CN109721536B - Phenyl-substituted fused tricyclic compounds and their uses - Google Patents

Abstract

The present invention relates to a phenyl-substituted fused tricyclic compound and use thereof, and further relates to a pharmaceutical composition comprising the compound. The compounds of the present invention or the pharmaceutical compositions can be used as mineralocorticoid receptor antagonists.

Description

Phenyl-substituted fused tricyclic compounds and their uses

technical field

The invention belongs to the technical field of medicine, in particular to phenyl-substituted fused tricyclic compounds and uses thereof, and further relates to a pharmaceutical composition comprising the compounds. The compound or the pharmaceutical composition can be used as a mineralocorticoid receptor antagonist.

Background technique

The Mineralocorticoid Receptor (MR) is an aldosterone-activated nuclear hormone receptor that regulates the expression of many genes involved in electrolyte homeostasis and cardiovascular disease. An increase in circulating aldosterone increases blood pressure through its effect on urinary sodium excretion, with potential effects on the brain, heart and vascular system. In addition, hyperaldosteronism is associated with a number of disease physiologic processes that contribute to renal and cardiovascular disease. Although hyperaldosteronism is usually caused by aldosterone-producing adenomas, patients with resistant hypertension often have elevated aldosterone levels, commonly referred to as "aldosterone escape," due to serum potassium Increased content or residual AT1R activity. Hyperaldosteronism and aldosterone escape typically result in increased MR activity, and MR antagonists have been shown to be effective antihypertensive agents and also effective in the treatment of heart failure and primary aldosteronism .

Aldosterone is a steroid hormone formed in the adrenal cortex. Its production is indirectly regulated largely by renal blood flow. Any reduction in renal blood flow results in the release of the enzyme renin in the kidneys and into the circulating blood. This in turn 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 in the blood circulation, and thus indirectly as a volume sensor, and the severe loss of volume is counteracted by the renin-angiotensin-aldosterone system, on the one hand by increasing blood pressure (vascular tensin II effect), on the other hand by increasing the reabsorption of sodium and water in the kidneys to rebalance the filling state of the vascular system (aldosterone effect).

This control system can become compromised in various ways. For example, chronic reductions in renal blood flow (eg, due to heart failure and consequent blockage of blood in the venous system) lead to chronic excess release of aldosterone. This is followed by an expansion of blood volume and thus increased heart weakness by increasing the supply of blood volume to the heart. Obstruction of blood in the lungs, along with shortness of breath and limb edema, and ascites and pleural effusions may result; renal blood flow is further reduced. In addition, the effect of excess aldosterone leads to a decrease in potassium concentration in the blood and extracellular fluid. In myocardium that has been otherwise damaged before, the presence of deviations below a critical minimum level can induce fatal cardiac arrhythmias. This is likely to be one of the main causes of sudden cardiac death frequently seen in patients with heart failure.

In addition, aldosterone has also been reported to determine many of the myocardial remodeling processes typically observed in heart failure. Thus, hyperaldosteronism is a decisive component in the pathogenesis and prognosis of heart failure, which may be initially induced by various types of injury such as myocardial infarction, myocardial inflammation or hypertension. This hypothesis is supported by the fact that in extensive clinical studies by the use of aldosterone antagonists in a patient population with chronic heart failure and post-acute myocardial infarction, overall mortality was significantly reduced (B. Pitt, F. Zannad, W.J. 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)).

Additionally, in visceral tissues, such as the kidney and bowel, MR regulates sodium retention, potassium excretion, and water balance in response to aldosterone. 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 cognitive aspects of behavioral performance (Castren et al., J. of Neuroendocrinology, 3, 461-66 (1993). )).

Elevated levels of aldosterone or overstimulation of mineralocorticoid receptors are associated with several physiological disorders or pathological disease states, including Conn's syndrome, primary and secondary hyperaldosteronism, and sodium retention Increased excretion of magnesium and potassium (polyuria), increased water retention, hypertension (isolated systolic hypertension and combined systolic/diastolic hypertension), arrhythmias, myocardial fibrosis, myocardial infarction , Barthes syndrome, and conditions associated with excess catecholamine levels. (Hadley, M.E., 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 that act as MR antagonists are of therapeutic value for any of the aforementioned conditions.

Despite significant advances in the treatment of hypertension and heart failure with mineralocorticoid receptor antagonists, the current standard of care is only near optimal and there is a significant unmet medical need for other therapeutic/pharmacological interventions. The present invention addresses those needs by providing compounds and compositions that can be used to treat or prevent hypertension, heart failure, other cardiovascular disorders, and other aldosterone disorders.

Summary of Invention

The present invention provides a phenyl-substituted fused tricyclic compound with mineralocorticoid receptor (MR) antagonism and a pharmaceutical composition thereof, as well as the use of the compound or the pharmaceutical composition in preparing a medicine, The medicament is used for treating, preventing or alleviating diseases such as hyperaldosteronism, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure and stroke.

In one aspect, the present invention relates to a compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compound represented by formula (I) compounds, solvates, metabolites, esters, pharmaceutically acceptable salts or prodrugs,

in,

Ring A is an aromatic ring consisting of 3-8 atoms, a heteroaromatic ring consisting of 3-8 atoms, a partially unsaturated carbocyclic ring consisting of 3-8 atoms, or a partially unsaturated heterocyclic ring consisting of 3-8 atoms ring;

Each of R ¹ , R ² , R ³ and R ⁴ is independently H, D, amino, hydroxy, mercapto, cyano, nitro, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 Haloalkyl, C _1-6 haloalkoxy, C _1-6 alkylamino, carboxyl, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, aminoacyl, aminosulfonyl, C _3-6 cycloalkyl , a C _6-10 aryl group, a heterocyclic group consisting of 3-8 atoms or a heteroaryl group consisting of 3-8 atoms;

R ⁵ is cyano or -C(=O)NR ^a R ^b ;

R ⁶ is H, D, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkylamino, C _3-6 cycloalkane base, C _6-10 aryl, heterocyclic group consisting of 3-8 atoms or heteroaryl group consisting of 3-8 atoms;

Each R ⁷ and R ⁸ is independently H, D, halogen, cyano, C _1-6 alkoxyacyl, carboxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl , C _1-6 haloalkoxy, C _1-6 alkylamino, C _1-6 alkanoyl, C _1-6 alkylsulfonyl, aminoacyl or aminosulfonyl;

Each R ^is independently H, D, halogen, hydroxy, cyano, nitro, mercapto, amino, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylamino, carboxyl, C _1-6 alkanoyl, C _1-6 alkoxyacyl, C _1-6 alkylsulfonyl, aminoacyl or aminosulfonyl;

n is 0, 1, 2, 3 or 4.

In some embodiments, Ring A is an aromatic ring of 6 atoms, a heteroaromatic ring of 5-6 atoms, a partially unsaturated carbocyclic ring of 5-6 atoms, or a moiety of 5-6 atoms Unsaturated heterocycle.

In some embodiments, Ring A is

In some embodiments, each R ¹ , R ² , R ³ and R ⁴ is independently H, D, F, Cl, Br, amino, hydroxyl, mercapto, cyano, nitro, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkylamino, carboxyl, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, aminoacyl , aminosulfonyl, C _5-6 cycloalkyl, C _6-10 aryl, heterocyclic group consisting of 5-6 atoms or heteroaryl group consisting of 5-6 atoms.

In some embodiments, each R ¹ , R ² , R ³ and R ⁴ is independently H, D, amino, hydroxyl, mercapto, cyano, nitro, methyl, ethyl, propyl, butyl, methyl Oxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoro Ethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, carboxyl, methylacyl, ethylacyl, methylsulfonyl, aminoacyl or aminosulfonyl Acyl.

In some embodiments, R ⁵ is cyano or -C(=O)NH ₂ .

In some embodiments, R ⁶ is H, D, C _1-4 alkyl or C _1-4 haloalkyl.

In some embodiments, R ⁶ is H, D, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl , monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino , dimethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxiranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridyl , pyrrolyl, thiazolyl, pyrazolyl or pyrimidinyl.

In some embodiments, each R ⁷ and R ⁸ is independently H, D, halogen, cyano, C _1-4 alkoxyacyl, carboxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkylamino, C _1-4 alkanoyl, C _1-4 alkylsulfonyl, aminoacyl or aminosulfonyl.

In some embodiments, each ^R7 and ^R8 is independently H, D, F, Cl, Br, cyano, methylacyl, ethylacyl, propylacyl, methoxyacyl, ethoxyacyl, Propoxyacyl, carboxyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, Methylsulfonyl, aminosulfonyl or aminoacyl.

In some embodiments, each R ^is independently H, D, F, Cl, Br, hydroxy, cyano, nitro, mercapto, amino, methyl, ethyl, propyl, butyl, methoxy, Ethoxy, propoxy, butoxy, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, trifluoroethyl, Trifluoromethoxy, difluoromethoxy, monofluoromethoxy, methylamino, dimethylamino, methylacyl, ethylacyl, methoxyacyl, ethoxyacyl, carboxyl, methylsulfonyl acyl, aminoacyl or aminosulfonyl.

In some embodiments, the compound of the present invention is one of the following compounds,

or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof.

In another aspect, the present invention relates to a pharmaceutical composition comprising the compound of the present invention.

In some embodiments, the pharmaceutical composition of the present invention further comprises at least one of pharmaceutically acceptable carriers, excipients, diluents, adjuvants and vehicles.

In some embodiments, the pharmaceutical composition of the present invention further comprises one or more other active ingredients selected from ACE inhibitors, renin inhibitors, angiotensin II receptor antagonists, Beta-blockers, acetylsalicylic acid, diuretics, calcium antagonists, statins, digitalis derivatives, calcium sensitizers, nitrates, and antithrombotics.

In one aspect, the present invention relates to the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament, wherein the medicament is used to treat, prevent or alleviate hyperaldosteronism, hypertension in a patient , chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure and stroke.

In another aspect, the present invention relates to the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for use as a mineralocorticoid receptor antagonist.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The present invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the present invention as defined by the claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of multiple separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

Unless otherwise stated, the following definitions as used herein shall apply. For the purposes of the present invention, chemical elements are in accordance with the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, general principles of organic chemistry may be referred to as described in "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, Its entire contents are incorporated herein by reference.

As used herein, the articles "a", "an" and "the" are intended to include "at least one" or "one or more" unless stated otherwise or otherwise clearly contradicted by context. Thus, as used herein, these articles refer to one or more than one (ie, at least one) object of the article. For example, "a component" refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is an open-ended expression, that is, it includes the contents specified in the present invention, but does not exclude other aspects.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .

"Enantiomer" refers to two nonsuperimposable, but mirror-image isomers of a compound.

"Diastereomer" refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.

Stereochemical definitions and rules used in the present invention generally follow 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.

Any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

The resulting mixtures of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution). For example, protontautomers (also known as prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some of the bonding electrons. A specific example of keto-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(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.

In addition, it should be noted that, unless clearly stated otherwise, the description modes "each independently" and "...independently" and "...independently" used in the present invention can be interchanged, and both are interchangeable. It should be understood in a broad sense. It can either mean that in different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that in the same group, the specific options expressed between the same symbols do not affect each other. Likewise, the "independent" in the description manner "...independently and optionally" should also be understood in the broad sense described above.

The term "optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, that is, the description includes instances where said event or circumstance occurs and instances in which it does not.

In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " _{C1 - C6} alkyl" or " _C1-6 alkyl" specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, _C4 alkyl, _C5 alkyl and _C6 alkanes "C _1-4 alkyl" specifically refers to independently disclosed methyl, ethyl, C ₃ alkyl (ie propyl, including n-propyl and isopropyl), C ₄ alkyl (ie butyl, including n-butyl, isobutyl, sec-butyl and tert-butyl).

In various parts of the present invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood to be the linking group. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively represents the linking An alkylene group or an arylene group.

The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group can be any is optionally substituted with one or more substituents described herein. In some embodiments, the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, ie, _C1-6 alkyl; in yet other implementations In schemes, alkyl groups contain 1-4 carbon atoms, ie, _C1-4 alkyl; in still some embodiments, alkyl groups contain 1-3 carbon atoms, ie, _C1-3 alkyl. In some embodiments, the C _1-6 alkyl group described in the present invention can be a C _1-4 alkyl group; in other embodiments, the C _1-6 alkyl group described in the present invention can be C _{1 -3} alkyl.

Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, sec-butyl, tert-butyl) base), n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl Base-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 base, wait.

The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including 1-propoxy or 2-propoxy), butoxy (including n-butoxy, isobutoxy, sec-butoxy, tert-butoxy) and the like.

The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl, trifluoromethoxy , chloroethyl (eg, 2-chloroethyl), 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-chloro-1-methylethyl, and the like.

The term "amino" refers to the group _-NH2 . The term "carboxy" refers to the group -COOH. The terms "hydroxy", "cyano", "nitro", "mercapto" represent the groups -OH, -CN, _-NO2 , -SH, respectively. The term "oxo" represents the group =O.

The term "alkylamino" denotes that the group _-NH2 is substituted by one or two alkyl groups, wherein the alkyl groups have the meanings as described herein. Examples of alkylamino groups include, but are not limited to, methylamino, dimethylamino, and the like.

The term "carbocycle" refers to a saturated, unsaturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In some embodiments, the carbocycle contains 3-8 ring atoms. Examples of carbocycles include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. The carbocyclic group may be optionally substituted with one or more substituents described herein.

The term "cycloalkyl" denotes a saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 ring carbon atoms. In some embodiments, the cycloalkyl group contains 3-10 ring carbon atoms, such as C _3-10 cycloalkyl; in other embodiments, the cycloalkyl group contains 3-8 ring carbon atoms, such as C _{3- 8} cycloalkyl; in yet other embodiments, cycloalkyl contains 3-6 ring carbon atoms, eg, _C3-6 cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like; wherein the C _3-6 ring Alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group may be optionally substituted with one or more substituents described herein.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system comprising 3-12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the Heterocyclyl groups are non-aromatic and do not contain any aromatic rings. Unless otherwise specified, heterocyclyl can be carbon or nitrogen, and _-CH2- groups can be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. Ring nitrogen atoms can optionally be oxidized to N-oxides. The term "heterocyclyl" is used interchangeably with the term "heterocycle." The heterocyclyl group may be optionally substituted with one or more substituents described herein.

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

The term "aryl" refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring is aromatic , and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, 2,3-dihydro-1H-indenyl, naphthyl, and anthracenyl. The aryl group may be optionally substituted with one or more substituents described herein. Unless otherwise specified, the group " _C6-10 aryl" refers to an aryl group containing 6-10 ring carbon atoms.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic, and At least one ring contains 1, 2, 3 or 4 ring heteroatoms selected from nitrogen, oxygen, sulfur, and the heteroaryl group has one or more points of attachment to the rest of the molecule. When a _-CH2- group is present in a heteroaryl group, the _-CH2- group can optionally be replaced by -C(=O)-. Unless otherwise specified, the heteroaryl group can be attached to the remainder of the molecule (eg, the host structure in the formula) through any reasonable site (which can be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". In some embodiments, the heteroaryl group is a heteroaryl group of 5-10 atoms, meaning that the heteroaryl group contains 1-9 ring carbon atoms and 1, 2, 3, or 4 atoms selected from O, S, and N Ring heteroatom; in other embodiments, heteroaryl is a heteroaryl group consisting of 5-6 atoms, meaning that the heteroaryl group contains 1-5 ring carbon atoms and 1, 2, 3 or 4 selected from O , S, and N ring heteroatoms. Examples of such include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, Pyrazinyl, thienyl, thiazolyl, etc. The heteroaryl group may be optionally substituted with one or more substituents described herein.

The term "consisting of 3-8 atoms", "consisting of 5-10 atoms" or "consisting of 5-6 atoms" means that the cyclic group consists of 3-8, 5-10 or 5-6 atoms It consists of ring atoms, and the ring atoms include carbon atoms or heteroatoms such as O, N, S, P, etc.

"Partially unsaturated carbocyclic ring composed of 3-8 atoms" and "partially unsaturated heterocyclic ring composed of 3-8 atoms" in the present invention refer to unsaturated carbon composed of 3-8 ring atoms ring or an unsaturated heterocyclic ring composed of 3-8 ring atoms, wherein the heterocyclic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, S, and the carbocyclic or heterocyclic ring CH ₂ in can be further oxidized to form C(=O), similarly, S or N in the heterocycle can also be further oxidized to form S(=O), S(=O) ₂ or N( =O). In some embodiments, the "partially unsaturated carbocyclic or heterocyclic ring consisting of 3-8 atoms" described in the present invention may be a partially unsaturated carbocyclic or heterocyclic ring consisting of 5-6 atoms.

The "aromatic ring composed of 3-8 atoms" and "heteroaromatic ring composed of 3-8 atoms" in the present invention refer to an aromatic ring containing 3-8 ring atoms, an aromatic ring containing 3-8 ring atoms A heteroaromatic ring, wherein the heteroaromatic ring contains 1, 2, 3 or 4 heteroatoms selected from N, O, and S. In some embodiments, the "aromatic ring composed of 3-8 atoms" described in the present invention may be an aromatic ring composed of 5-6 atoms; in other embodiments, the "3-8 atomic ring" described in the present invention An aromatic ring consisting of 1 atoms" may be an aromatic ring consisting of 6 atoms, that is, a benzene ring. In some embodiments, the "heteroaromatic ring composed of 3-8 atoms" described in the present invention may be a heteroaromatic ring composed of 5-6 atoms; specific examples include, but are not limited to, pyridine ring, pyrimidine ring, Pyrazine ring, thiophene ring, thiazole ring, furan ring, pyrrole ring, pyrazole ring, imidazole ring, triazole ring, etc.

The term "alkanoyl" means -C(=O)-alkyl, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, methylacyl (-C(=O) ) _CH3 ), ethyl acyl (-C(=O) _{CH2CH3 )} , and the like.

The term "alkoxyacyl" means -C(=O)-R, wherein R is an alkoxy group having the meaning as described herein, examples of which include, but are not limited to, methoxy acyl (-C(=O) _OCH3 ), ethoxyacyl (-C(=O) _{OCH2CH3 )} , and the like.

The term "alkylsulfonyl" means -S(=O) ₂ -alkyl, wherein the alkyl group has the meaning as described herein, examples of which include, but are not limited to, methylsulfonyl (- S(=O) _{2CH3 )} , ethylsulfonyl (-S( ₌ O) _{2CH2CH3 )} , and the like.

The term "aminosulfonyl" means -S(=O) _{2NH2 ;} the term "aminoacyl" means -C(=O) _NH2 .

The term "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like. Preferably, the term "pharmaceutically acceptable" as used herein means approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly in humans.

The term "carrier" refers to a diluent, adjuvant, excipient or base with which the compound is administered. These pharmaceutical 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. Water and aqueous solutions (eg, saline, aqueous dextrose, aqueous glycerol) are preferred for use as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin.

The term "prodrug" as used in the present invention refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue. The prodrug compounds of the present invention can be esters. In the existing invention, esters that can be used as prodrugs include phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxyl group, which can be acylated to give the compound in prodrug form. Other prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium 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.

"Metabolite" refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate; organic acid salts such as ethyl acetate salts, oxalates, maleates, tartrates, citrates, succinates, malonates; or by other methods described in books such as ion exchange to obtain these salts. Other pharmaceutically acceptable salts include, adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphor acid salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerin Phosphate, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate , Malate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3-Phenylpropane acid salt, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by reaction with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ ( _C1-4alkyl ) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali or alkaline earth metals that can form salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, _{C1 -8} Sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association in which the solvent molecule is water.

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

"Nitrogen oxide" in the present invention means that when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides containing nitrogen heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (eg, peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages). In particular, N-oxides can be prepared by the method of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which, for example, in an inert solvent such as dichloromethane, an amine compound is combined with m-chloroperoxybenzoic acid (MCPBA) reaction.

The "compound of the present invention", "the compound described in the present invention", "the compound described in the present invention" or similar expressions used in the present invention all refer to the compound represented by formula (I) in the present invention.

The term "treating" any disease or disorder, as used herein, in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, "treating" refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, "treating" refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.

Any structural formula given herein is also intended to represent both isotopically unenriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of ^hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ^15N , ^17O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined by the present invention, for example, those in which radioactive isotopes, such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes, such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetic studies (using eg ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including drugs or Single photon emission computed tomography (SPECT) for substrate tissue distribution measurements, or may be used in radiation therapy 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 familiar to those skilled in the art or as described in the examples and preparation procedures of the present invention, using suitable isotopically labeled reagents to replace the previously used unlabeled reagents.

In addition, substitution of heavier isotopes, particularly deuterium (ie, ² H or D), may provide certain therapeutic advantages that result from greater metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compounds of formula (I). The concentration of such heavier isotopes, especially deuterium, can be defined by an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a given isotope. If a substituent of a compound of the present invention is designated as deuterium, the compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporated), at least 5000 (75% deuterium incorporated), at least 5500 (82.5% deuterium incorporated), at least 6000 (90% deuterium incorporated), at least 6333.3 (95% deuterium incorporated) deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, _D2O , acetone _- d6, _DMSO -d6.

Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are included within the scope of the present invention. Additionally, unless otherwise indicated, the structural formulae of the compounds described herein include enriched isotopes of one or more different atoms.

Any abbreviations for protecting groups, amino acids and other compounds used in the present invention, unless otherwise stated, are based on their commonly used, recognized abbreviations, or with reference to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

The compounds of the present invention competitively antagonize the aldosterone receptor (MR), and thus they may be useful agents for the treatment and prevention of disorders associated with elevated aldosterone levels.

The present invention encompasses the use of compounds of the present invention, and pharmaceutically acceptable salts thereof, for the manufacture of pharmaceutical products for the treatment of patients with mineralocorticoid receptor- or aldosterone-related diseases, including those described herein. The present invention includes a pharmaceutical composition comprising a compound represented by formula (I) in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle required for effective treatment quantity.

Unless otherwise indicated, all hydrates, solvates and pharmaceutically acceptable salts of the compounds of the present invention are within the scope of the present invention.

Specifically, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes substances or compositions that must be chemically or toxicologically suitable in relation to the other components that make up the formulation and the mammal for which it is to be treated.

The salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or salts of separated enantiomers of the compounds of formula (I), but are not necessarily pharmaceutically acceptable Salt.

Salts of the compounds of the present invention can be prepared by any suitable method provided in the literature, for example, using mineral acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Alternatively use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranonic acids such as glucuronic acid and galactose aldehydes; alpha-hydroxy acids, such as citric and tartaric acids; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic and cinnamic acids; sulfonic acids, such as p-toluenesulfonic acid, ethanesulfonic acid, and many more.

The biological activity of the compounds of the present invention can be assessed using any conventionally known method. Suitable detection methods are well known in the art. For example, the compounds of the present invention can be tested for MR antagonistic activity, pharmacokinetic activity, and/or liver microsome stability, etc. by appropriate conventional methods. The detection methods provided by the present invention are presented only as examples and do not limit the present invention. The compounds of the present invention are active in at least one of the detection methods provided herein.

PHARMACEUTICAL COMPOSITIONS, FORMULATIONS, ADMINISTRATION AND USE OF THE COMPOUNDS OF THE INVENTION

On the other hand, the characteristics of the pharmaceutical composition of the present invention include the phenyl-substituted fused tricyclic compounds represented by formula (I), the compounds listed in the present invention, or the compounds of Examples 1-3, and pharmacy an acceptable carrier, adjuvant, or excipient. The amount of the compound in the compositions of the present invention is effective to treat or alleviate a mineralocorticoid receptor or aldosterone-related disease in a patient.

As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988-1999, Marcel Dekker, New York, integrated the contents of this document, showing that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their well-known methods of preparation. Except to the extent that any conventional carrier vehicle is incompatible with the compounds of the present invention, such as any adverse biological effect or interaction in a detrimental manner with any other component of a pharmaceutically acceptable composition, they The use of is also within the scope of the present invention.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, sorbitan Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive oil, corn oil, and soybean oil; glycols such as propylene glycol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, Sweeteners, Flavours and Fragrances, Preservatives and Antioxidants.

The pharmaceutical compositions of the present invention can be administered directly or in the form of pharmaceutical compositions or pharmaceuticals with suitable carriers or excipients, which are well known in the art. The methods of treatment of the present invention may comprise administering to an individual in need thereof an effective compound of the present invention. In some embodiments, the individual is a mammalian individual, and in some preferred embodiments, the individual is a human individual.

An effective amount of a compound, pharmaceutical composition or medicament of the present invention can be readily determined by routine experimentation, as can the most effective and convenient route of administration and the most appropriate formulation.

Pharmaceutical dosage forms of the compounds of the present invention may be provided in 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, ovules, implants, amorphous Or crystalline powder, aerosol and lyophilized preparations. Depending on the route of administration used, special devices may be required to administer or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators, or special flasks. A pharmaceutical dosage form often consists of a drug, an excipient, and a container/closure system. One or more excipients (also known as inactive ingredients) may be added to the compounds of the present invention to improve or facilitate the manufacture, stability, administration and safety of the drug and may provide for the desired drug release Curve method. Thus, the type of excipients added to the drug may depend on various factors, such as the physical and chemical properties of the drug, the route of administration, and the steps of preparation. Pharmaceutically acceptable excipients exist in the art and include those listed in various pharmacopeias. (See U.S. Pharmacopeia (USP), Japanese Pharmacopoeia (JP), European Pharmacopoeia (EP) and British Pharmacopoeia (BP); the U.S. Food and Drug Administration (the U.S. Food and Drug Administration) , www.fda.gov) Center for Drug Evaluation and Research (CEDR) publications, such as the Inactive Ingredient Guide (1996); the Handbook of Drug Additives by Ash and Ash ( Handbook of Pharmaceutical Additives, 2002, Synapse Information Resources, Inc., Endicott NY; etc..

Pharmaceutical dosage forms of the compounds of this invention can be manufactured by any of the methods well known in the art, such as by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extrusion, spray drying, Milling, emulsification, (nano/micro) encapsulation, encapsulation or lyophilization processes. As noted above, the compositions of the present invention may include one or more physiologically acceptable inactive ingredients that facilitate processing of the active molecule into formulations for pharmaceutical use.

Appropriate formulations depend on the desired route of administration. For example, for intravenous injection, the compositions can be formulated in aqueous solutions, using physiologically compatible buffers as necessary, including, for example, phosphate, histidine, or citrate for adjusting the pH of the formulation, and salts such as chloride Sodium or dextrose tonicity agent. For transmucosal or nasal administration, semisolid, liquid formulations or patches may be preferred, possibly containing penetration enhancers; such penetration agents are generally known in the art. For oral administration, the compounds can be formulated in liquid or solid dosage forms and as immediate release or controlled/sustained release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, ointments, suspensions and emulsions. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

Solid oral dosage forms can be obtained using excipients including fillers, disintegrants, binders (dry and wet), dissolution delaying agents, lubricants, glidants, antiadherents, cationic exchange agents Resins, humectants, antioxidants, preservatives, colorants and flavors. These excipients can be of synthetic or natural origin. Examples of such excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate/sodium lauryl sulfate, mannitol, polyethylene glycol, polyvinylpyrrolidone, silicic acid Salt, 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 wax. Ethanol and water can be used as granulation aids. In some cases, it is desirable to coat the tablet with, for example, a taste masking film, a gastric acid resistant film, or a delayed release film. Natural and synthetic polymers are often used to coat tablets in combination with colorants, sugars and organic solvents or water, resulting in dragees. While capsules are preferred over tablets, their pharmaceutical powders, suspensions or solutions can be delivered in the form of compatible hard- or soft-shell capsules.

In some embodiments, the compounds of the present invention may be administered topically, eg, via a skin patch, semi-solid or liquid formulations such as gels, (micro)emulsions, ointments, solutions, (nano/micron) suspensions or foams . Skin and underlying tissue penetration of drugs can be modulated by, for example, the use of penetration enhancers; the use of appropriate selection and combinations of lipophilic, hydrophilic and amphiphilic excipients, including water, organic solvents, waxes, oils, Synthetic and natural polymers, surfactants, emulsifiers; by adjusting pH; and the use of complexing agents. Other techniques, such as iontophoresi, may also be used to modulate skin penetration of the compounds of the present invention. For example, where topical administration is desired with minimal systemic exposure, transdermal or topical administration will be preferred.

For administration by inhalation or nasal administration, the compounds used according to the invention are conveniently administered in the form of solutions, suspensions, emulsions or semisolid aerosols from pressurized packs or nebulizers, usually by means of propellants, For example halocarbons derived from methane and ethane, carbon dioxide or any other suitable gas. For topical aerosols, hydrocarbons such as butane, isobutylene and pentane are suitable. In the case of a pressurized aerosol, the appropriate dosage unit can be determined by providing a valve to deliver the metering. Capsules and cartridges with eg gelatin can be formulated for use in an inhaler or insufflator. These typically contain a powder mix of the compound with a suitable powder base such as lactose or starch.

Compositions formulated for parenteral administration by injection are generally sterile and can be presented in unit dosage form, eg, ampoules, syringes, injection pens, or multi-dose containers, the latter usually containing a preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as buffers, tonicity agents, viscosity enhancers, surfactants, suspending and 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 co-solvents. In some cases, such as for lyophilized products or concentrates, the parenteral formulation will be reconstituted or diluted prior to administration. Depot formulations to provide controlled or sustained release of the compounds of the invention may include nano/micron sized particles or injectable suspensions of nano/micron sized or non-micronized crystals. Other matrices well known in the art, polymers such as poly(lactic acid), poly(glycolic acid), or copolymers thereof, can be used as controlled/sustained release matrices. Other depot delivery systems can be provided in the form of implants and pumps that require an incision.

Suitable carriers for the compounds of the invention for intravenous injection are well known in the art and include aqueous based solutions containing bases such as sodium hydroxide for forming ionic compounds; sucrose or sodium chloride as tonicity agents; for example Buffers containing phosphate or histidine. Co-solvents such as polyethylene glycol can be added. These water-based systems effectively dissolve the compounds of the present invention and produce low toxicity following systemic administration. The proportions of the components of the solution system can be greatly varied without destroying the solubility and toxicity characteristics. In addition, the properties of the components can be changed. For example, low toxicity surfactants such as polysorbates or poloxamers can be used, polyethylene glycol or other co-solvents can also be used, biocompatible polymers such as polyvinylpyrrolidone can be added and other sugars and polyols can be used in place of dextrose.

The compounds of the present invention may act systemically and/or locally. They can be administered in a suitable manner, for example, by oral administration, parenteral administration, pulmonary administration, nasal administration, sublingual administration, translingual administration, buccal administration, rectal administration, dermal administration Drug, transdermal, conjunctival, ear canal, or as a graft or stent. The compounds of the present invention are preferably administered orally or parenterally.

Suitable modes of administration for oral administration are as follows: modes of administration that release compounds of the invention rapidly and/or in an improved manner, which contain crystalline and/or amorphous and/or dissolved forms of A compound of the invention in a form, such as a tablet (uncoated tablet or tablet coated, for example, with a gastric-tolerant or dissolution-retarding or insoluble coating that controls the release of the compound of the invention), in the oral cavity Rapidly disintegrating tablets or films/flakes, films/lyophilisates, capsules (eg hard or soft capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can bypass the absorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or include absorption (eg, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal) absorb). Administration forms suitable for parenteral administration include solutions, suspensions, emulsions, lyophilisates or sterile powders in the form of formulations for injection and infusion.

For other routes of administration, suitable examples are pharmaceutical forms for inhalation (including powder inhalers, nebulizers), nasal drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, films/ Sheets or capsules, suppositories, ear or ophthalmic formulations, vaginal capsules, aqueous suspensions (lotions, shakes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg, patches), emulsions (Milch ), pastes, foams, spray powders, implants or stents.

A therapeutically effective amount of a compound of the present invention should be present in the aforementioned pharmaceutical formulation at a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight of the entire mixture.

In addition to the compounds of the present invention, the above-mentioned pharmaceutical formulations may also contain other pharmaceutically active ingredients.

A therapeutically effective dose can first be estimated using various methods well known in the art. Initial doses for animal studies can be based on effective concentrations established in cell culture assays. Dosage ranges suitable for human subjects can be determined, for example, using data obtained from animal studies and cell culture assays. In certain embodiments, the compounds of the present invention can be prepared as medicaments for oral administration. An exemplary dose of a compound of the invention in a medicament for oral administration is from about 0.01 to about 100 mg/kg (where kg represents the subject's body weight). In some embodiments, the agent comprises from about 0.01 to about 20 mg/kg (wherein kg represents the subject's body weight), or optionally from about 0.01 to about 10 mg/kg (wherein kg represents the subject's body weight), Or optionally from about 0.01 to about 5.0 mg/kg (where kg represents the subject's body weight). In certain embodiments, the compounds of the present invention are administered parenterally at an effective dose of about 0.001-1 mg/kg, preferably about 0.01-0.5 mg/kg body weight.

Dosage regimens for agents typically used 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 certain embodiments, the compounds of the present invention are administered as the active ingredient in a total amount of about 0.001 to about 50, preferably 0.001 to 10 mg/kg body weight per 24 hours, optionally with multiple Administration in single dose form. A single dose may preferably contain a compound of the invention in an amount of about 0.001 to about 30, especially 0.001 to 3 mg/kg body weight.

An effective or therapeutically effective amount or dose of an agent (eg, a compound of the present invention) refers to the amount of the agent or compound that results in an improvement in symptoms or prolonged survival in an individual. Toxicity and therapeutic efficacy of the molecule can be determined in cell cultures or experimental animals by standard pharmaceutical procedures, for example by determining the _LD50 (the dose lethal to 50% of the population) and the _ED50 (the dose effective to treat 50% of the population). dose). The dose ratio of toxic to therapeutic effects is the therapeutic index and can be expressed as _LD50 / _ED50 . Agents that exhibit high therapeutic indices are preferred.

An effective or therapeutically effective amount is the amount of a compound or pharmaceutical composition that will elicit a biological or medical response in a tissue, system, animal or human being sought by a researcher, veterinarian, physician or other clinician. The dosage lies preferably within a range of circulating concentrations that include the _ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and/or the route of administration employed. The correct formulation, route of administration, dosage and dosing interval should be selected according to methods known in the art, taking into account the particularities of the individual situation.

Doses and intervals can be adjusted individually to provide plasma levels of the active moiety sufficient to achieve the desired effect; ie, the minimal effective concentration (MEC). The MEC for each compound will vary, but can be estimated, for example, from in vitro data and animal experiments. The dose necessary to obtain MEC will depend on individual characteristics and route of administration. In the case of topical administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

The amount of the agent or composition administered may depend on various factors, including the sex, age and weight of the individual being treated, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

The compositions of the present invention can be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient, as required. For example, the package or device may comprise metal or plastic foil (eg, blister packs) or glass and rubber stoppers. The pack or dispenser device may be accompanied by instructions for use. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

The compounds of the present invention can be used alone or, if desired, in combination with other active compounds. The present invention also provides a combination comprising at least one compound of the present invention and one or more further active substances, in particular medicaments for the treatment and/or prophylaxis of the diseases described in the present invention.

The compounds of the present invention act as antagonists of the mineralocorticoid receptor and exhibit an unpredictable range of valuable pharmacological effects. They are therefore suitable for use as medicaments for the treatment and/or prevention of human and animal diseases.

The compounds of the present invention are suitable for the prevention and/or treatment of various disorders and disease-related conditions, in particular disorders characterized by an increase in plasma aldosterone concentration or a change in plasma aldosterone concentration relative to plasma renin concentration, or in combination with these changes related illnesses. Examples which may be mentioned are: spontaneous primary aldosteronism, hyperaldosteronism associated with adrenal hyperplasia, adrenal adenoma and/or adrenal carcinoma, hyperaldosteronism associated with liver cirrhosis, Hyperaldosteronism associated with heart failure, and (relative) hyperaldosteronism associated with essential hypertension.

Due to their mechanism of action, the compounds of the present invention are also useful in the prevention of sudden cardiac death in patients at increased risk of death from sudden cardiac death. These are in particular patients with one of the following conditions: primary and secondary hypertension, hypertensive heart disease with or without congestive heart failure, therapy-resistant hypertension, acute and chronic heart failure, coronary heart disease, Stable and unstable angina, myocardial ischemia, myocardial infarction, dilated cardiomyopathy, congenital primary cardiomyopathy (eg Bmgada syndrome), cardiomyopathy induced by Chagas disease, shock, arteriosclerosis, Atrial and ventricular disturbances, transient and ischemic attacks, stroke, inflammatory cardiovascular disorders, peripheral and cardiovascular disorders, peripheral blood flow disturbances, arterial occlusive disorders such as intermittent claudication, asymptomatic left ventricular dysfunction, myocarditis , cardiac hypertrophic changes, pulmonary hypertension, coronary and peripheral arterial spasm, thrombosis, thromboembolic disorders and vasculitis.

The compounds of the present invention may additionally be used for the prevention and/or treatment of edema formation, such as pulmonary edema, nephrogenic edema or heart failure-related floating lung, and restenosis such as in thrombolytic therapy, percutaneous transluminal angioplasty ( PTA) and coronary angioplasty (PTCA), after heart transplantation and bypass procedures.

The compounds of the present invention are further suitable for use as potassium depleted diuretics and for the treatment of electrolyte disturbances such as hypercalcemia, hypernatremia or hypokalemia.

The compounds of the present invention are also suitable for the treatment of renal disorders such as acute and chronic renal failure, hypertensive nephropathy, arteriosclerotic nephritis (chronic and interstitial), nephrosclerosis, chronic renal failure and bladder renal disorders, for the prevention of renal damage ( For example kidney injury caused by immunosuppressive agents of cyclosporin A associated with organ transplantation) and for renal cancer.

The compounds of the present invention may additionally be used for the prevention and/or treatment of diabetes and sequelae of diabetes, such as renal disease.

The compounds of the present invention may further be used for the prevention and/or treatment of microalbuminuria, eg caused by diabetes or hypertension, and proteinuria.

The compounds of the present invention are also suitable for the prevention and/or treatment of disorders associated with increased plasma glucocorticoid concentrations or with localized increases in glucocorticoid concentrations in tissues such as the heart. Examples that may be mentioned are: adrenal dysfunction leading to overproduction of glucocorticoids (Cushing's syndrome), tumors of the adrenal cortex leading to overproduction of glucocorticoids, and pituitary tumors, which spontaneously produce ACTH (Adrenocorticotropic Syndrome). hormones) and the resulting adrenal hyperplasia and consequent Cushing's disease.

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

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

The compounds of the present invention may further be useful in the treatment of central neurological disorders such as depression, anxiety states and chronic pain, in particular migraine, and for neurodegenerative disorders such as Alzheimer's disease and Parkinson's syndrome.

The compounds of the present invention are also suitable for the prevention and/or treatment of vascular injury, for example after procedures such as percutaneous coronary angioplasty (PTCA), stent grafting, coronary transillumination, reocclusion or restenosis after bypass procedures, and for endothelial dysfunction, for Raynaud's disease, for thromboangiitis obliterans (Buerger's syndrome) and for tinnitus syndrome.

The compounds of the present invention can be used alone or, if desired, in combination with other active ingredients. The present invention further relates to a medicament comprising at least one compound of the present invention and one or more further active ingredients, especially for the treatment and/or prophylaxis of the abovementioned disorders. Suitable active ingredients for combination are for example and preferably:

blood pressure lowering active ingredients, for example and preferably selected from calcium antagonists, angiotensin II receptor antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, Beta-adrenergic receptor blockers and rho-(Rho-) kinase inhibitors;

Diuretics, especially loop diuretics, thiazides and thiazide-like diuretics;

Agents with antithrombotic effect, for example and preferably selected from platelet aggregation inhibitors, anticoagulants or plasminogen substances;

Active ingredients that alter lipid metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors such as and 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 sorbents, bile acid reuptake inhibitors and lipoproteins ( a) antagonists;

organic nitrates/esters and NO donors such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, morphine or SIN-1, and inhaled NO;

Compounds with positive inotropes, such as cardiac glycosides (digoxin), beta-adrenergic and dopaminergic agonists such as isoproterenol, epinephrine, norepinephrine, dopamine and dopamine Butylamine;

Compounds that inhibit the breakdown of cyclic guanosine monophosphate (cGMP) and/or cyclic adenosine monophosphate (cAMP), such as phosphodiesterase (PDE) 1, 2, 3, 4 and/or 5 inhibitors, in particular PDE5 inhibitors such as sildenafil, vardenafil and tadalafil, and PDE3 inhibitors such as amrinone and milrinone;

natriuretic peptides such as atrial natriuretic peptides (ANP, anaritide), B-type natriuretic peptides or brain natriuretic peptides (BNP, nesiritide), C natriuretic peptide (CNP) and urodilagin;

a calcium sensitizer, such as and preferably levosimendan;

NO-independent but heme-dependent guanylate cyclase stimulators, in particular compounds such as those described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

NO- and heme-independent guanylate cyclase activators, such as described in particular in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO Compounds of 02/070510;

Inhibitors of human neutrophilic elastase (HNE), such as civelestat 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 ethimoxer, dichloroacetate, ranolazine or trimetazidine.

The compounds of the present invention may also be administered in combination with other active ingredients as described above. For example, in a preferred embodiment of the present invention, the compounds of the present invention are combined with diuretics such as, and preferably, paraben, bumetanide, torsemide, benzflurothiazide, crises, hydrochlorothiazide, mechlorothiazide , polithiazide, trichlorothiazide, chlorthalidone, indapamide, metolazone, quetiazone, acetazolamide, dichlorosulfanil, methazolamide, glycerin, isosorbide, mannitol , amiloride or triamterene combined administration.

General synthetic procedure

In this specification, if there is any difference between chemical name and chemical structure, the structure will prevail.

In general, the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the substituents are as defined in formula (I). The following reaction schemes and examples serve to further illustrate the content of the present invention.

Those skilled in the art will recognize that the chemical reactions described in this invention may be used to suitably prepare other compounds of this invention, and that other methods for preparing compounds of this invention are considered to be within the scope of this invention . For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.

In the examples described below, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, and were used without further purification; general reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory can be purchased.

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

The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. NMR spectral data were determined by Bruker Avance 400 NMR spectrometer or Bruker Avance III HD 600 NMR spectrometer with CDC1 ₃ , DMSO-d ₆ , CD ₃ OD or Acetone-d ₆ as solvent (reported in ppm ), with TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets are present, the following abbreviations are used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), q (quartet, four doublet), br (broadened, broad peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet), dq (doublet of quartets, double quartet), ddd (doublet of doublet of doublets, double double doublet), ddt (doublet of doublet of triplets, double double triplet), dddd (doublet of doublet of doublet of doublets, double double double doublet). Coupling constant, expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6320 Series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315B DAD detector applied to For analysis, the ESI source was applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data were determined by an Agilent 6120 series LC-MS spectrometer equipped with a G1311A quaternary pump and G1316A TCC (column temperature maintained at 30°C), a G1329A autosampler and a G1315D DAD detector for analysis , ESI source applied to LC-MS spectrometer.

Both of the above spectrometers were equipped with an Agilent Zorbax SB-C18 column with a size of 2.1 × 30 mm, 5 μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were read by recording 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 Gradient elution conditions of mobile phase for low-resolution mass spectrometry

time (min) A(CH₃CN, 0.1%HCOOH) B(H₂O, 0.1%HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

The following abbreviations are used throughout this disclosure:

DMSO-d ₆ deuterated dimethyl sulfoxide; g grams; mg mg; mol moles; mmol millimoles; mL milliliters; μL microliters

The following reaction schemes describe the steps for the preparation of the compounds disclosed herein. Wherein, unless otherwise specified, R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ^a , and n all have the meanings described in the present invention.

reaction scheme

Reaction scheme 1

Compound I-A can be prepared by the method described in Reaction Scheme 1. Amino compound A-i, substituted 4-cyanobenzaldehyde compound A-iii and substituted sodium cyanovinyl alcoholate compound A-ii react under the action of acid to obtain tricyclic compound I-A.

Reaction scheme 2

Compounds of formula I-B can be prepared by the method described in Reaction Scheme 2. Substituted 4-cyanobenzaldehyde compound A-iii reacts with ester B-i to obtain compound B-ii, and then reacts with amino compound A-i under the action of acid to obtain compound B-iii, and then undergoes catalytic hydrogenation reaction, ammoniation reaction in turn The amide compound I-B is obtained.

The following examples may further describe the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Example

Example 1 1-(4-cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carbonitrile

Step 1) 3-methylnaphthalene-2-amine

Add 3-amino-2-naphthoic acid (4.0g, 21mmol) and xylene (150mL) to a 500mL double-necked flask, under nitrogen protection, dropwise add dihydrobis(2-methoxyethoxy)aluminum at 0°C Sodium (45mL, 161.4mmol) was added, heated to 150°C for 6 hours, then cooled to room temperature and added dropwise again with sodium dihydrobis(2-methoxyethoxy)aluminate (14mL, 50.22mmol), again Heat to 150°C and stir for 16 hours. Cooled to 0°C, quenched with 20% potassium hydroxide aqueous solution (80 mL), suction filtered through diatomaceous earth, the filtrate was separated, and the organic phase was sequentially washed with 1 mol/L potassium hydroxide aqueous solution (100 mL) and saturated brine (100 mL). ), and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=15/1) to obtain a brown solid (2.06 g, 61%).

MS(ESI,pos.ion)m/z:158.2(M+1).

Step 2) Sodium 1-cyanoprop-3-en-2-olate

Sodium hydroxide (0.24g, 6.0mmol) and anhydrous methanol (10mL) were added to a 50mL double-necked flask, 5-methylisoxazole (0.49mL, 6.0mmol) was added dropwise at 30°C, and then stirred at room temperature overnight. The solvent was evaporated, the residue was washed with diethyl ether (80 mL), filtered with suction, and the filter cake was dried in vacuo to obtain a white solid (0.57 g, 90%).

Step 3) 1-(4-Cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carbonitrile

Add 4-cyano-2-methoxybenzaldehyde (0.050g, 0.31mmol) and isopropanol (4mL) to a 50mL double-necked flask, and then add sodium 1-cyanoprop-3-en-2-olate (0.033 g, 0.31 mmol), 3-methylnaphthalen-2-amine (0.049 g, 0.31 mmol) and acetic acid (0.027 mL, 0.47 mmol), then heated to reflux overnight. It was cooled to room temperature, diluted with ethyl acetate (40 mL), washed with water (40 mL) and saturated brine (40 mL) successively, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain a yellow solid (0.062 g, 55%)

MS(ESI, pos.ion) m/z: 364.2(M-1);

¹ H NMR(400MHz, CDCl ₃ )δ(ppm) 7.73-7.66(m,1H),7.61(s,1H),7.58-7.51(m,1H),7.36-7.30(m,2H),7.19(s) ,1H),7.04(d,J＝7.9Hz,1H),6.86(d,J＝7.9Hz,1H),6.27(s,1H),6.10(s,1H),4.10(s,3H),2.51 (s,3H),2.27(s,3H).

Example 2 1-(4-cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carboxamide

Step 1) Benzyl 2-(4-cyano-2-methoxybenzylidene)-3-oxobutanoate

In a 250mL single-neck flask, add 4-cyano-2-methoxybenzaldehyde (8.50g, 52.7mmol), benzyl acetylacetonate (10.1g, 52.5mmol) and dichloromethane (100mL), then add piperidine ( 0.97 mL, 11 mmol) and acetic acid (0.60 mL, 10 mmol), then separated and refluxed overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=20/1) to obtain a pale yellow solid (10.31 g, 58.3%).

Step 2) Benzyl 1-(4-cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carboxylate

2-(4-cyano-2-methoxybenzylidene)-3-oxobutyric acid benzyl ester (0.85g, 2.5mmol), 3-methylnaphthalene-2- Amine (0.40 g, 2.5 mmol) and glacial acetic acid (5 mL) were raised to 100°C for 3 hours. It was cooled to room temperature, the solvent was evaporated, ethyl acetate (60 mL) was added, washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) successively, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=10/1) to obtain a pale yellow solid (0.19 g, 16%).

MS(ESI,pos.ion)m/z:475.2(M+1).

Step 3) 1-(4-Cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carboxylic acid

Add 1-(4-cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carboxylate benzyl ester to a 50mL single-neck flask (0.12 g, 0.25 mmol), 10% palladium on carbon (0.20 g) and methanol (15 mL), and stirred at room temperature for 1 hour under a hydrogen atmosphere. Suction filtration, and the filtrate was spin-dried to obtain a pale yellow solid (0.073 g, 75%).

MS(ESI,pos.ion)m/z:385.2(M+1).

Step 4) 1-(4-Cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carboxamide

Add 1-(4-cyano-2-methoxyphenyl)-3,5-dimethyl-1,4-dihydrobenzo[f]quinoline-2-carboxylic acid (0.071 g, 0.18 mmol), ammonium chloride (0.020 g, 0.37 mmol) and N,N-dimethylformamide (6 mL), cooled to 0 °C, added 2-(7-azobenzotriazole)- N,N,N',N'-tetramethylurea hexafluorophosphate (0.11 g, 0.29 mmol) and N,N-diisopropylethylamine (0.092 mL, 0.56 mmol), warmed to room temperature and stirred overnight. Water was added to quench, extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with water (50 mL) and saturated brine (50 mL) successively, and dried over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v)=60/1) to obtain a pale yellow solid (0.028 g, 40%).

MS(ESI,pos.ion)m/z:384.2(M+1).

¹ H NMR (400MHz, DMSO-d ₆ )δ(ppm) 7.77(d, J=8.5Hz, 1H), 7.62(d, J=8.0Hz, 1H), 7.53(s, 1H), 7.49(s, 1H), 7.40(s, 1H), 7.35–7.24(m, 2H), 7.14(dd, J=14.4, 7.5Hz, 2H), 7.05(d, J=7.8Hz, 1H), 6.60(d, J =4.1Hz,1H),5.85(d,J=4.0Hz,1H),3.90(s,3H),2.39(s,3H),2.28(s,3H).

Example 3 9-(4-cyano-2-methoxyphenyl)-5,7-dimethyl-6,9-dihydrothieno[3,2-f]quinoline-8-carbonitrile

Step 1) 2-Bromo-4-methyl-5-nitrobenzaldehyde

Concentrated sulfuric acid (15mL) was added to a 50mL double-necked flask, 2-bromo-4-methylbenzaldehyde (3.00g, 15.1mmol) was added dropwise at 5°C, and then concentrated nitric acid (1.9mL, 66mass%) was added dropwise, Continue stirring for 30 minutes. Pour into ice water, extract with ethyl acetate (90 mL×2), combine the organic phases, wash with water (100 mL×2) and saturated brine (100 mL) successively, and dry over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=50/1) to obtain a pale yellow solid (2.24 g, 60.9%).

Step 2) Ethyl 6-methyl-5-nitrobenzo[b]thiophene-2-carboxylate

Ethanol (40 mL) was added to a 100 mL two-necked flask, sodium metal (0.25 g, 11 mmol) was added under nitrogen protection, and after stirring for 20 minutes, ethyl mercaptoacetate (1.21 mL, 11.0 mmol) was added at 5°C, and stirring was continued for 30 minutes 2-Bromo-4-methyl-5-nitrobenzaldehyde (2.70 g, 11.1 mmol) was then added and heated to reflux for 3 hours. After cooling to room temperature, the solvent was evaporated, dichloromethane (100 mL) was added to the residue, followed by washing with water (100 mL) and saturated brine (100 mL) successively, and drying over anhydrous sodium sulfate. After suction filtration, the solvent was evaporated and dried in vacuo to obtain a pale yellow solid (2.93 g, 99.8%).

MS(ESI,pos.ion)m/z:265.9(M+1).

Step 3) 6-Methyl-5-nitrobenzo[b]thiophene-2-carboxylic acid

In a 100mL single-neck flask, add ethyl 6-methyl-5-nitrobenzo[b]thiophene-2-carboxylate (2.93g, 11.0mmol), ethanol (40mL) and water (24mL), and then add hydroxide Sodium (1.77 g, 44.3 mmol) and the mixture was heated to reflux for 3 hours. The organic solvent was evaporated, diluted with water, adjusted to pH=3 with 2mol/L hydrochloric acid, suction filtered, washed with water, and the filter cake was vacuum dried to obtain a yellow solid (2.42 g, 92.4%).

MS(ESI,pos.ion)m/z:236.0(M-1).

Step 4) 6-Methyl-5-nitrobenzo[b]thiophene

In a 50mL single-neck flask, add 6-methyl-5-nitrobenzo[b]thiophene-2-carboxylic acid (2.30g, 9.70mmol), copper powder (1.23g, 19.4mmol) and quinoline (20mL), Heated to 190°C and reacted for 2 hours. Cool to room temperature, add methyl tert-butyl ether to dilute (100 mL), wash with 5 mol/L hydrochloric acid (80 mL×2), water (90 mL) and saturated brine (90 mL) successively, and dry the organic phase with anhydrous sodium sulfate. After suction filtration, the solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=100/1) to obtain a white solid (1.72 g, 91.8%).

Step 5) 6-methylbenzo[b]thiophene-5-amino

6-methyl-5-nitrobenzo[b]thiophene (0.20 g, 1.0 mmol) and methanol (10 mL) were added to a 50 mL single-necked flask, and then palladium carbon (0.050 g, 10 mass%) was added, and under a hydrogen atmosphere Stir at room temperature for 2 hours. After suction filtration, the solvent was evaporated to obtain a pale yellow solid (0.16 g, 95%).

MS(ESI,pos.ion)m/z:164.1(M+1).

Step 6) 9-(4-Cyano-2-methoxyphenyl)-5,7-dimethyl-6,9-dihydrothieno[3,2-f]quinoline-8-carbonitrile

4-cyano-2-methoxybenzaldehyde (0.11 g, 0.68 mmol), 6-methylbenzo[b]thiophene-5-amino (0.11 g, 0.67 mmol), 1-methylbenzo[b]thiophene-5-amino (0.11 g, 0.67 mmol), 1- Sodium cyanoprop-3-en-2-olate (0.072 g, 0.69 mmol) and isopropanol (15 mL), followed by addition of acetic acid (0.059 mL, 1.0 mmol), then heated to reflux for 4 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to obtain a pale yellow solid (0.046 g, 18%).

MS(ESI,pos.ion)m/z:372.1(M+1).

¹ H NMR (400MHz, CDCl ₃ )δ(ppm) 7.58(s, 1H), 7.30(s, 1H), 7.17(s, 1H), 7.10(d, J=7.7Hz, 1H), 6.98(t, J=5.8Hz, 2H), 6.10(s, 1H), 5.90(s, 1H), 4.04(s, 3H), 2.44(s, 3H), 2.27(s, 3H).

Example 4 In vitro activity test

Experimental principle:

Taking advantage of the chemiluminescence reaction of luciferase binding to the substrate, a plasmid containing the ligand-binding domain (LBD) of the mineralocorticoid receptor and Gal4 DNA-binding domain (DBD) fused to Gal4 UAS (upstream activation sequence) Human embryonic kidney cells (HEK293) were transfected with a controlled firefly luciferase reporter plasmid. The effects of firefly luciferase activity before and after stimulation or different stimulations on mineralocorticoid receptor activity were judged. At the same time, in order to reduce the influence of internal change factors on the accuracy of the experiment, the plasmid with the Renilla luciferase gene was used as a control plasmid to transfect cells to provide an internal control for transcriptional activity, so that the test results were not disturbed by changes in experimental conditions. .

experimental method:

1) Collect HEK293 cells after trypsinization and adjust the cell density to 500,000 cells/ml;

2) Add FuGENE HD transfection reagent to the cell suspension;

3) Inoculate the above-mentioned cell suspension into a 96-well cell culture plate at 100 μL/well, and culture at 37° C. and 5% CO ₂ for 24 hours;

4) Add a series of concentrations of the test compound solution and the agonist aldosterone with an EC ₈₀ concentration into each well, and incubate for 18 hours;

5) The firefly and Renilla luciferase signals were detected by the Promega dual luciferase reporter gene assay system.

Result processing:

1) After obtaining the firefly luciferase signal (F) and the Renilla luciferase signal (R), use the Renilla luciferase signal for correction, that is, use the F/R value for subsequent inhibition rate calculation;

2) % inhibition rate=(Max-X)/(Max-Min)×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 well of the compound to be tested at different concentrations F/R value;

3) _IC50 calculation was performed by GraphPrism 5.0 graphing software.

Experimental results:

Table 2

Example number MR IC₅₀(nM) Example 1 19.6

in conclusion:

From the experimental results in Table 2, it can be seen that the compound of the present invention (for example, Example 1 of the present invention) has a good mineralocorticoid receptor (MR) antagonistic activity, which can be used as an effective mineralocorticoid receptor antagonist .

In the description of this specification, description with reference to the terms "one embodiment," "some embodiments," "example," "specific example," or "some examples", etc., mean specific features described in connection with the embodiment or example , structure, material or feature is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, those skilled in the art may combine and combine the different embodiments or examples described in this specification, as well as the features of the different embodiments or examples, without conflicting each other.

Although the embodiments of the present invention have been shown and described above, it should be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. Embodiments are subject to variations, modifications, substitutions and variations.

Claims (8)

1. a compound, it is the pharmaceutically acceptable salt of the compound shown in formula (I) or the compound shown in formula (I),

in, Ring A is

each of R ¹ , R ³ and R ⁴ is independently H or D; R ² is C _1-6 alkoxy or C _1-6 haloalkoxy; R ⁵ is cyano or -C(=O)NH ₂ ; R ⁶ is C _1-6 alkyl; each R ⁷ and R ⁸ is independently H, D or C _1-6 alkyl; each ^Ra is independently H or D; n is 0, 1, 2, 3 or 4. 2. The compound of claim 1, wherein, R ² is methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy, difluoromethoxy or monofluoromethoxy. 3. The compound of claim ¹ , wherein R6 is methyl, ethyl, propyl or butyl. 4. The compound of claim 1, wherein each ^R7 and ^R8 is independently H, D, methyl, ethyl, propyl, or butyl. 5. The compound of claim 1 having the structure of one of the following:

6. A pharmaceutical composition comprising the compound of any one of claims 1-5; optionally, it further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof . 7. Use of the compound according to any one of claims 1-5 or the pharmaceutical composition of claim 6 in the preparation of a medicament, wherein the medicament is used for treating, preventing or reducing hyperaldosterone in a patient disease, hypertension, chronic heart failure, sequelae of myocardial infarction, liver cirrhosis, renal failure and stroke. 8. Use of the compound of any one of claims 1-5 or the pharmaceutical composition of claim 6 in the manufacture of a medicament, wherein the medicament is used as a mineralocorticoid receptor antagonist.