Pyrrole amide compounds and their uses

Abstract

Pyrrole amide compounds, pharmaceutical compositions thereof and uses thereof The compounds or pharmaceutical compositions can be used as mineralocorticoid receptor antagonists.

Description

[Technical field]

[0001] The present invention belongs to the technical field of medicine, particularly relates to pyrrole amide compounds and their uses, and further relates to pharmaceutical compositions comprising said compounds, which can be used as mineralocorticoid receptor antagonists. [Background technology]

[0002] The mineralocorticoid receptor (MR) is a nuclear hormone receptor activated by aldosterone that regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular disease. Increased circulating aldosterone increases blood pressure through its natriuretic effects and potentially affects the brain, heart, and vasculature. Hyperaldosteronism is also associated with many pathophysiological processes that lead to renal and cardiovascular disease. Although hyperaldosteronism is usually caused by aldosterone-producing adenomas, patients with refractory hypertension very often suffer from elevated aldosterone levels as a result of elevated serum potassium or residual elevated AT1R activity, which is often referred to as "aldosterone breakthrough." Hyperaldosteronism and aldosterone breakthrough typically result in elevated MR activity, and MR antagonists can be used as antihypertensive drugs and have also been shown to be effective in the treatment of heart failure and primary aldosteronism.

[0003] Aldosterone is a steroid hormone formed in the adrenal cortex. Its production is indirectly and quite substantially regulated depending on the renal blood flow. Any reduction in renal blood flow leads to the release of the enzyme renin in the kidney into the circulation. This then activates the formation of angiotensin II, which on the one hand has a constricting effect on the arterial blood vessels, but on the other hand also stimulates the formation of aldosterone in the adrenal cortex. The kidney thus acts as a blood pressure sensor, and therefore an indirect volume sensor, in the blood circulation and counters critical volume losses, via the renin-angiotensin-aldosterone system, on the one hand by increasing blood pressure (angiotensin II effect) and, on the other hand, by rebalancing the filling state of the vasculature by increasing sodium and water reabsorption in the kidney (aldosterone effect).

[0004] This control system can be pathologically impaired in various ways. For example, a chronic reduction in renal blood flow (e.g., heart failure and the resulting congestion in the venous system) leads to a chronic excess release of aldosterone. This is then followed by an expansion of the blood volume, which weakens the heart through an excess supply of blood to it. Congestion in the lungs with shortness of breath and edema formation in the limbs, as well as ascites and pleural effusion, can occur, further reducing renal blood flow. Excessive aldosterone effects also lead to a decrease in the potassium concentration in the blood and in the extracellular fluid. If there is a deviation below a critical minimum level in the myocardium previously damaged by other factors, cardiac arrhythmias with fatal consequences can be induced. This is likely one of the main causes of the frequent sudden cardiac death in patients with heart failure.

[0005] Aldosterone is also believed to be responsible for a number of myocardial remodeling processes typically observed in heart failure. Thus, aldosteronism is a crucial component in the pathogenesis and prognosis of heart failure (which may be originally induced by various types of damage, such as myocardial infarction, myocardial inflammation, or hypertension). This hypothesis is supported by the fact that in extensive clinical studies on groups of patients with chronic heart failure and after acute myocardial infarction, the use of aldosterone antagonists has significantly reduced overall mortality (B. Pitt, F. Zannad, WJ Remme et al., N. Engl. J. Med. ML 709-717 (1999); B. Pitt, W. Remme, F. Zannad et al., N. Engl. J. Med 1309-1321 (2003)).

[0006] In visceral tissues such as the kidney and intestine, MR also responds to aldosterone to regulate sodium retention, potassium excretion, and water balance. MR expression in the brain also appears to play a role in the control of neuronal excitability, negative feedback regulation of the hypothalamic-pituitary-adrenal axis, and cognition of behavioral performance (Castren et al., J. of Neuroendocrinology, 3, 461-66(1993)). Elevated aldosterone levels or overstimulation of mineralocorticoid receptors are associated with several physiological disorders or pathological disease states, such as Conn's syndrome, primary and secondary aldosteronism, increased sodium retention, increased magnesium and potassium excretion (frequent urination), increased water retention, hypertension (isolated systolic hypertension and combined systolic / diastolic hypertension), arrhythmias, myocardial fibrosis, myocardial infarction, Bartter's syndrome, and disorders associated with excess catecholamine levels (Hadley, ME, ENDOCRINOLOGY, 2nd Ed., pp366-81, (1988); and Brilla et al., Journal of Molecular and Cellular Cardiology, 25 (5), pp563-75(1993)). Compounds and / or pharmaceutical compositions with MR antagonism are useful in treating any of the above disorders.

[0007] International application WO2006012642 A2 discloses a racemic compound of Esaxerenone (CS-3150, the chemical structure of which is shown below), a pyrrole derivative that modulates the activity of one or more nuclear steroid receptors, and patent application WO2008126831 A1 discloses an Esaxerenone compound having a stereoconfiguration that can be used to treat diseases such as hypertension. According to the Examination Report issued by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan (January 8, 2019), the compound has phototoxicity, for example, the results of an in vitro test of neutral red uptake by Balb / c 3T3 fibroblasts show that the compound has phototoxicity (photoirritation factor PIF>17). [ka]

[0008] Although mineralocorticoid receptor antagonists have been a major breakthrough in the treatment of hypertension and heart failure, current care is only suboptimal, and there is clearly an unmet medical need for other therapeutic / pharmacological interventions. The present invention addresses these needs by providing compounds and compositions that can be used to treat or prevent hypertension, heart failure, other cardiovascular disorders, and other aldosterone disorders. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2006012642 [Patent Document 2] International Publication No. 2008126831 [Non-patent literature]

[0010] [Non-Patent Document 1] B. Pitt, F. Zannad, WJ Remme et al., N. Engl. J. Med. ML 709-717 (1999) [Non-Patent Document 2] B. Pitt, W. Remme, F. Zannad et al., N. Engl. J. Med 1309-1321 (2003) [Non-Patent Document 3] Castren et al., J. of Neuroendocrinology, 3, 461-66 (1993) [Non-Patent Document 4] Hadley, ME, ENDOCRINOLOGY, 2nd Ed., pp366-81, (1988) [Non-Patent Document 5] Brilla et al., Journal of Molecular and Cellular Cardiology, 25 (5), pp563-75(1993) Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention provides a pyrrole amide compound having mineralocorticoid receptor (MR) antagonistic activity and a pharmaceutical composition thereof, as well as the use of the compound or the pharmaceutical composition in the manufacture of a drug, which is used to treat, prevent or alleviate diseases in patients, such as aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis and / or stroke. [Means for solving the problem]

[0012] In one aspect, the compound of the present invention is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt, or prodrug of a compound of formula (I). [ka] (In the formula, R 1 is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 The aryl group, the 3- to 6-membered heterocyclic group, and the 5- to 10-membered heteroaryl group each independently have 1, 2, 3, or 4 R a may be substituted with Each R a are independently D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 The aryl group, the 3- to 6-membered heterocyclic group, and the 5- to 10-membered heteroaryl group are independently unsubstituted or substituted with D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy groups and C 1-6 may be substituted with 1, 2, 3 or 4 substituents selected from halogenated alkyl groups; R 2a , R 2b , R 2c , R 2d and R 2e are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)C1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; R 2 and R 3 are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group or C 1-6 is a halogenated alkyl group, R 4 , R 5 , R 6 and R 7 are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2NR b R c , -S(=O)2OC 1-6 Alkyl group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, R5 and R 6 along with the carbon atom to which they are attached, C 3-6 carbocycle, C 6-10 Forms an aromatic ring, a 3- to 6-membered heterocyclic ring, or a 5- to 10-membered heteroaryl ring, 3-6 carbocycle, C 6-10 The aromatic ring, the 3- to 6-membered heterocyclic ring, and the 5- to 10-membered heteroaryl ring are each independently unsubstituted or ═O, D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups and C 1-6 substituted with 1, 2, 3, 4 or 5 substituents selected from alkylamino groups; Each R 8 , R b and R c are independently H, D, and C 1-6 Alkyl group or C 1-6 It is a halogenated alkyl group.

[0013] In some embodiments, R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a trifluoromethyl group, or a difluoromethyl group; R 4 , R 5 , R 6 and R 7 are each independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)CH3, -C(=O)OCH3, -S-CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2NR b R c, -S(=O)2OCH3, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, methylamino, dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, ethylene oxide, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrole, pyridyl, pyrimidinyl or quinolyl, or R 5 and R 6 form, together with the carbon atom to which they are attached, cyclobutene, cyclopentene, cyclohexene, a benzene ring, dihydrofuran, dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole, dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridyl, pyrimidinyl or quinolyl, among which the cyclobutene, cyclopentene, cyclohexene, benzene ring, dihydrofuran, dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole, dihydropyrrole, tetrahydropyridine, dihydro- 1,4-oxazine, pyrrole, pyridyl, pyrimidinyl and quinolyl are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from =O, D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, methylamino and dimethylamino; Each R 8 , R b and R care independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, or 2,2-difluoroethyl.

[0014] In some embodiments, the compound of formula (I) according to the present invention is preferably a compound of formula (Ia) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt or prodrug of a compound of formula (Ia). [ka] (In the formula, R 1 , R 2a , R 2b , R 2c , R 2d and R 2e has the definition described in the present invention.

[0015] In some embodiments, R 2a , R 2b , R 2c , R 2d and R 2e are each independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)CH3, -C(=O)OCH3, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, trifluoromethoxy group, methylamino group, dimethylamino group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, ethylene oxide group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, pyrrole group, pyridyl group, pyrimidinyl group, or quinolyl group.

[0016] In some embodiments, the compound of formula (I) according to the present invention is preferably a compound of formula (IIa) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt or prodrug of a compound of formula (IIa). [ka] (In the formula, R 1 has the definition described in the present invention.

[0017] In some embodiments, R 1 is C 1-4 Alkyl group, C 3-6 a cycloalkyl group, a phenyl group, a 3- to 6-membered heterocyclic group, or a 5- to 6-membered heteroaryl group, 1-4 Alkyl group, C 3-6 The cycloalkyl group, the phenyl group, the 3- to 6-membered heterocyclic group, and the 5- to 6-membered heteroaryl group each independently represent 1, 2, 3, or 4 R a may be substituted with Each R aare independently D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, ethylene oxide group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, pyrrole group, pyridyl group, pyrimidinyl group, or quinolyl group. and the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, ethylene oxide, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrole, pyridyl, pyrimidinyl, and quinolyl groups are independently unsubstituted or substituted with D, F, Cl, Br, OH, NH, SH, CN, NO, C, ... 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy groups and C 1-4 It is substituted with 1, 2, 3 or 4 substituents selected from halogenated alkyl groups.

[0018] In some embodiments, R 1is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an ethylene oxide group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a pyrrole group, a pyridyl group, or a pyrimidinyl group, and the methyl group, the ethyl group, the ... is independently one, two, three, or four R a may be substituted with Each R aare independently D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, ethylene oxide group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, pyrrole group, pyridyl group, pyrimidinyl group, or quinolyl group, and the methyl group, ethyl group, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, ethylene oxide, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrole, pyridyl, pyrimidinyl, and quinolyl are independently unsubstituted or substituted with D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl, ethyl, n-propyl, isopropyl, C 2-4 Alkenyl group, C 2-4 It is substituted with 1, 2, 3 or 4 substituents selected from alkynyl, methoxy, ethoxy, isopropoxy, trifluoromethyl, difluoromethyl, monofluoromethyl and 2,2-difluoroethyl groups.

[0019] In another aspect, the pharmaceutical composition of the present invention comprises a compound according to the present invention and may further comprise at least one of a pharma- cologically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

[0020] In some embodiments, the pharmaceutical compositions according to the present invention further comprise one or more other active ingredients, which are ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates, or antithrombotic agents.

[0021] In one aspect, the use of a compound according to the invention or a pharmaceutical composition according to the invention in the manufacture of a medicament, said medicament being used to treat, prevent or alleviate a disease in a patient, such as aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis of the liver, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis and / or stroke.

[0022] In another aspect, the use of the compound according to the present invention or the pharmaceutical composition according to the present invention in the manufacture of a medicament, wherein said medicament is used as a mineralocorticoid receptor antagonist. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Definitions and General Terms In the following, some embodiments of the present invention are described in detail, and examples thereof are illustrated by the accompanying structural and chemical formulae. The present invention is intended to include all alternatives, modifications, and equivalent technical solutions, all of which are included within the scope of the present invention as defined in the claims. It will be apparent to those skilled in the art that many methods and materials similar or equivalent to those described herein can all be applied to the practice of the present invention. The present invention is not limited to the methods and materials described herein. In the event that one or more of the referenced literature, patents, or similar materials differ or contradict this application (including but not limited to defined terms, term usage, described techniques, etc.), this application shall control.

[0024] It should be noted that certain features of the invention are, for clarity, described in multiple independent embodiments, but may also be provided in combination in a single embodiment. Conversely, various features of the invention may, for convenience, be described in a single embodiment, but may also be provided alone or in any suitable subcombination.

[0025] Unless otherwise specified, all scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents and publications related to this invention are incorporated herein by reference in their entirety.

[0026] The following definitions as used herein apply unless otherwise specified. For the purposes of the present invention, the chemical elements are consistent with the Periodic Table of the Elements, CAS edition, and the Handbook of Chemistry and Physics, 75th edition, 1994. In addition, for general principles of organic chemistry, reference may be made to Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0027] Unless otherwise specified or clearly contradicted by context, the articles "a," "an," "one," and "said" as used herein are intended to include "at least one" or "one or more." Thus, as used herein, these articles refer to one or more (i.e., at least one) of the object article. For example, "a component" means one or more components, i.e., one or more components may be employed or used in the embodiments.

[0028] As used herein, the term "patient" refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

[0029] The term "comprises" is an open expression, that is to say, it includes the contents expressly stated in the present invention, but does not exclude other contents.

[0030] "Stereoisomers" refer to compounds that have identical chemical constitution, but differ with respect to the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereoisomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0031] "Enantiomers" refer to two isomers of a compound which are non-superimposable mirror images of one another.

[0032] "Diastereoisomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties and reactivities. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography (e.g., HPLC).

[0033] "Atropisomer" refers to a structural isomer based on axial or planar chirality caused by the restriction of intramolecular rotation. The compound of the present invention has two atropisomers, for example, the compound represented by formula (II) of the present invention has two atropisomers, which is due to the axial chirality caused by the restriction of the rotation of the bond connecting the phenyl group substituted with a trifluoromethyl group at the ortho position and the substituted pyrrole ring due to steric hindrance. The "atropisomer" of the present invention is either one of the two atropisomers of the compound of the present invention. However, atropisomers having advantageous properties as drugs are preferred because they have higher pharmacological activity, stability, in vivo kinetic properties, safety, etc. Separation of atropisomers can be achieved by chiral separation techniques such as selective crystallization and high performance liquid chromatography.

[0034] The stereochemical definitions and rules used in the present invention are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994.

[0035] Any asymmetric atom (e.g., carbon, etc.) of the compounds disclosed herein can be present in racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R,S)-configuration. In some embodiments, each asymmetric atom has at least 50% enantiomeric excess in the (R)- or (S)-configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0036] Any resulting mixture of stereoisomers can be separated, for example, by chromatographic and / or fractional crystallization techniques, into pure or nearly pure geometric isomers, enantiomers, or diastereoisomers on the basis of differences in the physical and chemical properties of the components.

[0037] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible by a low energy barrier. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of a proton, such as ketone-enol and imine-enamine isomerizations. Valence tautomers include interconversions by rearrangement of some of the bond electrons. A specific example of ketone-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-ketone tautomerism. A specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-ketone tautomers. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

[0038] As described herein, the compounds of the present invention are compounds that may be substituted with one or more substituents, such as compounds of the general formula above, or specific examples, subclasses, and compounds included in the examples of the present invention.

[0039] In addition, unless otherwise clearly stated, the phrases "each ... independently", "... each independently", and "... independently" used in the present invention can be used interchangeably and can be understood in a broad sense, and may mean that specific objects represented by the same reference numerals in different groups do not affect each other, and may mean that specific objects represented by the same reference numerals in the same group do not affect each other. Similarly, "independent" in the phrase "may be ... independently" should be understood in the broad sense as above.

[0040] The terms "may" or "may" mean that the described event or circumstance can, but does not necessarily, occur; that is, the statement includes cases where the event or circumstance occurs and cases where it does not occur. For example, "may be independently substituted with one or more substituents..." means that the group is unsubstituted or is substituted with one or more of the same or different substituents.

[0041] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to the type or range of groups. It is to be noted that the present invention includes all subcombinations of each member of these types and ranges of groups. For example, the terms "C1-C6 alkyl group" or "C 1-6 Alkyl groups" refer to the methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups, as disclosed separately, and "C 1-4 "Alkyl group" refers specifically to methyl, ethyl, C3 alkyl groups (i.e., propyl groups, including n-propyl and isopropyl groups), and C4 alkyl groups (i.e., butyl groups, including n-butyl, isobutyl, s-butyl, and tert-butyl groups), which are disclosed separately.

[0042] Each part of the present invention describes a linking substituent.When the structure clearly requires a linking group, the Markush variable listed in the group should be understood to be a linking group.For example, when the structure requires a linking group and the definition of the Markush group of the variable lists "alkyl group" or "aryl group", the "alkyl group" or "aryl group" should be understood to represent a linking alkylene group or arylene group, respectively.

[0043] The term "alkyl" or "alkyl group" as used herein refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, which may be substituted with one or more substituents as described herein. In some embodiments, an alkyl group contains 1 to 12 carbon atoms, and in other embodiments, an alkyl group contains 1 to 6 carbon atoms, i.e., C 1-6An alkyl group, and then in another embodiment, the alkyl group contains 1 to 4 carbon atoms, ie, C 1-4 An alkyl group, and in some other embodiments, the alkyl group contains 1 to 3 carbon atoms, ie, C 1-3 It is an alkyl group. In some embodiments, the C of the present invention 1-6 Alkyl groups are C 1-4 In another embodiment, C according to the present invention, comprising an alkyl group 1-6 Alkyl groups are C 1-3 Contains an alkyl group.

[0044] Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and tert-butyl), n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like.

[0045] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule by an oxygen atom, where alkyl has the definition set forth in the present invention. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy or 2-propoxy), butoxy (n-butoxy, isobutyloxy, sec-butoxy, tert-butoxy), and the like.

[0046] The term "halogenated alkyl group" or "halogenated alkoxy group" indicates that an alkyl or alkoxy group is substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoromethoxy, chloroethyl (e.g., 2-chloroethyl), trifluoroethyl (including, but not limited to, 2,2,2-trifluoroethyl), 2,2-difluoroethyl, 2-chloro-1-methylethyl, and the like.

[0047] The term "amino group" refers to the -NH2 group. The term "carboxyl group" refers to the -COOH group. The terms "hydroxyl group", "cyano group", "nitro group" and "mercapto group" refer to the -OH, -CN, -NO2 and -SH groups, respectively. The term "oxo" refers to the =O group.

[0048] The term "alkylamino group" or "alkylamino" refers to an -NH2 group substituted with one or two alkyl groups, said alkyl groups having the definition as defined in the present invention. Examples of alkylamino groups include, but are not limited to, methylamino group, ethylamino group, methylethylamino group, dimethylamino group, etc.

[0049] The term "carbocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 14 ring carbon atoms having one or more points of attachment to the rest of the molecule, said carbocyclic rings being optionally substituted with substituents as described herein. The term "carbocyclic group" can be used interchangeably with the term "carbocycle". Examples of carbocyclic groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, and the like.

[0050] The term "cycloalkyl group" refers to a saturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring carbon atoms. In some embodiments, a cycloalkyl group contains 3 to 10 ring carbon atoms, such as C 3-10A cycloalkyl group, in another embodiment, the cycloalkyl group contains from 3 to 8 ring carbon atoms, for example, C 3-8 A cycloalkyl group, and in another embodiment, the cycloalkyl group contains from 3 to 6 ring carbon atoms, for example, C 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. As described herein, C 3-8 Cycloalkyl groups are C 3-6 Contains a cycloalkyl group, 3-6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, which may be substituted with one or more substituents according to the invention.

[0051] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, at least one ring atom being selected from nitrogen, sulfur and oxygen atoms, said heterocyclic group being non-aromatic and not containing any aromatic rings. Unless otherwise specified, a heterocyclic group is a carbon or nitrogen group, and -CH2- groups may be replaced with -C(=O)-. Sulfur atoms of the ring may be oxidized to S-oxides. Nitrogen atoms of the ring may be oxidized to N-oxides. The term "heterocyclic group" may be used interchangeably with the term "heterocycle". Examples of heterocyclic groups include, but are not limited to, an ethylene oxide group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydrothienyl group, a thiazolidinyl group, a pyrazolidinyl group, an oxazolidinyl group, an imidazolidinyl group, an isoxazolidinyl group, a piperidinyl group, a piperazinyl group, or a morpholinyl group. As described in the present invention, the heterocyclic group may be composed of 3 to 8 atoms or 3 to 6 atoms, the atoms may be selected from C, N, O, or S, and at least one atom is N, O, or S. The heterocyclic group composed of 3 to 8 atoms includes a heterocyclic group composed of 3 to 6 atoms, and the heterocyclic group composed of 3 to 6 atoms includes a heterocyclic group composed of 3 to 5 atoms. Specifically, the heterocyclic group composed of 3 to 6 atoms includes an ethylene oxide group ( [ka] ), aziridinyl group ( [ka] ), azetidinyl group ( [ka] ), oxetanyl group ( [ka] ), pyrrolidinyl group ( [ka] ), tetrahydrofuranyl group ( [ka] ), tetrahydrothienyl group ( [ka] ), thiazolidinyl group ( [ka] ), dihydrothiazoles (e.g. [ka] ), pyrazolidinyl group ( [ka] ), pyrazolinyl group ( [ka] ), oxazolidinyl group ( [ka] ), imidazolidinyl group ( [ka] ), dihydrooxazoles (e.g. [ka] ), dihydroimidazole ( [ka] ), piperidinyl group ( [ka] ), piperazinyl group ( [ka] ), dihydro-1,4-oxazine ( [ka] ) or a morpholinyl group ( [ka] ) and the like. The heterocyclic group may be substituted with one or more substituents described in the present invention.

[0052] The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0053] The term "aryl group" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, in which at least one ring is aromatic and has one or more points of attachment to other parts of the molecule. The term "aryl group" can be used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, 2,3-dihydro-1H-indenyl, naphthyl and anthryl groups. The above aryl groups may be substituted with one or more substituents according to the present invention. Unless otherwise specified, "C 6-10 The group "aryl group" refers to an aryl group containing 6 to 10 ring carbon atoms.

[0054] The term "heteroaryl group" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring is aromatic and at least one ring contains 1, 2, 3 or 4 cycloheteroatoms selected from nitrogen, oxygen and sulfur atoms, and at the same time, the heteroaryl group has one or more points of attachment to the rest of the molecule. If a -CH2- group is present in the heteroaryl group, the -CH2- group may be replaced with -C(=O)-. Unless otherwise specified, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) by any reasonable site (which may be C in CH or N in NH). The term "heteroaryl group" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrrole, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, etc. The heteroaryl group may be substituted with one or more of the substituents described in the present invention. In some embodiments, the heteroaryl group is a 5-10 membered heteroaryl group, which means that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3 or 4 cycloheteroatoms selected from O, S and N, and in other embodiments, the heteroaryl group is a 5-6 membered heteroaryl group, which means that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3 or 4 cycloheteroatoms selected from O, S and N, and examples of 5-6 membered heteroaryl groups include, but are not limited to, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrole, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, etc.

[0055] The term "j to k-membered" is generally used to describe a cyclic group, and indicates that the cyclic group is composed of j to k ring atoms, the ring atoms including carbon atoms and / or heteroatoms such as O, N, S, P, and the like, and the j and k are each independently any non-zero natural number and k>j, and the "j to k" includes j, k and any natural numbers therebetween. For example, "3 to 8-membered", "5 to 10-membered" or "5 to 6-membered" indicates that the cyclic group is composed of 3 to 8, 5 to 10 or 5 to 6 ring atoms, the ring atoms including carbon atoms and / or heteroatoms such as O, N, S, P, and the like.

[0056] The term "pharmacologically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not cause allergic or similar unpleasant reactions, such as gastrointestinal discomfort, dizziness, etc. Preferably, as used herein, the term "pharmacologically acceptable" refers to those that are available for use in animals, particularly humans, as approved by a federal regulatory agency or national government or as listed in the United States Pharmacopeia or other generally recognized pharmacopoeias.

[0057] The term "carrier" refers to a diluent, adjuvant, excipient or matrix with which the compound is applied. These drug carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. As the carrier, water, aqueous solutions (e.g., saline solutions, glucose solutions and glycerin solutions), particularly injection solutions, are preferred. Suitable drug carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin.

[0058] The term "prodrug" as used in the present invention refers to a compound that is converted in vivo to a compound represented by formula (I). Such conversion is effected by the prodrug being hydrolyzed in blood or by enzymatic conversion to the parent structure in blood or tissue. The prodrug compound of the present invention may be an ester, and in the prior art, esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, the compounds of the present invention contain a hydroxyl group, which can be acylated to provide the prodrug form of the compound. Other prodrug forms include phosphate esters, for example, these phosphate compounds are obtained by phosphorylation of the parent hydroxy group. For a complete discussion of prodrugs, see the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 2328-2345.

[0059] "Metabolite" refers to a product produced by metabolism in vivo of a specific compound or a salt thereof. Metabolites of a compound can be identified using techniques known in the art, and their activity can be characterized by test methods such as those described in the present invention. Such products can result from processes such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of an administered compound. Correspondingly, the present invention includes metabolites of a compound, including metabolic products produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

[0060] The term "pharmacologically acceptable salts" as used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmacologically acceptable salts are well known in the art and are described, for example, in the literature: SM Berge et al., describe soluble salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Salts formed with pharmacologically acceptable non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or these salts are obtained by other methods described in books and literature, such as ion exchange methods. Other pharmacologically acceptable salts include salts obtained by reaction with a suitable alkali, such as alkali metal, alkaline earth metal, ammonium and N. + (C 1-4 The quaternary ammonium salts are salts of any compound containing an N group. Water or oil soluble or dispersible products can be obtained by quaternary ammonium salt formation. Alkali metals or alkaline earth metals capable of forming salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts include suitable non-toxic ammonium and quaternary ammonium salts, as well as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8It further includes cations of the amine formed using counterions such as sulfonic acid compounds and aromatic sulfonic acid compounds.

[0061] The "solvate" of the present invention is an association formed between one or more solvent molecules and the compound of the present invention. The solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

[0062] The "ester" of the present invention refers to an in vivo hydrolyzable ester formed with a compound containing a hydroxyl group or a carboxyl group. Such esters are pharmacologically acceptable esters that, for example, undergo in vivo hydrolysis in humans or animals to yield the parent alcohol or acid. The compounds of formula (I) of the present invention contain a carboxyl group and can form in vivo hydrolyzable esters with suitable groups, such groups including, but not limited to, alkyl groups, arylalkyl groups, and the like.

[0063] The term "nitrogen oxide" as used herein refers to compounds that contain multiple amine functional groups, where one or more of the nitrogen atoms can be oxidized to form an N-oxide. A specific example of an N-oxide is trimethylamine-N-oxide or an N-oxide containing a nitrogen-containing heterocyclic nitrogen atom. The N-oxide can be formed by treating the corresponding amine with an oxidizing agent, such as hydrogen peroxide or a peracid (e.g., a carboxylic acid peroxide) (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages). In particular, the N-oxide can be prepared by the LW Deady method (Syn. Comm. 1977, 7, 509-514), for example, by reacting an amine compound with meta-chloroperoxybenzoic acid (MCPBA) in an inert solvent such as dichloromethane.

[0064] As used herein, the term "compound of the present invention", "compound described in the present invention", "compound described in the present invention" or similar expressions refer to a compound represented by any one of the general formula structures described in the present invention. For example, the compound of the present invention may be a compound represented by formula (I) or formula (Ia) or formula (II) or formula (IIa) of the present invention. The compound of the present invention further includes the specific compound of any one of the embodiments.

[0065] The term "treatment" as used herein refers to treating any disease or disorder, and in some embodiments, ameliorating the disease or disorder (i.e., alleviating, inhibiting, or reducing the worsening of the disease or at least one clinical symptom thereof). In another embodiment, "treatment" refers to alleviating or improving at least one physical parameter, including physical parameters that are not perceptible to the patient. In another embodiment, "treatment" refers to modulating the disease or disorder physically (e.g., stable perceptible symptoms) or physiologically (e.g., stable physical parameters), or both. In another embodiment, "treatment" refers to preventing or delaying the onset, onset, or worsening of the disease or disorder.

[0066] Any structural formulas provided herein are intended to represent isotopically non-enriched and isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures shown in the general formulas provided herein except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Exemplary isotopes that can be introduced into the compounds of the present invention are: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as I.

[0067] On the other hand, the compounds described in the present invention include isotopic enriched compounds defined in the present invention, for example, 3 H, 14 C and 18 A compound in which a radioactive isotopes such as F is present, or 2 H and 13 It is a compound in which non-radioactive isotopes such as C exist. The isotopic enriched compounds are metabolic studies ( 14 Using C), kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or for radiation treatment of patients. 18 F-enriched compounds are particularly ideal for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared by conventional techniques known to those skilled in the art or by methods described in the examples and preparations of the present invention, using suitable isotopically labeled reagents in place of previously used non-labeled reagents.

[0068] Heavy isotopes, particularly deuterium (i.e. 2Substitution with H or D) can bring about several therapeutic advantages, which are due to improved metabolic stability, for example, increased in vivo half-life or reduced required dosage, or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). The isotopic enrichment factor can define the concentration of the heavier isotope (especially deuterium) of the class. The term "isotopic enrichment factor" as used in the present invention refers to the ratio between the isotopic abundance and the natural abundance of a designated isotope. When a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In the present invention, pharma- ceutically acceptable solvates include those in which the crystallization solvent, such as DO, acetone-d6, DMSO-d6, etc., may be isotopically substituted.

[0069] Unless otherwise specified, all tautomeric forms of the compounds of the invention are included within the scope of the invention. Additionally, unless otherwise specified, the structural formulae of the compounds described in the invention include enriched isotopes of one or more of the different atoms.

[0070] Abbreviations for all protecting groups, amino acids and other compounds used in the present invention follow their commonly used and well-known abbreviations or those in accordance with the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11:942-944), unless otherwise specified.

[0071] Description of the compounds of the present invention The present invention provides a pyrrole amide compound capable of competitively antagonizing mineralocorticoid receptor (MR) and its use, as well as a pharmaceutical composition containing the compound and the use of the compound or the pharmaceutical composition in the manufacture of a drug, which is used to treat, prevent or alleviate diseases in patients with aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis and / or stroke. Research has unexpectedly discovered that the change in the substitution position of F on the benzene ring bonded to the amide has a significant effect on the properties of the compound, for example, when F is in the meta position of the acyl group, the activity of the compound (i.e., the compound of the present invention) is the highest. Overall, the compound of the present invention has excellent mineralocorticoid receptor antagonist activity and pharmacokinetic properties, and more excellently, the compound of the present invention has virtually no phototoxicity.

[0072] In one aspect, the compound of the present invention is a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt, or prodrug of a compound of formula (I). [ka] (In the formula, R 1 , R 2 , R 2a , R 2b , R 2c , R 2d , R 2e , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 has the definitions set forth in the present invention. )

[0073] In some embodiments, R 2 and R 3 are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C2-6 Alkynyl group or C 1-6 It is a halogenated alkyl group.

[0074] In some embodiments, R 2 and R 3 are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group or C 1-4 It is a halogenated alkyl group.

[0075] In some embodiments, R 2 and R 3 are each independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a trifluoromethyl group, or a difluoromethyl group.

[0076] In some embodiments, R 4 , R 5 , R 6 and R 7 are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, -SC 1-6 Alkyl group, -S(=O)C 1-6 Alkyl group, -S(=O)2C 1-6 Alkyl group, -S(=O)2NR b R c , -S(=O)2OC 1-6 Alkyl group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino group, C 3-6 Cycloalkyl groups, C 6-10An aryl group, a 3-6-membered heterocyclic group or a 5-10-membered heteroaryl group, b and R c has the definitions set forth in the present invention; alternatively R 5 and R 6 along with the carbon atom to which they are attached, C 3-6 carbocycle, C 6-10 A aromatic ring, a 3-6-membered heterocyclic ring or a 5-10-membered heteroaryl ring, and C is formed. 3-6 carbocycle, C 6-10 The aromatic ring, the 3- to 6-membered heterocyclic ring, and the 5- to 10-membered heteroaryl ring are each independently unsubstituted or ═O, D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups and C 1-6 Substituted with 1, 2, 3, 4 or 5 substituents selected from alkylamino groups.

[0077] In some embodiments, R 4 , R 5 , R 6 and R 7 are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, -SC 1-4 Alkyl group, -S(=O)C 1-4 Alkyl group, -S(=O)2C 1-4 Alkyl group, -S(=O)2NR b R c , -S(=O)2OC 1-4 Alkyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups, C 1-4Alkylamino group, C 3-6 Cycloalkyl groups, C 6-10 An aryl group, a 3-6-membered heterocyclic group or a 5-6-membered heteroaryl group, and R b and R c has the definitions set forth in the present invention; alternatively R 5 and R 6 along with the carbon atom to which they are attached, C 3-6 A carbocyclic ring, a benzene ring, a 3- to 6-membered heterocyclic ring or a 5- to 6-membered heteroaromatic ring, and a C is formed. 3-6 Carbocycles, benzene rings, 3-6-membered heterocyclic rings and 5-6-membered heteroaromatic rings are independently unsubstituted or =O, D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups and C 1-4 Substituted with 1, 2, 3, 4 or 5 substituents selected from alkylamino groups.

[0078] In some embodiments, R 4 , R 5 , R 6 and R 7 are each independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)CH3, -C(=O)OCH3, -S-CH3, -S(=O)CH3, -S(=O)2CH3, -S(=O)2CH2CH3, -S(=O)2NR b R c, -S(=O)2OCH3, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, trifluoromethoxy group, methylamino group, dimethylamino group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, ethylene oxide group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, pyrrole group, pyridyl group, pyrimidinyl group, or quinolyl group; R b and R c has the definitions set forth in the present invention; alternatively R 5 and R 6 together with the carbon atoms to which they are attached, form cyclobutene, cyclopentene, cyclohexene, a benzene ring, dihydrofuran, dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole, dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridyl, pyrimidinyl or quinolyl, and said cyclobutene, cyclopentene, cyclohexene, a benzene ring, dihydrofuran, dihydrothiazole, dihydroimidazole, dihydropyrazole, dihydrooxazole, dihydropyrrole, tetrahydropyridine, dihydro-1,4-oxazine, pyrrole, pyridyl, pyrimidinyl or quinolyl -oxazine, pyrrole, pyridyl, pyrimidinyl and quinolyl are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from =O, D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, trifluoromethoxy, methylamino and dimethylamino.

[0079] Preferably, R4 , R 5 and R 7 are each independently H or D, and 6 is -S(=O)2CH3 or -S(=O)2CH2CH3.

[0080] In some embodiments, each R 8 , R b and R c are independently H, D, and C 1-6 Alkyl group or C 1-6 It is a halogenated alkyl group. In some embodiments, each R 8 , R b and R c are independently H, D, and C 1-4 Alkyl group or C 1-4 It is a halogenated alkyl group.

[0081] In some embodiments, each R 8 , R b and R c are independently H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trifluoromethyl, difluoromethyl, monofluoromethyl, or 2,2-difluoroethyl.

[0082] In some embodiments, the compound of formula (I) according to the present invention is preferably a compound of formula (Ia) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt or prodrug of a compound of formula (Ia). [ka] (In the formula, R 1 , R 2a , R 2b , R 2c , R 2d and R 2e has the definitions described in the present invention. )

[0083] In some embodiments, R 2a , R 2b , R 2c , R 2d and R 2e are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)C 1-6 Alkyl group, -C(=O)OC 1-6 Alkyl group, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 1-6 Alkylamino group, C 3-6 Cycloalkyl groups, C 6-10 It is an aryl group, a 3-6-membered heterocyclic group or a 5-10-membered heteroaryl group.

[0084] In some embodiments, R 2a , R 2b , R 2c , R 2d and R 2e are independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)C 1-4 Alkyl group, -C(=O)OC 1-4 Alkyl group, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylamino group, C 3-4 Cycloalkyl groups, C 6-10 It is an aryl group, a 3-6-membered heterocyclic group or a 5-6-membered heteroaryl group.

[0085] In some embodiments, R 2a , R 2b , R 2c , R 2d and R 2eare each independently H, D, F, Cl, Br, OH, NH2, SH, CN, NO2, -C(=O)CH3, -C(=O)OCH3, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, trifluoromethoxy group, methylamino group, dimethylamino group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, ethylene oxide group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, pyrrole group, pyridyl group, pyrimidinyl group, or quinolyl group.

[0086] In some embodiments, the compound of formula (I) according to the present invention is preferably a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt or prodrug of a compound of formula (II). [ka] (In the formula, R 1 has the definitions set forth in the present invention. )

[0087] In some embodiments, the compound of formula (I) according to the present invention is preferably a compound of formula (IIa) or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt or prodrug of a compound of formula (IIa). [ka] (In the formula, R 1 has the definitions described in the present invention. )

[0088] In some embodiments, R 1is C 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, 1-6 Alkyl group, C 3-6 Cycloalkyl groups, C 6-10 The aryl group, the 3- to 6-membered heterocyclic group, and the 5- to 10-membered heteroaryl group each independently have 1, 2, 3, or 4 R a and R a has the definitions set forth in the present invention.

[0089] In some embodiments, R 1 is C 1-4 Alkyl group, C 3-6 a cycloalkyl group, a phenyl group, a 3- to 6-membered heterocyclic group, or a 5- to 6-membered heteroaryl group, 1-4 Alkyl group, C 3-6 The cycloalkyl group, the phenyl group, the 3- to 6-membered heterocyclic group, and the 5- to 6-membered heteroaryl group each independently represent 1, 2, 3, or 4 R a and R a has the definitions set forth in the present invention.

[0090] In some embodiments, R 1 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an ethylene oxide group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a pyrrole group, a pyridyl group, or a pyrimidinyl group, and the methyl group, the ethyl group, the ... is independently one, two, three, or four R a and Ra has the definitions set forth in the present invention.

[0091] In some embodiments, each R a are independently D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group, 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 The aryl group, the 3- to 6-membered heterocyclic group, and the 5- to 10-membered heteroaryl group are independently unsubstituted or substituted with D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, C 1-6 Halogenated alkyl groups, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, C 6-10 It is substituted with 1, 2, 3 or 4 substituents selected from an aryl group, a 3-6-membered heterocyclic group and a 5-10-membered heteroaryl group.

[0092] In some embodiments, each R a are independently D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 3-4 Cycloalkyl groups, C 6-10An aryl group, a 3-6-membered heterocyclic group or a 5-6-membered heteroaryl group, and C is described above. 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 3-6 Cycloalkyl groups, C 6-10 The aryl group, 3-6-membered heterocyclic group and 5-6-membered heteroaryl group are independently unsubstituted or D, F, Cl, Br, OH, NH2, SH, CN, NO2, C 1-4 Alkyl group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Alkoxy group, C 1-4 Halogenated alkyl groups, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl groups, C 6-10 It is substituted with 1, 2, 3 or 4 substituents selected from an aryl group, a 3-6-membered heterocyclic group and a 5-6-membered heteroaryl group.

[0093] In some embodiments, each R aare independently D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, vinyl group, ethynyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, naphthyl group, ethylene oxide group, azetidinyl group, oxetanyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperidinyl group, morpholinyl group, pyrrole group, pyridyl group, pyrimidinyl group, or quinolyl group, and the methyl group, ethyl group, n-propyl, isopropyl, n-butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, tert-butoxy, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, ethylene oxide, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrole, pyridyl, pyrimidinyl, and quinolyl are independently unsubstituted or substituted with D, F, Cl, Br, OH, NH2, SH, CN, NO2, methyl, ethyl, n-propyl, isopropyl, C 2-4 Alkenyl group, C 2-4 Alkynyl group, methoxy group, ethoxy group, isopropoxy group, trifluoromethyl group, difluoromethyl group, monofluoromethyl group, 2,2-difluoroethyl group, C 3-6 It is substituted with 1, 2, 3 or 4 substituents selected from a cycloalkyl group, a phenyl group, a 3-6-membered heterocyclic group and a 5-6-membered heteroaryl group.

[0094] In some embodiments, the compounds described herein have a structure represented by any of the following formulas, or a stereoisomer, geometric isomer, tautomer, atropisomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmacologically acceptable salt, or prodrug of said structure: [ka]

[0095] In another aspect, the pharmaceutical composition according to the present invention comprises the compounds according to the present invention.

[0096] In some embodiments, the pharmaceutical composition according to the present invention further comprises at least one of a pharmacologically acceptable carrier, excipient, diluent, adjuvant, and vehicle.

[0097] In another embodiment, the pharmaceutical composition according to the present invention further comprises one or more other active ingredients, said other active ingredients being ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates and / or antithrombotic agents.

[0098] In one aspect, the present invention relates to the use of a compound or a pharmaceutical composition according to the present invention in the manufacture of a medicament, wherein the medicament is used to treat, prevent or alleviate a disease in a patient, such as aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis of the liver, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis or stroke.

[0099] In another aspect, the present invention relates to the use of a compound or a pharmaceutical composition according to the present invention in the manufacture of a medicament, said medicament being used as a mineralocorticoid receptor antagonist.

[0100] In one aspect, the compounds or pharmaceutical compositions according to the present invention are used to treat, prevent or alleviate a disease in a patient, such as aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis or stroke.

[0101] In other aspects, the compounds or drug compositions described in the present invention can be used to antagonize mineralocorticoid receptors.

[0102] In one aspect, the method of the present invention for treating, preventing or alleviating a disease in a patient, such as aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis or stroke, using a compound or pharmaceutical composition according to the present invention comprises treating the patient with a therapeutically effective amount of a compound or pharmaceutical composition according to the present invention.

[0103] In another aspect, a further method of the present invention for antagonizing a mineralocorticoid receptor using a compound or pharmaceutical composition according to the present invention comprises contacting a living body (including in vivo or in vitro) with an effective amount of a compound or pharmaceutical composition according to the present invention.

[0104] The compounds or pharmaceutical compositions according to the present invention competitively antagonize the aldosterone receptor (MR) and are therefore useful agents for the treatment and prevention of disorders associated with elevated aldosterone levels.

[0105] The compounds or pharmaceutical compositions according to the present invention can be used to treat or prevent diseases mediated by the aldosterone receptor.The present invention also includes a method for treating or alleviating a disease mediated by the aldosterone receptor in a patient or having susceptibility to these disorders, comprising treating the patient with a therapeutically effective amount of the compounds or pharmaceutical compositions according to the present invention.

[0106] The present invention includes the use of the compounds of the present invention and their pharmacologically acceptable salts for the manufacture of pharmaceutical products for treating patients with mineralocorticoid receptor or aldosterone-related disorders, including those described in the present invention. The present invention includes pharmaceutical compositions comprising an effective therapeutic amount of a compound of formula (I) in combination with at least one pharmacologically acceptable carrier, excipient, diluent, adjuvant, or vehicle.

[0107] Unless otherwise specified, all hydrates, solvates and pharmacologically acceptable salts of the compounds of the present invention fall within the scope of the present invention.

[0108] Specifically, the salts are pharmacologically acceptable salts. The phrase "pharmacologically acceptable" means that the substance or composition must be chemically or toxicologically compatible with the other ingredients of the formulation and / or with the mammal being treated therewith.

[0109] The salts of the compounds of the present invention further include salts of intermediates for preparing or purifying the compounds represented by formula (I) or enantiomers separated from the compounds represented by formula (I), but are not necessarily pharmacologically acceptable salts.

[0110] Salts of the compounds of the present invention can be prepared by any suitable method provided in the literature, for example using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, acetonic acid, oxalic acid, glycolic acid and salicylic acid, pyranose acids such as glucuronic acid and galacturonic acid, α-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid, ethylsulfonic acid, etc.

[0111] The biological activity of the compounds of the present invention can be evaluated by any conventional method. Suitable detection methods are well known in the art. For example, the MR antagonistic activity, pharmacokinetic activity and / or liver microsomal stability of the compounds of the present invention can be detected by suitable conventional methods. The detection methods of the present invention are provided only as examples and are not intended to limit the present invention. The compounds of the present invention exhibit activity in at least one detection method of the present invention. For example, the compounds of the present invention have high antagonistic activity against the aldosterone receptor, excellent in vivo pharmacokinetic properties such as excellent absorption and exposure, high bioavailability, and the compounds of the present invention have low toxicity and side effects.

[0112] Pharmaceutical compositions, formulations, administration and uses of the compounds of the present invention In another embodiment, the pharmaceutical composition of the present invention is characterized in that it comprises a pyrrole amide compound represented by formula (I) or formula (Ia) or formula (II) or formula (IIa), a compound listed in the present invention, or a compound of Examples 1 to 8, and a pharmacologically acceptable carrier, adjuvant, or excipient. The amount of the compound in the composition of the present invention can effectively treat or alleviate a patient's disease related to mineralocorticoid receptor or aldosterone.

[0113] As described in the present invention, the pharma- cologically acceptable compositions of the present invention further comprise pharma- cologically acceptable carriers, adjuvants, or excipients, which may be used in the present invention include any of the following, suitable for the particular intended dosage form: solvents, diluents, or other liquid excipients, dispersing or suspending agents, surfactants, isotonicity agents, thickening agents, emulsifiers, preservatives, solid binders, or lubricants. In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams& Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference, reveal various carriers used in the formulation of pharma- cologically acceptable compositions and known in the art for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effects or interacting in a deleterious manner with any other component of the pharma- cologically acceptable composition, its use is contemplated within the scope of the present invention.

[0114] Some examples of substances that can act as pharmacologically acceptable carriers are ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, buffer substances such as glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; sodium carboxymethylcellulose, ethyl ... These include, but are not limited to, cellulose and its derivatives, such as cellulose acetate and cellulose tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; diol compounds, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol, phosphate buffer solution, and other suitable non-toxic lubricants, colorants, releasing agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and antioxidants, such as sodium lauryl sulfate and magnesium stearate.

[0115] The pharmaceutical composition of the present invention can be administered directly or in the form of a pharmaceutical composition or drug together with suitable carriers or excipients known in the art. The therapeutic method of the present invention comprises administering an effective amount of the compound of the present invention to an individual in need thereof. In some embodiments, the individual is a mammalian individual, and in some preferred embodiments, the individual is a human individual.

[0116] The effective amount of the compound, pharmaceutical composition or drug according to the present invention can be easily determined by routine testing, and the most effective and convenient administration route and the optimal formulation can also be determined by routine testing.

[0117] Pharmaceutical dosage forms of the compounds of the present invention can be provided in the form of immediate release, controlled release, sustained release or targeted drug release systems. For example, common dosage forms include solutions and suspensions, (micro)emulsions, ointments, gels and patches, liposomes, tablets, dragees, soft or hard shell capsules, suppositories, ovoids, implants, amorphous or crystalline powders, aerosols and lyophilized preparations. Depending on the route of administration, specific devices such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks may be required to give or administer the drug. Drug dosage forms often consist of a drug, excipients and a container / closure system. One or more excipients (also called inactive ingredients) can be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration and safety of the drug, and to provide a desired drug release profile. Thus, the type of excipients added to a drug is determined by various factors such as the physical and chemical properties of the drug, the route of administration, and the preparation steps. Pharmaceutical excipients exist in the art and include those listed in various pharmacopoeias (US Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and British pharmacopoeia (BP); the US Food and Drug Administration (www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications such as Inactive Ingredient Guide (1996); Handbook of Pharmaceutical Additives by Ash and Ash (2002, Synapse Information Resources, Inc., Endicott NY; etc.).

[0118] The pharmaceutical dosage forms of the compounds of the present invention can be prepared by any method known in the art, such as conventional mixing, sieving, dissolving, melting, granulating, dragee making, tabletting, suspending, extruding, spray drying, pulverizing, emulsifying, (nano / micrometer) encapsulation, coating or lyophilization processes. As mentioned above, the compositions of the present invention may contain one or more physiologically acceptable inactive ingredients, which can easily process the active molecules into formulations for pharmaceutical use.

[0119] The appropriate formulation depends on the desired route of administration. For example, for intravenous injection, the composition can be formulated in an aqueous solution, using physiologically compatible buffers, including, for example, phosphates, histidine or citrates to adjust the pH value of the formulation, if necessary, and isotonicity agents, such as sodium chloride or dextrose. For transmucosal or nasal administration, it can be preferably a semi-solid, liquid formulation or patch, and can include a penetration enhancer, which is generally known in the art. For oral administration, the compound can be formulated in a liquid or solid dosage form, and can be formulated for immediate release or controlled / sustained release. Suitable dosage forms for oral ingestion by an individual include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions. The compound can also be formulated in rectal compositions, such as suppositories or retention enemas, including conventional suppository matrices, such as cocoa butter or other glycerides.

[0120] Solid oral dosage forms can be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution retarders, lubricants, glidants, anti-adherents, cationic exchange resins, wetting agents, antioxidants, preservatives, colorants and flavorings. These excipients can be synthetic or natural. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, sugars (i.e., dextrose, sucrose, lactose, etc.), talc, tragacanth mucilage, vegetable oils (hydrogenated) and waxes. Ethanol and water can be used as granulation aids. In some cases, it is necessary to coat the tablets, for example with a taste masking film, a gastric acid resistant film or a release retarding film. Sugar-coated tablets are often prepared by coating tablets with natural or synthetic polymers in combination with colorants, sugars, organic solvents or water. Where capsules are preferred over tablets, drug powders, suspensions or solutions can be delivered in hard or soft shell capsules.

[0121] Compositions prepared for parenteral administration by injection are usually sterilized and can be provided in unit dosage form such as ampoules, syringes, injection pens, or multi-dose containers (usually containing a preservative). The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous carriers and may contain formulation reagents such as buffers, isotonicity agents, thickening agents, surfactants, suspending agents, dispersing agents, antioxidants, biocompatible polymers, chelating agents, and preservatives. Depending on the injection site, the carrier may contain water, synthetic or vegetable oils, and / or organic cosolvents. In some cases, the parenteral formulation is reconstituted or diluted before administration, for example in the case of lyophilized or concentrated formulations. Depot formulations that provide controlled or sustained release of the compounds of the invention may include injectable suspensions of nano / microparticles or nano / micro or non-micronized crystals. Other matrices known in the art, polymers such as poly(lactic acid), poly(glycolic acid) or other copolymers, can be used as controlled / sustained release matrices. Other depot delivery systems may be provided in the form of implants and pumps that require incision.

[0122] Suitable carriers for intravenous injection of the compounds of the present invention are known in the art and include aqueous solutions containing bases (e.g., sodium hydroxide) that form ionic compounds and sucrose or sodium chloride as isotonicity agents, and buffers, for example, contain phosphate or histidine. Cosolvents such as polyethylene glycol may be added. These aqueous systems effectively dissolve the compounds of the present invention and have low toxicity after systemic administration. The ratio of components of the solution system can be changed significantly without compromising the solubility or toxicity characteristics. The properties of the components can also be changed. For example, low toxicity surfactants such as polysorbates or poloxamers can be used, as well as polyethylene glycol or other cosolvents, biocompatible polymers such as polyvinylpyrrolidone can be added, and other sugars or polyols can be used instead of dextrose.

[0123] The compounds of the present invention can act systemically and / or locally. They can be administered in any suitable manner, for example, orally, gastrointestinal, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or ear canal, or as an implant or stent. The compounds of the present invention are preferably administered orally or parenterally.

[0124] Suitable forms for oral administration include crystalline and / or amorphous and / or dissolved forms of the compound of the invention according to prior art working methods, fast-release and / or improved release methods of the compound of the invention, such as tablets (uncoated or coated, e.g. with a gastro-resistant or slow-dissolving coating or an insoluble coating that controls the release of the compound of the invention), tablets or films / wafers that disintegrate quickly in the oral cavity, films / lyophilisates, capsules (e.g. hard or soft shell capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0125] Parenteral administration can be performed by avoiding the absorption step (e.g., intravenously, intraarterially, intracardially, intraspinally or intralumbarly) or by including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal). Suitable administration methods for parenteral administration are injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0126] Suitable for other administration routes are, for example, pharmaceutical forms for inhalation (including powder inhalers, nebulizers), nose drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. patches), milks, pastes, foams, powders for dusting, implants or stents.

[0127] A therapeutically effective amount of the compound of the present invention should be present in the above pharmaceutical formulations at a concentration of about 0.1-99.5%, preferably about 0.5-95%, by weight of the total mixture.

[0128] In addition to the compounds of the present invention, the pharmaceutical formulations may also contain other active pharmaceutical ingredients.

[0129] The therapeutically effective amount can be initially estimated by various methods well known in the art. The initial dose for animal studies can be based on effective concentrations established in cell culture assays. A suitable dosage range for a human individual can be determined, for example, from data obtained from animal studies and cell culture assays. In some embodiments, the compounds of the present invention can be prepared as a pharmaceutical for oral administration. In a pharmaceutical for oral administration, an exemplary dosage of the compounds of the present invention is about 0.01 to about 100 mg / kg (kg represents the subject's body weight).

[0130] Commonly used drug dosing regimens for oral administration are three times a week, twice a week, once a week, three times a day, twice a day, or once a day. In some embodiments, the compounds of the present invention are administered in a total amount of about 0.001 to about 50 mg / kg body weight of active ingredient every 24 hours, and optionally multiple single doses can be used for administration to achieve the desired results.

[0131] An effective amount or therapeutically effective amount or dose of an agent (e.g., a compound of the invention) refers to that amount of agent or compound that results in amelioration of symptoms or a prolongation of survival in an individual. Toxicity and therapeutic efficacy of such molecules can be determined by standard pharmaceutical procedures in cell cultures or test animals, e.g., LD 50 (lethal dose for 50% of the population) and ED 50 The dose ratio of toxic to therapeutic effects is the therapeutic index, and the LD 50 / ED 50 Agents that exhibit large therapeutic indices are preferred.

[0132] An effective amount or therapeutically effective amount is that amount of a compound or pharmaceutical composition that elicits the biological or medical response in a tissue, system, animal or human that a researcher, veterinarian, physician or other clinician is seeking. The dosage is preferably within the range of ED with little or no toxicity. 50 The range of circulating concentrations includes: 100 mg / kg / day, ...

[0133] Dosage and interval times can be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect, i.e., the minimal effective concentration (MEC). The MEC for each compound varies but can be estimated, for example, from in vitro data and animal studies. The dose required to obtain the MEC depends on individual characteristics and the route of administration. In cases of localized administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0134] The amount of drug or composition administered will depend on a variety of factors, including the sex, age, and weight of the individual being treated, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0135] If necessary, the compositions of the present invention can be provided in a package or dispenser device containing one or more unit dosage forms (containing the active ingredient). For example, the package or dispenser device can contain metal or plastic foil (e.g., foam package) or glass or rubber stopper. The package or dispenser device can be accompanied by pharmaceutical instructions. The compositions containing the compounds of the present invention can be formulated and prepared in a compatible pharmaceutical carrier, placed in an appropriate container and labeled for the treatment of a specified disorder.

[0136] The compounds of the present invention may be used alone or, if necessary, in combination with other active compounds.The present invention further provides a combination comprising at least one compound of the present invention and one or more additional active substances, in particular with a drug for treating and / or preventing the diseases described in the present invention.

[0137] The compounds of the present invention act as antagonists of the mineralocorticoid receptor and exhibit a valuable and unexpected range of pharmacological effects, making them suitable for use as drugs for the treatment and / or prevention of diseases in humans and animals.

[0138] The compounds of the invention are suitable for the prevention and / or treatment of various disorders and disease-related conditions, in particular disorders characterized by or associated with an increase in plasma aldosterone concentration or an alteration of plasma aldosterone concentration relative to plasma renin concentration. Examples to be mentioned are: idiopathic primary aldosteronism, aldosteronism associated with adrenal hyperplasia, adrenal adenoma and / or adrenal carcinoma, aldosteronism associated with liver cirrhosis, aldosteronism associated with heart failure, (relative) aldosteronism associated with primary hypertension, etc.

[0139] Due to their mechanism of action, the compounds of the present invention are also suitable for the prevention of sudden cardiac death in patients at high risk of death from sudden cardiac death.These are in particular patients suffering from one of the following disorders: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, refractory hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathies (e.g. Brugada syndrome), cardiomyopathy caused by Chagas disease, shock, arteriosclerosis, atrial and ventricular arrhythmias, transient ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disorders, arterial occlusive diseases such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis, hypertrophic changes in the heart, pulmonary arterial hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disorders and vasculitis.

[0140] The compounds of the present invention can additionally be used for the prevention and / or treatment of edema formation, such as pulmonary edema, renal edema or edema associated with heart failure, as well as restenosis, e.g. after thrombolytic therapy, percutaneous transluminal angioplasty (PTA) and percutaneous transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery.

[0141] The compounds of the invention are further suitable for use as potassium-sparing diuretics and for the treatment of electrolyte abnormalities such as hypercalcemia, hypernatremia or hypokalemia.

[0142] The compounds of the invention are likewise suitable for the treatment of renal diseases such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerosis nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and cystic renal disease, for the prevention of renal damage (e.g. renal damage caused by immunosuppressants (e.g. cyclosporin A) in connection with organ transplantation) and for renal cancer.

[0143] The compounds of the present invention can further be used in the prevention and / or treatment of diabetes and its diabetic sequelae such as neuropathy and diabetic nephropathy.

[0144] The compounds of the invention can further be used for the prevention and / or treatment of microalbuminuria and proteinuria caused, for example, by diabetes or hypertension.

[0145] The compounds of the present invention may further be used for the prevention and / or treatment of fibrotic diseases such as renal fibrosis, pulmonary fibrosis (including idiopathic pulmonary fibrosis), and liver fibrosis.

[0146] The compounds of the invention are also suitable for the prevention and / or treatment of disorders associated with an elevated plasma glucocorticoid concentration or a localized elevated glucocorticoid concentration in tissues (e.g. the heart). Examples which may be mentioned are insufficiency of the adrenal glands leading to an overproduction of glucocorticoids (Cushing's syndrome), tumors of the adrenal cortex leading to an overproduction of glucocorticoids, and pituitary tumors, which autonomously produce ACTH (adrenocorticotropic hormone), leading to hyperplasia of the adrenal glands and Cushing's disease.

[0147] The compounds of the present invention may further be used for the prevention and / or treatment of obesity, metabolic syndrome and obstructive sleep apnea.

[0148] The compounds of the invention can further be used for the prevention and / or treatment of inflammatory disorders caused by viruses, spirochetes, fungi, bacteria or mycobacteria and inflammatory disorders of unknown etiology such as polyarthritis, lupus erythematosus, periarthritis or polyarteritis nodosa, dermatomyositis, scleroderma and sarcoidosis.

[0149] The compounds of the invention may further be used in the treatment of disorders of the central nervous system, such as depression, anxiety states and chronic pain, especially migraine headaches, and neurodegenerative disorders, such as Alzheimer's disease and Parkinsonism.

[0150] The compounds of the invention are also suitable for the prevention and / or treatment of vascular damage following percutaneous transluminal coronary angioplasty (PTCA), stent placement, coronary angioscopy, reocclusion or restenosis after bypass surgery, as well as for endothelial cell dysfunction, Raynaud's disease, thrombotic occlusive vasculitis (Buergers' syndrome) and tinnitus syndrome.

[0151] The compounds of the present invention can be used alone or, if necessary, in combination with other active ingredients.The present invention further relates to a drug comprising at least one compound of the present invention and one or more other active ingredients, particularly for the treatment and / or prevention of the above-mentioned disorders.Active ingredients suitable for combination include, but are not limited to, the following: Active ingredients which lower blood pressure, such as those preferably selected from calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, α-receptor blockers, β-receptor blockers and Rho kinase inhibitors; diuretics, in particular loop diuretics, as well as thiazides and thiazide diuretics; drugs with antithrombotic action, such as, for example, preferably selected from platelet aggregation inhibitors, anticoagulants or profibrinolytic substances; active ingredients which modify lipid metabolism, such as, for example, those preferably selected from thyroid receptor agonists, preferably HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and / or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile adsorbents. adsorbents), cholesterol synthesis inhibitors such as bile acid reabsorption inhibitors and lipoprotein(a) antagonists; organic nitrates and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO; compounds with positive inotropic action, for example cardiac glycosides (digoxin), β-adrenergic and dopamine agonists, for example isoproterenol, adrenaline, noradrenaline, dopamine and dobutamine; compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), for example inhibitors of phosphodiesterase (PDE) 1, 2, 3, 4 and / or 5, in particular PDE5 inhibitors, for example sildenafil, vardenafil and tadalafil, and PDE3 inhibitors, for example aminone and milrinone;Natriuretic peptides, such as atrial natriuretic peptide (ANP, anaritide), B-type natriuretic peptide or brain natriuretic peptide (BNP, nesiritide), C-type natriuretic peptide (CNP) and urodilatin; calcium sensitizers, such as, and preferably, levosimendan; stimulators of NO-independent but heme-dependent guanylate cyclase, in particular the compounds described in WO00 / 06568, WO00 / 06569, WO02 / 42301 and WO03 / 095451 (e.g. riociguat); stimulators of NO- and heme-independent guanylate cyclase activators, in particular the compounds described in WO01 / 19355, WO01 / 19776, WO01 / 19778, WO02 / 070462 and WO02 / 070510; inhibitors of human neutrophil elastase (HNE), such as sivelestat or DX-890 (Reltran); compounds that inhibit signal transduction cascades, such as tyrosine kinase inhibitors, in particular sorafenib, imatinib, gefitinib and erlotinib; and / or compounds that affect cardiac energy metabolism, such as, preferably, etomoxir, dichloroacetic acid, ranolazine or trimetazidine;

[0152] The compound of the present invention can also be administered in combination with other active ingredients other than the above-mentioned active ingredients.For example, in a preferred embodiment of the present invention, the compound of the present invention can be administered in combination with diuretics such as furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

[0153] General synthetic procedure In this specification, if there is any discrepancy between the chemical name and the chemical structure, the structure is governed.

[0154] In general, the compounds of the present invention can be prepared by the methods described in this invention. The following reaction schemes and examples are presented to further illustrate the present invention.

[0155] Those skilled in the art will recognize that the chemical reactions described in this invention can be easily adapted to the preparation of other compounds of the invention, and all other methods of preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of unexemplified compounds according to the invention can be successfully carried out by modifications obvious to those skilled in the art, such as by appropriate protection of interfering groups, by utilizing known reagents other than those described in this invention, or by making routine modifications to reaction conditions. Also, the reactions disclosed in this invention or known reaction conditions can be applied to the preparation of other compounds of the invention.

[0156] In the examples described below, all temperatures are in degrees Celsius unless otherwise specified. Unless otherwise specified, reagents are purchased from commodity suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and used without further purification, and common reagents are purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

[0157] Anhydrous tetrahydrofuran, dioxane, toluene, and ethyl ether were obtained by refluxing and drying over metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, petroleum ether, normal hexane, N,N-dimethylacetamide, and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.

[0158] The following reactions are generally carried out in anhydrous solvents under a positive pressure of nitrogen or argon gas, or with drying tubes (unless otherwise noted), reaction flasks are fitted with appropriate rubber stoppers, and substrates are injected via syringe. All glassware was dried.

[0159] A silica gel column is used as the chromatography column. Silica gel (300-400 mesh) is purchased from Qingdao Haiying Factory. Nuclear magnetic resonance spectral data are measured on a Bruker Avance 400 nuclear magnetic resonance spectrometer or a Bruker Avance III HD 600 nuclear magnetic resonance spectrometer, using CDC13, DMSO-d6, CD3OD or Acetone-d6 (reported in ppm) as solvents, with TMS (0 ppm) or chloroform (7.26 ppm) as reference standard. When multiple peaks appear, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), q (quartet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets, dddd (doublet of doublet of doublet of doublets). Coupling constants are given in Hertz (Hz).

[0160] Low-resolution mass spectral (MS) data were measured by an Agilent 6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature was maintained at 30 °C), a G1329A autosampler and a G1315B DAD detector were used for the analysis, and an ESI source was used for the LC-MS spectrometer.

[0161] Low-resolution mass spectral (MS) data were measured by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and a G1316A TCC (column temperature was maintained at 30 °C), a G1329A autosampler and a G1315D DAD detector were used for the analysis, and an ESI source was used for the LC-MS spectrometer.

[0162] Both spectrometers were equipped with an Agilent Zorbax SB-C18 column with a specification of 2.1 × 30 mm, 5 μm. The injection volume was determined by the sample concentration, the flow rate was 0.6 mL / min, and the HPLC peaks were recorded by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). The gradient elution conditions are shown in Table 1. Table 1. Low-resolution mass spectrometry mobile phase gradient elution conditions [Table 1]

[0163] The HPLC method for measuring the atropisomer excess (%ee) described in this invention is as follows: Chromatography column: CHIRALPAK AS-H 4.6 × 250 mm 5 μm, flow rate: 1.0 mL / min, column temperature: 30 °C, detection wavelength: 290 nm, diluent: ethanol, mobile phase A: 0.1% TFA: ETOH, mobile phase B: normal hexane, run duration: 30 min. Gradient elution conditions are shown in Table 2. Table 2 [Table 2]

[0164] Based on the peak area ratio of the S and R configurations, calculate the corresponding enantiomeric excess (%ee). The calculation formula is as follows: %ee of S configuration = (peak area ratio of S configuration - peak area ratio of R configuration) ÷ (peak area ratio of S configuration + peak area ratio of R configuration) × 100, or %ee of R configuration = (peak area ratio of R configuration - peak area ratio of S configuration) ÷ (peak area ratio of R configuration + peak area ratio of S configuration) × 100.

[0165] The following abbreviations are used throughout this application: DMSO-d6 deuterated dimethyl sulfoxide; g grams; mg milligrams; mol moles; mmol millimole; mL milliliters; μL microliters

[0166] The following reaction schemes describe steps for preparing compounds of the invention. Unless otherwise indicated, R 1 , R 2a , R 2b , R 2c , R 2d and R 2e Each of the above has the definition described in the present invention, and L 1 is a leaving group such as Cl, Br, I, methylsulfonyl or p-toluenesulfonyl. Unless otherwise specified, all reaction steps in each reaction scheme described in the present invention are carried out in a solvent inert to the reaction, which includes, but is not limited to, the solvents according to the embodiments of the present invention or their substitutes.

[0167] Reaction scheme Synthesis of intermediate compound S5 [ka] The intermediate compound S5 can be prepared by the following method: compound S1 is subjected to a substitution reaction with bromine to give compound S2, compound S2 is subjected to a substitution reaction with ethyl cyanoacetate to give compound S3, compound S3 is reacted under acidic conditions to give compound S4, and finally, compound S4 is desalted under the action of a suitable hydrogen transfer reagent to give intermediate compound S5.

[0168] The intermediate compound S5 can also be prepared by the following method: compound S6 is subjected to a substitution reaction with N-bromosuccinimide (NBS) to give compound S7, which is then subjected to a coupling reaction with a phenylboronic acid compound Sa to give intermediate compound S5.

[0169] Synthesis of intermediate compound S11 [ka] The intermediate compound S11 can be prepared by either of the following methods (1) or (2).

[0170] (1) Compound S5 is saponified to give compound S8, which is then substituted with benzyl bromide under alkaline conditions to give intermediate compound S9, which is then reacted with a suitable reagent L 1 -R 1 to give compound S12, which is then saponified to give compound S11.

[0171] (2) Compound S5 is suitable for reagent L 1 -R 1 to obtain compound S10, which is then saponified to obtain compound S11.

[0172] Reaction Scheme 1 [ka] Compound S15 can be prepared by the method described in Reaction Scheme 1, in which the reaction process is as follows: compound S11 is reacted with a suitable acylating agent (e.g., oxalyl chloride) to give compound S14, and then S14 is acylated with 3-fluoro-4-methylsulfonylaniline to give compound S15.

[0173] Reaction Scheme 2 [ka] Compound S15 can also be prepared by the method described in Reaction Scheme 2, in which the reaction process is as follows: Compound S11 undergoes a condensation reaction with 3-fluoro-4-methylsulfonylaniline under the action of a suitable reagent (e.g., a condensation reagent) to obtain compound S15.

[0174] Reaction Scheme 3 [ka] Compound S16 can be prepared as described in Reaction Scheme 3, in which the reaction process is as follows: Compound S14 undergoes an acylation reaction with the corresponding aromatic amine substrate to give Compound S16.

[0175] The following examples further illustrate the present invention, but these examples are not intended to limit the scope of the invention.

[0176] Working Example Intermediate 1: Synthesis of ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate [ka] Method 1: Step 1) 2-Bromo-1-(2-(trifluoromethyl)phenyl)propan-1-one 2'-(trifluoromethyl)propiophenone (139g, 687.5mmol) was weighed and placed in a 2000mL four-neck flask, dichloromethane (800mL) was added, and one drop of hydrobromic acid (content 48%) and one drop of liquid bromine were added to the reaction flask, and the color of bromine disappeared while stirring, and then liquid bromine (121.5g, 760.3mmol) was gradually added dropwise and stirred at room temperature for 0.5h. Saturated sodium sulfite solution (300mL) was added to the reaction flask, and dichloromethane was removed by rotary evaporation under reduced pressure, and water (600mL) and ethyl acetate (1000mL) were added to the residue, and the organic phase was separated and washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and directly spun dry to obtain a pale yellow solid (193g, 99.9%).

[0177] Step 2) Ethyl 2-cyano-3-methyl-4-oxo-4-(2-(trifluoromethyl)phenyl)butanoate Potassium carbonate (166.6 g, 1205 mmol) was weighed and placed in a 2000 mL flask, ethyl cyanoacetate (128 mL, 1203 mmol) was added, and the mixture was heated to 50° C. and stirred for 2 h. The reaction flask was removed and cooled to room temperature, and a solution of 2-bromo-1-(2-(trifluoromethyl)phenyl)propan-1-one (188 g, 668.9 mmol) in acetone (1000 mL) was added dropwise, followed by stirring at room temperature overnight. The reaction solution was suction filtered through diatomaceous earth, the filter cake was washed with acetone (50 mL x 3), the filtrate was concentrated, extracted with ethyl acetate (200 mL x 4), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a beige solid (180.4 g, 86.09%).

[0178] MS(ESI, pos. ion)m / z: 314.2(M+1). Step 3) Ethyl 2-chloro-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate Ethyl 2-cyano-3-methyl-4-oxo-4-(2-(trifluoromethyl)phenyl)butanoate (30 g, 95.8 mmol) was weighed and placed in a 200 mL sealed tube, and hydrogen chloride in ethyl acetate (120 mL, 480 mmol, 4 mol / L) was added, followed by heating to 65° C. for 48 h. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1) to give a beige solid (31.7 g, 99.8%).

[0179] MS(ESI, pos. ion)m / z: 332.0(M+1). Step 4) Ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate 2-Chloro-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-ethyl carboxylate (93.1 g, 281 mmol) was weighed and placed in a 2000 mL flask, and ethanol (635 mL), tetrahydrofuran (115 mL), water (47 mL), sodium formate (25.17 g, 370.1 mmol) and palladium carbon (9.79 g, 10 mass%) were added, followed by heating to 65 ° C. and stirring for 4.5 h. The reaction solution was cooled to room temperature, tetrahydrofuran (93 mL) was added to the reaction solution, suction filtered, the filter cake was washed with ethanol (93 mL × 4), and the filtrate was concentrated. Water (750 mL) was added and stirred at room temperature overnight. It was filtered by suction, the filter cake was washed with a mixed solution of ethanol / water (280 mL, v / v=7 / 8), and the filter cake was collected and dried under reduced pressure at 40° C. to give an off-white solid (71.3 g, 85.4%).

[0180] MS(ESI, pos. ion)m / z: 298.3(M+1). Method 2: Step 1) Ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate Ethyl 4-methylpyrrole-3-carboxylate (6.0 g, 39 mmol) was weighed and placed in a 100 mL flask, tetrahydrofuran (50 mL) was added, the mixture was cooled to -78°C, N-bromosuccinimide (6.99 g, 39.3 mmol) was added, the mixture was stirred at -78°C for 15 min, 6 drops of pyridine were added, and the mixture was gradually warmed to 5°C and stirred overnight. The reaction mixture was extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a white solid (7.41 g, 82%).

[0181] MS(ESI, pos. ion)m / z: 232.1(M+1). 1H NMR(400MHz,DMSO-d6)δ(ppm)11.97(s,1H),7.40(s,1H),4.15(q,J=7.1Hz,2H),2.11(s,3H),1.24(t,J=7.1Hz,3H). Step 2) Ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate Ethyl 5-bromo-4-methyl-1H-pyrrole-3-carboxylate (15.8 g, 68.1 mmol) was weighed and placed in a 500 mL flask, and 2-(trifluoromethyl)phenylboronic acid (20.9 g, 110 mmol), lithium chloride (289.3 mg, 6.83 mmol), sodium carbonate solution (68 mL, 136 mmol, 2 mol / L), 1,4-dioxane (200 mL) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (3.49 g, 4.19 mmol) were added, followed by heating to 90°C and reacting for 22 h. The solvent was removed by rotary evaporation under reduced pressure, extracted with ethyl acetate (80 mL × 4), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / dichloromethane (v / v) = 5 / 1) to give a white solid (6.9 g, 34%).

[0182] MS(ESI, pos. ion)m / z: 298.2(M+1). Example 1: N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) Ethyl 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate Ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (25 g, 84.1 mmol) was weighed and placed in a 500 mL flask, and N,N-dimethylformamide (160 mL), cesium carbonate (41.7 g, 128 mmol) and benzyl 2-bromoethyl ether (16 mL, 101 mmol) were added, and the mixture was heated to 70° C. and stirred for 12 h. The reaction solution was extracted with ethyl acetate (150 mL×3), and the combined organic phase was washed with saturated brine (150 mL×3), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1) to give a tan solid (36.2 g, 99.8%).

[0183] MS(ESI, pos. ion)m / z: 432.4(M+1). Step 2) 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid Ethyl 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (36.2 g, 83.9 mmol) was weighed into a 1000 mL flask and sodium hydroxide solution (60 mL, 960 mmol, 16 mol / L) and ethanol (200 mL) were added. The mixture was then heated to 70 °C and stirred overnight. Ethanol was removed by rotary evaporation under reduced pressure, and water (1000 mL) was added to the residue and stirred at room temperature for 30 min, washed with methyl tert-butyl ether (200 mL x 3), the aqueous phase was adjusted to pH = 2 with 6 M HCl solution, extracted with ethyl acetate (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and spun dry to give a tan solid (33.4 g, 98.7%).

[0184] MS(ESI, pos. ion)m / z: 404.2(M+1). Step 3) 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (401 mg, 0.994 mmol) was weighed into a 100 mL flask, dichloromethane (15 mL) and 2 drops of N,N-dimethylformamide were added, and oxalyl chloride (0.40 mL, 4.7 mmol) was added dropwise under ice bath conditions. The reaction was then carried out at room temperature for 2.5 h. The solvent was removed by rotary evaporation under reduced pressure to give a tan solid (400 mg, 95.40%).

[0185] Step 4) 1-(2-(benzyloxy)ethyl)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride (400 mg, 0.948 mmol) was weighed into a 50 mL sealed tube, and tetrahydrofuran (10 mL), pyridine (0.14 mL, 1.7 mmol), 3-fluoro-4-methylsulfonylaniline (160 mg, 0.846 mmol) and 4-dimethylaminopyridine (10.7 mg, 0.0876 mmol) were added, followed by heating to 80° C. and stirring overnight. The solvent was removed by rotary evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=2 / 1) to give a pale yellow solid (337 mg, 69.36%).

[0186] MS(ESI, pos. ion)m / z: 575.2(M+1). Step 5) N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide 1-(2-(benzyloxy)ethyl)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (337 mg, 0.587 mmol) was weighed and placed in a 100 mL flask, and methanol (10 mL) and palladium carbon (66.7 mg, 10 mass%) were added, followed by stirring at room temperature for 1.5 h under a hydrogen gas atmosphere. The reaction solution was suction filtered through diatomaceous earth, the filter cake was washed with methanol (10 mL x 3), the filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1 / 2) to obtain a white solid (220.5 mg, 77.60%).

[0187] MS(ESI, pos. ion)m / z: 485.3(M+1). 1 H NMR(400MHz,DMSO-d6)δ(ppm): 10.15(s,1H),7.99(dd,J=13.4,1.1Hz,1H),7.90(d,J=7.7Hz,1H),7.83-7.76(m,3H),7.74-7.69(m,2H),7. 47(d,J=7.4Hz,1H),4.94(t,J=4.8Hz,1H),3.73-3.64(m,1H),3.55-3.44(m,3H),3.28(s,3H),1.93(s,3H).

[0188] Example 2: (S)-1-(2-hydroxyethyl)-4-methyl-N-(3-fluoro-4-(methylsulfonyl)phenyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Weigh out N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (3.4 g, 7.02 mmol) and place it in a 25 mL flask. Add anhydrous acetonitrile (8 mL) to dissolve the entire sample, and then eluate by high performance liquid chromatography (instrument: Waters SFC, chromatography column: Daicel AS-H 10 mm × 250 mm 5 μm, condition: isogradient 20% MeOH + 80% CO 2、 Chiral separation was performed at a flow rate of 8 mL / min, column temperature of 35° C., back pressure of 100 bar, and 10 μL of sample was injected each time), and the solvent was removed by rotary evaporation under reduced pressure to obtain the target white solid (1.43 g, 42.1%, HPLC retention time 8.627 min, purity 99.85%, ee value 99.80%).

[0189] MS(ESI, pos. ion)m / z: 485.1(M+1). 1 H NMR(400MHz,DMSO-d6)δ(ppm): 10.15(s,1H),7.98(dd,J=13.5,1.3Hz,1H),7.90(d,J=7.8Hz,1H),7.82-7.76(m,3H),7.75-7.68(m,2H),7. 47(d,J=7.4Hz,1H),4.94(t,J=4.9Hz,1H),3.73-3.64(m,1H),3.56-3.45(m,3H),3.28(s,3H),1.92(s,3H).

[0190] Example 3: N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-((1-hydroxycyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) Methyl 1-(benzyloxy)cyclopropanecarboxylate 1-Hydroxycyclopropane-1-methyl carboxylate (1.02 g, 8.78 mmol) was weighed and placed in a 100 mL flask, N,N-dimethylformamide (30 mL) was added, the mixture was cooled to 0 ° C, sodium hydride (521.6 mg, 13.04 mmol, 60 mass%) was added, and the mixture was stirred at 0 ° C for 20 min, and benzyl bromide (1.1 mL, 9.3 mmol) was added, and the mixture was reacted at room temperature for 3 h. The reaction solution was extracted with ethyl acetate (80 mL × 3), and the combined organic phase was washed with saturated saline (50 mL × 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow-brown liquid (1.465 g, 80.9%).

[0191] MS(ESI, pos. ion)m / z: 207.2(M+1). Step 2) (1-(benzyloxy)cyclopropyl)methanol Lithium aluminum hydride (233.1 mg, 6.14 mmol) was weighed and placed in a 100 mL flask, tetrahydrofuran (15 mL) was added, and a solution of 1-(benzyloxy)methyl cyclopropanecarboxylate (1.40 g, 6.79 mmol) in tetrahydrofuran (15 mL) was added dropwise, followed by stirring at room temperature for 1.5 h. Sodium sulfate decahydrate was added to the reaction flask until the solution became transparent, and the mixture was suction filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (20 mL x 3), the filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to obtain a yellow liquid ((871.9 mg, 72.1%)).

[0192] MS(ESI, pos. ion)m / z: 196.2(M+NH4). Step 3) (1-(benzyloxy)cyclopropyl)methyl methanesulfonate (1-(benzyloxy)cyclopropyl)methanol (511 mg, 2.87 mmol) was weighed and placed in a 50 mL flask, dichloromethane (15 mL) was added, the mixture was cooled to 0°C, triethylamine (0.80 mL, 5.8 mmol) was added, methanesulfonyl chloride (0.29 mL, 3.7 mmol) was added dropwise, and the mixture was reacted at room temperature for 2 h. The reaction solution was extracted with dichloromethane (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a yellow liquid (730 mg, 99.34%).

[0193] MS(ESI, pos. ion)m / z: 279.0(M+Na). Step 4) Ethyl 1-((1-(benzyloxy)cyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate 4-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-ethyl carboxylate (450 mg, 1.51 mmol) was weighed and placed in a 50 mL flask, N,N-dimethylformamide (15 mL) and sodium hydride (186.3 mg, 4.66 mmol, 60 mass%) were added, and the mixture was stirred at room temperature for 10 min. A solution of (1-(benzyloxy)cyclopropyl)methyl methanesulfonate (730 mg, 2.85 mmol) in N,N-dimethylformamide (5 mL) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate (80 mL x 3), the organic phase was combined, washed with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a pale yellow oily liquid (617 mg, 89.10%).

[0194] MS(ESI, pos. ion)m / z: 458.1(M+1). Step 5) 1-((1-(benzyloxy)cyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid Ethyl 1-((1-(benzyloxy)cyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (617 mg, 1.35 mmol) was weighed into a 50 mL flask, ethanol (10 mL), sodium hydroxide solution (2.0 mL, 12 mmol, 6 mol / L) were added, and the mixture was heated to 70 °C and stirred for 8 h. The solvent was removed by rotary evaporation under reduced pressure, and water (50 mL) was added to the residue, washed with methyl tert-butyl ether (30 mL x 2), and the aqueous phase was adjusted to pH = 2 with 1 M HCl solution, extracted with ethyl acetate (60 mL x 4), dried over anhydrous sodium sulfate, filtered, and directly spun to dryness to give a pale yellow solid (523.1 mg, 90.33%).

[0195] MS(ESI, pos. ion)m / z: 430.3(M+1). Step 6) 1-((1-(benzyloxy)cyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride A reaction flask was charged with 1-((1-(benzyloxy)cyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (300 mg, 0.699 mmol) and dichloromethane (20 mL), oxalyl chloride (0.30 mL, 3.5 mmol) and N,N-dimethylformamide (5 mg, 0.0684 mmol) were added dropwise and the reaction was stirred at room temperature for 22 h. The solvent was removed by evaporation under reduced pressure to give a yellow solid (312 mg, 99.70%).

[0196] Step 7) 1-((1-(benzyloxy)cyclopropyl)methyl)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide Into a sealed tube, 3-fluoro-4-methylsulfonylaniline (110 mg, 0.581 mmol), 1-((1-(benzyloxy)cyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride (312 mg, 0.697 mmol) and pyridine (10 mL) were added, and the reaction was heated to 100° C. and stirred for 29 h. Cooled to room temperature, 1 M HCl solution was added to adjust pH=3, extracted with ethyl acetate (80 mL), and the organic phase was adjusted to pH=8 with saturated aqueous sodium bicarbonate, washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure to remove the solvent gave the residue, which was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1-4 / 1) to give a pale yellow solid (140 mg, 40.10%).

[0197] MS(ESI,pos.ion)m / z: 601.0(M+1). Step 8) N-(3-fluoro-4-(methylsulfonyl)phenyl)-1-((1-hydroxycyclopropyl)methyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide 1-((1-(benzyloxy)cyclopropyl)methyl)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (140 mg, 0.233 mmol), methanol (10 mL) and palladium on carbon (30 mg, 10 mass%) were added to the reaction flask, and the reaction system was stirred at room temperature under a hydrogen gas atmosphere for 3 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1-4 / 1), slurried with petroleum ether / ethyl acetate (10 mL / 1 mL) for 1 h, filtered and dried to give a white solid (80 mg, 67.23%).

[0198] MS(ESI,pos.ion)m / z: 511.1(M+1). 1H NMR(400MHz,CDCl3)δ(ppm): 8.00(d,J=12.1Hz,1H),7.94-7.79(m,3H),7.72-7.56(m,3H),7.41(d,J=7.6Hz,1H),3.73-3. 69(m,2H),3.24(s,3H),2.11(s,3H),0.92-0.87(m,2H),0.54-0.48(m,1H),0.44-0.40(m,1H). 19 F NMR(376MHz,CDCl3)δ(ppm): -60.95,-107.35.

[0199] Example 4: 1-Cyclobutyl-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) 4-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid Ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (30 g, 100.9 mmol) was weighed into a 1000 mL flask, sodium hydroxide solution (60 mL, 1020 mmol, 17 mol / L) and ethanol (300 mL) were added, and the mixture was heated to 70 °C and stirred for 12 h. The solvent was removed by rotary evaporation under reduced pressure, and water (1000 mL) was added to the residue and stirred at room temperature for 30 min, washed with methyl tert-butyl ether (100 mL x 3), the aqueous phase was adjusted to pH = 2 with 6 M HCl solution, extracted with ethyl acetate (200 mL x 3), dried over anhydrous sodium sulfate, filtered, and directly spun to dryness to give a tan solid (27.1 g, 99.8%).

[0200] MS(ESI, pos. ion)m / z: 270.2(M+1). Step 2) Benzyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate 4-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (27.3 g, 101 mmol) was weighed and placed in a 500 mL flask, N,N-dimethylformamide (250 mL) was added, and the mixture was cooled to 0°C. Cesium carbonate (33.09 g, 101.6 mmol) and benzyl bromide (12 mL, 101 mmol) were added, and the mixture was reacted at 0°C for 7 h. Cesium carbonate (3.31 g, 10.16 mmol) and benzyl bromide (1.2 mL, 10.1 mmol) were added to the reaction system, and the reaction was continued at 0°C overnight. The reaction mixture was extracted with ethyl acetate (200 mL x 3), and the combined organic phase was washed with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to give a tan solid (29.7, 81.5%).

[0201] MS(ESI, pos. ion)m / z: 360.1(M+1). Step 3) 1-Cyclobutyl-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate 4-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate (1.0 g, 2.8 mmol) was weighed and placed in a 100 mL flask, N,N-dimethylformamide (25 mL) and sodium hydride (334.6 mg, 8.37 mmol, 60 mass%) were added, and the mixture was stirred at room temperature for 10 min, followed by the addition of bromocyclobutane (1.0 mL, 11 mmol). The mixture was then heated to 100 °C and stirred for 15 h. The reaction solution was cooled to room temperature, extracted with ethyl acetate (60 mL x 3), the combined organic phase was washed with saturated saline (50 mL x 2), dried over anhydrous sodium sulfate, filtered, spin-dried, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1) to obtain a pale yellow oily liquid (839 mg, 73%).

[0202] MS(ESI, pos. ion)m / z: 414.3(M+1). Step 4) 1-Cyclobutyl-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid 1-Cyclobutyl-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate (830 mg, 2.01 mmol) was weighed and placed in a 100 mL flask, and methanol (25 mL) and palladium carbon (216.1 mg, 10 mass%) were added, followed by stirring at room temperature for 5 h under a hydrogen gas atmosphere. The reaction solution was suction filtered through diatomaceous earth, the filter cake was washed with methanol (10 mL x 3), the filtrate was concentrated, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2 / 1) to obtain a white solid (183.6 mg, 28.29%).

[0203] MS(ESI, pos. ion)m / z: 324.2(M+1). Step 5) 1-Cyclobutyl-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride A reaction flask was charged with 1-cyclobutyl-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (210 mg, 0.65 mmol) and dichloromethane (20 mL), oxalyl chloride (0.27 mL, 3.2 mmol) and N,N-dimethylformamide (5 mg, 0.0684 mmol) were added dropwise and the reaction was stirred at room temperature for 21 h. The solvent was removed by evaporation under reduced pressure to give a yellow solid (222 m, 99.99%).

[0204] Step 6) 1-Cyclobutyl-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide In a sealed tube, 3-fluoro-4-methylsulfonylaniline (102 mg, 0.539 mmol), 1-cyclobutyl-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride (221 mg, 0.647 mmol) and pyridine (10 mL) were added, and the reaction was heated to 90 °C and stirred for 24 h. It was cooled to room temperature, adjusted to pH = 3 by adding 1 M HCl solution, extracted with ethyl acetate (80 mL), and the organic phase was adjusted to pH = 8 by adding saturated aqueous sodium bicarbonate solution, washed with saturated brine (60 mL), and dried over anhydrous sodium sulfate. It was filtered and evaporated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1-4 / 1) to give a yellow solid (116 mg, 43.51%).

[0205] MS(ESI,pos.ion)m / z: 495.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 7.99(d,J=12.4Hz,1H),7.90(s,1H),7.89-7.76(m,2H),7.72-7.60(m,3H),7.59(s,1H),7.32-7.28(m,2H),4.13-4 .00(m,1H),3.23(s,3H),2.45-2.31(m,1H),2.25-2.18(m,2H),2.17-2.08(m,2H),2.07(s,3H),1.80-1.74(m,1H). 19 F NMR(376MHz,CDCl3)δ(ppm): -60.91,-107.38,-107.41,-107.43.

[0206] Example 5: N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) 4-Methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate benzyl 4-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate (1.09 g, 3.03 mmol) and N,N-dimethylformamide (20 mL) were added to the reaction flask, sodium hydride (133 mg, 3.33 mmol, 60 mass%) was added under ice bath, and the mixture was stirred for 0.5 h under nitrogen gas protection. 2-Bromomethyloxetane (687 mg, 4.55 mmol) was added dropwise, and the reaction system was stirred at room temperature for 24.5 h. Saturated ammonium chloride solution (40 mL) was added to the reaction flask to quench the reaction, and the mixture was extracted with ethyl acetate (80 mL x 2). The organic phase was combined, washed with saturated saline (40 mL x 2), and dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure to remove the solvent gave a residue which was separated by silica gel column chromatography (dichloromethane / ethyl acetate (v / v)=100 / 1-50 / 1) to give a pale yellow solid (660 mg, 50.7%).

[0207] MS(ESI,pos.ion)m / z: 430.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 7.81(d,J=7.5Hz,1H),7.67-7.51(m,3H),7.46(d,J=7.5Hz,2H),7.39(t, J=7.4Hz,2H),7.33(t,J=7.2Hz,2H),5.35-5.25(m,2H),4.94-4.74(m,1H) ,4.67-4.57(m,1H),4.43(ddt,J=34.0,9.2,5.9Hz,1H),3.96-3.62(m,2H ),2.59(qd,J=14.1,7.0Hz,1H),2.36-2.19(m,1H),2.03(d,J=4.6Hz,3H). Step 2) 4-Methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid 4-Methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate (650 mg, 1.51 mmol), methanol (20 mL) and palladium on carbon (130 mg, 10 mass%) were added to the reaction flask, and the mixture was stirred at room temperature under a hydrogen gas atmosphere for 11 h. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1-1 / 1) to obtain a pale yellow solid (480 mg, 93.46%).

[0208] MS(ESI,pos.ion)m / z: 340.2(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 7.81(d,J=7.4Hz,1H),7.70-7.54(m,3H),7.37(d,J=7.3Hz,1H),4.97-4.79(m,1H),4.70-4.57(m,1H),4.45(ddt,J=31.5,9.2 ,5.9Hz,1H),3.88(ddd,J=19.1,14.7,5.6Hz,1H),3.76-3.64(m,1H),2.69-2.55(m,1H),2.40-2.20(m,1H),2.06-2.00(m,3H). Step 3) N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide A reaction flask was charged with 4-methyl-1-(oxetan-2-ylmethyl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (320 mg, 0.943 mmol), 3-fluoro-4-methylsulfonylaniline (178 mg, 0.941 mmol), pyridine (20 mL) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (365 mg, 1.89 mmol) and the reaction was stirred at room temperature for 47 h. The solvent was removed by evaporation under reduced pressure and ethyl acetate (60 mL) was added to dissolve the residue, which was then washed with 1 M HCl solution (20 mL), saturated aqueous sodium bicarbonate solution (20 mL) and saturated brine (20 mL) and dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure to remove the solvent gave a residue which was separated by silica gel column chromatography (dichloromethane / ethyl acetate (v / v)=50 / 1-20 / 1) to give a pale yellow solid (90 mg, 18.69%).

[0209] MS(ESI,pos.ion)m / z: 511.2(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 8.18-8.13(m,1H),7.99-7.94(m,1H),7.86-7.81(m,2H),7.69-7.60(m,2H),7.59-7.51(m,1H),7.37-7.31(m,2H),5.01-4.78(m,1) H),4.71-4.59(m,1H),4.57-4.40(m,1H),3.84-3.53(m,2H),3.22(s,3H),2.64-2.58(m,1H),2.37-2.22(m,1H),2.11-2.05(m,3H). 19 F NMR(376MHz,CDCl3)δ(ppm): -60.99,-61.07,-107.65,-107.68.

[0210] Example 6: N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) Ethyl 4-methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate Ethyl 4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (401 mg, 1.35 mmol) was weighed and placed in a 50 mL flask, and N,N-dimethylformamide (12 mL) and sodium hydride (168.9 mg, 4.22 mmol, 60 mass%) were added under ice bath conditions, and the mixture was stirred at room temperature for 10 min. Then, 3-iodooxetane (0.36 mL, 4.2 mmol) was added, and the mixture was heated to 100 °C and stirred for 24 h. Sodium hydride (168.9 mg, 4.22 mmol, 60 mass%) and 3-iodooxetane (0.36 mL, 4.2 mmol) were added to the reaction system, and the mixture was heated to 100 °C and stirred for 24 h. The reaction mixture was extracted with ethyl acetate (40 mL x 3), and the combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5 / 1) to give a pale yellow solid (365 mg, 76.59%).

[0211] MS(ESI, pos. ion)m / z: 354.3(M+1). Step 2) 4-Methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid Ethyl 4-methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate (365 mg, 1.03 mmol) was weighed into a 50 mL flask, ethanol (10 mL) and sodium hydroxide solution (3.0 mL, 12 mmol, 4 mol / L) were added, and the mixture was heated to 70 °C and stirred overnight. The solvent was removed by rotary evaporation under reduced pressure, and the residue was dissolved by adding water (60 mL), washed with methyl tert-butyl ether (20 mL x 2), the aqueous phase was adjusted to pH = 2 with 1 M HCl solution, extracted with ethyl acetate (30 mL x 4), dried over anhydrous sodium sulfate, filtered, and spun dry to give an orange-red solid (319.7 mg, 95.13%).

[0212] MS(ESI, pos. ion)m / z: 326.2(M+1). Step 3) 1-(1-chloro-3-hydroxypropan-2-yl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride A reaction flask was charged with 4-methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (400 mg, 1.23 mmol) and dichloromethane (20 mL), oxalyl chloride (0.52 mL, 6.1 mmol) and N,N-dimethylformamide (9 mg, 0.123 mmol) were added dropwise and the reaction was stirred at room temperature for 16 h. The solvent was removed by evaporation under reduced pressure to give a yellow solid (467 mg, 99.89%).

[0213] Step 4) 1-(1-chloro-3-hydroxypropan-2-yl)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide Into a sealed tube, 3-fluoro-4-methylsulfonylaniline (193 mg, 1.02 mmol), 1-(1-chloro-3-hydroxypropan-2-yl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride (465 mg, 1.286 mmol) and pyridine (10 mL) were added, and the reaction was heated to 90° C. and stirred for 29 h. It was cooled to room temperature, adjusted to pH=3 by adding 1M HCl solution, extracted with ethyl acetate (80 mL), and the organic phase was adjusted to pH=8 by adding saturated aqueous sodium bicarbonate solution, washed with saturated brine (60 mL), and dried over anhydrous sodium sulfate. It was filtered and evaporated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1-4 / 1) to give a pale yellow solid (100 mg, 18.40%).

[0214] MS(ESI,pos.ion)m / z: 533.0(M+1). Step 5) N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-1-(oxetan-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide To the reaction was added 1-(1-chloro-3-hydroxypropan-2-yl)-N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (100 mg, 0.188 mmol), sodium hydroxide (22 mg, 0.55 mmol) and tetrahydrofuran (50 mL), and the reaction was heated to 70° C. and stirred for 4 h. The reaction was cooled to room temperature, adjusted to pH=7 by adding 1M HCl solution, extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure to remove the solvent, the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=10 / 1-4 / 1) to give a pale yellow solid (40 mg, 42.93%).

[0215] MS(ESI,pos.ion)m / z: 497.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 8.25-7.77(m,5H),7.66(s,2H),7.28(s,2H),4.90-4.72(m,5H),3.25(s,3H),2.09(s,3H). 19 F NMR(376MHz,CDCl3)δ(ppm): -61.26,-107.28.

[0216] Example 7: N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) 4-Methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylate benzyl 4-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate (1.00 g, 2.78 mmol), 3-fluoropyridine (1.35 g, 13.9 mmol), cesium carbonate (2.72 g, 8.35 mmol) and N,N-dimethylformamide (20 mL) were added to a sealed tube and heated to 100° C. under nitrogen gas protection for 73 h. The reaction was cooled to room temperature and quenched by adding water (40 mL), extracted with ethyl acetate (80 mL), and the organic phase was washed with saturated brine (40 mL×2) and dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure to remove the solvent gave a yellow solid (1.10 g, 90.6%).

[0217] Step 2) 4-Methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid 4-Methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-benzyl carboxylate (1.10 g, 2.52 mmol), methanol (20 mL) and palladium on carbon (110 mg, 10 mass%) were added to the reaction flask, and the reaction system was stirred at room temperature under a hydrogen gas atmosphere for 17 h. The reaction solution was suction filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1-1 / 1) to obtain a pale yellow solid (340 mg, 39.0%).

[0218] MS(ESI,pos.ion)m / z: 347.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 8.49(d,J=4.1Hz,1H),8.44(s,1H),7.70(d,J=7.7Hz,2H),7.54(dd,J=18.7,7.4 Hz,2H),7.41(dd,J=16.2,7.8Hz,2H),7.22(dd,J=8.1,4.8Hz,1H),2.15(s,3H). Step 3) 4-Methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride A reaction flask was charged with 4-methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxylic acid (340 mg, 0.982 mmol) and dichloromethane (20 mL), oxalyl chloride (0.42 mL, 5.0 mmol) and N,N-dimethylformamide (7 mg, 0.0958 mmol) were added dropwise and the reaction was stirred at room temperature for 14.5 h. The solvent was removed by evaporation under reduced pressure to give a yellow solid (358 mg, 99.95%).

[0219] Step 4) N-(3-fluoro-4-(methylsulfonyl)phenyl)-4-methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide 3-Fluoro-4-methylsulfonylaniline (131 mg, 0.692 mmol), 4-methyl-1-(pyridin-3-yl)-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride (358 mg, 0.981 mmol), pyridine (0.17 mL, 2.1 mmol) and tetrahydrofuran (20 mL) were added to a sealed tube, and the reaction was heated to 90 ° C. and stirred for 49 h. The reaction was cooled to room temperature, 1 M HCl solution was added to pH = 3, extracted with ethyl acetate (80 mL), and the organic phase was adjusted to pH = 8 by adding saturated aqueous sodium bicarbonate solution, and the organic phase was washed with saturated brine (60 mL) and dried over anhydrous sodium sulfate. Filtration and evaporation under reduced pressure to remove the solvent gave a residue which was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=2 / 1-1 / 1) to give a pale yellow solid (100 mg, 27.91%).

[0220] MS(ESI,pos.ion)m / z: 518.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 8.46(d,J=17.9Hz,2H),8.22(s,1H),7.97(d,J=12.2Hz,1H),7.85(t,J=8.1Hz,1H),7.71(d,J=7.3Hz,1 H),7.60(s,1H),7.59-7.48(m,2H),7.47-7.30(m,3H),7.23(d,J=4.7Hz,1H),3.23(s,3H),2.18(s,3H). 19 F NMR(376MHz,CDCl3)δ(ppm): -60.42,-107.35.

[0221] Example 8: N-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide [ka] Step 1) 4-Fluoro-6-nitrobenzo[d]thiazol-2(3H)-one At -10°C, 4-fluoro-2(3H)-benzothiazolone (5.00g, 29.6mmol) and concentrated H2SO4 (50mL) were added to the reaction flask, and concentrated HNO3 (2.03mL, 29.5mmol) was slowly added dropwise, and stirring was continued for 1h at -10°C. The reaction solution was poured into ice water, stirred for 1h, suction filtered, the filter cake was washed with ice water (20mL x 2), the filter cake was collected, and dried in vacuum at 60°C for 12h to obtain a pale yellow solid (5.40g, 85.3%).

[0222] MS(ESI,pos.ion)m / z: 215.0(M+1). Step 2) 4-Fluoro-3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one 4-Fluoro-6-nitrobenzo[d]thiazol-2(3H)-one (1.00 g, 4.67 mmol), DBU (0.84 mL, 5.6 mmol) and N,N-dimethylformamide (20 mL, 375.2 mmol) were added to the reaction flask, methyl iodide (0.35 mL, 5.6 mmol) was slowly added dropwise, and the mixture was heated to 65 °C and stirred for 16.5 h. The reaction solution was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with 1 M HCl solution (50 mL) and saturated brine (50 mL), respectively, and dried over anhydrous sodium sulfate. The solvent was removed by filtration and evaporation under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1-4 / 1) to give a yellow solid (1.07 g, 100%).

[0223] MS(ESI,pos.ion)m / z: 229.1(M+1). Step 3) 6-Amino-4-fluoro-3-methylbenzo[d]thiazol-2(3H)-one To the reaction flask were added 4-fluoro-3-methyl-6-nitrobenzo[d]thiazol-2(3H)-one (1.07 g, 4.69 mmol), tetrahydrofuran (50 mL), methanol (50 mL) and palladium on carbon (107 mg, 10 mass%), and the reaction was allowed to react at room temperature for 9 h under a hydrogen gas atmosphere. Palladium on carbon (107 mg, 10 mass%) was added to the reaction, and the reaction was allowed to continue to react at room temperature for 12 h under a hydrogen gas atmosphere. The reaction solution was suction filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and the crude product was slurried in ethyl acetate / methanol (10 mL / 2 mL) to give a yellow solid (400 mg, 43.0%).

[0224] MS(ESI,pos.ion)m / z: 199.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 6.53(s,1H),6.41(d,J=13.7Hz,1H),3.71(s,2H),3.61(d,J=3.2Hz,3H). Step 4) 1-(2-(benzyloxy)ethyl)-N-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide Into a sealed tube, 1-(2-(benzyloxy)ethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbonyl chloride (312 mg, 0.740 mmol), 6-amino-4-fluoro-3-methylbenzo[d]thiazol-2(3H)-one (122 mg, 0.615 mmol) and pyridine (10 mL) were added, and the reaction system was heated to 90 ° C. and reacted for 30 h. The reaction solution was cooled to room temperature, and a saturated aqueous solution of sodium bicarbonate was added to adjust the pH to 8, and extracted with dichloromethane (40 mL × 2), and the combined organic phase was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. After filtration and evaporation under reduced pressure to remove the solvent, the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10 / 1-5 / 1) to give a pale yellow solid (300 mg, 83.52%).

[0225] MS(ESI,pos.ion)m / z: 584.2(M+1). Step 5) N-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-1-(2-hydroxyethyl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide 1-(2-(benzyloxy)ethyl)-N-(4-fluoro-3-methyl-2-oxo-2,3-dihydrobenzo[d]thiazol-6-yl)-4-methyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide (300 mg, 0.514 mmol), methanol (20 mL) and palladium on carbon (60 mg, 10 mass%) were added to the reaction flask, and the reaction system was reacted at room temperature for 22 h under a hydrogen gas atmosphere. Palladium on carbon (60 mg, 10 mass%) was added to the reaction system, and the temperature was raised to 50 ° C. and stirred for 24 h. The reaction mixture was filtered through diatomaceous earth with suction, the filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 4 / 1-1 / 2), slurried in petroleum ether / ethyl acetate (20 mL / 2 mL) for 1 h, filtered with suction, and the filter cake was collected and dried at 50 °C to give a white solid (100 mg, 39.42%).

[0226] MS(ESI,pos.ion)m / z: 494.1(M+1). 1 H NMR(400MHz,CDCl3)δ(ppm): 7.84(d,J=7.5Hz,1H),7.70-7.60(m,2H),7.58(d,J=15.8Hz,2H),7.47(s,1H ),7.403-7.38(m,2H),3.85-3.67(m,4H),3.67(d,J=2.9Hz,3H),2.09(s,3H). 19 F NMR(376MHz,CDCl3)δ(ppm): -60.97,-131.08.

[0227] Example A In vitro activity testing Test principle: Taking advantage of the property of luciferase to bind to a substrate and produce a chemiluminescent reaction, a plasmid containing the mineralocorticoid receptor (MR) ligand-binding domain (LBD) fused to the Gal4 DNA-binding domain (DBD) and a firefly luciferase reporter gene plasmid under the control of the Gal4 UAS (upstream activating sequence) were transfected into human embryonic kidney cells (HEK293). The change in activity of the mineralocorticoid receptor before and after stimulation, or the effect of different stimuli on the activity of the mineralocorticoid receptor, was judged by the level of firefly luciferase activity. In addition, to reduce the effect of intrinsic variables on the accuracy of the test, the cells were transfected with a plasmid carrying the Renilla luciferase gene as a control plasmid to provide an internal control of transcription activity, so that the test results would not be affected by changes in the test conditions.

[0228] Test Method: 1) HEK293 cells were harvested after trypsin digestion and the cell density was adjusted to 500,000 cells / mL. 2) Add FuGENE HD Transfection Reagent to the cell suspension. 3) The above cell suspension is inoculated into a 96-well cell culture plate at 100 μL / well and cultured at 37° C. and 5% CO2 for 24 hours. 4) A series of concentrations of the test compound and EC 80 A concentration of the agonist aldosterone was added to each well and incubated for 18 hours. 5) Firefly luciferase and Renilla luciferase signals were measured using the Promega Dual Luciferase Reporter Assay System.

[0229] Result Processing: 1) After obtaining the firefly luciferase signal (F) and the Renilla luciferase signal (R), the Renilla luciferase signal was used for correction, i.e., the F / R value was used to perform subsequent inhibition rate calculations; 2) % Inhibition = (Max-X) / (Max-Min) x 100%, where Max is the F / R value of the positive control well, Min is the F / R value of the negative control well, and X is the F / R value of the wells containing different concentrations of the test compound; 3) ICs were analyzed using GraphPrism 5.0 mapping software. 50 was calculated.

[0230] Test results: Table 3. In vitro activity data for compounds of the invention [Table 3] Test conclusion: As can be seen from the test results in Table 3, the compounds of the examples of the present invention have high mineralocorticoid receptor (MR) antagonistic activity and can be used as effective mineralocorticoid receptor antagonists.

[0231] Example B Pharmacokinetic testing of compounds of the invention Preparation of test compound solution: The test compound was prepared into a solution using 5% dimethyl sulfoxide, 60% PEG400 and 35% physiological saline, and used for oral or intravenous administration.

[0232] Example B1 In vivo pharmacokinetic study of compounds of the invention in beagle dogs Beagle dogs weighing 8-10 kg were randomly divided into two groups, and the test compounds were orally administered at a dose of 5.0 mg / kg, respectively, and blood was collected at 0.0833, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0, 32.0, and 48.0 hours after administration. A standard curve with an appropriate range was prepared based on the sample concentration, and the concentration of the test compounds in the plasma samples was measured using an AB SCIEX API4000 LC-MS / MS in MRM mode. Based on the drug concentration-time curves, the pharmacokinetic parameters were calculated using the non-compartmental model method of WinNonLin 6.3 software.

[0233] Test results: Table 4. In vivo pharmacokinetic data of compounds of the present invention in Beagle dogs. [Table 4] Study Conclusion: As can be seen from the data in Table 4, the compounds of the present invention have excellent in vivo pharmacokinetic properties, for example, compared to the control compound CS-3150, the compound of Example 2 of the present invention showed higher exposure, blood concentration and long half-life in beagle dogs.

[0234] Example B2 In vivo pharmacokinetic study of compounds of the invention in cynomolgus monkeys The test compound was orally administered at a dose of 3 mg / kg to three female cynomolgus monkeys weighing 3.0-3.5 kg, and blood was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 32, and 48 hours after administration. A standard curve with an appropriate range was prepared based on the sample concentration, and the concentration of the test compound in the plasma samples was measured using an AB SCIEX API 5000 LC-MS / MS in MRM mode. Based on the drug concentration-time curve, the pharmacokinetic parameters were calculated using the non-compartmental model method of WinNnonlin 6.3 software.

[0235] Test results: Table 5. In vivo pharmacokinetic data of compounds of the invention in cynomolgus monkeys [Table 5] Conclusion: The compounds of the present invention have excellent pharmacokinetic properties in cynomolgus monkeys. Specifically, compared with the control compound CS-3150, the compound of Example 2 of the present invention has better pharmacokinetic properties, such as higher exposure, blood concentration and bioavailability.

[0236] Example C In vitro phototoxicity testing of compounds of the invention Preparation of test compound solutions: Test compounds were dissolved in dimethyl sulfoxide to prepare 10 mg / mL solutions, and then serially diluted with dimethyl sulfoxide in 2.15-fold increments to different concentrations.

[0237] Balb / c 3T3 cells were seeded in a 96-well culture plate and cultured for 24 hours, after which the culture medium was discarded and a balanced salt solution (HBSS) containing different concentrations of the test compounds or positive control (chlorpromazine hydrochloride, CPZ) and a solvent control was added. Each concentration of the test compounds and the positive control were seeded in two culture plates, a light-irradiated (+UV) plate and a non-light-irradiated (-UV) plate, respectively. After 1 hour of culture, the light dose was 5.0 J / cm 2 Irradiate the plate with light until the light intensity is approximately 1.7mW / cm 2 The plates were irradiated under UVA conditions at 100°C, and the non-irradiated plate was left at room temperature in the dark for the same period of time. After irradiation, the culture medium was replaced with fresh medium and cultured for 18 to 22 hours. Approximately 3 hours before the end of culture, the culture medium was replaced with a culture medium containing neutral red and not containing serum. After culture, the neutral red eluate was added, and the wells were shaken and the absorbance value (OD540) of each well was measured at 540 nm. The 50% inhibitory concentration (IC 50 ), photoirritability factor (PIF) and / or mean photo effect (MPE) were calculated. Phototoxicity of the compounds was determined according to the following criteria: PIF>5 was considered positive for phototoxicity, 5>PIF>2 was considered possible phototoxicity, and 2>PIF was considered non-phototoxic.

[0238] Table 6. In vitro 3T3 cell neutral red uptake phototoxicity test results for compounds of the present invention [Table 6] Conclusion: The results of the in vitro phototoxicity test of the compound of Example 2 of the present invention are shown in Table 6. As can be seen from the test results, the compound of Example 2 of the present invention does not have in vitro phototoxicity. That is, the compound of Example 2 of the present invention has low toxicity, high safety, and high drug discovery potential.

[0239] In the present description, the reference words "one embodiment", "some embodiments", "examples", "particular examples", or "some examples" mean that the specific features, structures, materials, or features described with reference to the embodiment or example are included in at least one embodiment or example of the present invention. In the present description, the exemplary expressions of the above terms do not necessarily refer to the same embodiment or example. And, the specific features, structures, materials, or features described can be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine or combine different embodiments or examples and different embodiment or example features described in the present description, unless they are mutually inconsistent.

[0240] Although the embodiments of the present invention have been shown and described above, the above embodiments are merely illustrative and do not limit the present invention. Those skilled in the art may change, modify, substitute or alter the above embodiments without departing from the scope of the present invention.

Claims

1. A compound which is a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, an atropisomer, a nitrogen oxide, a hydrate, a solvate or a pharmacologically acceptable salt of a compound represented by formula (I). 【Chemistry 1】 (In the formula, R １ is a C1-3 alkyl group, C ３－６ Cycloalkyl group, C ６－１０ an aryl group, a 3- to 6-membered heterocyclic group, or a 5- to 10-membered heteroaryl group; ３－６ Cycloalkyl group, C ６－１０ The aryl group, the 3- to 6-membered heterocyclic group, and the 5- to 10-membered heteroaryl group each independently have 1, 2, 3, or 4 R ａ may be substituted with Each R ａ are independently D, F, Cl, Br, OH, NH ２ , S.H., C.N., N.O. ２ , C １－６ Alkoxy group, C １－６ Halogenated alkyl group, C ３－６ a cycloalkyl group or a 3- to 6-membered heterocyclic group; R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ are each independently H or D; R 2e is a C 1-6 halogenated alkyl group; R ２ is H, D or C １－６ is an alkyl group, R 3 is a C 1-6 alkyl group; R ４ , R ５ and R ７ are each independently H or D; R 6 is a —S(═O) 2 C 1-6 alkyl group; R8 is H, D or C １－６ is an alkyl group.

2. R ２ is H, D, a methyl group, an ethyl group, an n-propyl group or an isopropyl group, R 3 is a methyl group, an ethyl group, an n-propyl group, or an isopropyl group; R ４ , R ５ and R ７ are each independently H or D; R 6 is —S(═O) 2 CH 3 , —S(═O) 2 CH 2 CH 3 , The compound of claim 1, wherein R 8 is H, D, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, or a tert-butyl group.

3. The compound according to claim 1 or 2, which is a compound represented by formula (Ia) or a stereoisomer, a geometric isomer, a tautomer, an atropisomer, a nitrogen oxide, a hydrate, a solvate or a pharmacologically acceptable salt of a compound represented by formula (Ia). 【Chemistry 2】 4. The compound according to claim 1, wherein R 2e is a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a 2,2-difluoroethyl group, or a trifluoromethoxy group.

5. The compound according to any one of claims 1 to 4, which is a compound represented by formula (IIa) or a stereoisomer, a geometric isomer, a tautomer, an atropisomer, a nitrogen oxide, a hydrate, a solvate, or a pharmacologically acceptable salt of a compound represented by formula (IIa). 【Chemistry 3】

6. R １ is a C1-3 alkyl group, C ３－６ a cycloalkyl group, a phenyl group, a 3- to 6-membered heterocyclic group, or a 5- to 6-membered heteroaryl group, ３－６ The cycloalkyl group, the phenyl group, the 3- to 6-membered heterocyclic group, and the 5- to 6-membered heteroaryl group each independently have 1, 2, 3, or 4 R ａ may be substituted with Each R ａ are independently D, F, Cl, Br, OH, NH ２ , S.H., C.N., N.O. ２ 6. The compound according to claim 1, wherein the aryl group is a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a 2,2-difluoroethyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an ethylene oxide group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group.

7. R １ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, an ethylene oxide group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, a morpholinyl group, a pyrrole group, a pyridyl group, or a pyrimidinyl group, and the methyl group, the ethyl group, the ... is independently one, two, three, or four R ａ may be substituted with Each R ａ are independently D, F, Cl, Br, OH, NH ２ , S.H., C.N., N.O. ２ , a methoxy group, an ethoxy group, an isopropoxy group, a tert-butoxy group, a trifluoromethyl group, a difluoromethyl group, a monofluoromethyl group, a 2,2-difluoroethyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an ethylene oxide group, an azetidinyl group, an oxetanyl group, a tetrahydrofuranyl group, a pyrrolidinyl group, a piperidinyl group, or a morpholinyl group.

8. The compound according to any one of claims 1 to 7, having a structure represented by any one of the following formulas: 【Chemistry 4】

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, and optionally further comprising at least one of a pharmacologically acceptable carrier, excipient, diluent, adjuvant and vehicle.

10. 10. The pharmaceutical composition of claim 9, further comprising one or more other active ingredients, which are ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, beta-receptor blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates or antithrombotic agents.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 10 for treating, preventing or alleviating a disease in a patient suffering from aldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, cirrhosis of the liver, non-alcoholic steatohepatitis, chronic kidney disease, diabetic nephropathy, renal failure, fibrosis or stroke.

12. A mineralocorticoid receptor antagonist comprising a compound according to any one of claims 1 to 8 or a pharmaceutical composition according to any one of claims 9 to 10.

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