Dihydroquinoline-2-ketone derivative and application thereof

Abstract

The invention belongs to the technical field of chemical drugs, and provides a dihydroquinoline-2-ketone derivative and application thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and provides a dihydroquinoline-2-one derivative, a preparation method thereof, and a medical use thereof. Background Art

[0002] Aldosterone is a steroid hormone with mineralocorticoid activity. It is mainly produced by the adrenal zona glomerulosa in response to angiotensin II, adrenocorticotropic hormone, and increased serum potassium content. The main physiological role of aldosterone in the kidney is to maintain sodium and potassium balance by regulating cation exchange (Na+ reabsorption and K+ secretion) in the distal renal unit. However, aldosterone has also been shown to be a pro-inflammatory and profibrotic hormone in blood vessels, the heart, and the kidney. The effect of aldosterone on gene expression is regulated by binding to the mineralocorticoid receptor (MR) and the classical nuclear hormone receptor pathway.

[0003] CYP11B2 (aldosterone synthase) is a cytochrome P450 enzyme and is known as the enzyme that catalyzes a series of reactions from 11-deoxycorticosterone (i.e., the aldosterone precursor) to aldosterone. CYP11B2 is mainly expressed in the adrenal zona glomerulosa, and the aldosterone in plasma is regulated by the activity of this enzyme in the adrenal gland. In addition, the expression of aldosterone has also been confirmed in parts outside the adrenal gland such as the cardiovascular system, kidney, adipose tissue, and brain, and the finding that aldosterone locally produced in each organ is related to organ dysfunction has attracted attention. It has been reported that CYP11B2 inhibitors can inhibit the production of aldosterone in studies using enzymes and cultured cells, and have the effect of inhibiting aldosterone production and therapeutic effects in studies using various experimental animal models. In addition, it has been confirmed that CYP11B2 inhibitors show the effects of reducing the levels of aldosterone in plasma and urine and antihypertensive effects in patients with hypertension and primary aldosteronism. Finding a means to block the aldosterone biosynthesis pathway is a highly feasible solution for establishing effective treatment methods for various diseases related to aldosterone.

[0004] Currently, there have been reports on aldosterone synthase (CYP11B2) inhibitors. For example, patent application CN103827101B reports a bicyclic dihydroquinoline-2-one derivative. Although this compound has good CYP11B2 inhibitory activity, its selectivity is poor;

[0005] CN114853755A also reports an aldosterone synthase inhibitor, but this compound is a chiral compound and is relatively difficult to synthesize. In addition, it has relatively large side effects. In addition, existing CYP11B2 inhibitors also have problems such as poor activity, difficult synthesis, poor stability, and low bioavailability. Therefore, there is an urgent need to provide more CYP11B2 inhibitors. Summary of the Invention

[0006] In view of the problems existing in the prior art, the present invention provides a dihydroquinolin-2-one derivative and its use to solve the problems existing in the prior art.

[0007] The present invention is achieved by the following technical solutions:

[0008] The present invention provides a dihydroquinolin-2-one derivative, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, wherein the structure of the dihydroquinolin-2-one derivative is shown in general formula I:

[0009]

[0010] Wherein, R1 is selected from: H or C1-C8 alkyl; R2 is selected from: H, C1-C8 alkyl, halogenated C1-C8 alkyl or halogen; R3 is selected from: H, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl or halogen; R4 is selected from: H or halogen;

[0011] X, Y, Z or W are each independently selected from N or CR5;

[0012] R5 is selected from: H, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkoxy, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted 3-8 membered heterocycloalkoxy, substituted or unsubstituted C6-C 12 aryl, substituted C6-C 12 aryloxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted 5-12 membered heteroaryloxy;

[0013] The substituents in the substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C3-C8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-C 12 aryl, substituted 5-12 membered heteroaryl, substituted C3-C8 cycloalkoxy, substituted 3-8 membered heterocycloalkoxy, substituted C6-C 12 aryloxy or substituted 5-12 membered heteroaryloxy are each independently selected from: C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, -NR6R7, hydroxy, oxo, carboxy, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamide, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C3-C8 cycloalkyl-substituted C1-C8 alkoxy, C6-C 12 aryl, C6-C 12 aryloxy, C1-C8 alkyl-substituted C6-C12 aryloxy, C6-C substituted with C1-C8 alkoxy 12 aryloxy, C6-C substituted with halogenated C1-C8 alkyl 12 aryloxy, 5- to 12-membered heteroaryl, 5- to 12-membered heteroaryloxy, 5- to 12-membered heteroaryloxy substituted with C1-C8 alkyl, 5- to 12-membered heteroaryloxy substituted with C1-C8 alkoxy, 5- to 12-membered heteroaryloxy substituted with halogenated C1-C8 alkyl, or one or more of halogens;

[0014] Both R6 and R7 are independently selected from: H or C1-C8 alkyl;

[0015] m or q is independently selected from integers of 0, 1 or 2; n or p are both independently selected from integers of 0, 1, 2 or 3.

[0016] Further, as a preferred technical solution of the present invention, R1 is selected from: H or C1-C6 alkyl; R2 is selected from: H, C1-C6 alkyl, halogenated C1-C6 alkyl or halogen; R3 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkyl or halogen; R4 is selected from: H or halogen;

[0017] X, Y, Z or W are all independently selected from N or CR5;

[0018] R5 is selected from: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkoxy, substituted or unsubstituted 3- to 8-membered heterocycloalkyl, substituted 3- to 8-membered heterocycloalkoxy, substituted or unsubstituted C6-C 10 aryl, substituted C6-C 10 aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryloxy;

[0019] The substituents in the substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C8 cycloalkyl, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C 10 aryl, substituted 5- to 10-membered heteroaryl, substituted C3-C8 cycloalkoxy, substituted 3- to 8-membered heterocycloalkoxy, substituted C6-C 10 aryloxy or substituted 5- to 10-membered heteroaryloxy are all independently selected from: C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, -NR6R7, hydroxy, oxo, carboxyl, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamide, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyloxy, C6-C12 Aryl, C6-C 12 One or more of aryloxy, 5- to 12-membered heteroaryl, 5- to 12-membered heteroaryloxy or halogen;

[0020] Both R6 and R7 are independently selected from: H or C1-C6 alkyl;

[0021] m or q is independently selected from the integers 0, 1 or 2; n or p are both independently selected from the integers 0, 1, 2 or 3.

[0022] Further, as a preferred technical solution of the present invention, R1 is selected from C1-C3 alkyl; R2 is selected from H, C1-C3 alkyl, halo C1-C3 alkyl or halogen; R3 is selected from H, C1-C3 alkyl, C1-C3 alkoxy, halo C1-C3 alkyl or halogen; R4 is selected from H or halogen;

[0023] X, Y, Z or W are each independently selected from N or CR5;

[0024] R5 is selected from: H, halogen, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkoxy, substituted or unsubstituted 3- to 6-membered heterocycloalkyl, substituted 3- to 6-membered heterocycloalkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted C6-C 10 Aryloxy, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted 5- to 10-membered heteroaryloxy;

[0025] The substituents in the substituted C1-C3 alkyl, substituted C1-C3 alkoxy, substituted C3-C6 cycloalkyl, substituted 3- to 6-membered heterocycloalkyl, substituted C6-C 10 Aryl, substituted 5- to 10-membered heteroaryl, substituted C3-C6 cycloalkoxy, substituted 3- to 6-membered heterocycloalkoxy, substituted C6-C 10 The substituents in aryloxy or substituted 5- to 10-membered heteroaryloxy are each independently selected from: C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, -NR6R7, hydroxy, oxo, carboxy, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamido, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkyloxy, C6-C 10 Aryl, C6-C 10 One or more of aryloxy, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryloxy or halogen;

[0026] Both R6 and R7 are independently selected from: H or C1-C3 alkyl;

[0027] m or q is independently selected from an integer of 0, 1 or 2; n or p is independently selected from an integer of 0, 1, 2 or 3.

[0028] Furthermore, the present invention also provides a dihydroquinolin-2-one derivative, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the dihydroquinolin-2-one derivative is shown in General Formula II:

[0029]

[0030] wherein X, Y, Z or W is independently selected from N or CR5;

[0031] R5 is selected from: H, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkoxy, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted 3-8 membered heterocycloalkoxy, substituted or unsubstituted C6-C 12 aryl, substituted C6-C 12 aryloxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted 5-12 membered heteroaryloxy;

[0032] The substituents in the substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C3-C8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-C 12 aryl, substituted 5-12 membered heteroaryl, substituted C3-C8 cycloalkoxy, substituted 3-8 membered heterocycloalkoxy, substituted C6-C 12 aryloxy or substituted 5-12 membered heteroaryloxy are independently selected from: C1-C8 alkyl, halo C1-C8 alkyl, C1-C8 alkoxy, halo C1-C8 alkoxy, -NR6R7, hydroxy, oxo, carboxyl, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamide, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C3-C8 cycloalkyl substituted C1-C8 alkoxy, C6-C 12 aryl, C6-C 12 aryloxy, C1-C8 alkyl substituted C6-C 12 aryloxy, C1-C8 alkoxy substituted C6-C 12 aryloxy, halo C1-C8 alkyl substituted C6-C 12One or more of aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, C1-C8 alkyl substituted 5-12 membered heteroaryloxy, C1-C8 alkoxy substituted 5-12 membered heteroaryloxy, halo C1-C8 alkyl substituted 5-12 membered heteroaryloxy or halogen;

[0033] Both R6 and R7 are independently selected from: H or C1-C8 alkyl;

[0034] m or q is independently selected from an integer of 0, 1 or 2; n or p are both independently selected from an integer of 0, 1, 2 or 3.

[0035] Further, as a preferred technical solution of the present invention, X, Y, Z or W are all independently selected from N or CR5;

[0036] R5 is selected from: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkoxy, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted 3-8 membered heterocycloalkoxy, substituted or unsubstituted C6-C 10 aryl, substituted C6-C 10 aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryloxy;

[0037] The substituents in the substituted C1-C6 alkyl, substituted C1-C6 alkoxy, substituted C3-C8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-C 10 aryl, substituted 5-10 membered heteroaryl, substituted C3-C8 cycloalkoxy, substituted 3-8 membered heterocycloalkoxy, substituted C6-C 10 aryloxy or substituted 5-10 membered heteroaryloxy are all independently selected from: C1-C8 alkyl, halo C1-C8 alkyl, C1-C8 alkoxy, halo C1-C8 alkoxy, -NR6R7, hydroxy, oxo, carboxy, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamido, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C6-C 12 aryl, C6-C 12 aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy or halogen;

[0038] Both R6 and R7 are independently selected from: H or C1-C6 alkyl.

[0039] Furthermore, the present invention also provides a dihydroquinolin-2-one derivative, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the dihydroquinolin-2-one derivative is as shown in general formula IIA or IIB:

[0040] The definitions of X, Y, Z or W are the same as those defined above.

[0041] Furthermore, as a preferred technical solution of the present invention, X, Y, Z or W are each independently selected from N or CR5; R5 is selected from: H, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, 2-hydroxyethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halocyclobutyl, halocyclopentyl, halocyclohexyl, methoxyethyl, 2-methoxypropyl, acetamidoethyl, carboxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl, sulfolanyl, 1,1-dioxotetrahydro-2H-thiopyranyl, cyclopropylmethyl, cyclobutylmethyl, 1,1,1-trifluoropropan-2-yl, piperidinyl, N-methylsulfonylpiperidinyl, N-ethylsulfonylpiperidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, N-methylpyrazolyl, N-methylimidazolyl, pyrazinyl, methoxypyrazinyl, pyridinyl, pyrimidinyl, pyrimidin-2-yloxyethyl, indol-3-ylmethyl, indol-2-ylmethyl, α-methylbenzyl, 5-methylisoxazolyl, methylpyrazinyl, 3-chloropyridinyl, indazolyl, phenyl; more preferably, R5 is selected from: H, halogen, methyl, ethyl, trifluoromethyl, methoxy.

[0042] As a preferred technical solution of the present invention, the methylpyrazinyl is selected from:

[0043] As a preferred technical solution of the present invention, the methylpyrazinyl is selected from:

[0044] As a preferred technical solution of the present invention, the 1,1-dioxotetrahydro-2H-thiopyranyl is selected from:

[0045] As a preferred technical solution of the present invention, the N-methylpyrazolyl is selected from:

[0046] As a preferred technical solution of the present invention, the N-methylimidazolyl is selected from:

[0047] As a preferred technical solution of the present invention, the pyrimidinyl group is selected from:

[0048] As a preferred technical solution of the present invention, the indazolyl group is selected from indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl;

[0049] As a preferred technical solution of the present invention, the methylisoxazolyl group is selected from 5-methylisoxazolyl, 4-methylisoxazolyl or 3-methylisoxazolyl; more preferably 5-methylisoxazol-3-yl, 5-methylisoxazol-4-yl;

[0050] As a preferred technical solution of the present invention, the C 1- alkyl group of C8 is preferably C 1- alkyl group of C2, C 1- alkyl group of C3, C 1- alkyl group of C4, C 1- alkyl group of C5 or C 1- alkyl group of C6; examples of the alkyl group include: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, 1-ethylpropyl, 2-methylbutyl, tert-pentyl, 1,2-dimethylpropyl, isopentyl, neopentyl, n-hexyl, isohexyl, sec-hexyl, tert-hexyl, neohexyl, 2-methylpentyl, 1,2-dimethylbutyl, 1-ethylbutyl.

[0051] As a preferred technical solution of the present invention, the C 1- alkoxy group of C8 is preferably C 1- alkoxy group of C2, C 1- alkoxy group of C3, C 1- alkoxy group of C4, C 1- alkoxy group of C5 or C 1- alkoxy group of C6. Further, examples of the alkoxy group include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0052] As a preferred technical solution of the present invention, the C 3- cycloalkyl group of C8 is preferably selected from: C 3- cycloalkyl group of C6 or C 3- cycloalkyl group of C5, and the cycloalkyl group is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0053] As a preferred technical solution of the present invention, the C 3- cycloalkoxy group of C8 is preferably selected from: C 3- cycloalkoxy group of C6 or C 3- cycloalkoxy group of C5, and the cycloalkyl group is specifically selected from cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0054] As a preferred technical solution of the present invention, the heterocyclic alkyl group is selected from 3- to 12-membered heterocyclic alkyl groups, preferably: 3- to 10-membered heterocyclic alkyl groups, 3- to 8-membered heterocyclic alkyl groups, 3- to 6-membered heterocyclic alkyl groups or 3- to 5-membered heterocyclic alkyl groups. Examples of the heterocyclic alkyl group include: aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazepanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl and 2,6-diaza-spiro[3.3]heptyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl, or dihydropyranyl; preferred examples of the heterocyclic alkyl group are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazepanyl and 2,6-diaza-spiro[3.3]heptyl. More preferred examples of the heterocyclic alkyl group are pyrrolidinyl, piperidinyl, thiomorpholinyl, thiazepanyl and 2,6-diaza-spiro[3.3]heptyl.

[0055] As a preferred technical solution of the present invention, the C 1- C8 haloalkyl or halo-C 1- C8 alkyl, preferably halo-C 1- C2, C 1- C3, C 1- C4, C 1- C5 or C 1- C6 alkyl or C 1- C2, C 1- C3, C 1- C4, C 1- C5 or C 1- C6 haloalkyl. Examples of the haloalkyl group include: fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl. Particular haloalkyl groups are trifluoromethyl and trifluoroethyl.

[0056] As a preferred embodiment of the present invention, the substituted or unsubstituted C6-C12 Aryl is preferably: substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C6-C8 aryl, substituted or unsubstituted C6-C 12 aryl. Examples of the substituted or unsubstituted aryl include: phenyl, o-tolyl, m-tolyl, p-tolyl, phenolyl, xylyl, chlorophenyl, dichlorophenyl, nitrophenyl, cyanophenyl or naphthyl.

[0057] As a preferred embodiment of the present invention, the substituted or unsubstituted 3- to 12-membered heteroaryl is preferably: substituted or unsubstituted 3- to 10-membered heteroaryl, substituted or unsubstituted 3- to 8-membered heteroaryl, substituted or unsubstituted 5- to 8-membered heteroaryl, substituted or unsubstituted 5- to 7-membered heteroaryl, substituted or unsubstituted 5- to 6-membered heteroaryl. Examples of the substituted or unsubstituted heteroaryl include: pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuryl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particular heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl. More particular heteroaryls include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, indazolyl, isoxazolyl and isothiazolyl.

[0058] As a preferred technical solution of the present invention, the halogen is selected from fluorine, chlorine, bromine and iodine.

[0059] As a preferred technical solution of the present invention, the dihydroquinolin-2-one derivatives, or their isomers, or their racemates, or their pharmaceutically acceptable salts are selected from:

[0060]

[0061]

[0062]

[0063] The present invention further provides a method for preparing a dihydroquinolin-2-one derivative, or its isomer, or its racemate, or its pharmaceutically acceptable salt, which is prepared with reference to Patent CN103827101B and conventional methods in the art.

[0064] The present invention further provides a pharmaceutical composition, which is characterized by comprising a dihydroquinoline-2-one derivative represented by General Formula I, General Formula II, General Formula IIA or General Formula IIB, or an isomer, or a racemate or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0065] The present invention further provides the use of a dihydroquinoline-2-one derivative, or an isomer, or a racemate or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a drug for treating or preventing a related disease caused by an elevated CYP11B2 activity level.

[0066] As a preferred technical solution of the present invention, the related diseases caused by an elevated CYP11B2 activity level are selected from: hypertension, etc.

[0067] The beneficial effects of the present invention relative to the prior art include but are not limited to:

[0068] Compared with the prior art, the dihydroquinoline-2-one derivative of the present invention can selectively inhibit CYP11B2, while weakly inhibiting CYP11B1, and has better CYP11B2 inhibitory activity.

[0069] For clarity, general terms used in the description of the compounds are defined herein.

[0070] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood in accordance with its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding commodity or its active ingredient. The term "pharmaceutically acceptable" used herein refers to those compounds, materials, compositions and / or dosage forms that are within the scope of reliable medical judgment, suitable for contact with human and animal tissues, without excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0071] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, prepared from a compound having specific substituents found in the present invention and a pharmaceutically acceptable acid or base.

[0072] In addition to the salt form, the compounds provided by the present invention also exist in prodrug forms. The prodrugs of the compounds described herein are readily chemically changed under physiological conditions to convert into the compounds of the present invention. In addition, the prodrug can be converted into the compounds of the present invention by chemical or biochemical methods in the in vivo environment.

[0073] Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrate forms. Generally, the solvated forms are equivalent to the unsolvated forms and are all included within the scope of the present invention.

[0074] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomer- or diastereoisomer-enriched mixtures, all of which mixtures are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and their mixtures are included within the scope of the present invention.

[0075] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereoisomer mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), diastereoisomeric salts are formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (such as formation of carbamates from amines).

[0076] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups having from 1 to 20 carbon atoms. Alkyl groups preferably contain from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof, etc.

[0077] The term "haloalkyl" means that at least one of the hydrogen atoms of the alkyl group has been replaced by the same or different halogen atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, and pentafluoroethyl. Particular haloalkyl groups are trifluoromethyl and trifluoroethyl.

[0078] The term "alkoxy" means -O-(alkyl), where alkyl is defined as above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. Particular alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0079] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0080] The term "haloalkoxy" means an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group has been replaced by the same or different halogen atoms. The term "perhaloalkoxy" means an alkoxy group in which all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethyl ethoxy, trifluorodimethyl ethoxy, and pentafluoroethoxy. Particular haloalkoxy groups are trifluoromethoxy and 2,2-difluoroethoxy.

[0081] The term "cycloalkyl" or "carbocyclic" means a saturated monocyclic or polycyclic hydrocarbon substituent, where the cycloalkyl ring contains from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; polycyclic cycloalkyl includes spiro, fused, and bridged cycloalkyl.

[0082] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic system of 3 to 8 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyls are aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, and thiazepanyl. Examples of bicyclic saturated heterocycloalkyls are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, and 2,6-diaza-spiro[3.3]heptyl. Examples of partially unsaturated heterocycloalkyls are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. More particular examples of heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazepanyl, and 2,6-diaza-spiro[3.3]heptyl. More particular examples of heterocycloalkyl are pyrrolidinyl, piperidinyl, thiomorpholinyl, thiazepanyl, and 2,6-diaza-spiro[3.3]heptyl.

[0083] The term "halocycloalkyl" refers to a cycloalkyl in which at least one of the hydrogen atoms of the cycloalkyl has been replaced by the same or different halogen atoms, particularly a fluorine atom. Examples of halocycloalkyls include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl, and difluorocyclobutyl.

[0084] The term "C 1- C6 alkylsulfonyl" means that 1 H atom on the C 1- C6 alkyl is replaced by a sulfonyl group, such as: mesyl, ethylsulfonyl, etc.;

[0085] The term "C 1- C6 alkylamido" means that 1 H atom on the C 1- C6 alkyl is replaced by an amido group, such as: formamido, acetamido, etc.;

[0086] The term "aryl" or "aromatic ring" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 8-membered, such as phenyl and naphthyl.

[0087] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 3 heteroatoms and 5 to 10 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 8-membered, more preferably 5- or 6-membered. Pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuryl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl. Particular heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl, and isothiazolyl. More particular heteroaryls include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl, and isothiazolyl.

[0088] The term "heterocyclic group" refers to a saturated, partially unsaturated or fully unsaturated 3- to 12-membered monocyclic or polycyclic heterocycle containing at least 1 carbon atom and 1, 2, 3 or 4 heteroatoms, where the heteroatoms are independently selected from N, O or S; examples of the heterocyclic group include: pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuryl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxalinyl. Particular heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl. More particular heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazepanyl, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl and 2,6-diaza-spiro[3.3]heptyl, dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridyl, dihydropyranyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuryl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazolyl and quinoxalinyl.

[0089] The term "heteroalkyl" means that one or more heteroatoms can be inserted in the middle of the alkyl chain, where the alkyl group and the heteroatom have the meanings as described in the present invention. Unless otherwise specified in detail, the heteroalkyl group contains 1-10 carbon atoms (C1-C 10 heteroalkyl), in some other embodiments, the heteroalkyl group contains 1-8 carbon atoms (C1-C8 heteroalkyl), in some other embodiments, the heteroalkyl group contains 1-6 carbon atoms (C1-C6 heteroalkyl), in some other embodiments, the heteroalkyl group contains 1-4 carbon atoms (C1-C4 heteroalkyl), in some other embodiments, the heteroalkyl group contains 1-3 carbon atoms (C1-C3 heteroalkyl). Such examples include, but are not limited to, CH3OCH2-, CH3CH2OCH2-, CH3SCH2-, CH3SCH2CH2-, (CH3)2NCH2-, (CH3)2CH2OCH2-, CH3OCH2CH2-, CH3CH2OCH2CH2-, etc.

[0090] The term "cycloalkyloxy" or "cyclic alkoxy" refers to cycloalkyl-O-, where the cycloalkyl is defined as above.

[0091] The term "heterocyclyloxy" or "heterocyclic alkoxy" refers to heterocyclyl-O-, where the heterocyclyl is defined as above.

[0092] The term "aryloxy" or "aromatic oxy" refers to aryl-O-, where the aryl is defined as above.

[0093] The term "heteroaryloxy" or "heteroaromatic oxy" refers to heteroaryl-O-, where the heteroaryl is defined as above.

[0094] The atoms of the compounds of the present invention are isotopes, and usually can achieve effects such as prolonging the half-life, reducing the clearance rate, metabolic stability and enhancing the in vivo activity through isotope derivatization. And, there is included an embodiment in which at least one atom is replaced by an atom having the same number of atoms (proton number) and different mass numbers (sum of protons and neutrons). Examples of the isotopes included in the compounds of the present invention include hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, phosphorus atoms, sulfur atoms, fluorine atoms, chlorine atoms, which respectively include 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl. In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or14 C can be used for the local anatomical examination of pharmaceutical preparations or in-vivo compounds. Stable isotopes neither decay or change in quantity nor are radioactive, so they can be used safely. When the atoms constituting the compound molecules of the present invention are isotopes, the isotopes can be transformed according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0095] The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compounds. For example, the compounds can be labeled with radioactive isotopes such as deuterium ( 2 H), iodine-125 ( 125 I) or C-14 ( 14 C). All transformations of the isotopic compositions of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

[0096] Furthermore, one or more hydrogen atoms of the compounds of the present invention are replaced by the isotope deuterium (2H). After the compounds of the present invention are deuterated, they have effects such as extended half-life, reduced clearance rate, metabolic stability and increased in-vivo activity.

[0097] The preparation methods of the isotopic derivatives generally include: phase transfer catalysis methods. For example, a preferred deuteration method uses a phase transfer catalyst (for example, tetraalkylammonium salts, NBu4HSO4). Using a phase transfer catalyst to exchange the methylene protons of diphenylmethane compounds results in a higher deuterium introduction than reduction with deuterosilane (such as triethyl deuterosilane) in the presence of an acid (such as methanesulfonic acid) or reduction with sodium borohydride using a Lewis acid such as aluminum trichloride.

[0098] The term "pharmaceutically acceptable carrier" refers to any preparation carrier or medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance and is non-toxic and side-effect-free to the host or patient. Representative carriers include water, oils, vegetables and minerals, paste bases, lotion bases, ointment bases, etc. These bases include suspending agents, thickening agents, transdermal promoters, etc. Their preparations are well-known to those skilled in the art of the cosmetics field or the local drug field. For other information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the content of which is incorporated herein by reference.

[0099] The term "excipient" generally refers to the carriers, diluents and / or media required for formulating an effective pharmaceutical composition.

[0100] For a drug or a pharmacological active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. For the oral dosage forms in the present invention, the "effective amount" of an active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in a particular case can be determined by those skilled in the art according to routine tests.

[0101] The terms "active ingredient", "therapeutic agent", "active substance" or "active agent" refer to a chemical entity that can effectively treat a target disorder, disease or condition.

[0102] "Optionally" or "optionally" means that the subsequently described event or condition may but does not necessarily occur, and this description includes the case where the described event or condition occurs and the case where the described event or condition does not occur. Detailed Description of the Invention

[0103] The present invention will be further described in detail below in conjunction with the embodiments, but the content of the invention is not limited to the embodiments.

[0104] Example 1

[0105] Synthesis of (R)-1-methyl-6-(8-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0106]

[0107] The specific synthesis route is as follows:

[0108] Step A: Synthesis of ethyl 5-bromo-4-methylnicotinate

[0109]

[0110] Dissolve 5-bromo-4-methylnicotinic acid (50.0 g, 231.45 mmol) and iodoethane (39.7 g, 254.59 mmol) in 500 mL of N,N-dimethylformamide, add potassium bicarbonate (46.3 g, 462.90 mmol), degas the mixed solution and protect it with nitrogen, and stir the reaction at room temperature for 12 hours.

[0111] After the reaction was completed, the mixture was filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate (300 mL × 3 times). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n - hexane = 1 / 10) to obtain 54.6 g of ethyl 5 - bromo - 4 - methylnicotinate. [M+H] + = 244.05.

[0112] Step B: Synthesis of methyl 4 - bromo - 8 - oxo - 5,6,7,8 - tetrahydroisoquinoline - 7 - carboxylate

[0113]

[0114] At - 78 °C, LDA (123 mL, 246.06 mmol, 2 M) was added dropwise to a solution of ethyl 5 - bromo - 4 - methylnicotinate (54.6 g, 223.69 mmol) in tetrahydrofuran (500 mL). The mixture was stirred for 30 minutes, and then a solution of methyl acrylate (48.1 g, 559.22 mmol) in tetrahydrofuran (200 mL) was added dropwise. The mixture was stirred at - 78 °C for an additional 2 hours.

[0115] After the reaction was completed, 400 mL of 10% aqueous acetic acid solution was added to the mixture to quench the reaction. The organic solvent was removed by rotary evaporation. The mixture was extracted with ethyl acetate (300 mL × 3 times). The organic phases were combined, washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n - hexane = 1 / 10) to obtain 31.5 g of methyl 4 - bromo - 8 - oxo - 5,6,7,8 - tetrahydroisoquinoline - 7 - carboxylate. [M+H] + = 284.06.

[0116] Step C: Synthesis of 4 - bromo - 6,7 - dihydroisoquinolin - 8(5H) - one

[0117]

[0118] 4 - Bromo - 8 - oxo - 5,6,7,8 - tetrahydroisoquinoline - 7 - carboxylate (31.5 g, 110.87 mmol) was dissolved in 300 mL of hydrochloric acid (6 M). The mixture was heated to 105 °C and refluxed with stirring for 16 hours.

[0119] After the reaction was completed, the solvent was removed by rotary evaporation. 300 mL of water was added, and the pH was adjusted to ~9 with 1N aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (200 mL × 3 times), and the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n - hexane = 1 / 8) to obtain 19.6 g of 4 - bromo - 6,7 - dihydroisoquinolin - 8(5H) - one. [M+H] + = 226.05.

[0120] Step D: Synthesis of (rac) - 4 - bromo - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol

[0121]

[0122] Sodium borohydride (3.94 g, 104.04 mmol) was added portionwise to a solution of 4 - bromo - 6,7 - dihydroisoquinolin - 8(5H) - one (19.6 g, 86.70 mmol) in methanol (200 mL) at 0 °C, and the mixture was stirred at 0 °C for an additional 20 minutes.

[0123] After the reaction was completed, the reaction was quenched by the addition of 50 mL of water, the solvent was removed by rotary evaporation, 300 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (300 mL × 3 times). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 10) to obtain 19.4 g of (rac) - 4 - bromo - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol. [M+H] + = 228.02.

[0124] Step E: Synthesis of (R) - 4 - (1 - methyl - 2 - oxo - 1,2,3,4 - tetrahydroquinolin - 6 - yl) - 5,6,7,8 - tetrahydroisoquinolin - 8 - ol

[0125]

[0126] (±)-4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-ol (4.81 g, 21.09 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (7.3 g, 25.31 mmol) were dissolved in a mixed solvent of 100 mL of dioxane and 20 mL of water. Cesium carbonate (13.7 g, 42.18 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.05 mmol) were added. The mixture was protected by nitrogen and reacted at 85 °C for 6 h. After the reaction was completed, the resulting suspension was filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 30) to give 5.7 g of (±)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol, [M+H] + = 309.11, 1 1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.20 (s, 1H), 7.29–7.22 (m, 2H), 7.17 (d, J = 8.6 Hz, 1H), 5.36 (d, J = 5.6 Hz, 1H), 4.74 (q, J = 5.5 Hz, 1H), 3.30 (s, 3H), 2.92 (t, J = 8.6 Hz, 2H), 2.69–2.55 (m, 4H), 1.94–1.72 (m, 3H).

[0127] The intermediate (±)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol was separated by supercritical fluid chromatography (SFC, Daicel Chiralpak AY 250*30 mm, 10 μm column, 27.5% ethanol isocratic elution method, flow rate 150 g / min), and the enantiomers were eluted successively (R T 1 = 5.20 min, R T 2 = 6.45 min), R T 1: (R)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol ([M+H] + = 309.13) and R T 2: (S)-4-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol ([M+H] + = 309.13).

[0128] Step F: Synthesis of (S)-6-(8-chloro-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0129]

[0130] Under an ice bath, (R)-6-(8-hydroxy-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (665 mg, 2.16 mmol), triethylamine (436 mg, 4.32 mmol) and 4-dimethylaminopyridine (132 mg, 1.08 mmol) were dissolved in dichloromethane (30 mL) solution. p-Nitrobenzenesulfonyl chloride (718 mg, 3.24 mmol) was slowly added, and stirring was continued for 2 hours. The reaction was monitored by LCMS until completion.

[0131] Water (30 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mL × 3 times). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 9 / 1) to obtain 512 mg of (S)-6-(8-chloro-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 327.10.

[0132] Step G: Synthesis of (R)-1-methyl-6-(8-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0133]

[0134] At room temperature, (S)-6-(8-chloro-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.31 mmol), pyridin-2(1H)-one (58 mg, 0.61 mmol) and cesium carbonate (199 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (3 mL) solution. The temperature was raised to 60 °C and stirring was continued for 5 hours. The reaction was monitored by LCMS until completion.

[0135] Add water (10 mL) to the reaction solution, extract with ethyl acetate (10 mL × 3 times), combine the organic phases, wash with saturated brine (10 mL × 3 times), then dry over anhydrous sodium sulfate, and finally concentrate under reduced pressure. The resulting residue was prepared by high performance liquid chromatography to obtain 31 mg of (R)-1-methyl-6-(8-(2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 386.11. NMR data: 1 1H NMR (500 MHz, DMSO-d6) δ 8.24 (s, 1H), 7.91 (s, 1H), 7.44 (ddd, J = 8.9, 6.5, 2.0 Hz, 1H), 7.39 (dd, J = 7.0, 2.0 Hz, 1H), 7.34–7.29 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 6.50–6.46 (m, 1H), 6.23 (td, J = 6.7, 1.4 Hz, 1H), 6.18 (t, J = 7.5 Hz, 1H), 3.30 (s, 3H), 2.94–2.91 (m, 2H), 2.89–2.83 (m, 1H), 2.66–2.61 (m, 1H), 2.60–2.56 (m, 2H), 2.11–2.08 (m, 1H), 2.05–1.98 (m, 1H), 1.87–1.84 (m, 1H), 1.76–1.71 (m, 1H).

[0136] Example 2

[0137] Synthesis of (R)-1-methyl-6-(8-(4-methyl-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0138]

[0139] Refer to the specific experimental procedures in Example 1 to obtain (R)-1-methyl-6-(8-(4-methyl-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 400.19.

[0140] Example 3

[0141] Synthesis of (R)-1-methyl-6-(8-(3-methyl-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0142]

[0143] For the specific experimental steps, refer to Example 1 to obtain (R)-1-methyl-6-(8-(3-methyl-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 400.14

[0144] Example 4

[0145] Synthesize (R)-1-methyl-6-(8-(5-methyl-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0146]

[0147] For the specific experimental steps, refer to Example 1 to obtain (R)-1-methyl-6-(8-(5-methyl-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 400.14

[0148] Example 5

[0149] Synthesize (R)-6-(8-(4-fluoro-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0150]

[0151] For the specific experimental steps, refer to Example 1 to obtain (R)-6-(8-(4-fluoro-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 404.10

[0152] Example 6

[0153] Synthesize (R)-6-(8-(5-fluoro-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0154]

[0155] Refer to Example 1 for the specific experimental procedures to obtain (R)-6-(8-(5-fluoro-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 404.07. NMR data: 1 HNMR(400MHz, DMSO-d6) δ 8.26(s, 1H), 7.94(s, 1H), 7.67–7.59(m, 2H), 7.38–7.29(m, 2H), 7.22(d, J = 8.2Hz, 1H), 6.55(dd, J = 9.9, 5.5Hz, 1H), 6.15(t, J = 7.7Hz, 1H), 3.31(s, 3H), 2.98–2.86(m, 3H), 2.63–2.57(m, 3H), 2.09–2.02(m, 2H), 1.90–1.86(m, 1H), 1.76–1.71(m, 1H).

[0156] Example 7

[0157] Synthesize (R)-6-(8-(3-methoxy-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0158]

[0159] Refer to Example 1 for the specific experimental procedures to obtain (R)-6-(8-(3-methoxy-2-oxopyridin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 416.06.

[0160] Example 8

[0161] Synthesize (R)-1-methyl-6-(8-(6-oxopyrimidin-1(6H)-yl)-5,6,7-8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0162]

[0163] Refer to Example 1 for the specific experimental procedures to obtain (R)-1-methyl-6-(8-(6-oxopyrimidin-1(6H)-yl)-5,6,7-8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 387.09. NMR data: 11H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 7.97 (d, J = 6.6 Hz, 1H), 7.35–7.32 (m, 2H), 7.21 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 6.6 Hz, 1H), 6.01 (t, J = 7.4 Hz, 1H), 3.31 (s, 3H), 2.97–2.93 (m, 2H), 2.91–2.84 (m, 1H), 2.69–2.57 (m, 3H), 2.17–2.11 (m, 2H), 1.90–1.65 (m, 2H).

[0164] Example 9

[0165] Synthesis of (R)-1-Methyl-6-(8-(4-methyl-6-oxopyrimidin-1(6H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0166]

[0167] For the specific experimental procedure, refer to Example 1 to obtain (R)-1-Methyl-6-(8-(4-methyl-6-oxopyrimidin-1(6H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 401.11. NMR data: 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.24 (s, 1H), 8.03 (s, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.23–7.19 (m, 2H), 5.97 (t, J = 7.4 Hz, 1H), 3.31 (s, 3H), 2.96–2.84 (m, 3H), 2.69–2.58 (m, 3H), 2.23 (s, 3H), 2.16–2.09 (m, 2H), 1.90–1.65 (m, 2H).

[0168] Example 10

[0169] Synthesis of (R)-6-(8-(5-Fluoro-6-oxopyrimidin-1(6H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0170]

[0171] Refer to Example 1 for the specific experimental procedures to obtain (R)-6-(8-(5-fluoro-6-oxopyrimidin-1(6H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 405.06. NMR data: 1 1H NMR(400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.15 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.1 Hz, 1H), 6.05 (t, J = 7.3 Hz, 1H), 3.31 (s, 3H), 2.99–2.88 (m, 3H), 2.68 (d, J = 4.3 Hz, 1H), 2.61 (dd, J = 8.7, 6.3 Hz, 2H), 2.25–2.09 (m, 2H), 1.91–1.68 (m, 2H).

[0172] Example 11

[0173] Synthesize (R)-1-methyl-6-(8-(6-oxopyridazin-1(6H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0174]

[0175] Refer to Example 1 for the specific experimental procedures to obtain (R)-1-methyl-6-(8-(6-oxopyridazin-1(6H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 387.10. NMR data: 1 1H NMR(400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.94 (s, 1H), 7.92 (dd, J = 3.8, 1.7 Hz, 1H), 7.45 (dd, J = 9.4, 3.8 Hz, 1H), 7.33–7.31 (m, 2H), 7.22–7.18 (m, 1H), 7.06 (dd, J = 9.5, 1.7 Hz, 1H), 6.34 (t, J = 7.2 Hz, 1H), 3.30 (s, 3H), 2.96–2.92 (m, 2H), 2.84–2.76 m, 1H), 2.69–2.64 (m, 1H), 2.62–2.58 (m, 2H), 2.16–2.05 (m, 2H), 1.97–1.88 (m, 1H), 1.80–1.72 (m, 1H).

[0176] Example 12

[0177] Synthesize (R)-1-methyl-6-(8-(2-oxopyrimidin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0178]

[0179] Refer to Example 1 for the specific experimental procedure to obtain (R)-1-methyl-6-(8-(2-oxopyrimidin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one (yield: 16.04%). [M+H] + = 387.09. NMR data: 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (dd, J = 4.1, 2.7 Hz, 1H), 8.28 (s, 1H), 8.08 (s, 1H), 7.92 (dd, J = 6.6, 2.8 Hz, 1H), 7.35–7.29 (m, 2H), 7.22 (d, J = 8.2 Hz, 1H), 6.44 (dd, J = 6.6, 4.1 Hz, 1H), 5.94 (t, J = 6.8 Hz, 1H), 3.31 (s, 3H), 2.96–2.92 (m, 2H), 2.89–2.81 (m, 1H), 2.65–2.59 (m, 3H), 2.18–2.05 (m, 2H), 1.81–1.69 (m, 2H).

[0180] Example 13

[0181] Synthesize (R)-1-methyl-6-(8-(2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0182]

[0183] Refer to Example 1 for the specific experimental procedure to obtain (R)-1-methyl-6-(8-(2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 387.09. NMR data: 11H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 8.06 (s, 1H), 7.34–7.29 (m, 4H), 7.20 (d, J = 8.2 Hz, 1H), 6.05 (t, J = 7.0 Hz, 1H), 3.30 (s, 3H), 2.94–2.92 (m, 2H), 2.89–2.83 (m, 1H), 2.65–2.62 (m, 1H), 2.61–2.57 (m, 2H), 2.16–2.08 (m, 1H), 2.07–1.98 (m, 1H), 1.84–1.68 (m, 2H).

[0184] Example 14

[0185] Synthesis of (R)-1-Methyl-6-(8-(3-methyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0186]

[0187] For the specific experimental procedure, refer to Example 1 to obtain (R)-1-Methyl-6-(8-(3-methyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 401.11. NMR data: 1 1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.05 (s, 1H), 7.33 (d, J = 8.9 Hz, 2H), 7.23–7.19 (m, 2H), 7.16 (d, J = 4.6 Hz, 1H), 6.09 (t, J = 7.3 Hz, 1H), 3.31 (s, 3H), 2.97–2.83 (m, 3H), 2.69–2.58 (m, 3H), 2.37 (s, 3H), 2.17–1.98 (m, 2H), 1.86–1.67 (m, 2H).

[0188] Example 15

[0189] Synthesis of (R)-1-Methyl-6-(8-(5-methyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one

[0190]

[0191] Refer to Example 1 for the specific experimental procedures to obtain (R)-1-methyl-6-(8-(5-methyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 401.15

[0192] Example 16

[0193] Synthesize (R)-6-(8-(3-ethyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0194]

[0195] Refer to Example 1 for the specific experimental procedures to obtain (R)-6-(8-(3-ethyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 415.04 1 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.36–7.28 (m, 2H), 7.20 (td, J = 4.6, 2.2 Hz, 3H), 6.09 (t, J = 7.2 Hz, 1H), 3.30 (s, 3H), 2.93 (dd, J = 8.6, 6.2 Hz, 2H), 2.90–2.82 (m, 1H), 2.77 (q, J = 7.4 Hz, 2H), 2.61 (td, J = 8.5, 5.8 Hz, 3H), 2.52–2.50 (m, 2H), 2.17–1.96 (m, 1H), 1.88–1.65 (m, 1H), 1.18 (t, J = 7.4 Hz, 3H).

[0196] Example 17

[0197] Synthesize (R)-6-(8-(3-isopropyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0198]

[0199] The specific synthetic route is as follows:

[0200] Step A: Synthesize 3-isopropylpyrazin-2-ol

[0201]

[0202] 2-Isopropyl-3-methoxypyrazine (150.0 mg, 0.99 mmol) was dissolved in acetic acid (1 mL), and then a 48% hydrobromic acid acetic acid solution (0.25 mL) was added. The reaction was carried out at 75 °C for 3 hours under a nitrogen atmosphere.

[0203] After the reaction was completed, the solution was adjusted to neutral with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate / methanol = 10 / 1 (8 mL × 3). The organic phases were combined, washed with saturated brine (8 mL), dried over anhydrous sodium sulfate, concentrated under vacuum, and the resulting residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 1 / 7) to obtain 20.0 mg of white solid 3-isopropylpyrazin-2-ol (yield 14.6%).

[0204] Step B: Synthesis of (R)-6-(8-(3-isopropyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0205] The synthesis method referred to Step G of Example 1 to obtain (R)-6-(8-(3-isopropyl-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 429.07.

[0206] Example 18

[0207] Synthesis of (R)-6-(8-(3-cyano-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one

[0208]

[0209] The specific experimental procedure referred to Example 1 to obtain (R)-6-(8-(3-cyano-2-oxopyrazin-1(2H)-yl)-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. [M+H] + = 412.07.

[0210] Biological Activity Evaluation of Example 19

[0211] Detection Method

[0212] In this article, the inventors used the H295R steroidogenesis assay system to test the enzyme activities of human CYP11B1, human CYP11B2, etc. The in vitro H295R steroidogenesis assay system uses the human adrenal cancer cell line (NCI-H295R cells) to constitute a two-level "in vitro test to provide mechanistic data" for screening and prioritization purposes. The development and standardization of this method were carried out in a multi-step process for screening the chemical effects of steroidogenesis. The H295R assay method has been optimized and validated according to the OECD test guideline (Test Guideline No. 456 H295R Steroidogenesis Assay).

[0213] Inhibition of aldosterone synthase

[0214] NCI-H295R cells can be purchased from ATCC. After culturing H295R cells starting from the original ATCC batch, the cells should be cultured for five generations (i.e., the cells divide 4 times), and then the cells passaged 5 times are frozen and stored in liquid nitrogen.

[0215] H295R cells are cultured in a 37 °C, 5% CO2 cell culture incubator, and the culture medium is changed 2 - 3 times a week. When the cells grow to approximately 85 - 90% confluence, they are passaged. Aspirate the culture medium and wash three times with DPBS (without Ca 2+ Mg 2+ ). Add trypsin and digest for 1 - 3 min, add 3 mL of culture medium to terminate digestion and pipette the cells down, then wash the remaining cells with 1 mL of culture medium, and combine and add them to a 15 mL centrifuge tube. At room temperature, centrifuge at 800 rpm for 5 min, discard the supernatant, resuspend the pellet with 3 mL of culture medium, and take the cell suspension for counting. Discard the edge wells of the 96-well plate, and seed 50,000 cells in each of the remaining wells, with 100 μL of 10% FBS DMEM:F12 (1:1) basal medium per well, recover overnight, and then replace it with basal medium containing 10 μM forskolin, 150 μL per well, and incubate for 48 h. After 48 h, replace it with basal medium containing 10 μM deoxycorticosterone. The compound is dissolved in DMSO to prepare a 100 mM stock solution. Starting from 100 mM, perform 3-fold serial dilutions with DMSO for a total of 10 concentration points. Then dilute the 10 concentration points 10-fold with DMEM:F12 (1:1) blank medium. The starting concentration is 10 mM. Take 1.5 μL of different concentrations of the compound and add it to the cells, with the final concentration of DMSO being 0.1% and the starting concentration of the compound being 100 μM. Incubate for 48 h, collect 40 μL of the cell supernatant, and detect and analyze the aldosterone and cortisol contents by LCMS.

[0216] Cell viability assay

[0217] After collecting the supernatant, add 100 μL of 10% CCK8 detection reagent to each well, incubate at 37 °C for 10 min, mix well by tapping, and then measure the OD value at a wavelength of 405 nm using an enzyme-linked immunosorbent assay (ELISA) reader. Set the 70% methanol group as the negative control and the DMSO solvent control group (solvent controls) as the positive control. Calculate using the following formula:

[0218] % viable cells = (OD cmpd – OD Avg MeOH[=100% dead]) ÷ (OD Avg SCs[=100% viability] – OD Avg MeOH[=100% dead])

[0219] Wells with a cell viability lower than 80% should not be included in the final data analysis. When there is nearly 20% cytotoxicity, the inhibition of steroidogenesis should be carefully evaluated to ensure that cytotoxicity is not the cause of the inhibition. In addition, if the cell viability exceeds 120%, the data should be marked to identify potential false positives.

[0220] The following formula is used to calculate the inhibition rate for result analysis:

[0221] Inhibition rate % = (PeakArea Avg SCs - PeakArea cmpd) / (PeakArea Avg SCs - PeakAreablank) × 100

[0222] Using the logarithm of the compound concentration value as the abscissa and the inhibition rate as the ordinate, perform non-linear regression curve fitting using Graphpad 9.0 to calculate the IC 50 value (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * HillSlope))), Ki = IC 50 / (1 + [S] / Km). The test results are shown in Table 1. Unless otherwise specified, all proteases are assumed to be competitively inhibited. Selectivity = CYP11B1 Ki (nM) / CYP11B2 Ki (nM); where A represents a selectivity value between 0 - 50, B represents a selectivity value between 51 - 100, C represents a selectivity value between 101 - 150, and D represents a selectivity value above 151;

[0223] Table 1. Inhibitory effect of compounds on CYP11B2

[0224]

[0225]

[0226] As can be seen from the experimental results in Table 1, the compounds of the present invention have good inhibitory effects on CYP11B2, and the effects are better than those of the control compound Baxdrostat. In addition, the compounds of the present invention have excellent selectivity for CYP11B2, can selectively inhibit CYP11B2, and weakly inhibit CYP11B1.

[0227] Pharmacokinetics Study of Rats in Example 20

[0228] Experimental Materials

[0229] SD rats: male, 180 - 250 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0230] Reagents: DMSO (dimethyl sulfoxide), PEG - 400 (polyethylene glycol 400), normal saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.

[0231] Instrument: AB SCIEX QTRAP 5500+.

[0232] Experimental Methods

[0233] Weigh the compounds of Examples 1 - 49 of the present invention and dissolve them in a DMSO - PEG - 400 - normal saline (5:60:35, v / v / v) system. After intravenous or intragastric administration to rats, 200 μL of venous blood is collected at 15 min, 30 min, 1 h, 2 h, 5 h, 7 h, 24 h (5 min is added for the iv group) into an EDTA - K2 anticoagulant tube, centrifuged at 12,000 rpm for 2 min, and the plasma is frozen at - 80 °C for later measurement. Weigh a certain amount of the test sample accurately and dissolve it in DMSO to 2 mg / mL as a stock solution. Accurately pipette an appropriate amount of the compound stock solution and dilute it with acetonitrile to prepare a standard series of solutions. Accurately pipette 10 μL of each of the above - mentioned standard series of solutions, add 90 μL of blank plasma, vortex - mix well, and prepare plasma samples with plasma concentrations equivalent to 1, 3, 5, 10, 30, 100, 300, 1000, 3000 ng / mL. Each concentration is analyzed in duplicate to establish a standard curve. Take 30 μL of plasma (the plasma at 5 min, 15 min, and 30 min after intravenous administration is diluted 5 times), add 150 μL of an acetonitrile solution of the internal standard propranolol (50 ng / mL), vortex - mix well, then add 100 μL of purified water, vortex - mix again, centrifuge at 4000 rpm for 5 min, and take the supernatant for LC - MS analysis. The LC - MS detection conditions are as follows:

[0234] Chromatographic column: YMC Triart C18, 50 * 3.0 mm, 2.1 μm.

[0235] Mobile phase: Water (0.1% formic acid)-acetonitrile was subjected to gradient elution as shown in the following table.

[0236] Time (min) Water (containing 0.1% formic acid) Acetonitrile 0 80％ 20％ 0.6 80％ 20％ 1.2 15％ 85％ 2.6 15％ 85％ 2.61 80％ 20％ 3.2 80％ 20％

[0237] Data processing

[0238] After LC-MS was used to detect the blood drug concentration, WinNonlin 6.1 software was adopted, and the pharmacokinetic parameters were calculated by the non-compartment model method. The test results are shown in Table 2.

[0239] Table 2: Pharmacokinetic results of the compounds of the present invention in rats

[0240]

[0241] It can be seen from the experimental results in Table 2 that the compounds of the present invention all have good pharmacokinetic characteristics in SD rats, and the Cmax, AUC last and half-life after intravenous and oral administration are superior to those of the positive control Baxdrostat.

[0242] It should be understood that the above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. For those of ordinary skill in the art, improvements or changes can be made according to the above description, and all such improvements and changes should fall within the protection scope of the appended claims of the present invention.

Claims

1. A dihydroquinolin-2-one derivative, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the dihydroquinoline-2-one derivative is shown in general formula I: Wherein, the R1 is selected from: H or C1-C8 alkyl; R2 is selected from: H, C1-C8 alkyl, halogenated C1-C8 alkyl or halogen; R3 is selected from: H, C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkyl or halogen; The R4 is selected from: H or halogen; Said X, Y, Z or W are independently selected from N or CR5; R5 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkoxy, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkoxy, substituted or unsubstituted C6-C 12 Aryl, substituted or unsubstituted C6-C 12 Aryloxy, substituted or unsubstituted 5-12-membered heteroaryl, substituted or unsubstituted 5-12-membered heteroaryloxy; The substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C3-C8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-C 12 Aryl, substituted 5-12 membered heteroaryl, substituted C3-C8 cycloalkoxy, substituted 3-8 membered heterocycloalkoxy, substituted C6-C 12 The substituents in the aryloxy or substituted 5-12 membered heteroaryloxy are independently selected from the group consisting of C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, -NR6R7, hydroxy, oxo, carboxyl, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamide, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C3-C8 cycloalkyl substituted C1-C8 alkoxy, C6-C 12 Aryl, C6-C 12 Aryloxy, C1-C8 alkyl substituted C6-C 12 Aryloxy, C1-C8 alkoxy substituted C6-C 12 Aryloxy, halogenated C1-C8 alkyl substituted C6-C 12 One or more of aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, 5-12 membered heteroaryloxy substituted by C1-C8 alkyl, 5-12 membered heteroaryloxy substituted by C1-C8 alkoxy, 5-12 membered heteroaryloxy substituted by halogenated C1-C8 alkyl or halogen; said R6 and R7 are independently selected from: H or C1-C8 alkyl; The m or q is independently selected from an integer of 0, 1 or 2; the n or p is independently selected from an integer of 0, 1, 2 or 3.

2. The dihydroquinolin-2-one derivative, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 1, characterized in that: The R1 is selected from C1-C3 alkyl; the R2 is selected from H, C1-C3 alkyl, halogenated C1-C3 alkyl or halogen; the R3 is selected from H, C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkyl or halogen; the R4 is selected from H or halogen; Said X, Y, Z or W are independently selected from N or CR5; R5 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted C3-C6 cycloalkoxy, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted 3-6 membered heterocycloalkoxy, substituted or unsubstituted C6-C 10 Aryl, substituted C6-C 10 Aryloxy, substituted or unsubstituted 5-10 membered heteroaryl, substituted 5-10 membered heteroaryloxy; The substituted C1-C3 alkyl, substituted C1-C3 alkoxy, substituted C3-C6 cycloalkyl, substituted 3-6 membered heterocycloalkyl, substituted C6-C 10 Aryl, substituted 5-10 membered heteroaryl, substituted C3-C6 cycloalkoxy, substituted 3-6 membered heterocycloalkoxy, substituted C6-C 10 The substituents in the aryloxy or substituted 5-10 membered heteroaryloxy are independently selected from the group consisting of C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR6R7, hydroxy, oxo, carboxyl, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamide, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C6-C 10 Aryl, C6-C 10 one or more of aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy or halogen; Said R6 and R7 are independently selected from: H or C1-C3 alkyl; The m or q is independently selected from an integer of 0, 1 or 2; the n or p is independently selected from an integer of 0, 1, 2 or 3.

3. The dihydroquinolin-2-one derivative according to any one of claims 1 to 2, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The structure of the dihydroquinoline-2-one derivative is shown in general formula II: Wherein, X, Y, Z or W are independently selected from N or CR5; R5 is selected from the group consisting of: H, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C8 cycloalkoxy, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted 3-8 membered heterocycloalkoxy, substituted or unsubstituted C6-C 12 Aryl, substituted C6-C 12 Aryloxy, substituted or unsubstituted 5-12 membered heteroaryl, substituted 5-12 membered heteroaryloxy; The substituted C1-C8 alkyl, substituted C1-C8 alkoxy, substituted C3-C8 cycloalkyl, substituted 3-8 membered heterocycloalkyl, substituted C6-C 12 Aryl, substituted 5-12 membered heteroaryl, substituted C3-C8 cycloalkoxy, substituted 3-8 membered heterocycloalkoxy, substituted C6-C 12 The substituents in the aryloxy or substituted 5-12 membered heteroaryloxy are independently selected from the group consisting of C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, -NR6R7, hydroxy, oxo, carboxyl, cyano, C1-C6 alkylsulfonyl, C1-C6 alkylamide, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C3-C8 cycloalkyl substituted C1-C8 alkoxy, C6-C 12 Aryl, C6-C 12 Aryloxy, C1-C8 alkyl substituted C6-C 12 Aryloxy, C1-C8 alkoxy substituted C6-C 12 Aryloxy, halogenated C1-C8 alkyl substituted C6-C 12 One or more of aryloxy, 5-12 membered heteroaryl, 5-12 membered heteroaryloxy, 5-12 membered heteroaryloxy substituted by C1-C8 alkyl, 5-12 membered heteroaryloxy substituted by C1-C8 alkoxy, 5-12 membered heteroaryloxy substituted by halogenated C1-C8 alkyl, or halogen; Said R6 and R7 are independently selected from: H or C1-C8 alkyl; The m or q is independently selected from an integer of 0, 1 or 2; the n or p is independently selected from an integer of 0, 1, 2 or 3.

4. The dihydroquinolin-2-one derivative according to any one of claims 1 to 3, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The structure of the dihydroquinoline-2-one derivatives is shown in the general formula IIA or IIB: The definition of X, Y, Z or W is the same as that of claim 4.

5. The dihydroquinolin-2-one derivative, or its isomer, or its racemate, or its pharmaceutically acceptable salt according to claim 4, characterized in that: The definition of X, Y, Z or W is the same as that of claim 5.

6. The dihydroquinolin-2-one derivative according to any one of claims 1 to 5, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The X, Y, Z or W are independently selected from N or CR5, and the R5 is selected from: H, F, Cl, cyano, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, hydroxyethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, isopropoxy, n-butoxy, tert-butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogenated cyclobutyl, halogenated cyclopentyl, halogenated cyclohexyl, methoxyethyl, methoxy-2-propyl, acetamidoethyl, carboxyethyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl, sulfolane, 1,1-dioxotetrahydro-2H-thiopyranyl, Cyclopropylmethyl, cyclobutylmethyl, 1,1,1-trifluoropropan-2-yl, piperidinyl, N-methylsulfonylpiperidinyl, N-ethylsulfonylpiperidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, N-methylpyrazolyl, N-methylimidazolyl, pyrazinyl, methoxypyrazinyl, pyridinyl, pyrimidinyl, pyrimidin-2-yloxyethyl, indole-3-methyl, indole-2-methyl, α-methylbenzyl, 5-methylisoxazolyl, methylpyrazinyl, 3-chloropyridinyl, indazolyl, phenyl.

7. The dihydroquinolin-2-one derivative according to any one of claims 1 to 6, or its isomer, or its racemate, or its pharmaceutically acceptable salt, characterized in that: The dihydroquinoline-2-one derivatives are selected from the following compounds:

8. A pharmaceutical composition, characterized in that The invention comprises the dihydroquinoline-2-one derivative according to any one of claims 1 to 7, or its isomer, or its racemate, or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients and / or carriers.

9. Use of the dihydroquinolin-2-one derivative according to any one of claims 1 to 7, or its isomer, or its racemate, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating or preventing diseases related to increased CYP11B2 activity levels.

10. The use according to claim 9, characterized in that The disease related to the increased activity level of CYP11B2 is selected from the group consisting of hypertension, chronic kidney disease, primary aldosteronism, diabetic nephropathy, congestive heart failure or Cushing's syndrome.

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