Mineral corticoid receptor antagonist compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, in particular to a salt corticoid receptor antagonist compound as well as a preparation method and application thereof. The compound disclosed by the invention is good in selectivity to a salt corticoid receptor, strong in affinity and simple and convenient to synthesize, can be potentially used for diseases caused by excessive action of salt corticoid, and particularly has a good development prospect and application potential in clinical application value of diabetic nephropathy.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a mineralocorticoid receptor antagonist compound, its preparation method, and its application. Background Technology

[0002] Overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes associated with multiple physiological systems, including the heart, vascular system, adipose tissue, and kidneys. Evidence from animal models suggests that MR activation is an inducer of renal oxidative stress and a key mediator of renal inflammation and fibrosis. A link between MR activation and insulin resistance exists in patients with primary aldosteronism, hypertension, chronic kidney disease, and heart failure. In the hypothalamus, MR activation may increase sympathetic nerve drive. Activation of the MR in vascular smooth muscle cells may contribute to vascular oxidative stress, aging, and stiffness.

[0003] Mineralocorticoids, represented by aldosterone, play a crucial role in the development of diabetic nephropathy by mediating inflammatory responses. Significantly elevated plasma aldosterone levels are frequently observed in patients with impaired renal function, suggesting their important role in the pathogenesis and progression of diabetic nephropathy. Studies have shown that abnormalities in the aldosterone-mineralocorticoid receptor (MR) signaling pathway can induce oxidative stress and inflammatory responses, further exacerbating renal hemodynamic disturbances, promoting renal cortical and medullary fibrosis, and thus causing damage to renal structure and function. Furthermore, excessive aldosterone can synergistically interact with angiotensin II (Ang II), leading to decreased vascular compliance and endothelial dysfunction, thereby inducing ventricular arrhythmias, renal fibrosis, proteinuria, and the progression of nephropathy, extensively affecting vital target organs such as the heart and kidneys. Further research has found that physiological concentrations of aldosterone can downregulate insulin receptor mRNA expression and inhibit the binding capacity of insulin in human monocyte precursor cells. In patients with primary aldosteronism, the number of insulin receptors in their adipocytes is reduced by about 34%, and the expression of insulin receptor genes is reduced by about 54%, indicating that aldosterone may also participate in glucose metabolism disorders by affecting the insulin signaling pathway.

[0004] Traditional steroidal mineralocorticoid receptor antagonists, such as spironolactone and eplerenone, are widely used to treat hypertension, chronic heart failure, and primary aldosteronism. However, due to their steroidal skeletal structure, they exhibit non-specific effects on sex hormone receptors, often causing adverse reactions such as gynecomastia, sexual dysfunction, and menstrual irregularities. Furthermore, the pharmacokinetic properties and tissue selectivity of steroidal MRAs are limited, restricting their further clinical application. In contrast, non-steroidal mineralocorticoid receptor antagonists (NSAIDs) have shown better safety and efficacy. For example, Finerenone, developed by Bayer, binds more selectively to MR receptors and exhibits strong anti-inflammatory and anti-fibrotic effects in kidney and heart tissues. In patients with type 2 diabetes and chronic kidney disease, it significantly reduces the risk of renal function deterioration and cardiovascular events, with a lower incidence of side effects, especially sex hormone-related adverse reactions. However, the variety of existing NSAIDs remains limited, and there is still a need to develop novel NSAIDs with novel structures, higher safety profiles, and stronger targeting to meet the clinical needs of treating cardiorenal and cardiovascular diseases. Summary of the Invention

[0005] To address the aforementioned problems, this invention provides a class of 2-hydrazine-4(3H)-keto mineralocorticoid receptor antagonists, their pharmaceutical compositions, and applications, in order to select compounds with better efficacy and selectivity for the treatment of diabetic nephropathy.

[0006] To address the above problems, the technical solution of the present invention is as follows.

[0007] The first aspect of this invention provides a mineralocorticoid receptor antagonist compound, characterized in that its general structural formula is shown in formula (1): Equation (1); Among them, R 1 It is selected from any one of alkyl, alkoxy, alkylacyl, alkoxyacyl, cycloalkyl, alkylsulfonyl, alkylamino, aryl, heterocyclic, heterocyclic acyl, fused ring, spirocyclic, and bridged ring groups; R 2 It is selected from any one of hydrogen, alkyl, alkoxy, alkylacyl, alkoxyacyl, cycloalkyl, alkylsulfonyl, alkylamino, aryl, heterocyclic, heterocyclic acyl, fused ring, spirocyclic, and bridged ring groups; R3 is selected from any one of C1 to C4 alkyl groups.

[0008] Specifically, R 1Selected from C1-C8 alkyl, C1-C8 alkyl containing one or more substituents, C1-C8 alkoxy, C1-C8 alkoxy containing one or more substituents, C1-C8 alkylacyl, C1-C8 alkylacyl containing one or more substituents, C1-C8 alkoxyacyl, C1-C8 alkoxyacyl containing one or more substituents, C1-C8 cycloalkyl, C1-C8 cycloalkyl containing one or more substituents, C1-C8 alkylsulfonyl, alkylsulfonyl containing one or more substituents, C1-C8 alkylamino, C1-C8 alkylamino containing one or more substituents, aryl, substituted aryl, C3-C8 heterocyclic, containing one or more substituents The C3-C8 heterocyclic group, C3-C8 heterocyclic acyl group, C3-C8 heterocyclic acyl group containing one or more substituents, C4-C8 fused heterobicyclic group or C4-C8 fused heterobicyclic group containing one or more substituents, C4-C8 fused heterobicyclic acyl group, C4-C8 fused heterobicyclic acyl group containing one or more substituents, spiro[ab]alkane, spiro[ab]ene or spiro[ab]heterocycle (a, b are integers from 3 to 8), the bridging ring group is selected from bicyclo[abc]alkane, bicyclo[abc]ene or bicyclo[abc]heterocycle (a, b, c are integers from 0 to 6); the substituents are selected from fluorine, chlorine, bromine, iodine, hydroxyl, nitro, amino, carboxylic acid, carboxylic acid ester, cyano, acyl.

[0009] R 2 Selected from hydrogen, C1-C8 alkyl, C1-C8 alkyl containing one or more substituents, C1-C8 alkoxy, C1-C8 alkoxy containing one or more substituents, C1-C8 alkylacyl, C1-C8 alkylacyl containing one or more substituents, C1-C8 alkoxyacyl, C1-C8 alkoxyacyl containing one or more substituents, C1-C8 cycloalkyl, C1-C8 cycloalkyl containing one or more substituents, C1-C8 alkylsulfonyl, alkylsulfonyl containing one or more substituents, C1-C8 alkylamino, C1-C8 alkylamino containing one or more substituents, aryl, substituted aryl, C3-C8 heterocyclic, containing one or more substituents The group consists of C3-C8 heterocyclic groups, C3-C8 heterocyclic acyl groups, C3-C8 heterocyclic acyl groups containing one or more substituents, C4-C8 fused heterobicyclic groups, or C4-C8 fused heterobicyclic groups containing one or more substituents, C4-C8 fused heterobicyclic acyl groups, C4-C8 fused heterobicyclic acyl groups containing one or more substituents, spiro[ab]alkane, spiro[ab]ene, or spiro[ab]heterocycles (a, b are integers from 3 to 8), and the bridging ring group is selected from bicyclo[abc]alkane, bicyclo[abc]ene, or bicyclo[abc]heterocycles (a, b, c are integers from 0 to 6); the substituents are selected from fluorine, chlorine, bromine, iodine, hydroxyl, nitro, amino, carboxylic acid, carboxylic acid ester, cyano, and acyl.

[0010] R3 Selected from C1-C4 alkyl groups.

[0011] In another preferred embodiment, the R 1 Selected from aryl or aryl ring substituents.

[0012] The mineralocorticoid receptor antagonist compound is specifically any one of the following compounds: ( E )-2-(2-(2-fluorobenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-methoxy-4-nitrobenzyl)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-methylbenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-fluorobenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-dimethylaminobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2,4-dimethoxybenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-nitrobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2,4-dihydroxybenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-chlorobenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-methoxy-4-cyanobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-trifluoromethylbenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(6-chloropyridin-3-ylbenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4,5-dimethoxy-2-nitrobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one.

[0013] A second aspect of this invention provides a method for preparing the aforementioned mineralocorticoid receptor antagonist compound, comprising the following steps: Starting with thiourea, intermediate 1 was obtained by methylation with dimethyl sulfate. Intermediate 1 is cyclized with ethyl alkyl acetate, introducing R 3 The group yields intermediate 2; Intermediate 2 reacts with hydrazine hydrate to give intermediate 3; Intermediate 3 condenses with the aldehyde substitute, introducing R 1 The group yields intermediate 4, which condenses with the bromine-substituted product, introducing R. 2 The mineralocorticoid receptor antagonist compound is obtained by adding a group.

[0014] The reaction equations for the above preparation method are as follows: .

[0015] In another preferred embodiment, the molar ratio of the thiourea to the dimethyl sulfate is 1~2:1, preferably 1.83:1, and the methylation reaction temperature is 70℃~90℃, and the time is 5~9h; The molar ratio of intermediate 1 to ethyl alkyl acetate is 0.5~1:1, preferably 0.81:1; The molar ratio of intermediate 2 to hydrazine hydrate is 2.5~3:1, preferably 2.37:1, the reaction temperature is 70℃~90℃, and the reaction time is 4h~8h; The molar ratio of intermediate 3 to the aldehyde-substituted product is 0.5 to 1:1, preferably 1:1, and the condensation reaction temperature is 70℃ to 90℃, and the time is 3h to 7h. The molar ratio of intermediate 4 to the bromine-substituted product was 0.84:1, the condensation reaction temperature was 40~60℃, and the time was 10h~15h.

[0016] In another preferred embodiment, the aldehyde substitute is arylformaldehyde.

[0017] A third aspect of the present invention provides a medicament for the prevention or treatment of diseases caused by the action of mineralocorticoids, wherein the mineralocorticoid receptor antagonist compound is the sole active ingredient.

[0018] In another preferred embodiment, the disease caused by excessive mineralocorticoid activity is any one of nephropathy, inflammatory disease, myocardial remodeling-related disease, fibrosis-related disease, heart failure, hypertension, diuresis, sodium excretion, and potassium retention-related conditions.

[0019] In another preferred embodiment, the drug is a drug used to treat or as an adjunct treatment for chronic kidney disease, diabetic nephropathy, primary aldosteronism, or refractory hypertension.

[0020] In another preferred embodiment, the drug further includes pharmaceutically acceptable excipients.

[0021] Compared with the prior art, the present invention has the following beneficial effects: The compound of this invention uses 2-hydrazylpyrimidine-4(3H)-one as its core framework. Compared to existing steroidal and dihydropyridine MR antagonists, this invention achieves an innovative change in the parent chain skeleton. By introducing hydrazine structural units onto the pyrimidineone core and flexibly substituting them at different positions on the hydrazine terminus and ring, this invention achieves a tunable stereoconfiguration and hydrogen bonding mode, thereby more precisely matching the mineralocorticoid receptor ligand binding pocket. This structural optimization enhances receptor selectivity, reduces off-target effects on corticosteroid receptors, improves safety, and also avoids the side effects on the circulatory system associated with the phenelzine dihydropyridine structure.

[0022] The compounds of this invention not only have high affinity and selectivity for mineralocorticoid receptors, but also have simple synthetic routes and ample room for structural modification, possessing good potential for expansion and scale-up. They are expected to be used in diseases related to excessive mineralocorticoid use, especially in the clinical application of diabetic nephropathy, showing good development prospects and application potential. Attached Figure Description

[0023] Figure 1 The figure shows the effects of Aldo+M71, Aldo+M72, and Aldo+M30 on the expression of FN and COL-III in aldosterone-induced NRK-52e cells. The groups with obvious bands are circled in red in the figure, and the same applies below.

[0024] Figure 2 The figure shows the effects of Aldo+M75, Aldo+M76, and Aldo+M77 on the expression of FN and COL-III in aldosterone-induced NRK-52e cells.

[0025] Figure 3 The figure shows the effects of Aldo+M78, Aldo+M29, Aldo+M79, and Aldo+M80 on the expression of FN and COL-III in aldosterone-induced NRK-52e cells.

[0026] Figure 4 for( E HRMS spectrum of 2-(2-(2,4-dihydroxybenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one (M78).

[0027] Figure 5 for( E )-2-(2-(2,4-dihydroxybenzylidene)hydrazino)-6-methylpyrimidin-4(3H)-one (M78) 1 HNMR spectrum.

[0028] Figure 6 for( E )-2-(2-(2,4-dihydroxybenzylidene)hydrazino)-6-methylpyrimidin-4(3H)-one (M78) 13 CNMR spectrum. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0030] Example 1: The synthesis equation for intermediate 1 is as follows: .

[0031] Weigh 5g (65.7mmol) of thiourea and 3.85ml of distilled water. Slowly add 4.53g (35.9mmol) of dimethyl sulfate dropwise at a controlled temperature of 25℃~30℃, completing the addition over approximately 1.5 hours. Increase the temperature to 80℃ and reflux for 5 hours. After the reaction is complete, cool to 25℃-30℃, add 6.6ml of isopropanol, stir for 60 minutes, filter, wash with a mixture of 2.5ml isopropanol and 1.2ml water, and dry the solid under reduced pressure to obtain 9.01g of a white powdery solid. S 1-Methylisothiourea sulfate is intermediate 1, with a yield of 72.9%.

[0032] Example 2: The synthesis equation for intermediate 2 is as follows: .

[0033] Weigh 5.87 g (31.2 mmol) of the product from 3.2.1 and dissolve it in 100 ml of distilled water. Add 8.14 g (76.8 mmol) of Na₂CO₃ and 5 g (38.4 mmol) of ethyl acetoacetate. Stir overnight at room temperature. A solid precipitates. Adjust the pH to 8 with dilute hydrochloric acid, filter, and dry the solid to obtain 3.32 g of a white powdery solid, which is 6-methyl-2-(methylthio)pyrimidine-4(3H)-one, i.e., intermediate 2, with a yield of 67.9%. HRMS-ESI ( m / z ):157.042 7[M+H] +(Theoretical value 157.0433); 1 HNMR (600MHz, DMSO-) d 6 ) δ 5.95(s,1H),3.33(s,1H),2.46(s,3H),2.16(s,3H).

[0034] Example 3: The synthesis equation for intermediate 3 is as follows: .

[0035] Take a 50 ml round-bottom flask, weigh 3.30 g (21.1 mmol) of intermediate product 2, dissolve it in 8.3 ml of ethanol, and add 4.37 ml of hydrazine hydrate dropwise with stirring. React at 80 °C for 6 h. After the reaction is complete, cool to room temperature, and a precipitate will form. Filter, dry the solid, and you will get 2.18 g of a light brown powdery solid, which is 2-hydrazino-6-methylpyrimidine-4(3H)-one, i.e., intermediate 3, with a yield of 73.6%. HRMS-ESI ( m / z ):141.077 6 [M+H] + (Theoretical value 141.0776); 1 H NMR (600MHz, DMSO-) d 6 ) δ 8.57(s,2H),5.36(s,1H),4.49(s,2H),2.00(s,3H).

[0036] Example 4: The synthesis equation for the target product is as follows: .

[0037] Take a 25 ml round-bottom flask, weigh out 1 mmol of the aryl formaldehyde substitute and 140 mg (1 mmol) of 2-hydrazino-6-methylpyrimidin-4(3H)-one, add 5 ml of anhydrous ethanol, reflux at 80 °C for 5 h. After the reaction is complete, cool to room temperature (23 °C), add 5 ml of distilled water while stirring, and a solid will precipitate. Filter to obtain a filter cake, dissolve the filter cake in an appropriate amount of methanol, mix with an appropriate amount of silica gel, and evaporate to dryness. Purify by column chromatography, using methanol and dichloromethane in a volume ratio of 30:1 as eluent.

[0038] Table 1 shows the target product information obtained from different aryl aldehyde substitutes, among which the structural characterization of M78 is as follows: Figures 4-6 As shown.

[0039] Table 1 Target Products Example 5: Mineralocorticoid receptor antagonistic activity test The mineralocorticoid receptor (MR) is a member of the steroid nuclear receptor superfamily, primarily mediating hormone-induced inflammation and fibrosis, including aldosterone. MR activity can be indirectly reflected by the expression of its target genes, such as FN and COL-III. Therefore, in in vitro cell models, MR pathway activation is induced by aldosterone stimulation, followed by treatment with different test compounds to observe their inhibitory effects on downstream target protein expression, thus assessing MR antagonistic activity. Finerenone is a new generation of nonsteroidal antagonist MR antagonist; its high selectivity and low side effects make it an ideal positive control for screening MR inhibitory drugs.

[0040] NRK-52e cells were seeded in 6-well plates and pre-cultured for 24 hours in DMEM / F12 low-serum medium containing 1% fetal bovine serum after reaching 70%–80% confluence. Cells were then divided into six groups for treatment: the NC group served as a negative control, receiving no aldosterone or other drugs; the Aldo group received 150 nM aldosterone to activate the MR pathway; the Aldo (150 nM) + Fin (10 μM) group served as a positive control, receiving both aldosterone and fenelazol; and the remaining groups received 150 nM aldosterone and 10 μM of different test compounds listed in Table 1, respectively. Cells were collected after 48 hours of treatment, lysed, and total protein was extracted. Western blot analysis was performed to detect the expression levels of fibronectin (FN), type III collagen (COL-III), and β-actin.

[0041] Western blot results show as follows: Figures 1-3 As shown, the aldosterone treatment group (Aldo group) significantly upregulated the expression of FN and COL-III, indicating successful activation of the MR pathway. The fenelazol treatment group (Aldo+Fin group) effectively inhibited the expression of the above proteins, verifying its positive control effect as an MR antagonist. Among the synthesized compounds tested, the treatment groups M29, M71, M76, M77, M78, M79, and M80 all significantly downregulated the expression levels of FN and COL-III, and some of the inhibitory effects were close to or better than the positive control fenelazol, suggesting that these compounds may have strong MR antagonistic activity. In particular, the M78 (Aldo+M78) group showed the most significant inhibition of FN and COL-III expression, performing similarly to or even slightly better than the positive control fenelazol group. β-actin expression was relatively stable, indicating that the protein loading in each group was basically consistent, and the experimental results were highly comparable.

[0042] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0043] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. A mineralocorticoid receptor antagonist compound, characterized in that, The general structural formula is shown in equation (1): Equation (1); Among them, R 1 It is selected from any one of alkyl, alkoxy, alkylacyl, alkoxyacyl, cycloalkyl, alkylsulfonyl, alkylamino, aryl, heterocyclic, heterocyclic acyl, fused ring, spirocyclic, and bridged ring groups; R 2 It is selected from any one of hydrogen, alkyl, alkoxy, alkylacyl, alkoxyacyl, cycloalkyl, alkylsulfonyl, alkylamino, aryl, heterocyclic, heterocyclic acyl, fused ring, spirocyclic, and bridged ring groups; R3 is selected from any one of C1 to C4 alkyl groups.

2. The mineralocorticoid receptor antagonist compound according to claim 1, characterized in that, The R 1 Selected from aryl or aryl ring substituents.

3. The mineralocorticoid receptor antagonist compound according to claim 1, characterized in that, The mineralocorticoid receptor antagonist compound is specifically any one of the following compounds: ( E )-2-(2-(2-fluorobenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-methoxy-4-nitrobenzyl)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-methylbenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-fluorobenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-dimethylaminobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2,4-dimethoxybenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-nitrobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2,4-dihydroxybenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-chlorobenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(2-methoxy-4-cyanobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4-trifluoromethylbenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(6-chloropyridin-3-ylbenzyl)hydrazino)-6-methylpyrimidin-4(3H)-one, ( E )-2-(2-(4,5-dimethoxy-2-nitrobenzylidene)hydrazyl)-6-methylpyrimidin-4(3H)-one.

4. A method for preparing a mineralocorticoid receptor antagonist compound according to any one of claims 1 to 3, characterized in that, Includes the following steps: Starting with thiourea, intermediate 1 was obtained by methylation with dimethyl sulfate. Intermediate 1 is cyclized with ethyl alkyl acetate, introducing R 3 The group yields intermediate 2; Intermediate 2 reacts with hydrazine hydrate to give intermediate 3; Intermediate 3 condenses with the aldehyde substitute, introducing R 1 The group yields intermediate 4, which condenses with the bromine-substituted product, introducing R. 2 The mineralocorticoid receptor antagonist compound is obtained by adding a group.

5. The preparation method according to claim 4, characterized in that, The molar ratio of thiourea to dimethyl sulfate is 1~2:1, the methylation reaction temperature is 70℃~90℃, and the time is 5h~9h; The molar ratio of intermediate 1 to ethyl alkyl acetate is 0.5~1:1; The molar ratio of intermediate 2 to hydrazine hydrate is 2.5~3:1, the reaction temperature is 70℃~90℃, and the reaction time is 4h~8h; The molar ratio of intermediate 3 to the aldehyde-substituted product is 0.5 to 1:1, the condensation reaction temperature is 70℃ to 90℃, and the time is 3h to 7h.

6. A drug for the prevention or treatment of diseases caused by the action of mineralocorticoids, characterized in that, The mineralocorticoid receptor antagonist compound as described in claim 1 is the sole active ingredient.

7. The medicament for preventing or treating diseases caused by the action of mineralocorticoids according to claim 6, characterized in that, The disease mentioned is any one of the following: kidney disease, inflammatory disease, myocardial remodeling-related disease, fibrosis-related disease, heart failure, hypertension, diuresis, sodium excretion, and potassium retention-related conditions.

8. The medicament according to claim 7, characterized in that, The drug is used to treat or as an adjunct treatment for chronic kidney disease, diabetic nephropathy, primary aldosteronism, or refractory hypertension.

9. The drug according to claim 7, characterized in that, The drug also includes pharmaceutically acceptable excipients.

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