RU2783521C1 - Human cytochrome 11b2 inhibitors - Google Patents

Abstract

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to a compound of the general formula (I) or its pharmaceutically acceptable salt, where R1 is selected independently and is: (C1-C5)-alkyl, which is replaced by a nitrile group, (C3-C7)-cycloalkyl, a 5-6-membered heterocycle containing 1 oxygen atom and/or 1 nitrogen atom and optionally substituted with 1-2 R2 substituents, a 5-6-membered heteroaryl containing 1 sulfur atom and/or 1-2 nitrogen atoms and optionally substituted with 1-2 R3 substituents, a C6-aryl, optionally substituted with 1-4 R4 substituents, a bicycle consisting of a phenyl ring connected to a 5-membered heterocycle, containing -C(=O)-, 1 nitrogen atom and optionally substituted with 1-3 R5 substituents; R2 is selected independently and is hydrogen, -C(=O)-CH₃; R3 is selected independently and is hydrogen, (C1-C3)-alkyl or partially or completely halogenated (C1-C3)-alkyl; R4 is selected independently and represents hydrogen, halogen, (C1-C3)-alkyl, -O(C1-C3)-alkyl, -CONR6''R7''; R5 is selected independently and represents hydrogen, (C1-C3)-alkyl; R6'' is selected independently and represents (C2-C3)-alkyl; R7'' is selected independently and represents (C2-C3)-alkyl; alternatively, R6'' and R7'' together with the nitrogen atom to which they are attached can form a 5-7-membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur; Q1 is selected independently and is a carbon or nitrogen atom, optionally substituted with hydrogen, halogen; Q2 is selected independently and it is a carbon atom, optionally substituted with hydrogen; Q3 is selected independently and is a carbon atom, optionally substituted with hydrogen, (C1-C3)-alkyl, and (C1-C3)-alkyl may optionally be partially or completely halogenated; Q4 is selected independently and is a carbon or nitrogen atom, optionally substituted with hydrogen; Q5 is selected independently and is a carbon or nitrogen atom, optionally substituted with hydrogen; n is selected independently and represents 1 or 2; dotted bonds mean that the ring is aromatic; or connection 1-(4-((4-( pyridine-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-yl)sulfonyl)phenyl)ethane-1-on with the formula

The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: new compounds and a pharmaceutical composition based on them have been obtained that can be used in medicine for the treatment and/or prevention of a disease or condition that is mediated or supported by aldosterone hyper-synthesis.

45 cl, 2 tbl, 18 ex

Description

This invention relates to organic chemistry, pharmacology, medicine, namely the invention relates to compounds for use in inhibiting the activity of human cytochrome 11B2 (CYP11B2) and their use in the treatment and/or prevention of various diseases and disorders that are mediated or supported by the activity of the hormone aldosterone. The present invention also relates to pharmaceutical compositions containing the compounds of the invention and methods for preparing these compounds.

BACKGROUND OF THE INVENTION

Aldosterone is a steroid hormone whose main physiological role is to maintain the balance of sodium and potassium by regulating cation exchange (Na + reabsorption and K + secretion) in the distal nephron, which in turn leads to an increase in blood pressure. In addition to its physiological role, aldosterone is also involved in the pathogenesis of diseases or pathological conditions caused (primary hyperaldosteronism) and/or accompanied by its hypersynthesis (secondary hyperaldosteronism), including a number of diseases of the cardiovascular system, kidneys and metabolic syndrome.

Modern approaches to the treatment of conditions caused and/or accompanied by hypersynthesis of aldosterone include the impact on various levels of the renin-angiotensin-aldosterone system (RAAS). Modern standards of care are represented by such classes of drugs as renin inhibitors (IRs), angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), and mineralocorticoid receptor (MR) blockers. However, in 25-50% of patients treated with IRs, ARBs, and ACE inhibitors alone or in combination, serum aldosterone levels eventually return to pre-treatment levels or higher (aldosterone breakthrough) (Bomback et al., 2007, Nature Clinical Practice. Nephrology, 3, 486-492; Bomback et al., 2012, J Am Soc Hypertens, 6(5):338-45), and administration of MR blockers results in a compensatory increase in serum aldosterone levels (Pitt at al., 2013, Eur Heart J, 34:2453-2463; Calhoun et al., 2011, Circulation, 124, 1945-1955). In this regard, to date, there is still no solution that can fully cover all the pathological effects of aldosterone in humans, including both MR-mediated and non-MR-mediated effects. The latter include the following: a) acting through GPER receptors, aldosterone has a so-called “rapid effect”, leading to apoptosis and preventing the proliferation of vascular endothelial and smooth muscle cells [Namsolleck et al., 2014, Nephrology, Dialysis, Transplantation, 29(Suppl. 1), i62-i68), impaired vasoconstriction (Feldman et al., 2013, Clinical and Experimental Pharmacology & Physiology, 40, 916-921) and endothelial inflammation [Ziwei Tang et al., 2021, International Journal of Endocrinology, Volume 2021 , Article ID 5575927]. In addition, recent in vitro and ex vivo studies have shown that aldosterone, also through GPER activation, enhances CYP11B2 gene expression and therefore enhances its own biosynthesis and release (Caroccia et al., 2019, The Journal of Clinical Endocrinology & Metabolism, Volume 104 , Issue 12, 6316-6324); b) damage to pancreatic beta cells (Luther et al., 2011, Diabetologia, 54, 2152-2163; Fang Chen et al., 2015, Scientific Reports volume 5, Article number: 13215 (2015), which can lead to tolerance to glucose c) interaction with IGF-I receptors in vascular smooth muscle cells with stimulation of elastin production by fibroblasts (Mitts et al., 2010, Journal of Investigative Dermatology, Volume 130, Issue 10, 2396-2406) , to vascular remodeling and point to a mechanism by which aldosterone can accelerate the development of atherosclerosis (Cascella et al., 2010, Endocrinology, 151(12):5851-64); d) induction of vasoconstriction through protein kinase C-dependent pathways, possibly through membrane receptors, which leads to deterioration of contractile and metabolic functions of the heart in ischemic hearts, therefore, an increase in plasma or cardiac tissue aldosterone levels may have an adverse effect in coronary heart disease ( Fujita et al., 2005, Hypertension, 46(1):113-7); e) MP-independent activation of potassium current (IK1) by aldosterone has been shown to be the main mechanism explaining the increase in ventricular arrhythmia and sudden cardiac death accompanied by high aldosterone levels during ST-segment elevation myocardial infarction (STEMI) (Alexandre et al., 2015, PLoS One v.10(7) f) dimerization of the angiotensin II receptor (AT1) by aldosterone may play an important role in pathological conditions including hypertension and atherosclerosis (Sinphitukkul et al., 2019, Arch Med Sci, 15(6) :1589-1598). In addition, aldosterone has demonstrated a non-genomic endothelium-independent vasoconstrictor effect, also mediated through the AT1 receptor (Yamada et al., 2008, Cardiovasc Res, 79(1):169-78).

Based on the foregoing, it follows that the inhibition of aldosterone synthesis will have a therapeutic advantage over existing therapies, as well as overcome the limitations of existing standards of care.

Aldosterone is synthesized by a single enzyme, CYP11B2 (aldosterone synthase), which catalyzes a 3-step conversion of 11-deoxycorticosterone (11-DOC) to aldosterone via corticosterone and 18-hydroxycorticosterone, so CYP11B2 is a potential therapeutic target for inhibiting aldosterone synthesis, which may have an excellent pharmacodynamic profile. from that observed in other RAAS modulators.

DISCLOSURE OF THE INVENTION

BRIEF DESCRIPTION OF THE INVENTION

In its multiple embodiments, the present invention provides novel chemicals capable of inhibiting the activity of the human CYP11B2 enzyme, and their biological activity has been investigated. Thus, the invention relates to compounds, pharmaceutical compositions containing these compounds, the use of the compounds, methods of their use in the treatment of various diseases and disorders, as well as methods for obtaining these compounds.

DETAILED DESCRIPTION OF THE INVENTION

The compounds disclosed herein inhibit the activity of the human CYP11B2 enzyme and their biological activity has been investigated.

Thus, the invention relates to compounds, pharmaceutical compositions containing these compounds, the use of these compounds, methods of their use in the treatment of various diseases and disorders, as well as methods for obtaining these compounds.

In one embodiment, the present invention provides a compound of general formula (I).

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1 is chosen independently and is:

- (C1-C5)-alkyl, which may be optionally substituted with a nitrile group,

- C1-alkyl or C3-C5-alkyl, which may optionally be substituted with a C1-C3-alkylsulfonyl group,

- (C3-C7)-cycloalkyl optionally substituted with 1-3 R2 substituents,

- 5-7 membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, and optionally substituted with 1-2 R2 substituents,

- 5-7 membered heteroaryl containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, and optionally substituted with 1-2 R3 substituents,

C6-aryl optionally substituted with 1-4 R4 substituents,

11-membered bicycle consisting of a phenyl ring connected to a 5-membered heterocycle containing -C(=O)-, 1-2 nitrogen atoms, and optionally substituted with 1-3 R5 substituents;

R2 is independently selected and is hydrogen, deuterium, halogen, -C(=O)-CH ₃ , (C1-C3)-alkyl or (C1-C3)-alkyl substituted with 1-7 halogen atoms;

R3 is independently selected and is hydrogen, deuterium, halogen, (C1-C3) alkyl, or partially or fully halogenated (C1-C3) alkyl;

R4 is independently selected and is hydrogen, deuterium, halogen, (C1-C3)-alkyl optionally substituted with 1-7 halogen atoms, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1- C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen atoms, -SO ₂ NR6'R7', -CONR6''R7'', -(C1 -C3)-alkyl-O-(C1-C3)-alkyl, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;

R5 is independently selected and is a keto group -C(=O), hydrogen, deuterium, halogen, (C1-C3) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, or partially or fully halogenated ( C1-C3)-alkyl;

R6 ' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

R7 ' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

alternatively, when R6 ' is methyl, then R7 ' is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl, or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl;

alternatively R6 ' and R7 ' together with the nitrogen atom to which they are attached may form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur;

R6 '' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

R7 '' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with (C1-C3)-alkyl;

alternatively whenR6'' is methyl, thenR7'' is (C1-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

alternatively, R6 '' and R7 '', together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur;

Q1 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, where (C1-C3)-alkyl may optionally be partially or fully halogenated;

Q2 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, where (C1-C3)-alkyl may optionally be partially or fully halogenated;

Q3 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, where (C1-C3)-alkyl may optionally be partially or fully halogenated;

Q4 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, where (C1-C3)-alkyl may optionally be partially or fully halogenated;

Q5 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, where (C1-C3)-alkyl may optionally be partially or fully halogenated;

n is independently selected and is 1, 2 or 3;

dashed bonds mean the ring is aromatic.

In another embodiment, the present invention includes a compound of Formula (IIa):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2 or 3;

X1 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, and (C1-C3)-alkyl, optionally partially or fully halogenated;

X2 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, with (C1-C3)-alkyl optionally partially or fully halogenated;

X3 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, and (C1-C3)-alkyl, optionally partially or fully halogenated;

X4 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, and (C1-C3)-alkyl, optionally partially or fully halogenated;

t is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of Formula (IIb1) or Formula (IIb2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2 or 3;

dotted bonds mean that the rings are aromatic;

Z1 is independently selected and represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z2 is independently selected and represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z3 is independently selected and represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z4 is independently selected and represents a carbon, nitrogen, oxygen or sulfur atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z5 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z6 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z7 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z8 is independently selected and is a carbon or nitrogen atom optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated;

Z9 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated.

In another embodiment, the present invention includes a compound of Formula (IIc):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2 or 3;

R8 is independently selected and is hydrogen, deuterium, halogen, (C1-C3)-alkyl optionally substituted with 1-7 halogens, (C2-C3)-alkenyl, (C2-C3)alkynyl, -O-(C1-C3 )-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SO ₂ NR6'R7', -CONR6''R7'', (C1-C3 )-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;

R9 is independently selected and is hydrogen, deuterium, halogen, (C1-C3)-alkyl optionally substituted with 1-7 halogen atoms, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1- C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen atoms, -SO ₂ NR6'R7', -CONR6''R7'', -(C1 -C3-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;

R10 is independently selected and is hydrogen, deuterium, halogen, (C1-C3)-alkyl optionally substituted with 1-7 halogen atoms, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1- C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SO ₂ NR6'R7', -CONR6''R7'', (C1- C3)-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;

R11 is independently selected and is hydrogen, deuterium, halogen, (C1-C3)-alkyl optionally substituted with 1-7 halogen atoms, (C2-C3)-alkenyl, (C2-C3)-alkynyl, -O-(C1- C3)-alkyl, 5-7-membered heterocycle containing 0-2 oxygen atoms, 0-2 sulfur and/or 0-3 nitrogen, -SO ₂ NR6'R7', -CONR6''R7'', (C1- C3)-alkoxy, (C3-C7)-cycloalkyloxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyloxy;

R6 ' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

R7 ' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)cycloalkyl or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl;

alternatively, when R6 ' is methyl, then R7 ' is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl, or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl,

alternatively R6 ' and R7 ' together with the nitrogen atom to which they are attached may form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur;

R6 '' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one C1-C3)-alkyl;

R7 '' is independently selected and is hydrogen, (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

alternatively whenR6'' is hydrogen, thenR7'' is (C2-C3)-alkyl, (C3-C7)-cycloalkyl or (C3-C7)-cycloalkyl substituted with one (C1-C3)-alkyl;

alternatively, R6 '' and R7 '', together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur;

n is independently selected and is 1, 2 or 3;

dotted bonds mean the rings are aromatic.

In another embodiment, the present invention includes a compound of Formula (IId):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

A1 is independently selected and is -C(=O)-, carbon or nitrogen, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl , (C3-C7)-cycloalkyl or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl, wherein (C1-C3)-alkyl may be optionally substituted with 1-7 halogen atoms;

A2 is independently selected and is -C(=O)-, carbon or nitrogen, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl , (C3-C7)-cycloalkyl or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl, wherein (C1-C3)-alkyl may be optionally substituted with 1-7 halogen atoms;

A3 is independently selected and is -C(=O)-, carbon or nitrogen, optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl , (C3-C7)-cycloalkyl or C3-C7-cycloalkyl substituted with one (C1-C3)-alkyl, wherein (C1-C3)-alkyl may be optionally substituted with 1-7 halogen atoms;

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of Formula (IIe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1e is independently selected and is:

- (C1-C5)-alkyl optionally substituted with a nitrile group,

- C1-alkyl or (C3-C5)-alkyl optionally substituted with (C1-C3)-alkylsulfonyl group,

- (C3-C7)-cycloalkyl group;

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of Formula (III):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1 , Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

In another embodiment, the present invention includes a compound of Formula (IIIa):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

X ₅ is independently selected and represents a carbon or nitrogen atom,

X ₆ is chosen independently and represents an atom of carbon, oxygen, nitrogen, sulfur, andX ₅ andX ₆ optionally substituted with hydrogen, deuterium, halogen, (C1-C3)-alkyl, ethan-1-one, (C1-C3)-alkyl substituted with 1-7 halogen atoms,

m1 and m2 are chosen independently and are 0, 1, 2, reception m1+m2 <4.

In another embodiment, the present invention includes a compound of general Formula (IIIb1) or Formula (IIIb2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

Z1 , Z2 , Z3 , Z4 , Z5 , Z6 , Z7 , Z8 , Z9 take the values as described above in the description of formula (IIb1) and (IIb2);

dotted bonds mean the rings are aromatic.

In another embodiment, the present invention includes a compound of general Formula (IIIc):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R8 , R9 , R10 , R11 are as defined above in the description of formula (IIc);

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

dotted bonds mean the rings are aromatic.

In another embodiment, the present invention includes a compound of general Formula (IIId):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

A1 , A2 , A3 take the values as described above in the description of formula (IId).

In another embodiment, the present invention includes a compound of general Formula (IIIe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1e take the values as described above in the description of formula (IIe);

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

n is 1,2 or 3.

In another embodiment, the present invention includes a compound of general Formula (IV):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1 , Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I).

In another embodiment, the present invention includes a compound of general Formula (IVa):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

X ₅ and X ₆ take the values as described above in the description of formula (IIIa);

t and m are chosen independently and are 0, 1, 2, with t+m<4.

In another embodiment, the present includes a compound of general Formula (IVb1) and (IVb2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

dotted bonds mean that the rings are aromatic;

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

Z1 , Z2 , Z3 , Z4 , Z5 , Z6 , Z7 , Z8 , Z9 are as defined above in the description of formulas (IIb1) and (IIb2).

In another embodiment, the present includes a compound of general Formula (IVc):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R8, R9, R10, R11 are as defined above in the description of formula (IIc);

Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in the description of formula (I);

dotted bonds mean the rings are aromatic.

In another embodiment, the present invention includes a compound of general Formula (IVd):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

A1 , A2 , A3 take the values as described above in the description of formula (IId).

In another embodiment, the present invention includes a compound of general Formula (IVe):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1e take the values as described above in the description of formula (IIe);

Q1 , Q2 , Q3 , Q4 , Q5 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (V-1):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (V-2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1 take the values as described above in the description of formula (I);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (Va-1):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

X ₅ and X ₆ take the values as described above in the description of formula (IIIa);

t and m are chosen independently and are 0, 1, 2, with t+m<4.

In another embodiment, the present invention includes a compound of general Formula (Va-2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

X ₅ and X ₆ take the values as described above in the description of formula (IIIa);

t and m are chosen independently and are 0, 1, 2, with t+m<4.

In another embodiment, the present invention includes a compound of general Formula (Vb-1):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

dotted bonds mean that the rings are aromatic;

Z1 , Z2 , Z3 , Z4 , Z5 , Z6 , Z7 , Z8 , Z9 take the values as described above in the description of the formula (IIb1 and IIb2);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (Vb-2-1) or Formula (Vb-2-2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, where:

dotted bonds mean that the rings are aromatic;

Z1 , Z2 , Z3 , Z4 , Z5 , Z6 , Z7 , Z8 , Z9 take the values as described above in the description of the formula (IIb1 and IIb2);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (Vc-1):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R8 , R9 , R10 , R11 are as defined above in the description of formula (IIc);

n is independently selected and is 1, 2 or 3;

dotted bonds mean the rings are aromatic.

In another embodiment, the present invention includes a compound of general Formula (Vc-2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R8 , R9 , R10 , R11 are as defined above in the description of formula (IIc);

n is independently selected and is 1, 2 or 3;

dotted bonds mean the rings are aromatic.

In another embodiment, the present invention includes a compound of general Formula (Vd-1):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

A1 , A2 , A3 take the values as described above in the description of formula (IId);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (Vd-2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

A1 , A2 , A3 includes a compound of general formula (IId);

n is independently selected and is 1, 2, or 3.

In another embodiment, the present invention includes a compound of general Formula (Ve-1):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1e take the values as described above in the description of formula (IIe).

In another embodiment, the present invention includes a compound of general Formula (Ve-2):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R1e take the values as described above in the description of formula (IIe).

In another embodiment, the present invention includes a compound of general Formula (VI):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R12 is independently selected and is:

1-acetylpiperidin-3-yl;

4-morpholinyl;

1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl;

1-methyl-1H-pyrazol-4-yl;

3,5-difluoro-4-methoxy-phenyl;

4-(4-morpholinocarbonyl)phenyl;

2-oxo-indolin-5-yl;

1-methyl-2-oxo-indolin-5-yl;

or 4-acetylphenyl.

In another embodiment, the present invention includes a compound of general Formula (VII):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein:

R13 is independently selected and is:

cyclopropyl;

2,5-difluorophenyl;

2,4-difluorophenyl;

1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl;

4-fluoro-3-methylphenyl;

4-fluorophenyl;

3-pyridyl;

thiophen-2-yl;

or cyanomethyl.

In a particular embodiment, the present invention includes compounds selected from the group (names are given in accordance with IUPAC):

1. 5-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)indolin-2-one;

2. 2-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)sulfonyl)acetonitrile;

3. 1-(cyclopropylsulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

4. 4.1-(3-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)piperidin-1-yl)ethane .-1-he;

5. 4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)morpholine;

6. 1-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo [2,3-c]pyridine;

7. 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine;

8. 1-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2, 3,4-tetrahydro-1,7-naphthyridine;

9. 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

10. 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

11. 1-(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)ethan-1-one ;

12. 1-((2,5-difluorophenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

13. 1-((2,4-difluorophenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

14. 1-((4-fluoro-3-methylphenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

15. 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine;

16. 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine;

17. 1-methyl-5-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)indolin-2-one;

18. morpholino(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)methanone.

This invention also relates to the use of the compounds of the invention for the inhibition of CYP11B2.

The present invention also relates to the use of the compounds of the invention to lower the level of aldosterone in a subject.

In particular embodiments of the invention, the subject is a human.

The invention also includes a pharmaceutical composition for the treatment and/or prevention of a disease or condition that is mediated or maintained by aldosterone hypersynthesis, comprising a therapeutically or prophylactically effective amount of a compound of the invention and at least one pharmaceutically acceptable excipient.

In particular embodiments of the invention, the pharmaceutically acceptable excipient is a carrier, adjuvant and/or solvent.

In particular embodiments of the invention, the disease is selected from the group including primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, heart and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.

In particular embodiments of the invention, primary hyperaldosteronism is Conn's syndrome, including the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, familial hyperaldosteronism of the first and second types, aldosterone-producing carcinoma, and aldosteronectopic.

The invention also relates to a method for lowering aldosterone levels in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention.

The invention also includes a method for treating and/or preventing a disease or condition that is mediated or maintained by aldosterone hypersynthesis in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of the invention.

In particular embodiments of the invention, the disease or condition is selected from the group including primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension , coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, heart and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.

In particular embodiments of the invention, primary hyperaldosteronism is Conn's syndrome, including the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, familial hyperaldosteronism of the first and second types, aldosterone-producing carcinoma, and aldosteronectopic.

In particular embodiments of the invention, the subject is a human.

The technical result of the present invention is to develop chemical compounds that are highly effective in inhibiting the activity of human cytochrome 11B2 (CYP11B2). These compounds are promising for the prevention and/or therapy of diseases or pathological conditions or disorders that are mediated or maintained by hypersynthesis of aldosterone.

Detailed disclosure of the invention

Definitions (terms)

For a better understanding of the present invention, below are some of the terms used in the present description of the invention. The following definitions apply in this document unless otherwise stated. In addition, unless otherwise noted, all occurrences of functional groups are selected independently, which may be indicated by the use of a slash to determine that two occurrences can be either the same or different (for example, R, R′, R″, etc. .). In the description of the present invention, the terms "comprises" and "comprising" are interpreted to mean "comprises, among other things." These terms are not intended to be construed as "consisting only of".

The term "alkyl" as used herein, by itself or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the indicated number of carbon atoms, refers to groups typically having from one to ten carbon atoms. For example, the term -C _1-3 -alkyl means methyl, ethyl, propyl, etc. Similar conventions apply to another general term, such as "alkenyl" , where the position of one or more double bonds is defined at any C _2-10 carbon atom. Similar conventions apply to another general term, such as "alkynyl" , where the position of one or more triple bonds is defined at any C _2-10 carbon atom.

The term "partially or fully halogenated" includes branched or straight hydrocarbon chains in which one or more hydrogen atoms have been replaced by a halogen. Examples of haloalkyl groups include, but are not limited to, the following groups: trifluoromethyl, trichloromethyl, -C(CF ₃ ) ₂ CH ₃ , etc.

The term "halogen" by itself or in part of another term refers to a fluorine, chlorine, bromine or iodine atom.

The term "aryl" , unless otherwise indicated, means mono - and bicyclic aromatic rings containing 5-12 carbon atoms, in accordance with Hückel's aromaticity rule: a cyclic, planar molecule has 4n + 2 π (Pi) electrons. Examples of aryl specifically include phenyl, naphthyl.

The term " alkoxy " refers to alkyl groups as defined above, which are attached to the molecule via a bridging oxygen atom. For example, the term " alkoxy " means -O-alkyl, where the alkyl group contains from 1 to 3 carbon atoms in the form of a linear (straight) or branched chain. By way of illustration, alkoxy groups include, but are not limited to, the following groups: methoxy, ethoxy, n-propoxy, etc.

The term "aryl" , whether used alone or as part of a larger moiety such as "aralkyl", "aralkoxy", or "aryloxyalkyl", means aromatic ring containing groups or polycyclic aromatic systems having six to twelve carbon atoms. Examples of useful aryl cyclic groups include, but are not limited to, groups such as phenyl, naphthyl, phenanthryl, anthryl, phenanthro, etc., as well as naphth-1-yl, naphth-2-yl, anthrac-1 -yl and anthrac-2-yl. In addition, the meaning of the term "aryl", as used herein, includes groups in which the aromatic ring is connected to one or more non-aromatic rings, such as indanyl, phenanthridinyl, or tetrahydronaphthyl, in which the radical atom or junction belongs to the aromatic ring. . The term "aryl" also includes monocyclic rings fused to an aryl group. Examples include dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl and the like.

The term "heteroaryl" as used herein means a 5- or 6-membered aromatic ring according to Hückel's aromaticity rule: a cyclic, planar molecule has 4n+2 π (Pi) electrons containing one to 4 heteroatoms selected from nitrogen atoms , oxygen and/or sulfur. Examples of heteroaryl include pyridinyl, pyrazinyl, pyridazinyl, triazinyl, thiophenyl, furanyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isthiothiazolyl, triazolyl, tetrazolyl and the like. The term "heteroaryl" can be used equivalently with the terms "heteroaryl ring" or "heteroaromatic".

The term "heterocycle" in the sense of the invention used here, means 5 -, 7-membered non-aromatic ring containing from one to 4 heteroatoms selected from nitrogen, oxygen and/or sulfur atoms. The definition also includes partially saturated rings. Examples of the heterocycle include azepine, pyrrolidine, piperidine, azepine, oxirane, tetrahydrofuran, tetrahydropyran, oxepan, piperazine, morpholine, thiomorpholine, diazepine, oxazepane, thiazepine, homopiperazine, homomorpholine and the like. The term "heterocycle", "heterocyclyl" or "heterocyclic" also refers to rings, saturated or partially unsaturated, which may be substituted.

This invention contains only such combinations of substituents and derivatives that form a stable or chemically possible compound. A stable or chemically possible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40°C in the absence of reactive conditions, for at least one week.

Unless otherwise stated, the structures of the compounds given in the application materials also imply all stereoisomers, that is, the R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, the present invention embraces each diastereomer or enantiomer substantially free of other isomers (>90%; more preferably >95% molar purity), as well as a mixture of such isomers.

A particular optical isomer can be obtained by separating a racemic mixture according to a standard procedure, for example, by obtaining diastereomeric salts by treatment with an optically active acid or base, followed by separation of the mixture of diastereomers by crystallization, followed by isolating the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate. The resulting diastereomers can be separated by conventional means, such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

Optically active compounds of this invention can be obtained using optically active starting materials. Such isomers may be in free acid, free base, ester or salt form.

The term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term "hydrate" refers to a complex where the solvent molecules are water.

The compounds of the present invention may exist in a radiolabeled form, ie. these compounds may contain one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the most common natural isotopes. Radioisotopes of hydrogen, carbon, phosphorus, chlorine include ³ H, ¹⁴ C, ³² P, ³⁵ S, and ³⁶ Cl, respectively. Compounds of this invention which contain such radioisotopes and/or other radioisotopes of other atoms are within the scope of the present invention. Tritium, i.e. ³ H and carbon, i.e. ¹⁴ C radioisotopes are particularly preferred due to their ease of preparation and detection.

Compounds of the present invention, labeled with radioactive isotopes, can be obtained using methods well known to specialists in this field. Labeled compounds can be prepared using the procedures described here, by simply replacing unlabeled reagents with the appropriate labeled reagents.

The compounds of the present invention may exist in free form or, if required, in the form of a pharmaceutically acceptable salt or other derivative. The term "pharmaceutically acceptable salt" as used herein refers to those salts which, within the limits of medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable ratio of benefit. and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be obtained in situ during the isolation or purification of the compounds of the invention, and can also be obtained separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic acid salts are amino salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids, or obtained other methods used in this field, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanate, valeriate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium, and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic ammonium, quaternary ammonium and amine cations derived from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

By " therapeutically effective amount " is meant that amount of a compound administered or delivered to a patient that is most likely to result in the desired response to treatment (prophylaxis) in the patient. The exact amount required may vary from subject to subject, depending on the age, body weight and general condition of the patient, the severity of the disease, the method of administration of the drug, combination treatment with other drugs, and the like.

The term "patient" embraces all species of mammals, preferably humans, who use the compounds of this invention, either by self-administration and/or administration to a patient by another person, for the treatment and/or prevention of a disease or medical condition.

The terms "treatment" , "therapy" cover the treatment of pathological conditions in mammals, preferably in humans, and include: a) blocking (suspension) of the course of the disease, b) alleviating the severity of the disease, i.e. induction of disease regression.

The term "prevention" , "prevention" , "preventive therapy" covers the elimination of risk factors, as well as prophylactic treatment of subclinical stages of the disease in humans, aimed at reducing the likelihood of clinical stages of the disease. Patients for prophylactic therapy are selected on the basis of factors that, based on known data, entail an increased risk of clinical stages of the disease compared with the general population. Preventive therapy includes a) primary prevention and b) secondary prevention. Primary prevention is defined as prophylactic treatment in patients who have not yet reached the clinical stage of the disease. Secondary prevention is the prevention of the recurrence of the same or a similar clinical disease state.

The term "risk reduction" encompasses therapy that reduces the incidence of the clinical stage of the disease. Examples of disease risk reduction are primary and secondary disease prevention.

Implementation of the invention

Examples

Specific compounds of the invention disclosed herein are provided for purposes of illustrating the present invention so that the invention may be more fully understood. Table 1 shows particular examples of compounds of the invention that can be prepared by the methods described in the General Synthesis Schemes, Examples, and known methods in the art. The methods listed are not exhaustive and are subject to reasonable modifications. These reactions must be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, it is necessary to change the order of the stages or give preference to one of several alternative synthesis schemes. The compounds below are not to be considered as the only examples within the scope of the present invention, and in no way limit the invention.

In particular embodiments of the invention, the compounds of general Formula I are compounds No. 1-18 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.

In particular embodiments of the invention, the compounds of general formula IIa are compounds No. 4-5 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.

In an embodiment of formulas IIb1 and IIb2, the invention relates to a compound selected from the group consisting of 6-10 depicted in Table 1 below, and their pharmaceutically acceptable salts and stereoisomers.

In particular embodiments of the invention, the compounds of general formula IIc are compounds Nos. 11-16 and 18 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.

In particular embodiments of the invention, the compounds of general formula IId are compounds No. 1 and 17 listed in Table 1 below, as well as their pharmaceutically acceptable salts and/or stereoisomers.

General synthesis methods

Optimum reaction conditions and reaction time may vary depending on the specific reagents used. Unless otherwise indicated, solvents, temperatures, pressures, and other reaction conditions can be freely chosen by one skilled in the art.

The general formula of the intermediates for the synthesis (n, R1 and Q1-Q5 are defined as above):

Synthesis intermediates (general structure) and sulfonyl chloride derivatives are either commercially available or readily prepared by methods known to those skilled in the art.

As an example: dimethylaminopyridine or diisopropylethylamine (1.0-4.4 eq.) is added to a solution of the intermediate (1 equiv.) in dichloromethane or benzene, stirred for 15 min, and sulfonyl chloride (1-1.2 equiv. ). The reaction mixture was stirred at room temperature for 18-24 hours. Upon completion, H ₂ O is added and the reaction mixture is extracted. The combined organic fractions are washed with saturated aqueous NaHCO ₃ and dried over Na ₂ SO ₄ . Filtration and removal of the solvent provides crude products, which are purified by liquid chromatography on silica gel to obtain the corresponding reaction products.

Specific procedures for the synthesis of the compounds of the invention are given below.

Synthesis of compounds 1, 4-7, 11, 16-18 according to the invention.

Intermedat A1

2-{1H,2H,3H-pyrrolo[2,3-c]pyridin-4-yl}pyridine dihydrochloride intermediate A1 is either commercially available or readily prepared by methods known to those skilled in the art.

To a solution of 2-{1H,2H,3H-pyrrolo[2,3-c]pyridin-4-yl}pyridine dihydrochloride of intermediate A1 (1 eq.) in dichloromethane (C: 0.1 mmol/mL) at 0°C diisopropylethylamine (4.4 eq.) is added, stirred for 15 min and then the sulfonyl chloride derivative (1.2 eq.) in dichloromethane (C: 0.5 mmol/ml) is added. The reaction mixture was stirred at room temperature for 18 hours. Upon completion, H ₂ O is added and the reaction mixture is extracted with dichloromethane. The combined organic fractions are washed with saturated aqueous NaHCO ₃ and dried over Na ₂ SO ₄ . Filtration and solvent removal provides crude products which are purified by HPLC (silica gel, CHCl ₃ :iPrOH=4:1) to give the corresponding products.

Key intermediates for the synthesis of compounds 1, 4-7, 11, 16-18 according to the invention. Preparation of 2-{1Н,2Н,3Н-pyrrolo[2,3-c]pyridin-4-yl}pyridine dihydrochloride - intermediate A1

A mixture of 1,1-Dimethylethyl 4-bromo-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (CAS#850892-97-6) - intermediate B1 (2 g, 6.7 mmol), Pd(PPh ₃ )4 (0.4 g, 0.34 mmol, 0.05 eq) and 2-(tributylstannyl)-pyridine (5 g, 13.5 mmol, 2 eq) in dioxane (50 ml) are heated to 100°C .In an argon atmosphere. After stirring overnight, the reaction mixture is then cooled to room temperature and concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate, 30-70) to give the desired tert -butyl 4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate intermediate B2 (0.45 g, yield: 22.5%) as a pale yellow oil.

To a mixture of tert -butyl 4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate of intermediate B2 (0.45 g, 1.5 mmol) in MeOH (methanol) (50 ml) add Pt/C (0.06 g, with a Pt content of 10%). The mixture is stirred at 40° C. overnight under a hydrogen atmosphere (50 atm). The mixture is filtered and the filtrate concentrated in vacuo. The resulting residue was purified by HPLC (MeOH/H2O, 15-40%) to give tert -butyl 4-(pyridin-2-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate - intermediate B3 (0.216 g, 50%) as a white solid.

To a solution of tert -butyl 4-(pyridin-2-yl)-1H,2H,3H-pyrrolo[2,3-c]pyridine-1-carboxylate, intermediate B3 (0.216 g, 1 equiv.) in tetrahydrofuran (0. 25 M) add a solution of HCl in dioxane (10%) 10 ml and stir overnight at room temperature. The reaction mixture was concentrated and the residue was treated with methyl tert -butyl ether (20 ml). The resulting solid is filtered and washed with methyl tert -butyl ether, then with hexane and dried in vacuo to give 2-{1H,2H,3H-pyrrolo[2,3-c]pyridin-4-yl}pyridine dihydrochloride - intermediate A1 (0.19 g, 96%) as a white solid.

Synthesis of compounds 2, 3, 8-10, 12-15 according to the invention.

Intermediate A2 (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine) is either commercially available or readily prepared by methods known to those skilled in the art. areas.

To a solution of 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine - intermediate A2 (1 eq.) in benzene (concentration: 0.041 mmol/ml) dimethylaminopyridine (1 eq.) is added, stirred for 15 minutes and then the sulfonyl chloride derivative (1 eq.) is added. The reaction is stirred at room temperature for 24 hours. Within 48 hours, aliquots of dimethylaminopyridine (0.6 eq.) and sulfonyl chloride (0.5 eq.) are added again 4 times. The reaction is stirred at room temperature for 4 hours. Upon completion, the solution is diluted 9 times. The solution is then washed with H ₂ O. The combined organic layers are dried over Na ₂ SO ₄ . Filtration and removal of the solvent provide crude products which are purified by chromatography (silica gel, dichloromethane:methanol=99.5:0.5) to give the corresponding products.

Key intermediates for the synthesis of compounds 2, 3, 8-10, 12-15 according to the invention. Preparation of (5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine) intermediate A2

To a stirred solution of 1,7-naphthyridine-1(2H)-carboxylic acid, 5-bromo-3,4-dihydro-, 1,1-dimethylethyl ether (CAS#2167382-76-3) - intermediate C1 (1.1 g, 3.5 mmol), 2-fluoro-4-(trifluoromethyl)phenylboronic acid (880 mg, 4.2 mmol) and Cs ₂ CO ₃ (1.7 g, 5.2 mmol) in a mixture of dioxane (10 ml ) and water (3 ml) was added with Pd(PPh ₃ ) ₄ (200 mg, 0.15 mmol) under argon. The resulting mixture was stirred at 100° C. overnight. After completion of the reaction, the reaction mixture is diluted with water and dichloromethane. The organic layer is separated, washed with brine, dried over sodium sulfate, filtered and the filtrate is evaporated. The evaporation residue was subjected to silica gel column chromatography eluting with dichloromethane/ethyl acetate (8:2) to give compound 7 (1.2 g, 94%) of the invention.

To a stirred solution of intermediate C2 (1.2 g, 3.0 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (1.8 ml, 22.7 mmol) and the reaction mixture was stirred at room temperature for 12 h. The solvent was evaporated , and the evaporation residue is mixed with dichloromethane (50 ml) and saturated aqueous NaOH solution (final pH 10). The organic layer is separated and filtered through anhydrous sodium sulfate. The filtrate is evaporated under reduced pressure and the evaporation residue is purified by recrystallization from Et ₂ O(diethyl ether)/hexane to give intermediate A2 (800 mg, 90%).

Experimental Analysis

LC-MS analysis of compounds 1, 6, 8, 14, 16, 17 according to the invention

Mass spectra (LCMS, ESI, positive mode) were recorded on an Accela HPLC system in combination with an LCQ Fleet mass detector, mass to charge ratio (m/z) and relative intensity (%) are given for the dominant peaks. HPLC was performed using a C18 HYPERSIL Gold reverse phase column (50 mm x 2.1 mm x 1.9 µm). The mobile phase was acetonitrile (solvent A) in water (solvent B).

LC-MS analysis of compounds 2, 3, 9, 10, 12, 13, 15 according to the invention

Mass spectra (LCMS) were recorded on a Shimadzu 10Avp series analytical HPLC system in combination with a PE SCIEX API 165 mass detector, mass to charge ratio (m/z) and relative intensity (%) are indicated for the dominant peaks. HPLC was performed using a Waters XBridge C18 3.5 µm, 4.6 x 100 mm (100 mm x 4.6 mm x 3.5 µm) reverse phase column. Acetonitrile with trifluoroacetic acid in water was used as the mobile phase.

LC-MS analysis of compounds 4, 5, 7, 11, 17, 18 according to the invention

Mass spectra (LCMS) were recorded on an Agilent 1260 series HPLC system with DAD\ELSD. in combination with an Agilent LC/MSD Mass Spectrometer (G6120B), the dominant peaks are reported as mass-to-charge ratio (m/z) and relative intensity (%). All LC/MS data were acquired using positive/negative mode switching. HPLC was performed using an Agilent Poroshell 120 SB-C18 4, 6x30 mm 2.7 µm reverse phase column with UHPLC Guard Infinity Lab Poroshell 120 SB-C18 4.6 x 5 mm 2.7 µm. Acetonitrile in water containing formic acid was used as the mobile phase.

Example 1

Compound 1: 5-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)indolin-2-one; MW = 392.43; Purity (by HPLC) >95%, APCI [MH]+, m/z 392.95 [M+H]+ (an impurity with m/z 391 [M+H]+ is present in the preparation of the substance).

Example 2

Compound 2: 2-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)sulfonyl)acetonitrile; MW = 399.36; Purity (by HPLC) >95%, MS (TIS+), m/z 400.3 [M+H]+.

Example 3

Compound 3: 1-(cyclopropylsulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 400.39; Purity (by HPLC) >95%, MS (TIS+), m/z 401.4 [M+H]+.

Example 4

Compound 4: 1-(3-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)piperidin-1-yl) ethane-1-one; MW = 386.47; Purity (by HPLC) >95%, MS (ESI+), m/z 387.0 [M+H]+.

Example 5

Compound 5: 4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)morpholine; MW = 346.41; Purity (by HPLC) >95%, MS (ESI+), m/z 347.2 [M+H]+.

Example 6

Compound 6: 1-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H- pyrrolo[2,3-c]pyridine; MW = 405.42; APCI [MH]+, m/z [406.00 [M+H]+ (an impurity with m/z 403.98 [M+H]+ is present in the preparation of the substance).

Example 7

Compound 7: 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; MW = 341.39; Purity (by HPLC) >95%, MS (ESI+), m/z 342.2 [M+H]+.

Example 8

Compound 8: 1-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2 ,3,4-tetrahydro-1,7-naphthyridine; MW = 504.45; Purity (by HPLC) >95%, APCI [MH]+, m/z 505.05 [M+H]+.

Example 9

Compound 9: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 437.41; Purity (by HPLC) >95%, MS (TIS+), m/z 438.3 [M+H]+.

Example 10

Compound 10: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 442.45; Purity (by HPLC) >95%, MS (TIS+), m/z 443.2 [M+H]+.

Example 11.

Compound 11: 1-(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)ethane-1- he; MW = 379.43; Purity (by HPLC) >95%, MS (ESI+), m/z 380.2 [M+H]+.

Example 12.

Compound 12: 1-((2,5-difluorophenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 472.41; (Purity (by HPLC) >95%, MS (TIS+), m/z 473.1 [M+H]+.

Example 13

Compound 13: 1-((2,4-difluorophenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 472.41; Purity (by HPLC) >95%, MS (TIS+), m/z 473.1 [M+H]+.

Example 14

Compound 14: 1-((4-fluoro-3-methylphenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 468.44; Purity (by HPLC) >95%, APCI [MH]+, m/z 469.01 [M+H]+.

Example 15

Compound 15: 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; MW = 454.42; Purity (by HPLC) >95%, MS (TIS+), m/z 455.4 [M+H]+.

Example 16

Compound 16: 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; MW = 403.40; Purity (by HPLC) >95%, APCI [MH]+, m/z 403.98 [M+H]+ (an impurity with m/z 402.24 [M+H]+ is present in the substance preparation).

Example 17.

Compound 17: 1-methyl-5-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)indolin-2-one ; MW = 406.46; Purity (by HPLC) >95%, APCI [MH]+, m/z 407.01 [M+H]+. (in the preparation of the substance there is an impurity with m/z 404.98 [M+H]+).

Example 18.

Compound 18: morpholino(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)methanone; MW = 450.51; Purity (by HPLC) >95%, MS (ESI+), m/z 451.0 [M+H]+.

CHARACTERISTICS OF THE BIOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION

The authors of the present invention investigated the activity of the compounds according to the invention as inhibitors of CYP11B2 when analyzed in a reconstructed system containing 0.5 μm recombinant CYP11B2, 0.3 μm human adrenodoxin reductase, 2 μm human adrenodoxin, 100 μm corticosterone as a control reaction to detect the formation of a product with using an HPLC system with a UV detector. The test compound is added to the reaction mixture to a final concentration of 2 μM. The concentrated protein mixture was diluted with buffer to a final volume of 0.5 ml, pre-incubated for 10 min at 37°C, followed by addition of the substrate. Reactions are initiated by adding NADPH (nicotinamide adenine dinucleotide phosphate) to a final concentration of 0.25 mM with a regenerating system (glucose-6-phosphate and glucose-6-phosphate dehydrogenase) in 25 mM potassium phosphate buffer, pH 7.4, containing 0.1 mM DTT (dithiothreitol) , 0.1% Tween-20.4 mM MgCl ₂ . and incubated at 37°C. After 30 minutes of incubation, the reaction is stopped by adding 5 ml of dichloromethane. The organic phase is isolated by centrifugation, evaporation, dissolution in ethanol and transferred to a vial for HPLC studies. A C18 Luna 100 Å 250x4, 6 mm column was used on an Agilent Technologies 1200 series instrument (USA) with ethanol as the mobile phase.

Activity (a) is calculated as the amount of product in nmol per minute per 1 nmol CYP.

where k is the correction factor (k=1 is used as the molar extinction coefficients of steroid substrates and products similar at the detection wavelength of 254 nm), A _s is the peak area of the substrate, c _s is the concentration of the substrate, A _p is the peak area of the product, c _e is the concentration of CYP (cytochrome P450), t is the reaction time.

The level of inhibition of CYP11B2 activity is expressed as a percentage, where 0% is defined as no inhibition in reactions without test compound and 100% is absolute inhibition by test compound. Compounds of all embodiments of the invention are suitable for inhibiting CYP11B2 activity, and a preferred subgroup includes compounds with inhibition of CYP11B2 activity in the range of 1-100% (+). Within this subgroup, there is another subgroup of more preferred compounds with inhibition of CYP11B2 activity in the range of 20-100% (++). In the latter, there is another subgroup of more preferred compounds with inhibition of CYP11B2 activity in the range of 50-100% (+++). See Table 2. The connection code numbers correspond to the earlier codes given in Table 1.

table 2

Connection number Level of inhibition of CYP11B2 activity one +++ 2 ++ 3 + four ++ 5 +++ 6 +++ 7 +++ eight +++ 9 ++ ten + eleven +++ 12 + 13 + fourteen ++ fifteen + 16 +++ 17 +++ eighteen +++

PHARMACEUTICAL COMPOSITIONS

The invention also relates to pharmaceutical compositions which contain a compound of general formula I, IIa, IIb1, IIb2, IIc, IId, IIe, III, IIIa, IIIb1, IIIb2, IIIc, IIId, IIIe, IV, IVa, IVb1, IVb2, IVc, IVd, IVe, V-1, Va-1, Vb-1-1, Vb-1-2, Vc-1, Vd-1, Ve-1, V-1, Va-2, Vb-2-1, Vb-2-2, Vc-2, Vd-2, Ve-2, VI and VII (or a pro-drug, pharmaceutically acceptable salt or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, diluents and/ or excipients, such as can be administered to a patient along with a compound of the invention that do not interfere with the pharmacological activity of the compound and are non-toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions of this invention contain the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, binders, lubricants, etc. .d. Suitable for the specific dosage form. Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, mono - and oligosaccharides, as well as their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, sesame, olive, corn and soybean oils and others; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffer substances such as magnesium hydroxide and aluminum hydroxide; alginic acid; depyrogenated water; isotonic solution, Ringer's solution; alcohol and phosphate buffer solutions. Other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, filming agents, sweeteners, flavors and fragrances, preservatives and antioxidants may also be included in the composition.

The subject of the present invention are also dosage forms - a class of pharmaceutical compositions, the structure of which is optimized for a certain method of administration to the body in a therapeutic effective dose, for example, for administration to the body intravenously, intramuscularly, orally, subcutaneously, intraocularly, inhalation, intranasal and sublingual, in recommended dosages.

Dosage forms of this invention may contain structures obtained by liposome methods, microencapsulation methods, nanoformulation methods of the drug, or other methods known in the pharmaceutical art.

When preparing a composition, for example in the form of a tablet, the active principle is mixed with one or more pharmaceutical excipients, such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide, Arabic gum, mannitol, microcrystalline cellulose, hypromellose or similar compounds.

Tablets may be coated with sucrose, cellulose derivatives, or other suitable coating agents. Tablets can be prepared in a variety of ways such as direct compression, dry or wet granulation, or hot doping.

A pharmaceutical composition in the form of a gelatin capsule can be obtained by mixing the active principle with a solvent and filling the resulting mixture into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used, the compatible agents of which contain pharmacological agents such as propylene glycol or butylene glycol.

While the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for the purpose of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be clear that various modifications are possible without departing from the essence of the present invention.

THERAPEUTIC METHODS

The compounds of the present invention are inhibitors of CYP11B2 (aldosterone synthase), and therefore they are useful agents for the therapy and/or prevention of diseases or conditions that can be alleviated by lowering the level of aldosterone. Due to their ability to inhibit aldosterone synthase, the compounds of the present invention are useful for the treatment and/or reduction of the risk of developing: primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, heart and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia and insulin resistance.

These disorders are well characterized in humans, but are also present in other mammals with a similar etiology and can be treated with the pharmaceutical compositions of the present invention.

For therapeutic use, the compounds of the invention may be administered by pharmaceutical composition in any pharmaceutical dosage form by any route of administration. Dosage forms generally include a pharmaceutically acceptable carrier suitable for the particular dosage form chosen. In particular, the compound of the invention may be administered daily for a period of time necessary for the treatment and/or prevention of diseases relevant to the patient, including a course of therapy lasting days, months, years or the entire life of the patient. Routes of administration include, but are not limited to, intravenous, intramuscular, oral, subcutaneous, intraocular, inhalation, intranasal, and sublingual. Preferred routes of administration are oral and intravenous.

The invention also relates to a pharmaceutical composition containing a daily dose of said compound in the form of a fixed dosage unit, and to a combination containing said pharmaceutical composition or said compound. In a preferred embodiment, said composition for use according to the invention is administered once a day at a dosage of 1 mg or more of the selected compound of the invention. The preferred dosage is 1-500 mg. The most preferred dosage is 10-200 mg.

One or more additional pharmacologically active agents may be administered in combination with a compound of formula I, IIa, IIb1, IIb2, IIc, IId, IIe, III, IIIa, IIIb1, IIIb2, IIIc, IIId, IIIe, IV, IVa, IVb1, IVb2, IVc, IVd, IVe, V-1, Va-1, Vb-1-1, Vb-1-2, Vc-1, Vd-1, Ve-1, V-1, Va-2, Vb-2- 1, Vb-2-2, Vc-2, Vd-2, Ve-2, VI and VII. Generally, any additional single or multiple active agents other than a compound of Formula I, IIa, IIb1, IIb2, IIc, IId, IIe, III, IIIa, IIIb1, IIIb2, IIIc, IIId, IIIe, IV, IVa, IVb1, IVb2 , IVc, IVd, IVe, V-1, Va-1, Vb-1-1, Vb-1-2, Vc-1, Vd-1, Ve-1, V-1, Va-2, Vb-2 -1, Vb-2-2, Vc-2, Vd-2, Ve-2, VI and VII, including but not limited to antihypertensive agents, antidiabetic agents and/or antiobesity agents, may be used in any combination with the compound formulas I, IIa, IIb1, IIb2, IIc, IId, IIe, III, IIIa, IIIb1, IIIb2, IIIc, IIId, IIIe, IV, IVa, IVb1, IVb2, IVc, IVd, IVe, V-1, Va-1 , Vb-1-1, Vb-1-2, Vc-1, Vd-1, Ve-1, V-1, Va-2, Vb-2-1, Vb-2-2, Vc-2, Vd -2, Ve-2, VI and VII in a single or separate dosage form, allowing simultaneous or sequential therapeutic action of the active agents.

While the invention has been described with reference to the disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for the purpose of illustrating the present invention only and should not be construed as limiting the scope of the invention in any way. It should be clear that various modifications are possible without departing from the essence of the present invention.

Claims (263)

1. Compound of general formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R1 is chosen independently and is: - (C1-C5)-alkyl which is substituted by a nitrile group, - (C3-C7) -cycloalkyl, - 5-6-membered heterocycle containing 1 oxygen atom and/or 1 nitrogen atom and optionally substituted with 1-2 R2 substituents, - 5-6 membered heteroaryl containing 1 sulfur atom and/or 1-2 nitrogen atoms and optionally substituted with 1-2 R3 substituents, - C6-aryl optionally substituted with 1-4 R4 substituents, - bicycle consisting of a phenyl ring connected to a 5-membered heterocycle containing -C(=O)-, 1 nitrogen atom and optionally substituted with 1-3 R5 substituents; R2 is independently selected and is hydrogen, -C(=O)-CH ₃ ; R3 is independently selected and is hydrogen, (C1-C3)-alkyl, or partially or fully halogenated (C1-C3)-alkyl; R4 is independently selected and is hydrogen, halogen, (C1-C3)-alkyl, -O(C1-C3)-alkyl, -CONR6''R7''; R5 is independently selected and is hydrogen, (C1-C3)-alkyl; R6'' is independently selected and is (C2-C3)-alkyl; R7'' is independently selected and is (C2-C3)-alkyl; alternatively, R6'' and R7'', together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur; Q1 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, halogen; Q2 is independently selected and is a carbon atom optionally substituted with hydrogen; Q3 is independently selected and represents a carbon atom optionally substituted with hydrogen, (C1-C3)-alkyl, and (C1-C3)-alkyl may optionally be partially or fully halogenated; Q4 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen; Q5 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen; n is independently selected and is 1 or 2; dotted bonds mean that the ring is aromatic; or compound 1-(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)ethan-1-one with formula

2. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIa):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); n is independently selected and is 1 or 2; X1 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, ethane-1-one; X2 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, ethane-1-one; X3 is independently selected and represents a carbon or nitrogen atom, optionally substituted with hydrogen, ethane-1-one; X4 is independently selected and represents a carbon atom optionally substituted with hydrogen, ethane-1-one; t is chosen independent and is 1 or 2. 3. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIb1) or formula (IIb2):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); n is independently selected and is 1 or 2; dotted bonds mean that the rings are aromatic; Z1 is independently selected and represents a carbon, nitrogen or sulfur atom, optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z2 is independently selected and represents a carbon, nitrogen or sulfur atom, optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z3 is independently selected and represents a carbon, nitrogen or sulfur atom, optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z4 is independently selected and represents a carbon, nitrogen or sulfur atom, optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z5 is independently selected and represents a carbon or nitrogen atom optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z6 is independently selected and represents a carbon or nitrogen atom optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z7 is independently selected and represents a carbon or nitrogen atom optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z8 is independently selected and represents a carbon or nitrogen atom optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated; Z9 is independently selected and represents a carbon or nitrogen atom optionally substituted with hydrogen, (C1-C3)-alkyl or (C1-C3)-alkyl, partially or fully halogenated. 4. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIc):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); n is independently selected and is 1 or 2; R8 is independently selected and is hydrogen, halogen, (C1-C3)-alkyl, -O-(C1-C3)-alkyl, -CONR6''R7''; R9 is independently selected and is hydrogen, halogen, (C1-C3)-alkyl, -CONR6''R7''; R10 is independently selected and is hydrogen, halogen, (C1-C3)-alkyl, -CONR6''R7''; R11 is independently selected and is hydrogen, halogen, (C1-C3)-alkyl, -CONR6''R7''; R6'' is independently selected and is (C2-C3)-alkyl; R7'' is independently selected and is (C2-C3)-alkyl; alternatively, R6'' and R7'', together with the nitrogen atom to which they are attached, may form a 5-7 membered heterocycle containing 1-3 heteroatoms selected from nitrogen, oxygen and/or sulfur; n is independently selected and is 1 or 2; dotted bonds mean the rings are aromatic. 5. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IId):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); A1 is independently selected and is -C(=O)-, carbon or nitrogen optionally substituted with hydrogen, (C1-C3)-alkyl; A2 is independently selected and is -C(=O)-, carbon or nitrogen optionally substituted with hydrogen, (C1-C3)-alkyl; A3 is independently selected and is -C(=O)-, carbon or nitrogen optionally substituted with hydrogen, (C1-C3)-alkyl; n is chosen independently and is 1 or 2. 6. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIe):

or a pharmaceutically acceptable salt thereof, wherein: R1e is independently selected and is: - (C1-C5)-alkyl substituted with a nitrile group, - (C3-C7)-cycloalkyl group; Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I). n is chosen independently and is 1 or 2. 7. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (III):

or a pharmaceutically acceptable salt thereof, wherein: R1, Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I). 8. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); X ₅ is independently selected and represents a carbon or nitrogen atom, X ₆ is independently selected and represents a carbon or nitrogen atom, with X ₅ and X ₆ optionally substituted with hydrogen, ethane-1-one, m1 is independently selected from 0, 1, 2, m2 is independently selected from 1, 2, with m1+m2 <2. 9. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIIb1) or formula (IIIb2):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 take the meanings as described in paragraph 3 above in the description of formulas (IIb1) and (IIb2); dotted bonds mean the rings are aromatic. 10. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIIc):

or a pharmaceutically acceptable salt thereof, wherein: R8, R9, R10, R11 take on the meanings as described above in paragraph 4 in the description of formula (IIc); Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); dotted bonds mean the rings are aromatic. 11. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIId):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); A1, A2, A3 take the values as described above in paragraph 5 in the description of formula (IId). 12. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IIIe):

or a pharmaceutically acceptable salt thereof, wherein: R1e takes the values as described above in paragraph 6 in the description of formula (IIe); Q1, Q2, Q3, Q4, Q5 are as defined above in the description of formula (I). 13. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IV):

or a pharmaceutically acceptable salt thereof, wherein: R1, Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I). 14. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IVa):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); X ₅ and X ₆ take the values as described above in paragraph 8 in the description of formula (IIIa); t is independently selected from 0, 1, 2, m is independently selected from 1, 2, with t+m<2. 15. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IVb1) or formula (IVb2):

or a pharmaceutically acceptable salt thereof, wherein: dotted bonds mean that the rings are aromatic; Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 take on the meanings as described in paragraph 3 above in the description of formulas (IIb1) and (IIb2). 16. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IVc):

or a pharmaceutically acceptable salt thereof, wherein: R8, R9, R10, R11 take the meanings as described above in paragraph 4 in the description of formula (IIc); Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); dotted bonds mean the rings are aromatic. 17. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IVd):

or a pharmaceutically acceptable salt thereof, wherein: Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I); A1, A2, A3 take the values as described above in paragraph 5 in the description of formula (IId). 18. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (IVe):

or a pharmaceutically acceptable salt thereof, wherein: R1e takes the values as described above in paragraph 6 in the description of formula (IIe); Q1, Q2, Q3, Q4, Q5 take on the meanings as described above in paragraph 1 in the description of formula (I). 19. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (V-1):

or a pharmaceutically acceptable salt thereof, wherein: R1 takes on the values as described above in paragraph 1 in the description of formula (I); n is chosen independently and is 1 or 2. 20. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (V-2):

or a pharmaceutically acceptable salt thereof, wherein: R1 takes on the values as described above in paragraph 1 in the description of formula (I); n is chosen independently and is 1 or 2. 21. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Va-1):

or a pharmaceutically acceptable salt thereof, wherein: X ₅ and X ₆ take the values as described above in paragraph 8 in the description of formula (IIIa); t is independently selected from 0, 1, 2, m is independently selected from 1, 2, with t+m<2. 22. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Va-2):

or a pharmaceutically acceptable salt thereof, wherein: X ₅ and X ₆ take the values as described above in paragraph 8 in the description of formula (IIIa); t is independently selected from 0, 1, 2, m is independently selected from 1, 2, with t+m<2. 23. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Vb-1):

or a pharmaceutically acceptable salt thereof, wherein: dotted bonds mean that the rings are aromatic; Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 take the meanings as described in paragraph 3 above in the description of formulas (IIb1) and (IIb2); n is chosen independently and is 1 or 2. 24. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Vb-2-1) or formula (Vb-2-2):

or a pharmaceutically acceptable salt thereof, wherein: dotted bonds mean that the rings are aromatic; Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9 take the meanings as described in paragraph 3 above in the description of formulas (IIb1) and (IIb2); n is chosen independently and is 1 or 2. 25. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Vc-1):

or a pharmaceutically acceptable salt thereof, wherein: R8, R9, R10, R11 take on the meanings as described above in paragraph 4 in the description of formula (IIc); n is independently selected and is 1 or 2; dotted bonds mean the rings are aromatic. 26. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Vc-2):

or a pharmaceutically acceptable salt thereof, wherein: R8, R9, R10, R11 take on the meanings as described above in paragraph 4 in the description of formula (IIc); n is independently selected and is 1 or 2; dotted bonds mean the rings are aromatic. 27. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (Vd-1):

or a pharmaceutically acceptable salt thereof, wherein: A1, A2, A3 take the values as described above in paragraph 5 in the description of formula (IId); n is chosen independently and is 1 or 2. 28. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by the formula (Vd-2):

or a pharmaceutically acceptable salt thereof, wherein: A1, A2, A3 include the compound of General in paragraph 5 in the description of formula (IId); n is chosen independently and is 1 or 2. 29. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by the formula (Ve-1):

or a pharmaceutically acceptable salt thereof, wherein: R1e takes the values as described above in paragraph 6 in the description of formula (IIe). 30. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by the formula (Ve-2):

or a pharmaceutically acceptable salt thereof, wherein: R1e takes the values as described above in paragraph 6 in the description of formula (IIe). 31. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (VI):

or a pharmaceutically acceptable salt thereof, wherein: R12 is independently selected and is: 1-acetylpiperidin-3-yl; 4-morpholinyl; 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl; 1-methyl-1H-pyrazol-4-yl; 3,5-difluoro-4-methoxy-phenyl; 4-(4-morpholinocarbonyl)phenyl; 2-oxo-indolin-5-yl; 1-methyl-2-oxo-indolin-5-yl or 4-acetylphenyl. 32. The compound according to claim 1, where the compound of formula (I) is a compound whose structure is described by formula (VII):

or a pharmaceutically acceptable salt thereof, wherein: R13 is independently selected and is: cyclopropyl; 2,5-difluorophenyl; 2,4-difluorophenyl; 1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl; 4-fluoro-3-methylphenyl; 4-fluorophenyl; 3-pyridyl or thiophen-2-yl. 33. Connection under item 1, selected from the group: 5-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)indolin-2-one; 2-((5-(2-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydro-1,7-naphthyridin-1(2H)-yl)sulfonyl)acetonitrile; 1-(cyclopropylsulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 1-(3-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)piperidin-1-yl)ethan-1 -he; 4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)morpholine; 1-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2 ,3-c]pyridine; 1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; 1-((1-(2,2-difluoroethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3, 4-tetrahydro-1,7-naphthyridine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(pyridin-3-ylsulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-(thiophen-2-ylsulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 1-(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)ethan-1-one; 1-((2,5-difluorophenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 1-((2,4-difluorophenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 1-((4-fluoro-3-methylphenyl)sulfonyl)-5-(2-fluoro-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 5-(2-fluoro-4-(trifluoromethyl)phenyl)-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,7-naphthyridine; 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; 1-methyl-5-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)indolin-2-one; morpholino(4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)methanone. 34. The use of a compound according to any one of paragraphs. 1-33 for CYP11B2 inhibition. 35. The use of a compound according to any one of paragraphs. 1-33 to reduce aldosterone levels in a subject. 36. The use of claim 35, wherein the subject is a human. 37. A pharmaceutical composition for the treatment and/or prevention of a disease or condition that is mediated or maintained by hypersynthesis of aldosterone, comprising a therapeutically or prophylactically effective amount of a compound according to any one of paragraphs. 1-33 and at least one pharmaceutically acceptable excipient. 38. The pharmaceutical composition according to claim 37, characterized in that the pharmaceutically acceptable excipient is a carrier, adjuvant and/or solvent. 39. The pharmaceutical composition according to claim 37, characterized in that the disease is selected from the group including primary hyperaldosteronism, chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, liver cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance . 40. Pharmaceutical composition according to claim 39, characterized in that primary hyperaldosteronism is Conn's syndrome, including the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, familial hyperaldosteronism of the first and second types, aldosterone-producing carcinoma and aldosterone ectopic syndrome. 41. A method for reducing the level of aldosterone in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of paragraphs. 1-33. 42. A method of treating and/or preventing a disease or condition that is mediated or maintained by aldosterone hypersynthesis in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound according to any one of paragraphs. 1-33. 43. The method according to p. 42, characterized in that the disease or condition is selected from the group including primary hyperaldosteronism, chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, cirrhosis of the liver, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, postinfarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance. 44. The method according to p. 43, characterized in that the primary hyperaldosteronism is Conn's syndrome, including the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, familial hyperaldosteronism of the first and second types, aldosterone-producing carcinoma and aldosteronectopic syndrome . 45. The method of claim 42, wherein the subject is a human.