KR20160014610A - 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 such compounds and methods of use of such compounds:
(I)

In this 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 are as described herein.

Description

The novel 3,4-dihydro-2H-isoquinolin-1-one and the 2,3-dihydro-isoindol-1-one compound {NEW 3,4-DIHYDRO- 2H-ISOQUINOLINE- 3-DIHYDRO-ISOINDOL-1-ONE COMPOUNDS}

The present invention relates to an aldosterone synthase inhibitor for the treatment or prevention of organic compounds useful for the treatment or prevention of mammals, especially 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:

(I)

In this 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, 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 said 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 with potential to protect against organ / tissue damage induced by absolute or relative excess of aldosterone. Hypertension occurs in 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 represent an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease, and renal failure. The renin-angiotensin aldosterone system is a pathway associated with hypertension, volume and salt balance, and more recently contributes directly to termination of organ damage in the progressive stages of heart failure or renal disease. ACE inhibitors and angiotensin receptor blockers (ARBs) have been successfully used to improve the quality and duration of patients' lives. These drugs do not cause maximum protection. In a relatively large number of patients, ACE and ARB cause a so-called aldosterone breakthrough (a phenomenon in which aldosterone levels return to pathological levels after an initial decrease). It has been demonstrated that the detrimental consequences of improperly increased aldosterone levels (compared to salt intake / levels) can be minimized by aldosterone blockade by mineral corticosteroid receptor antagonists. Direct inhibition of aldosterone synthesis is expected to provide even better protection since this would also reduce the non-genomic effect of aldosterone.

The effect of aldosterone on Na / K transport leads to increased reabsorption of sodium and water and secretion of potassium in the kidneys. Overall, this leads to increased blood volume and consequently increased blood pressure. In addition to its role in the regulation of renal sodium reabsorption, aldosterone can have deleterious effects on the kidney, 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. Injection of aldosterone into the kidneys with poorly functioning rats (by high salt treatment or unilateral renal resection) is associated with renal exacerbations, including glomerular swelling, podocyte injury, interstitial inflammation, Causing many damages. More specifically, aldosterone has been shown to increase the 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 interleukin IL-lb and IL-6, MCP-I and osteopontin. At the cellular level, in vascular fibroblasts, aldosterone has been shown to increase the expression of type I collagen mRNA (the mediator of fibrosis). In addition, aldosterone stimulates type IV collagen accumulation in rat vascular septum cells and induces expression of plasminogen activator inhibitor-1 (PAI-1) in smooth muscle cells. Briefly, aldosterone has been known as a key hormone involved in kidney damage. Aldosterone also plays an important role in mediating cardiovascular risk.

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

More recent preclinical studies emphasize 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-dose angiotensin II exposure; high salt and unilateral renal resection). Angiotensin II and high salt treatment resulted in albuminuria, hyperglycemia, renal vascular hypertrophy, glomerular injury, increased PAI-1 and osteopontin mRNA expression, and tubular interstitial fibrosis. Both drugs prevented their renal effects and weakened cardiac and aortic insufficiency. After 4 weeks of treatment with FAD286, plasma aldosterone decreased, while 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 renal function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, to patients with primary aldosteronism effectively concluded that such administration effectively inhibited CYP11B2 in patients with primary aldosteronism, resulting in significantly lower circulating aldosterone levels, correction of hypokalemia and a slight reduction in blood pressure . The effect on the glucocorticoid axis was consistent with the poor selectivity of the compound and the potential inhibition of cortisol synthesis. These data support the notion that CYP11B2 inhibitors can inappropriately lower elevated aldosterone levels. Achieving good selectivity for CYP11B1 will be important for distinguishing unwanted side effects on the HPA axis and distinguishing between different CYP11B2 inhibitors.

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

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

The term "alkyl" denotes a monovalent linear or branched 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 has 1 to 4 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and sec-butyl. Particular 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 of 3 to 10 ring carbon atoms. In a specific embodiment, cycloalkyl represents a monovalent saturated monocyclic hydrocarbon group consisting 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. Particular halogens are chloro and fluoro. A specific halogen is chloro.

The term "heteroaryl" refers to a monovalent aromatic heterocycle consisting of 5 to 12 ring atoms comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S and the remaining ring atoms are carbon, System. Examples of heteroaryl groups include pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, Benzothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofurancyl, benzimidazolyl, isothiazolyl, benzothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, isothiazolyl, , Benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl and quinoxaline Work. A specific heteroaryl group is pyridinyl. In addition, 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 salts "refers to salts which possess the biological effectiveness and properties of the free bases or free acids and which are biologically otherwise preferred. Such salts include those derived from 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, , Citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N- acetylcysteine and the like. In addition, such salts can 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 Ethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resin and the like. Specific pharmaceutically acceptable salts of the compounds of formula I include hydrochloride salts, methane sulfonic acid salts and citric acid salts.

"Pharmaceutically acceptable ester" means that the compound of formula I is derivatized at the 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 esters, methylthiomethyl esters and pivaloyloxymethyl esters. Also within the scope of the invention are any physiologically acceptable equivalents of compounds of formula I, analogous to the metabolically labile esters, which are capable of producing the parent compound of formula I in vivo.

The term "protecting group (PG)" refers to a group that selectively blocks the reactive sites of a polyfunctional compound so that the chemical reaction can be selectively performed at other unprotected reactive sites in a conventionally relevant sense in synthetic chemistry. The protecting group may be removed at an appropriate point in time. An exemplary protecting group is an amino-protecting group, a carboxy-protecting group, or a hydroxy-protecting group. 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 a micromolar and is equivalent to the symbol "mu M ".

In addition, the compounds of the present invention may contain isotopes of atoms in an abnormal ratio in at least one of the atoms constituting such compounds. For example, the present invention provides isotopically-labeled compounds of the invention as described herein, except that one or more atoms are replaced with atoms having a different atomic mass or mass number, ≪ / RTI > Any isotope of any specified atom or element is contemplated to be within the scope of the compounds of the invention and their uses. Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, isotopes of carbon, isotopes of nitrogen, isotopes of oxygen, isotopes of phosphorus, isotopes of sulfur, isotopes of fluorine, isotopes of fluorine, isotopes of the element, and 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 , a ^{33 P, 35 S, 18 F} , 36 Cl, 123 I and ¹²⁵ I. Certain isotopically labeled compounds of the invention (e. G. Labeled with ³ H or ¹⁴ C) are useful in compound and / or substrate tissue distribution assays. Tritiated ( ³ H) isotopes and carbon-14 ( ¹⁴ C) isotopes are useful for their ease of manufacture and detection. In addition, substitution using heavier isotopes such as deuterium (i.e., ² H) may provide a specific therapeutic advantage (e.g., reduced in vivo half-life or reduced dosage requirements) from greater metabolic stability And for this reason it 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 to study substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by substituting isotopically labeled reagents with non-isotopically labeled reagents according to procedures similar to those described in the following Schemes and / or Examples. In particular, compounds of formula I wherein at least one H atom is replaced by a ² H atom are also embodiments of the invention.

The compounds of formula (I) may contain a large number of asymmetric centers and may be prepared from optically pure enantiomers, mixtures of enantiomers, for example racemates, optically pure diastereoisomers, mixtures of diastereoisomers, Or in the form of mixtures of racemates or diastereoisomeric racemates.

According to the Cahn-Ingold-Prelog Convention, an asymmetric carbon atom may be in an " R "or" S "

An embodiment of the present invention also relates to the compounds of formula I and their pharmaceutically acceptable salts or esters described herein, particularly the compounds of formula I and their pharmaceutically acceptable salts described herein, more particularly the compounds of formula I < / RTI >

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

(I)

In this 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, 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 said 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 embodiments of the invention are compounds of formula I as described herein wherein A is -S (O) ₂ -.

Another embodiment of the invention are the compounds of formula I as described herein wherein A is -C (O) -.

Also, a specific embodiment of the present invention is a compound of formula I as described herein wherein B is -C-.

Another embodiment of the invention are the compounds of formula I as described herein, wherein R < ¹² > is cycloalkyl or substituted pyridinyl, wherein said substituted pyridinyl is substituted with 1 to 3 substituents independently selected from H, alkyl and halogen to be.

A particular embodiment of the invention are the compounds of formula I as described herein, wherein R < ¹² > is cycloalkyl or substituted pyridinyl, wherein said substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen.

A further aspect of the invention is a compound of formula I as described herein wherein R < ¹² > is cycloalkyl.

A further additional aspect of the invention are the compounds of formula I as described herein, wherein R < ¹² > is substituted heteroaryl, said substituted heteroaryl being optionally substituted with 1 to 3 substituents independently selected from alkyl and halogen.

Another specific embodiment of the present invention is that wherein R ¹² is substituted pyridinyl, substituted imidazolyl or substituted pyrazolyl, said substituted pyridinyl, substituted imidazolyl and substituted pyrazolyl being optionally substituted with one alkyl or Lt; RTI ID = 0.0 > (I) < / RTI >

Another specific embodiment of the present invention are the compounds of formula I as described herein, wherein R < ¹² > is substituted pyridinyl, wherein said substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen.

Another embodiment of the present invention are the compounds 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 the compounds of formula I as described herein wherein R < ¹ > and R < ² > are methyl.

Also, a specific embodiment of the present invention is a compound of formula I as described herein wherein m, n and p are 0.

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

A specific embodiment of the invention are the compounds of formula I as described herein wherein R < ³ > and R < ⁴ >

Another aspect of the invention is a compound of formula (I) as set forth in the R ^5, R ⁷ and R ⁹ are H herein.

Also, a specific embodiment of the present invention is a compound of formula I as described herein, wherein R ⁹ is H and R ¹⁰ and R ¹¹ together form - (CH ₂ ) _w -.

A particular embodiment of the invention are the compounds of formula I as described herein wherein R < ¹⁴ > is H or alkyl.

A further specific embodiment of the invention are the compounds of formula I as described herein wherein R < ¹⁴ > is H.

Also embodiments of the invention are compounds of formula I as described herein wherein R < ¹³ > is cyano or halogen.

A further specific embodiment of the invention is the compound of formula I, wherein R < ¹³ > is chloro, as described herein.

A more specific embodiment of the present invention is a compound of formula I as described herein wherein R < ¹⁵ >

Specific examples of the compounds of formula (I) or pharmaceutically acceptable salts thereof as described herein include

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

5-Chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3-yl) -methylamino] pyridin-3-yl] -3,3-dimethylisoindol-1-one;

3-yl] - methylamino] pyridin-3-yl] -3,3-dimethyl isoindole- 1-one;

3-yl] - methylamino] pyridin-3-yl] -3,3-dimethyl isoindole- 1-one;

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

3-yl] amino] pyridin-3-yl] -3,3-dimethylisoindol-1- On;

3-yl] amino] pyridin-3-yl] -3,3-dimethylisoindol-1- On;

Azetidin-3-yl] amino] pyridin-3-yl] -3,3-dimethylisoindole-1 -On;

3-yl] amino] pyridin-3-yl] isoindole-1 < RTI ID = 0.0 &-On;

3-yl] amino] pyridin-3-yl] isoindole-1 < RTI ID = 0.0 &-On;

3-yl] amino] pyridin-3-yl] -3-methyl-3H-isoindole-1 -On;

3-yl] amino] pyridin-3-yl] -3H-isoindole-1 < / RTI &-On;

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

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

Azetidin-3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;

Azetidin-3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;

3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On; And

3.3] heptan-6-yl] amino] pyridin-3-ylmethyl] -3-methyl-2- [5- [ -Yl] isoindol-1-one

.

Further, specific examples of the compound of the formula (I) or a pharmaceutically acceptable salt thereof include

Amino] -3-pyridyl] isoindole-1-carboxylic acid methyl ester was prepared from 5-chloro-3,3-dimethyl-2- [5- [[1- (1-methylimidazole- 1-one;

Azetidin-3-yl] amino] -3-pyridyl] -3,4-dihydro-5H-pyrrolo [ Isoquinolin-1-one;

3-yl] amino] -3-pyridyl] -3,4-dihydroisoquinoline-2-carboxylic acid 1-one;

Azetidin-3-yl] amino] -3-pyridyl] -3,4-dihydroisoquinoline < / RTI >Lt; / RTI >

3-yl] amino] -3-pyridyl] -3,3-dimethyl-isoquinolin- - isoindolin-1-one;

3-yl] amino] -3-pyridyl] isoindoline (hereinafter referred to as "Lt; / RTI >

(3R or 3S) -5-chloro-3-methyl-2- [5 - [[1- (4-methylpyridine-3-carbonyl) azetidin- Indolin-1-one;

(3S or 3R) -5-chloro-3-methyl-2- [5 - [[1- (4-methylpyridine- 3-carbonyl) azetidin- Indolin-1-one;

(3R or 3S) -5-chloro-2- [5- [[l- (3- chloropyridine-2- carbonyl) azetidin- Isoindolin-1-one;

(3S or 3R) -5-chloro-2- [5 - [[l- (3- chloropyridine-2- carbonyl) azetidin- Isoindolin-1-one;

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

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

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

3-yl] amino] -3-pyridyl] -1-oxo-isoindoline (hereinafter referred to as "-5-carbonitrile;

3-yl] amino] -3-pyridyl] -1-oxo-isoindole-1-carboxylic acid 5-carbonitrile;

Amino] -3-pyridyl] -1-oxo-iso < / RTI >Indolin-5-carbonitrile;

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

Amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline (hereinafter referred to as "-5-carbonitrile;

3-dimethyl-2- [5 - [[1- (4-methylpyridine-3-carbonyl) -4-piperidyl] amino] -3-pyridyl] -5-carbonitrile;

Azetidin-3-yl] amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline -5-carbonitrile;

Amino] -3-pyridyl] -1-oxo-iso < / RTI >Indolin-5-carbonitrile;

3-dimethyl-2- [5 - [[1- (1-methylpyrazole-4-carbonyl) -4-piperidyl] amino] -3-pyridyl] 5-carbonitrile;

3-dimethyl-2- [5 - [[1- (1-methylimidazole-2-carbonyl) -4-piperidyl] amino] -3-pyridyl] Indolin-5-carbonitrile; And

3-dimethyl-2- [5 - [[1- (3-methylimidazole-4-carbonyl) -4-piperidyl] amino] -3-pyridyl] Indolin-5-carbonitrile

.

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

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

3-yl] - methylamino] pyridin-3-yl] -3,3-dimethyl isoindole- 1-one;

3-yl] amino] pyridin-3-yl] isoindole-1 < RTI ID = 0.0 &-On; And

3-yl] amino] pyridin-3-yl] isoindole-1 < RTI ID = 0.0 & -On

.

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

Amino] -3-pyridyl] isoindole-1-carboxylic acid methyl ester was prepared from 5-chloro-3,3-dimethyl-2- [5- [[1- (1-methylimidazole- 1-one;

Azetidin-3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;

3-yl] amino] -3-pyridyl] -3,4-dihydroisoquinoline-2-carboxylic acid 1-one;

3-yl] amino] -3-pyridyl] isoindoline (hereinafter referred to as "Lt; / RTI >

(3R or 3S) -5-chloro-3-methyl-2- [5 - [[1- (4-methylpyridine-3-carbonyl) azetidin- Indolin-1-one;

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

Amino] -3-pyridyl] -1-oxo-iso < / RTI > Indolin-5-carbonitrile

.

The process for preparing the compounds of formula (I) as described herein is an object of the present invention.

The preparation of compounds of formula I of the present invention can be carried out by sequential or converging synthetic routes. The synthesis of the present invention is shown in the following reaction formula. The techniques necessary to perform the reaction and purification of the resulting product are well known to those skilled in the art. When a mixture of enantiomers or diastereoisomers is produced in the course of the reaction, such enantiomers or diastereomers can be separated by methods described herein or by methods known to those skilled in the art, such as chiral chromatography or crystallization. The substituents and indications used in the following description of this method have the meanings provided herein.

The following abbreviations are used herein:

Acyl = acetic acid, BOC = t-butyloxycarbonyl, BuLi = butyllithium, CDI = 1,1- carbonyldiimidazole, DCM = dichloromethane, DBU = 2,3,4,6,7,8, DCE = 1,2-dichloroethane, DIBALH = di-i-butyl aluminum hydride, DCC = N, N'-dicyclohexyl Carbodiimide, DMA = N, N-dimethylacetamide, DMAP = 4-dimethylaminopyridine, DMF = N, N- dimethylformamide, EDCI = N- (3- Et ₃ O = diethyl ether, Et ₃ N = triethylamine, eq = equivalent, HATU = O- (7-azabenzotriazol- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate, HPLC = high performance liquid chromatography, HOBT = 1-hydroxybenzo-triazole, Huenig base = iPr ₂ NEt = N-ethyldiisopropylamine, IPC = Of the process control, LAH = Lithium aluminum hydride, LDA = lithium diisopropyl amide, LiBH ₄ = Lithium borohydride, MeOH = methanol, NaBH ₃ CN = hydride as a hydride, NaBH ₄ = sodium beam sodium cyanoborohydride , 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.

(I), potassium carbonate or cesium carbonate in a solvent, such as 1,4-dioxane, in the presence of a halogen or a triflate, preferably an iodo-substituted pyridine compound (2 or 8) , Chelated 1,2-diamino compounds such as N, N'-dimethylethylenediamine or trans-1,2-diamino-cyclohexane, or chelated beta- ketoester compounds such as 2-isobutyryl- Is reacted with the aryl lactam (1) with the aid of the preferred microwave heating at elevated temperature in the presence of cyclohexanone to form the lactam substituted heterocyclic compounds (3 and 5) (step a). The amino compound (4 or 6) (a known compound or a compound which can be easily prepared by methods known in the art) is reacted under similar conditions to the conditions used in step a (step b) (Pd (OAc) ₂ , and chelating at elevated temperature in a solvent such as dioxane in the presence of Buchwald's conditions, such as a base such as t-BuONa, Is reacted with a substituted pyridine compound (3) by using a ligand, for example, a compound (5 or 7) by using conditions (preferred conditions for the secondary amino compound (4 or 6) Compound (5) having a protecting group, for example a Boc group R ¹⁰¹ , can then be converted to compound (7) by removing protecting group R ¹⁰¹ and reacting with a suitable activated carboxy or sulfonyl compound (steps c, d ; Scheme 1a and 1b).

[Reaction Scheme 1a]

In Scheme 1a above,

X is halogen or OSO ₂ CF ₃ and;

R < ¹⁰¹ > is a suitable protecting group.

[Reaction Scheme 1b]

In Scheme 1b above,

X is halogen or OSO ₂ CF ₃ and;

R ¹⁰¹ is a suitable protecting group or AR ¹² .

The carbamate 101 (Scheme 2a) is reacted with polyphosphoric acid at elevated temperature (e.g., 100-180 占 폚) to form the 3,4-dihydro-2H-isoquinolin-1-one derivative 102 a). (103) is cyclized by treatment with paraformaldehyde in a mixture of concentrated sulfuric acid and acetic acid, preferably at about room temperature to give l- (3,4-dihydro-lH-isoquinolin- , 2,2-trifluoro-ethanone Compound (104) can be obtained. For example, by treatment with potassium hydroxide in a solvent, such as ethanol, at a temperature near room temperature to provide the tetrahydro-isoquinoline compound 105 (step c), by removing the trifluoroacetyl group. Dihydro-2H-isoquinolin-1-one (102) is provided by oxidation of the tetrahydro-isoquinoline compound (105) with, for example, iodobenzene and potassium bromide, preferably in water Step d). The isoindole-1,3-dione compound 106 (scheme 2b) is reacted with a Grignard reagent R ¹ MgX, preferably at about 0 ° C in a solvent such as THF to provide the adduct 107 Step e). Subsequent treatment with triethylsilane and boron trifluoride etherate in a solvent, such as dichloromethane, preferably at a temperature in the range of -25 ° C to RT provides the isoindole compound 108 (step f). The isoindole compound 109 is treated with sodium bis (trimethylsilyl) amide and 1-bromomethyl-4-methoxy-benzene in THF at 0 < 0 & ) Protected compound 110 (step g); Similarly, a methoxybenzyl protecting group can be introduced into compound (108). After treatment of compound (108) or compound (110) with an additional methoxybenzyl protecting group in a solvent such as THF with a base such as sodium hydride, 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) with 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 preferably it provides one or sequentially two different alkyl halides, mesylates, or by treatment with a tosylate or a structurally structurally the same, R ¹ and R ² compound (111) having a group at the reflux temperature of the solvent to -78 ℃ (Step h). The protecting group is removed, for example, by treatment with trifluoroacetic acid at elevated temperature to provide isoindole compound 112 (step i). Alternatively, compound (114), wherein R ¹ and R ² are alkyl groups, is reacted with a cyano compound (113) and a suitable Grignard reagent, preferably in the presence of titanium tetra-isopropoxide in a solvent such as THF Two different reagents may be added sequentially at a temperature preferably in the range of 0 ° C to RT, or an excess of a single Grignard reagent (to obtain compounds having the same R ¹ and R ² ) can be obtained (step k ). (Step k) after obtaining compound 114, wherein R ¹ = H and R ² is an alkyl group, from cyano compound 113 and a suitable Grignard reagent in a solvent such as THF, preferably at a temperature in the range of 0 ° C to RT, For example, an imine formed by using sodium borohydride in the vicinity of RT in methanol is reduced (step k). Compound 114 can be reacted with a catalyst in the presence of carbon monoxide in an autoclave, for example in DMF, in the presence of a base, such as iPr ₂ Net, preferably at a temperature in the range of about 100 to 150 ° C, such as dichloro [ (Diphenylphosphino) -ferrocene] palladium (II) (step l).

[Reaction Scheme 2a]

[Reaction Scheme 2b]

[Reaction Scheme 2c]

Halogen or triflate substituted compounds (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).

[Reaction Scheme 3]

In Scheme 3,

X is halogen or OSO ₂ CF ₃ and;

R ¹⁰¹ is a suitable protecting group or AR ¹² .

In addition, aspects of the present invention

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

; 또는

; or

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

Lt; RTI ID = 0.0 > (I) < / RTI > comprising:

In this 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 Lt; / RTI > are as described herein;

X in step a) is halogen or triflate;

X in step b) is halogen.

In particular, step a) may be carried out using copper (I) iodide, potassium carbonate or cesium carbonate, chelated 1,2-diamino compounds such as N, N'-dimethylethylenediamine or trans- For example 1,4-dioxane, with the aid of the preferred microwave heating at elevated temperature in the presence of a suitable base, such as hexane, or a chelated beta- ketoester compound such as 2-isobutyryl-cyclohexanone.

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 comprised between -10 ° C and RT.

It is also an object of the present invention to provide a compound of formula I as described herein for use as a therapeutically active substance.

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

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

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

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

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

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

Another specific aspect of the invention is a compound of formula I as described herein for the treatment or prevention of renal fibrosis or cardiomyopathy.

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

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

The 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 prevention 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 prevention of renal fibrosis or cardiomyopathy.

It is also the use of a compound of formula I as described herein for the manufacture of a medicament for the treatment or prophylaxis of the chronic renal disease of the present invention.

In addition, aspects of the invention are the use of a compound of formula I as described herein for the manufacture of a medicament for the treatment or prevention of congestive heart failure.

An aspect of the invention is also the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of hypertension.

In addition, aspects of the invention are the use of a compound of formula (I) as described herein for the manufacture of a medicament for the treatment or prevention of primary aldosteronism.

Also, an object of the present invention is a method for the treatment or prevention 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.

It is also an object of the present invention to provide a method of treating or preventing diabetic nephropathy comprising administering an effective amount of a compound of formula I as described herein.

It is also an object of the present invention to provide a method for the treatment or prevention of renal fibrosis or cardiac fibrosis comprising administering an effective amount of a compound of formula I as described herein.

Also, embodiments of the invention are methods of treating or preventing chronic kidney disease, comprising administering an effective amount of a compound of formula (I) as described herein.

Also, embodiments of the invention are methods of treating or preventing congestive heart failure, comprising administering an effective amount of a compound of formula (I) as described herein.

Also, embodiments of the invention are methods of treating or preventing hypertension comprising administering an effective amount of a compound of formula (I) as described herein.

Also, embodiments of the invention are methods of treating or preventing primary aldosteronism, comprising administering an effective amount of a compound of formula (I) as described herein.

Also embodiments of the invention are compounds of formula I as described herein, prepared according to any of the methods described.

Analysis procedure

Herein, the present inventors confirmed the use of the G-402 cell line as a host cell to express (temporarily or stably) a CYP11 family of enzymes. Specifically, the present inventors have developed stable G-402 cells expressing human CYP11B1, human CYP11B2, human CYP11A1, cynomologus CYP11B1, or cynomolgus CYP11B2 enzyme activity ectopically. Significantly, the confirmed cell line G-402 expressed important co-factors (adrenocortin and adrenoceptor reductase) for the activity of the CYP11 family, and any relevant enzymatic activity of the CYP11 family (compared to H295R cells) Lt; / RTI > Thus, the G-402 cell line is uniquely suited as a host cell for isoform expression of the enzyme from the CYP11 family.

G-402 cells can be obtained from the ATCC (CRL-1440) and originally originated from the renal epithelial leiomyomas.

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

G-402 cells expressing the CYP11 construct were identified as described above and were cultured at 37 占 폚 under an atmosphere of 5% CO ₂ /95% air, containing 10% FCS and 400 μg / mL G418 (Geneticin) McCoy's 5a Medium Modified (ATCC Catalog No. 30-2007). Cellular enzyme assays were performed in DMEM / F12 medium containing 2.5% charcoal treated FCS and an appropriate concentration of substrate (0.3-10 μM 11-deoxycorticosterone, 11-deoxycortisol or corticosterone). To analyze the enzyme activity, cells were plated on 96-well plates and incubated for 16 hours. Subsequently, aliquots of the supernatant were transferred and analyzed for the expected product concentration (aldosterone for CYP11B2; cortisol for CYP11B1). The concentration of such steroids can be measured using HTRF analysis from CisBio, which analyzes aldosterone or cortisol.

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

[Equation 1]

In this 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.

The 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 [mu] M deoxycorticosterone and a variable amount of inhibitor; Cyp11B1 enzyme activity was tested in the presence of 1 [mu] M deoxycortisol and a variable amount of inhibitor.

The compounds of formula I and their pharmaceutically acceptable salts or esters described herein have an EC ₅₀ (CYP11B2) value of 0.000001 to 1000 μM, a specific compound has an EC ₅₀ (CYP11B2) value of 0.00005 to 500 μM, more specific compounds of 0.0005 to 50 μM has a EC ₅₀ (CYP11B2) values, more specific compounds have EC ₅₀ (CYP11B2) value ranging from 0.0005 to 5 μM. These results were obtained by using the above enzyme analysis.

The compounds of formula I and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, for example, orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), into the nasal cavity (E.g., in the form of suppositories). However, administration can also be performed parenterally, e.g., intramuscularly or intravenously (e.g., in the form of injection solutions).

The compounds of formula I and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic auxiliaries for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts 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 materials and liquid polyols and the like.

Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, galena, glucose and the like.

Suitable adjuvants for injection 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, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. In addition, they may contain another therapeutically valuable substance.

The dosage can vary widely and will, of course, be tailored to the individual requirements in each particular case. Generally, in the case of oral administration, for example, about 0.1 to 20 mg / kg body weight, preferably about 0.5 to 4 mg / kg body weight, divided into 1 to 3 individual doses, kg body weight (e.g., about 300 mg / person) should be appropriate. It is evident, however, that the upper limit provided herein may be exceeded if indicated to be indicated.

In accordance with the present invention, compounds of formula I, or pharmaceutically acceptable salts and esters thereof, can be used for the treatment or prevention of aldosterone mediated diseases.

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

In accordance with the present invention, the compounds of formula I or their pharmaceutically acceptable salts and esters are useful for the treatment of cardiovascular diseases (including hypertension and heart failure), vascular diseases, endothelial dysfunction, Inflammatory diseases, retinopathy, neuropathy (e.g., peripheral neuropathy), pain, insulinopathy, edema, edematous disease, depression, and the like.

Cardiovascular diseases include congestive heart failure, coronary heart disease, arrhythmia, atrial fibrillation, cardiac lesions, reduced ejection fraction, dilated and contractile heart dysfunction, coronary fibrosing necrosis, cardiac fibrosis, hypertrophic cardiomyopathy, damaged arterial flexibility, diastolic filling, ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrosis lesion, cardiac arrhythmia, sudden cardiac death, restenosis, stroke, vascular injury.

Kidney diseases include, but are not limited to, acute and chronic renal failure, kidney disease, end stage renal disease, diabetic kidney disease, reduced creatinine clearance, reduced glomerular filtration rate, swelling of the reticulated vascular septum matrix with or without significant hypervascularity, thrombosis, global fibrinoid necrosis, glomerulosclerosis, ischemic lesion, malignant neuropathy (e.g., ischemic shrinkage, microalbuminuria, proteinuria, reduced renal blood flow, renal artery disease, endothelial and vascular occlusion) And / or infiltration and proliferation of extracapillary cells (crescent)).

In addition, the renal disease may be selected from the group consisting of glomerulonephritis (e.g., proliferative proliferative, local proliferative, angiostatic, proliferative, microglial glomerulonephritis), lupus nephritis, non- ), Renal fibrosis and glomerulosclerosis (e.g., nodular or complete and local segmental glomerulosclerosis).

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

Vascular diseases include, but are not limited to, thrombotic vascular diseases (e. G., Wall fibrosing necrosis, erythrocytic extravasation and division of red blood cells, and tubal and / or wall thrombosis), proliferative arterial disease (Eg, swollen intimal endothelial cells and nodular hypertrophy), atherosclerosis, reduced vascular compliance (eg, rigidity, reduced ventricular flexibility and reduced vascular compliance), endothelial dysfunction, and the like.

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

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

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

Insulinophores 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 intrinsic fibrosis, kidney fibrosis and hepatic fibrosis.

In addition, the compounds of formula (I) or pharmaceutically acceptable salts and esters thereof 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 therapeutic-resistant hypertension.

In another embodiment, the cardiovascular disease is heart failure.

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

In another embodiment, cardiovascular disease is congestive heart failure in a patient having a more specifically conserved 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, can be used for the treatment or prevention of kidney diseases.

In another embodiment, the kidney disease is kidney disease.

In another embodiment, the renal disease is autoimmune glomerulonephritis.

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

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

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

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

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

The invention is illustrated by way of non-limiting embodiments.

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

Example

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

Intermediate A-1

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

[A] [2- (3- Chloro - Phenyl )-ethyl]- Carbamic acid methyl  Ester

From 0 ℃, methyl chloroformate (4.6 g, 48 mmol) of 2- (3-chloro-phenyl) in DCM (100 mL) ethylamine (5.0 g, 32 mmol) and Et ₃ N (6.4 g, 64 < / RTI > mmol). After the addition, the mixture was stirred at room temperature for 0.5 hour. 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 ^& lt ^{; +} & gt ^; ).

[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) Lt; / RTI > 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. Then, the mixture was extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and filtered. After removal of the solvent under reduced pressure, the resultant 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 ^& lt ^{; +} & gt ^; ).

Intermediate A-2

5- Chloro -3- methyl -2,3- Dihydro - Isoindole -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 SIMILAR 5 DEG C for 5 hours, MeOH (500 mL) was added dropwise. The solution was stirred for a further 15 minutes, the mixture is noted by the addition of _{NaBH 4 (28 g, 740 mmol} ) and the resulting mixture was stirred at room temperature for 16 hours. The reaction solution was then 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 to give the crude product in vacuo and it was purified by column chromatography to give the title compound (30 g, 34.6%) (petroleum ether: 1: EtOAc = 3) As a yellowish oil. MS: 235.5 [M + H ^& lt ^{; +} & gt ^; ].

[B] 5- Chloro -3- methyl -2,3- Dihydro - Isoindole -1-one

(30 g, 127.9 mmol), Pd (dppf) Cl ₂ (3.2 g, 12.79 mmol) and DIPEA (49.5 g, 383.7 mmol) in DMF (1.2 L) mmol) was stirred in an autoclave at 2O < 0 > C under 2 MPa of CO for 24 h. After cooling the reaction product 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 ^& lt ^{; +} & gt ^; ].

Intermediate A-3

5- Chloro -3,3- Dimethyl -2,3- Dihydro - Isoindole -1-one

[A] 1- (2- Bromo -5- Chloro - Phenyl )-One- methyl - Ethylamine

MeMgBr (77 mL, 230 mmol) was added dropwise to a stirred solution of 2-bromo-5-chloro-benzonitrile (10 g, 46 mmol) in THF (200 mL) at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Ti (Oi-Pr) ₄ (13 g, 46 mmol) was added and the solution was stirred for an additional 16 h before it was quenched with aqueous HCl solution and washed with EtOAc. The aqueous phase was adjusted to 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 ^& lt ^{; +} & gt ^; ) [

[B] 5- Chloro -3,3- Dimethyl -2,3- Dihydro - Isoindole -1-one

(3.8 g, 15.3 mmol), Pd (dppf) CI ₂ (0.4 g, 0.55 mmol) and DIPEA (0.5 g) in DMF (20 mL) (6 g, 45.9 mmol) was stirred in an autoclave at 2O < 0 > C under 2 MPa 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 afford the title compound (1.13 g, 38%) as a brown solid. MS: 195.70 (M + H ^& lt ^{; +} & gt ^; ) [

Intermediate A-4

3,3- Dimethyl -1-oxo-2,3- Dihydro -1H- Isoindole -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 thionylchloride (20.25 mL, 0.28 mol) and the reaction mixture was stirred at 70 & 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 <0> C for 5 hours and then poured into ice-water. The solid precipitate was collected by vacuum filtration to yield a 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

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) ) Was heated at reflux temperature 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- Isoindole -5- Carbonitrile

THF (300 mL) solution of 2-bromomethyl-4-cyano-benzoic acid methyl ester was added to _{PMBNH 2 (23.4 g, 178.1 mmol} ) at 0 ℃ To a solution of (18.1 g, 71.24 mmol), at room temperature and the reaction mixture Lt; / RTI &gt; for 16 h. After vacuum filtration, the filtrate was concentrated in vacuo. The residue obtained 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- Isoindole -5-car Bonit 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) g, 208.4 mmol, 60% in mineral oil) was added and the reaction mixture was stirred at room temperature for 1 hour before iodomethane (35.5 g, 250.1 mmol) was added. After the addition, the reaction mixture was stirred at 70 &lt; 0 &gt; C for 2 hours until all starting material was consumed. After cooling to room temperature, a saturated aqueous NH ₄ Cl solution was added and the mixture was extracted with EtOAc (200 mL x 3). 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 (7.22 g, 56.5%) as a solid.

[F] 3,3- Dimethyl -1-oxo-2,3- Dihydro -1H- Isoindole -5- Carbonitrile

To a solution of 2- (4-methoxy-benzyl) -3,3-dimethyl-l-oxo-2,3-dihydro-lH-isoindole-5- carbonitrile (3.5 g, 11.42 mmol ) At 0 C was added CAN (18.79 g, 34.27 mmol) in water (30 mL). The resulting reaction mixture was stirred at 0 &lt; 0 &gt; 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 to give the crude product under reduced pressure, and was purified by column chromatography to give (1.06 g, 49.8%) solid .

Intermediate A-5

3,5- Taiyodo - pyridine

To a solution of 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- , 2-diamine (4.4 g, 50.4 mmol) was stirred at 110 &lt; 0 &gt; C for 16 hours. During this period, the progress of the reaction was monitored by LC / MS. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a solid which was then 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 ^& lt ^{; +} & gt ^; ). This was used in the next step without further purification.

Intermediate A-6

3- [5- (6- Chloro -1,1- Dimethyl -3-oxo-1,3- Dihydro - Isoindole Yl) -pyridin-3- Amino ] - Azetidine -One- Carboxy acid tert - butyl ester

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

(Intermediate A-5, 6.6 g, 20 mmol), 5-chloro-3,3-dimethyl-2,3-dihydro-isoindole- (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 &lt; 0 &gt; C for 3 h before it was poured into water (50 mL) and extracted with EtOAc (2 x 125 mL). The combined organic layers are washed with brine, dried over anhydrous Na ₂ SO _4, filtered, and the obtained crude product was concentrated in vacuo and 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 ^& lt ^{; +} & gt ^; ).

[B] 3- [5- (6- Chloro -1,1- Dimethyl -3-oxo-1,3- Dihydro - Isoindole Yl) -pyridin-3- Amino ] - Azetidine -One- Carboxy acid tert - butyl ester

To a solution of 5-chloro-2- (5-iodo-pyridin-3-yl) -3,3-dimethyl-2,3-dihydro-isoindol- 1 -one (2.16 g, 5.4 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-isopropyl Butylyl-cyclohexanone (0.36 mL, 2.16 mmol) was stirred at 100 &lt; 0 &gt; C for 12 hours. 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 the obtained crude product was concentrated in vacuo, which was purified by silica gel flash chromatography (30-100% EtOAc- hexanes gradient) to give the title compound (1.1 g , 48%) as a pale yellow foam. MS: 443.2 (M + H ^& lt ^{; +} & gt ^; ).

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

[Table 1]

Example  One

5- Chloro -2- [5 - [(1- Cyclopropylsulfonyl azetidine Yl) amino] pyridin-3-yl] -3,3-di This methyl iso Indol-1-one

[A] 2- [5- ( Azetidine -3- Amino ) -Pyridin-3-yl] -5- Chloro -3,3- Dimethyl -2,3-dihydro- Isoindole -1-one

To a solution of 3- [5- (6-chloro-l, l-dimethyl-3-oxo-l, 3- dihydro-isoindol-2- yl) -pyridin- 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 hours. 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 ^& lt ^{; +} & gt ^; ).

[B] 5- Chloro -2- [5 - [(1- Cyclopropylsulfonyl azetidine Yl) amino] pyridin-3-yl] -3,3- Dimethyl isoindole -1-one

To a solution of 2- [5- (azetidin-3-ylamino) -pyridin-3-yl] -5-chloro-3,3- dimethyl-2,3-dihydro-isoindole- -one (56 mg, 0.163 mmol) and Et ₃ N cycles adding a propane sulfonyl chloride (30 mg, 0.21 mmol) at 0 ℃ to a stirred solution of (0.5 mL) and continued for 1 hour and stirred at 0 ℃ Respectively. Extracting the resulting reaction mixture with EtOAc (2 x 100 mL), washed the combined organic layers with brine, dried over anhydrous Na ₂ SO _4, filtered, and the obtained crude product was concentrated in vacuo and was purified by preparative -HPLC The title compound (22 mg, 30%) was obtained as a white foam. MS: 447.1 (M + H ^& lt ^{; +} & gt ^; ).

Example  2

5- Chloro -3,3- Dimethyl -2- [5 - [[1- (1- Methylimidazole -2-carbonyl) Azetidine Yl] amino] -3- Pyridyl ] Isoindoline -1-one

To a solution of 2- [5- (azetidin-3-ylamino) -pyridin-3-yl] -5-chloro-3,3- dimethyl-2,3-dihydro-isoindole- - one (example 1 [a], 56 mg, 0.163 mmol) and Et ₃ N (0.5 mL) at room temperature was added HATU (124 mg, 0.326 mmol) and 1-methylimidazole-2-carboxy of Acid (27 mg, 0.212 mmol) was added and stirring was continued at room temperature for 1 hour. Extracting the resulting reaction mixture with EtOAc (2 x 50 mL) and the combined organics were washed with brine and dried over anhydrous Na ₂ SO _4, filtered, and the obtained crude product was concentrated in vacuo and was purified by preparative -HPLC The title compound (15.4 mg, 21%) was obtained as a white foam. MS: 451.1 (M + H ^& lt ^{; +} & gt ^; ).

Example  3

5- Chloro -2- [5 - [(1- Cyclopropylsulfonyl azetidine -3 days)- Methyl amino ] Pyridin-3-yl] -3,3- Dimethyl isoindole -1-one

[A] 3 - {[5- (6- Chloro -1,1- Dimethyl -3-oxo-1,3- Dihydro - Isoindole Yl) -pyridin-3-yl] - methyl -Amino} - Azetidine -One- Carboxy acid tert - butyl ester

To a solution of 5-chloro-2- (5-iodo-pyridin-3-yl) -3,3-dimethyl-2,3-dihydro-isoindol- 1- one (398 mg, 3-methylamino-azetidine-1-carboxylic acid tert-butyl ester (250 mg, 1.3 mmol), Pd (OAc) ₂ (35 mg, 10% (70 mg, 20% by weight) and t-BuONa (192 mg, 2 mmol) was stirred at 115 &lt; 0 &gt; C for 2 hours. 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 the obtained crude product was concentrated in vacuo, which was purified by silica gel flash chromatography (40-100% EtOAc- hexanes gradient) to give the title compound (196 mg , 43%) as a pale yellow foam. MS: 457.1 (M + H ^& lt ^{; +} & gt ^; ).

[B] 2- [5- ( Azetidine -3 days- methyl -Amino) -pyridin-3-yl] -5- Chloro -3,3- Dimethyl -2,3- Lee Hi Draw- Isoindole -1-one

To a solution of 3 - {[5- (6-chloro-1,1-dimethyl-3-oxo-l, 3-dihydro-isoindol-2-yl) -pyridin- 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 hours. It was then concentrated in vacuo to give the crude product as a pale yellow foam. This was used in the next step without further purification. MS: 357.2 (M + H ^& lt ^{; +} & gt ^; ).

[C] 5- Chloro -2- [5 - [(1- Cyclopropylsulfonyl azetidine -3 days)- Methyl amino ] Pyridin-3-yl] -3,3- Dimethyl isoindole -1-one

To a solution of 2- [5- (azetidin-3-yl-methyl-amino) -pyridin-3-yl] -5-chloro-3,3-dimethyl- 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 cyclopropanesulfonyl chloride (31 mg, 0.22 mmol) Lt; / RTI &gt; The resulting mixture was extracted with EtOAc (2 x 100 mL) and the combined organics were washed with brine and dried over anhydrous Na ₂ SO _4, filtered, and the obtained crude product was concentrated in vacuo and purified by preparative -HPLC title The compound (19 mg, 24%) was obtained as a white foam. MS: 461.1 (M + H ^& lt ^{; +} & gt ^; ).

Example  4 and Example  5

(+) - 5- Chloro -2- [5 - [[(3R or 3S) -1- Cyclopropylsulfonylpyrrolidine Yl] -methylamino] pyridin-3-yl] -3,3- Dimethyl isoindole One and (-) - 5- Chloro -2- [5 - [[(3S or 3R) -1- Cyclopropylsulfonylpyrrolidine -3 days]- Methyl amino ] Pyridin-3-yl] -3,3-di This methyl isoindole -1-one

[A] 3 - {[5- (6- Chloro -1,1- Dimethyl -3-oxo-1,3- Dihydro - Isoindole Yl) -pyridin-3-yl] - methyl -Amino} - Pyrrolidine -One- Carboxy acid tert - butyl ester

The title compound was obtained as a pale yellow foam (47%) using 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester in a similar manner to the procedure described in the preparation of Example 3 [A]. MS: 471.1 (M + H ^& lt ^{; +} & gt ^; ).

[B] 5- Chloro -3,3- Dimethyl -2- [5- ( methyl - Pyrrolidine 3-yl-amino) -pyridin-3-yl] -2,3- Dihydro - Isoindole -1-one

Example 3 By a similar procedure to that described in the preparation of [B] the title compound was obtained as a crude product of a yellow foam. This was used in the next step without further purification. MS: 371.2 (M + H ^& lt ^{; +} & gt ^; ).

[C] ( rac ) -5- Chloro -2- {5 - [(1- Cyclopropylsulfonyl - Pyrrolidine -3 days)- methyl -Amino] -pyridin-3-yl} -3,3- Dimethyl -2,3- Dihydro - Isoindole -1-one

Example 3 Using a similar procedure to that described for the preparation of [C], the title compound (105 mg, 40%) was obtained as a racemic mixture of white foam using cyclopropanesulfonyl chloride. MS: 475.1 (M + H ^& lt ^{; +} & gt ^; ).

[D] (+) - 5- Chloro -2- [5 - [[(3R or 3S) -1- Cyclopropylsulfonylpyrrolidine -3 days]- Methyl amino ] Pyridin-3-yl] -3,3- Dimethyl isoindole -1-one ( Example  4) and (-) - 5- Claw RTI ID = 0.0 &gt; 2- [5 - [[(3S or 3R) -1- Cyclopropylsulfonylpyrrolidine -3 days]- Methyl amino ] Pyridin-3-yl] -3,3- Dimethyl isoindole -1-one ( Example  5)

To a solution of (rac) -5-chloro-2- {5 - [(1 -cyclopropylsulfonyl-pyrrolidin- ] - pyridin-3-yl} -3,3-dimethyl-2,3-dihydro-isoindol-1-one 3-yl] -3,3-dimethylisoindol-1-one (10 mg, 20 &lt; RTI ID = 0.0 & %, in example 4; MS: 475.1 (M + H +)) and (-) - 5-chloro -2- [5 - [[(3S or 3R) -1- cyclopropyl-3-yl sulfone ilpi ] - 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 Respectively.

The examples listed in Table 2 were prepared in analogy to the procedures 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 the active ingredient for the preparation of tablets of the following composition:

Example  B

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

Claims (30)

Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &
(I)

In this 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, 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 said 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; The method according to claim 1,
A is -S (O) ₂ -. 3. The method according to claim 1 or 2,
A is -C (O) -. 4. The method according to any one of claims 1 to 3,
Wherein R ¹² is cycloalkyl or substituted pyridinyl, wherein said substituted pyridinyl is substituted with 1 to 3 substituents independently selected from H, alkyl and halogen. 5. The method according to any one of claims 1 to 4,
Wherein R ¹² is cycloalkyl or substituted pyridinyl, wherein said substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen. 6. The method according to any one of claims 1 to 5,
Wherein R &lt; ¹² &gt; is cycloalkyl. 6. The method according to any one of claims 1 to 5,
Wherein R ¹² is substituted heteroaryl, wherein said substituted heteroaryl is substituted with 1 to 3 substituents independently selected from alkyl and halogen. 8. The method according to any one of claims 1 to 5 and 7,
Wherein R ¹² is substituted pyridinyl, wherein said substituted pyridinyl is substituted with 1 to 3 substituents independently selected from alkyl and halogen. 9. The method according to any one of claims 1 to 8,
R &lt; ¹ &gt; and R &lt; ² &gt; are independently selected from H and alkyl. 10. The method according to any one of claims 1 to 9,
Wherein R &lt; ¹ &gt; and R &lt; ² &gt; are alkyl. 11. The method according to any one of claims 1 to 10,
R ¹ and R ² are methyl. 12. The method according to any one of claims 1 to 11,
m, n and p are 0. 13. The method according to any one of claims 1 to 12,
and w is 1 or 2. 14. The method according to any one of claims 1 to 13,
R &lt; ³ &gt; and R &lt; ⁴ &gt; are H. 15. The method according to any one of claims 1 to 14,
R &lt; ⁵ &gt;, R &lt; ⁷ &gt; and R &lt; ⁹ &gt; 16. The method according to any one of claims 1 to 15,
R ⁹ is H, and R ¹⁰ and R ¹¹ together form - (CH ₂ ) _w -. 17. The method according to any one of claims 1 to 16,
Wherein R &lt; ¹⁴ &gt; is H. 18. The method according to any one of claims 1 to 17,
R &lt; ¹³ &gt; is chloro. 19. The method according to any one of claims 1 to 18,
Wherein R &lt; ¹⁵ &gt; is H. 20. The method according to any one of claims 1 to 19,
5-chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3-yl) amino] pyridin-3-yl] -3,3-dimethylisoindol-1-one;
5-Chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3-yl) -methylamino] pyridin-3-yl] -3,3-dimethylisoindol-1-one;
3-yl] - methylamino] pyridin-3-yl] -3,3-dimethyl isoindole- 1-one;
3-yl] - methylamino] pyridin-3-yl] -3,3-dimethyl isoindole- 1-one;
5-Chloro-2- [5 - [(1-cyclopropylsulfanylpiperidin-4-yl) -methylamino] pyridin-3-yl] -3,3-dimethylisoindol-1-one;
3-yl] amino] pyridin-3-yl] -3,3-dimethylisoindol-1- On;
3-yl] amino] pyridin-3-yl] -3,3-dimethylisoindol-1- On;
Azetidin-3-yl] amino] pyridin-3-yl] -3,3-dimethylisoindole-1 -On;
3-yl] amino] pyridin-3-yl] isoindole-1 &lt; RTI ID = 0.0 &-On;
3-yl] amino] pyridin-3-yl] isoindole-1 &lt; RTI ID = 0.0 &-On;
3-yl] amino] pyridin-3-yl] -3-methyl-3H-isoindole-1 -On;
3-yl] amino] pyridin-3-yl] -3H-isoindole-1 &lt; / RTI &-On;
5-chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3-yl) amino] pyridin-3-yl] -3-methyl-3H-isoindol-1-one;
6-chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3-yl) amino] pyridin-3-yl] -3,4-dihydroisoquinolin-1-one;
Azetidin-3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;
Azetidin-3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;
3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;
3.3] heptan-6-yl] amino] pyridin-3-ylmethyl] -3-methyl-2- [5- [ -Yl] isoindol-1-one;
Amino] -3-pyridyl] isoindole-1-carboxylic acid methyl ester was prepared from 5-chloro-3,3-dimethyl-2- [5- [[1- (1-methylimidazole- 1-one;
Azetidin-3-yl] amino] -3-pyridyl] -3,4-dihydro-5H-pyrrolo [ Isoquinolin-1-one;
3-yl] amino] -3-pyridyl] -3,4-dihydroisoquinoline-2-carboxylic acid 1-one;
Azetidin-3-yl] amino] -3-pyridyl] -3,4-dihydroisoquinoline &lt; / RTI &gt;Lt; / RTI &gt;
3-yl] amino] -3-pyridyl] -3,3-dimethyl-isoquinolin- - isoindolin-1-one;
3-yl] amino] -3-pyridyl] isoindoline (hereinafter referred to as &quot;Lt; / RTI &gt;
(3R or 3S) -5-chloro-3-methyl-2- [5 - [[1- (4-methylpyridine-3-carbonyl) azetidin- Indolin-1-one;
(3S or 3R) -5-chloro-3-methyl-2- [5 - [[1- (4-methylpyridine- 3-carbonyl) azetidin- Indolin-1-one;
(3R or 3S) -5-chloro-2- [5- [[l- (3- chloropyridine-2- carbonyl) azetidin- Isoindolin-1-one;
(3S or 3R) -5-chloro-2- [5 - [[l- (3- chloropyridine-2- carbonyl) azetidin- Isoindolin-1-one;
(3R or 3S) -5-chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3- yl) amino] -3-pyridyl] -3-methyl-isoindolin- ;
(3S or 3R) -5-chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3- yl) amino] -3-pyridyl] -3-methyl-isoindolin- ;
2- [5 - [(1 -cyclopropylsulfonyl azetidin-3-yl) amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
3-yl] amino] -3-pyridyl] -1-oxo-isoindoline (hereinafter referred to as &quot;-5-carbonitrile;
3-yl] amino] -3-pyridyl] -1-oxo-isoindole-1-carboxylic acid 5-carbonitrile;
Amino] -3-pyridyl] -1-oxo-iso &lt; / RTI &gt;Indolin-5-carbonitrile;
2- [5 - [(1-cyclopropylsulfonyl-4-piperidyl) amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile;
Amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline (hereinafter referred to as &quot;-5-carbonitrile;
3-dimethyl-2- [5 - [[1- (4-methylpyridine-3-carbonyl) -4-piperidyl] amino] -3-pyridyl] -5-carbonitrile;
Azetidin-3-yl] amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline -5-carbonitrile;
Amino] -3-pyridyl] -1-oxo-iso &lt; / RTI &gt;Indolin-5-carbonitrile;
3-dimethyl-2- [5 - [[1- (1-methylpyrazole-4-carbonyl) -4-piperidyl] amino] -3-pyridyl] 5-carbonitrile;
3-dimethyl-2- [5 - [[1- (1-methylimidazole-2-carbonyl) -4-piperidyl] amino] -3-pyridyl] Indolin-5-carbonitrile; And
3-dimethyl-2- [5 - [[1- (3-methylimidazole-4-carbonyl) -4-piperidyl] amino] -3-pyridyl] Indolin-5-carbonitrile
&Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof. 21. The method according to any one of claims 1 to 20,
5-chloro-2- [5 - [(1-cyclopropylsulfonyl azetidin-3-yl) amino] pyridin-3-yl] -3,3-dimethylisoindol-1-one;
3-yl] - methylamino] pyridin-3-yl] -3,3-dimethyl isoindole- 1-one;
3-yl] amino] pyridin-3-yl] isoindole-1 &lt; RTI ID = 0.0 &-On;
3-yl] amino] pyridin-3-yl] isoindole-1 &lt; RTI ID = 0.0 &-On;
Amino] -3-pyridyl] isoindole-1-carboxylic acid methyl ester was prepared from 5-chloro-3,3-dimethyl-2- [5- [[1- (1-methylimidazole- 1-one;
Azetidin-3-yl] amino] pyridin-3-yl] -3,4-dihydroisoquinoline-l- -On;
3-yl] amino] -3-pyridyl] -3,4-dihydroisoquinoline-2-carboxylic acid 1-one;
3-yl] amino] -3-pyridyl] isoindoline (hereinafter referred to as &quot;Lt; / RTI &gt;
(3R or 3S) -5-chloro-3-methyl-2- [5 - [[1- (4-methylpyridine-3-carbonyl) azetidin- Indolin-1-one;
2- [5 - [(1 -cyclopropylsulfonyl azetidin-3-yl) amino] -3-pyridyl] -3,3-dimethyl-1-oxo-isoindoline-5-carbonitrile; And
Amino] -3-pyridyl] -1-oxo-iso &lt; / RTI &gt; Indolin-5-carbonitrile
&Lt; / RTI &gt; 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 a compound of formula IV in the presence of a compound of formula V:

22. A process for preparing a compound according to any one of claims 1 to 21, comprising:
In this 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 21,
A compound for use as a therapeutically active substance. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a therapeutically inert carrier. 21. The use of a compound according to any one of claims 1 to 21 for the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome. 22. The method according to any one of claims 1 to 21,
A compound for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome. 21. The use of a compound according to any one of claims 1 to 21 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. 21. A method for the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and Cushing's syndrome, comprising administering an effective amount of a compound according to any one of claims 1 to 21. 22. The method according to any one of claims 1 to 21,
29. A compound according to claim 22 which is prepared according to the process of claim 22. The invention as hereinbefore described.