RH (open) for seven days. All results are shown in Table 26.

[1090] The physical and chemical properties of the free base Form I were stable at 60°C, 40°C / 75%RH and RT / 92.5%RH for 7 days. The benzenesulfonate Form I did not change its crystalline form under the three test conditions, but the impurity with an RRT of 1.78 at RT / 92.5%RH for 7 days increased by 0.16%.

[1091] Table 26 Stability results of free base crystal form I and benzenesulfonate crystal form I

[1092]

[1093] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[1094] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.

Claims

1. A crystal of a compound and a salt thereof, characterized in that: Selected from compounds shown in formula I: 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.

2. The crystal of the compound and its salt according to claim 1, characterized in that: The compound is compound 36, and its structural formula is as follows:

3. The crystal of the compound and its salt according to claim 2, 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.

4. The crystal of the compound and its salt according to claim 2, 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%.

5. The crystal of the compound and its salt according to claim 2, characterized in that: The crystalline form of compound 36 is a free base crystalline form; preferably, the free base crystalline form is a free base crystalline form I; preferably, the X-ray diffraction spectrum of the free base crystalline form and the free base crystalline form I comprises a diffraction peak at 2θ of 9.35±0.2°, preferably comprises a diffraction peak at 2θ of 8.16±0.2°, 9.35±0.2°, 12.80±0.2°, 21.92±0.2°, 22.10±0.2°, Diffraction peak at 24.38±0.2°; preferably, the X-ray diffraction pattern of the free base crystal form is shown in Figure 37.

6. The crystal of the compound and its salt according to claim 1, characterized in that: is the acid salt of compound 36; 7. The crystal of the compound and its salt according to claim 6, characterized in that: 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.

8. The crystal of the compound and its salt according to claim 6, characterized in that: 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, further preferably 1.

9. The crystal of the compound and its salt according to any one of claims 6 to 8, characterized in that: The acid salt is a non-solvate or a solvate; the solvent is selected from 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, One or more of 1,2-dioxane, benzene or toluene.

10. The crystal of the compound and its salt according to claim 9, characterized in that: 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, further preferably 1.

11. The crystal of the compound and the salt thereof according to any one of claims 6 to 10, characterized in that: 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 spectrum of the benzenesulfonate crystalline form and the benzenesulfonate crystalline form I comprises a diffraction peak with 2θ at 17.31±0.2°, preferably including a diffraction peak with 2θ at 4.28±0.2°, Diffraction peaks at 17.31±0.2° and 26.12±0.2°; Preferably, the X-ray diffraction pattern of the benzenesulfonate salt form I is shown in Figure 30.

12. The crystal of the compound and its salt according to claim 1, characterized in that: The compound is compound 62, and its structural formula is as follows:

13. The crystal of the compound and its salt according to claim 12, 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 in the unit cell is Z=8.

14. The crystal of the compound and its salt according to claim 12, characterized in that: The crystals or crystalline forms of the compound 62 have an XRPD spectrum as shown in FIG8 or substantially as shown in FIG8 , wherein substantially means that the difference in the number of peaks is within 85%.

15. Use of the crystal of the compound or salt thereof according to any one of claims 1 to 14 in the preparation of medicines, characterized in that: 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.

16. Use of the crystal of the compound or salt thereof according to any one of claims 1 to 14 in the preparation of a drug, characterized in that: The drug acts as a mineralocorticoid receptor antagonist.

17. A high performance liquid chromatography method for resolving crystals of the compound according to any one of claims 2 to 5 or 12 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; 18. The method according to claim 17, characterized in that: The concentration of compound 11 in the sample was 6.9- 10.9 mg / mL, preferably 7.9-9.9 mg / mL, preferably 8.9 mg / mL; preferably, the concentration of compound 14 in the sample compound is 15-35 mg / mL, preferably 20-30 mg / mL, preferably 25 mg / mL; Preferably, 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 CHIRALART Cellulose-SB; preferably, when the compound is compound 62, the chromatographic column is CHIRAL ARTAmylose-C NEO; Preferably, 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; Preferably, 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%; Preferably, the flow rate is 16-24 mL / min, preferably 18-22 mL / min, preferably 20 mL / min; Preferably, 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 212-226nm, preferably 216-222nm, preferably 218nm, and the second wavelength is 262-278nm, preferably 266-274nm, preferably 270nm; preferably, when splitting the crystals of compound 62, the first wavelength is 208-222nm, preferably 212-218nm, preferably 214nm, and the second wavelength is 246-262nm, preferably 250-258nm, preferably 254nm; Preferably, when the compound is compound 36, the chromatographic conditions are: Chromatographic column: Chiral column CHIRAL ART Cellulose-SB, 2*25cm, 5μm; Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol, the concentration of ammonia is 10mmol / L n-hexane, and the volume ratio of alcohol to n-hexane is 1:4; Mobile phase B: ethanol; Flow rate: 20 mL / min; Isocratic elution: 20 vt% mobile phase B and 80 vt% mobile phase A; Elution time: 15min; Wavelength: 218 / 270nm; Preferably, when the compound is compound 62, the chromatographic conditions are: Chromatographic column: Chiral column CHIRAL ART Amylose-C NEO; Mobile phase A: a mixed solution of n-hexane, ammonia and alcohol, the concentration of ammonia is 10mmol / L n-hexane, and the volume ratio of alcohol to n-hexane is 1:9; Mobile phase B: ethanol; Flow rate: 20 mL / min; Isocratic elution: 10 vt% mobile phase B and 90 vt% mobile phase A; Elution time: 28min; Wavelength: 214 / 254nm.

19. A pharmaceutical preparation, characterized in that Contains compound 36 and / or compound 62 or their salts, crystals thereof, and pharmaceutically acceptable excipients.

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