Aldosterone synthetase inhibitor, and preparation method therefor and use thereof

Abstract

The present invention belongs to the technical field of chemical pharmaceuticals. Provided in the present invention are an aldosterone synthetase inhibitor, and a preparation method therefor and the use thereof.

Description

An aldosterone synthase inhibitor and its preparation method and use Technical Field

[0001] The present invention belongs to the technical field of chemical medicines and provides an aldosterone synthase inhibitor and a preparation method and use thereof. Background Art

[0002] Aldosterone is a steroid hormone with mineralocorticoid activity. It is produced primarily by the zona glomerulosa of the adrenal glands in response to angiotensin II, adrenocorticotropic hormone, and increased serum potassium levels. The primary 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 nephron. However, aldosterone has also been shown to be a proinflammatory and profibrotic hormone in blood vessels, heart, and kidneys. The effect of aldosterone on gene expression is regulated by binding to the mineralocorticoid receptor (MR) and the canonical nuclear hormone receptor pathway.

[0003] CYP11B2 (aldosterone synthase) is a cytochrome P450 enzyme, known as an enzyme that catalyzes a series of reactions from 11-deoxycorticosterone (i.e., aldosterone precursor) to aldosterone. CYP11B2 is mainly expressed in the zona glomerulosa of the adrenal cortex, and the aldosterone in the plasma is regulated by the activity of this enzyme in the adrenal gland. In addition, the expression of aldosterone has also been confirmed in the cardiovascular system, kidney, adipose tissue, brain and other parts of the adrenal gland, and the discovery that the aldosterone produced locally 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 and therapeutic effect of inhibiting the production of aldosterone in studies using various experimental animal models. In addition, it has been confirmed that CYP11B2 inhibitors show the effect of reducing the aldosterone level in the plasma and urine and the antihypertensive effect in patients with hypertension and primary aldosteronism. Finding a means to inhibit the biosynthetic pathway of aldosterone is a highly feasible approach for establishing effective treatments for various aldosterone-related diseases.

[0004] Aldosterone synthase (CYP11B2) inhibitors have been reported. For example, patent application CN103827101B reports a bicyclic dihydroquinolin-2-one derivative. Although the compound has good CYP11B2 inhibitory activity, its selectivity is poor.

[0005] CN114853755A also reports an aldosterone synthase inhibitor, but the compound is a chiral compound and is relatively difficult to synthesize. In addition, it has significant side effects. In addition, existing CYP11B2 inhibitors also have problems such as poor activity, difficulty in 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 an aldosterone synthase inhibitor and a preparation method and use thereof to solve the problems existing in the prior art.

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

[0008] The present invention provides an aldosterone synthase inhibitor, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof. The structure of the aldosterone synthase inhibitor is shown in Formula I or Formula IA:

[0009] Wherein, R1 and R2 are independently selected from: H, halogen, hydroxyl, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, C1-C6 alkylsulfonyl, substituted or unsubstituted C6-C 12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;

[0010] Said R5 is independently selected from: substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;

[0011] The ring A is independently selected from: 5-12 membered fused heteroaryl or C 10 -C 12 aryl;

[0012] The substituents in the "substituted" are independently selected from: C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, -NR3R4, hydroxy, oxo, carboxyl, cyano, halogen, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, 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 12one 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, or 5-12-membered heteroaryloxy substituted by halogenated C1-C8 alkyl;

[0013] Said R3 and R4 are independently selected from: H or C1-C8 alkyl;

[0014] The n, p or q are independently selected from integers of 0, 1, 2 or 3.

[0015] Furthermore, as a preferred technical solution of the present invention, the present invention also provides an aldosterone synthase inhibitor, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof, wherein the structure of the aldosterone synthase inhibitor is shown in the general formula IB:

[0016] Wherein, R1 and R2 are independently selected from: H, halogen, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;

[0017] Said R5 is independently selected from: substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C 12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;

[0018] The ring A is independently selected from: 5-12 membered fused heteroaryl;

[0019] The substituents in the "substituted" are independently selected from: C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, -NR3R4, hydroxyl, oxo, carboxyl, cyano, halogen, 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 12one 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, or 5-12-membered heteroaryloxy substituted by halogenated C1-C8 alkyl;

[0020] Said R3 and R4 are independently selected from: H or C1-C8 alkyl;

[0021] The n, p or q are independently selected from integers of 0, 1, 2 or 3.

[0022] Furthermore, as a preferred technical solution of the present invention, the R1 or R2 are independently selected from: H, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted 5-10 membered heteroaryl;

[0023] Said R5 is independently selected from: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C 10 aryl or substituted or unsubstituted 5-10 membered heteroaryl;

[0024] The ring A is independently selected from: 6-10 membered fused heteroaryl;

[0025] The substituents in the "substituted" are independently selected from: C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, -NR3R4, hydroxyl, oxo, carboxyl, cyano, halogen, 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-C6 alkoxy, C6-C 10 Aryl, C6-C 10 Aryloxy, C1-C6 alkyl substituted C6-C 10 Aryloxy, C1-C6 alkoxy substituted C6-C 10 Aryloxy, halogenated C1-C6 alkyl substituted C6-C 10 One or more of aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, 5-10 membered heteroaryloxy substituted by C1-C6 alkyl, 5-10 membered heteroaryloxy substituted by C1-C6 alkoxy, or 5-10 membered heteroaryloxy substituted by halogenated C1-C6 alkyl;

[0026] Said R3 and R4 are independently selected from: H or C1-C6 alkyl;

[0027] The n, p or q are independently selected from integers of 0, 1, 2 or 3.

[0028] Furthermore, as a preferred technical solution of the present invention, R1 or R2 are independently selected from: H, halogen, cyano, substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C8 aryl or substituted or unsubstituted 5-8 membered heteroaryl;

[0029] R5 is independently selected from: substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C1-C3 alkoxy, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted 5-8 membered heteroaryl;

[0030] The ring A is independently selected from: 6-9 membered fused heteroaryl;

[0031] The substituents in the "substituted" are independently selected from: C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, -NR3R4, hydroxy, oxo, carboxyl, cyano, halogen, C1-C3 alkylsulfonyl, C1-C3 alkylamide, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyloxy, C3-C6 cycloalkyl substituted C1-C3 alkoxy, C6- One or more of C8 aryl, C6-C8 aryloxy, C6-C8 aryloxy substituted by C1-C3 alkyl, C6-C8 aryloxy substituted by C1-C3 alkoxy, C6-C8 aryloxy substituted by halogenated C1-C3 alkyl, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, 5-8 membered heteroaryloxy substituted by C1-C3 alkyl, 5-8 membered heteroaryloxy substituted by C1-C3 alkoxy, or 5-8 membered heteroaryloxy substituted by halogenated C1-C3 alkyl;

[0032] Said R3 and R4 are independently selected from: H or C1-C3 alkyl;

[0033] The n, p or q are independently selected from integers of 0, 1, 2 or 3.

[0034] Furthermore, the present invention also provides an aldosterone synthase inhibitor, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof, wherein the structure of the aldosterone synthase inhibitor is shown in Formula IIA or IIB:

[0035] Wherein, the definitions of R1, R2, ring A, n, p and q are the same as those above.

[0036] Furthermore, the present invention also provides an aldosterone synthase inhibitor, or an isomer, or a racemate, or a pharmaceutically acceptable salt thereof, wherein the structure of the aldosterone synthase inhibitor is shown in Formula IIIA, IIIB, IIIC, or IIID:

[0037] Wherein, the definitions of R1, R2, ring A, n, p and q are the same as those above.

[0038] Furthermore, as a preferred technical solution of the present invention, the ring A is selected from: Preferably, the ring A is selected from:

[0039] Wherein, the ring B is selected from 5-10 membered heteroaryl or C6-C 10 Aryl; said X, Y, Z1, Z2 or Z3 are independently selected from C or N.

[0040] Furthermore, as a preferred technical solution of the present invention, the ring A is selected from: wherein the ring B is selected from a 5-10 membered heteroaryl group; and the X or Y is independently selected from C or N.

[0041] Furthermore, as a preferred technical solution of the present invention, the ring A is selected from: wherein the ring B is selected from a 5-10 membered heteroaryl group; and the X or Y is independently selected from C or N.

[0042] Furthermore, as a preferred technical solution of the present invention, the ring B is selected from a 5-10 membered heteroaryl group, preferably a 5-8 membered heteroaryl group; more preferably a 5-6 membered heteroaryl group. Examples of the ring B include but are not limited to: pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, triazinyl, isoxazolyl, and isothiazolyl.

[0043] Furthermore, as a preferred technical solution of the present invention, the ring A is selected from: benzothiophenyl, benzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, imidazopyridinyl, naphthyridinyl, and naphthyl.

[0044] Furthermore, as a preferred technical solution of the present invention, the ring A is selected from:

[0045] Furthermore, as a preferred technical solution of the present invention, the R1 or R2 are independently selected from: H, hydroxyl, halogen, cyano, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; further, as a preferred technical solution of the present invention, said R1 or R2 are independently selected from: H, halogen, cyano, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy, halogenated C1-C3 alkoxy, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C8 aryl or 5-8 membered heteroaryl;

[0046] Furthermore, as a preferred technical solution of the present invention, R1 or R2 are independently selected from: H, hydroxyl, F, Cl, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, trifluoromethoxy, trifluoroethoxy, cyclopropyl, cyclopropyloxy, methylsulfonyl, ethylsulfonyl, formyl or acetyl;

[0047] Furthermore, as a preferred technical solution of the present invention, R1 or R2 are independently selected from: H, F, Cl, cyano, methyl, methoxy, trifluoromethyl.

[0048] As a preferred technical solution of the present invention, the C 1- The alkyl group of C8 is preferably C 1- C2, C 1- C3, C 1- C4, C 1- C5 or C 1- C6 alkyl; 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.

[0049] As a preferred technical solution of the present invention, the C 1- C8 alkoxy preferably C 1- C2, C 1- C3, C 1- C4, C 1- C5 or C 1-C6 alkoxy, further, examples of the alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy.

[0050] As a preferred technical solution of the present invention, the C 3- C8 cycloalkyl is preferably selected from: C 3- C6 cycloalkyl or C 3- C5 cycloalkyl, wherein the cycloalkyl is specifically selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0051] As a preferred technical solution of the present invention, the C 3- C8 cycloalkoxy is preferably selected from: C 3- C6 cycloalkoxy or C 3- C5 cycloalkoxy, wherein the cycloalkyl group is specifically selected from cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

[0052] As a preferred technical solution of the present invention, the heterocycloalkyl group is selected from 3-12 membered heterocycloalkyl groups, preferably: 3-10 membered heterocycloalkyl groups, 3-8 membered heterocycloalkyl groups, 3-6 membered heterocycloalkyl groups or 3-5 membered heterocycloalkyl groups, and examples of the heterocycloalkyl groups include: aziridine groups, oxirane groups, azetidinyl groups, oxetanyl groups, pyrrolidinyl groups, tetrahydrofuranyl groups, tetrahydro-thienyl groups, pyrazolidinyl groups, imidazolidinyl groups, oxazolidinyl groups, isoxazolidinyl groups, thiazolidinyl groups, piperidinyl groups, tetrahydropyranyl groups, tetrahydrothiopyranyl groups, piperazinyl groups, morpholinyl groups , thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazinyl, 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]heptanyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl; preferred examples of heterocycloalkyl groups are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl. More preferred examples of heterocycloalkyl groups are pyrrolidinyl, piperidinyl, thiomorpholinyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0053] As a preferred technical solution of the present invention, the halogenated C 1- C8 alkyl or halogenated C 1- C8 alkyl, preferably halogenated 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 which include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl and pentafluoroethyl, particular haloalkyl groups are trifluoromethyl and trifluoroethyl.

[0054] As a preferred embodiment of the present invention, the substituted or unsubstituted C6-C 12 Aryl is preferably: substituted or unsubstituted C6-C 10 Aryl, substituted or unsubstituted C6-C8 Aryl, substituted or unsubstituted C6-C 12 Examples of the substituted or unsubstituted aryl group include phenyl, o-tolyl, m-tolyl, p-tolyl, phenol, xylyl, chlorophenyl, dichlorophenyl, nitrophenyl, cyanophenyl, and naphthyl.

[0055] As a preferred embodiment of the present invention, the substituted or unsubstituted 5-12 membered heteroaryl group is preferably: a substituted or unsubstituted 5-10 membered heteroaryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 5-8 membered heteroaryl group, a substituted or unsubstituted 5-7 membered heteroaryl group, a substituted or unsubstituted 5-6 membered heteroaryl group, and examples of the substituted or unsubstituted heteroaryl group include: pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl , thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepine, diazepine, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolyl, isoquinolyl, quinazolinyl and quinoxalinyl. Particular heteroaryl includes pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, isoxazolyl and isothiazolyl. More particular heteroaryl groups include imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, indazolyl, isoxazolyl and isothiazolyl.

[0056] As a preferred technical solution of the present invention, the 5-12 membered fused heteroaryl group is preferably: a 5-10 membered fused heteroaryl group, a 6-10 membered fused heteroaryl group, a 6-9 membered fused heteroaryl group, and a 6-8 membered fused heteroaryl group; examples of the fused heteroaromatic hydrocarbon group include but are not limited to: benzothiophenyl, benzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, benzopyridazinyl, imidazopyridinyl, naphthyridinyl, and naphthyl.

[0057] As a preferred technical solution of the present invention, the C6-C 12 Aryl, preferably C6-C 10 Aryl or C 10 -C 12 Aryl, the C6-C 10 The aryl group is preferably a C6-C8 aryl group, more preferably a phenyl group; 10 -C 12 The aryl group is more preferably a naphthyl group.

[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 aldosterone synthase inhibitor, or its isomer, or its racemate, or its pharmaceutically acceptable salt is selected from:

[0060] The present invention also provides a deuterated compound of the aforementioned aldosterone synthase inhibitor, or its isomer, racemate, or pharmaceutically acceptable salt. Furthermore, as a preferred embodiment of the present invention, the deuterated compound is selected from the following structures:

[0061] The present invention further provides a pharmaceutical composition comprising an aldosterone synthase inhibitor of Formula I, Formula IA, Formula IB, Formula IIA, Formula IIB, Formula IIIA, Formula IIIB, Formula IIIC or Formula HID, or an isomer, racemate, pharmaceutically acceptable salt or deuterated compound thereof, and one or more pharmaceutically acceptable excipients and / or carriers.

[0062] The present invention further provides a use of an aldosterone synthase inhibitor of Formula I, Formula IA, Formula IB, Formula IIA, Formula IIB, Formula IIIA, Formula IIIB, Formula IIIC or Formula HID, or an isomer, racemate or pharmaceutically acceptable salt thereof, or deuterated compound thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing diseases caused by elevated CYP11B2 activity, including chronic kidney disease, congestive heart failure, hypertension, diabetic nephropathy, primary aldosteronism and Cushing's syndrome.

[0063] As a preferred technical solution of the present invention, the related diseases caused by the increased activity level of CYP11B2 are selected from: hypertension, etc.

[0064] The present invention further provides a method for preparing an aldosterone synthase inhibitor, or an isomer thereof, or a racemate thereof, or a pharmaceutically acceptable salt thereof, which is prepared by referring to patent CN103827101B and conventional methods in the art. The advantages of the present invention over the prior art include, but are not limited to:

[0065] Compared with the prior art, the aldosterone synthase inhibitor of the present invention can selectively inhibit CYP11B2 and weakly inhibit CYP11B1, and has better CYP11B2 inhibitory activity.

[0066] For the sake of clarity, general terms used in the description of the compounds are defined herein.

[0067] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered as undefined or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0068] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared by reacting a compound having a specific substituent discovered in the present invention with a pharmaceutically acceptable acid or base.

[0069] In addition to the form of salts, the compounds provided by the present invention also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.

[0070] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrates. In general, the solvated forms are equivalent to the unsolvated forms and are encompassed within the scope of the present invention.

[0071] 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, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which 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 mixtures thereof are encompassed within the scope of the present invention.

[0072] 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 one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric 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), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, separation of enantiomers and diastereomers is typically accomplished by using chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., formation of carbamates from amines).

[0073] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups having 1 to 20 carbon atoms. Preferably, the alkyl group contains 1 to 8 carbon atoms, and more preferably, the alkyl group contains 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 chain isomers thereof.

[0074] The term "haloalkyl" means that at least one of the alkyl hydrogen atoms 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.

[0075] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined 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.

[0076] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0077] The term "haloalkoxy" refers to 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" refers to 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 groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy, and pentafluoroethoxy. Particular haloalkoxy groups are trifluoromethoxy and 2,2-difluoroethoxy.

[0078] The term "cycloalkyl" or "carbocycle" refers to a saturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0079] The term "heterocycloalkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system of 3 to 8 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. In a particular embodiment, 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, and the remaining ring atoms are carbon. Examples of monocyclic saturated heterocycloalkyl groups 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 thiazinyl. Examples of bicyclic saturated heterocycloalkyl groups 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]heptanyl. Examples of partially unsaturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. More specific 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, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl. More specific examples of heterocycloalkyl are pyrrolidinyl, piperidinyl, thiomorpholinyl, thiazinyl and 2,6-diaza-spiro[3.3]heptanyl.

[0080] The term "halocycloalkyl" refers to a cycloalkyl group in which at least one of the hydrogen atoms of the cycloalkyl group has been replaced by the same or different halogen atoms, in particular a fluorine atom. Examples of halocycloalkyl groups include fluorocyclopropyl, difluorocyclopropyl, fluorocyclobutyl and difluorocyclobutyl.

[0081] The term "C 1- C6 alkylsulfonyl" refers to C 1- One H atom on the C6 alkyl group is replaced by a sulfonyl group, such as methylsulfonyl, ethylsulfonyl, etc.

[0082] The term "C 1- "C6 alkyl acyl" means C 1- One H atom on the C6 alkyl group is replaced by an acyl group, such as formyl, acetyl, etc.

[0083] The term "C1- "C6 alkylamide" refers to C 1- One H atom on the C6 alkyl group is replaced by an amide group, such as formamide, acetamide, etc.

[0084] The term "aryl" or "aromatic ring" refers to a 6- to 12-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, preferably a 6- to 12-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, more preferably 8- to 10-membered, most preferably 6- to 8-membered, such as phenyl and naphthyl.

[0085] The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing 1 to 3 heteroatoms, 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 8-membered, more preferably 5-membered or 6-membered. Pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, 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.

[0086] The term "fused heteroaryl" refers to a fused bicyclic ring system containing one to four heteroatoms selected from N, O, or S and their oxidation states and having aromaticity, which may be a heteroaryl fused to an aryl or a heteroaryl fused to a heteroaryl, wherein either the heteroaryl or the aryl group can be the site of attachment. Non-limiting examples include benzothiophenyl, benzofuranyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzisoxazolyl, isobenzofuranyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, and benzopyridazinyl.

[0087] The term "cycloalkyloxy" or "cycloalkoxy" refers to a cycloalkyl-O- group in which cycloalkyl is as defined above.

[0088] The term "heterocyclyloxy" or "heterocycloalkoxy" refers to a heterocyclyl-O- group in which heterocyclyl is as defined above.

[0089] The term "aryloxy" or "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0090] The term "heteroaryloxy" or "heteroaryloxy" refers to heteroaryl-O-, in which heteroaryl is as defined above.

[0091] The atoms of the molecules of the compounds of the present invention are isotopes, and isotope derivatization can generally extend half-life, reduce clearance, stabilize metabolism, and increase in vivo activity. In addition, an embodiment is included in which at least one atom is replaced by an atom having the same atomic number (number of protons) and a different mass number (protons and neutrons). Examples of 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 In particular, radioactive isotopes that emit radiation as they decay, such as 3 H or 14 C can be used for local anatomy testing of pharmaceutical preparations or compounds in vivo. Stable isotopes neither decay nor change with their amount nor are they radioactive, so they can be used safely. When the atoms constituting the molecules of the compounds of the present invention are isotopes, the isotopes can be converted according to general methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.

[0092] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as deuterium ( 2 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0093] Furthermore, one or more hydrogen atoms of the compounds of the present invention are replaced by the isotope deuterium (2H). After deuteration, the compounds of the present invention have the effects of extending half-life, reducing clearance rate, metabolic stability and improving in vivo activity.

[0094] The preparation method of the isotopic derivative generally includes a phase transfer catalytic method. For example, a preferred deuteration method uses a phase transfer catalyst (e.g., a tetraalkylammonium salt, NBu4HSO4). The use of a phase transfer catalyst to exchange the methylene protons of the diphenylmethane compound results in a higher deuterium incorporation than reduction with a deuterated silane (e.g., triethyldeuterated monosilane) in the presence of an acid (e.g., methanesulfonic acid) or with a Lewis acid such as aluminum trichloride using sodium deuterated borate.

[0095] The term "pharmaceutically acceptable carrier" refers to any formulation 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 has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical medicine. For additional information about carriers, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0096] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0097] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0098] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0099] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. DETAILED DESCRIPTION

[0100] The present invention is further described in detail below with reference to the embodiments, but the content of the invention is not limited to the embodiments.

[0101] Example 1

[0102] Synthesis of (R)-N-(4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0103] The specific synthetic route is as follows:

[0104] Step A: Synthesis of 5-bromo-4-methylnicotinate

[0105] 5-Bromo-4-methylnicotinic acid (50.0 g, 231.45 mmol) and iodoethane (39.7 g, 254.59 mmol) were dissolved in 500 ml of N,N-dimethylformamide, and potassium bicarbonate (46.3 g, 462.90 mmol) was added. The mixed solution was degassed and protected with nitrogen, and the reaction was stirred at room temperature for 12 hours.

[0106] After the reaction, the mixture was filtered, water was added to the filtrate, and the mixture was extracted with ethyl acetate (300 ml x 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.

[0107] Step B: Synthesis of methyl 4-bromo-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate

[0108] To a solution of ethyl 5-bromo-4-methylnicotinate (54.6 g, 223.69 mmol) in tetrahydrofuran (500 ml) was added dropwise LDA (123 ml, 246.06 mmol, 2 M) at -78°C, and the mixture was stirred for 30 minutes. Subsequently, a solution of methyl acrylate (48.1 g, 559.22 mmol) in tetrahydrofuran (200 ml) was added dropwise, and the mixture was stirred at -78°C for 2 hours.

[0109] After the reaction, 400 ml of 10% aqueous acetic acid was added to the mixture to quench the reaction. The organic solvent was removed by vortexing, and the mixture was extracted with ethyl acetate (300 ml x 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.

[0110] Step C: Synthesis of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one

[0111] Methyl 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), and the mixture was heated to 105° C. and refluxed with stirring for 16 hours.

[0112] After the reaction, the solvent was removed by vortexing, 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 x 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: ethyl acetate / n-hexane = 1 / 8) to obtain 19.6 g of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one. [M+H] + =226.05.

[0113] Step D: Synthesis of (S)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-ylidene)-2-methylpropane-2-sulfonamide

[0114] 4-Bromo-6,7-dihydroisoquinolin-8(5H)-one (10.0 g, 44.23 mmol) was dissolved in 200 ml of tetrahydrofuran, (S)-tert-butylsulfenamide (5.9 g, 48.66 mmol) and tetraisopropyl titanate (37.7 g, 132.70 mmol) were added, and the mixture was heated to 65°C under nitrogen protection and stirred for 24 hours.

[0115] After the reaction was completed, 100 ml of water was added to quench the reaction, the solid was filtered, and the filtrate was concentrated. 100 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (100 ml x 3 times). The organic phases were combined, washed with saturated brine (100 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 / 5) to obtain 13.3 g of (S)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-ylidene)-2-methylpropane-2-sulfonamide. [M+H] + =329.12.

[0116] Step E: Synthesis of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-2-methylpropane-2-sulfonamide

[0117] To a solution of (S)-N-(4-bromo-6,7-dihydroisoquinolin-8(5H)-ylidene)-2-methylpropane-2-sulfonamide (13.3 g, 40.39 mmol) in methanol (400 ml) was added sodium borohydride (2.3 g, 60.59 mmol) in portions at -42°C, and the mixture was stirred at -42°C for 1 hour.

[0118] After the reaction, 100 ml of water was added to quench the reaction, and the solvent was removed by vortexing. 100 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (100 ml x 3 times). The organic phases were combined, washed with saturated brine (100 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 / 20) to obtain 11.1 g of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-2-methylpropane-2-sulfonamide. [M+H] + =331.06. 1 H NMR(400MHz, CDCl3)δ8.58(s,1H),8.57(s,1H),4.59–4.51(m,1H),3.41(d,J=10.0Hz,1H) ,2.83–2.68(m,2H),2.38–2.28(m,1H),2.05–1.95(m,2H),1.94–1.84(m,1H),1.29(s,9H).

[0119] Step F: Synthesis of (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine

[0120] To a solution of (S)-N-((R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)-2-methylpropane-2-sulfonamide (11.1 g, 9.86 mmol) in dichloromethane (100 ml) was added 40 ml of a hydrogen chloride-dioxane solution (4 M), and the mixture was stirred at room temperature for 5 hours.

[0121] After the reaction, the mixture was vortexed to remove the solvent. 100 ml of water was added to the residue, and the pH was adjusted to 9 with sodium hydroxide solution (1 M). Ethyl acetate (100 ml x 3 times) was added for extraction. The organic phases were combined, washed with saturated brine (100 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 7.2 g of (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine. [M+H] + =227.11.

[0122] Step G: Synthesis of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0123] (R)-4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (7.2 g, 31.70 mmol) and triethylamine (8.8 ml, 63.41 mmol) were dissolved in dichloromethane (100 ml), and propionyl chloride (3.1 ml, 34.87 mmol) was added dropwise at 0°C, and the mixture was stirred at room temperature for 5 minutes.

[0124] After the reaction, water was added to the mixture, and the mixture was extracted with dichloromethane (100 ml x 3 times). The organic phases were combined, washed with saturated brine (100 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 / 20) to obtain 8.5 g of (R)-N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =283.12.

[0125] Step H: Synthesis of (R)-N-(4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0126] (R)-4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (100 mg, 0.35 mmol) and 6-quinolinylboronic acid pinacol ester (108 mg, 0.42 mmol) were dissolved in a mixed solvent of 5.0 ml of dioxane and 1.0 ml of water. Sodium carbonate (76 g, 0.71 mmol) and tetrakistriphenylphosphine palladium (8 mg, 0.0071 mmol) were added. The mixture was protected by nitrogen and reacted at 85°C for 6 hours.

[0127] After the reaction, the resulting suspension was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to obtain 87 mg of (R)-N-(4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =332.09. 1H NMR(400MHz,DMSO-d6)δ9.11(dd,J=4.5,1.7Hz,1H),8.69–8.61(m,3H),8.46(d ,J=8.0Hz,1H),8.25(d,J=8.7Hz,1H),8.19(d,J=2.0Hz,1H),7.94(dd,J=8.7,2. 0Hz,1H),7.78(dd,J=8.3,4.5Hz,1H),5.18(q,J=6.8Hz,1H),2.87–2.73(m,2H), 2.27–2.16(m,2H),2.01–1.91(m,1H),1.89–1.72(m,3H),1.08(t,J=7.6Hz,3H).

[0128] Examples 2-7

[0129] Example 8

[0130] Synthesis of (R)-N-(4-(2-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0131] The specific experimental steps were as described in Example 1 to obtain (R)-N-(4-(2-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide.

[0132] Specific steps:

[0133] Step A:

[0134] (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine was prepared by the method of Example 1, [M+H] + =283.12.

[0135] Step B:

[0136] (R)-4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-amine (100 mg, 0.35 mmol) and 2-cyanoquinoline-6-boronic acid pinacol ester (119 mg, 0.42 mmol) were dissolved in a mixed solvent of 5.0 ml of dioxane and 1.0 ml of water. Sodium carbonate (76 g, 0.71 mmol) and tetrakistriphenylphosphine palladium (8 mg, 0.0071 mmol) were added. The mixture was protected by nitrogen and reacted at 85°C for 6 hours.

[0137] After the reaction, the resulting suspension was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 20) to obtain 109 mg of (R)-N-(4-(2-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide.

[0138] [M+H] + =357.00. NMR data: 1 H NMR (400MHz, DMSO-d6) δ8.74(d,J=8.5Hz,1H),8.45(s,1H),8.39(s,1H),8.34(d,J=8.4Hz,1H),8.25(d,J=8.7Hz,1H),8.18(d,J=2.0Hz,1H),8.14( d,J=8.4Hz,1H),7.99(dd,J=8.7,2.0Hz,1H),5.15(q,J=6.5Hz,1H),2.71– 2.63(m,2H),2.26–2.12(m,2H),1.99–1.66(m,4H),1.09(t,J=7.6Hz,3H).

[0139] Examples 9-25

[0140] Example 26

[0141] Synthesis of (R)-N-(1'-cyano-5,6,7,8-tetrahydro-[4,6'-diisoquinolin-8-yl))propionamide

[0142] Step A: Synthesis of 6-bromoquinoline 2-oxide

[0143] 6-Bromoisoquinoline (500 mg, 2.40 mmol), dichloromethane (10 ml), and m-chloroperbenzoic acid (621 mg, 3.60 mmol) were added to the reaction flask and reacted at room temperature for 15 hours.

[0144] After the reaction, 1 mol / L sodium hydroxide aqueous solution was added to adjust the pH to 9, extracted with dichloromethane (20 ml × 2 times), dried over sodium sulfate, and concentrated. The residue was slurried with ethyl acetate / n-hexane = 1 / 5 (10 ml) at room temperature for 1 hour and filtered to obtain 401 mg of white solid 6-bromoquinoline-2-oxide, [M+H] + =224.04.

[0145] Step B: Synthesis of 6-bromoisoquinoline-1-carbonitrile

[0146] To the reaction flask were added 6-bromoquinoline-2-oxide (400 mg, 1.79 mmol), anhydrous tetrahydrofuran (10 ml), trimethylsilyl cyanide (354 mg, 3.57 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (326 mg, 2.14 mmol), and the mixture was reacted at room temperature for 3 hours.

[0147] After the reaction, tap water (10 ml) was added, and the mixture was extracted with ethyl acetate (20 ml x 2 times), dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 3) to obtain 337 mg of 6-bromoisoquinoline-1-carbonitrile, [M+H] + =232.01.

[0148] Step C: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1-carbonitrile

[0149] Dioxane (5 mL), 6-bromoisoquinoline-1-carbonitrile (300 mg, 1.29 mmol), pinacol diboron (393 mg, 1.55 mmol), potassium acetate (317 mg, 3.23 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (47 mg, 0.07 mmol) were added, the atmosphere was replaced with nitrogen, and the temperature was raised to 100°C for reaction for 18 hours.

[0150] After the reaction, the temperature was lowered to room temperature, and water (10 ml) was added for dissolution. The mixture was extracted with ethyl acetate (10 ml x 2 times) and concentrated. The residue was purified by silica gel column chromatography (eluent / ethyl acetate / n-hexane = 1 / 3) to give 315 mg of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1-carbonitrile as a yellow solid.

[0151] Step D: Synthesis of (R)-N-(1'-cyano-5,6,7,8-tetrahydro-[4,6'-diisoquinolin-8-yl)propionamide

[0152] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline-1-carbonitrile undergo a coupling reaction to obtain (R)-N-(1'-cyano-5,6,7,8-tetrahydro-[4,6'-diisoquinolin]-8-yl)propionamide. [M+H] + =357.00. NMR data: 1H NMR (400MHz, DMSO-d6) δ8.80(d,J=5.5Hz,1H),8.46(d,J=0.7Hz,1H),8.38(s,1H),8.37–8.30(m,3H),8.25(d,J=1.6Hz,1H),7.99(dd,J=8.6,1.7Hz, 1H),5.15(q,J=6.6Hz,1H),2.65(q,J=5.6Hz,2H),2.19(qd,J=7.4,5.0Hz, 2H), 1.94 (dd, J=9.9, 4.8Hz, 1H), 1.87–1.65 (m, 3H), 1.09 (t, J=7.6Hz, 3H).

[0153] Example 27

[0154] Synthesis of (R)-N-(1'-(methylsulfonyl)-5,6,7,8-tetrahydro-[4,6'-diisoquinolin-8-yl)propionamide

[0155] Step A: 6-Chloro-1-(methylsulfonyl)isoquinoline

[0156] To the reaction flask were added 1,6-dichloroisoquinoline (450 mg, 2.27 mmol), sodium methanesulfinate (348 mg, 3.41 mmol), potassium carbonate (784 mg, 5.67 mmol), and dimethyl sulfoxide (10 ml). The atmosphere was replaced with nitrogen and the temperature was raised to 115° C. for reaction for 2 hours.

[0157] After the reaction was complete, the mixture was cooled to room temperature. Water (30 ml) was slowly added to the reaction solution to induce crystallization for 1 hour. The crude product was filtered and purified by silica gel column chromatography (ethyl acetate / n-hexane = 1 / 5) to obtain 150 mg of a white solid 6-chloro-1-(methylsulfonyl)isoquinoline, [M+H] + =241.93.

[0158] Step B: 1-(Methylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

[0159] The synthesis method was as follows: Referring to Step C of Example 26, 1-(methylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline was obtained.

[0160] Step C: Synthesis of (R)-N-(1'-(methylsulfonyl)-5,6,7,8-tetrahydro-[4,6'-diisoquinolin-8-yl)propionamide

[0161] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 1-(methylsulfonyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline undergo a coupling reaction to obtain (R)-N-(1'-(methylsulfonyl)-5,6,7,8-tetrahydro-[4,6'-diisoquinolin]-8-yl)propanamide. [M+H] + =410.00. NMR data: 1 H NMR(400MHz,DMSO-d6)δ8.89(d,J=8.8Hz,1H),8.68(d,J=5.6Hz,1H),8.46(s,1H ),8.39(s,1H),8.34(d,J=8.4Hz,1H),8.29(dd,J=5.7,0.9Hz,1H),8.25(d,J=1.7 Hz,1H),7.94(dd,J=8.8,1.8Hz,1H),5.15(d,J=7.2Hz,1H),3.62(s,3H),2.70–2. 63(m,2H),2.19(qd,J=7.4,5.1Hz,2H),1.99–1.65(m,4H),1.09(t,J=7.6Hz,3H).

[0162] Examples 28-33

[0163] Example 34

[0164] Synthesis of (R)-N-(4-(3-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0165] The specific synthetic route is as follows:

[0166] Step A: Synthesis of 3-fluoroquinolin-6-ol

[0167] 3-Fluoro-6-methoxyquinoline (400.0 mg, 2.26 mmol) was dissolved in dichloromethane (5 ml), and a dichloromethane solution of boron tribromide (23.0 ml, 1 mol) was added under nitrogen, and the mixture was reacted at room temperature for 12 hours.

[0168] After the reaction was completed, methanol was added dropwise under ice bath to quench the reaction. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 0 / 1) to give 230 mg of 3-fluoroquinolin-6-ol as a white solid.

[0169] Step B: Synthesis of 3-fluoroquinolin-6-yl trifluoromethanesulfonate

[0170] 3-Fluoroquinolin-6-ol (180.0 mg, 1.13 mmol) and pyridine (450.0 mg, 5.65 mmol) were dissolved in dichloromethane (20 ml), and trifluoromethanesulfonic anhydride (410.0 mg, 1.47 mmol) was added under ice-cooling, and the mixture was reacted at room temperature under nitrogen atmosphere for 2 hours.

[0171] After the reaction was completed, 10 ml of water was added, and the mixture was extracted with dichloromethane (10 ml × 3 times). The organic phases were combined, washed with saturated brine (10 ml), then dried over anhydrous sodium sulfate, and concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 3 / 1) to give 124.0 mg of colorless liquid 3-fluoroquinolin-6-yl trifluoromethanesulfonate.

[0172] Step C: Synthesis of 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. Refer to Step C of Example 26 for the synthesis method to obtain 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. [M+H] + =274.08.

[0173] Step D: Synthesis of (R)-N-(4-(3-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0174] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline undergo a coupling reaction to obtain (R)-N-(4-(3-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =350.08.

[0175] Example 35

[0176] Synthesis of (R)-N-(4-(5-methylquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0177] The specific experimental steps refer to Example 1 to obtain (R)-N-(4-(5-methylquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =346.07. NMR data: 1H NMR (400MHz, DMSO-d6) δ8.96 (dd, J=4.1, 1.6Hz, 1H), 8.57 (d, J=8.8Hz, 1H), 8.40 (d, J=2. 5Hz,1H),8.31(dd,J=8.4,5.6Hz,1H),8.19(d,J=5.0Hz,1H),8.06–7.85(m,1H),7.63(dd ,J=8.6,4.1Hz,1H),7.47(dd,J=30.6,8.6Hz,1H),5.12(t,J=7.0Hz,1H),2.38(d,J=10.0 Hz,3H),2.36–2.12(m,4H),1.87(s,1H),1.82–1.62(m,3H),1.08(td,J=7.6,2.4Hz,3H).

[0178] Example 36

[0179] Synthesis of (R)-N-(4-(5-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0180] The specific synthetic route is as follows:

[0181] Step A: Synthesis of 5-fluoroquinolin-6-amine

[0182] Quinolin-6-amine (721 mg, 5.0 mmol), sodium bicarbonate (1.26 g, 15.0 mmol), and Selectfluor (2.30 g, 6.5 mmol) were dissolved in 1,4-dioxane solution (25 ml), and the reaction solution was stirred at 40° C. for 10 hours.

[0183] After the reaction is complete, the mixture is filtered, the filter cake is washed with acetonitrile (50 ml), the filtrate is collected, dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 / 5 to 1 / 3) to obtain 330 mg of 5-fluoroquinolin-6-amine. [M+H] + =163.19.

[0184] Step B: Synthesis of 6-bromo-5-fluoroquinoline

[0185] 5-Fluoroquinolin-6-amine (324 mg, 2.0 mmol) and cuprous bromide (344 mg, 2.4 mmol) were dissolved in acetonitrile (12 ml) and stirred at 60°C for 0.5, followed by the slow addition of tert-butyl nitrite (268 mg, 2.6 mmol). The reaction solution was stirred at 60°C for 8 hours, then cooled to room temperature and continued to react for 6 hours.

[0186] After the reaction, 1N hydrochloric acid was added to the reaction mixture and stirred at room temperature for 1 hour. Ethyl acetate (50 ml x 3 times) was then added for extraction. The organic phases were combined, washed with saturated brine (25 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 / 4) to obtain 50 mg of 6-bromo-5-fluoroquinoline. [M+H] + =225.89.

[0187] Step C: Synthesis of 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

[0188] The synthesis method was similar to that of Example 26, Step C, to obtain 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. [M+H] + =274.24.

[0189] Step D: Synthesis of (R)-N-(4-(5-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0190] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline undergo a coupling reaction to obtain (R)-N-(4-(5-fluoroquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =350.22. NMR data: 1 H NMR (400MHz, DMSO-d6) δ9.05(dd,J=4.2,1.7Hz,1H),8.55(dt,J=8.4,1.3Hz,1H),8.43(s,1H),8.40–8.28(m,2H),7.99(d,J=8.7Hz,1H),7.72(d,J =4.2Hz,1H),7.70(d,J=4.3Hz,1H),5.14(q,J=6.6Hz,1H),2.60–2.50(m, 2H)2.17(qd,J=7.4,5.8Hz,2H),2.00–1.60(m,4H),1.07(t,J=7.6Hz,3H).

[0191] Example 37

[0192] Synthesis of (R)-N-(4-(5-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide

[0193] The specific synthetic route is as follows:

[0194] Step A: Synthesis of 6-aminoquinoline-5-carbonitrile

[0195] 6-Nitroquinoline (2.0 g, 11.48 mmol), ethyl 2-cyanoacetate (3.9 g, 26.52 mmol), and potassium hydroxide (1.9 g, 33.86 mmol) were added to N,N-dimethylformamide (30 mL) and stirred at room temperature overnight. The next day, the solvent was evaporated under reduced pressure, and 10% aqueous hydrochloric acid (30 mL) was added, followed by reflux for 3 hours.

[0196] After the reaction was complete, the mixture was cooled and the pH of the reaction mixture was adjusted to 8 with saturated sodium hydroxide solution. The mixture was extracted with ethyl acetate (30 ml x 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: dichloromethane / ethyl acetate = 1 / 3) to obtain 1.9 g of 6-aminoquinoline-5-carbonitrile. [M+H] + =170.05.

[0197] Step B: Synthesis of 6-bromoquinoline-5-carbonitrile

[0198] 6-Aminoquinoline-5-carbonitrile (600 mg, 3.55 mmol) and cuprous bromide (609 mg, 4.26 mmol) were added to acetonitrile (12 mL). After 10 minutes, a solution of tert-butyl nitrite (474 ​​mg, 4.61 mmol) in acetonitrile (1 mL) was added. Under nitrogen protection, the mixture was heated to 60°C for 8 hours, then allowed to react at room temperature overnight. The next day, 1N aqueous hydrochloric acid (5 mL) was added and the reaction was continued for 3 hours.

[0199] After the reaction was complete, the mixture was extracted with ethyl acetate (20 ml x 3 times). The organic phases were combined, washed with saturated brine (20 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 4) to obtain 300 mg of 6-bromoquinoline-5-carbonitrile. [M+H] + =232.95.

[0200] Step C: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-5-carbonitrile

[0201] The synthesis method was similar to that of Example 26, Step C, to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-5-carbonitrile. [M+H] + =281.10.

[0202] Step D: (R)-N-(4-(5-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0203] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-5-carbonitrile undergo a coupling reaction to obtain (R)-N-(4-(5-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide as a white solid. [M+H] + =357.04.

[0204] Example 38

[0205] Synthesis of (R)-N-(4-(8-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0206] The specific synthetic route is as follows:

[0207] Step A: Synthesis of 6-chloroquinoline-8-carbonitrile

[0208] 8-Bromo-6-chloroquinoline (500 mg, 2.05 mmol), zinc cyanide (145 mg, 1.23 mmol) and tetrakis(triphenylphosphine)palladium (235 mg, 0.21 mmol) were added to N,N-dimethylformamide (5 mL) and microwaved at 130° C. for 45 minutes.

[0209] After the reaction was complete, the mixture was cooled and diluted with water. The mixture was extracted with ethyl acetate (20 ml x 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: n-hexane / ethyl acetate = 3 / 1) to obtain 380 mg of 6-chloroquinoline-8-carbonitrile. [M+H] + =189.14.

[0210] Step B: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-8-carbonitrile

[0211] 6-Bromoquinoline-5-carbonitrile (190 mg, 1.01 mmol), pinacol diboron (381 mg, 1.50 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (79 mg, 0.10 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (48 mg, 0.10 mmol) and potassium acetate (294 mg, 3.00 mmol) were added to dioxane (3 mL), replaced with nitrogen, and heated to 100° C. for reaction for 4 hours.

[0212] After the reaction was complete, the reaction mixture was diluted with water and extracted with ethyl acetate (10 ml x 3 times). The organic phases were combined, washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1 / 2) to obtain 160 mg of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-8-carbonitrile. [M+H] + =281.34.

[0213] Step C: (R)-N-(4-(8-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0214] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-8-carbonitrile undergo a coupling reaction to obtain (R)-N-(4-(8-cyanoquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propionamide as a white solid. [M+H] + =357.03. NMR data: 1 H NMR (400MHz, DMSO-d6) δ9.17(dd,J=4.2,1.8Hz,1H),8.63(dd,J=8.4,1.8Hz,1H),8.47(d,J=8.4Hz,2H),8.41(d,J=4.2Hz,2H),8.36(d,J=8.4Hz,1H),7. 82(dd,J=8.4,4.2Hz,1H),5.15(d,J=7.2Hz,1H),2.69(t,J=6.0Hz,2H),2.2 6–2.13(m,2H),1.98–1.92(m,1H),1.85–1.69(m,3H),1.09(t,J=7.6Hz,3H).

[0215] Example 39

[0216] Synthesis of (R)-N-(4-(8-methoxyquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0217] The specific experimental steps refer to Example 1 to obtain (R)-N-(4-(8-methoxyquinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =362.06. NMR data: 1 H NMR(400MHz,DMSO-d6)δ8.90(dd,J=4.2,1.8Hz,1H),8.41–8.31(m,3H),8.32 (d,J=8.4Hz,1H),7.61(dd,J=8.4,4.2Hz,1H),7.49(d,J=1.8Hz,1H),7.15(d ,J=1.8Hz,1H),5.15(q,J=6.6Hz,1H),4.01(s,3H),2.70(t,J=6.0Hz,2H),2. 25–2.12(m,2H),1.96–1.87(m,1H),1.86–1.68(m,3H),1.09(t,J=7.6Hz,3H).

[0218] Example 40

[0219] Synthesis of (R)-N-(4-(quinolin-6-yl-2-d)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0220] The specific synthetic route is as follows:

[0221] Step A: Synthesis of 6-bromoquinoline-1-oxide

[0222] To a solution of 6-bromoquinoline (208 mg, 1.0 mmol) in dichloromethane (5 ml) was added m-chloroperbenzoic acid (304 mg, 1.5 mmol) at room temperature, and the mixture was stirred while warming for 3 hours.

[0223] After the reaction is complete, add saturated sodium thiosulfate solution (20 ml) and stir for 30 minutes. Then add 2N sodium hydroxide solution to adjust the pH to 9, separate the layers, dry over anhydrous sodium sulfate, concentrate and use directly in the next step. [M+H] + =223.96.

[0224] Step B: Synthesis of 6-bromoquinoline-1-oxide-2d

[0225] To a solution of 6-bromoquinoline-1-oxide (224 mg, 1.0 mmol) in deuterated water (3 mL) was added sodium tert-butoxide (240 mg, 2.5 mmol) at room temperature, and the mixture was stirred under reflux for 5 hours. The reaction was completed by LCMS.

[0226] After the reaction is completed, water (20 ml) is added to dilute the mixture, and the mixture is extracted with dichloromethane (20 ml x 3 times). The mixture is then washed with saturated brine (20 ml x 3 times), separated, dried over anhydrous sodium sulfate, concentrated, and used directly in the next step. [M+H] + =224.92.

[0227] Step C: Synthesis of 6-bromoquinoline-2-d

[0228] Reduced iron powder (140 mg, 2.5 mmol) was added to a solution of 6-bromoquinoline-1-oxide-2-d (225 mg, 1.0 mmol) in acetic acid (3 ml) at room temperature, and the mixture was refluxed and stirred for 5 hours.

[0229] After the reaction is complete, the mixture is dried and diluted with water (20 ml). 2N sodium hydroxide solution is then added to adjust the pH to 9. The mixture is separated, dried over anhydrous sodium sulfate, concentrated, and filtered. The resulting solid is used directly in the next step. [M+H] + =209.02.

[0230] Step D: Synthesis of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-d

[0231] The synthesis method was similar to that of Example 26, Step C, to obtain 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-d. [M+H] + =257.10.

[0232] Step E: Synthesis of (R)-N-(4-(quinolin-6-yl-2-d)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide

[0233] The synthesis method is similar to that of Step H in Example 1. (R)-4-bromo-5,6,7,8-tetrahydroisoquinolin-8-amine and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-d undergo a coupling reaction to obtain (R)-N-(4-(quinolin-6-yl-2-d)-5,6,7,8-tetrahydroisoquinolin-8-yl)propanamide. [M+H] + =333.03. NMR data: 1H NMR (400MHz, DMSO-d6) δ8.45(d,J=8.3Hz,1H),8.42(s,1H),8.36(s,1H),8.33(d,J=8.4Hz,1H),8.12(d,J=8.6Hz,1H),8.01(d,J=1.9Hz,1H),7.79( dd,J=8.6,1.9Hz,1H),7.62(d,J=8.3Hz,1H),5.15(q,J=6.6Hz,1H),2.69– 2.63(m,2H),2.30–2.12(m,2H),1.97–1.65(m,4H),1.09(t,J=7.6Hz,3H).

[0234] Examples 41-43

[0235] Examples 44-46

[0236] Compounds 44A-46A were prepared by referring to the aforementioned preparation methods:

[0237] Example 47

[0238] Synthesis of 4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[0239] The specific synthetic route is as follows:

[0240] Step A: Synthesis of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one

[0241] 4-Bromo-6,7-dihydroisoquinolin-8(5H)-one was prepared by the method of Example 1. [M+H]+=226.05.

[0242] Step B: Synthesis of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-ol

[0243] To a solution of 4-bromo-6,7-dihydroisoquinolin-8(5H)-one (1.96 g, 8.67 mmol) in methanol (20 ml) was added sodium borohydride (0.39 g, 10.4 mmol) in portions at 0°C, and the mixture was stirred at 0°C for 20 minutes.

[0244] After the reaction, 10 ml of water was added to quench the reaction, and the solvent was removed by vortexing. 30 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (30 ml x 3). The combined organic phases were 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: methanol / dichloromethane = 1 / 10) to obtain 1.94 g of 4-bromo-5,6,7,8-tetrahydroisoquinolin-8-ol. [M+H]+ = 228.02.

[0245] Step C: Synthesis of 4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol

[0246] 4-Bromo-5,6,7,8-tetrahydroisoquinolin-8-ol (100 mg, 0.44 mmol) and 1-methyl-6-boronic acid pinacol ester-3,4-dihydroquinolin-2(1H)-one (134 mg, 0.53 mmol) were dissolved in a mixed solvent of 100 ml of dioxane and 20 ml of water. Cesium carbonate (285 mg, 0.88 mmol) and tetrakistriphenylphosphine palladium (25 mg, 0.022 mmol) were added. The mixture was protected by nitrogen and reacted at 85°C for 6 hours.

[0247] After the reaction, the resulting suspension was filtered, the filter cake was washed with dichloromethane, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 1 / 30) to obtain 149 mg of 4-(quinolin-6-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol. [M+H] + =277.11. 1 H NMR (400MHz, DMSO-d6) δ8.97 (dd, J=4.2, 1.7Hz, 1H), 8.64 (s, 1H), 8.43 (d, J= 7.9Hz,1H),8.34(s,1H),8.11(d,J=8.6Hz,1H),8.00(d,J=2.0Hz,1H),7.79( dd,J=8.6,2.0Hz,1H),7.60(dd,J=8.3,4.2Hz,1H),5.44(d,J=5.5Hz,1H),4. 78(q,J=5.5Hz,1H),2.70–2.54(m,2H),1.98–1.75(m,3H),1.69–1.59(m,1H).

[0248] Examples 48 and 49

[0249] The synthesis of the compounds of Examples 48 and 49 was carried out by referring to the method of Example 47. The specific structures and characterization data are as follows:

[0250] Compound 48: [M+H]+ =302.17; 1 H NMR (400MHz, DMSO-d6) δ8.72(d,J=8.4Hz,1H),8.66(s,1H),8.36(s,1H),8.23(d,J=8.8Hz,1H),8.18(d,J=1.9Hz,1H),8.12(d,J=8.4Hz, 1H),7.99(dd,J=8.7,2.0Hz,1H),5.46(d,J=5.5Hz,1H),4.79(q,J=5.5Hz,1H),2.71–2.55(m,2H),1.99–1.75(m,3H),1.69–1.60(m,1H).

[0251] Compound 49: [M+H] + =302.12; 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=5.6Hz,1H),8.68(s,1H),8.38–8.30(m,3H),8.25(d,J=1.6Hz,1H),8.00(dd,J=8. 5,1.7Hz,1H),5.47(d,J=5.5Hz,1H),4.79(q,J=5.5Hz,1H),2.70–2.56(m,2H),2.00–1.75(m,3H),1.70–1.60(m,1H).

[0252] Example 50 Biological Activity Evaluation

[0253] Detection method

[0254] Here, the inventors used the H295R Steroidogenesis Assay System to test the enzymatic activities of human CYP11B1, human CYP11B2, and others. The in vitro H295R Steroidogenesis Assay System utilizes a human adrenal cancer cell line (NCI-H295R cells) and constitutes a Level 2 "in vitro assay providing mechanistic data" for screening and prioritization purposes. The method was developed and standardized in a multi-step process for screening chemistries involved in steroidogenesis. The H295R assay has been optimized and validated according to the OECD Test Guideline No. 456 (H295R Steroidogenesis Assay).

[0255] Inhibition of aldosterone synthase

[0256] NCI-H295R cells can be purchased from ATCC. After culturing H295R cells from the original ATCC batch, the cells should be cultured for five passages (i.e., the cells divide four times). The cells at passage 5 should then be frozen in liquid nitrogen for storage.

[0257] H295R cells were cultured in a 37°C, 5% CO2 incubator, with medium changed 2-3 times weekly. Cells were passaged when they reached approximately 85-90% confluency. The medium was aspirated and washed three times with DPBS (Ca2+-free and Mg2+-free). Trypsin was added for 1-3 minutes. 3 mL of culture medium was added to terminate digestion and remove the cells. Remaining cells were then washed with 1 mL of culture medium and added to a 15 mL centrifuge tube. Centrifuge at 800 rpm for 5 minutes at room temperature. The supernatant was discarded, and the pellet was resuspended in 3 mL of culture medium. The cell suspension was counted. The edge wells of a 96-well plate were discarded, and 50,000 cells were plated per well in the remaining wells. 100 μL of 10% FBS DMEM:F12 (1:1) basal medium was added to each well. After overnight recovery, the medium was replaced with 150 μL of basal medium containing 10 μM forskolin per well and incubated for 48 hours. After 48 hours, the medium was replaced with 10 μM deoxycorticosterone. The compound was dissolved in DMSO to prepare a 100mM stock solution. Starting at 100mM, the DMSO was serially diluted 3-fold for a total of 10 concentration points. Each of the 10 concentration points was further diluted 10-fold with blank DMEM:F12 (1:1) medium, starting at a 10mM concentration. 1.5µL of each compound at each concentration was added to cells, resulting in a final DMSO concentration of 0.1% and a starting compound concentration of 100µM. After incubation for 48 hours, 40µL of the cell supernatant was collected and analyzed for aldosterone and cortisol levels by LCMS.

[0258] Cell viability assay

[0259] After collecting the supernatant, add 100 μL of 10% CCK8 detection reagent to each well and incubate at 37°C for 10 minutes. After swishing to mix, measure the OD value at 405 nm using a microplate reader. Set the 70% methanol group as the negative control and the DMSO solvent control group as the positive control. Calculate the OD value using the following formula:

[0260] %viable cells=(OD cmpd–OD Avg MeOH[=100%dead])÷(OD Avg SCs[=100%viability]–OD Avg MeOH[=100%dead])

[0261] Wells with viability below 80% should not be included in the final data analysis. In the presence of cytotoxicity approaching 20%, inhibition of steroidogenesis should be carefully evaluated to ensure that cytotoxicity is not the cause of inhibition. In addition, if cell viability exceeds 120%, the data should be flagged to identify potential false positives.

[0262] The inhibition rate was calculated using the following formula:

[0263] Inhibition rate %=(Peak Area Avg SCs-Peak Area cmpd) / (Peak Area Avg SCs-Peak Area blank)×100

[0264] Graphpad 9.0 was used for nonlinear regression curve fitting, with the logarithm of compound concentration as the abscissa and the inhibition rate as the ordinate, to calculate IC50 values ​​(Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X) * HillSlope))), Ki = IC50 / (1 + [S] / Km). The test results are shown in Table 1. Unless otherwise stated, all proteases were assumed to be competitively inhibited. Selectivity = CYP11B1Ki (nM) / CYP11B2Ki (nM); where A indicates a selectivity value between 0 and 50, B indicates a selectivity value between 51 and 100, C indicates a selectivity value between 101 and 150, and D indicates a selectivity value above 151.

[0265] Table 1 Inhibitory effects of compounds on CYP11B2

[0266] The experimental results in Table 1 show that the compounds of the present invention have a good inhibitory effect on CYP11B2, and the effect is better than that of the control compound Baxdrostat. In addition, the compounds of the present invention have excellent selectivity for CYP11B2 and can selectively inhibit CYP11B2 while weakly inhibiting CYP11B1.

[0267] Example 51 Pharmacokinetic Study in Rats

[0268] Experimental Materials

[0269] SD rats: male, 180-250 g, purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd.

[0270] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), normal saline, heparin, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0271] Instrument: AB SCIEX QTRAP 5500+.

[0272] Experimental methods

[0273] The compounds of Examples 1-49 of the present invention were weighed and dissolved in a DMSO-PEG-400-normal saline (5:60:35, v / v / v) system. After intravenous or oral administration to rats, 200 μL of venous blood was collected in EDTA-K2 anticoagulant tubes at 15 minutes, 30 minutes, 1 hour, 2 hours, 5 hours, 7 hours, and 24 hours (5 minutes additionally for the IV group). The blood was centrifuged at 12,000 rpm for 2 minutes, and the plasma was frozen at -80°C for testing. Accurately weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg / mL to prepare a stock solution. Accurately pipette an appropriate amount of the stock solution and dilute it with acetonitrile to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard series solutions, add 90 μL of blank plasma, vortex mix, and prepare plasma samples equivalent to plasma concentrations of 1, 3, 5, 10, 30, 100, 300, 1000, and 3000 ng / mL. Perform double sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma (plasma diluted 5 times 5 minutes, 15 minutes, and 30 minutes after intravenous administration), add 150 μL of acetonitrile solution of internal standard propranolol (50 ng / mL), vortex mix, add 100 μL of purified water, vortex mix again, centrifuge at 4000 rpm for 5 minutes, and take the supernatant for LC-MS analysis. LC-MS detection conditions are as follows:

[0274] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0275] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0276] Data processing

[0277] After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The test results are shown in Table 2.

[0278] Table 2 Pharmacokinetic results of the compounds of the present invention in rats

[0279] The experimental results in Table 2 show that the compounds of the present invention have good pharmacokinetic characteristics in SD rats. max and AUC last All of them were superior to the positive control, with good absorption, high absolute bioavailability, and half-life comparable to or better than that of the control compound.

[0280] Example 52 In vitro liver microsome stability study in different animal species

[0281] Preparation of stock solution and working solution

[0282] The compound of Example 1-49 (test sample) and the positive drug were dissolved in DMSO to obtain a 10 mM stock solution, which was diluted with acetonitrile-water (1:1, v / v) to obtain a 100 μM solution, and then further diluted with 0.1 M potassium phosphate buffer solution to obtain a 30 μM working solution.

[0283] Weigh NADPH powder and dissolve it in 0.1 M potassium phosphate buffer solution to obtain a 5 mg / mL solution.

[0284] Each type of liver microsome (20 mg / mL) was diluted with 0.1 M potassium phosphate buffer solution to a 0.8 mg / mL liver microsome working solution.

[0285] Liver microsome stability assay

[0286] 25 μL of the test article or positive drug working solution was added to 475 μL of liver microsome working solution and mixed thoroughly. The mixture was aliquoted into 96-well plates at 30 μL / well (n=2). 150 μL of internal standard acetonitrile solution was added to the 0-min sample to precipitate the protein. Then, 15 μL of NADPH solution was added and the plate was placed in a 4°C refrigerator. After preincubation of the other samples at 37°C for 10 min, 15 μL of NADPH solution was added to the 20-min and 60-min samples to initiate the reaction. 15 μL of potassium phosphate buffer solution was added to the sample without NADPH, and the plates were incubated at 37°C. After the reaction time expired, 150 μL of internal standard acetonitrile solution was added to precipitate the protein.

[0287] The precipitated sample was vortexed and centrifuged at 4000 rpm for 5 min. 100 μL of purified water was added to the supernatant and analyzed by LC-MS.

[0288] Data Analysis

[0289] The peak area ratio of the analyte to the internal standard is used to calculate the relative percentage content (residual rate %) of the compound after incubation and perform exponential function fitting. The calculation formula is as follows:

[0290] Residual rate % = peak area ratio of analyte to internal standard at each time point / peak area ratio of analyte to internal standard at time 0 × 100

[0291] CL Hep (liver clearance) = (0.693 / t 1 / 2 )×1 / (liver microsome concentration (0.5 mg / mL))×conversion factor

[0292] CL invivo (Clearance in vivo) = CL Hep * Liver blood flow / (CL Hep + liver blood flow)

[0293] ER (extraction rate) = CLin vivo / Hepatic blood flow

[0294] Physiological parameters

[0295] Classification criteria: slow metabolism (ER < 0.3), medium metabolism (0.3 < ER < 0.7), fast metabolism (ER > 0.7).

[0296] The test results are shown in Table 3.

[0297] Table 3 Stability of the compound in human liver microsomes

[0298] The experimental results in Table 3 show that the stability of the compound of the present invention in human liver microsomes is better than that of the positive drug Baxdrostat.

[0299] Pharmacokinetic study of the compound in cynomolgus monkeys in Example 53

[0300] Experimental materials

[0301] Cynomolgus monkeys: male, 180 - 250 g, purchased from Guangxi Xiongsen Primate Experimental Animal Breeding and Development Co., Ltd.

[0302] Reagents: DMSO (dimethyl sulfoxide), PEG400, normal saline, heparin, acetonitrile, formic acid, propranolol (internal standard) are all commercially available.

[0303] Instruments: AB SCIEX 7500.

[0304] Experimental methods

[0305] Weigh the compound and dissolve it in DMSO-PEG-400-saline (5:60:35, v / v / v). After gavage administration to cynomolgus monkeys, collect 200 μL of venous blood into EDTA-K2 anticoagulant tubes at 30, 60, 90, 2, 3, 5, 8, and 24 hours. Centrifuge at 12,000 rpm for 2 minutes, and freeze the plasma at -80°C for testing. Accurately weigh a certain amount of the test sample and dissolve it in DMSO to 2 mg / mL to prepare a stock solution. Accurately pipette an appropriate amount of the stock solution and dilute it with acetonitrile to prepare a series of standard solutions. Accurately pipette 10 μL of each of the above standard series solutions, add 90 μL of blank plasma, vortex mix, and prepare plasma samples equivalent to plasma concentrations of 0.3, 1, 3, 10, 30, 100, 300, 1000, and 3000 ng / mL. The quality control sample plasma concentration is 2.4, 120, and 2400. Perform double sample analysis for each concentration to establish a standard curve. Take 30 μL of plasma, add 150 μL of acetonitrile solution of internal standard propranolol (50 ng / mL), vortex mix, add 100 μL of purified water, vortex mix again, centrifuge at 4000 rpm for 5 minutes, and take the supernatant for LC-MS analysis. The LC-MS detection conditions are as follows:

[0306] Chromatographic column: YMC Triart C18, 50*3.0mm, 2.1μm.

[0307] Mobile phase: water (0.1% formic acid)-acetonitrile with gradient elution as shown in the table below.

[0308] Data processing

[0309] After LC-MS detection of blood drug concentration, WinNonlin 6.1 software was used to calculate the pharmacokinetic parameters using the non-compartmental model method. The test results are shown in Table 4.

[0310] Table 4 Pharmacokinetic results of the compounds of the present invention in cynomolgus monkeys

[0311] The experimental results in Table 4 show that the compounds of the present invention have good pharmacokinetic characteristics in cynomolgus monkeys. The exposure after oral administration is higher or equivalent to that of the positive control Baxdrostat. max and AUC last All of them are superior to the positive control, with more advantageous half-life, good absorption and high absolute bioavailability.

[0312] It should be understood that the above embodiments are preferred implementations of the present invention, but the implementation of the present invention is not limited to the above embodiments. For ordinary technicians in this field, they can make improvements or changes based on the above description, and all these improvements and changes should fall within the scope of protection of the claims attached to the present invention.

Claims

1. A compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the compound is as shown in Formula I or Formula IA:wherein,R1 and R2 are each independently selected from H, halogen, hydroxyl, cyano, substituted orunsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, C1-C6 alkylsulfonyl, substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;R5 is independently selected from substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3-8 membered heterocycloalkyl, substituted or unsubstituted C6-C12 aryl or substituted or unsubstituted 5-12 membered heteroaryl;ring A is independently selected from 5-12 membered fused heteroaryl or C10-C12 aryl;the substituents in the above “substituted” are each independently selected from one or more of C1-C8 alkyl, halo C1-C8 alkyl, C1-C8 alkoxy, halo C1-C8 alkoxy, -NR3R4, hydroxyl, oxo, carboxyl, cyano, halogen, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, C1-C6 alkylamido, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, 3-8 membered heterocycloalkyl, 3-8 membered heterocycloalkyloxy, C3-C8 cycloalkyl-substituted C1-C8 alkoxy, C6-C12 aryl, C6-C12 aryloxy, C1-C8 alkyl-substituted C6-C12 aryloxy, C1-C8 alkoxy-substituted C6-C12 aryloxy, halo C1-C8 alkyl-substituted C6-C12 aryloxy, 512 membered heteroaryl, 5-12 membered heteroaryloxy, C1-C8 alkyl-substituted 5-12 membered heteroaryloxy, C1-C8 alkoxy-substituted 5-12 membered heteroaryloxy or halo C1-C8 alkylsubstituted 5-12 membered heteroaryloxy;R3 and R4 are each independently selected from H or C1-C8 alkyl;n, p or q are each independently selected from an integer of 0, 1, 2 or 3.

2. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the structure of the compound is as shown in Formula IIIA, Formula IIIB, Formula IIIC or Formula IIID:IIIBHIDwherein, the definitions of R1, ring A and n are the same as in claim 1.

3. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable saltthereof according to any one of claims 1-2, characterized in that ring A is selected from4. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that R1 and R2 are each independently selected from H, hydroxyl, halogen, cyano, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkoxy, C3-C8 cycloalkyl, C3-C8 cycloalkyloxy, C1-C6 alkylsulfonyl, C1-C6 alkylacyl, 3-8 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl.

5. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that R1 and R2 are eachindependently selected from H, hydroxyl, F, Cl, cyano, methyl, methoxy, trifluoromethyl, methylsulfonyl, or cyclopropyloxy.

6. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, characterized in that the compound is selected from the following compounds:No. Structure No. Structure No. Structure 1 ■'''nV 1A ''AZ 'A 1B Hl aA\ XX XX a AA / AyAN^A^ L L H N 2 2A Xv....... 'A 2B nA, |1 1 XX XX a A / AAAA-'NAA L L H N 3 Xp* zpX IZ 3A c4 AA IZ V 3B cX ZMA IZ r 4 (x XX XX a A^AiAA nA / I L H N 4A X^x IZ r 4B 4^4 z^xx IZ 5 44 Xi n I N "A / LL J H N 5A 44 XX XXl a AA / AyAA / L H N 5B iX aA,      „ XX XX a AAyAA-'NA / L L H N 6 4 vX XX \=z o 6A fPP N^ Xa   ^a XX XX a ciXX:^ A 6B Xi XX XX A o^^XXn 7 aX N, An          „ XX XX a L H N 7A X| nA\ Xi XX a A^yAA^N^A / L L H N 7B X| AaA AL A i AyA / ''Na L J H8 ZI AA / z o z 8A NC^x xXa 8B X ZI MXz Xm o 9 111 N k             - XX XX x F X H N 9A XiA..... 9B XX a.A\ xX jO 1 X^XXXXa^^ i O H N 11 F3C ^ 7 I nJ       „ XX XX a I 2 H N 11A CF’YJ ■ 1, <v 11B F’°A. ’'kA 12 111 XX jXXX a XjAX^n^^ i O H N 12A Xa- 12B xx A. O H A A A A. A / Y A A ''N I I X H A 13 o XX XX X X O H N 13A Xa’...... 13B XX N „ A O H A A A A A / ^AAAA zn X IX H 14 IM XX XX X f"^XXjX ^IA 14A XX XX XX ? k^ II 1 ^A U f                  n ( H N 14B xx / A AAA A / F     Af A ''N II J H KA 15 XX nA. / \ „ XX XX a I I H N 15A XX xx xx ? k^ II 1 (A U I H N 15B xx n-A\ XX ? A^ AAA A / X 'N I J H A 16 Syf,V 16A |A n. A.          ~ XX XX ? k A 1 r«L N I H N 16B n^A H nA iX XX ? A A A A- A •^ A' A 'N 1 X H N 17 17A iiX Xn XX ? k II 1 <A 11 kf A^n I H N 17B AA.....18 ‘’''nV 18A Aa-..... A 18B A,r^L 'A 19 N= / 19A N=A o' A xx xx 1 i h N 19B / N=Y A A YA A x '^'■''^A t Y H N 20 N—A Xx«^ 20A N-NZ A [ XX XX a i j h N 20B n-nZ A9 =3........ A 22 7w'' 22A "N A O ft AAA "A A ( H N 22B ^-N A O H A A A A A / ^AT A 'N Il H N 23 YY- Y x XY a I h N 23A W..... N^ 23B aa / ...... 'A 24 Xl £X 1 I 1 H N 24A Aa;..... 'A 24B -AA..... A 25 r-s Xl XX a I J H N 25A A,A;..... A 25B aa°....... A 26 N'X X ^X nc'^a''^ A^A o I Y H N 26A '° u"=: 26B A ZI <X3z yXY z \ o z 27 ZI MY? XX z \ ,o ,w O' \ 27A ’• 'jM 27B Av 28 =4 ZT Qa XY z \ 28A N^X A Xy. xYl n a yayAann / V- / tL J H N 28B C I-29 CN 29A CN ’ / V 29B CN n^Y I Y XX At X Il / H N 31 0 Jx l! jTI a \XXYyzY / I J H N 31A X / X " / / 31B - / / YY / - / 32 HXY -: =■ 32A -:-- 32B HOXJ -', / / 33 XT N. X. XI Cl A --^ I J H N 33A 1 - / / 33B Xi M X H A A A A- A / / / <—< 'N / / I d H N 34 F N. A\ Yx XX a I J H N 34A 1 / , / 34B F / A / \ XI X ? A A A A- A / / / / ^ / 'N / / I d H N 35 hX N. X / / \ YX Cl a / -YiY'^n'^ / I d H N 35A x N^ X\ / Air ri ? k X 1 (ryL JI / Y ^N It J H N 35B Xi YX X h A A A A- A / / / [<—< 'N / / I d H N 36 111 n. Y / \  „ yx XX X / ' / Y'n -' I J H N 36A Yd n. J. ,f /    „ YX X u AAA ^A A I / H N 36B Xi XX [i ? A A A A- A / / YY ’'N — I d H N 37 X N Ac Nx ° / YyXXnX / i j h N 37A X N. J. .CN / \ YX X ? AAA Y A . / / Yi Yr N / / I / H N 37B Xi YC A ? A A A A- A / / / Ar a / / I d H N 38 Xi XXXX a n c •'a / AXA n X / I J H N 38A AA N\A / y Xx fl ? 1. II       1 (R)l JI nc ^ y X n I d H N 38B iX YY X h 1. AAA- A nc / / / ■ / / ''n / / I d H N 39 iX XX XX a °"Y 39A Xj fl ? \ Xa. A A xL A / 0 ^ Y I d H N 39B / ZT / xXz XM \=z O / 41 A-' 41A pJ PX yj / TZ r 41B X ?....... 'GT 42 €1 N ii                  0 j h N 42A ° o‘ 42B / AN 0' G,! . NT 43 z o ry) zXa IZ r 43A INC I 1 XI £X a I 4 H N 43B »4 ZI ^X3z fx o z 44 z o X) ZZ r 44A z o pp IZ r 44B jX NC'i^ii fX 0 'X'X --N X / 4 4 H N 45 !-,GG 45A A Gy 45B A Xii ri ? k 1 1 A. JL N X    ''N 4 4 H N 46 »4 ZI Qa z=< pp \=Z 46A X’ 46B X X" n        O L k A A- A / ' / ■' / G / ''N 4 4 H N 47 Ay. N 47A I o op ^= Z 47B Xi n\Xg, XX 14 X J ''^''X , / oh 'NT 48 z o zx / =44 Xp o 48A xa ^hT 48B X p / =2 o z 49 I o Q\ / X XX z \ o z 49A N^A jl 1 nc^gjA AA AA 49B z o z0x 6 X7. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, characterized in that one or more hydrogen atoms of the compound are substituted by the isotope deuterium (2H).

8. The compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that the compound substituted by deuterium is selected from the following structures:No. Structure No. Structure No. Structure 40 ■4 ZI / z Q 40A V'l -V 40B V*.

9. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises the compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, and one or more pharmaceutically acceptable excipients and / or carriers.

10. Use of the compound, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating or preventing diseases associated with elevated activity level of CYP11B2.

11. The use according to claim 10, characterized in that the diseases associated with elevated activity level of CYP11B2 are selected from hypertension, chronic kidney disease, primary aldosteronism, diabetic nephropathy, congestive heart failure or Cushing’s syndrome.