Heteroaromatic compound, preparation method therefor and use thereof

Abstract

Provided are a CYP11B2 inhibitor compound, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. The compound and a pharmaceutical composition thereof have a use in preparation of a drug for treating and / or preventing CYP11B2-mediated diseases.

Description

A class of aromatic heterocyclic compounds, their preparation methods and applications

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to International Patent Application No. PCT / CN2024 / 140826, filed with the China National Intellectual Property Administration on December 20, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This application relates to the field of pharmaceutical technology, and more specifically, to a class of aromatic heterocyclic compounds, as well as methods for preparing and using said compounds. Background Technology

[0004] Antihypertensive drugs are a class of medications that control blood pressure and treat hypertension. They can prevent damage to target organs such as the heart, brain, and kidneys caused by long-term high blood pressure and reduce the risk of major cardiovascular and cerebrovascular diseases such as stroke. Based on their mechanism of action, antihypertensive drugs can be classified into: diuretics, alpha-blockers, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and combination preparations, etc.

[0005] In hypertensive patients receiving long-term ACEIs or ARBs, the "aldosterone escape" phenomenon leads to a rebound in aldosterone levels after an initial decrease, which is associated with end-organ damage. Mineralocorticoid receptor antagonists (MRAs), after suppressing plasma aldosterone levels, can lead to an increase in aldosterone levels through compensatory mechanisms, thus limiting their efficacy. Furthermore, the adverse reactions of steroidal MRAs are mostly related to renal impairment or hyperkalemia, which is particularly detrimental to patients with renal damage, thus limiting their clinical application.

[0006] Aldosterone, a component of the renin-angiotensin-aldosterone system (RAAS), plays a crucial role in regulating fluid and electrolyte homeostasis and is also a significant factor in end-organ damage in various cardiovascular and renal diseases. Elevated aldosterone levels are a major cause of hypertension, leading to water and sodium retention, increased blood volume, and consequently, hypertension. Furthermore, elevated aldosterone can further contribute to cardiovascular and renal events such as inflammation, organ damage, and fibrosis. Therefore, lowering aldosterone levels may be an effective strategy for managing hypertension and diseases caused by elevated aldosterone.

[0007] Aldosterone synthase (CYP11B2) is a mitochondrial cytochrome P450 enzyme that obtains molecular oxygen and electrons from NADPH via adrenocortical ferredoxin reductase (AdR) and adrenocortical ferredoxin (Adx), catalyzing a three-step oxidation sequence to convert 11-deoxycorticosterone (11-DOC) into aldosterone via the intermediates corticosterone and 18-hydroxycorticosterone. CYP11B2 is a key enzyme in the final three steps of aldosterone biosynthesis. Inhibiting CYP11B2 can prevent aldosterone formation and reduce its level in circulating plasma, thus showing promise as an effective strategy for treating diseases caused by hyperaldosteronism. Therefore, in recent years, blocking aldosterone biosynthesis with aldosterone synthase inhibitors has been explored as an alternative approach, and the development of aldosterone synthase inhibitors is of great significance in the treatment of cardiovascular and renal diseases.

[0008] Currently, the development of CYP11B2 inhibitors is in the clinical development stage. For example, baxdrostat, lorundrostat, and BI-690517 have completed Phase II clinical trials. Clinical trial results show that patients with refractory hypertension treated with baxdrostat (structural formula shown below) experienced dose-related reductions in blood pressure. An international multicenter Phase III clinical trial has been initiated to evaluate efficacy and safety in subjects with uncontrolled hypertension receiving two or more medications. In addition, Phase II or III clinical trials are underway for patients with essential aldosteronism and chronic kidney disease complicated by hypertension. Other studies have shown that lorundrostat met the pre-specified primary efficacy endpoint in pivotal Phase III and Phase II clinical trials for uncontrolled and refractory hypertension, demonstrating good safety and tolerability. No CYP11B2 inhibitors have yet been approved for marketing. Therefore, the discovery of effective and safe CYP11B2 inhibitors remains crucial. Summary of the Invention

[0009] This application provides a class of novel compounds, pharmaceutical compositions comprising the same, methods for their preparation, and their use as an inhibitor of aldosterone synthase (CYP11B2).

[0010] In a first aspect, this application provides compounds of formula (V), their stereoisomers, tautomers, isotopic derivatives (preferably deuterated derivatives), or pharmaceutically acceptable salts:

[0011] in,

[0012] X3 is selected from N and CR X3 ;

[0013] R is selected from -N(R2)R3, -S(O)2R4, or can be any one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) R. w1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic, 5-12 membered heteroaryl, C 6-12 Aryl; wherein, R w1 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, -C(O)-N(R2)R3, or optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R groups. w2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-12 membered heteroaryl; among which, R w2 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally by one or more (e.g., 2, 3, 4, 5, 6, 7, or 8) R w3 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 Aryl, 5-12 membered heteroaryl; among which, R w3 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, C 1-4 Halogenated alkyl groups and C1-4 halogenated alkoxy groups;

[0014] R X3 Selected from hydrogen, deuterium, halogens, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkyl groups and C1-3 halogenated alkoxy groups;

[0015] Ra R b Selected independently from hydrogen, deuterium, and C. 1-4 alkyl;

[0016] R A Selected from hydrogen, C 1-3 Alkyl (e.g., methyl), deuterated methyl (-CD3), and cyclopropyl;

[0017] R2 and R3 are each independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups; wherein the optional substitution refers to unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) and C 1-4 Alkylthio (preferably C) 1-3 Alkylthio (e.g., methylthio, ethylthio);

[0018] R4 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl and C 3-6 Cycloalkyl; wherein the optional substitution refers to unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) and C 1-4 Alkylthio (preferably C) 1- 3-alkylthio group, for example, methylthio or ethylthio;

[0019] R5 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl and C 3-6 Cycloalkyl; wherein the optional substitution refers to unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C)1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) and C 1-4 Alkylthio (preferably C) 1- 3-alkylthio group, for example, methylthio or ethylthio;

[0020] R6 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl, C 3-6 cycloalkyl and C 4-6 Heterocyclic group; wherein the optional substitution refers to unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) and C 1-4 Alkylthio (preferably C) 1-3 Alkylthio (e.g., methylthio, ethylthio);

[0021] R7 and R8 are each independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl, C 3-6 cycloalkyl and C 4-6 Heterocyclic group; wherein the optional substitution refers to unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) and C 1-4 Alkylthio (preferably C) 1-3 Alkylthio (e.g., methylthio, ethylthio);

[0022] R9 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl and C 3-6Cycloalkyl; wherein the optional substitution refers to unsubstituted or substituted by one or more (e.g., 2, 3, 4, 5, 6, 7 or 8) substituents, each of which is independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl (preferably C) 1-3 Alkyl groups (e.g., methyl, ethyl, n-propyl, n-butyl, isopropyl, tert-butyl), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) and C 1-4 Alkylthio (preferably C) 1- 3-alkylthio group, for example, methylthio or ethylthio;

[0023] Unless otherwise stated, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4;

[0024] The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

[0025] In some implementation schemes, R A It is selected from hydrogen, deuterated methyl (-CD3) and cyclopropyl.

[0026] In some implementation schemes, R A Selected from hydrogen and deuterated methyl (-CD3).

[0027] In some implementation schemes, R A It is a deuterated methyl (-CD3).

[0028] In some implementation schemes, R a R b They are selected independently from hydrogen and deuterium, respectively.

[0029] In some implementations, R is -N(R2)R3, -S(O)2R4, or optionally R is one or more of the following: w1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, 3-10-membered heterocyclic, 5-10-membered heteroaryl, 6-12-membered aryl; wherein, R w1 Selected from deuterium, halogens, oxo groups, -CN, -OH, -NR2R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally, radicals containing one or more R groups. w2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C6-10 Aryl, 5-12 membered heteroaryl; among which, R w2 Selected from deuterium, halogens, oxo groups, -CN, -OH, -NR2R3, -S(O)2R4, -C(O)NR7R8, -C(O)OR9, or optionally, radicals with one or more R groups. w3 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 Substituents of aryl and 5-12 heteroaryl groups; R w3 Selected from deuterium, halogens, oxo groups, -CN, -OH, -NR2R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups.

[0030] In some implementations, R is -N(R2)R3, -S(O)2R4, or optionally R is one or more of the following: w1 The following groups are substituted: C 1-4 Alkyl, C 3-8 Cycloalkyl groups (e.g., 3-, 4-, 5-, 6-, 7-, 8-membered), 4-10-membered heterocyclic groups (e.g., 4-, 5-, 6-, 7-, 8-, 9-, 10-membered), 5-10-membered heteroaryl groups (e.g., 5-, 6-, 7-, 8-, 9-, 10-membered); wherein R w1 Selected from deuterium, halogens (e.g., F, Cl), oxo groups, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally composed of one or more R groups. w2 The following groups are substituted: C 1-4 Alkyl groups (e.g., 1, 2, 3, 4), C 1-4 Alkoxy (preferably C) 1-3 Substituents of alkoxy groups (e.g., methoxy, ethoxy), 3-8 membered heterocyclic groups (preferably 4-7 membered heterocyclic groups, more preferably 4-6 membered heterocyclic groups, more preferably 5-6 membered heterocyclic groups), phenyl groups, and 5-6 membered heteroaryl groups; R w2 Selected from deuterium, halogens (e.g., F, Cl), oxo groups, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally composed of one or more R groups. w3 The following groups are substituted: C 1-3 Alkyl (e.g., methyl, ethyl), C 1-3 Substituents of alkoxy groups (e.g., methoxy, ethoxy) and 5-6 membered heteroaryl groups; Rw3 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3 and C 1-3 Alkyl (e.g., methyl, ethyl).

[0031] In some implementations, R2 and R3 are independently selected from hydrogen, deuterium, and C, respectively. 1-4 alkyl.

[0032] In some implementations, R4 is selected from hydrogen, deuterium, and C. 1-3 Alkyl and C 3-4 Cycloalkyl.

[0033] In some implementations, R5 is selected from hydrogen, deuterium, and C. 1-3 alkyl.

[0034] In some implementations, R6 is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl and C 3-6 Cycloalkyl.

[0035] In some implementation schemes, R7 and R8 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 Alkyl and C 3-6 Cycloalkyl.

[0036] In some implementations, R9 is selected from hydrogen, deuterium, and C. 1-4 alkyl.

[0037] In some implementations, R2 and R3 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 alkyl;

[0038] R4 is selected from hydrogen, deuterium, and C. 1-3 Alkyl and C 3-4 cycloalkyl;

[0039] R5 is selected from hydrogen, deuterium, and C. 1-3 alkyl;

[0040] R6 is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl and C 3-6 cycloalkyl;

[0041] R7 and R8 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 Alkyl and C 3-6 cycloalkyl;

[0042] R9 is selected from hydrogen, deuterium, and C. 1-4 alkyl.

[0043] In some implementations, R is -N(R2)R3, -S(O)2R4, or optionally R is one or more of the following: w1 The following groups are substituted: C 1-4 Alkyl, C3-12 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl; wherein R w1 Selected from deuterium, halogens, oxo groups, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally, radicals containing one or more R groups. w2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, 3-10 membered heterocyclic groups, C 6-10 Substituents of aryl and 5-10 heteroaryl groups; R w2 Selected from deuterium, halogens, oxo groups, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally, radicals containing one or more R groups. w3 The following groups are substituted: C 1-4 Alkyl, C 1-4 Substituents of alkoxy, phenyl, and 5-6 membered heteroaryl groups; R w3 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio;

[0044] R2 and R3 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 alkyl;

[0045] R4 is selected from hydrogen, deuterium, and C. 1-3 Alkyl and C 3-4 cycloalkyl;

[0046] R5 is selected from hydrogen, deuterium, and C. 1-3 alkyl;

[0047] R6 is independently selected from hydrogen, deuterium, and C. 1-3 Alkyl and C 3-6 cycloalkyl;

[0048] R7 and R8 are independently selected from hydrogen, deuterium, and C, respectively. 1-3 Alkyl and C 3-6 cycloalkyl;

[0049] R9 is selected from hydrogen, deuterium, and C. 1-4 alkyl.

[0050] In some implementations, R is -N(R2)R3, -S(O)2R4, or optionally R is one or more of the following: w1 The following groups are substituted: C 1-4 Alkyl, C 3-8 Cycloalkyl, 3-10 membered heterocyclic, 5-10 membered heteroaryl; wherein R w1Selected from deuterium, halogens, oxo groups, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, or optionally, radicals containing one or more R groups. w2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Substituents include alkoxy, 3-8 membered heterocyclic, phenyl, and 5-6 membered heteroaryl groups; R w2 Selected from deuterium, halogens, oxo groups, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally, radicals containing one or more R groups. w3 The following groups are substituted: C 1-3 Alkyl, C 1-3 Substituents of alkoxy groups and 5-6 heteroaryl groups; R w3 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3 and C 1-3 alkyl;

[0051] R2 and R3 are independently selected from hydrogen, deuterium, methyl, ethyl, and isopropyl, respectively;

[0052] R4 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, and cyclopropyl;

[0053] R5 is selected from hydrogen, deuterium, methyl, and ethyl;

[0054] R6 is independently selected from hydrogen, deuterium, methyl, and ethyl;

[0055] R7 and R8 are independently selected from hydrogen, deuterium, methyl, and ethyl, respectively;

[0056] R9 is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, and tert-butyl.

[0057] In some implementations, R is -N(R2)R3, -S(O)2C 1-3 Alkyl groups, or optionally, those with one or more (e.g., two or three) R w1 The following groups are substituted: cyclohexyl, pyridyl, piperidinyl, n-propyl, isopropyl, pyrazolyl, pyrrolidinyl, methyl. Piperazine-based Azahexacyclic butyl, Cyclobutane, Cyclopropyl Morpholinyl, oxetane, and tert-butyl; of which R w1 Selected from one or more (e.g., 2 or 3) R w2The following groups are substituted: -NH-C(O)-CH3, -OH, methyl, -N(CH3)2, oxo, morpholino, -S(O)2CH3, piperidinyl, -NH-C(O)-CH(CH3)2, methoxy. Ethyl, pyrimidinyl, -NH-C(O)-cyclopropyl, piperazine, methoxy, fluorine, -C(O)OC(CH3)3, -S(O)2cyclopropane, -S(O)2C2H5 and -S(O)2CH3; R w2 Selected from fluorine, oxo, methyl, and methoxy groups.

[0058] In some implementations, R is

[0059] In some implementations, R is -CH3、

[0060] In some implementations, R is

[0061] In some implementations, R is

[0062] In some implementations, R is

[0063] In some implementations, R is optionally defined by one or more Rs. w1 The following groups are substituted: C 1-4 Alkyl, C 3-8 Cycloalkyl groups (e.g., 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered), 4-10-membered heterocyclic groups (e.g., 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered); wherein R w1 Selected from deuterium, halogens (e.g., F, Cl), oxo groups, -OH, or optionally oxidized by one or more R groups. w2 The following groups are substituted: C 1-4 Alkyl groups (e.g., 1, 2, 3, 4), C 1-4 Alkoxy (preferably C) 1-3 The substituent is an alkoxy group (e.g., methoxy, ethoxy), a 3-8 membered heterocyclic group (preferably a 4-7 membered heterocyclic group, more preferably a 4-6 membered heterocyclic group, more preferably a 5-6 membered heterocyclic group); R w2 Selected from deuterium, halogens (e.g., F, Cl), oxo groups, or optionally oxidized by one or more R groups. w3 The following groups are substituted: C 1-3Alkyl (e.g., methyl, ethyl), C 1-3 Substituents of alkoxy groups (e.g., methoxy, ethoxy); R w3 Selected from deuterium, halogens, oxo groups, -CN, -OH, and C. 1-3 Alkyl (e.g., methyl, ethyl).

[0064] In some implementations, R is optionally deuterium, halogen (e.g., F, Cl), -OH, C 1-4 Alkyl groups (e.g., 1, 2, 3, 4), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) substituted C 1-6 alkyl.

[0065] In some implementations, R is optionally deuterium, halogen (e.g., F, Cl), -OH, C 1-4 Alkyl groups (e.g., 1, 2, 3, 4), C 1-4 Alkoxy (preferably C) 1-3 Alkyl groups (e.g., methoxy, ethoxy) substituted C 1-4 alkyl.

[0066] In some implementations, R is C that is optionally substituted with -OH. 1-6 alkyl.

[0067] In some implementations, R is -CH3 or

[0068] In some implementations, R is

[0069] In some implementations, R is -CH3 or

[0070] In some implementations, R is

[0071] In some implementations, R is C 1-4 alkyl.

[0072] In some implementations, R is n-propyl, isopropyl, or methyl.

[0073] In some implementations, X3 is CR X3 And R X3 It is hydrogen.

[0074] In some implementation schemes, R a and R b Both are hydrogen.

[0075] In some implementation schemes, R a and R b All are deuterium.

[0076] Secondly, this application provides the following compounds, or their stereoisomers, tautomers, isotopic derivatives (preferably deuterated derivatives), or pharmaceutically acceptable salts, wherein the compounds are selected from:

[0077] This application also provides the following compounds, or their stereoisomers, tautomers, isotopic derivatives (preferably deuterated derivatives), or pharmaceutically acceptable salts, wherein the compounds are selected from:

[0078] Thirdly, this application provides a pharmaceutical composition comprising a compound of formula (V) as described in the first aspect of this application or a compound as described in the second aspect, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, or isotope derivative (preferably deuterated derivative), and optionally, further comprising a pharmaceutically acceptable carrier.

[0079] Fourthly, this application provides the use of the compound of formula (V) described in the first aspect of this application, or the compound described in the second aspect, or its tautomers, stereoisomers, pharmaceutically acceptable salts, isotope derivatives (preferably deuterated derivatives), or the pharmaceutical composition described in the third aspect, as a drug or in the preparation of a drug; preferably, the drug is a drug as a CYP11B2 inhibitor; more preferably, the drug is a drug for the prevention and / or treatment of CYP11B2-mediated diseases; more preferably, the drug is a drug for the treatment and / or prevention of diseases or conditions caused by hyperaldosteronism; more preferably, the drug is a drug for the treatment and / or prevention of cardiovascular or cerebrovascular diseases or kidney diseases; more preferably, the drug... The drug is a medicine for treating and / or preventing hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; more preferably, the drug is a medicine for treating and / or preventing uncontrolled hypertension, hypertension caused by primary aldosteronism (or, hypertension caused by primary aldosteronism), primary aldosteronism (or simply, primary aldosteronism), heart failure, or chronic kidney disease, or complications thereof; more preferably, the drug is a medicine for treating and / or preventing refractory hypertension, hypertension caused by primary aldosteronism, primary aldosteronism, heart failure, or chronic kidney disease; more preferably, the drug is a medicine for treating and / or preventing refractory hypertension, primary aldosteronism, heart failure, or chronic kidney disease.

[0080] In some embodiments, the use of the compound of formula (V) of the first aspect or the compound of the second aspect, or its tautomers, stereoisomers, pharmaceutically acceptable salts, isotope derivatives (preferably deuterated derivatives), or the pharmaceutical composition of the third aspect in the preparation of a medicament for the treatment and / or prevention of cardiovascular or cerebrovascular diseases or kidney diseases; more preferably, the medicament is a medicament for the treatment and / or prevention of hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; more preferably, the medicament is a medicament for the treatment and / or prevention of uncontrolled... The drug is a medication for treating and / or preventing one or more of the following: hypertension, hypertension caused by primary aldosteronism (or, hypertension caused by primary aldosteronism), primary aldosteronism (or simply, primary aldosteronism), heart failure, and chronic kidney disease, or complications thereof; more preferably, the drug is a medication for treating and / or preventing refractory hypertension, hypertension caused by primary aldosteronism, primary aldosteronism, Cushing's disease, heart failure, or chronic kidney disease; more preferably, the drug is a medication for treating and / or preventing refractory hypertension, primary aldosteronism, heart failure, or chronic kidney disease.

[0081] In some embodiments, the drug is a drug for treating and / or preventing uncontrolled hypertension; preferably, the drug is a drug for treating and / or preventing refractory hypertension, primary aldosteronism hypertension, or intractable hypertension.

[0082] In some embodiments, the drug is a drug for treating and / or preventing diseases or conditions caused by hyperaldosteronism; preferably, it is a drug for treating and / or preventing hyperaldosteronism or primary hyperaldosteronism.

[0083] In some embodiments, the drug is a drug for treating and / or preventing kidney disease or its complications; preferably, it is a drug for treating and / or preventing chronic kidney disease or its complications.

[0084] In some implementations, the drug is a drug used to treat and / or prevent heart failure.

[0085] In some implementations, the drug is a drug for treating and / or preventing Cushing's disease.

[0086] Fifthly, this application provides a compound of formula (V) as described in the first aspect or a compound as described in the second aspect, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, isotope derivative (preferably deuterated derivative), or a pharmaceutical composition as described in the third aspect, for the prevention and / or treatment of a disease; preferably, the disease is a CYP11B2-mediated disease; preferably, the disease is a cardiovascular or cerebrovascular disease or kidney disease; more preferably, the disease is hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; more preferably, the pharmaceutical composition... The drug is a medicine for treating and / or preventing one or more of uncontrolled hypertension, hypertension caused by primary aldosteronism (or, hypertension caused by primary aldosteronism), primary aldosteronism (or simply, primary aldosteronism), heart failure, and chronic kidney disease, or complications thereof; more preferably, the disease is refractory hypertension, hypertension caused by primary aldosteronism, Cushing's disease, primary aldosteronism, heart failure, or chronic kidney disease; more preferably, the drug is a medicine for treating and / or preventing refractory hypertension, primary aldosteronism, heart failure, or chronic kidney disease.

[0087] In some embodiments, the compound of formula (V) described in the first aspect or the compound described in the second aspect, or its tautomers, stereoisomers, pharmaceutically acceptable salts, isotope derivatives (preferably deuterated derivatives), or the pharmaceutical composition described in the third aspect, is used for the prevention and / or treatment of a disease; preferably, the disease is a cardiovascular or cerebrovascular disease or a kidney disease; more preferably, the disease is hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; more preferably, the drug is a drug for the treatment and / or prevention of one or more of uncontrolled hypertension, hypertension caused by primary aldosteronism (or, hypertension caused by primary aldosteronism), primary aldosteronism (or simply, primary aldosteronism), heart failure, or chronic kidney disease, or complications thereof; more preferably, the disease is refractory hypertension, hypertension caused by primary aldosteronism, Cushing's disease, primary aldosteronism, heart failure, or chronic kidney disease; more preferably, the drug is a drug for the treatment and / or prevention of refractory hypertension, primary aldosteronism, heart failure, or chronic kidney disease.

[0088] In the absence of contradictions and conflicts, the technical solutions or features described in the fourth aspect are applicable to the fifth aspect.

[0089] Sixthly, this application provides a method for treating a disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula (V) as described in the first aspect or a compound as described in the second aspect, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, isotope derivative (preferably a deuterated derivative), or a pharmaceutical composition as described in the third aspect; preferably, the disease is a CYP11B2-mediated disease; more preferably, the disease is a cardiovascular or cerebrovascular disease or kidney disease; even more preferably, the disease is hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; Preferably, the drug is a drug for treating and / or preventing one or more of uncontrolled hypertension, hypertension caused by primary aldosteronism (or, hypertension caused by primary aldosteronism), primary aldosteronism (or simply, primary aldosteronism), heart failure, and chronic kidney disease, or their complications; more preferably, the disease is refractory hypertension, hypertension caused by primary aldosteronism, Cushing's disease, primary aldosteronism, heart failure, or chronic kidney disease; more preferably, the drug is a drug for treating and / or preventing refractory hypertension, primary aldosteronism, heart failure, or chronic kidney disease.

[0090] In some embodiments, this application provides a method of treating a disease, comprising administering to a subject a therapeutically effective amount of a compound of formula (V) as described in the first aspect or the compound as described in the second aspect, or a tautomer, stereoisomer, pharmaceutically acceptable salt thereof, isotope derivative (preferably deuterated derivative), or pharmaceutical composition as described in the third aspect; preferably, the disease is a cardiovascular or cerebrovascular disease or a kidney disease; more preferably, the disease is hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; even more preferably, The drug is a medication for treating and / or preventing one or more of uncontrolled hypertension, hypertension caused by primary aldosteronism (or, hypertension caused by primary aldosteronism), primary aldosteronism (or simply, primary aldosteronism), heart failure, and chronic kidney disease, or their complications; more preferably, the disease is refractory hypertension, hypertension caused by primary aldosteronism, Cushing's disease, primary aldosteronism, heart failure, or chronic kidney disease; more preferably, the drug is a medication for treating and / or preventing refractory hypertension, primary aldosteronism, heart failure, or chronic kidney disease.

[0091] In the absence of contradictions and conflicts, the technical solutions or features described in the fourth aspect are applicable to the sixth aspect.

[0092] In some embodiments, the compound of formula (V) as described in the first aspect or the compound of the second aspect, or its tautomers, stereoisomers, pharmaceutically acceptable salts, isotope derivatives (preferably deuterated derivatives), or the pharmaceutical composition of the third aspect may be used in combination with other therapeutic agents to treat the diseases described in the fourth to sixth aspects.

[0093] definition

[0094] Unless otherwise stated, the following terms as used in this application have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0095] C in this article m-n This refers to the part having an integer number of carbon atoms within a given range. For example, "C 1-6 "" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

[0096] It refers to the connection site.

[0097] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl groups, more preferably containing 1-4 carbon atoms (i.e., C464-C ... 1-4 Alkyl groups, more preferably containing 1-3 carbon atoms (i.e., C464-C ... 1-3 Alkyl), for example, "C 1- "6-alkyl" refers to a group that is an alkyl group, and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0098] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, I; preferably F, Cl, Br; more preferably F, Cl.

[0099] The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms (e.g., 3, 4, 5, 6, 7, 8) or all of the hydrogen atoms are replaced by a halogen, such as C. 1-6 Alkyl substitution by halogens refers to C 1-6 Haloalkyl groups, such as CCl3, CH2F, CHF2, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc.

[0100] The term "haloalkoxy" refers to an alkoxy group in which one, two, or more hydrogen atoms (e.g., 3, 4, 5, 6, 7, or 8) or all hydrogen atoms are substituted with a halogen. As defined herein for each individual part, the haloalkoxy group may be optionally substituted.

[0101] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 Cycloalkyl, or 3-12 membered cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, more preferably 3-6 carbon atoms (C 3-6 cycloalkyl groups, 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0102] Unless otherwise specified, the term "alkoxy" refers to an alkyl residue in which one or more carbons (and associated hydrogens) are replaced by oxygen, as in "alkoxy". Examples include methoxy, ethoxy, propoxy, etc.

[0103] Unless otherwise specified, the term "alkoxy" refers to the replacement of oxygen in the above "alkoxy group" with sulfur or nitrogen.

[0104] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, having a non-aromatic structure, containing 3-20 ring atoms, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are selected from N, O, or S, and the remaining ring atoms are C. Preferably, it contains 3-14 ring atoms, 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused (or fused) and bridged heterocyclic groups. The heterocyclic group may be attached (e.g., bridged, spiro-attached, or fused (or fused)) to other cyclic groups (including cycloalkyl, cycloalkenyl, heterocyclic alkenyl, aryl, or heteroaryl), but the attachment point must be on a carbon atom or heteroatom of the heterocyclic group. Each heterocyclic group or other cyclic group may be optionally substituted, as defined herein with respect to each individual section.

[0105] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms (6-16 membered aryl), 6-14 carbon atoms, 6-12 carbon atoms, or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring." Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthrene, or pyreneyl. "Aryl" also includes ring systems in which the aryl group as defined above is fused or fused with one or more cycloalkyl, heterocyclic, or heteroaryl groups, but the point of attachment to the parent group must be on a carbon atom of the aryl group. As defined herein for each individual section, each aryl or other cyclic group may be optionally substituted.

[0106] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more (e.g., four, five, six, seven, or eight) ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, three, or four; more preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrrole, pyrazolyl, imidazole, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzene. Pyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc. "Heteroaryl" also includes ring systems in which the heteroaryl groups as defined above are fused or fused with one or more cycloalkyl, heterocyclic, or aryl groups, but the point of attachment to the parent group must be on an atom of the heteroaryl group. As defined herein for each individual part, each aryl or other cyclic group may be optionally substituted.

[0107] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within the bounds of reasonable medical judgment, is suitable for contact with the tissues of mammals, particularly humans, without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art. The salt can be prepared in situ during the final isolation and purification of the compounds of this application, or solely by reacting a free base or free acid with a suitable reagent.

[0108] Unless otherwise specified, the term "stereoisomer" refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups. Stereoisomers include optical isomers, enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (or cis / trans isomers), and trans-reactive isomers. Any mixture of stereoisomers can be separated into pure or substantially pure optical isomers, geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0109] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0110] Unless otherwise indicated, the structural formulas described in this application include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compound of this application, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), are within the scope of this application.

[0111] The compounds in this application also include their isotopic derivatives. Unless otherwise specified, the term "isotopic derivative" refers to compounds in this application that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds. The isotope derivatives are preferably deuterated derivatives.

[0112] The compounds in this application also include their metabolites. Unless otherwise specified, the term "metabolite" refers to a product obtained in vivo by the metabolic processes of a specific compound or its salt. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by experimental methods as described in this application. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this application includes metabolites of compounds, including metabolites produced by sufficient contact of the compounds of this application with mammals for a period of time.

[0113] The terms “optional” or “optional” mean that the event or situation described below may but does not have to happen, and the description includes the occasions in which the event or situation does not occur.

[0114] The word “comprise” or “include” and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, meaning “including but not limited to”.

[0115] The term “subject” can also be referred to as “individual” or “subject”, referring to a cell or animal, including but not limited to mammals such as laboratory animals or humans.

[0116] "Effective amount" means an amount of the compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to the treatment of a disease or the relief of its symptoms. In some embodiments, for example, the amount may be a dose that can induce a specific response in cells, or a dose that exerts a therapeutic effect on a disease in a model animal. The specific amount will vary depending on, for example, the specific compound selected, the type of subject and their age / pre-existing health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue of administration, and the physical delivery system carrying it.

[0117] The term "uncontrolled hypertension," also known as uncontrolled hypertension, uncontrolled hypertension, or uncontrollable hypertension, refers to hypertension that is not controlled by two or more medications, including refractory hypertension, which further includes persistent hypertension.

[0118] Some of the compounds in this application are optically active. The compounds in this application can be racemic, optical isomers or mixtures thereof. The optical isomers in the compounds in this application can be synthesized either by using the starting materials of the optical isomers or by separating the racemic mixtures.

[0119] Unless otherwise specified, the term "pharmaceuticalally acceptable carrier," also known as "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable excipient," refers to a generally recognized medium in the field of delivering bioactive agents to animals (specifically, mammals). Pharmaceutically acceptable carriers are formulated based on a number of factors well understood by those skilled in the art. These include (but are not limited to) the type and nature of the formulated active agent, the subject to whom the composition containing the pharmaceutical agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include aqueous and non-aqueous liquid media, as well as various solid and semi-solid dosage forms. The preparation of pharmaceutical compositions described herein includes, but is not limited to, mixing, for example, the compounds described in the first or second aspect, or their tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier.

[0120] The above embodiments represent exemplary embodiments of this application, but this application is not limited to the above embodiments. Furthermore, the various technical features in the above embodiments of this application can be combined with each other to constitute one or more new technical solutions, which also fall within the scope of this application, provided that such new technical solutions are technically feasible. Detailed Implementation

[0121] The present application is further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the application. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this application. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0122] The structures of the compounds in this application were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The NMR measurements were performed using a Bruker 400MHz and / or Varian 400MHz instrument; the LC-MS instrument used was an Agilent 1260 Infinity II-6120 / 6125MSD; and the HPLC instrument used was a Waters Acquity UPLC_2 and / or Shimadzu LC2030 and / or Agilent 1260 Infinity II. Chiral compound separation was performed using an SFC-150 (Waters) instrument and a DAICEL chiral column. Column volume: 20×250mm (10μm particle size packing).

[0123] The starting materials used in the embodiments of this application are known and commercially available, or can be synthesized using methods known in the art.

[0124] This application provides a method for preparing the compound. The compound can be prepared by the steps described below, or by the method described in PCT / CN2024 / 140826.

[0125] The abbreviations used in this application have the following meanings:

[0126] PE: Petroleum ether; EA: Ethyl acetate; DCM: Dichloromethane; MeOH: Methanol; FA: Formic acid; MeCN: Acetonitrile; THF: Tetrahydrofuran; TFA: Trifluoroacetic acid.

[0127] The beneficial effects of this application are as follows:

[0128] The compounds of this application have achieved one or more of the following beneficial effects:

[0129] (1) The compound of this application has a strong inhibitory effect on CYP11B2;

[0130] (2) The compounds in this application have good CYP11B2 / CYP11B1 selectivity;

[0131] (3) The compound of this application has good oral absorption properties;

[0132] (4) The compound of this application has no inhibitory effect on CYP enzymes; it has good safety and few side effects;

[0133] (5) The compounds of this application have good stability (e.g., liver microsomal stability);

[0134] (6) The compounds of this application can exert an effective and stable effect in reducing plasma aldosterone levels in animals.

[0135] Example 1

[0136] Preparation of N-isopropyl-2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide-2,2-d2 (compound 155):

[0137] Step 1: Synthesis of tert-butyl 4-(5-bromopyridin-3-yl)piperazine-1-carboxylate:

[0138] Toluene (400 mL) was added to a mixture of piperazine-1-carboxylic acid tert-butyl ester (30 g, 1 eq), 3,5-dibromopyridine (49.6 g), sodium tert-butoxide (23.22 g), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (XANT PHOS, 5.59 g), and tris(dibenzylacetone)dipalladium (2.95 g). The mixture was reacted at 100 °C under nitrogen protection for 16 hours. Water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 4:1) to give the product (42 g). LCMS (ESI) [M+H] + =341.9; 1 HNMR (400MHz, CDCl3) δ8.21(d,J=2.6Hz,1H),8.15(d,J=1.8Hz,1H),7.32-7.29(m,1H),3.61-3.57(m,4H),3.21-3.16(m,4H),1.49(s,9H).

[0139] Step 2: Synthesis of 6-bromo-1-(methyl-d3)-3,4-dihydroquinoline-2(1H)-one:

[0140] 6-Bromo-3,4-dihydroquinoline-2(1H)-one (4 g, 1 eq) was dissolved in N,N-dimethylformamide (40 mL). Sodium hydride (813.55 mg) was slowly added under ice bath conditions. After stirring at 0 °C for 30 minutes, deuterated iodomethane (3.01 g) was added dropwise. After the addition was complete, the reaction was continued at room temperature for 3 hours. The reaction solution was quenched with water (120 mL) and extracted with ethyl acetate (70 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to give the product (3.5 g). LCMS [ESI][M+H] +=245.4 (isotope peak); 1 H NMR (400MHz, CDCl3) δ7.36 (dd, J=8.6, 2.3Hz, 1H), 7.31-7.28 (m, 1H), 6.83 (d, J=8.6Hz, 1H), 2.91-2.86 (m, 2H), 2.66-2.62 (m, 2H).

[0141] Step 3: Synthesis of 1-(methyl-d3)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydroquinoline-2(1H)-one:

[0142] The product from step two (4 g, 1 eq), pinacol diborate (8.36 g), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (1.21 g), and potassium acetate (4.84 g) were dissolved in 1,4-dioxane (60 mL) and reacted at 90 °C for 16 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain the product (3.5 g). LCMS [ESI][M+H] + =291.3.

[0143] Step 4: Synthesis of tert-butyl 4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazine-1-carboxylate:

[0144] 4-(5-bromopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (1.5 g, 1 eq), the product from step three (1.91 g), potassium carbonate (1.82 g), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (321.37 mg) were dissolved in 1,4-dioxane (30 mL) and water (6 mL) and reacted at 80 °C for 2 hours under nitrogen protection. The reaction mixture was diluted with water (70 mL) and extracted with ethyl acetate (45 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 2:1) to give the product (1 g). LCMS (ESI) [M+H] + =426.5; 1HNMR (400MHz, CDCl3) δ8.33(d,J=1.6Hz,1H),8.28(d,J=2.6Hz,1H),7.46(dd,J=8.4,2.0Hz,1H),7.38-7.36(m,1H),7.31(t,J =2.1Hz,1H),7.06(d,J=8.4Hz,1H),3.65-3.61(m,4H),3.27-3.22(m,4H),3.01-2.96(m,2H),2.73-2.68(m,2H),1.49(s,9H).

[0145] Step 5: Synthesis of 1-(methyl-d3)-6-(5-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one:

[0146] The product from step four (1 g, 1 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The mixture was reacted at room temperature for 16 hours. The reaction solution was concentrated to give the product (750 mg, in trifluoroacetate form). LCMS (ESI) [M+H] + =326.5.

[0147] Step 6: Synthesis of methyl acetate d2 (4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)piperazin-1-yl)acetate:

[0148] The product from step 5 (750 mg, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), and methyl 2-bromoacetate-d2 (0.43 mL) and potassium carbonate (955.6 mg) were added. The mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with water (55 mL) and extracted with ethyl acetate (35 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether:tetrahydrofuran = 1:4) to give the product (660 mg). 1 H NMR(400MHz,DMSO-d6)δ8.27(m,2H),7.65-7.59(m,2H),7.51-7.47(m,1H),7.19-7.14(m,1H ),3.64(s,3H),3.31-3.27(m,4H),2.98-2.91(m,2H),2.70-2.65(m,4H),2.61-2.56(m,2H).

[0149] Step 7: Synthesis of 2,2-d2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)piperazin-1-yl)acetic acid:

[0150] The product from step 6 (660 mg, 1 eq) was dissolved in methanol (8 mL) and water (8 mL), and lithium hydroxide (197.83 mg) was added. The mixture was reacted at 50 °C for 2 hours. Dilute hydrochloric acid (3 M) was added dropwise to the reaction solution to adjust the pH to 5–6. After the solid precipitated, the mixture was filtered, and the filter cake was dried to obtain the product (600 mg). LCMS(ESI)[M+H] + =386.5.

[0151] Step 8: Synthesis of Compound 155:

[0152] The product from step 7 (300 mg, 1 eq) and HATU (355.11 mg) were dissolved in N,N-dimethylformamide (5 mL). Triethylamine (236.26 mg) and isopropylamine (55.2 mg) were added sequentially under ice bath conditions, and the reaction was carried out at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was concentrated and purified by rapid chromatography (C18, 0.1% NH4HCO3 in H2O / ACN) to obtain the target compound (114.5 mg). LCMS (ESI) [M+H] + =427.5; 1 H NMR(400MHz, DMSO-d6)δ:8.30-8.25(m,2H),7.65-7.60(m,2H),7.56-7.48(m,2H),7.18-7.14(m,1H),3.95-3. 85(m,1H),3.35-3.33(m,2H),3.31-3.29(m,2H),2.97-2.92(m,2H),2.63-2.56(m,6H),1.08(d,J=6.6Hz,6H).

[0153] Example 2

[0154] Preparation of N-isopropyl-2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (compound 159):

[0155] Step 1: Synthesis of ethyl 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)ethyl acetate:

[0156] 1-(methyl-d3)-6-(5-(piperazin-1-yl)pyridin-3-yl)-3,4-dihydroquinoline-2(1H)-one (2 g, 1 eq, trifluoroacetate form) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (1.7 g) and ethyl 2-bromoacetate (923.73 mg) were added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed as detected by LCMS, the reaction solution was filtered, the filtrate was concentrated, and then purified by reversed-phase chromatography (C18; acetonitrile / pure water) to obtain the product (1 g). LCMS(ESI)[M+H] + =412.3; 1 HNMR(400MHz,DMSO-d6)δ8.33-8.22(m,2H),7.66-7.58(m,2H),7.53-7.46(m,1H),7.19-7.13(m,1H),4.17-4. 05(m,2H),3.32-3.25(m,6H),3.00-2.89(m,2H),2.72-2.66(m,4H),2.62-2.55(m,2H),1.21(t,J=7.1Hz,3H).

[0157] Step 2: Synthesis of 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetic acid:

[0158] 1 g (1 eq) of ethyl 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)acetate was dissolved in 10 mL of methanol and 10 mL of water. Lithium hydroxide (174.6 mg) was added, and the mixture was reacted at 50 °C for 2 hours. After the reaction was complete as determined by LCMS, the reaction solution was concentrated, the pH was adjusted to 6 with 1 M hydrochloric acid, and the product was purified by reversed-phase chromatography (acetonitrile / 0.1% formic acid aqueous solution) to obtain 900 mg (96% yield). LCMS(ESI)[M+H] + =384.2; 1 HNMR(400MHz, DMSO-d6)δ8.29(d,J=1.7Hz,1H),8.26(d,J=2.7Hz,1H),7.67-7.59(m,2H),7.55-7.46(m,1H), 7.20-7.12(m,1H),3.34-3.30(m,4H),3.23(s,2H),2.97-2.91(m,2H),2.78-2.71(m,4H),2.61-2.55(m,2H).

[0159] Step 3: Synthesis of Compound 159

[0160] Ethyl 2-(4-(5-(1-(methyl-d3)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)pyridin-3-yl)piperazin-1-yl)ethyl acetate (800 mg, 1 eq) was dissolved in N,N-dimethylformamide (8 mL), and N,N-diisopropylethylamine (808.89 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1189.89 mg), and isopropylamine (123.32 mg) were added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed as detected by LCMS, the reaction solution was purified by reversed-phase chromatography (C18; acetonitrile / 0.1% ammonia solution) to obtain the target compound (393.15 mg). LCMS (ESI) [M+H] + =425.4; 1 HNMR(400MHz, DMSO-d6)δ8.29(d,J=1.7Hz,1H),8.27(d,J=2.7Hz,1H),7.67-7.60(m,2H),7.58-7.46(m,2H),7 .21-7.13(m,1H),3.91(m,1H),3.33-3.29(m,4H),3.00-2.88(m,4H),2.66-2.54(m,6H),1.08(d,J=6.6Hz,6H).

[0161] Example 3

[0162] Preparation of N-isopropyl-2-(4-(5-(2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide (compound 163):

[0163] Step 1: Synthesis of benzyl 4-(2-(isopropylamino)-2-oxoethyl)piperazine-1-carboxylate:

[0164] 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid (1.2 g, 1 eq), isopropyl amino hydrochloride (535.71 mg), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 2.46 g), and N,N-diisopropylethylamine (1.67 g) were added to N,N-dimethylformamide (20 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water (200 mL) and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography (silica gel, petroleum ether:ethyl acetate = 1:4) to give the product (900 mg, crude product). LCMS (ESI) [M+H] + =320.0.

[0165] Step 2: Synthesis of N-isopropyl-2-(piperazin-1-yl)acetamide:

[0166] The product from the first step (900 mg, 1 eq) was dissolved in methanol (20 mL), and 5% wet palladium on carbon (300 mg) was added. The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was directly concentrated to obtain the product (600 mg, crude product).

[0167] Step 3: Synthesis of 2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide:

[0168] 3,5-Dibromopyridine (500 mg, 1 eq), the product from step two (312.84 mg), sodium tert-butoxide (243.4 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (XantPhos, 61.06 mg), and tris(dibenzylacetone)palladium (38.66 mg) were added to 1,4-dioxane (15 mL). The mixture was stirred at 100 °C for 5 hours under nitrogen protection. The reaction solution was concentrated and purified by rapid chromatography (silica gel, dichloromethane:methanol = 10:1) to obtain the target compound (400 mg). LCMS (ESI) [M+H] + =341.18. 1 HNMR(400MHz,DMSO-d6)δ8.29(d,J=2.6Hz,1H),8.03(d,J=1.8Hz,1H),7.57-7.48(m,2H),3 .95-3.84(m,1H),3.30-3.26(m,4H),2.94(s,2H),2.58-2.54(m,4H),1.07(d,J=6.6Hz,6H).

[0169] Step 4: Synthesis of Compound 163:

[0170] A mixture of 2-(4-(5-bromopyridin-3-yl)piperazin-1-yl)-N-isopropylacetamide (200 mg, 1 eq), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,4-dihydroquinoline-2(1H)-one (160.08 mg), potassium carbonate (243.01 mg), and 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (43 mg) was reacted with dioxane (5 mL) and water (1 mL) and reacted at 80 °C for 3 hours. After the reaction was complete as detected by LCMS, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by reversed-phase chromatography (0.1% ammonia solution / acetonitrile system) to obtain the target compound (112.72 mg). LCMS(ESI)[M+H] + =408.0; 1 HNMR (400MHz, DMSO-d6) δ10.17(s,1H),8.24(d,J=3.4Hz,2H),7.59-7.55(m,1H),7.55-7.48(m,2H),7.48-7.44(m,1H),6.94(d,J= 8.2Hz,1H),3.98-3.84(m,1H),3.31-3.26(m,4H),2.98-2.91(m,4H),2.63-2.57(m,4H),2.49-2.46(m,2H),1.08(d,J=6.6Hz,6H).

[0171] Example 4

[0172] Preparation of N-isopropyl-2-(4-(5-(2-oxo-1,2,3,4-tetrahydroquinoline-6-yl)pyridin-3-yl)piperazin-1-yl)acetamide-2,2-d2 (compound 197):

[0173] Using 2-(4-((benzyloxy)carbonyl)piperazin-1-yl)acetic acid-2,2-d2 (prepared according to the first and second steps of the reaction in Example 1 (Compound 1) of International Patent No. PCT / CN2024 / 140826, or a similar method described in WO2023018471A1) as the starting material, the target compound was prepared according to Example 3 of this application, LCMS(ESI)[M+H] + =410.2.

[0174] Biological Experiment Examples

[0175] Experimental Example 1: Assay for human aldosterone synthase (CYP11B2) inhibitory activity

[0176] Experimental reagents and instruments: Aldosterone kit (Cisbio, Cat#64ALDPEG); Envision microplate reader (PerkinElmer)

[0177] Experimental Principle and Methods: In the human body, aldosterone synthase (CYP11B2) converts 11-deoxycorticosterone (11-DOC) into aldosterone through a series of metabolic processes. In this experiment, a stable G402 cell line overexpressing human CYP11B2 was constructed in vitro (see reference: Valentín-Goyco J, et al. Selectivity of osilodrostat as an inhibitor of human steroidogenic cytochromes P450. J Steroid Biochem Mol Biol. 2023, 231:106316.). Using 11-deoxycorticosterone (11-DOC) as a substrate, the test compound was added, and after co-incubation, the supernatant was collected. The aldosterone content in the supernatant was then detected by HTRF, and the inhibitory effect of the compound on aldosterone synthase (CYP11B2) was calculated.

[0178] Experimental Procedure: 11-Deoxycorticosterone (11-DOC) was added to wells (10,000 cells / well) that had been plated one day in advance. Then, compounds diluted to different gradients were added to the corresponding wells and mixed thoroughly. A control well was also included. The final concentration of DMSO was 0.1%. The plates were incubated at 37°C / 5% CO2 for 24 hours. The collected supernatant was added to 384-well plates (10 μL / well), along with 5 μL of acceptor working solution and 5 μL of donor antibody. The plates were centrifuged at 1000 rpm for 1 min and incubated at room temperature for 60–120 min. Finally, the fluorescence signal ratio at 665 nm / 615 nm was read using an Envision microplate reader (PerkinElmer).

[0179] Experimental data processing method: GraphPad Prism 5 software was used for test data processing and analysis. First, the average response signals of the high-signal and low-signal control wells were calculated separately. Then, the inhibition rate of each compound well was calculated using the formula: "Inhibition rate per well % = 100 - (Average signal value of high-signal control group - Signal value per well) / (Average signal value of high-signal control group - Average signal value of low-signal control group)". The concentration and corresponding inhibition rate data were then imported into Prism 5 software. The inhibition rate-concentration curve was fitted using the log(inhibitor) vs. response – Variable slop method in the software, and the IC50 of the compound was calculated. 50 value.

[0180] The compounds of this application have good CYP11B2 inhibitory activity, and the activity data of exemplary compounds are shown in the table below.

[0181] Table 1. Assay for human aldosterone synthase (CYP11B2) inhibitory activity.

[0182] IC50 of CYP11B2 enzyme inhibition 50 Value: A++≤3nM, 3nM <A+≤10nM,10nM<A≤20nM.

[0183] Experimental Example 2: Assay for human aldosterone synthase (CYP11B1) inhibitory activity

[0184] Experimental reagents and instruments: Cortisol reagent kit (Cisbio, Cat#62ALDPEG); Envision microplate reader (PerkinElmer)

[0185] Experimental Principle and Methods: In the human body, 11β-hydroxylase (CYP11B1) is a key enzyme responsible for cortisol biosynthesis. This experiment involved constructing a stable G402 cell line overexpressing human CYP11B1 in vitro. Using 11-deoxycortisol as a substrate, the test compound was added, and the cells were incubated together. The supernatant was then collected. The cortisol content in the supernatant was then detected using HTRF, and the inhibitory effect of the compound on 11β-hydroxylase (CYP11B1) was calculated.

[0186] Experimental Procedure: 11-Deoxycortisol (11-Deoxycortisol) was added to wells plated one day in advance (10,000 cells / well). Then, compounds diluted to different gradients were added to the corresponding wells and mixed thoroughly. A control well was also included. The final concentration of DMSO was 0.1%. The plates were incubated at 37°C / 5% CO2 for 24 hours. The collected supernatant was added to 384-well plates (10 μL / well), along with 5 μL of Acceptor working solution and 5 μL of Donor Antibody. The plates were centrifuged at 1000 rpm for 1 min and incubated at room temperature for 60–120 min. Finally, the fluorescence signal ratio at 665 nm / 615 nm was read using an Envision microplate reader (PerkinElmer).

[0187] Experimental data processing method: GraphPad Prism 5 software was used for test data processing and analysis. First, the average response signals of the high-signal control wells and the low-signal control wells were calculated separately. Then, the inhibition rate of each compound well was calculated using the formula: "Inhibition rate per well % = 100 - (Average signal value of high-signal control group - Signal value per well) / (Average signal value of high-signal control group - Average signal value of low-signal control group)". The concentration and corresponding inhibition rate data were then imported into Prism 5 software. The log(inhibitor) vs. response – Variable slop method in the software was used to fit the inhibition rate-concentration curve, and the IC50 of the compound was calculated. 50 value.

[0188] The compounds of this application have good CYP11B2 / CYP11B1 selectivity, and the selectivity data of exemplary compounds are shown in the table below.

[0189] Table 2 Selectivity results of CYP11B2 / CYP11B1

[0190] CYP11B1 IC 50 With CYP11B2 IC 50 The ratios are: 500 ≥ B > 200; 200 ≥ C > 100; D ≤ 100

[0191] The structure of control compound 1 is as follows:

[0192] Experiment Example 3: Accompanied PK Study of Crab-Eating Macaques

[0193] Laboratory animals: healthy adult males Crab-eating macaques, 40-65 months old.

[0194] Drug preparation: 5% DMSO + 10% Solutol + 85% Saline (1 / 2 / 17, V / V / V). Weigh an appropriate amount of the test compound and add it to a centrifuge tube. Add an appropriate volume of DMSO, vortex to dissolve and obtain a clear solution, then add Solutol, vortex again to mix, then add Saline, vortex to mix, and obtain a clear solution.

[0195] Animal model: After 7 days of acclimatization, animals were intramuscularly injected with ACTH (ACTH challenge model). Plasma samples were collected before and 1 hour after injection for PD index testing. Animals with a fold greater than 2-fold change in PD index compared to pre-injection levels were used for PD efficacy testing.

[0196] Grouping and administration:

[0197] (1) Administration method: oral administration; dosage: 1 mg / kg or 0.3 mg / kg; administration volume: 5 mL / kg; administration frequency: once on the day of the test.

[0198] (2) ACTH injection method: intramuscular injection; injection time: 1 hour after oral administration; dosage: 14.5ug / kg; injection volume: 0.1ml / kg.

[0199] Sample Collection: Blood samples were collected before oral administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration to prepare plasma. Approximately 0.3 mL or 0.5 mL of blood was collected from venous sites in the limbs and placed in EDTA-K2 tubes. The tubes were gently vortexed to mix and then centrifuged in an ice-water bath for 30 min (4℃, 2000g, 10 min). Plasma was separated and stored at -80℃. The separated blood samples were frozen for later analysis. The entire sample processing procedure was performed using an ice-water bath.

[0200] Analysis and testing: The concentration of the test compound in plasma at each time point was detected by LC-MS / MS. When the measured concentration of the formulation was within 100.0 ± 20.0% of the theoretical concentration, the pharmacokinetic parameters were calculated based on the theoretical dose; otherwise, the dose was calculated based on the dose converted from the actual measured concentration.

[0201] Data analysis methods: Pharmacokinetic parameters of cynomolgus monkeys after drug administration were calculated using a non-compartmental model in Phoenix WinNonlin software. Plasma drug concentration-time data and curves for each test animal are presented, along with the mean, standard deviation, and curves for each dose group. Microsoft Office Excel (Microsoft, USA) was used for data processing and graphing.

[0202] Experimental results:

[0203] The compounds in this application exhibit good oral absorption performance. The results for exemplary compounds are shown in the table below:

[0204] Experimental Example 4: CYP Inhibition Test Method

[0205] Objective: To determine the inhibitory effect of the test compound on the activity of human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A (with midazolam as substrate)).

[0206] Experimental steps:

[0207] 1) Prepare working solutions for the test compound and positive control. Remove human liver microsomes from the refrigerator and thaw them on ice.

[0208] 2) Transfer 20 μL of substrate working solution to the corresponding well, and transfer 20 μL of PB buffer to the blank wells of the culture plate. Transfer 158 μL of human liver microsome working solution to all wells of the culture plate. Transfer 2 μL of the test compound or positive control working solution to the well, and transfer 2 μL of the blank control working solution to the inhibitor-free control well. Preheat the prepared incubation plate at 37.0 °C for 10 min, then add 20 μL of NADPH working solution to initiate the reaction, and incubate the plate at 37.0 °C for 10 min.

[0209] 3) After incubation, add 400 μL of stop solution containing internal standard to terminate the reaction, shake for 10 min, and centrifuge at 3220 g for 20 min. Take 200 μL of the supernatant and mix it with 100 μL of ultrapure water. Shake for 10 min and then inject into LC-MS / MS to analyze the substrate metabolites.

[0210] Data Analysis

[0211] L-fit was used to plot the percentages of negative control, positive control, and test compound concentrations, and for nonlinear regression analysis of the data. IC50 was determined using a 3- or 4-parameter logistic equation. 50 Value. When the % inhibition rate is less than 50% at the highest test concentration (50.0 μM), IC50 value is... 50 The value is ">50.0μM".

[0212] The compounds in this application do not inhibit CYP enzymes. The results for exemplary compounds are as follows:

[0213] Experimental Example 5: Liver Microsomal Stability Test

[0214] The aim of this study was to evaluate the phase-dependent metabolic stability of the test compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys, and human liver microsomes.

[0215] Experimental steps:

[0216] Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively. Prepare eight 96-well sample plates, named T0, T5, T15, T30, T45, T60, Blank60 and NCF60 respectively. The reaction time points corresponding to the first six sample plates are 0 min, 5 min, 15 min, 30 min, 45 min and 60 min respectively.

[0217] Add 445 μL of microsomal working solution (liver microsomal protein concentration of 0.562 mg / mL) to T60 and NCF60 incubation plates and pre-incubate at 37.0 °C for approximately 10 min. Add 54.0 μL of microsomal working solution and 6.00 μL of NADPH working solution to Blank60 sample plates and incubate for 60 min, then add 180 μL of stop solution (acetonitrile solution containing 250 nM tolbutamide and 250 nM labetalol).

[0218] After pre-incubation, add 5.00 μL of the test compound or control working solution to both the T60 and NCF60 incubation plates. Add 50.0 μL of potassium phosphate buffer to each well of the NCF60 incubation plate and incubate for 60 min. For the T0 plate samples, first add 180 μL of stop solution and 6.00 μL of NADPH working solution, then add 54.0 μL of the mixture taken from the T60 incubation plate.

[0219] To initiate the reaction, 44.0 μL of NADPH working solution was added to each well of the T60 incubation plate. Therefore, for wells containing working solutions of the test compound or reference standard, the final reaction concentrations of the test compound, testosterone, diclofenac, and propafenone were 1.00 μM, the concentration of liver microsomes was 0.500 mg / mL, and the final concentrations of DMSO and acetonitrile in the reaction system were 0.01% (v / v) and 0.99% (v / v), respectively.

[0220] After incubation for appropriate times (e.g., 5 min, 15 min, 30 min, 45 min, and 60 min), 60.0 μL of the reaction mixture was removed from the incubation plate and added to T5, T15, T30, T45, T60, and NCF60 plates containing 180 μL of the stop solution to terminate the reaction.

[0221] All sample plates were shaken well and centrifuged at 3220g, 4℃ for 20 min. 80 μL of the supernatant was then diluted in 240 μL of pure water for LC-MS / MS analysis. This study used liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the test compounds and control compounds testosterone, diclofenac, and propafenone in the samples. Semi-quantitative analysis was performed using the analyte / internal standard peak area ratio.

[0222] The compounds of this application exhibit good stability, and the results for exemplary compounds are as follows:

[0223] Experimental Example 6: Study of PK / PD in Monkeys

[0224] Research objective: To evaluate the in vivo efficacy of the compound described in this application in an ACTH challenge stimulation model using cynomolgus monkeys as test animals.

[0225] Laboratory animals: healthy adult males Crab-eating macaques, 40-65 months old.

[0226] Preparation of the test compound:

[0227] Solvent: 5% DMSO + 10% Solutol + 85% Saline (1 / 2 / 17, V / V / V).

[0228] Method: Weigh an appropriate amount of the test compound and add it to a centrifuge tube. Add an appropriate volume of DMSO, vortex to dissolve and obtain a clear solution. Add Solutol, vortex again to mix, and then add Saline. Vortex to mix and obtain a clear solution.

[0229] Animal model: After 7 days of acclimatization, animals were intramuscularly injected with ACTH (ACTH challenge model). Plasma samples were collected before and 1 hour after injection for PD index testing. Animals with a fold greater than 2-fold change in PD index compared to pre-injection levels were used for PD efficacy testing.

[0230] Grouping and administration:

[0231] a. Animal grouping: Animals were randomly grouped into: 1) control compound group, 2) test compound group and 3) vehicle group.

[0232] b. Administration method: Oral administration; Dosage: 0.3 mg / kg, 0.1 mg / kg or 0.025 mg / kg; Administration volume: 0.2 mL / kg; Frequency of administration: Once a day;

[0233] c. ACTH injection method: intramuscular injection; injection time: 1 hour after oral administration; dosage: 14.5 ug / kg; injection volume: 0.1 ml / kg.

[0234] Sample collection:

[0235] Blood samples were collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after oral administration to prepare plasma. Approximately 0.5 mL of blood was collected from each limb vein and placed in an EDTA-K2 tube. The tube was gently vortexed to mix and then centrifuged in an ice-water bath for 30 min (4℃, 2000g, 10 min). The plasma was separated and frozen at -70℃ for analysis. The entire sample processing procedure was performed using an ice-water bath.

[0236] Analysis and Testing:

[0237] The concentrations of steroid metabolites in plasma at various time points were determined using LC-MS / MS.

[0238] Data analysis methods:

[0239] Excel, Phoenix WinNonlin, and Graphpad Prism 9 software were used to process and analyze the data, observe the steroid metabolite chemistry trends, provide the concentrations of each metabolite at each time point, and select time points for intergroup comparisons.

[0240] Experimental results and conclusions:

[0241] Compared with the vehicle group,

[0242] (1) Two hours after oral administration of 0.1 mg / kg (i.e., one hour after ACTH stimulation), the plasma aldosterone level in the control compound Baxdrostat group decreased by 80.29%, and the plasma aldosterone level in the compound 155 group of this application decreased by 91.47%; 24 hours after administration (i.e., 23 hours after ACTH stimulation), the aldosterone level in the control compound Baxdrostat group decreased by 40.50%, and the aldosterone level in the compound 155 group of this application decreased by 76.85%.

[0243] (2) Two hours after oral administration of 0.025 mg / kg (i.e., 1 hour after ACTH stimulation), the plasma aldosterone level in the control compound Baxdrostat group decreased by 80.09%, while the plasma aldosterone level in compound 159 of this application decreased by 83.67%. Twenty-four hours after administration (i.e., 23 hours after ACTH stimulation), the aldosterone level in the control compound Baxdrostat group decreased by only 13.63%, while the aldosterone level in the compound 159 group remained at a decrease of 45.39%.

[0244] Conclusion: Compounds 155 and 159 of this application showed more effective and stable effects in reducing plasma aldosterone levels.

[0245] The embodiments of this application have been described above. However, this application is not limited to the embodiments described above. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A compound, its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts, wherein, The compound is shown in formula (V). in, X3 is selected from N and CR X3 ; R is selected from -N(R2)R3, -S(O)2R4, or is arbitrarily selected by one or more R w1 The following groups are substituted: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic, 5-12 membered heteroaryl, C 6-12 Aryl; wherein, R w1 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, -N(R5)-C(O)-R6, -S(O)2R4, -C(O)OR2, -C(O)-N(R2)R3, or optionally by one or more R groups. w2 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-12 membered heteroaryl; among which, R w2 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, -S(O)2R4, -C(O)N(R7)R8, -C(O)OR9, or optionally, radicals containing one or more R groups. w3 The following groups are substituted: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 6-10 Aryl, 5-12 membered heteroaryl; among which, R w3 Selected from deuterium, halogens, oxo groups, -CN, -OH, -N(R2)R3, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 3-6 cycloalkyl, 3-6 membered heterocyclic, 5-6 membered heteroaryl, phenyl, C 1-4 Halogenated alkyl groups and C 1-4 Halogenated alkoxy groups; R X3 Selected from hydrogen, deuterium, halogens, -OH, -CN, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 1-3 Halogenated alkyl groups and C 1- 3-Haloalkoxy; R a R b Selected independently from hydrogen, deuterium, and C. 1-4 alkyl; R A Selected from hydrogen, -CD3, and cyclopropyl; R2 and R3 are each independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclic groups; wherein, the optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, oxo, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R4 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl and C 3-6 Cycloalkyl; wherein the optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1-4 Alkyl, C 1- 4-alkoxy and C 1-4 Alkylthio; R5 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl and C 3-6 Cycloalkyl; wherein the optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1-4 Alkyl, C 1- 4-alkoxy and C 1-4 Alkylthio; R6 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl, C 3-6 cycloalkyl and C 4-6 Heterocyclic group; wherein, the optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1- 4-alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R7 and R8 are each independently selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-3 Alkyl, C 3-6 cycloalkyl and C 4-6 Heterocyclic group; wherein, the optional substitution refers to unsubstituted or substituted by one or more substituents, each of which is independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkylthio; R9 is selected from hydrogen, deuterium, or optionally substituted groups of the following: C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein the optional substitution refers to unsubstituted or substituted by one or more substituents, each substituent being independently selected from deuterium, halogen, oxo group, -CN, -NH2, C 1-4 Alkyl, C 1- 4-alkoxy and C 1-4 Alkylthio; Unless otherwise stated, the heteroatoms in the above heterocyclic or heteroaryl groups are independently selected from O, N or S, and the number of heteroatoms is 1, 2, 3 or 4; The prerequisite is that the combination of the definitions of the above variables forms a stable chemical structure.

2. The compound of claim 1, its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts, wherein, R is optional, consisting of deuterium, halogen, -OH, or C. 1-4 Alkyl, C 1-4 alkoxy-substituted C 1-6 Alkyl; or, R is a C that is optionally substituted with -OH. 1- 6-alkyl; or, R is... -CH3 or Alternatively, R is C 1-4 Alkyl; or, R is alkyl; -CH3 or Alternatively, R can be n-propyl, isopropyl, or methyl; or, R can be...

3. The compound of claim 1 or 2, its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts, wherein, R A Selected from hydrogen and -CD3; or, R A It is -CD3.

4. The compound, its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts as described in any one of claims 1-3, wherein, X3 is CR X3 And R X3 It is hydrogen.

5. The compound, its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts as described in any one of claims 1-4, wherein, R a and R b All are hydrogen; or R a and R b All are deuterium.

6. A compound, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein, The compound is selected from:

7. A pharmaceutical composition comprising the compound of any one of claims 1-6, or a tautomer, stereoisomer, isotope derivative thereof, or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable carrier.

8. The compound of any one of claims 1-6, or its tautomers, stereoisomers, isotopic derivatives or pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 7, for use as a drug or in the preparation of a drug; preferably, the drug is a drug as a CYP11B2 inhibitor; the drug is a drug for the prevention and / or treatment of CYP11B2-mediated diseases; more preferably, the drug is a drug for the treatment and / or prevention of diseases or conditions caused by hyperaldosteronism; more preferably, the drug is a drug for the treatment and / or prevention of cardiovascular or cerebrovascular diseases or kidney diseases; more preferably, the drug is a drug for the treatment and / or prevention of hypertension, hyperaldosteronism, Cushing's disease, heart failure, or chronic kidney disease; more preferably, the disease is one or more of uncontrolled hypertension, primary aldosteronism hypertension, essential aldosteronism, heart failure, chronic kidney disease, refractory hypertension, and intractable hypertension, or complications thereof.

9. A compound, or its stereoisomers, tautomers, isotopic derivatives, or pharmaceutically acceptable salts thereof, wherein, The compound is selected from:

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