KR102322959B1 - New 3,4-dihydro-2h-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds - Google Patents

Abstract

상기 식에서,
R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, A, m, n 및 p는 본원에 기재된 바와 같다. The present invention provides novel compounds of formula (I), compositions comprising said compounds and methods of using said compounds:
[Formula I]

In the above formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , A, m, n and p is as described herein.

Description

Novel 3,4-dihydro-2H-isoquinolin-1-one and 2,3-dihydro-isoindol-1-one compounds {NEW 3,4-DIHYDRO-2H-ISOQUINOLINE-1-ONE AND 2; 3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS}

The present invention relates to organic compounds useful for the treatment or prophylaxis of mammals, in particular to aldosterone synthase inhibitors for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

The present invention provides a novel compound of formula (I), or a pharmaceutically acceptable salt thereof:

[Formula I]

In the above formula,

R ¹ , R ² , R ³ and R ⁴ are independently selected from H, alkyl and cycloalkyl;

R ⁵ , R ⁷ and R ⁹ are independently selected from H or alkyl,

R ⁸ and R ¹¹ together form -CH ₂ -CH ₂ -,

R ¹⁰ is H or R ¹⁰ and R ¹¹ together form —(CH ₂ ) _w —;

R ⁶ and R ⁹ together _{form —CH 2} —, R ⁸ is H, and R ¹⁰ and R ¹¹ together _{form —CH 2} —;

A is -C(O)- or -S(O) ₂ -;

B is -C- or -N-;

R ¹² is cycloalkyl or substituted heteroaryl, wherein the substituted heteroaryl is substituted with 1 to 3 substituents independently selected from H, alkyl, cycloalkyl, hydroxy, alkoxy, cyano and halogen;

R ¹³ is halogen, cyano, alkoxy or haloalkoxy;

R ¹⁴ is H, alkyl or cycloalkyl;

R ¹⁵ is H, alkyl, cycloalkyl or halogen;

m, n and p are independently selected from 0 and 1;

w is 1, 2 or 3.

Herein, we describe inhibitors of aldosterone synthase that have the potential to protect against organ/tissue damage caused by absolute or relative excess of aldosterone. Hypertension affects about 20% of the adult population in developed countries. In individuals over 60 years of age, this percentage rises to more than 60%. Hypertensive subjects present an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease and renal impairment. The renin-angiotensin-aldosterone system is a pathway involved in hypertension, volume and salt balance, and more recently, directly contributes to the termination of organ damage in advanced stages of heart failure or kidney disease. ACE inhibitors and angiotensin receptor blockers (ARBs) are successfully used to improve the duration and quality of life of patients. These drugs do not result in maximum protection. In a relatively large number of patients, ACE and ARB cause a so-called aldosterone breakthrough (first an initial decrease, followed by a return of aldosterone levels to pathological levels). It has been demonstrated that the deleterious consequences of inappropriately elevated aldosterone levels (relative to salt intake/levels) can be minimized by aldosterone blockade with mineralocorticoid receptor antagonists. Direct inhibition of aldosterone synthesis is expected to provide even better protection as it will also reduce the non-genomic effects of aldosterone.

The effect of aldosterone on Na/K transport results in increased reabsorption of sodium and water and excretion of potassium in the kidneys. Overall, this results in increased blood volume and thus increased blood pressure. In addition to its role in the regulation of renal sodium reabsorption, aldosterone may have deleterious effects on the kidneys, heart and vascular system, particularly in terms of "high sodium". Under these conditions, aldosterone has been shown to cause increased oxidative stress that can ultimately contribute to organ damage. Infusion of aldosterone into renal dysfunctional rats (either by high-salt treatment or unilateral nephrectomy) has been shown to have adverse effects on the kidneys, including glomerular expansion, podocyte damage, interstitial inflammation, mesenteric cell proliferation, and fibrosis reflected by proteinuria. Causes multiple damage. More specifically, aldosterone has been shown to increase expression of the adhesion molecule ICAM-1 in the kidney. ICAM-1 is closely related to glomerular inflammation. Similarly, aldosterone has been shown to increase the expression of inflammatory cytokines such as the interleukins IL-1b and IL-6, MCP-1 and osteopontin. On the cellular level, it was demonstrated that in vascular fibroblasts, aldosterone increased the expression of type I collagen mRNA (a mediator of fibrosis). In addition, aldosterone stimulates type IV collagen accumulation in rat mesenteric cells and induces plasminogen activator inhibitor-1 (PAI-1) expression in smooth muscle cells. Briefly, aldosterone has been identified as a key hormone associated with kidney damage. Aldosterone also plays an important role in mediating cardiovascular risk.

Sufficient preclinical evidence exists that MR-antagonists (spironolactone and eplerenone) improve blood pressure, cardiac and renal function in various pre-clinical models.

More recent preclinical studies highlight the important contribution of CYP11B2 to cardiovascular and renal morbidity and mortality. The CYP11B2 inhibitor FAD286 and the MR antagonist spironolactone were evaluated in a rat model of chronic kidney disease (high angiotensin II exposure; high salt and unilateral nephrectomy). Treatment with angiotensin II and high salts resulted in albuminuria, hyperazotemia, renal vascular hypertrophy, glomerular damage, increased PAI-1 and osteopontin mRNA expression, and tubulointerstitial fibrosis. Both drugs prevented their renal effects and attenuated cardiac and aortic medial hypertrophy. After 4 weeks of treatment with FAD286, plasma aldosterone decreased, whereas spironolactone increased aldosterone at 4 and 8 weeks of treatment. Similarly, only spironolactone, but not FAD286, enhanced angiotensin II and salt-stimulated PAI-1 mRNA expression in the aorta and heart. In another study, the CYP11B2 inhibitor FAD286 improved blood pressure, cardiovascular function and structure in rats with experimental heart failure. In the same study, FAD286 was shown to improve kidney function and morphology.

We conclude that administration of LCI699, an orally active CYP11B2 inhibitor, to patients with primary aldosteronism effectively inhibits CYP11B2 in patients with primary aldosteronism, resulting in significantly lower circulating aldosterone levels, correcting hypokalemia, and slightly reducing blood pressure. caused The effect on the glucocorticoid axis was consistent with poor selectivity of the compound and potential inhibition of cortisol synthesis. Together, these data support the notion that CYP11B2 inhibitors can lower inappropriately high aldosterone levels. Achieving good selectivity for CYP11B1 is important to eliminate unwanted side effects on the HPA axis and will distinguish different CYP11B2 inhibitors.

The compounds of formula (I) of the present invention are potent inhibitors of CYPB11B2 and provide improved selectivity and improved metabolic stability for CYP11B2 compared to CYP11B1.

It is an object of the present invention to provide compounds of formula (I) and salts and esters thereof, and their use as therapeutically active substances, methods for the preparation of said compounds, intermediates, pharmaceutical compositions, containing said compounds, pharmaceutically acceptable salts or esters thereof medicaments, the use of said compounds, salts or esters for the treatment or prophylaxis of diseases, in particular for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism or Cushing's syndrome, and chronic kidney disease, congestive heart failure, Use of said compound, salt or ester for the manufacture of a medicament for the treatment or prophylaxis of hypertension, primary aldosteronism or Cushing's syndrome.

The term “alkyl” denotes a monovalent linear or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms. In a specific embodiment, alkyl has 1 to 7 carbon atoms, and in a more specific embodiment 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and sec-butyl. Specific alkyl groups include methyl, ethyl, propyl and isopropyl. A more specific alkyl group is methyl.

The term “cycloalkyl” denotes a monovalent saturated monocyclic hydrocarbon group consisting of 3 to 10 ring carbon atoms. In a specific embodiment, cycloalkyl represents a monovalent saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. Examples of cycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl or cycloheptyl. A specific cycloalkyl group is cyclopropyl.

The terms “halogen” and “halo” are used interchangeably herein and refer to fluoro, chloro, bromo or iodo. Specific halogens are chloro and fluoro. A specific halogen is chloro.

The term "heteroaryl" refers to a monovalent or bicyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the monovalent aromatic heterocycle consisting of 5 to 12 ring atoms, the remaining ring atoms being carbon. represents the system. Examples of heteroaryl groups are pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyrazolyl Dazinyl, pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolyl , benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxaline includes work A specific heteroaryl group is pyridinyl. Also specific heteroaryl groups are imidazolyl, isoxazolyl, oxazolyl, pyrazolyl and pyrimidinyl. More specific heteroaryl groups are pyridinyl, imidazolyl, isoxazolyl and pyrazolyl.

The term “hydroxy” refers to the group —OH.

The term “pharmaceutically acceptable salt” refers to a salt that retains the biological potency and properties of the free base or free acid and which is biologically or otherwise desirable. Such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, especially hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid. , citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, and the like. These salts can also be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines, substituted amines such as naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, di and salts of ethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resin and the like. Specific pharmaceutically acceptable salts of compounds of formula (I) include hydrochloride salts, methanesulfonic acid salts and citric acid salts.

"Pharmaceutically acceptable ester" means that a compound of formula (I) is derivatized at a functional group to provide a derivative that can be converted back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester. Also within the scope of the present invention are any physiologically acceptable equivalents of the compounds of formula (I), analogous to the metabolically labile esters, capable of generating the parent compound of formula (I) in vivo.

The term "protecting group (PG)" denotes a group that selectively blocks a reactive site of a polyfunctional compound, such that a chemical reaction can be carried out selectively at another unprotected reactive site in the sense traditionally associated in synthetic chemistry. The protecting group may be removed at any suitable point. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Specific protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). More specific protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc).

The abbreviation “uM” means micromolar and is equivalent to the symbol “μM”.

In addition, the compounds of the present invention may contain unusual proportions of isotopes of atoms at one or more of the atoms constituting such compounds. For example, the present invention provides an isotopic-label of the present invention that is identical to that recited herein except that one or more atoms are replaced by an atom having a different atomic mass or mass number than the predominant atomic mass or mass number for the atom generally found in nature. including mutants. All isotopes of any specific atom or element specified are contemplated as being within the scope of the compounds of this invention and their uses. Exemplary isotopes that may be incorporated into the compounds of the present invention are isotopes of hydrogen, isotopes of carbon, isotopes of nitrogen, isotopes of oxygen, isotopes of phosphorus, isotopes of sulfur, isotopes of fluorine, isotopes of chlorine Elements and isotopes of iodine, such as ² H (“D”), ³ H (“T”), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³² P , ³³ P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I and ¹²⁵ I. Certain isotopically labeled compounds of the present invention (eg those labeled with ³ H or ¹⁴ C) are useful for compound and/or substrate tissue distribution analysis. Tritiated ( ³ H) isotopes and carbon-14 ( ¹⁴ C) isotopes are useful for their ease of preparation and detection. In addition, substitutions with heavier isotopes, such as deuterium (i.e., ² H), may offer specific therapeutic advantages (e.g., reduced in vivo half-life or reduced dosage requirements) from greater metabolic stability. and for this reason may be desirable in some circumstances. Positron emitting isotopes such as ¹⁵ O, ¹³ N, ¹¹ C and ¹⁸ F are useful in positron emission tomography (PET) studies examining substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent according to procedures analogous to those disclosed in the Schemes and/or Examples below. In particular, compounds of formula (I) in which at least one ^{H atom has been replaced by 2 H atoms are also embodiments of the present invention.}

The compounds of formula (I) may contain multiple asymmetric centers and are optically pure enantiomers, mixtures of enantiomers, eg racemates, optically pure diastereomers, mixtures of diastereomers, diastereomers It may exist in the form of a racemate or a mixture of diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom may be in either the “R” or “S” configuration.

Also aspects of the present invention are the compounds of formula (I) described herein and pharmaceutically acceptable salts or esters thereof, particularly the compounds of formula (I) and pharmaceutically acceptable salts thereof as described herein, more particularly the compounds of formula (I) described herein It is a compound of I.

The present invention also relates to a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof:

[Formula I]

In the above formula,

R ¹ , R ² , R ³ and R ⁴ are independently selected from H, alkyl and cycloalkyl;

R ⁵ , R ⁷ and R ⁹ are independently selected from H or alkyl,

R ⁸ and R ¹¹ together form -CH ₂ -CH ₂ -,

R ¹⁰ is H or R ¹⁰ and R ¹¹ together form —(CH ₂ ) _w —;

R ⁶ and R ⁹ together _{form —CH 2} —, R ⁸ is H, and R ¹⁰ and R ¹¹ together _{form —CH 2} —;

A is -C(O)- or -S(O) ₂ -;

R ¹² is cycloalkyl or substituted heteroaryl, wherein the substituted heteroaryl is substituted with 1 to 3 substituents independently selected from H, alkyl and halogen;

R ¹³ is halogen;

R ¹⁴ is H, alkyl or cycloalkyl;

R ¹⁵ is H, alkyl, cycloalkyl or halogen;

m, n and p are independently selected from 0 and 1;

w is 1, 2 or 3.

Also an aspect of the invention are compounds of formula (I _{) as described herein, wherein A is -S(O) 2 -.}

Another aspect of the invention is a compound of formula (I) as described herein, wherein A is -C(O)-.

Also a specific embodiment of the invention are the compounds of formula (I) as described herein, wherein B is -C-.

Another embodiment of the invention ^{is a compound of formula (I) as described herein, wherein R 12} is cycloalkyl or substituted pyridinyl, wherein the substituted pyridinyl is substituted with 1 to 3 substituents independently selected from H, alkyl and halogen am.

A specific embodiment of the invention ^{is a compound of formula (I) as described herein, wherein R 12} is cycloalkyl or substituted pyridinyl, wherein the substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen.

A further aspect of the invention are compounds of formula (I) as described herein, wherein ^{R 12 is cycloalkyl.}

Another further aspect of the invention ^{is a compound of formula (I) as described herein, wherein R 12} is substituted heteroaryl, wherein said substituted heteroaryl is substituted with 1 to 3 substituents independently selected from alkyl and halogen.

Another specific embodiment of the present invention is that R ¹² is substituted pyridinyl, substituted imidazolyl or substituted pyrazolyl, wherein the substituted pyridinyl, substituted imidazolyl and substituted pyrazolyl are one alkyl or is a compound of formula (I) as described herein, substituted with halogen.

Another specific embodiment of the present invention ^{is a compound of formula (I) as described herein, wherein R 12} is substituted pyridinyl, wherein the substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen.

Another aspect of the invention is a compound of formula (I) as described herein, wherein ^{R 1} and R ^{2 are independently selected from H and alkyl.}

A specific embodiment of the present invention is a compound of formula (I) as described herein, wherein ^{R 1} and R ^{2 are alkyl.}

A further specific embodiment of the invention are compounds of formula (I) as described herein, wherein ^{R 1} and R ^{2 are methyl.}

Also a specific embodiment of the invention are the compounds of formula (I) as described herein, wherein m, n and p are 0.

A further specific embodiment of the invention are the compounds of formula (I) as described herein, wherein w is 1 or 2.

A specific embodiment of the present invention is a compound of formula (I) as described herein, wherein ^{R 3} and R ^{4 are H.}

Another aspect of the invention is a compound of formula (I) as described herein, wherein ^{R 5} , R ⁷ and R ^{9 are H.}

Also a specific embodiment of the present invention are compounds of formula (I) as described herein, wherein ^{R 9} is H and R ¹⁰ and R ¹¹ together form —(CH ₂ ) _{w —.}

A specific embodiment of the present invention is a compound of formula (I) as described herein, wherein ^{R 14 is H or alkyl.}

A further specific embodiment of the present invention are compounds of formula (I) as described herein, wherein ^{R 14 is H.}

Also an aspect of the present invention are compounds of formula (I) as described herein, wherein ^{R 13 is cyano or halogen.}

A further specific embodiment of the invention are compounds of formula (I) as described herein, wherein ^{R 13 is chloro.}

A more specific embodiment of the present invention is a compound of formula (I) as described herein, wherein ^{R 15 is H.}

Specific examples of compounds of formula (I) or pharmaceutically acceptable salts thereof described herein are

5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;

5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;

5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindole- 1-one;

5-Chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindole- 1-one;

5-chloro-2-[5-[(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;

5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindole-1- On;

5-Chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindole-1- On;

5-Chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindole-1 -On;

5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On;

5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On;

5-Chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindole-1 -On;

5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindole-1 -On;

5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;

6-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;

6-Chloro-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;

6-Chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;

6-Chloro-2-[5-[[1-(5-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On; and

5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridin-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3 -yl] isoindole-1-one

is selected from

In addition, specific examples of the compound of formula (I) or a pharmaceutically acceptable salt thereof are

5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoin dolin-1-one;

6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydro isoquinolin-1-one;

6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinoline- 1-one;

6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinoline -1-one;

5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl -isoindolin-1-one;

5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindoline -1-one;

(3R or 3S)-5-chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]iso indolin-1-one;

(3S or 3R)-5-chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]iso indolin-1-one;

(3R or 3S)-5-chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl- isoindolin-1-one;

(3S or 3R)-5-chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl- isoindolin-1-one;

(3R or 3S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one ;

(3S or 3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one ;

2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline -5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoin Doline-5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-iso indoline-5-carbonitrile;

2-[5-[(1-cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;

2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline -5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline -5-carbonitrile;

2-[5-[[1-(3-Chloropyridin-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline -5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-iso indoline-5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoin Doline-5-carbonitrile;

3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-iso indoline-5-carbonitrile; and

3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-iso Indoline-5-carbonitrile

is selected from

Further specific examples of compounds of formula (I) or pharmaceutically acceptable salts thereof described herein are

5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;

5-Chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindole- 1-one;

5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On; and

5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On

is selected from

In addition, further specific examples of the compounds of formula (I) or pharmaceutically acceptable salts thereof described herein are

5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoin dolin-1-one;

6-Chloro-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;

6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinoline- 1-one;

5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindoline -1-one;

(3R or 3S)-5-chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]iso indolin-1-one;

2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; and

3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-iso Indoline-5-carbonitrile

is selected from

Processes for the preparation of compounds of formula (I) described herein are an object of the present invention.

The preparation of the compounds of formula (I) of the present invention may be carried out by sequential or convergent synthetic routes. The synthesis of the present invention is shown in the following scheme. The techniques necessary to carry out the reaction and purification of the resulting product are known to those skilled in the art. When mixtures of enantiomers or diastereomers are produced during the reaction, such enantiomers or diastereomers can be separated by methods described herein or known to those skilled in the art, such as chiral chromatography or crystallization. Substituents and designations used in the following description of these methods have the meanings provided herein.

The following abbreviations are used herein:

AcOH = acetic acid, BOC = t-butyloxycarbonyl, BuLi = butyllithium, CDI = 1,1-carbonyldiimidazole, DCM = dichloromethane, DBU = 2,3,4,6,7,8, 9,10-octahydro-pyrimido[1,2-a]azepine, DCE = 1,2-dichloroethane, DIBALH = di-i-butylaluminum hydride, DCC = N,N'-dicyclohexyl Carbodiimide, DMA = N,N-dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMF = N,N-dimethylformamide, EDCI = N-(3-dimethylaminopropyl)-N' -Ethylcarbodiimide hydrochloride, EtOAc = ethyl acetate, EtOH = ethanol, Et ₂ O = diethylether, Et ₃ N = triethylamine, eq = equivalent, HATU = O-(7-azabenzotriazole- 1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, HPLC = high performance liquid chromatography, HOBT = 1-hydroxybenzo-triazole, Huenig base = iPr ₂ NEt = N-ethyl diisopropylamine, IPC = under process control, LAH = lithium aluminum hydride, LDA = lithium diisopropylamide, LiBH ₄ = lithium borohydride, MeOH = methanol, NaBH ₃ CN = sodium cyanoboro hydride, NaBH ₄ = sodium borohydride, NaI = sodium iodide, Red-Al = sodium bis(2-methoxyethoxy) aluminum hydride, RT = room temperature, TBDMSCl = t-butyldimethylsilyl chloride, TFA = trifluoroacetic acid, THF = tetrahydrofuran, quant = quantitative.

As described in Scheme 1a and Scheme 1b below, halogen or triflate, preferably iodo substituted pyridine compound (2 or 8) is dissolved in a solvent such as 1,4-dioxane copper(I) iodide, potassium carbonate or cesium carbonate , a chelated 1,2-diamino compound such as N,N'-dimethylethylenediamine or trans-1,2-diamino-cyclohexane, or a chelated beta keto ester compound such as 2-isobutyryl- Reaction with aryl lactam (1) with the aid of preferred microwave heating at high temperature in the presence of cyclohexanone to form lactam-substituted heterocyclic compounds (3 and 5) (step a). The amino compound (4 or 6) (a known compound or a compound that can be readily prepared by a method known in the art) was subjected to conditions similar to those used in step a (step b) (a primary amino compound (4 or 6) or under 'Buchwald' conditions, for example in the presence of a base such as t-BuONa at elevated temperature in a solvent such as dioxane, catalyst such as Pd(OAc) ₂ , and chelation Reaction with the substituted pyridine compound (3) by using conditions using a ligand such as xanphos (preferred conditions for the secondary amino compound (4 or 6)) gives compound (5 or 7). Compound (5) having ^{R 101} as a protecting group, for example a Boc group ^{, can then be converted to compound (7) by removing the protecting group R 101} and reacting with a suitable activated carboxy or sulfonyl compound (steps c, d) ; Schemes 1a and 1b).

[Scheme 1a]

In Scheme 1a,

X is halogen or OSO ₂ CF ₃ ;

R ¹⁰¹ is a suitable protecting group.

[Scheme 1b]

In Scheme 1b,

X is halogen or OSO ₂ CF ₃ ;

R ¹⁰¹ is a suitable protecting group or AR ¹² .

Carbamate 101 (Scheme 2a) is reacted with polyphosphoric acid at high temperature (eg, 100 to 180° C.) to form 3,4-dihydro-2H-isoquinolin-1-one derivative 102 (step a). 1-(3,4-dihydro-1H-isoquinolin-2-yl)-2 by cyclization by treatment of trifluoroacetamide (103) with paraformaldehyde in a mixture of concentrated sulfuric acid and acetic acid, preferably near room temperature. ,2,2-trifluoro-ethanone compound (104) can be obtained. Removal of the trifluoroacetyl group by, for example, treatment with potassium hydroxide in a solvent such as ethanol at a temperature near room temperature provides the tetrahydro-isoquinoline compound (105) (step c). Tetrahydro-isoquinoline compound (105) is oxidized, preferably in water, with, for example, iodoso benzene and potassium bromide to give 3,4-dihydro-2H-isoquinolin-1-one compound (102). step d). ^{Isoindole-1,3-dione compound 106 (Scheme 2b) is reacted with Grignard reagent R 1} MgX in a solvent such as THF, preferably near 0° C., to give adduct 107 (Scheme 2b). step e). Subsequent treatment with triethylsilane and boron trifluoride etherate in a solvent such as dichloromethane, preferably at a temperature ranging from -25°C to RT, provides the isoindoleone compound (108) (step f). Introduction of a methoxybenzyl protecting group to the isoindoleone compound (109) (e.g. treatment with sodium bis(trimethylsilyl) amide and 1-bromomethyl-4-methoxy-benzene in THF at 0°C to RT ) provides protected compound 110 (step g); Similarly, a methoxybenzyl protecting group can be introduced into compound (108). After treatment of compound (108) or compound (110) carrying an additional methoxybenzyl protecting group with a base such as sodium hydride in a solvent such as THF, preferably at RT to the reflux temperature of the solvent, an alkyl halide, mesylate or tosylate to give compound (111) having structurally different or structurally identical R ¹ and R ² groups (step h). Alternatively, after treatment of compound (108) or compound (110) carrying an additional methoxybenzyl protecting group with a base such as NaH, LDA or LiHMDS in a solvent such as DMF, tetrahydrofuran or 1,2-dimethoxyethane Treatment with one or sequentially two different alkyl halides, mesylates or tosylates, preferably at -78°C to the reflux temperature of the solvent, provides compound (111) having ^{structurally identical or structurally identical R 1} and R ^{2 groups} (step h). For example, treatment with trifluoroacetic acid at high temperature removes the protecting group to give isoindoleone compound 112 (step i). Alternatively (Scheme 2c), ^{compound 114 in which R 1} and R ² are alkyl groups is prepared from cyano compound 113 and a suitable Grignard reagent, preferably in the presence of titanium tetra-isopropoxide in a solvent such as THF. It can be obtained by sequentially adding two different reagents or by adding a single Grignard reagent in excess (to obtain a compound with the ^{same R 1} and R ^{2 ), preferably at a temperature ranging from 0° C. to RT (step k)} ). After R ¹ =H and R ² is an alkyl group, compound 114 is obtained from cyano compound 113 and a suitable Grignard reagent in a solvent such as THF, preferably at a temperature ranging from 0° C. to RT (step k) Reduce the formed imine using sodium borohydride near RT, for example in methanol (step k). Compound 114 is reacted with a catalyst such as dichloro[1,1′-bis in the presence of carbon monoxide in an autoclave in a _{solvent such as DMF in the presence of a base such as iPr 2 Net, preferably at a temperature ranging from about 100 to 150° C.} Ring closure by reaction with (diphenylphosphino)-ferrocene]palladium(II) (step 1).

[Scheme 2a]

[Scheme 2b]

[Scheme 2c]

Halogen or triflate substituted compound (8) can be prepared by reacting amino compound (4) with di-halo or di-triflate substituted pyridine (2) using the conditions described in Scheme 1 (Scheme 3) (Step a).

[Scheme 3]

In Scheme 3,

X is halogen or OSO ₂ CF ₃ ;

R ¹⁰¹ is a suitable protecting group or AR ¹² .

In addition, an aspect of the present invention is

a) reacting a compound of formula II in the presence of a compound of formula III:

; 또는

; or

b) reacting the compound of formula IV in the presence of the compound of formula V:

A process for the preparation of a compound of formula (I) as defined above comprising:

In the above formula,

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , A, m, n and p are as described herein;

X in step a) is halogen or triflate;

X in step b) is halogen.

In particular, step a) comprises copper(I) iodide, potassium or cesium carbonate, chelated 1,2-diamino compounds such as N,N'-dimethylethylenediamine or trans-1,2-diamino-cyclo In the presence of hexane, or a chelated beta keto ester compound such as 2-isobutyryl-cyclohexanone, at elevated temperature with the aid of preferred microwave heating in a solvent such as 1,4-dioxane.

In particular, step b) is carried out in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature comprising from −10° C. to RT.

Also an object of the present invention are the compounds of formula (I) as described herein for use as therapeutically active substances.

Also an object of the present invention is a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.

The present invention also relates to the use of the compounds of formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

The invention also relates to the use of the compounds of formula (I) as described herein for the treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound of formula (I) as described herein for the treatment or prophylaxis of renal fibrosis or cardiac fibrosis.

The present invention also relates to the use of a compound of formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease.

The present invention also relates to the use of a compound of formula (I) as described herein for the treatment or prophylaxis of congestive heart failure.

The present invention also relates to the use of a compound of formula (I) as described herein for the treatment or prophylaxis of hypertension.

The present invention also relates to the use of the compounds of formula (I) as described herein for the treatment or prophylaxis of primary aldosteronism.

A specific embodiment of the present invention is a compound of formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

Also a specific embodiment of the present invention is a compound of formula (I) as described herein for the treatment or prophylaxis of diabetic nephropathy.

Another specific embodiment of the invention is a compound of formula (I) as described herein for the treatment or prophylaxis of renal fibrosis or cardiac fibrosis.

Also a specific embodiment of the present invention is a compound of formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease.

Also a specific embodiment of the present invention is a compound of formula (I) as described herein for the treatment or prophylaxis of congestive heart failure.

Also a specific embodiment of the present invention is a compound of formula (I) as described herein for the treatment or prophylaxis of hypertension.

Also a specific embodiment of the present invention is a compound of formula (I) as described herein for the treatment or prophylaxis of primary aldosteronism.

The present invention also relates to the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome.

The present invention also relates to the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of diabetic nephropathy.

The present invention also relates to the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of renal fibrosis or cardiac fibrosis.

Also of the present invention is the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of chronic kidney disease.

Also an aspect of the invention is the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of congestive heart failure.

Also an aspect of the invention is the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of hypertension.

Also an aspect of the invention is the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prophylaxis of primary aldosteronism.

Also an object of the present invention is a method for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome, comprising administering an effective amount of a compound of formula (I) as described herein.

Also an object of the present invention is a method for treating or preventing diabetic nephropathy comprising administering an effective amount of a compound of formula (I) as described herein.

Also an object of the present invention is a method for the treatment or prophylaxis of renal fibrosis or cardiac fibrosis comprising administering an effective amount of a compound of formula (I) as described herein.

Also an aspect of the present invention is a method for treating or preventing chronic kidney disease comprising administering an effective amount of a compound of formula (I) as described herein.

Also an aspect of the present invention is a method for the treatment or prevention of congestive heart failure comprising administering an effective amount of a compound of formula (I) as described herein.

Also an aspect of the present invention is a method for the treatment or prevention of hypertension comprising administering an effective amount of a compound of formula (I) as described herein.

Also an aspect of the present invention is a method for treating or preventing primary aldosteronism comprising administering an effective amount of a compound of formula (I) as described herein.

Also an aspect of the invention is a compound of formula (I) as described herein prepared according to any one of the methods described.

analysis procedure

Here, the present inventors confirmed the use of the G-402 cell line as a host cell ectopically expressing (transiently or stably) enzymes of the CYP11 family. Specifically, the present inventors developed stable G-402 cells ectopically expressing human CYP11B1, human CYP11B2, human CYP11A1, cynomolgus CYP11B1 or cynomolgus CYP11B2 enzymatic activity. Importantly, the identified cell line G-402 expressed co-factors (adrenodoxine and adrenodoxine reductase) important for the activity of the CYP11 family, and no relevant enzymatic activity of the CYP11 family (compared to H295R cells) was found in these cells. was not detected in Therefore, the G-402 cell line is uniquely suitable as a host cell for ectopic expression of enzymes from the CYP11 family.

G-402 cells can be obtained from ATCC (CRL-1440) and originally derived from renal epithelial leiomyoma.

The expression plasmid contains an ORF for human/cyno CYP11B1 or CYP11B2 under the control of a suitable promoter (CMV-promoter) and a suitable resistance marker (neomycin). Using standard techniques, the expression plasmid is transfected into G-402 cells, and these cells are then selected to express the desired resistance marker. Then, individual cell-clones were selected and evaluated for exhibiting the desired enzymatic activity using 11-deoxycorticosterone (Cyp11B2) or 11-deoxycortisol (Cyp11B1) as substrates.

G-402 cells expressing the CYP11 construct were identified as described above and contained 10% FCS and 400 μg/mL G418 (Geneticin) at 37° C. under an atmosphere of _{5% CO 2 /95% air.} were maintained in McCoy's 5a Medium Modified (ATCC Cat. No. 30-2007). Cell enzyme assays were performed in DMEM/F12 medium containing 2.5% charcoal-treated FCS and appropriate concentrations of substrate (0.3-10 μM 11-deoxycorticosterone, 11-deoxycortisol or corticosterone). To assay for enzymatic activity, cells were plated on 96 well plates and incubated for 16 hours. An aliquot of the supernatant was then removed and analyzed for the expected product concentration (aldosterone for CYP11B2; cortisol for CYP11B1). Concentrations of these steroids can be determined using the HTRF assay from CisBio assaying for aldosterone or cortisol.

Inhibition of the release of the resulting steroid can be used as a measure of inhibition of each enzyme by the test compound added during the cellular enzyme assay. The dose dependent inhibition of enzyme activity by a compound is calculated by plotting inhibitor concentration added (x-axis) versus measured steroid/product level (y-axis). Then, the inhibition is calculated by fitting the 4-parameter sigmoid function of Equation 1 (Morgan-Mercer-Flodin (MMF) model) to the raw data points using the least squares method. :

[Equation 1]

In the above formula,

A is the maximum y value;

B is the EC ₅₀ factor measured using XLFit;

C is the minimum y value;

D is the slope value.

The maximum value A corresponds to the amount of steroid produced in the absence of the inhibitor, and the value C corresponds to the amount of steroid detected when the enzyme is completely inhibited.

_{EC 50} values for the compounds claimed herein were tested with the G402-based assay system. Cyp11B2 enzyme activity was tested in the presence of 1 μM deoxycorticosterone and variable amounts of inhibitor; Cyp11B1 enzyme activity was tested in the presence of 1 μM deoxycortisol and varying amounts of inhibitor.

Salt of the compounds and their pharmaceutically acceptable of the formula (I) described herein, or ester has an EC ₅₀ (CYP11B2) value of 0.000001 to 1000 μM, specific compounds have an EC ₅₀ (CYP11B2) value of 0.00005 to 500 μM, The more specific compound has an EC ₅₀ (CYP11B2) value of 0.0005 to 50 μM, and the more specific compound has an EC ₅₀ (CYP11B2) value of 0.0005 to 5 μM. These results were obtained by using the above enzymatic assay.

The compounds of formula (I) and pharmaceutically acceptable salts thereof can be used as medicaments (eg, in the form of pharmaceutical preparations). Pharmaceutical preparations may be administered internally, eg, orally (eg, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (eg, in the form of nasal drops) or rectally. (eg, in the form of suppositories). However, administration can also be performed parenterally, such as intramuscularly or intravenously (eg, in the form of an injection solution).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like can be used, for example, as adjuvants for tablets, dragees and hard gelatine capsules.

Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like.

Suitable auxiliaries for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like.

Suitable adjuvants for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. In addition, they may contain other therapeutically valuable substances.

The dosage can vary widely and will, of course, be fitted to the individual requirements in each particular case. In general, for oral administration, for example, about 0.1 to 20 mg/kg body weight divided into 1 to 3 separate doses, preferably about 0.5 to 4 mg/kg, which may consist of equal amounts. A daily dose of kg body weight (eg about 300 mg/individual) should be adequate. It is evident, however, that the upper limits provided herein, where indicated, may be exceeded.

According to the present invention, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof can be used for the treatment or prophylaxis of aldosterone mediated diseases.

The compounds of formula (I) herein, or pharmaceutically acceptable salts and esters thereof, are also inhibitors of CYP11B2. In addition, the compounds of formula (I) herein, or pharmaceutically acceptable salts and esters thereof, exhibit variable inhibition of CYP11B1, but provide improved selectivity for CYP11B2 compared to CYP11B1. Such compounds may be used in conditions that exhibit excessive cortisol production/levels or excessive levels of both cortisol and aldosterone (e.g. Cushing's syndrome, burn trauma patients, depression, post-traumatic stress disorder, chronic stress, adrenocortical adenoma, Morbus Cushing). ) can be used for the treatment or prevention of

According to the present invention, the compound of formula (I), or pharmaceutically acceptable salts and esters thereof, is used for treating cardiovascular diseases (including hypertension and heart failure), vascular diseases, endothelial cell disorders, baroreceptor disorders, kidney diseases, liver diseases, fibrotic diseases, It can be used for the treatment or prevention of inflammatory diseases, retinopathy, neuropathy (eg, peripheral neuropathy), pain, insulinopathy, edema, edematous disease, depression, and the like.

Cardiovascular diseases include congestive heart failure, coronary heart disease, arrhythmias, atrial fibrillation, cardiac lesions, decreased ejection fraction, diastolic and contractile heart dysfunction, fibrinous necrosis of coronary arteries, cardiac fibrosis, hypertrophic cardiomyopathy, impaired arterial flexibility, impaired diastolic action (diastolic filling), ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrotic lesions, cardiac arrhythmias, sudden cardiac death, restenosis, stroke, vascular damage.

Renal diseases include acute and chronic renal failure, nephropathy, end-stage renal disease, diabetic nephropathy, decreased creatine clearance, decreased glomerular filtration rate, expansion of the reticular mesenteric matrix with or without significant hypercellularity, focal thrombosis of the glomerular capillaries. thrombosis), global fibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignant neuropathy (e.g., ischemic constriction, microalbuminuria, proteinuria, decreased renal blood flow, renal artery disease, intracapillary (endothelial and mesenteric) and/or expansion and proliferation of extracapillary cells (crescents).

Renal diseases also include glomerulonephritis (eg diffuse proliferative, focal proliferative, intervascular proliferative, membrane proliferative, micro-change membranous glomerulonephritis), lupus nephritis, non-immune basement membrane abnormalities (eg Alport's syndrome). ), renal fibrosis and glomerulosclerosis (such as nodular or complete and focal segmental glomerulosclerosis).

Liver diseases include, but are not limited to, hepatic steatosis, nonalcoholic fatty liver, liver cirrhosis, hepatic ascites, hepatic congestion, and the like.

Vascular diseases include, but are not limited to, thrombotic vascular diseases (eg, parietal fibrinous necrosis, extravasation and division of red blood cells, and luminal and/or wall thrombosis), proliferative arterial diseases (eg, surrounded by an extracellular matrix of mucin). stacked swollen endomyocytes and nodular thickening), atherosclerosis, decreased vascular flexibility (eg, spasticity, decreased ventricular flexibility and decreased vascular flexibility), endothelial dysfunction, and the like.

Inflammatory diseases include, but are not limited to, arthritis (eg, osteoarthritis), inflammatory airway disease (eg, chronic obstructive pulmonary disease (COPD)), and the like.

Pain includes, but is not limited to acute pain, chronic pain (eg, arthralgia), and the like.

Edema includes, but is not limited to, peripheral tissue edema, hepatic congestion, hepatic ascites, splenic congestion, respiratory or pulmonary congestion, and the like.

Insulinoper seeds include, but are not limited to, insulin resistance, type I diabetes mellitus, type II diabetes mellitus, glucose sensitivity, pre-diabetic state, syndrome X, and the like.

Fibrotic diseases include, but are not limited to, myocardial and intrarenal fibrosis, renal interstitial fibrosis, and liver fibrosis.

In addition, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof as described herein may also be used for the treatment or prevention of cardiovascular diseases selected from the group consisting of hypertension, heart failure (especially heart failure after myocardial infarction), left ventricular hypertrophy and stroke. can be used

In another embodiment, the cardiovascular disease is hypertension.

In a specific embodiment, the cardiovascular disease is treatment-resistant hypertension.

In another embodiment, the cardiovascular disease is heart failure.

In another embodiment, the cardiovascular disease is left ventricular hypertrophy.

In another embodiment, the cardiovascular disease is congestive heart failure, more particularly in a patient with a preserved left ventricular ejection fraction.

In another embodiment, the cardiovascular disease is stroke.

In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof may be used for the treatment or prophylaxis of kidney disease.

In another embodiment, the kidney disease is kidney disease.

In another embodiment, the kidney disease is autoimmune glomerulonephritis.

In another embodiment, the chronic kidney disease is diabetic nephropathy.

In another embodiment, the fibrotic disease is renal fibrosis or cardiac fibrosis.

In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof may be used for the treatment or prophylaxis of type II diabetes mellitus.

In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof may be used for the treatment or prophylaxis of type I diabetes mellitus.

In another embodiment, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof may be used for the treatment or prevention of diabetic retinopathy.

The present invention is illustrated by way of non-limiting features.

Where the preparation examples are obtained as mixtures of enantiomers, the pure enantiomers may be separated by the methods described herein, or methods known to those skilled in the art, such as chiral chromatography or crystallization.

Example

All examples and intermediates were prepared under an argon atmosphere unless otherwise specified.

Intermediate A-1

6- Chloro -3,4- dihydro -2H-isoquinolin-1-one

[A] [2-(3- Chloro - phenyl )-ethyl]- carbamic acid methyl ester

At 0° C., methyl chloroformate (4.6 g, 48 mmol) was mixed with 2-(3-chloro-phenyl)-ethylamine (5.0 g, 32 mmol) and Et ₃ N (6.4 g, 64) in DCM (100 mL). mmol) was added dropwise. After addition, the mixture was stirred at room temperature for 0.5 h. The organic layer was washed with water (3 x 30 mL), 1 N HCl (20 mL) and brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. After vacuum drying, the title compound (6.49 g, 95%) was obtained as a white solid. MS: 214.1 (M+H ⁺ ).

[B] 6- Chloro -3,4- dihydro -2H-isoquinolin-1-one

Under N ₂ protection, a mixture of [2-(3-chloro-phenyl)-ethyl]-carbamic acid methyl ester (5.0 g, 23.4 mmol) and PPA (polyphosphoric acid) (20 g) was heated in a 250 mL round bottom flask at 120° C. vigorously stirred for 2 hours. After cooling to room temperature, the reaction mixture was treated with ice-water and aqueous ammonia solution to adjust the pH to 8. The mixture was then extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. After the solvent was removed under reduced pressure, the obtained crude product was further washed with ethyl ether to give the title compound (1.66 g, 39%) as a white solid. MS: 182.0 (M+H ⁺ ).

Intermediate A-2

5- Chloro -3- methyl -2,3- dihydro - isoindol -1-one

[A] 1-(2- Bromo -5- Chloro - phenyl )- ethylamine

To a stirred solution of 2-bromo-5-chlorobenzonitrile (80 g, 370 mmol) in THF (1000 mL) at 0 °C was added EtMgBr (370 mL, 1110 mmol) dropwise. After the reaction mixture was stirred at 0-5° C. for 5 h, MeOH (500 mL) was added dropwise. After the solution was stirred for an additional 15 min, NaBH ₄ (28 g, 740 mmol) was carefully added and the resulting mixture was stirred at room temperature for 16 h. Then, the reaction solution was poured into water and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography (petroleum ether:EtOAc =3:1) to give the title compound (30 g, 34.6%) was obtained as a yellowish oil. MS: 235.5 [M+H ⁺ ].

[B] 5- Chloro -3- methyl -2,3- dihydro - isoindol -1-one

1-(2-Bromo-5-chlorophenyl)-ethylamine (30 g, 127.9 mmol), Pd(dppf)Cl ₂ (3.2 g, 12.79 mmol) and DIPEA (49.5 g, 383.7) in DMF (1.2 L) mmol) was stirred in an autoclave under 2 MPa of CO at 130° C. for 24 h. After the reaction was cooled to room temperature, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with brine, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography (PE:EtOAc = 3:1) to give the title compound (5.2 g, 22.5 %) as a brown solid. MS: 181.7 [M+H ⁺ ].

Intermediate A-3

5- Chloro -3,3- Dimethyl -2,3- dihydro - isoindol -1-one

[A] 1-(2- Bromo -5- Chloro - phenyl )-One- methyl - ethylamine

To a stirred solution of 2-bromo-5-chloro-benzonitrile (10 g, 46 mmol) in THF (200 mL) at 0° C. was added MeMgBr (77 mL, 230 mmol) dropwise. The reaction mixture was warmed to room temperature and stirred for 2 h. Ti(Oi-Pr) ₄ (13 g, 46 mmol) was added and the solution was stirred for an additional 16 h, after which it was quenched with aqueous HCl solution and washed with EtOAc. The aqueous phase was adjusted to about pH 10 with aqueous NaOH solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were concentrated to give the crude title product (3.8 g, 33% yield) as an oil, which was used directly in the next step without further purification. MS: 249.30 (M+H ⁺ ).

[B] 5- Chloro -3,3- Dimethyl -2,3- dihydro - isoindol -1-one

1-(2-Bromo-5-chloro-phenyl)-1-methyl-ethylamine (3.8 g, 15.3 mmol), Pd(dppf)Cl ₂ (0.4 g, 0.55 mmol) and DIPEA in DMF (20 mL) (6 g, 45.9 mmol) was stirred in an autoclave under 2 MPa CO at 130° C. for 16 h. It was then cooled to room temperature and the reaction mixture was diluted with EtOAc (300 mL). The organic layer was washed with brine (2 x 80 mL), filtered and concentrated in vacuo to give the crude product, which was purified by chromatography to give the title compound (1.13 g, 38%) as a brown solid. MS: 195.70 (M+H ⁺ ).

Intermediate A-4

3,3- Dimethyl -1-oxo-2,3- dihydro -1H- isoindol -5- carbonitrile

[A] 4- Bromo -2- methyl -benzoic acid methyl ester

To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in methanol (115 mL) was slowly added thionyl chloride (20.25 mL, 0.28 mol) and the reaction mixture was stirred at 70° C. for 2 h. After stirring, it was concentrated to give the crude product, which was then purified by column chromatography to give the title compound (30.03 g, 93.6%) as a solid.

[B] 4- cyano -2- methyl -benzoic acid methyl ester

A mixture of 4-bromo-2-methyl-benzoic acid methyl ester (26.0 g, 113.5 mmol) and CuCN (12.48 g, 140.7 mmol) was heated at 180° C. for 5 h, after which it was poured into ice-water. The solid precipitate was collected by vacuum filtration to give the crude product, which was purified by column chromatography to give the title compound (12.53 g, 63%) as a solid.

[C] 2- bromomethyl -4- cyano -benzoic acid methyl ester

₄ -cyano-2-methyl-benzoic acid methyl ester (12.5 g, 71.35 mmol), NBS (12.7 g, 71.35 mmol) and di-benzoyl peroxide (BPO) (0.8 g, 3.28 mmol) in CCl 4 (200 mL) (0.8 g, 3.28 mmol) ) was heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated in vacuo to give the crude product (18.2 g), which was used in the next step reaction without further purification.

[D] 2-(4- methoxy -benzyl)-1-oxo-2,3- dihydro -1H- isoindol -5- carbonitrile

To a solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester (18.1 g, 71.24 mmol) in THF (300 mL) at 0° C. was added PMBNH ₂ (23.4 g, 178.1 mmol) and the reaction mixture was brought to room temperature. stirred for 16 hours. After vacuum filtration, the filtrate was concentrated in vacuo. The obtained residue was redissolved in EtOAc and washed with water and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by column chromatography to give the title compound as a solid (11.69 g, 56.0%).

[E] 2-(4- methoxy -benzyl)-3,3- Dimethyl -1-oxo-2,3- dihydro -1H- isoindol -5-car Bonnet reel

To a solution of 2-(4-methoxy-benzyl)-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (11.6 g, 41.7 mmol) in THF (300 mL) NaH (8.34) g, 208.4 mmol, 60% in mineral oil) was added and the reaction mixture was stirred at room temperature for 1 h before iodomethane (35.5 g, 250.1 mmol) was added. After addition, the reaction mixture was stirred at 70° C. for 2 h until all starting material was consumed. After cooling to room temperature, saturated aqueous NH ₄ Cl solution was added and the mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the title compound (7.22 g, 56.5%) as a solid.

[F] 3,3- Dimethyl -1-oxo-2,3- dihydro -1H- isoindol -5- carbonitrile

2-(4-Methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (3.5 g, 11.42 mmol) in MeCN (70 mL) ) was added CAN (18.79 g, 34.27 mmol) in water (30 mL) at 0 °C. The resulting reaction mixture was stirred at 0° C. for 1 h until all starting material was consumed. The reaction mixture was extracted between water and EtOAc, and the combined organic layers were dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give the title compound (1.06 g, 49.8%) as a solid. was obtained with

Intermediate A-5

3,5- Daiyo-do -pyridine

3,5-Dibromopyridine (20 g, 84 mmol), CuI (4.76 g, 25 mmol), KI (83.7 g, 504 mmol) and N ¹ ,N ² -dimethylethane-1 in dioxane (400 mL) A mixture of ,2-diamine (4.4 g, 50.4 mmol) was stirred at 110° C. for 16 h. During this period, the reaction progress was monitored by LC/MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a solid which was washed with EtOAc (100 mL) and DCM (100 mL) to give the crude title compound as a gray solid (13 g, 47%). . MS: 331.50 (M+H ⁺ ). It was used in the next step without further purification.

Intermediate A-6

3-[5-(6- Chloro -1,1- Dimethyl -3-oxo-1,3- dihydro - isoindol -2-yl)-pyridin-3- ilamino ]- azetidine -One- carboxylic acid tert -Butyl ester

[A] 5- Chloro -2-(5- Iodo -pyridin-3-yl)-3,3- Dimethyl -2,3- dihydro - isoindol -1-one

In a 75-mL sealed tube, 3,5-diiodo-pyridine (intermediate A-5, 6.6 g, 20 mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindole- 1-one (intermediate A-3, 1.95 g, 10 mmol), CuI (571 mg, 3 mmol), K ₃ PO ₄ (4.24 g, 20 mmol) and (+)-(S,S)-1,2 -Diaminocyclohexane (0.7 mL, 6 mmol) was dissolved in dioxane (20 mL). The resulting reaction mixture was heated at 120° C. for 3 h, then it was poured into water (50 mL) and extracted with EtOAc (2×125 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel flash chromatography (0-30% EtOAc-hexanes gradient) to give the title compound (1.8 g) , 45%) as a pale yellow solid. MS: 399.2 (M+H ⁺ ).

[B] 3-[5-(6- Chloro -1,1- Dimethyl -3-oxo-1,3- dihydro - isoindol -2-yl)-pyridin-3- ilamino ]- azetidine -One- carboxylic acid tert -Butyl ester

5-Chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (2.16 g, 5.4) in DMF (12 mL) mmol), 3-amino-azetidine-1-carboxylic acid tert-butyl ester (1.8 g, 10.8 mmol), CuI (103 mg, 0.54 mmol), Cs ₂ CO ₃ (3.5 g, 10.8 mmol) and 2-iso A mixture of butyryl-cyclohexanone (0.36 mL, 2.16 mmol) was stirred at 100° C. for 12 h. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel flash chromatography (30-100% EtOAc-hexane gradient) to give the title compound (1.1 g) , 48%) as a pale yellow foam. MS: 443.2 (M+H ⁺ ).

The following intermediates listed in Table 1 were prepared analogously to the procedure described for the preparation of intermediates A-6 using the appropriate reaction partners.

[Table 1]

Example One

5- Chloro -2-[5-[(1- Cyclopropylsulfonylazetidine -3-yl)amino]pyridin-3-yl]-3,3-da ethyliso Indol-1-one

[A] 2-[5-( azetidine -3- ilamino )-pyridin-3-yl]-5- Chloro -3,3- Dimethyl -2,3-dihydro- isoindol -1-one

3-[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-ylamino]- in methanol (12 mL) A mixture of azetidine-1-carboxylic acid tert-butyl ester (intermediate A-6, 360 mg, 0.812 mmol) and acetyl chloride (0.56 mL) was stirred at room temperature for 2 h. After concentration under reduced pressure, the crude product was obtained as a pale yellow foam, which was used in the next step without further purification. MS: 343.2 (M+H ⁺ ).

[B] 5- Chloro -2-[5-[(1- Cyclopropylsulfonylazetidine -3-yl)amino]pyridin-3-yl]-3,3- Dimethylisoindole -1-one

2-[5-(azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindole-1 in DCM (5 mL) To a stirred solution of -one (56 mg, 0.163 mmol) and Et ₃ N (0.5 mL) at 0 °C was added cyclopropane sulfonyl chloride (30 mg, 0.21 mmol) and stirring at 0 °C was continued for 1 h. did. The resulting reaction mixture was extracted with EtOAc (2 x 100 mL), the combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by prep-HPLC The title compound (22 mg, 30%) was obtained as a white foam. MS: 447.1 (M+H ⁺ ).

Example 2

5- Chloro -3,3- Dimethyl -2-[5-[[1-(1- methylimidazole -2-carbonyl) azetidine -3-yl]amino]-3- pyridyl ] isoindoline -1-one

2-[5-(azetidin-3-ylamino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-isoindole-1 in DCM (5 mL) HATU (124 mg, 0.326 mmol) and 1-methylimidazole-2-carboxy in a stirred solution of -one (Example 1 [A], 56 mg, 0.163 mmol) and Et _{3 N (0.5 mL) at room temperature} Acid (27 mg, 0.212 mmol) was added and stirring was continued at room temperature for 1 h. The resulting reaction mixture was extracted with EtOAc (2 x 50 mL), the combined organics were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by prep-HPLC The title compound (15.4 mg, 21%) was obtained as a white foam. MS: 451.1 (M+H ⁺ ).

Example 3

5- Chloro -2-[5-[(1- Cyclopropylsulfonylazetidine -3 days)- methylamino ]pyridin-3-yl]-3,3- Dimethylisoindole -1-one

[A] 3-{[5-(6- Chloro -1,1- Dimethyl -3-oxo-1,3- dihydro - isoindol -2-yl)-pyridin-3-yl]- methyl -amino}- azetidine -One- carboxylic acid tert -Butyl ester

5-Chloro-2-(5-iodo-pyridin-3-yl)-3,3-dimethyl-2,3-dihydro-isoindol-1-one (398 mg, 1) in dioxane (6 mL) mmol, intermediate A-6[A]), 3-methylamino-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.3 mmol), Pd(OAc) ₂ (35 mg, 10% by weight), residue A mixture of phos (70 mg, 20 wt %) and t-BuONa (192 mg, 2 mmol) was stirred at 115° C. for 2 h. After cooling to room temperature, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by silica gel flash chromatography (40-100% EtOAc-hexane gradient) to give the title compound (196 mg) , 43%) as a pale yellow foam. MS: 457.1 (M+H ⁺ ).

[B] 2-[5-( azetidine -3 days- methyl -amino)-pyridin-3-yl]-5- Chloro -3,3- Dimethyl -2,3-C Lee Hi draw- isoindol -1-one

3-{[5-(6-Chloro-1,1-dimethyl-3-oxo-1,3-dihydro-isoindol-2-yl)-pyridin-3-yl]- in methanol (12 mL) A mixture of methyl-amino}-azetidine-1-carboxylic acid tert-butyl ester (196 mg, 0.43 mmol) and acetyl chloride (0.56 mL) was stirred at room temperature for 2 h. It was then concentrated in vacuo to give the crude product as a pale yellow foam. It was used in the next step without further purification. MS: 357.2 (M+H ⁺ ).

[C] 5- Chloro -2-[5-[(1- Cyclopropylsulfonylazetidine -3 days)- methylamino ]pyridin-3-yl]-3,3- Dimethylisoindole -1-one

2-[5-(azetidin-3-yl-methyl-amino)-pyridin-3-yl]-5-chloro-3,3-dimethyl-2,3-dihydro-iso in DCM (5 mL) To a stirred solution of indol-1-one (60 mg, 0.17 mmol) and Et ₃ N (0.50 mL) at 0 °C was added cyclopropane sulfonyl chloride (31 mg, 0.22 mmol), stirring at 0 °C was 1 continued for hours. The resulting mixture was extracted with EtOAc (2 x 100 mL), the combined organics were washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product, which was purified by prep-HPLC to give the title The compound (19 mg, 24%) was obtained as a white foam. MS: 461.1 (M+H ⁺ ).

Example 4 and Example 5

(+)-5- Chloro -2-[5-[[(3R or 3S)-1- Cyclopropylsulfonylpyrrolidine -3-yl]-methylamino]pyridin-3-yl]-3,3- Dimethylisoindole -1-one and (-)-5- Chloro -2-[5-[[(3S or 3R)-1- Cyclopropylsulfonylpyrrolidine -3 days]- methylamino ]pyridin-3-yl]-3,3-da Emethylisoindole -1-one

[A] 3-{[5-(6- Chloro -1,1- Dimethyl -3-oxo-1,3- dihydro - isoindol -2-yl)-pyridin-3-yl]- methyl -amino}- pyrrolidine -One- carboxylic acid tert -Butyl ester

In a procedure analogous to the procedure described for the preparation of Example 3 [A], using 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester, the title compound was obtained as a pale yellow foam (47%). MS: 471.1 (M+H ⁺ ).

[B] 5- Chloro -3,3- Dimethyl -2-[5-( methyl - pyrrolidine -3-yl-amino)-pyridin-3-yl]-2,3- dihydro - isoindol -1-one

By a procedure analogous to the procedure described for the preparation of Example 3 [B], the title compound was obtained as a yellow foam crude product. It was used in the next step without further purification. MS: 371.2 (M+H ⁺ ).

[C] ( rac )-5- Chloro -2-{5-[(1- Cyclopropylsulfonyl - pyrrolidine -3 days)- methyl -Amino]-pyridin-3-yl}-3,3- Dimethyl -2,3- dihydro - isoindol -1-one

In a procedure analogous to that described for the preparation of Example 3 [C], using cyclopropane sulfonyl chloride, the title compound (105 mg, 40%) was obtained as a white foamy racemic mixture. MS: 475.1 (M+H ⁺ ).

[D] (+)-5- Chloro -2-[5-[[(3R or 3S)-1- Cyclopropylsulfonylpyrrolidine -3 days]- methylamino ]pyridin-3-yl]-3,3- Dimethylisoindole -1-one ( Example 4) and (-)-5- claw rho-2-[5-[[(3S or 3R)-1- Cyclopropylsulfonylpyrrolidine -3 days]- methylamino ]pyridin-3-yl]-3,3- Dimethylisoindole -1-one ( Example 5)

(rac)-5-chloro-2-{5-[(1-cyclopropylsulfonyl-pyrrolidin-3-yl)-methyl-amino on a Chiralpak IA column (10% ACN in ethanol) Prepared the title compound by chiral separation of ]-pyridin-3-yl}-3,3-dimethyl-2,3-dihydro-isoindol-1-one (+)-5-chloro-2-[5 -[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one (10 mg, 20 %, Example 4; MS: 475.1 (M+H ⁺ )) and (-)-5-chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl ]-Methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one (12.5 mg, 25%, Example 5; MS: 475.1 (M+H ⁺ )) as an off-white foam did.

The examples listed in Table 2 were prepared analogously to the procedure described for the preparation of Examples 1, 2, 3, 4 (or 5) using the appropriate starting materials.

[Table 2]

Example A

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of tablets of the composition:

Example B

The compounds of formula (I) can be used in a manner known per se as active ingredients for the preparation of capsules of the composition:

Claims (30)

A compound of formula (I): or a pharmaceutically acceptable salt thereof:
[Formula I]

In the above formula,
R ¹ , R ² , R ³ and R ⁴ are independently H or alkyl;
(i) R ⁹ is H, R ¹⁰ and R ¹¹ together form —(CH ₂ ) _w —, n is 0 and p is 0,
(ii) R ⁷ , R ⁹ and R ¹⁰ are independently H, R ⁸ and R ¹¹ together form —CH ₂ —CH ₂ —, n is 0 and p is 1,
(iii) R ⁵ , R ⁷ and R ⁸ are independently H, R ⁶ and R ⁹ together _{form —CH 2} —, R ¹⁰ and R ¹¹ together _{form —CH 2} —, and n is 1 and p is 1;
A is -C(O)- or -S(O) ₂ -;
B is -C-;
R ¹² is cycloalkyl or substituted heteroaryl, wherein the substituted heteroaryl is substituted with 1 to 3 substituents independently selected from H, alkyl, cycloalkyl, hydroxy, alkoxy, cyano and halogen;
R ¹³ is halogen, cyano, alkoxy or haloalkoxy;
R ¹⁴ is H, alkyl or cycloalkyl;
R ¹⁵ is H, alkyl, cycloalkyl or halogen;
m is 0 or 1;
w is 1, 2 or 3. According to claim 1,
A is -S(O) ₂ -. According to claim 1,
A is -C(O)-. According to claim 1,
R ¹² is cycloalkyl or substituted pyridinyl, wherein the substituted pyridinyl is substituted with 1 to 3 substituents independently selected from H, alkyl and halogen. 5. The method of claim 4,
R ¹² is cycloalkyl or substituted pyridinyl, wherein the substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen. 6. The method of claim 5,
and R ¹² is cycloalkyl. According to claim 1,
R ¹² is substituted heteroaryl, wherein the substituted heteroaryl is substituted with 1-3 substituents independently selected from alkyl and halogen. 8. The method of claim 7,
R ¹² is substituted pyridinyl, wherein the substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen. delete According to claim 1,
wherein R ¹ and R ² are alkyl. 11. The method of claim 10,
wherein R ¹ and R ² are methyl. According to claim 1,
m, n and p are 0. According to claim 1,
w is 1 or 2. According to claim 1,
and R ³ and R ⁴ are H. delete According to claim 1,
A ^{compound wherein R 9} is H and R ¹⁰ and R ¹¹ together form —(CH ₂ ) _w —. According to claim 1,
The compound wherein ^{R 14 is H.} According to claim 1,
The ^{compound wherein R 13} is chloro. According to claim 1,
The compound wherein ^{R 15 is H.} According to claim 1,
5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindole- 1-one;
5-Chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindole- 1-one;
5-chloro-2-[5-[(1-cyclopropylsulfonylpiperidin-4-yl)-methylamino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3R or 3S)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindole-1- On;
5-Chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpiperidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindole-1- On;
5-Chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,3-dimethylisoindole-1 -On;
5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On;
5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On;
5-Chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3-methyl-3H-isoindole-1 -On;
5-Chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3H-isoindole-1 -On;
5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3-methyl-3H-isoindol-1-one;
6-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,4-dihydroisoquinolin-1-one;
6-Chloro-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;
6-Chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;
6-Chloro-2-[5-[[1-(5-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;
5-Chloro-3,3-dimethyl-2-[5-[[2-(4-methylpyridin-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl]amino]pyridin-3 -yl] isoindole-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoin dolin-1-one;
6-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydro isoquinolin-1-one;
6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinoline- 1-one;
6-Chloro-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinoline -1-one;
5-Chloro-2-[5-[[1-(3,5-dimethylisoxazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl -isoindolin-1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindoline -1-one;
(3R or 3S)-5-chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]iso indolin-1-one;
(3S or 3R)-5-chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]iso indolin-1-one;
(3R or 3S)-5-chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl- isoindolin-1-one;
(3S or 3R)-5-chloro-2-[5-[[1-(3-chloropyridin-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3-methyl- isoindolin-1-one;
(3R or 3S)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one ;
(3S or 3R)-5-Chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3-methyl-isoindolin-1-one ;
2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoindoline -5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-isoin Doline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-iso indoline-5-carbonitrile;
2-[5-[(1-cyclopropylsulfonyl-4-piperidyl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
2-[5-[[1-(3-Chloropyridine-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline -5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(4-methylpyridine-3-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoindoline -5-carbonitrile;
2-[5-[[1-(3-Chloropyridin-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline -5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-iso indoline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-isoin Doline-5-carbonitrile;
3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-iso indoline-5-carbonitrile; and
3,3-Dimethyl-2-[5-[[1-(3-methylimidazole-4-carbonyl)-4-piperidyl]amino]-3-pyridyl]-1-oxo-iso Indoline-5-carbonitrile
A compound selected from or a pharmaceutically acceptable salt thereof. 21. The method of claim 20,
5-chloro-2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]pyridin-3-yl]-3,3-dimethylisoindol-1-one;
5-Chloro-2-[5-[[(3S or 3R)-1-cyclopropylsulfonylpyrrolidin-3-yl]-methylamino]pyridin-3-yl]-3,3-dimethylisoindole- 1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On;
5-Chloro-3,3-dimethyl-2-[5-[[1-(5-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]isoindole-1 -On;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoin dolin-1-one;
6-Chloro-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]pyridin-3-yl]-3,4-dihydroisoquinoline-1 -On;
6-Chloro-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-3,4-dihydroisoquinoline- 1-one;
5-Chloro-3,3-dimethyl-2-[5-[[1-(1-methylpyrazole-4-carbonyl)azetidin-3-yl]amino]-3-pyridyl]isoindoline -1-one;
(3R or 3S)-5-chloro-3-methyl-2-[5-[[1-(4-methylpyridin-3-carbonyl)azetidin-3-yl]amino]-3-pyridyl]iso indolin-1-one;
2-[5-[(1-cyclopropylsulfonylazetidin-3-yl)amino]-3-pyridyl]-3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; and
3,3-Dimethyl-2-[5-[[1-(1-methylimidazole-2-carbonyl)azetidin-3-yl]amino]-3-pyridyl]-1-oxo-iso Indoline-5-carbonitrile
A compound selected from or a pharmaceutically acceptable salt thereof. a) reacting a compound of formula II in the presence of a compound of formula III:

; or
b) reacting the compound of formula IV in the presence of the compound of formula V:

A method for preparing a compound according to any one of claims 1 to 8, 10 to 14 and 16 to 21, comprising:
In the above formula,
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , A, m, n and p are as defined in claim 1;
X in step a) is halogen or triflate;
X in step b) is halogen. 22. The method according to any one of claims 1 to 8, 10 to 14 and 16 to 21,
A compound for use as a therapeutically active substance. 22. Chronic kidney disease, congestive heart failure, hypertension, primary comprising a compound according to any one of claims 1 to 8, 10 to 14 and 16 to 21 and a therapeutically inert carrier. A pharmaceutical composition for the treatment or prevention of aldosteronism or Cushing's syndrome. 22. The method according to any one of claims 1 to 8, 10 to 14 and 16 to 21,
A compound for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism or Cushing's syndrome. delete delete delete delete delete