N-alkoxy acetamide compound, pharmaceutical composition thereof, and use thereof

Abstract

Disclosed in the present invention are an N-alkoxy acetamide compound, a pharmaceutical composition thereof, and use thereof. Specifically, the present invention provides a compound represented by formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. The compound of the present invention can effectively treat or prevent chronic kidney disease, congestive heart failure, hypertension, complications of hypertension, or primary aldosteronism, for example, hypertension or primary aldosteronism.

Description

An N-alkoxyacetamide compound, a pharmaceutical composition thereof and application thereof

[0001] This application claims priority to Chinese patent application 2024106853942 with a filing date of 2024 / 5 / 30 and Chinese patent application 2025107114162 with a filing date of 2025 / 5 / 29. This application incorporates the entire text of the above-mentioned Chinese patent applications. TECHNICAL FIELD

[0002] The present application relates to an N-alkoxyacetamide compound, a pharmaceutical composition thereof and application thereof. BACKGROUND

[0003] The renin-angiotensin-aldosterone system (RAAS) is the core regulatory system of human blood flow blood pressure and water-salt balance, in which aldosterone is a key regulatory molecule downstream of the system. Aldosterone is a kind of steroid hormone (salt corticosteroid family), which promotes the reabsorption of water and sodium in the distal tubule and collecting duct epithelial cells by binding and activating the salt corticosteroid receptor (MR), while inducing the excretion of potassium and hydrogen ions, maintaining the balance of water and electrolytes, participating in maintaining proper blood pressure, vascular tension and tissue perfusion. In addition, recent studies have shown that aldosterone can also up-regulate the expression of AT1R on vascular smooth muscle cells, change the tension of vascular smooth muscle, the response to vasoconstrictor signals and the structure of arterial wall, increase the pressure response of blood vessels to norepinephrine, cause blood pressure to rise, vascular smooth muscle cell proliferation, vascular wall thickening and hyalinization.

[0004] Under normal circumstances, the plasma aldosterone concentration is regulated by related stimulating factors such as RAAS, blood potassium concentration, adrenocorticotropic hormone (ACTH), etc. Elevated aldosterone levels can induce blood pressure disorders, cause inflammation, vascular remodeling and tissue fibrosis related to cardiac metabolic diseases, ultimately leading to decreased organ function, cardiovascular complications, end-stage kidney disease, and increased risk of death. Therefore, countering the harmful effects of excess aldosterone in the body of patients has been a targeted clinical strategy for many years.

[0005] For aldosterone and its receptor related cardio-renal system diseases, blocking the effect of aldosterone is an effective treatment method. Aldosterone receptor antagonists (MRA) and renin-angiotensin-aldosterone system antagonists (RAS inhibitors) are currently used in clinical therapy to antagonize aldosterone. MRA (such as spironolactone) inhibits the effect of aldosterone by competitive binding to the mineralocorticoid receptor, while RAS inhibitors (such as sartan drugs) indirectly reduce aldosterone levels by blocking the upstream stimulation of angiotensin II. Clinically, on the one hand, MRA can over-antagonize the receptor effect (the aldosterone receptor can also be stimulated by estrogen), and there are off-target side effects of androgen receptor antagonism, and on the other hand, RAS inhibitors are not completely inhibited by excessive aldosterone, and there are clinical drug resistance problems. Therefore, specific inhibitors of aldosterone synthase (ASI) that directly inhibit the synthesis of aldosterone can completely reduce the production of aldosterone while not producing additional effects, and can be an efficient iterative product of MRA and RAS inhibitors.

[0006] Aldosterone synthase (encoded by the CYP11B2 gene) controls the synthesis of aldosterone, catalyzes the last step of the synthesis of aldosterone from cholesterol, and has been a pharmacological target for the treatment of hypertension for decades. Potassium ions, angiotensin II, and leptin can activate the production of CYP11B2, and then synthesize aldosterone. Importantly, CYP11B2 is the only enzyme that catalyzes the final oxidation to generate aldosterone, and is mainly expressed in the glomerular zone of the adrenal gland, and is basically not produced in other parts of the body, so it is expected that there will be no off-target effects.

[0007] Because the enzyme that produces aldosterone and the enzyme that produces cortisol are 93% identical (CYP11B1, which is a cortisol synthase, is the final enzyme in the cortisol synthesis pathway), this high degree of similarity leads to cross-reactivity and inhibition of cortisol synthesis by early aldosterone synthase inhibitors. Therefore, it is currently difficult and painful to develop a drug that can inhibit the production of aldosterone without affecting cortisol.

[0008] LCI699 is the first aldosterone synthase inhibitor with oral activity and enters the clinical trial for the treatment of primary aldosterone hyperplasia. After oral administration of LCI699, the plasma aldosterone level is found to be reduced, and the blood pressure is reduced. However, LCI699 has poor selectivity for CYP11B2 and CYP11B1, and has a more inhibitory effect on the cortisol synthase, resulting in side effects. Therefore, it cannot be developed for hypertension indications due to poor patient tolerance. Thereafter, a new generation of highly selective ASI inhibitors is developed in clinical trials, and currently only a few products have entered clinical trials.

[0009] Patent US20230365513 A1 discloses the specific structure of Lorundrostat, Lorundrostat (Mineralys) is a highly selective aldosterone synthase inhibitor, which inhibits aldosterone synthase CYP11B2, reduces the level of aldosterone in vivo, and does not inhibit CYP11B1 (www.mineralystx.com). Another compound is Baxdrostat (CinCor Pharma / AstraZeneca), preclinical studies of Baxdrostat show that Baxdrostat has 100 times more inhibitory effect on aldosterone synthase than on cortisol synthesis, and is a highly selective aldosterone synthesis inhibitor, which can dose-dependently reduce plasma aldosterone levels by >70% (New Eng. J. Med. 2023, Vol 388, p395).

[0010] Although there are two clinical research products, it is not yet clear whether they will ultimately prove safe and effective in large clinical phase III. Therefore, a highly selective aldosterone synthase inhibitor with better selectivity, higher safety and better effectiveness is still needed by patients. SUMMARY

[0011] The technical problem to be solved by the present application is to provide a highly selective aldosterone synthase inhibitor with a new structure. The present application aims to provide a novel N-alkoxyacetamide compound, a pharmaceutical composition thereof and an application thereof. Such compounds have a strong inhibitory effect on aldosterone synthase, have little effect on cortisol synthase, have high selectivity, have high safety, and have good application prospects in the prevention and / or treatment of various diseases related to aldosterone.

[0012] The present application solves the above technical problems by the following technical solutions.

[0013] The present application provides a compound as shown in formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

[0014] wherein,

[0015] R 1 is H, halogen, -CN, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0016] R 2 is H, C1-C6 alkyl, C1-C6 alkyl substituted with 1, 2 or 3 R 2-3 , C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted with 1, 2 or 3 R 2-1substituted C3-C7cycloalkyl, "4-8 membered heterocycloalkyl, 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3", 1, 2 or 3 R 2-2 substituted "4-8 membered heterocycloalkyl, 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3", C6-C 10 aryl, 1, 2 or 3 R 2-3 substituted C6-C 10 aryl, "5-10 membered heteroaryl, 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3" or 1, 2 or 3 R 2-3 substituted "5-10 membered heteroaryl, 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3";

[0017] R 2-1 independently R 2-3 or -NR a -C(=O)-R 2-1-1 ;

[0018] R 2-1-1 is C1-C6alkyl or C1-C6alkoxy;

[0019] R 2-2 independently R 2-3 or -C(=O)-C1-C6alkyl;

[0020] R 2-3 independently halogen, -CN, -NO2, -OR a , -NR b R c , -C(=O)-OR a , -C(=O)-NR b R c , C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C7cycloalkyl, "4-8 membered heterocycloalkyl, 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3", C6-C 10 aryl or "5-10 membered heteroaryl, 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3";

[0021] R a , R b and R c are independently H, C1-C6alkyl or C1-C6haloalkyl.

[0022] R 4hydrogen, deuterium, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C3-C7cycloalkyl, “4-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms,” C6-C 10 aryl or “5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms.”

[0023] or R 4 and R 2 together with the intervening atoms to which they are attached form a 4-10 membered heterocycloalkyl; said heterocycloalkyl containing, in addition to the attached N, O atoms, 0, 1, 2, or 3 additional heteroatoms selected from N, O, and S;

[0024] R 3 independently are hydrogen, deuterium, oxo (=O), halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C3-C7cycloalkyl, “4-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms,” C6-C 10 aryl or “5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms.”

[0025] n is 0, 1, 2, or 3;

[0026] m is 0 or 2; when m is 0, R 5 is absent;

[0027] when m is 2, the two R 5 together with the C to which they are attached form a C3-C7cycloalkyl or “4-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms”; or, two adjacent R 5 together with the C to which they are attached form a C3-C7cycloalkyl or “4-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms”;

[0028] X = CH or N;

[0029] Ring A is C6-C 10 aryl or “5-10 membered heteroaryl having 1, 2, or 3 heteroatoms selected from N, O, and S, and 1, 2, or 3 occurrences of said heteroatoms.”

[0030] The present application provides a kind of as shown in formula (I) compound, its pharmaceutically acceptable salt or its stereoisomer,

[0031] Wherein, R 1 It is H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy;

[0032] R 2 It is H, C1-C6 alkyl, C1-C6 alkyl substituted by 1, 2 or 3 R 2-3 , C3-C7 cycloalkyl, C3-C7 cycloalkyl substituted by 1, 2 or 3 R 2-1 , "4-8 membered heterocycloalkyl, 1, 2 or 3 of which are selected from N, O and S, and the number of heteroatoms is 1, 2 or 3", "4-8 membered heterocycloalkyl, 1, 2 or 3 of which are selected from N, O and S, and the number of heteroatoms is 1, 2 or 3", C6-C 2-2 Aryl, C6-C 10 Aryl, "5-10 membered heteroaryl, 1, 2 or 3 of which are selected from N, O and S, and the number of heteroatoms is 1, 2 or 3", or "5-10 membered heteroaryl, 1, 2 or 3 of which are selected from N, O and S, and the number of heteroatoms is 1, 2 or 3", substituted by 1, 2 or 3 R 2-3 ; 10 ; 2-3 ;

[0033] R 2-1 It is independently R 2-3 , -NR a , -C(=O)-R 2-1-1 ;

[0034] R 2-1-1 It is C1-C6 alkyl or C1-C6 alkoxy;

[0035] R 2-2 It is independently R 2-3 , or -C(=O)-C1-C6 alkyl;

[0036] R 2-3 It is independently halogen, -CN, -NO2, -OR a , -NR b R c , -C(=O)-OR a , -C(=O)-NR b R cC1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C7cycloalkyl, "4-8 membered heterocycloalkyl wherein the heteroatoms are selected from 1, 2, or 3 N, O, and S, and the number of heteroatoms is 1, 2, or 3," C6-C10aryl, or "5-10 membered heteroaryl wherein the heteroatoms are selected from 1, 2, or 3 N, O, and S, and the number of heteroatoms is 1, 2, or 3;" 10 C6-C10aryl or "5-10 membered heteroaryl wherein the heteroatoms are selected from 1, 2, or 3 N, O, and S, and the number of heteroatoms is 1, 2, or 3;"

[0037] R a , R b , and R c are independently H, C1-C6alkyl, or C1-C6haloalkyl.

[0038] In certain preferred embodiments of the application, certain groups in the compounds (including those of Formula (I) and Formula (II)), pharmaceutically acceptable salts thereof, or stereoisomers thereof, are defined as follows, and the groups not mentioned are as described in any of the schemes of the application (simply referred to as "in a scheme of the application"). The halogen is independently fluorine, chlorine, bromine, or iodine, preferably fluorine.

[0039] In a scheme of the application, the C1-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl, preferably methyl, i-propyl, or t-butyl.

[0040] In a scheme of the application, the C3-C7cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferably cyclobutyl.

[0041] In a scheme of the application, the 4-8 membered heterocycloalkyl is independently 5- or 6-membered heterocycloalkyl wherein the heteroatoms are N or O, and the number of heteroatoms is 1, preferably tetrahydropyrrolyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl, for example

[0042] In a scheme of the application, each C6-C10aryl is independently phenyl or naphthyl; for example, phenyl. 10 C6-C10aryl or "5-10 membered heteroaryl wherein the heteroatoms are selected from 1, 2, or 3 N, O, and S, and the number of heteroatoms is 1, 2, or 3;"

[0043] In a scheme of the application, the 4-10 membered heterocycloalkyl is independently 6-8 membered bicyclic heterocycloalkyl wherein the heteroatoms are selected from 1 or 2 N and O; and the number of heteroatoms is 3, for example

[0044] In a scheme of the application, R 1 is C1-C6alkyl or C1-C6haloalkoxy; for example, C1-C6haloalkoxy.

[0045] In a certain embodiment of the present application, R 2 is independently selected from the group consisting of Ci-C6-alkyl, C3-C7- cycloalkyl, "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3", "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is substituted by 1, 2 or 3 R 2-1 is independently selected from the group consisting of Ci-C6-alkyl, C3-C7- cycloalkyl, "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3", "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is substituted by 1, 2 or 3 R 2-2 is independently selected from the group consisting of Ci-C6-alkyl, C3-C7- cycloalkyl, "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3", "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is substituted by 1, 2 or 3 R 2-1 is independently selected from the group consisting of Ci-C6-alkyl, C3-C7- cycloalkyl, "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3", "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is substituted by 1, 2 or 3 R 2-2 is independently selected from the group consisting of Ci-C6-alkyl, C3-C7- cycloalkyl, "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3", "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is substituted by 1, 2 or 3 R 2-1 is independently selected from the group consisting of Ci-C6-alkyl, C3-C7- cycloalkyl, "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3", "4- to 8-membered heterocycloalkyl, wherein the heteroatoms are selected from the group consisting of N, O and S, and the number of heteroatoms is 1, 2 or 3, which is substituted by 1, 2 or 3 R

[0046] In a certain embodiment of the present application, R 2-1 is -NR a -C(=O)-R 2-1-1 .

[0047] In a certain embodiment of the present application, R 2-1-1 is Ci-C6-alkyl.

[0048] In a certain embodiment of the present application, R 2-2 is independently R 2-3 or -C(=O)-Ci-C6-alkyl.

[0049] In a certain embodiment of the present application, R a is H.

[0050] In a certain embodiment of the present application, n is 0.

[0051] In a certain embodiment of the present application, R 4 is hydrogen.

[0052] In a certain embodiment of the present application, X is N.

[0053] In a certain embodiment of the present application, ring A is C6-C 10 aryl.

[0054] In a certain embodiment of the present application, R 1 is -CH3 or is preferably

[0055] In an embodiment of the present application, R 2 is is preferably is more preferably

[0056] In an embodiment of the present application, R 2 is is preferably is more preferably is further preferably,

[0057] In an embodiment of the present application, the 4-10 membered heterocycloalkyl is

[0058] In an embodiment of the present application, ring A is phenyl.

[0059] In an embodiment of the present application, the compound of formula (II) is a compound of formula (II-1),

[0060] wherein R 1 , R 2 and R 4 are as defined in any one of the present application.

[0061] In an embodiment of the present application, the compound of formula (I) is a compound of formula (I-1),

[0062] wherein R 1 and R 2 are as defined in any one of the present application.

[0063] In an embodiment of the present application, wherein the compound is:

[0064] The present application also provides a pharmaceutical composition comprising:

[0065] (1) the above-mentioned compound of formula (I), pharmaceutically acceptable salt thereof or stereoisomer thereof; and

[0066] (2) a pharmaceutically acceptable excipient.

[0067] The present application also provides the use of the above-mentioned compound of formula (I), pharmaceutically acceptable salt thereof or stereoisomer thereof, the above-mentioned pharmaceutical composition, which use is selected from:

[0068] (1) preparing an aldosterone synthase inhibitor;

[0069] (2) preparing a medicament for the treatment and / or prevention of a disease or condition, which is chronic kidney disease, congestive heart failure, hypertension, a complication of hypertension, or primary aldosteronism; preferably hypertension or primary aldosteronism; preferably the hypertension is resistant hypertension;

[0070] (3) preparing a medicament for the treatment and / or prevention of a disease or condition associated with aldosterone synthase; which is chronic kidney disease, congestive heart failure, hypertension, a complication of hypertension, or primary aldosteronism; preferably hypertension or primary aldosteronism; preferably the hypertension is resistant hypertension.

[0071] Explanation of terms

[0072] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the application.

[0073] The term "halogen" means fluorine, chlorine, bromine, or iodine.

[0074] The term "alkyl" means a straight or branched chain alkyl group having the number of carbon atoms specified (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.

[0075] The term "haloalkyl" means an alkyl group substituted with halogen, wherein halogen and alkyl are as defined above.

[0076] The term "deuteroalkyl" means an alkyl group substituted with deuterium, wherein alkyl is as defined above.

[0077] The term "alkynyl" means a straight or branched chain monovalent hydrocarbon group having at least one unsaturated location, i.e., a carbon-carbon sp triple bond (e.g., C2-C6alkynyl).

[0078] The term "alkoxy" means the group R Z -O-, wherein R Z is alkyl as defined above.

[0079] The term "haloalkoxy" means an alkoxy group substituted with halogen, wherein halogen and alkoxy are as defined above.

[0080] The term "deuteroalkoxy" means an alkoxy group substituted with deuterium, wherein alkoxy is as defined above.

[0081] The term "cycloalkyl" refers to a saturated monocyclic ring radical consisting only of carbon atoms having the specified number of carbon atoms (e.g., C3-C7). Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0082] The term "heterocycloalkyl" refers to a cyclic, saturated, monovalent radical having the specified number of ring atoms (e.g., 4-8 membered or 4-10 membered), the specified number of heteroatoms (e.g., 1, 2, or 3), and the specified kind of heteroatoms (one or more of N, O, and S). Heterocycloalkyl groups are attached to the remainder of the molecule through a carbon atom or a heteroatom. Heterocycloalkyl groups include, but are not limited to: and the like.

[0083] The term "aryl" refers to a cyclic, unsaturated hydrocarbon radical having the specified number of carbon atoms (e.g., C6-C 10 ) which is monocyclic or polycyclic (e.g., 2 or 3), sharing two atoms and one bond between the rings when polycyclic, and each ring having aromaticity. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0084] The term "heteroaryl" refers to a cyclic radical having the specified number of ring atoms (e.g., 5-10 membered), the specified number of heteroatoms (e.g., 1, 2, or 3), and the specified kind of heteroatoms (one, two, or three of N, O, and S), which is monocyclic or polycyclic, and each ring having aromaticity (complying with Hückel's rule). Heteroaryl groups are attached to the remainder of the molecule through a carbon atom or a heteroatom; heteroaryl groups are attached to the remainder of the molecule through a ring having heteroatoms or a ring having no heteroatoms. Heteroaryl groups include, but are not limited to, furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, indole, benzopyrrole, and the like.

[0085] The term "pharmaceutically acceptable salt" includes "pharmaceutically acceptable salts with organic or inorganic acids" and "pharmaceutically acceptable salts with organic or inorganic bases".

[0086] The term "stereoisomer" includes configurational isomers, wherein configurational isomers include optically active isomers, e.g., enantiomers, diastereomers, or mixtures thereof.

[0087] The term "pharmaceutically acceptable excipient" refers to any formulation or carrier medium that is capable of delivering an effective amount of active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative excipients include water, oils, vegetables and minerals, ointment bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, and the like.

[0088] The term "pharmaceutical composition" denotes a mixture or solution of a therapeutically effective amount of an active pharmaceutical ingredient with a pharmaceutically acceptable excipient which is ready for administration to a mammal, such as a human in need of such treatment.

[0089] The term "treatment" relates to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the act of treating as defined before.

[0090] The above-mentioned preferred conditions can be combined arbitrarily without departing from the common general knowledge of the skilled person, i.e. to obtain preferred embodiments of the present application.

[0091] The reagents and starting materials used in the present application are commercially available.

[0092] The positive progress effect of the present application is that:

[0093] (1) The present application provides an aldosterone synthase inhibitor having a novel structure.

[0094] (2) The compound provided by the present application has the following advantages: ① superior hCYP11B2 inhibitory activity, good hCYP11B2 inhibitory activity, weak hCYP11B1 inhibitory activity, and excellent hCYP11B2 / hCYP11B1 selectivity; ② excellent pharmacokinetic properties and high safety: strong membrane permeability, good plasma protein binding rate, and good metabolic stability in liver S9. DETAILED DESCRIPTION

[0095] The present application will be further described by way of examples, but the present application is not limited to the examples described below. The experimental methods in the following examples, for which no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the commercial products.

[0096] The starting materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art

[0097] Example 1 (S)-N-((1-acetylpiperidin-3-yl)oxy)-2-(4-(5-(p-tolyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0098] Step one:

[0099] Intermediate 1 (5 g, 39.3 mmol) was dissolved in THF (150 mL), cooled to 0 °C, and Intermediate 2 (1 M in THF, 78.6 mL, 78.6 mmol) was added dropwise. After the addition was complete, the mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to 0 °C and quenched with 1 N HCl. The pH was adjusted to neutral with saturated NaHC03. After the addition of EA, the mixture was washed with water, dried over Na2S04, filtered, concentrated, and EA (20 mL) and n-hexane (40 mL) were added. The mixture was slurried and filtered to give yellow solid of Intermediate 3 (6.07 g, yield: 71%).

[0100] LCMS (ESI) m / z: 218.1 [M+H] + .

[0101] 1 H NMR (400 MHz, CDCl3) δ 10.29 (s, 1H), 8.33 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 3.56 (s, 3H), 2.42 (s, 3H).

[0102] Step two:

[0103] Intermediate 3 (6.07 g, 27.94 mmol) was added to DCM (120 mL) and m-CPBA (14.2 g, 83.81 mmol) in DCM was added. The mixture was stirred at room temperature overnight, quenched with Na2S203, and saturated NaHC03 / water was added. The aqueous phase was extracted with DCM and the combined DCM was washed with saturated NaCl, dried over Na2S04, filtered, and concentrated. The mixture was slurried with EA:n-hexane = 2:1, filtered to give yellow solid of Intermediate 4 (3.22 g, yield: 46%).

[0104] LCMS (ESI) m / z: 250.1 [M+H] + .

[0105] 1 H NMR (400 MHz, DMSO) δ 10.32 (s, 1H), 8.35 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 3.59 (s, 3H), 2.45 (s, 3H).

[0106] Step three:

[0107] Intermediate 4 (3.22 g, 12.92 mmol) and intermediate 5 (4.64 g, 25.83 mmol) were added to ACN (100 mL) and stirred at room temperature overnight. After adding water, the ACN was evaporated, extracted with DCM, and the solvent was evaporated. Purification was performed by reverse phase column with ACN: water (0.1% NH4HCO3) = 80% to obtain intermediate 6 (1.58 g, yield: 35%) as a yellow liquid.

[0108] LCMS (ESI) m / z: 342.2 [M+H] + .

[0109] 1 H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 8.22 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 4.02 - 3.91 (m, 4H), 3.37 (s, 2H), 2.75 - 2.68 (m, 4H), 2.46 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H).

[0110] Step four:

[0111] Intermediate 6 (1.58 g, 4.63 mmol) was dissolved in ethanol (20 mL) / THF (20 mL), 2M NaOH (3.0 mL) was added, and the mixture was stirred at room temperature overnight. The reaction was complete according to TLC detection. The solvent was evaporated under reduced pressure to obtain 1.62 g of crude intermediate 7, which was directly used in the next step.

[0112] LCMS (ESI) m / z: 314.2 [M+H] + .

[0113] Step five:

[0114] (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (intermediate 8, 4 g, 21.36 mmol) was dissolved in THF (200 mL), and intermediate 9 (14.95 g, 64.09 mmol) was added at 0 °C. Potassium tert-butoxide (7.2 g, 64.09 mmol) was added portionwise. The mixture was stirred at 0 °C overnight. Water (100 mL) and saturated sodium chloride (100 mL) were added, and the mixture was stirred at room temperature for 30 min. Extraction was performed with EA (100 mL*3), and the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate 10 (3.0 g, yield: 69%) as a yellow oil.

[0115] Step six:

[0116] Intermediate 10 (360 mg, 1.78 mmol), intermediate (597 mg, 1.78 mmol) and DIEA (575 mg, 4.45 mmol) were added to DMF (10 mL), and HATU (681 mg, 1.79 mmol) was added. The mixture was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated, and column chromatography (DCM:EtOH = 20:1) was used for purification to obtain intermediate 11 (320 mg, yield: 36%) of yellow solid product.

[0117] LCMS (ESI) m / z: 498.2 [M+H] + .

[0118] 1 H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.28 (s, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 4.51 (s, 1H), 3.92 (s, 4H), 3.45 (dd, J = 6.8, 5.3 Hz, 1H), 3.29 (dd, J = 11.4, 7.5 Hz, 3H), 3.03 (s, 2H), 2.59 (s, 4H), 2.40 (s, 3H), 2.04 (s, 1H), 1.96 - 1.85 (m, 1H), 1.40 (s, 9H).

[0119] Step seven:

[0120] Intermediate 11 (320 mg, 0.64 mmol) was added to DCM (10 mL), and HCl / EA (10 mL) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated to obtain intermediate 12 as a yellow solid crude product, which was directly used in the next step.

[0121] LCMS (ESI) m / z: 398.4 [M+H] + .

[0122] Step eight:

[0123] Intermediate 12 (400 mg, 1.01 mmol), acetic acid (78 mg, 1.31 mmol) and DIEA (390 mg, 3.02 mmol) were added to DMF (10 mL), and HATU (497 mg, 1.31 mmol) was added. The mixture was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with 30 mL of ethyl acetate, washed with water (10 mL*2) and saturated sodium chloride solution (10 mL*2) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. Reverse phase C 18Preparative chromatography purification (acetonitrile: water (0.1% NH4HCO3) = 72%) afforded Example 1 (53 mg, yield: 12.1%) 53 mg yellow solid.

[0124] LCMS (ESI) m / z: 440.2 [M+H] + .

[0125] 1 H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.28 (s, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.56 (d, J = 18.4 Hz, 1H), 3.93 (s, 4H), 3.53 (ddt, J = 26.5, 19.9, 10.8 Hz, 4H), 3.05 - 2.99 (m, 2H), 2.64 - 2.54 (m, 4H), 2.40 (s, 3H), 2.19 - 1.89 (m, 5H).

[0126] Following the similar experimental procedure, using (1s,3s)-3-hydroxycyclobutylcarbamic acid tert-butyl ester and (1R,3R)-3-hydroxycyclobutylcarbamic acid tert-butyl ester instead of intermediate 8 in Example 1, respectively, gave Examples 2 and 2a were synthesized:

[0127] Example 2 N-((1S,3S)-3-acetylamino cyclobutyloxy)-2-(4-(5-(p-tolyl)-1,2,4-triazin-3- yl)piperazin-1-yl)acetamide

[0128] LCMS (ESI) m / z: 440.2 [M+H] + .

[0129] 1 H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.28 (s, 1H), 8.15 (t, J = 9.5 Hz, 3H), 7.38 (d, J = 8.1 Hz, 2H), 4.12 (p, J = 7.2 Hz, 1H), 3.92 (s, 4H), 3.75 (dt, J = 16.3, 7.9 Hz, 1H), 2.99 (s, 2H), 2.57 (d, J = 4.5 Hz, 4H), 2.49 - 2.42 (m, 2H), 2.40 (s, 3H), 1.94 (ddd, J = 16.9, 9.1, 2.8 Hz, 2H), 1.77 (s, 3H).

[0130] Example 2a N-((1R,3R)-3-acetamidocyclobutoxy)-2-(4-(5-(p-tolyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0131] LCMS(ESI) m / z: 440.2 [M+H] + .

[0132] 1 H NMR (400MHz, DMSO) δ11.04(s,1H),9.28(s,1H),8.16(d,J=8.2Hz,3H),7.39(d,J=8.0Hz,2H),4.50(dq,J=9.8,3.3Hz,1H),4.28(dq ,J=14.3,7.2Hz,1H),3.92(s,4H),3.00(s,2H),2.64–2.54(m,4H),2.40(s,3H),2.36–2.27(m,2H),2.12–2.01(m,2H),1.78(s,3H).

[0133] Example 3: N-(tert-butoxy)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0134] Step 1:

[0135] Intermediate 13 (35 g, 156.94 mmol) was dissolved in THF (100 mL), cooled to 0 °C, and isopropyl magnesium chloride-lithium chloride (1.3 M, 145 mL, 188.33 mmol) was added dropwise. After the addition was complete, the mixture was heated to room temperature and stirred overnight. The reaction solution did not require further treatment and was directly used for the next step.

[0136] Step Two:

[0137] Intermediate 1 (10 g, 78.64 mmol) was dissolved in 50 mL of THF and added dropwise to the reaction solution from step one at 0 °C. After the addition was complete, the mixture was brought to room temperature and stirred overnight. The reaction solution was cooled to 0 °C, quenched with 100 mL of 1 N HCl, and the pH was adjusted to neutral with saturated sodium bicarbonate solution. 200 mL of ethyl acetate was added, and the mixture was washed with saturated sodium chloride solution (200 mL * 2), dried over anhydrous sodium sulfate, filtered, concentrated, and toluene (150 mL) and DDQ (11 g) were added to the residue. The mixture was stirred for 40 min. The reaction solution was washed with saturated sodium chloride solution (100 mL * 2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was mixed with n-hexane (40 mL) and EA (20 mL) and filtered to obtain intermediate 15 as a yellow solid product (5.8 g, yield: 25%).

[0138] LCMS(ESI) m / z: 270.0 [M+H] + .

[0139] 1 H NMR (400MHz, DMSO) δ9.81 (s, 1H), 8.45–8.34 (m, 2H), 7.62 (s, 0.25H), 7.44 (s, 0.5H), 7.39 (d, J = 8.8Hz, 2H), 7.26 (s, 0.25H), 2.68 (s, 3H).

[0140] Step 3:

[0141] Intermediate 15 (2.9 g, 10.77 mmol) was dissolved in DCM (90 mL), and a turbid solution of m-CPBA (5.5 g, 32.31 mmol) in DCM was added. The mixture was stirred overnight at room temperature, quenched with 50 mL of 10% sodium thiosulfate solution, and then 50 mL of saturated sodium bicarbonate aqueous solution was added. The mixture was separated into layers, and the aqueous phase was extracted with DCM (50 mL * 2). The organic phases were combined, washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The residue was mixed with 10 mL of ethyl acetate and 5 mL of ethanol, and a solid precipitated out. The mixture was filtered and dried to obtain intermediate 16 (1.6 g, yield: 49%) as a yellow solid.

[0142] LCMS(ESI) m / z: 302.1 [M+H] + .

[0143] 1 H NMR (400MHz, DMSO) δ10.36 (s, 1H), 8.56–8.50 (m, 2H), 7.67 (s, 0.25H), 7.49 (s, 0.5H), 7.46 (d, J = 8.9Hz, 2H), 7.31 (s, 0.25H), 3.60 (s, 3H).

[0144] Step Four:

[0145] Intermediate (1.6 g, 5.31 mmol) and 1-(ethoxycarbonylmethyl)piperazine (intermediate 5, 2.3 g, 13.28 mmol) were added to ACN (50 mL) and stirred overnight at room temperature. The reaction mixture was then diluted with 100 mL of water, extracted with DCM (50 mL x 3), and the organic phases were combined, concentrated, and purified by HPLC (acetonitrile:water (0.1% NH4HCO3) = 85%) to give intermediate 17 (1 g, yield: 48%).

[0146] LCMS(ESI) m / z: 394.2 [M+H] + .

[0147] 1 H NMR (400MHz, DMSO) δ9.32 (s, 1H), 8.37–8.30 (m, 2H), 7.60 (s, 0.25H), 7.42 (s, 0.5H), 7.36 (d, J = 8.8Hz, 2H), 7 .23(s,0.25H),4.11(q,J=7.1Hz,2H),3.91(d,J=4.7Hz,4H),3.32(s,2H),2.66(s,4H),1.21(t,J=7.1Hz,3H).

[0148] Step 5:

[0149] Intermediate 17 (1 g, 2.54 mmol) was dissolved in ethanol (20 mL) / THF (20 mL), 2 M NaOH (2 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was evaporated to obtain crude intermediate 18, which was then directly used for the next reaction.

[0150] LCMS(ESI) m / z: 366.1 [M+H] + .

[0151] Step Six:

[0152] Intermediate 18 (200 mg, 0.52 mol), o-tert-butylhydroxylamine hydrochloride (98 mg, 0.77 mmol), and DIEA (200 mg, 1.55 mmol) were added to DMF (6 mL), followed by the addition of HATU (295 mg, 0.77 mmol). The mixture was stirred overnight at room temperature, diluted with 20 mL of ethyl acetate, washed with saturated sodium chloride solution (10 mL * 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by HPLC (acetonitrile:water (0.1% NH4HCO3) = 50%) to obtain the yellow solid of Example 3 (50 mg, yield 22%).

[0153] LCMS(ESI) m / z: 437.2 [M+H] + .

[0154] 1 H NMR (400MHz, DMSO) δ10.37(s,1H),9.32(s,1H),8.34(d,J=8.9Hz,2H),7.60(s,0.25H),7.42(s,0.5H ),7.36(d,J=8.8Hz,2H),7.24(s,0.25H),3.92(s,4H),3.03(s,2H),2.66–2.56(m,4H),1.17(s,9H).

[0155] Following a similar experimental method, Examples 4-11 were synthesized:

[0156] Example 4 2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-N-isopropoxyacetamide

[0157] LCMS(ESI) m / z: 423.1 [M+H] + .

[0158] 1 H NMR(400MHz,DMSO)δ10.82(s,1H),9.31(s,1H),8.36–8.30(m,2H),7.60(s,0.25H),7.42(s,0.5H),7.35(m,2H),7 .23(s,0.25H),4.02(dp,J=12.4,6.2Hz,1H),3.93(s,4H),3.00(s,2H),2.64–2.55(m,4H),1.15(d,J=6.2Hz,6H).

[0159] Example 5 N-((1S,3S)-3-acetamidocyclobutoxy)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0160] LCMS(ESI) m / z: 491.7 [M+H] + .

[0161] 1 HNMR (400MHz, DMSO) δ11.02 (s, 1H), 9.32 (s, 1H), 8.40–8.29 (m, 2H), 8.15 (d, J = 7. 5Hz,1H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8.8Hz,2H),7.24(s,0.25H),4 .12(p,J=7.3Hz,1H),3.93(s,4H),3.76(dq,J=16.4,8.2Hz,1H),3.00(s,2H),2.63 –2.55(m,4H),2.50–2.41(m,2H),1.94(ddd,J=14.0,9.1,4.6Hz,2H),1.77(s,3H).

[0162] Example 5a N-((1R,3R)-3-acetamidocyclobutoxy)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0163] LCMS(ESI) m / z: 491.7 [M+H] + .

[0164] 1 H NMR (400MHz, DMSO) δ11.05(s,1H),9.31(s,1H),8.33(d,J=8.9Hz,2H),8.17(d,J=7 .2Hz,1H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8.8Hz,2H),7.23(s,0.25H), 4.55–4.44(m,1H),4.29(dq,J=14.4,7.3Hz,1H),3.93(s,4H),3.00(s,2H),2.58(s ,4H),2.33(ddd,J=13.3,8.2,3.2Hz,2H),2.10–2.02(m,2H),1.77(d,J=6.2Hz,3H).

[0165] Example 6 (S)-N-((1-acetylpyrrolidone-3-yl)oxy)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0166] LCMS(ESI) m / z: 491.7 [M+H] + .

[0167] 1 H NMR (400MHz, DMSO) δ11.13(d,J=6.5Hz,1H),9.32(s,1H),8.34(d,J=8.7Hz,2H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8.6Hz,2H),7 .23(s,0.25H),4.56(d,J=18.2Hz,1H),3.93(s,4H),3.54(ddt,J=26.6,20.0,11.0Hz,4H),3.04(s,2H),2.59(s,4H),2.18–1.87(m,5H).

[0168] Example 6a (R)-N-((1-acetylpyrrolidone-3-yl)oxy)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0169] LCMS(ESI) m / z: 492.2 [M+H] + .

[0170] 1 H NMR (400MHz, DMSO) δ11.13(d,J=7.0Hz,1H),9.32(s,1H),8.34(d,J=8.8Hz,2H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8.8 Hz,2H),7.24(s,0.25H),4.63–4.49(m,1H),3.93(s,4H),3.70–3.38(m,4H),3.04(s,2H),2.64–2.55(m,4H),2.18–1.83(m,5H).

[0171] Example 7 2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-N-((tetrahydro-2H-pyran-4-yl)oxy)acetamide

[0172] LCMS(ESI) m / z: 464.9 [M+H] + .

[0173] 1 H NMR (400MHz, DMSO) δ10.95(s,1H),9.32(s,1H),8.34(d,J=8.9Hz,2H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8.8Hz,2H),7.23(s,0.25H),3 .99(td,J=8.5,4.2Hz,1H),3.93(s,4H),3.87–3.80(m,2H),3.41–3.35( m,2H),3.02(s,2H),2.59(s,4H),1.90–1.80(m,2H),1.55–1.44(m,2H).

[0174] Example 8 (S)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-N-((tetrahydrofuran-3-yl)oxy)acetamide

[0175] LCMS(ESI) m / z: 450.8 [M+H] + .

[0176] 1 H NMR (400MHz, DMSO) δ11.11(s,1H),9.31(s,1H),8.40–8.29(m,2H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8.8Hz,2H),7.23(s ,0.25H),4.62(s,1H),3.93(s,4H),3.82(dt,J=15.3,9.0Hz,2H),3.72–3.59(m,2H),3.02(s,2H),2.59(s,4H),2.07–1.88(m,2H).

[0177] Example 8a (R)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-N-((tetrahydrofuran-3-yl)oxy)acetamide

[0178] LCMS(ESI) m / z: 451.0 [M+H] + .

[0179] 1 H NMR (400MHz, DMSO) δ11.10(s,1H),9.31(s,1H),8.36–8.30(m,2H),7.59(s,0.25H),7.41(s,0.5H),7.36(d,J=8.8Hz,2H),7.23(s,0. 25H),4.62(s,1H),3.93(s,4H),3.82(dt,J=15.3,9.0Hz,2H),3.73–3.60(m,2H),3.01(s,2H),2.65–2.56(m,4H),2.07–1.92(m,2H).

[0180] Example 9 N-((1-acetylpiperidin-4-yl)oxy)-2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)acetamide

[0181] LCMS(ESI) m / z: 505.8 [M+H] + .

[0182] 1H NMR (400MHz, DMSO) δ10.98(s,1H),9.32(s,1H),8.41–8.31(m,2H),7.60(s,0. 25H),7.42(s,0.5H),7.36(d,J=8.8Hz,2H),7.23(s,0.25H),4.08–3.98(m,1H ),3.93(s,4H),3.79–3.70(m,1H),3.70–3.59(m,1H),3.29–3.18(m,2H),3.02 (s,2H),2.65–2.57(m,4H),2.00(s,3H),1.92–1.72(m,2H),1.65–1.37(m,2H).

[0183] Example 10a 2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-N-((3aS,6aS)-oxacyclopentane[3,4-d]isoxazole-2(3H)-yl)acetamide

[0184] LCMS(ESI) m / z: 463.2 [M+H] + .

[0185] 1 H NMR (400MHz, DMSO) δ7.80–7.73(m,2H),7.28-7.05(m,4H),7,4.08–3.60(m,5H),3.30-3.20(m,2H),3.15-3.08(m,6H),2.30–2.16(m,5H).

[0186] Example 11 2-(4-(5-(4-(difluoromethoxy)phenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-N-cyclobutoxyacetamide

[0187] LCMS(ESI) m / z: 435.2 [M+H] + .

[0188] 1 H NMR (400MHz, DMSO) δ10.25(s,1H),9.30(s,1H),8.35-8.20(m,2H),7.60(s,0.25H),7.42(s,0.5H),7.36(d,J=8 .8Hz,2H),7.24(s,0.25H),4.02-3.95(m,1H),3.92(s,4H),3.03(s,2H),2.66–2.56(m,4H),2.50-2.20(m,6H).

[0189] Experimental Example 1: Inhibitory activity of compound on hCYP11B2 / hCYP11B1

[0190] 1. Experimental system: G-402CYP11B2 or CYP11B1 high-expression stable transgenic strains

[0191] The above-mentioned high-expression stable transgenic strains were constructed based on the human adrenal leiomyosarcoma cell line G-402 (ATCC, CRL-1440), and artificial lentiviruses were introduced into human CYP11B2 (NM_000498.3) and CYP11B1 (NM_000497.4), respectively.

[0192] Maintenance medium: McCoy's 5A (modified, #16600082, GIBCO) + 10% FBS (GIBCO) + 1 μg / mL puromycin (A1113803, GIBCO).

[0193] Resuscitation and seeding medium: McCoy's 5A (modified, #16600082, GIBCO) + 10% FBS (GIBCO).

[0194] Reaction medium: DMEM / F12 (#11320033, GIBCO) + 2.5% activated carbon filtered FBS (S11695, R&D).

[0195] 2. Experimental steps:

[0196] Seeding plates: After cell resuscitation, culture the cells in maintenance medium until they reach a suitable state, and seed them in 96-well flat-bottom plates at a rate of 1×10⁴ / 100μL / well (uniform cell quantity).

[0197] Medium change: After the seed plate adheres to the wall overnight (>12 hours), the supernatant is aspirated and washed with 100-150 μL / well of serum-free medium. After aspiration, 50 μL / well of reaction medium is added for later use.

[0198] Preparation: Dilute the compound with reaction medium containing 0.4 μM substrate (final experimental concentration: 0.2 μM).

[0199] CYP11B2 substrate: 11-deoxycorticosterone (S4243, selleckchem), with a final reaction concentration of 0.2 μM.

[0200] CYP11B1 substrate: 11-deoxycortisol (S4775, selleckchem), with a final reaction concentration of 0.2 μM.

[0201] Sample loading: Add the above compound dilution to the cell plate at a rate of 50 μL / well, and set up background wells and control wells at the same time.

[0202] Sample processing and collection: After adding the sample, incubate in a cell culture incubator for 16 hours, then spin each cell plate at 450g for 2 minutes, take 75μL of supernatant and transfer it to a collection plate, freeze at -80℃ for later use (or directly detect).

[0203] Detection: The concentration of aldosterone or cortisol in the supernatant was determined using a homogeneous time-resolved fluorescence kit (Cisbio HTRF kit, Cat.64ALDPEG, Cat.62CRTPEG).

[0204] Analysis: The absolute IC50 values ​​for each compound were calculated using a four-parameter fitting method. 50 (Abs IC 50 ).

[0205] Table 1. Inhibitory activity of some compounds against hCYP11B2

[0206] Table 2 shows the inhibitory activity of some compounds against hCYP11B1 and their selectivity for hCYP11B1 / 2.

[0207] The results in Tables 1 and 2 show that, compared with the reference Lorundrostat, the compounds of the present invention exhibit superior inhibitory activity against hCYP11B2 and weaker inhibitory activity against hCYP11B1. Specifically, Example 3 demonstrates 7 times the inhibitory activity against hCYP11B2 of Lorundrostat, with even better selectivity for hCYP11B2. This superior activity and selectivity are expected to result in high clinical safety and patient compliance, demonstrating significant clinical value and applicability.

[0208] Effect Experiment Example 2: Permeability Test

[0209] 1. Experimental Objective: To evaluate the permeability and efflux rate of the compounds in the examples using an MDR1-MDCKII monolayer cell model, and to determine the permeabilities of the compounds.

[0210] 2. Experimental Procedure: MDR1-MDCKII cells (from Piet Borst of the Netherlands Cancer Institute) were seeded in 96-well plates at a cell density of 3.33 x 10⁵ cells / mL and cultured for 4-7 days to form a copolymerized cell monolayer. Hank's balanced salt buffer (pH = 7.42) containing 10 mM 2-[4-(2-Hydroxyethyl)-1-piperazinyl]ethanesulfonic acid (HEPES) was used as the transport buffer.

[0211] The test compounds were diluted to a concentration of 2.00 μM (DMSO < 1.0%) using transfer buffer and then spread onto the top (A) or basal (B) side of a cell monolayer. Detection was repeated in the A-to-B and B-to-A directions. Digoxin was tested at a concentration of 10.0 μM in both the A-to-B and B-to-A directions, while naldolol and metoprolol were tested at a concentration of 2.0 μM in the A-to-B direction. Plates were incubated at 37 °C, 5.0% CO2, and saturated humidity for 2.5 h without shaking. After 2.5 h, end samples were collected from both the donor and acceptor sides of each well and then analyzed by LC-MS / MS.

[0212] After the initial assay, a lucifer yellow rejection assay was performed to determine the integrity of the cell monolayer. Buffer was removed from the top and basal chambers, and then 75 μL of transfer buffer containing 100 μM lucifer yellow and 250 μL of transfer buffer were added to the top and basal chambers, respectively. The plates were incubated at 37°C in a CO2 incubator for 30 minutes at 5.0% CO2 concentration and saturated humidity without shaking. After 30 minutes of incubation, 20 μL of lucifer yellow sample was taken from the top, and then 60 μL of transfer buffer was added. Subsequently, 80 μL of lucifer yellow sample was extracted from the basal chamber. The relative fluorescence units (RFU) of lucifer yellow were measured using an Envision multi-plate reader at 425 / 528 nm wavelength (excitation / emission).

[0213] The apparent permeability coefficient (P) is calculated using the following formula. app (cm / s) and efflux ratio (ER).

[0214] V R : Basal chamber volume (50 μL on top, 250 μL on bottom);

[0215] C R : Basal compartment concentration;

[0216] C0: Initial concentration in the top chamber;

[0217] Area: Surface area of ​​a single cell layer;

[0218] Time: time period;

[0219] P app (BA): From bottom to top;

[0220] P app (AB): From top to bottom;

[0221] The results are shown in the table below:

[0222] Table 3. Results of permeability tests on compounds from the examples.

[0223] Conclusion: The compounds of this invention are highly permeable and low efflux compounds with good drug-like properties, and have better permeability than Lorundrostat.

[0224] Experimental Example 3: Plasma Protein Binding Rate Test of the Compound

[0225] 1. Experimental Objective: To evaluate the protein binding rate of the compounds in the examples in cynomolgus monkey and human plasma using the equilibrium dialysis method.

[0226] 2. Experimental Procedure:

[0227] 2.1 Dilution of test and control compounds

[0228] Dilute 4 μL of the test compound stock solution with 96 μL of DMSO to prepare a working solution (400 μM) of the test compound.

[0229] To prepare a working solution (400 μM), dilute 4 μL of the DMSO stock solution of the control compound (Lorundrostat) with 96 μL of DMSO.

[0230] Prepare a 2 μM loading matrix solution of the test compound by diluting and mixing 3 μL of the working solution of the test compound with 597 μL of blank matrix (Thermo, #28372).

[0231] Dilute 3 μL of the working solution with 597 μL of blank matrix and mix thoroughly to prepare a 2 μM supported matrix solution of the control compound.

[0232] 2.2 Transfer three 50 μL portions of the loading matrix containing the test compound or control compound to a sample collection plate. Prepare a final volume of 100 μL by mixing the sample with the corresponding blank PBS at a matrix-to-PBS volume ratio of 1:1 (v:v). Immediately add the matrix-to-PBS mixture to each well at a 1:1 (v:v) volume ratio. Add 500 μL of stop solution (acetonitrile containing 250 nM toluene-butyronitrile) to the T0 samples of the test and control compounds. Seal the plate and shake at 800 rpm for 10 minutes. Then store these T0 samples together with other post-dialysis samples at 2–8 °C for further processing.

[0233] 2.3. Assemble the dialysis unit according to the manufacturer's instructions. Transfer 100 μL of the loaded matrix solution containing the test compound or control compound to the sample side of each dialysis well, in triplicate. Then, load 100 μL of PBS onto the sample side of each dialysis well. Rotate the dialysis plate in a humidified incubator at 37°C and 5% CO2 at approximately 100 rpm for 4 hours. After dialysis, collect 50 μL of sample from both the PBS (recipient) and matrix (donor) sides of the dialysis unit and place them into a new 96-well plate (sample collection plate). Add an equal volume of the opposite blank PBS or matrix to each sample to bring the final volume to 100 μL. The matrix volume ratio is 1:1 (v:1), and the matrix to PBS volume ratio in each well is 1:1 (v:v). Add 500 μL of stop solution to these samples.

[0234] 2.4 After protein precipitation, LC / MS / MS analysis was performed, and the free compound concentration and plasma protein binding rate were calculated using the formulas: Free compound concentration (%) = 100 * Fc / T, Plasma protein binding rate (%) = 100% - Free compound concentration (%). Fc is the concentration of the compound at the buffer end of the dialysis plate; T is the concentration of the compound at the plasma end of the dialysis plate. The results are as follows:

[0235] Table 4. Results of plasma protein binding rates of the compounds in the examples.

[0236] Conclusion: The compounds in the examples showed moderate binding to plasma proteins of different species, with a moderate proportion of free drug in the plasma, indicating good drug-like properties.

[0237] Experimental Example 4: In vitro study of liver S9 metabolic stability

[0238] Objective: To evaluate the metabolic stability of the test compound in liver S9.

[0239] Experimental Procedure: Transfer 100 μL of S9 solution into reaction plates (blank, T0, T5, T15, T30, T45, T60, and NCF60). Add 2 μL of the test compound solution (final concentration 1 μM) to all 96-well reaction plates except for the blank (T0, T5, T15, T30, T45, T60, and NCF60). Incubate the reaction plates containing the compound and S9 solution mixture at 37°C for 10 minutes. Add 98 μL of 100 mM potassium dihydrogen phosphate buffer to the NCF60 reaction plate.

[0240] After pre-incubation, 98 μL of cofactor working solution (2.71 mM NADP (nicotinamide adenine dinucleotide phosphate), 6.88 mM G6P (glucose-6-phosphate), 0.83 unit / mL G6PDH (glucose-6-phosphate dehydrogenase), 5.21 mM UDPGA (uridine diphosphate glucuronide), 0.21 mM PAPS (3'-adenosine-5'-phosphate sulfate), 10.42 mM GSH (glutathione), and 6.88 mM MgCl2 in 100 mL potassium phosphate buffer) was added to each reaction plate except NCF60 (blank, T0, T5, T15, T30, T45, and T60), and the reaction plates were incubated at 37 °C.

[0241] At the end time point, add 600 μL of stop solution (pre-cooled acetonitrile containing 250 nM toluenesulfonate) to terminate the reaction. Shake for 10 minutes, then centrifuge at 3220 x g for 20 minutes at 4 °C.

[0242] 100 μL of supernatant was transferred to 300 μL of pure water, mixed with a plate shaker for 10 minutes, and then analyzed by LC-MS / MS. The results are shown in the table below:

[0243] Table 5. Stability results of the compounds in human liver S9.

[0244] Conclusion: The compounds in this embodiment exhibited low clearance rates and good stability in the liver S9 cells of humans, rats, and cynomolgus monkeys.

[0245] Example 5: Pharmacokinetic Study of the Test Substance in Cynomolgus Monkeys

[0246] 1. Experimental objective: To study the pharmacokinetic behavior of the compounds of this invention when orally administered in cynomolgus monkeys, using cynomolgus monkeys as test animals.

[0247] 2. Experimental design: Three male adult cynomolgus monkeys of suitable weight and age were selected, with an acclimatization period of one week.

[0248] 3. Compound Preparation: Weigh 15 mg of the test compound and dissolve it directly in DMA (dimethylacetamide) to prepare a DMA stock solution of 10 mg / mL. Take 1.44 mL of the stock solution and add 7.2 mL of 30% Solutol and 57.6 mL of Saline. Vortex and mix until the DMA:30% Solutol:Saline ratio is 10:10:80 (v:v:v). Add an appropriate amount of 0.5 M HCl to adjust the pH to approximately 3-4 until the solution is completely dissolved, yielding a mixed drug solution with a final concentration of 0.2 mg / mL, for oral gavage administration.

[0249] 4. Administration: After fasting overnight, administer orally via gavage at a dose of 1 MPa.

[0250] 5. Sample collection:

[0251] Oral administration procedure: Crab-eating macaques were administered the medication via nasogastric feeding. After administration, the preparation was flushed with 3 mL (approximately three times the volume of the feeding tube). All tubes were of equal size and cut to the same length to control the flushing volume. On the day of administration, each group of cynomolgus macaques received a single oral dose of the mixed medication solution at a dose of 1 mg / kg. 0.5 mL of blood was collected venously at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-administration and placed in EDTA-K2 anticoagulant tubes.

[0252] Sample collection: Place the collected whole blood in an EDTA-K2 anticoagulant tube, invert it several times to mix thoroughly, store it on wet ice, and centrifuge (1500-1600g) for 10 minutes within 30 minutes to separate the plasma. Store the obtained plasma sample in an environment of -90 to -60°C for biological sample analysis.

[0253] Plasma drug concentrations were analyzed using linear regression. The corresponding pharmacokinetic parameters were calculated using a non-compartmental model in Pharsight Phoenix 8.3. The results are as follows.

[0254] Table 6. Pharmacokinetic results of the compounds in the examples in cynomolgus monkeys.

Claims

1. A compound as shown in Formula (II), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, R 1 H, halogen, -CN, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy; R 2 It is H, C1-C6 alkyl, and surrounded by 1, 2 or 3 Rs. 2-3 Substituted C1-C6 alkyl, C3-C7 cycloalkyl, with 1, 2 or 3 R 2-1 Substituted C3-C7 cycloalkyl, "a 4-8 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or surrounded by one, two, or three R atoms. 2-2 The substituted "heteroatom is selected from one, two or three of N, O and S, and is a 4-8 membered heterocyclic alkyl group with one, two or three heteroatoms" and C6-C 10 aryl, with 1, 2 or 3 R 2-3 Replacement C6-C 10 aryl, "a 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R 2-3 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-10 membered heteroaryl groups with one, two, or three heteroatoms. R 2-1 independently R 2-3 or -NR a -C(=O)-R 2-1-1 ; R 2-1-1 Ci-C6-alkyl or Ci-C6-alkoxy; R 2-2 independently R 2-3 or -C(=O)-C1-C6alkyl; R 2-3 independently halogen, -CN, -NO2, -OR a , -NR b R c , -C(=O)-OR a , -C(=O)-NR b R c , C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, C3-C7cycloalkyl, "4-8 membered heterocycloalkyl, with 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3", C6-C 10 aryl or "5-10 membered heteroaryl, with 1, 2 or 3 heteroatoms selected from N, O and S, the number of heteroatoms being 1, 2 or 3"; R a , R b , and R c are independently H, C1-C6alkyl, or C1-C6haloalkyl; R 4 hydrogen, deuterium, Ci-C6alkyl, Ci-C6deuterated alkyl, Ci-C6haloalkyl, C3-C7cycloalkyl, "4-8 membered heterocycloalkyl, wherein the heteroatoms are selected from N, O, and S, 1, 2, or 3 in number, and the number of heteroatoms is 1, 2, or 3", C6-Ci0aryl, or "5-10 membered heteroaryl, wherein the heteroatoms are selected from N, O, and S, 1, 2, or 3 in number, and the number of heteroatoms is 1, 2, or 3"; and 10 hydrogen, deuterium, Ci-C6alkyl, Ci-C6deuterated alkyl, Ci-C6haloalkyl, C3-C7cycloalkyl, "4-8 membered heterocycloalkyl, wherein the heteroatoms are selected from N, O, and S, 1, 2, or 3 in number, and the number of heteroatoms is 1, 2, or 3", C6-Ci0aryl, or "5-10 membered heteroaryl, wherein the heteroatoms are selected from N, O, and S, 1, 2, or; R 4 and R 2 with the intervening atoms to which they are attached form a 4-10 membered heterocycloalkyl; said heterocycloalkyl containing in addition to the attached N, O atoms, 0, 1, 2, or 3 additional heteroatoms selected from one, two, or three of N, O, S; R 3 independently deuterium, oxo (=0), halogen, C1-C6alkyl, C1-C6deuteroalkyl, C1-C6haloalkyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6deuteroalkoxy, C1-C6haloalkoxy, C3-C7cycloalkyl, "4-8 membered heterocycloalkyl with 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3," C6-C10aryl, or "5-10 membered heteroaryl with 1, 2, or 3 heteroatoms selected from N, O, and S," the number of heteroatoms being 1, 2, or 3; and 10 aryl or "5-10 membered heteroaryl with 1, 2, or 3 heteroatoms selected from N, O, and S," the number of heteroatoms being 1, 2, or 3. n is 0, 1, 2 or 3; m is 0 or 2; when m is 0, R 5 absent; when m is 2, two R 5 with the C to which they are attached form a C3-C7cycloalkyl or a "4-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3"; or, two adjacent R 5 with the C to which they are attached form a C3-C7cycloalkyl or a "4-8 membered heterocycloalkyl having 1, 2, or 3 heteroatoms selected from N, O, and S, the number of heteroatoms being 1, 2, or 3"; X = CH or N; Ring A is C6-C 10 The aryl group or "a 5-10 membered heteroaryl group selected from one, two or three of N, O and S, with one, two or three heteroatoms".

2. The compound of formula II as claimed in claim 1, its pharmaceutically acceptable salt, or its stereoisomer; characterized in that, said compound being a compound of formula (I), Among them, R 1 It can be H, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 2 It is H, C1-C6 alkyl, and surrounded by 1, 2 or 3 Rs. 2-3 Substituted C1-C6 alkyl, C3-C7 cycloalkyl, with 1, 2 or 3 R 2-1 Substituted C3-C7 cycloalkyl, "a 4-8 membered heterocycloalkyl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms", or surrounded by one, two, or three R atoms. 2-2 The substituted "heteroatom is selected from one, two or three of N, O and S, and is a 4-8 membered heterocyclic alkyl group with one, two or three heteroatoms" and C6-C 10 aryl, with 1, 2 or 3 R 2-3 Replacement C6-C 10 aryl, "a 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms" or surrounded by one, two, or three R... 2-3 The substituted heteroatoms are selected from one, two, or three of N, O, and S, and are 5-10 membered heteroaryl groups with one, two, or three heteroatoms. R 2-1 independently R 2-3 or -NR a -C(=O)-R 2-1-1 ; R 2-1-1 Ci-C6-alkyl or Ci-C6-alkoxy; R 2-2 independently R 2-3 or -C(=O)-C1-C6alkyl; R 2-3 Independently halogen, -CN, -NO2, -OR a -、-NR b R c -C(=O)-OR a -C(=O)-NR b R c - C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C7 cycloalkyl, "4-8 membered heterocyclic alkyl with one, two or three heteroatoms selected from N, O and S, and one, two or three heteroatoms", C6-C 10 The aryl group or "a 5-10 membered heteroaryl group selected from one, two, or three of N, O, and S, with one, two, or three heteroatoms"; R a , R b , and R c are independently H, C1-C6alkyl, or C1-C6haloalkyl.

3. The compound of formula (II) as described in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, which satisfies one or more than two of the following conditions: 1) said halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine; 2) said Ci-C6alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably methyl, i-propyl or t-butyl; 3) said C3-C7cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclobutyl; and 4) said 4-8 membered heterocycloalkyl is independently a 5- or 6-membered heterocycloalkyl having one heteroatom which is N or O, preferably tetrahydropyrrolyl, piperidinyl, tetrahydrofuranyl or tetrahydropyranyl, for example 4. The compound of formula (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, which satisfies one or more than two of the following conditions: 1) R 1 Ci-C6alkyl or Ci-C6haloalkoxy; 2) R 2 independently selected from C1-C6alkyl, C3-C7cycloalkyl, "heteroatoms selected from N, O and S, 1, 2 or 3 in number, 4-8 membered heterocycloalkyl, 1, 2 or 3 in number of heteroatoms" or C4-C6cycloalkyl, "heteroatoms are O, 1 in number of heteroatoms, 5 or 6 membered heterocycloalkyl"; 2-1 independently selected from C1-C6alkyl, C3-C7cycloalkyl, "heteroatoms selected from N, O and S, 1, 2 or 3 in number, 4-8 membered heterocycloalkyl, 1, 2 or 3 in number of heteroatoms" or C4-C6cycloalkyl, "heteroatoms are O, 1 in number of heteroatoms, 5 or 6 membered heterocycloalkyl"; 2-2 independently selected from C1-C6alkyl, C3-C7cycloalkyl, "heteroatoms selected from N, O and S, 1, 2 or 3 in number, 4-8 membered heterocycloalkyl, 1, 2 or 3 in number of heteroatoms" or C4-C6cycloalkyl, "heteroatoms are O, 1 in number of heteroatoms, 5 or 6 membered heterocycloalkyl"; 2-1 independently selected from C1-C6alkyl, C3-C7cycloalkyl, "heteroatoms selected from N, O and S, 1, 2 or 3 in number, 4-8 membered heterocycloalkyl, 1, 2 or 3 in number of heteroatoms" or C4-C6cycloalkyl, "heteroatoms are O, 1 in number of heteroatoms, 5 or 6 membered heterocycloalkyl"; 2-2 independently selected from C1-C6alkyl, C3-C7cycloalkyl, "heteroatoms selected from N, O and S, 1, 2 or 3 in number, 4-8 membered heter 3) R 2-1 -NR a -C(=O)-R 2-1-1 ; 4) R 2-1-1 is C1-C6alkyl; 5) R 2-2 independently R 2-3 or -C(=O)-C1-C6alkyl; and 6) R a is H.

5. The compound of formula (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, which satisfies one or more than two of the following conditions: 1) R 1 is -CH3or and 2) R 2 To 6. The compound of formula (II) as claimed in claim 5, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, R 2 For 7. The compound of formula (II) as claimed in claim 6, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, R 2 for 8. The compound of formula (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, The compound of formula (II) is a compound as shown in formula (I-1), wherein R 1 and R 2 are as defined in any one of claims 1 to 7.

9. The compound of formula (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, which satisfies one or more of the following conditions: (1) each said C6-Ci8-aryl is independently phenyl or naphthyl; for example, phenyl; 10 aryl is independently phenyl or naphthyl; for example, phenyl; (2) The 4-10 membered heterocyclic alkyl group is independently selected from one or both of N and O as the heteroatom; a 6-8 membered bicyclic heterocyclic alkyl group with 3 heteroatoms; for example... (3) R 1 Ci-C6haloalkoxy; (4) R 2 C4-C6-cycloalkyl or "5- or 6-membered heterocycloalkyl having 1 heteroatom which is N and having 1 double bond"; for example, C4-C6-cycloalkyl or "5- or 6-membered heterocycloalkyl having 1 heteroatom which is N and having 1 double bond" substituted by 1, 2 or 3 R 2-1 C4-C6-cycloalkyl or "5- or 6-membered heterocycloalkyl having 1 heteroatom which is O and having 1 double bond"; for example, C4-C6-cycloalkyl or "5- or 6-membered heterocycloalkyl having 1 heteroatom which is O and having 1 double bond" substituted by 1, 2 or 3 R (5) n is 0; (6) R 4 is hydrogen; (7) X is N; and (8) Ring A is C6-C 10 Aryl; preferably, which satisfies one or more of the following conditions: (1) R 1 To (2) R 2 To Preferably Also preferred is Further preferred is (3) the 4-10 membered heterocycloalkyl is (4) ring A is phenyl.

10. The compound of formula (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, The compound of formula (II) is a compound as shown in formula (II-1), wherein R 1 , R 2 and R 4 are as defined in any one of claims 1 to 9.

11. The compound of formula (II) as claimed in claim 1 or 2, its pharmaceutically acceptable salt or its stereoisomer, characterized in that, The compound as shown in formula (II) is any one of the following compounds:

12. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises: (1) a compound as shown in formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-11; and (2) a pharmaceutically acceptable excipient.

13. Use of a compound as shown in formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof according to any one of claims 1-11 or a pharmaceutical composition according to claim 12 in the manufacture of a medicament, said use being selected from: (1) the manufacture of an aldosterone synthase inhibitor; and (2) the manufacture of a medicament for the treatment and / or prevention of a disease or condition, said disease or condition being chronic kidney disease, congestive heart failure, hypertension, a complication of hypertension or primary aldosteronism; preferably hypertension or primary aldosteronism; said hypertension preferably being resistant hypertension; (3) the manufacture of a medicament for the treatment and / or prevention of a disease or condition associated with aldosterone synthase; chronic kidney disease, congestive heart failure, hypertension, a complication of hypertension or primary aldosteronism; preferably hypertension or primary aldosteronism; said hypertension preferably being resistant hypertension.

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