Deuterated 1,2,4-triazine compound and use thereof

Abstract

The present invention provides a deuterated 1,2,4-triazine compound or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, and diastereomer thereof, and a use thereof. The compound provided by the present invention has the effect of inhibiting aldosterone synthase, especially inhibiting CYP11B2 with high selectivity, and also has excellent potential to be manufactured as a drug. Therefore, the compound can be used for treating diseases related to aldosterone synthase.

Description

Deuterated 1,2,4-triazine compounds and their uses Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a deuterated 1,2,4-triazine compound and its use in the preparation of aldosterone synthase inhibitors. Background Technology

[0002] Aldosterone, a key mineralocorticoid secreted by the zona glomerulosa of the adrenal cortex, plays a crucial role in the fine-tuning of multiple organ systems, including the synergistic effects of genomic and non-genomic signaling pathways. In classical genomic pathways, after binding to the mineralocorticoid receptor (MR), aldosterone promotes sodium reabsorption in the distal convoluted tubule, collecting duct, and colonic epithelial cells by regulating the expression of target genes (such as serum and glucocorticoid-induced kinase SGK1, the ENaC subunit of epithelial sodium channels, and the α1 subunit of Na+ / K+-ATPase), while simultaneously enhancing potassium and hydrogen ion excretion, thereby precisely regulating extracellular fluid volume, serum potassium concentration, and acid-base balance. Furthermore, aldosterone enhances its regulation of water and electrolyte metabolism in response to hypovolemia, hyperkalemia, or angiotensin II stimulation by activating the positive feedback loop of the renin-angiotensin-aldosterone system (RAAS). Recent studies have revealed that the non-genomic effects of aldosterone can rapidly regulate sodium-hydrogen exchanger (NHE1) activity, intracellular calcium oscillations, and mitochondrial energy metabolism within minutes by activating signaling axes such as PI3K / Akt, MAPK / ERK, and PKC, thereby affecting vascular tone, endothelial function, and myocardial contractility. At the pathophysiological level, excessive aldosterone can induce vascular smooth muscle cell proliferation, myocardial fibrosis, and renal podocyte damage. Its pro-inflammatory effects (such as activating the macrophage NF-κB pathway and promoting the release of IL-6 and TNF-α) and oxidative stress (NADPH oxidase-dependent ROS generation) jointly contribute to the progression of hypertension, heart failure, and chronic kidney disease.

[0003] CYP11B2 (aldosterone synthase) and CYP11B1 (11β-hydroxylase) are both cytochrome P450 isoenzymes and play a crucial role in the synthesis of adrenal cortical steroid hormones, but their functions and regulatory mechanisms differ significantly. CYP11B2 is specifically expressed in the zona glomerulosa of the adrenal cortex and is responsible for catalyzing the final step of aldosterone biosynthesis: through successive 11β-hydroxylation, 18-hydroxylation, and 18-oxidation reactions, 11-deoxycorticosterone is converted to corticosterone, 18-hydroxycorticosterone, and the final product, aldosterone. Its expression is strictly regulated by the renin-angiotensin-aldosterone system (RAAS) and serum potassium concentration. CYP11B1, on the other hand, is mainly distributed in the zona fasciculata and mediates the key step in cortisol synthesis—the conversion of 11-deoxycortisol (11-deoxycortisol) to cortisol via 11β-hydroxylation. Adrenocorticotropic hormone (ACTH) stimulates the adrenal glands to release cortisol, which has a negative feedback effect on ACTH secretion, feeding back to the hypothalamus and pituitary gland. This negative feedback mechanism counteracts the regulatory effect of aldosterone on blood pressure. Selective inhibition of CYP11B2 can suppress hyperaldosteronism and refractory hypertension. Given the high homology (93%) between CYP11B1 and CYP11B2, the development of a highly selective inhibitor is necessary. Furthermore, aldosterone synthase inhibitors, which directly attenuate aldosterone synthesis, can be considered an alternative to mineralocorticoid receptor antagonists for patients with hyperaldosteronism.

[0004] Oselodrostat is a first-generation aldosterone synthase inhibitor that has been approved for marketing. It is a dual inhibitor of CYP11B1 and CYP11B2, and is only approved for the treatment of Cushing's syndrome. In patients with refractory hypertension, its antihypertensive effect is similar to placebo, but inferior to eplerenone. This is because oselodrostat lacks selectivity for both CYP11B1 and CYP11B2, leading to a simultaneous decrease in aldosterone and cortisol synthesis. This, in turn, causes an increased ACTH feedback release, which in turn stimulates mineralocorticoid receptors to activate steroid precursors (11-deoxycorticosterone), offsetting the antihypertensive effect of oselodrostat. Furthermore, in clinical trials, 20% of patients experienced cortisol reactions and pre-existing cortisol accumulation, potentially leading to further adverse reactions such as bleeding, infection, and acute myocardial infarction, resulting in adrenal insufficiency. Therefore, to develop safe and effective aldosterone synthase inhibitors, high selectivity for aldosterone synthase CYP11B2 is essential.

[0005] Aldosterone synthase inhibitors show great therapeutic potential for a variety of diseases. Mineralys Therapeutics' CYP11B2 inhibitor, Lorundrostat, has met its primary endpoint in the pivotal Phase 3 Launch-HTN (NCT06153693) clinical trial for the treatment of uncontrolled or drug-resistant hypertension. Furthermore, clinical trials for its treatment of kidney disease (Phase III), heart failure (Phase III), and essential aldosteronism (Phase II) are also underway. Multiple clinical trials of another drug, Baxdrostat, including those for hypertension (Phase III), chronic kidney disease (Phase II), and obstructive sleep apnea (Phase II), are also ongoing.

[0006] The physicochemical properties of a drug significantly influence its absorption, breakdown, metabolism, and excretion (ADME), thereby affecting its therapeutic effects. A significant and pressing clinical challenge is the rapid metabolism of drugs in the body, leading to excessively fast drug clearance. While sufficiently high plasma drug levels can be achieved through frequent dosing or increasing the dosage, this introduces numerous potential problems, such as patient compliance, safety concerns, and increased treatment costs. Favorable physicochemical properties also play a crucial role in determining a drug's development prospects.

[0007] Currently, very few drugs targeting CYP11B2 have entered clinical development. CYP11B2 inhibitors with good drug properties and selectivity will be of great significance in addressing current unmet clinical needs. Summary of the Invention

[0008] To overcome the deficiencies in the prior art, one object of the present invention is to provide a deuterated 1,2,4-triazine compound or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, which has highly selective inhibitory activity against aldosterone synthase CYP11B2 and also has excellent pharmacokinetic properties, thus exhibiting good drug-like properties.

[0009] Another object of the present invention is to provide the use of the deuterated 1,2,4-triazine compound.

[0010] The first aspect of this invention provides a deuterated 1,2,4-triazine compound of formula (A) or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof:

[0011] In formula (A),

[0012] R1 is selected from undeuterated or one or more deuterated C1-C4 alkyl groups;

[0013] R10 Selected from undeuterated or one or more deuterated C1-C4 alkyl groups, or undeuterated or one or more deuterated -C(O)-C1-C4 alkyl groups;

[0014] R 11 Selected from hydrogen, deuterium, or undeuterated or one or more deuterated C1-C4 alkyl groups;

[0015] R2, R3, R4, R5, R6, R7, R8, R9, R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 Each is independently selected from hydrogen or deuterium;

[0016] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 At least one of them is deuterated or selected from deuterium.

[0017] In some embodiments of the invention, in formula (A), R1 may be selected from undeuterated or one or more deuterated methyl groups.

[0018] In some embodiments of the present invention, in formula (A), R 10 It may be selected from undeuterated or one or more deuterated methyl groups, or undeuterated or one or more deuterated -C(O)-methyl groups.

[0019] In some embodiments of the present invention, in formula (A), R 11 It can be selected from hydrogen, deuterium, or undeuterated or one or more deuterated methyl groups.

[0020] In some preferred embodiments of the present invention, in formula (A), R1 may be selected from undeuterated or one or more deuterated methyl groups; R 10It may be selected from undeuterated or one or more deuterated methyl groups, or undeuterated or one or more deuterated -C(O)-methyl groups; and R 11 It can be selected from hydrogen, deuterium, or undeuterated or one or more deuterated methyl groups.

[0021] In some embodiments of the present invention, the substituents in formula (A) may satisfy one or more of the following conditions 1)-6), and the remaining substituents are undeuterated or not selected from deuterium.

[0022] 1) R1 is selected from -CH2D, -CHD2, or -CD3;

[0023] 2)R 10 Selected from -CH2D, -CHD2, -CD3, -C(O)CH2D, -C(O)CHD2, or -C(O)CD3;

[0024] 3)R 11 Selected from deuterium, -CH2D, -CHD2, or -CD3;

[0025] 4) R2, R3, R4, R5, R6, R7, R8, and R9 are all selected from deuterium;

[0026] 5)R 12 R 13 R 14 R 15 Simultaneously selected from deuterium;

[0027] 6)R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 It is also selected from deuterium.

[0028] The "remaining substituents" mentioned above refer to the substituents in formula (A) that are not subject to the limiting conditions. For example, when the substituents in formula (A) satisfy condition 1), substituent R1 is selected from deuterated groups (-CH2D, -CHD2, or -CD3), and in this case, "remaining substituents" refers to R2-R 23 They are all undeuterated or not selected from deuterium, that is, none of them contain deuterium; for example, when the substituents in formula (A) simultaneously satisfy conditions 1)-6), all substituents R1-R 23 All are limited to being deuterated or selected from deuterium. In this case, "other substituents" do not exist, that is, there are no substituents that are not deuterated or not selected from deuterium; and so on.

[0029] In some preferred embodiments of the present invention, the substituents in formula (A) may satisfy one or more of the following conditions 1)-6), and the remaining substituents are undeuterated or not selected from deuterium.

[0030] 1) R1 is selected from -CD3;

[0031] 2)R 10 Selected from -CD3 or -C(O)CD3;

[0032] 3)R 11 Selected from deuterium or CD3;

[0033] 4) R2, R3, R4, R5, R6, R7, R8, and R9 are all selected from deuterium;

[0034] 5)R 12 R 13 R 14 R 15 Simultaneously selected from deuterium;

[0035] 6)R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 It is also selected from deuterium.

[0036] In some preferred embodiments of the present invention, the substituents in formula (A) may satisfy one or more of the conditions 1)-4) above, and the remaining substituents are undeuterated or not selected from deuterium.

[0037] In some further preferred embodiments of the present invention, the substituents in formula (A) may satisfy one or more of the above conditions 1), 2), and 4), and the remaining substituents are undeuterated or not selected from deuterium.

[0038] In some preferred embodiments of the present invention, the deuterated 1,2,4-triazine compounds provided by the present invention are further shown as in formula (I):

[0039] In formula (I),

[0040] R1 is selected from undeuterated, or one or more deuterated, or all deuterated C1-C4 alkyl groups;

[0041] R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen or deuterium;

[0042] R 10Selected from -CH3, -CH2D, -CHD2, -CD3, -C(O)CH3, -C(O)CH2D, -C(O)CHD2 or -C(O)CD3;

[0043] R 11 Selected from hydrogen, deuterium, -CH3, -CH2D, -CHD2, or -CD3;

[0044] R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 At least one of them is deuterated or selected from deuterium.

[0045] In some embodiments of the present invention, in formula (I), R1 may be selected from -CH3 or -CD3.

[0046] In some embodiments of the present invention, in formula (I), R2, R3, R4, R5, R6, R7, R8, and R9 can be simultaneously selected from hydrogen or simultaneously selected from deuterium.

[0047] In some embodiments of the present invention, in formula (I), R 10 It can be selected from -CH3, -CD3, -C(O)CH3 or -C(O)CD3.

[0048] In some embodiments of the present invention, in formula (I), R 11 It can be selected from hydrogen, -CH3 or -CD3.

[0049] In some preferred embodiments of the present invention, in formula (I), R1 may be selected from -CH3 or -CD3; R2, R3, R4, R5, R6, R7, R8, and R9 may be simultaneously selected from hydrogen or simultaneously selected from deuterium; R 10 It can be selected from -CH3, -CD3, -C(O)CH3 or -C(O)CD3; and R 11 It can be selected from hydrogen, -CH3 or -CD3.

[0050] A second aspect of this invention provides a compound or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, selected from any of the following compounds:

[0051] A third aspect of the present invention provides a pharmaceutical composition comprising any one of the compounds described in the above-described technical solutions or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, and one or more pharmaceutically acceptable excipients or auxiliary ingredients.

[0052] The fourth aspect of the present invention provides the use of any compound, or pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer, of any of the above-described technical solutions, or the use of any pharmaceutical composition thereof as a medicament (i.e., for therapeutic purposes).

[0053] The fifth aspect of the present invention provides the use of any compound, pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer, or pharmaceutical composition as described in any of the above-described technical solutions, in the preparation of an aldosterone synthase inhibitor.

[0054] The sixth aspect of the present invention provides the use of any compound, or pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, or any pharmaceutical composition thereof, as described in any of the above-described technical solutions, in the preparation of a medicament for treating and / or preventing diseases regulated or maintained by aldosterone synthase.

[0055] The seventh aspect of the present invention provides the use of any compound, pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer, or pharmaceutical composition as described in any of the above-described technical solutions, in the preparation of a selective CYP11B2 inhibitory drug.

[0056] In some embodiments of the present invention, the drugs (including the above-described aldosterone synthase inhibitors, drugs for treating and / or preventing diseases regulated or maintained by aldosterone synthase, and selective CYP11B2 inhibitors) can be used to treat and / or prevent kidney disease, primary aldosteronism, obstructive sleep apnea, cardiovascular and cerebrovascular diseases, or fibrotic conditions. In some preferred embodiments, the cardiovascular and cerebrovascular diseases can be hypertension, heart failure, coronary heart disease, cerebrovascular disease, or aortic dissection; the kidney disease can be diabetic nephropathy, acute kidney injury, chronic renal insufficiency, renal fibrosis, or renal failure.

[0057] The eighth aspect of this invention provides the use of any compound, or pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer, of any of the above-described technical solutions, or a pharmaceutical composition thereof, in the preparation of a medicament for treating and / or preventing nephropathy, primary aldosteronism, obstructive sleep apnea, cardiovascular and cerebrovascular diseases, or fibrotic conditions. In some preferred embodiments, the cardiovascular and cerebrovascular diseases may be hypertension, heart failure, coronary heart disease, cerebrovascular disease, or aortic dissection; the nephropathy may be diabetic nephropathy, acute kidney injury, chronic renal insufficiency, renal fibrosis, or renal failure.

[0058] A ninth aspect of the present invention provides a method for treating and / or preventing diseases regulated or maintained by aldosterone synthase, comprising administering to a patient a therapeutically effective dose of any of the above-described technical solutions, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, or a pharmaceutical composition as described in any of the above-described technical solutions.

[0059] In some embodiments of the present invention, the diseases regulated or maintained by aldosterone synthase may include nephropathy, primary aldosteronism, obstructive sleep apnea, cardiovascular and cerebrovascular diseases, or fibrotic conditions. In some preferred embodiments, the cardiovascular and cerebrovascular diseases may be hypertension, heart failure, coronary heart disease, cerebrovascular disease, or aortic dissection; the nephropathy may be diabetic nephropathy, acute kidney injury, chronic renal insufficiency, renal fibrosis, or renal failure.

[0060] Beneficial technical effects:

[0061] (1) The compounds of the present invention have good inhibitory activity against aldosterone synthase and are highly selective against CYP11B2, which is significantly better than existing CYP11B2 inhibitors (such as Lorundrostat), and therefore have great potential as highly selective aldosterone synthase inhibitors.

[0062] (2) Compared with existing CYP11B2 inhibitors (such as Lorundrostat), the compounds of the present invention have superior ADME properties and thus significantly better drugability. Detailed Implementation

[0063] the term:

[0064] The terminology used in the technical solutions of this invention is explained below. Unless otherwise specified, the terminology herein has the following meanings.

[0065] In the compounds of this invention, any atom not specifically designated as a particular isotope means any stable isotope representing that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", that position should be understood to have hydrogen in its natural abundance isotopic composition. Similarly, unless otherwise stated, when a position is specifically designated as "D" or "deuterium", it should be understood to have a deuterium content greater than the natural abundance of deuterium (which is 0.015%), for example, containing more than 50% deuterium, for example, containing more than 75% deuterium, for example, containing more than 95% deuterium, for example, containing more than 99% deuterium, for example, containing more than 99.5% deuterium.

[0066] "alkyl" refers to an optionally substituted straight-chain or branched saturated aliphatic hydrocarbon group, preferably an alkyl group with 1 to 8 carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8), more preferably an alkyl group with 1 to 6 carbon atoms, and even more preferably an alkyl group with 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof.

[0067] “C1-C n "Including C1-C2, C1-C3, ... C1-C n For example, a "C1-C4" group refers to a moiety containing 1 to 4 carbon atoms, meaning the group comprises 1, 2, 3, or 4 carbon atoms. Therefore, for example, "C1-C4 alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, wherein the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges, such as "1-4," in this document refer to integers within a given range.

[0068] "Deuteration" refers to replacing one or more hydrogen atoms with a corresponding number of deuterium atoms. "Multiple" includes the case of complete replacement, where all hydrogen atoms are replaced by deuterium atoms.

[0069] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0070] "Pharmaceutical composition" means a mixture of one or more compounds of the present invention or their pharmaceutically acceptable salts, prodrugs, hydrates, solvates, enantiomers or diastereomers and other chemical components, wherein "other chemical components" means pharmaceutically acceptable excipients or auxiliary ingredients and / or one or more other therapeutic agents.

[0071] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino group in the compound of the present invention; this modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free amino group.

[0072] "Stereoisomers" are isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0073] "Solvate" refers to a physical aggregate of the compound of this invention and one or more solvent molecules formed through solvation, the physical aggregate including varying degrees of ions and covalent bonds, such as hydrogen bonds. "Hydrate" is a solvate with water (H2O) molecules as the solvent.

[0074] "Independent" or "independently" means that the definition of each group in the general formula is independent and not affected by other groups. When two or more groups have the same option, the options they choose can be the same or different.

[0075] "Optional" or "optionally" or "selectively" means that the event or condition described below may or may not occur, and the description includes both cases in which the event or condition occurs and cases in which it does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may or may not be present, and the description includes both cases in which the heterocyclic group is substituted with an alkyl group and cases in which the heterocyclic group is not substituted with an alkyl group.

[0076] The term "compound" as used herein includes all stereoisomers, geometric isomers, and tautomers. A "compound" as used herein may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, individual enantiomers and diastereomers or other stereoisomeric forms, or mixtures thereof. Compounds containing asymmetric carbon atoms as used herein can be isolated in optically active pure form or in racemic form. Optically active pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents. The term "compound" as used herein also includes geometric isomers, which are chiral forms of compounds where the substituents on the double bonds or rings have different cis-trans isomers. The term "compound" as used herein also includes tautomers. Tautomers can arise from the exchange of a single bond with an adjacent double bond, accompanied by the migration of a proton.

[0077] "Selectivity" indicates that the compounds of this invention have significantly stronger activity against CYP11B2 than against CYP11B1; for example, "selective CYP11B2 inhibitor" means that the inhibitory activity of the compounds of this invention against CYP11B2 is significantly better than that against CYP11B1; the selectivity factor can be calculated by any method known in the art, for example, by dividing the IC50 value of the compound against CYP11B1 by the IC50 value of the compound against CYP11B2. "Selective CYP11B2 inhibitor" can also be called "selective aldosterone synthase inhibitor".

[0078] "Subject" or "patient" refers to an animal, including human patients in need of treatment. In some respects, this article can also be applied in veterinary practice to any mammal or other animal in need of such immune-targeted therapy, including but not limited to non-human primates, dogs, felines, pigs, horses, and any other animals.

[0079] "Treatment" and other similar synonyms include relieving, reducing, or improving symptoms of a disease or condition; preventing other symptoms; improving or preventing the underlying metabolic causes of symptoms; inhibiting a disease or condition, such as preventing its progression; alleviating a disease or condition; improving a disease or condition; relieving symptoms caused by a disease or condition; or stopping the symptoms of a disease or condition. Furthermore, the term includes preventative purposes. The term also includes achieving therapeutic and / or preventative effects.

[0080] "Room temperature" refers to 25±5℃.

[0081] The present invention will be further described below with reference to embodiments, providing details of its implementation. However, it should be noted that the embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Modifications or substitutions made by those skilled in the art based on existing technology still fall within the protection scope of the present invention.

[0082] Preparation Examples

[0083] The separation and purification of products from each reaction stage were achieved using conventional separation techniques in the field of chemical synthesis. Specific methods included, but were not limited to, solvent extraction, solid-liquid filtration, vacuum distillation, recrystallization, and column chromatography. The forward and reverse MPLC used for separation and purification were SepaBean Machines manufactured by Sante Technology Co., Ltd. The forward column was a Leyan Flash Column Silica column, and the reverse column was an Agela Technologies C18 spherical 20-35μm column. The starting materials and reagents required for the experiment can be prepared by synthetic methods described in the literature or purchased directly from commercial channels. The structure of the target compound was confirmed using the following analytical methods: Nuclear magnetic resonance (NMR) spectroscopy was performed using a Bruker ASCEND 400 superconducting NMR spectrometer. The test solvent system was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), with tetramethylsilane (TMS) as an internal standard. All chemical shift values ​​were expressed in ppm (10⁻⁶). -6 The unit of measurement is 6120. Mass spectrometry (MS) analysis was performed using an Agilent SQD electrospray ionization mass spectrometer (equipment model: 6120) with ESI source ionization mode to ensure the accuracy of molecular weight determination.

[0084] Preparation of Compound A1 in Example 1

[0085] first step

[0086] Compound A1-1 (2 g, 7.19 mmol), compound A1-2 (1.54 g, 7.19 mmol), N,N-diisopropylethylamine (2.78 g, 21.51 mmol), and acetonitrile (10 mL) were added to a 500 mL single-necked flask and stirred at room temperature for ten minutes. Then, a 50% (w / w) solution of N,N-dimethylformamide in T3P (5.5 g) was added dropwise, and the reaction was allowed to proceed for 2 hours at room temperature. The reaction was confirmed to be complete by TLC. A 10% (w / w) potassium carbonate aqueous solution (20 mL) was added, and the mixture was stirred at room temperature for two hours. The suspension was filtered, the filter cake was washed with water and dried, and compound A1-3 (1.6 g, 3.37 mmol, yield 46.9%) was collected. ESI-LCMS: m / z 475.3 [M+H] + .

[0087] Step 2

[0088] In a 100 mL single-necked flask, compound A1-3 (1.6 g, 3.37 mmol), 10% palladium on carbon (320 mg), and methanol (20 mL) were added. The mixture was purged with hydrogen three times and reacted at room temperature for 4 hours. The reaction was confirmed complete by TLC and LCMS. The mixture was filtered, and the filtrate was concentrated to collect compound A1-4 (1.1 g, 3.23 mmol, yield 95.8%). ESI-LCMS: m / z 341.2 [M+H] + .

[0089] Step 3

[0090] In a 100 mL single-necked flask, compound A1-4 (1.1 g, 3.23 mmol), triethylamine (980 mg, 9.68 mmol), compound A1-5 (664 mg, 3.23 mmol), and N-methylpyrrolidone (5 mL) were added. After purging with nitrogen three times, the mixture was reacted at 60 °C for 3 hours. The reaction was confirmed to be complete by TLC and LCMS. Water (20 mL) was added, and the mixture was stirred for 2 hours. The suspension was filtered, the filter cake was washed with water and dried, and compound A1-6 (1.0 g, 1.96 mmol, yield 60.7%) was collected. ESI-LCMS: m / z 510.3 [M+H] + .

[0091] Step 4

[0092] Compound A1-6 (1.0 g, 1.96 mmol) was added to a 100 mL single-necked flask, followed by 5 mL of dichloromethane and 5 mL of trifluoroacetic acid. The mixture was reacted at room temperature for 30 minutes. The reaction was confirmed to be complete by TLC and LCMS. The reaction solution was concentrated, and compound A1-7 (600 mg, 1.47 mmol, yield 75.0%) was collected. ESI-LCMS: m / z 410.3 [M+H] + .

[0093] Step 5

[0094] A 5 mL solution of compound A1-7 (600 mg, 1.47 mmol) in dichloromethane, N,N-diisopropylethylamine (758 mg, 5.86 mmol), and deuterated acetic acid (99 mg, 1.54 mmol) were added to a 100 mL single-necked flask. The mixture was stirred at 0 °C for half an hour. HOBT (238 mg, 1.76 mmol) and EDCI (337 mg, 1.76 mmol) were then added, and the mixture was reacted at 0 °C for 2 hours. The reaction was confirmed to be complete by TLC and LCMS. The mixture was quenched with water and extracted with ethyl acetate (100 mL × 3). The organic phase was collected, dried, and concentrated. The residue was purified by forward MPLC (eluent: DCM containing 0–8% MeOH) to give the target product A1 (320 mg, 0.70 mmol, yield 47.6%). ESI-LCMS: m / z 455.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.12(s,1H),8.64(s,1H),7.99(d,J=8.0Hz,2H),7.35(d,J=7.9Hz,2H),5.27(d,J=7.8Hz,1H),3. 96–3.85(m,2H),3.85–3.72(m,4H),3.72–3.52(m,4H),3.23(s,2H),2.46(s,3H),2.10–2.02(m,4H),1.31–1.12(m,4H).

[0095] Preparation of compound A2 in Example 2

[0096] first step

[0097] In a 250 mL three-necked flask, compound A2-1 (3.50 g, 21.35 mmol), cesium carbonate (20.88 g, 64.08 mmol), 1,4-dioxane (35 mL), water (7 mL), and Pd(dppf)Cl2 (1.60 g, 2.19 mmol) were added sequentially, followed by purging with nitrogen three times. Then, deuterated iodomethane (9.28 g, 64.02 mmol) was added, and the mixture was heated to 40 °C and reacted overnight. The reaction was confirmed to be complete by TLC and LCMS. The reaction was quenched with water (100 mL), and the organic phase was collected (100 mL × 3) with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by normal chromatography (eluting with pure petroleum ether) to collect the target product, yielding a colorless oily substance A2-2 (2.15 g, 15.67 mmol, yield 73.4%). ESI-LCMS: m / z 138.1 [M+H] + .

[0098] Step 2

[0099] In a 150 mL three-necked flask, compound A2-2 (2.15 g, 15.67 mol) and DMSO (15 mL) were added sequentially, followed by the dropwise addition of HBr (5.28 g, 31.34 mmol, 48% by mass) aqueous solution (63 mL). After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 7 hours. The reaction was confirmed to be complete by TLC and LCMS. After the addition of water (100 mL), a solid precipitated out. The solid was filtered, washed with water, and dried to obtain A2-3. The crude product was used directly in the next reaction.

[0100] Step 3

[0101] In a 100 mL three-necked flask, the crude product A2-3 and water (20 mL) were added sequentially, followed by dropwise addition of an aqueous solution of aminourea hydrochloride (1.23 g, 11.03 mmol) (5 mL). The mixture was reacted at room temperature for 2 hours. The reaction was confirmed to be complete by TLC and LCMS. The mixture was filtered, the filter cake solid was collected and dried to obtain A2-4. The crude product was used directly in the next reaction step. ESI-LCMS: m / z 209.1 [M+H] + .

[0102] Step 4

[0103] In a 100 mL three-necked flask, the crude product A2-4 and water (20 mL) were added sequentially. The mixture was heated to 55 °C, and then an aqueous solution of sodium hydroxide (1.0 g, 25 mmol) (5 mL) was added dropwise. The reaction was allowed to proceed for 3 hours. The reaction was confirmed to be complete by TLC and LCMS. The mixture was then filtered at 55 °C. After cooling the collected filtrate to room temperature, acetic acid was added dropwise to adjust the pH to approximately 6, causing a solid to precipitate. The precipitate was filtered, and the filter cake was collected and dried to obtain A2-5 (1.80 g, 9.46 mmol, yield 60.4% (A2-2→A2-5)). ESI-LCMS: m / z 191.1 [M+H] + .

[0104] Step 5

[0105] In a 100 mL three-necked flask, compound A2-5 (1.80 g, 9.46 mmol), ethylene glycol dimethyl ether (15 mL), thionyl chloride (3.30 g, 27.74 mmol), and DMF (69 mg, 0.94 mmol) were added dropwise. The mixture was heated to 75 °C and reacted for 3 hours. After confirming the reaction was complete by TLC and LCMS, water (20 mL) was added dropwise to the reaction solution, causing a solid to precipitate. The solid was filtered, and the filter cake was collected. Ethanol (30 mL) was added, and the mixture was stirred for 1 hour. The filter cake was filtered again, and the solid was collected and dried to obtain A2-6 (600 mg, 2.88 mmol, yield 30.4%). ESI-LCMS: m / z 209.1 [M+H] + .

[0106] Step 6

[0107] In a 100 mL three-necked flask, compound A1-4 (981 mg, 2.88 mmol), methanol (10 mL), and triethylamine (586 mg, 5.79 mmol) were added sequentially, and the mixture was heated to 60 °C with stirring. A2-6 (570 mg, 2.7 mmol) was dissolved in N-methylpyrrolidone (5 mL) and added dropwise to the reaction mixture. The mixture was kept at 60 °C for 1 hour. After confirming the reaction was complete by TLC and LCMS, water (50 mL) was added to the reaction mixture and stirred for 30 minutes. The mixture was then cooled to 5–15 °C to allow crystallization for 1 hour. The crystals were filtered, and the filter cake was dried to obtain a light yellow solid, A2-7 (1.34 g, 2.61 mmol, yield 90.6%). ESI-LCMS: m / z 513.3 [M+H] + .

[0108] Step 7

[0109] Compound A2-7 (1.34 g, 2.61 mmol) was added to a 100 mL three-necked flask, followed by dropwise addition of an aqueous solution of hydrochloric acid (3.2 g concentrated hydrochloric acid dissolved in 10 mL of water). The mixture was heated to 40 °C and reacted for 30 minutes. Then, another aqueous solution of hydrochloric acid (3.2 g concentrated hydrochloric acid dissolved in 10 mL of water) was added, and the reaction was maintained at 40 °C for 2 hours. The reaction was confirmed to be complete by TLC and LCMS. The mixture was filtered while hot, and the filtrate was collected. The pH was adjusted to 11–12 with a 27% sodium hydroxide aqueous solution. The mixture was cooled to 5–15 °C and crystallized for 2 hours. The crystals were filtered, and the filter cake was dried to obtain a yellowish-brown solid A2-8 (1.04 g, 2.52 mmol, yield 96.6%). ESI-LCMS: m / z 413.3 [M+H] + .

[0110] Step 8

[0111] Compound A2-8 (500 mg, 1.21 mmol) was dissolved in methanol (2.5 mL) and toluene (2.5 mL). Activated carbon (50 mg) was added, and the mixture was stirred at 40 °C for 1 hour. The mixture was filtered, and the filter cake was washed with a mixed solvent (10 mL, methanol:toluene = 1:1). The filtrate was heated to 50 °C, and acetic anhydride (150 mg, 1.47 mmol) was added dropwise. The reaction was maintained at this temperature for 1 hour. The reaction was confirmed to be complete by TLC and LCMS. Sodium hydroxide (58 mg) was weighed, dissolved in water (2 mL), and added dropwise to the reaction system. The mixture was stirred at 50 °C for 30 minutes, then cooled to 5–15 °C to crystallize for 3 hours. The crystals were filtered and dried to obtain a pale yellow solid A2 (470 mg, 1.03 mmol, yield 85.1%). ESI-LCMS: m / z 455.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),7.93(d,J=8.3Hz,2H),7.25(d,J=8.3Hz,2H),6.95(s,1H),5.38(d,J=8.1Hz,1 H),3.97(s,4H),3.79–3.66(m,2H),3.00(s,2H),2.59(s,4H),2.02–1.92(m,4H),1.90(s,3H),1.32–1.15(m,4H).

[0112] Preparation of compound A3 in Example 3

[0113] Compound A1-7 (200 mg, 0.48 mmol) was dissolved in hexafluoroisopropanol (10 mL), followed by the addition of deuterated paraformaldehyde (138 mg, 4.31 mmol). The system was cooled to approximately 10 °C, and deuterated piperidine-d11 (184 mg, 1.92 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was slowly heated to reflux for 6 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction solution was concentrated under reduced pressure and purified by reverse-phase MPLC (eluent: CH3CN containing 0–40% H2O) to obtain the target product A3 (30 mg, 0.07 mmol, yield 14.6%). MS (ESI) m / z: 427.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.17(d,J=8.2Hz,2H),7.95(s,1H),7.38(d,J=8.1Hz,2 H),4.18–3.49(m,5H),3.18–2.59(m,8H),2.40(s,3H),1.88–1.79(m,4H),1.46–1.22(m,4H).

[0114] Preparation of compound A4 in Example 4

[0115] In a 25 mL three-necked flask, compound A1-7 (90 mg, 0.22 mmol), methanol (1 mL), deuterated paraformaldehyde (70 mg, 2.81 mmol), and acetic acid (20 μL) were added sequentially. After the additions, the mixture was heated to 40 °C and stirred for 5 hours. Then, sodium borodeuteride (37 mg, 0.88 mmol) was added, and the reaction was maintained at this temperature for 1 hour. The reaction was confirmed to be complete by TLC and LCMS. The reaction solution was then purified by forward MPLC (eluent: DCM containing 0–8% MeOH) to give a yellow solid A4 (17 mg, 0.04 mmol, yield 18.2%). ESI-LCMS: m / z 444.4 [M+H] + . 1 H NMR(400MHz, DMSO-d6)δ9.93(s,1H),9.37(s,1H),8.19(d,J=8.2Hz,2H),7.39(d,J=8.0Hz,2H),3.66–3.53(m,3H),3.45–3.33 (m,8H),3.17–3.14(m,1H),2.40(s,3H),2.00(d,J=12.2Hz,2H),1.92(d,J=11.1Hz,2H),1.62–1.46(m,2H),1.36–1.21(m,2H).

[0116] Preparation of compound A5 in Example 5

[0117] Compound A2-8 (200 mg, 0.48 mmol) was dissolved in hexafluoroisopropanol (2 mL), paraformaldehyde (44 mg, 1.47 mmol) was added, and tetrahydropyrrole (138 mg, 1.94 mmol) was added dropwise while maintaining the temperature at 5–15 °C. The mixture was then refluxed for 3 hours. The reaction was confirmed to be complete by TLC and LCMS. Dichloromethane (100 mL) and water (50 mL) were added to the system, and the mixture was extracted and separated. The organic phase was concentrated and then subjected to silica gel column chromatography (eluent: DCM / MeOH = 20 / 1–4 / 1, v / v) to give a pale yellow solid A5 (66 mg, 0.15 mmol, yield 31.3%). ESI-LCMS: m / z 427.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.93(s,1H),7.96–7.89(m,2H),7.30–7.22(m,2H),6.94(d,J=8.5Hz,1H),3.96(t,J=5.1Hz,4H),3.8 1–3.69(m,1H),2.99(s,2H),2.58(t,J=5.1Hz,4H),2.37(s,3H),2.34–2.27(m,1H),2.01–1.90(m,5H),1.23–1.13(m,4H).

[0118] Preparation of compound A6 in Example 6

[0119] first step

[0120] In a 100 mL three-necked flask, compound A6-1 (334 mg, 2 mmol), N,N-dimethylformamide (20 mL), ethyl bromoacetate (334 mg, 2 mmol), 3-chloro-5-(4-tolyl)-triazine (401 mg, 1.95 mmol), and N,N-diisopropylethylamine (1034 mg, 8 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 5 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried, filtered, concentrated under reduced pressure, and purified by forward MPLC (eluent: PE / EA = 2 / 1, v / v) to obtain intermediate A6-2 (195 mg, 0.56 mmol, yield 28.7%). ESI-LCMS: m / z 350.2 [M+H] + .

[0121] Step 2

[0122] In a 50 mL three-necked flask, compound A6-2 (180 mg, 0.52 mmol), lithium hydroxide monohydrate (168 mg, 4.0 mmol), water (2 mL), and methanol (2 mL) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction mixture was concentrated to obtain crude product A6-3 (300 mg), which was used directly in the next reaction step. ESI-LCMS: m / z 322.2 [M+H] + .

[0123] Step 3

[0124] In a 50 mL three-necked flask, compound A6-3 (100 mg, 0.31 mmol), N,N-dimethylformamide (3 mL), N-(trans-4-aminocyclohexyl)-acetamide hydrochloride (100 mg, 0.52 mmol), 1-propylphosphoric anhydride (300 mg, 50% DMF solution, 0.47 mmol), and N,N-diisopropylethylamine (160 mg, 1.24 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 2 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction mixture was diluted with water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried, filtered, concentrated under reduced pressure, and purified by forward MPLC (eluent: DCM / MeOH = 15 / 1, v / v) to obtain the target product A6 (12 mg, 0.026 mmol, yield 8.4%). ESI-LCMS: m / z 460.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),8.64(d,J=7.5Hz,1H),8.21(d,J=8.3Hz,2H),7.79(d,J=7.8Hz,1H),7.40(d,J=8. 4Hz,2H),3.96(s,2H),3.50–3.46(m,2H),2.41(s,3H),1.96–1.80(m,4H),1.77(s,3H),1.36–1.27(m,2H),1.19(s,2H).

[0125] Preparation of compound A7 in Example 7

[0126] first step

[0127] In a 100 mL three-necked flask, compound A7-1 (857 mg, 4.00 mmol), dichloromethane (15 mL), deuterated acetic acid (256 mg, 4.00 mmol), N,N-diisopropylethylamine (1551 mg, 12.00 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphate urea (2281 mg, 6.00 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 5 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction mixture was concentrated under reduced pressure and purified by MPLC (eluent: DCM / MeOH = 20 / 1, v / v) to give a white solid A7-2 (900 mg, 3.47 mmol, yield 86.8%). ESI-LCMS: m / z 260.2 [M+H] + .

[0128] Step 2

[0129] Compound A7-2 (900 mg, 3.47 mmol) was dissolved in methanol (10 mL), and dioxane hydrochloride solution (10 mL, 4.0 M) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction was confirmed to be complete by TLC and LCMS. The reaction solution was then concentrated to obtain A7-3 (600 mg). ESI-LCMS: m / z 160.2 [M+H] + .

[0130] Step 3

[0131] In a 50 mL three-necked flask, compound A6-3 (220 mg, 0.68 mmol), N,N-dimethylformamide (10 mL), compound A7-3 (216 mg, 1.36 mmol), 1-propylphosphonic anhydride (600 mg, 50% DMF solution, 0.94 mmol), and N,N-diisopropylethylamine (528 mg, 4.1 mmol) were added sequentially. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The reaction was confirmed to be complete by TLC and LCMS. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine, dried, filtered, concentrated under reduced pressure, and purified by forward MPLC (eluent: DCM / MeOH = 15 / 1, v / v) to obtain the target product A7 (18 mg, 0.038 mmol, yield 5.6%). ESI-LCMS: m / z 463.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.26(s,1H),8.15(d,J=8.3Hz,2H),7.71(d,J=7.7Hz,1H),7.60(d,J=8.2Hz,1H),7.38(d,J =8.0Hz,2H),3.54–3.46(m,2H),2.97(s,2H),2.40(s,3H),1.81–1.73(m,4H),1.38–1.29(m,2H),1.22–1.16(m,2H).

[0132] By selecting appropriate starting materials and referring to the synthetic route and conditions of Preparation Example 2, the following compounds were also prepared:

[0133] Experiment Example 1: Bioactivity Test

[0134] The cell lines used in this experiment were: stable monoclonal cells overexpressing human CYP11B1 and human CYP11B2, respectively, constructed on human renal smooth muscle tumor cells G-402 (purchased from ATCC, CRL-1440) (G-402-CYP11B1 and G-402-CYP11B2). Construction method: First, expression plasmids were constructed. The main components of the expression plasmids included the ORF of human CYP11B1 or human CYP11B2, a strong promoter, and a suitable antibiotic resistance marker (puromycin). The expression plasmids were transfected into G-402 cells. Then, selection was performed using puromycin to obtain stable monoclonal cells (G-402-CYP11B1 and G-402-CYP11B2) expressing CYP11B1 and CYP11B2.

[0135] The positive compound used in this experiment was Lorundrostat (purchased from MCE, LOT#:292639).

[0136] Experimental procedure: G-402-CYP11B1 and G-402-CYP11B2 cells were digested and diluted to 1×10⁻⁶ in McCoy's 5A complete medium (containing 0.5 μg / mL puromycin). 5 Cells / mL. Add 100 μL of cell suspension to a 96-well plate, 1×10⁻⁶ cells / mL. 4Cells / well. Incubate at 37°C, 5% CO2, and 95% relative humidity in a cell culture incubator. After 24 hours, discard the culture medium and add 90 μL of DMEM / F12 medium (containing 2.5% carbon-adsorbed FBS and 1% penicillin and streptomycin) to each well. Add 5 μL of working solution of the positive compound and the test compound to the cell plate. In the G-402-CYP11B1 cell experiments, the final concentration gradient of the test compounds was 50000 nM, 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, and 0 nM; in the G-402-CYP11B2 cell experiments, the final concentration gradient of the test compounds was 10000 nM, 2000 nM, 400 nM, 80 nM, 16 nM, 3.2 nM, 0.64 nM, 0.128 nM, 0.0256 nM, and 0 nM. After adding the drugs, the cell plate was gently shaken to mix, and incubated for 1 hour in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity. Add 5 μL of substrate working solution (final substrate concentration 1 μM) to each cell culture plate, gently shake to mix, and incubate for 16 hours in a cell culture incubator at 37°C, 5% CO2, and 95% relative humidity. The substrate for CYP11B1 experiments was 11-deoxycortisol; the substrate for CYP11B2 experiments was 11-deoxycorticosterone. After 16 hours, collect the supernatant and analyze the concentration of the products (product of CYP11B1 experiments: cortisol; product of CYP11B2 experiments: aldosterone). The concentrations of these products were determined by LC-MS / MS analysis. %Control activity was calculated based on the read mass spectrometry values ​​(%Control activity = (PeakArea)). Sample / IS PeakArea Sample ) / (PeakArea Control / IS PeakArea Control (%) × 100%). Plotting compound concentration on the x-axis and % control activity on the y-axis, nonlinear fitting was performed using XLfit 5.5.0 (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope))) to calculate the IC50 of the sample. 50 The values ​​are shown in Table 1.

[0137] Table 1. Results of bioactivity tests on some compounds (++): IC 50 ≤10nM; (+): 10nM < IC 50 ≤50nM; (-): IC 50 >50nM.

[0138] As can be seen from the experimental results in Table 1, the compounds of the present invention have significantly better selectivity for CYP11B2 than Lorundrostat, and most of the compounds have significantly better inhibitory activity against CYP11B2 than Lorundrostat (e.g., compounds A2, A3, A4, A5, and A6).

[0139] Experimental Example 2: Pharmacokinetic Test

[0140] Pharmacokinetic assays were performed on 6-8 week old male CD-1 mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.). The test compounds were dissolved in 10% DMSO + 90% (10% hydroxypropyl-β-cyclodextrin aqueous solution). Three mice were administered the compound to each group via intravenous injection (1 mg / kg) or gavage (5 mg / kg). Whole blood samples were collected from the paws of the intravenous injection group at 0.033 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h post-administration. Whole blood samples were collected from the paws of the gavage group at the same times. The concentrations of the compound in the centrifuged plasma samples were analyzed using LC-MS / MS. Pharmacokinetic calculations were performed using WinNonlin (Phoenix™, version 8.3). Pharmacokinetic parameters were calculated based on plasma concentration and time data. The parameter data were statistically calculated and described using average values, as shown in Table 2.

[0141] Table 2 shows representative pharmacokinetic data for some compounds.

[0142] As shown in Table 2, the C of the compound of this invention is higher than that of Lorundrostat. o C max AUC last Significantly improved and Cl_obs significantly reduced, which can effectively improve the dosage and help to achieve better efficacy and safety, thus making it more drug-like.

Claims

1. A deuterated 1,2,4-triazine compound of formula (A) or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof: In formula (A), R1 is selected from undeuterated or one or more deuterated C1-C4 alkyl groups; R 10 Selected from undeuterated or one or more deuterated C1-C4 alkyl groups, or undeuterated or one or more deuterated -C(O)-C1-C4 alkyl groups; R 11 Selected from hydrogen, deuterium, or undeuterated or one or more deuterated C1-C4 alkyl groups; R2, R3, R4, R5, R6, R7, R8, R9, R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 Each is independently selected from hydrogen or deuterium; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 At least one of them is deuterated or selected from deuterium.

2. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, R1 is selected from undeuterated or one or more deuterated methyl groups; and / or R 10 Selected from undeuterated or one or more deuterated methyl groups, or undeuterated or one or more deuterated -C(O)-methyl groups; and / or R 11 Selected from hydrogen, deuterium, or undeuterated or one or more deuterated methyl groups.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, The substituents in formula (A) satisfy one or more of the following conditions 1)-6), and the remaining substituents are undeuterated or not selected from deuterium. 1) R1 is selected from -CH2D, -CHD2, or -CD3; 2)R 10 Selected from -CH2D, -CHD2, -CD3, -C(O)CH2D, -C(O)CHD2, or -C(O)CD3; 3)R 11 Selected from deuterium, -CH2D, -CHD2, or -CD3; 4) R2, R3, R4, R5, R6, R7, R8, and R9 are all selected from deuterium; 5)R 12 R 13 R 14 R 15 Simultaneously selected from deuterium; 6)R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 Simultaneously selected from deuterium; Preferably, the substituents in formula (A) satisfy one or more of the following conditions 1)-6), and the remaining substituents are undeuterated or not selected from deuterium; 1) R1 is selected from -CD3; 2)R 10 Selected from -CD3 or -C(O)CD3; 3)R 11 Selected from deuterium or CD3; 4) R2, R3, R4, R5, R6, R7, R8, and R9 are all selected from deuterium; 5)R 12 R 13 R 14 R 15 Simultaneously selected from deuterium; 6)R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 Simultaneously selected from deuterium; More preferably, the substituents in formula (A) satisfy one or more of the above conditions 1)-4), and the remaining substituents are undeuterated or not selected from deuterium.

4. The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, The deuterated 1,2,4-triazine compound is shown in formula (I): In formula (I), R1 is selected from undeuterated, or one or more deuterated, or all deuterated C1-C4 alkyl groups; R2, R3, R4, R5, R6, R7, R8, and R9 are each independently selected from hydrogen or deuterium; R 10 Selected from -CH3, -CH2D, -CHD2, -CD3, -C(O)CH3, -C(O)CH2D, -C(O)CHD2 or -C(O)CD3; R 11 Selected from hydrogen, deuterium, -CH3, -CH2D, -CHD2, or -CD3; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 R 11 At least one of them is deuterated or selected from deuterium.

5. The compound according to claim 4, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, R1 is selected from -CH3 or -CD3.

6. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, R2, R3, R4, R5, R6, R7, R8, and R9 are all selected from hydrogen or all selected from deuterium.

7. The compound according to any one of claims 4-6, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, R 10 Selected from -CH3, -CD3, -C(O)CH3 or -C(O)CD3.

8. The compound according to any one of claims 4-7, or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, wherein, R 11 Selected from hydrogen, -CH3, or -CD3.

9. A compound or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer, or diastereomer thereof, selected from any of the following compounds:

10. A pharmaceutical composition comprising the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, and one or more pharmaceutically acceptable excipients or auxiliary ingredients.

11. The use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, or the pharmaceutical composition of claim 10, in the preparation of an aldosterone synthase inhibitor, or in the preparation of a medicament for treating and / or preventing diseases regulated or maintained by aldosterone synthase; Preferably, the drug is used to treat and / or prevent kidney disease, primary aldosteronism, obstructive sleep apnea, cardiovascular and cerebrovascular diseases, or fibrotic conditions. More preferably, the cardiovascular and cerebrovascular diseases are hypertension, heart failure, coronary heart disease, cerebrovascular disease, or aortic dissection; the kidney diseases are diabetic nephropathy, acute kidney injury, chronic renal insufficiency, renal fibrosis, or renal failure.

12. Use of the compound of any one of claims 1-9 or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, or the pharmaceutical composition of claim 10 in the preparation of a selective CYP11B2 inhibitory drug; Preferably, the drug is used to treat and / or prevent kidney disease, primary aldosteronism, obstructive sleep apnea, cardiovascular and cerebrovascular diseases, or fibrotic conditions. More preferably, the cardiovascular and cerebrovascular diseases are hypertension, heart failure, coronary heart disease, cerebrovascular disease, or aortic dissection; the kidney diseases are diabetic nephropathy, acute kidney injury, chronic renal insufficiency, renal fibrosis, or renal failure.

13. The use of any compound of claims 1-9 or a pharmaceutically acceptable salt, prodrug, hydrate, solvate, enantiomer or diastereomer thereof, or the pharmaceutical composition of claim 10, in the preparation of a medicament for the treatment and / or prevention of nephropathy, primary aldosteronism, obstructive sleep apnea, cardiovascular disease or fibrosis. Preferably, the cardiovascular and cerebrovascular diseases are hypertension, heart failure, coronary heart disease, cerebrovascular disease, or aortic dissection; the kidney diseases are diabetic nephropathy, acute kidney injury, chronic renal insufficiency, renal fibrosis, or renal failure.

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