Inhibitors of human aldosterone synthase (CYP11B2)

Abstract

The present invention relates to organic chemistry, pharmacology, and medicine. Specifically, the present 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 mediated or supported by the activity of the hormone aldosterone. The compounds are characterized by the general formula (I): wherein R, R, R, R, and R have the meanings specified in the detailed description. The present invention also relates to pharmaceutical compositions containing the compounds of the present invention and methods for preparing these compounds.

Description

[Technical Field]

[0001] The present invention relates to organic chemistry, pharmacology, and medicine, i.e., the present 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 mediated by or supported by the activity of the hormone aldosterone. The present invention also relates to pharmaceutical compositions containing the compounds of the present invention and methods for preparing these compounds. [Background technology]

[0002] Aldosterone is a steroid hormone whose primary physiological role is to maintain sodium and potassium balance by regulating cation exchange (Na+ reabsorption and K+ secretion) in the distal nephron, which leads to elevated blood pressure. In addition to its physiological role, aldosterone is also involved in the pathogenesis of diseases or pathological conditions caused by it (primary hyperaldosteronism) and / or accompanied by its excessive synthesis (secondary hyperaldosteronism), including several diseases of the cardiovascular system, kidney, and metabolic syndrome.

[0003] Modern approaches to the treatment of conditions caused by and / or associated with excessive aldosterone synthesis involve influencing different levels of the renin-angiotensin-aldosterone system (RAAS). The modern state of the art is represented by drug classes such as renin inhibitors (IRs), angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), and mineralocorticoid receptor (MR) antagonists. However, in 25–50% of patients treated with IR, ARB, and / or ACE inhibitors alone or in combination, serum aldosterone levels eventually return to pretreatment levels or above (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 the introduction of MR antagonists results in a compensatory increase in serum aldosterone levels (Pitt et 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. Non-MR-mediated effects include: a) Aldosterone, acting through GPCR receptors, has so-called "rapid effects," which induce apoptosis and prevent 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]. Furthermore, recent in vitro and ex vivo studies have shown that aldosterone enhances the expression of the CYP11B2 gene through activation of GPCRs, thus promoting 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 may result in glucose tolerance;c) vascular remodeling through interaction with IGF-I receptors in vascular smooth muscle cells and stimulation of elastin production by fibroblasts (Mitts et al., 2010, Journal of Investigative Dermatology, Volume 130, Issue 10, 2396-2406), and mechanisms by which aldosterone may accelerate the development of atherosclerosis (Cascella et al., 2010, Endocrinology, 151(12):5851-64); d) induction of vasoconstriction via a protein kinase C-dependent pathway, possibly via membrane receptors, leads to a decrease in cardiac contractile and metabolic function in the ischemic heart, so increased aldosterone levels in plasma or cardiac tissue may have adverse effects on coronary heart disease (Fujita et al., 2010, Endocrinology, 151(12):5851-64). al, 2005, Hypertension, 46(1):113-7; e) MR-independent activation of potassium current (IK1) by aldosterone has been shown to be a major mechanism explaining the increased incidence of ventricular arrhythmias and sudden cardiac death associated with elevated aldosterone levels in 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 such as hypertension and atherosclerosis (Sinphitukkul et al, 2019, Arch Med Sci, 15(6):1589-1598). Furthermore, aldosterone has demonstrated a non-genomic, endothelium-independent vasoconstrictor effect mediated through the AT1 receptor (Yamada et al, 2008, Cardiovasc Res, 79(1):169-78). ;

[0004] Based on the above, inhibiting aldosterone synthesis would have therapeutic advantages over existing therapies and overcome limitations of existing standard treatments.

[0005] Because aldosterone is synthesized by a single enzyme, CYP11B2 (aldosterone synthase), which catalyzes the three-step conversion of 11-deoxycorticosterone (11-DOC) to aldosterone via corticosterone and 18-hydroxycorticosterone, CYP11B2 is a potential therapeutic target for inhibiting aldosterone synthesis, which may have a pharmacodynamic profile superior to that observed for other RAAS mediators.

[0006] From the above, it is clear that agents capable of inhibiting CYP11B2 (aldosterone synthase) can be used to treat and / or prevent diseases or conditions mediated or maintained by excessive aldosterone synthesis. The translation of in vitro data on aldosterone synthase inhibition into in vivo results in both rodents and primates has been demonstrated for at least seven compounds with different chemical structures, three of which have shown aldosterone-lowering effects in clinical trials. LCI699 (Novartis), RO6836191 (Roche) and LY3045697 (Ely Lilly) [Aldosterone synthase inhibitors for cardiovascular diseases: A comprehensive review of preclinical, clinical and in silico data.Lenzini L et.al Pharmacol Res.2021;163:105332.doi:10.1016 / j.phrs.2020.105332;PMID:33271294], [Inhibitors of Aldosterone Synthase.Weldon SM,Brown NF.Vitam Horm.2019;109:211 -239.doi:10.1016 / bs.vh.2018.10.002;PMID:30678857;clinical [Trials: NCT00817635, NCT01995383, NCT01821703]. Therefore, inhibition of aldosterone synthase activity under in vitro conditions is also observed in vivo.

[0007] Furthermore, CYP11B2-specific molecules have been shown to be useful as diagnostic markers for various diseases associated with CYP11B2 overexpression [Development of [18F]AldoView as the First Highly Selective Aldosterone Synthase PET Tracer for Imaging of Primary Hyperaldosteronism. Sander K et al. J Med Chem. 2021;8;64(13):9321-9329. doi:10.1021 / acs.jmedchem.1c00539. PMID:34137616]. Summary of the Invention [Problem to be solved by the invention]

[0008] In its embodiments, the present invention provides novel chemical entities capable of inhibiting the activity of the human CYP11B2 enzyme, and their biological activities have been investigated. Accordingly, the present invention relates to compounds, pharmaceutical compositions containing these compounds, uses of the compounds, methods for their use in the treatment of various diseases and disorders, and methods for obtaining these compounds. DETAILED DESCRIPTION OF THE INVENTION

[0009] The compounds disclosed herein inhibit the activity of the human CYP11B2 enzyme and have been investigated for their biological activity.

[0010] Accordingly, the present invention relates to compounds, pharmaceutical compositions containing these compounds, uses of these compounds, methods for their use in the treatment of various diseases and disorders, and methods for obtaining these compounds.

[0011] Disclosed herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein below.

[0012] Disclosed herein are compounds of formula (I) or a pharmaceutically acceptable salt thereof, as defined hereinafter, for use as a pharmaceutical.

[0013] Further disclosed herein is a compound of formula (I), as defined herein below, for use in reducing aldosterone levels in a subject.

[0014] Further disclosed herein are compounds of formula (I), as defined herein below, for use in the treatment and / or prevention of diseases or conditions mediated or maintained by aldosterone excess synthesis.

[0015] Further disclosed herein are compounds of formula (I) as defined herein thereafter for use in the treatment of a disease selected from the group consisting of primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved systolic function, 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, nephrotic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction myocardial sclerosis, arteriosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, and insulin resistance.

[0016] Further disclosed herein are compounds of formula (I)

[0017] [ka] Formula (I)

[0018] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein R1 is a 5-6 membered heteroaryl containing 0-1 oxygen, 0-1 sulfur, and / or 0-4 nitrogen, optionally substituted with 1-5 substituents R1a, wherein R1a is independently selected from hydrogen, deuterium, halogen, (C1-C3) alkyl, (C3-C5) cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3) alkyl, (C1-C3) alkylsulfonyl, cyano, N,N-dimethylamine, N-methylamine, -C(=O)-NH-(C1-C5)-alkyl, and R2, R3, R4, R5 are each independently selected from the following and are: -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3)alkyl, or -(ii) -OH, -SH, or -(iii) -(C1-C3)-alkoxy, 3-7 membered heterocyclyl including 0-2 nitrogen atoms, 0-1 oxygen atoms, 0-1 sulfur atoms, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, each of the above groups optionally partially or fully substituted with substituents selected from: -OH, deuterium, 1-4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, (C1-C3)alkoxy, -NH , a 3- to 7-membered heterocycle containing one oxygen atom, (C1-C3)-alkylamino, di(C1-C3)-alkylamino or a 3- to 7-membered heterocycle containing one nitrogen atom and optionally 1 to 2 oxygen and / or sulfur heteroatoms, or -(iv) necessarily substituted with 1 to 4 substituents selected from 4- to 7-membered heterocyclyl containing 1 to 2 nitrogen atoms, 0 to 1 oxygen atoms, 0 to 1 sulfur atoms, oxo group or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and optionally substituted with 1 to 3 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl and (C1-C3)alkoxy, or -(v) -NRaRb, wherein each Ra and Rb independently represents hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms, wherein heteroaryl is (C1-C3)-alkyl; or partially or fully halogenated (C1-C3)-alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, optionally substituted by 1-4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, (C1-C3)alkoxy. or alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, which denotes the presence of a D / S-double or single bond, optionally substituted by 1-4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)alkynyl, oxo group or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl or (C1-C3)alkoxy, and the dashed bond denotes that the ring is aromatic.

[0019] In another embodiment, the present invention includes compounds of formula (I) as defined above, wherein at least two of R2, R3, R4 and R5 are other than hydrogen.

[0020] In another embodiment, the present invention includes compounds of formula (I) as defined above, wherein at least three of R2, R3, R4 and R5 are other than hydrogen.

[0021] In another embodiment, the present invention includes compounds of formula (I) as defined above, wherein R2, R3, R4 and R5 are other than hydrogen.

[0022] In another embodiment, the present invention includes compounds of formula (I) as defined above, wherein R2, R3, R4 and R5 are each independently selected from and represent: -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3)alkyl, -(ii) a group selected from (C1-C3)-alkoxy, (C3-C7)cycloalkyl, and halogenated (C1-C3)alkoxy groups containing 1 to 4 halogen atoms, -(iii) -NRaRb, wherein each Ra and Rb independently represents hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms, optionally substituted by 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 0-1 oxygen atoms, 0-1 sulfur atoms and / or a 5-7 membered heteroaryl containing 0-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl. or alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, optionally substituted with 1-4 substituents selected from deuterium, halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl or (C1-C3)-alkoxy.

[0023] In another embodiment, in the compounds of formula (I) defined above, at least one of R2, R3, R4 and R5 is in the para position and each is independently selected from: -OH, -SH, -(C1-C3)-alkoxy, 0-2 nitrogen atoms, 0-1 oxygen atoms, 0-1 sulfur atoms, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, each of the above groups optionally being partially or fully substituted with substituents selected from: -OH, 1 to 4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, a 3 to 7 membered heterocycle containing one oxygen atom, -NH2, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3 to 7 membered heterocycle containing one nitrogen atom and 1 to 2 oxygen and sulfur heteroatoms.or -NRaRb, wherein each Ra and Rb is independently hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and 1-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 1-2 nitrogen atoms, wherein heteroaryl is optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, or Ra and Rb are each independently hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and 1-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 1-2 nitrogen atoms, wherein heteroaryl is optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, or together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted with 1-2 substituents selected from (C-C)-alkyl, partially or fully halogenated (C-C)-alkyl; or alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6- to 14-membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atom, optionally substituted with 1-4 substituents selected from halogen, (C-C)-alkyl, partially or fully halogenated (C-C)-alkyl, (C-C)-alkenyl, (C-C)-alkynyl or (C-C)-alkoxy.

[0024] In another embodiment, in the compounds of formula (I) as defined above, R1 is independently selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazyl, and R1 is optionally substituted with the group consisting of methyl, methylsulfonyl, halogen, methylamino, cyano, and cyclopropyl.

[0025] In another embodiment, in the compounds of formula (I) as defined above, two of R2, R3, R4 and R5 are in the meta position and are a group selected from methyl or halogen, one of R2, R3, R4 and R5 is hydrogen and one of R2, R3, R4 and R5 is in the para position and is a group selected from methoxyisopropyloxy, cyclopropylmethoxy, difluoroethoxy, -NH2, -N(CH3)2, cyclopropylamino, -N(CH3)-cyclobutyl, -N(CH3)-methylthiazolyl, methylpiperidylamino, -NH-(C1-C3)-alkyl-N(CH3)2, morpholinyl, methylpiperazinyl, optionally methyl-substituted azetidinyl, thiomorpholinyl, optionally methyl-substituted hexahydropyrrolopyrrolyl, diazaspirononyl, optionally substituted with methyloctahydropyrrolopyridinyl.

[0026] In another embodiment, the present invention provides a compound of formula (Ia)

[0027] [ka] Formula (Ia)

[0028] or a pharmaceutically acceptable salt, or solvate or hydrate thereof, wherein R1 is as defined above and R6 is independently selected from, or is: -OH, -SH, -(C1-C3)-alkoxy, 0-1 oxygen atoms, 0-1 sulfur atoms, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, each of the foregoing groups optionally being partially or fully substituted with substituents selected from: -OH, 1 to 4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, a 3 to 7 membered heterocycle containing one oxygen atom, -NH2, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3 to 7 membered heterocycle containing one nitrogen atom and optionally 1 to 2 heteroatoms selected from oxygen and sulfur.or -NRaRb, wherein each Ra and Rb independently represents hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and 1-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 0-1 oxygen, 0-1 nitrogen, and / or 1-4 nitrogen, wherein heteroaryl is optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, or R a and R b together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted with 1-2 substituents selected from (C-C)-alkyl, partially or fully halogenated (C-C)-alkyl; or alternatively R a and R b together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atom, optionally substituted with 1-4 substituents selected from halogen, (C-C)-alkyl, partially or fully halogenated (C-C)-alkyl, (C-C)-alkenyl, (C-C)-alkynyl or (C-C)-alkoxy.

[0029] In another embodiment, the present invention provides a compound of formula (IIa)

[0030] [ka] Formula (IIa)

[0031] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R1 and R6 are as defined above.

[0032] In another embodiment, the present invention provides a compound of formula (Ib)

[0033] [ka] Formula (Ib)

[0034] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Q1, Q2, Q3, Q4, and Q5 are each independently selected from nitrogen or carbon and are nitrogen or carbon, wherein no more than two of Q1, Q2, Q3, Q4, and Q5 are nitrogen, and the carbon is optionally substituted with 1 to 5 substituents R1a, wherein R2, R3, R4, R5, and R1a are as defined above, and the dotted bond means that the ring is aromatic.

[0035] In another embodiment, the present invention provides a compound of formula (Ic)

[0036] [ka] Formula (Ic)

[0037] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Q6, Q7, Q8, and Q9 are each independently selected from oxygen, carbon, or nitrogen, and are oxygen, carbon, or nitrogen, and no more than two of Q6, Q7, Q8, and Q9 are nitrogen or oxygen, and the carbon is optionally substituted with 1 to 2 R1a groups, and R2, R3, R4, R5, and R1a are as defined above, and the dotted bond means that the ring is aromatic.

[0038] In another embodiment, the present invention provides a compound of formula (Id)

[0039] [ka] Formula (Id)

[0040] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Q1, Q2, Q3, Q4, Q5, and R6 are as defined above.

[0041] In another embodiment, the present invention provides a compound of formula (Ie)

[0042] [ka] Formula (Ie)

[0043] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Q6, Q7, Q8, Q9, and R6 are as defined above. In another embodiment, the present invention provides a compound of formula (If):

[0044] [ka] Expression (If)

[0045] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein R1 and R6 are as defined above. In another embodiment, the present invention provides a compound of formula (IIb):

[0046] [ka] Formula (IIb)

[0047] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Q1, Q2, Q3, Q4, Q5, R2, R3, R4, and R5 are as defined above. The dotted bond means that the ring is aromatic.

[0048] In another embodiment, the present invention provides a compound of formula (IId)

[0049] [ka] Formula (IId)

[0050] or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein Q1, Q2, Q3, Q4, Q5, and R6 are as defined above. In another embodiment, the present invention provides a compound of formula (IIId):

[0051] [ka] Formula (IIId)

[0052] or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein Q1, Q2, Q3, and Q4 each independently represent nitrogen or carbon; R' is hydrogen, deuterium, halogen, (C1-C3) alkyl, (C3-C5) cycloalkyl, -C(=O)-CH, partially or fully halogenated (C1-C3) alkyl, (C1-C3) alkylsulfonyl, cyano, N,N-dimethylamine, or N-methylamine; then R' independently represents a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms, 0-1 oxygen atoms and / or 0-1 sulfur atoms and containing 1-2 necessary substituted substituents selected from oxo group or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, optionally substituted with 1-3 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl and (C1-C3)alkoxy; or when -R' independently represents -C(=O)-NH-(C1-C5)-alkyl, R independently represents:-NRcRd, wherein each Rc and Rd independently represents hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms, and optionally 1-2 alkyl groups selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl. or Rc and Rd together with the nitrogen atom to which they are attached contain 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, or 5-7 membered heteroaryl optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl; or Rc and Rd together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, optionally substituted by 1 to 4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C1-C3)alkoxy, or alternatively Rc and Rd together with the nitrogen atom to which they are attached form 1 to 2 nitrogen atoms and 0 It forms a 6- to 14-membered bicyclic heterocyclyl containing up to 1 oxygen and / or 0-1 sulfur atom, which is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)alkynyl, oxo group or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl or (C1-C3)alkoxy.

[0053] In certain embodiments, the invention includes a compound selected from the group (names given according to IUPAC): 1_01 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridyl)pyrrolo[2,3-c]pyridine; 1_02 1-((4-Methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_03 1-((4-Methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine 1_04 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(6-methylpyridazin-3-yl)pyrrolo[2,3-c]pyridine; 1_05 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methylsulfonyl-2-pyridyl)pyrrolo[2,3-c]pyridine 1_06 1-((3,5-difluoro-4-isopropoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_07 1-((4-(cyclopropylmethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_08 1-((4-(2,2-difluoroethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_09 2,6-Difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1_10 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)morpholine; 1_11 2,6-Difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1_12 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_13 N-Cyclopropyl-2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1_14 N-Cyclobutyl-2,6-difluoro-N-methyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1_15 2,6-Difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1_16 2,6-Difluoro-4-((4-(pyridin-2-yl)-2,3-dehydro-H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenol; 1_17 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; 1_18 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_19 1-((3,5-difluoro-4-(3-methylazetidin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_20 N-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-N,4-dimethylthiazol-2-amine; 1_21 N-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-1-methylpiperidin-4-amine; 1_22 N1-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-N2,N2-dimethylethane-1,2-diamine; 1_23 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)thiomorpholine; 1_24 1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-s]pyridine; 1_25 1-((3,5-difluoro-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_26 2-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-2,7-diazaspiro[4.4]nonane; 1_27 2-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)oxazole-4-carbonitrile; 1_28 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; 1_29 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(5-fluoropyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1_30 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrazin-2-amine; 1_31 4-(5-cyclopropylpyridin-2-yl)-1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine; 1_32 2,6-Difluoro-4-((4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1_33 2,6-Difluoro-N,N-dimethyl-4-((4-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline 2_01 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-1-methylpiperazin-2-one; 2_02 1-((4-(4-(cyclopropylmethyl)piperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 2_03 N-(tert-butyl)-5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolamide; 3_01 1-((3,5-difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_02 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridin-3-amine; 3_03 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridin-2-amine; 3_04 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylpyridin-3-amine; 3_05 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazine-2-carbonitrile 3_06 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)nicotinonitrile; 3_07 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridazin-3-amine; 3_08 2-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrimidin-5-amine; 3_09 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidine-2-carbonitrile; 3_10 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridazine-3-carbonitrile; 3_11 1-((3,5-difluoro-4-(4-isopropylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_12 1-((4-(4-cyclopropylpiperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_13 1-((3,5-difluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_14 1-((4-(1,4-diazepan-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_15 1-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)piperidin-4-amine 3_16 1-((3,5-difluoro-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_17 1-((3,5-difluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_18 6-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-3-methyl-3,6-diazabicyclo[3.1.1]heptane; 3_19 1-((3,5-difluoro-4-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_20 1-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_21 1-((3,5-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_22 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrazin-2-amine; 3_23 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazine-2-carbonitrile; 3_24 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; 3_25 1-((4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt); 3_26 1-((4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 3_27 1-((3,5-Difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt) 3_28 5-(1-((3,5-difluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; 4_01 1-((3,5-Difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt).

[0054] The compounds of the present invention may exist as different stereoisomers, diastereomers or enantiomers or mixtures thereof, all of these forms being part of the present invention.

[0055] The present invention also relates to the use of the compounds of the present invention to inhibit CYP11B2.

[0056] The present invention also relates to the use of the compounds of the present invention to reduce the level of aldosterone in a subject.

[0057] In certain embodiments of the invention, the subject is a human.

[0058] The present invention also relates to the use of the compounds of the present invention in the manufacture of a CYP11B2 inhibitor.

[0059] The present invention also relates to the use of a compound of the present invention in the manufacture of an agent for lowering the level of aldosterone in a subject.

[0060] The present invention also relates to the use of a compound of the present invention in the manufacture of a pharmaceutical composition for treating and / or preventing a disease or condition mediated or maintained by CYP11B2 activity, comprising a therapeutically or prophylactically effective amount of a compound of the present invention and at least one pharmaceutically acceptable excipient.

[0061] The present invention also includes pharmaceutical compositions for treating and / or preventing diseases or conditions mediated or maintained by CYP11B2 activity, comprising a therapeutically or prophylactically effective amount of a compound of the present invention and at least one pharmaceutically acceptable excipient.

[0062] In certain embodiments of the invention, the pharmaceutically acceptable excipient is a carrier, adjuvant and / or solvent.

[0063] In certain embodiments of the invention, the disease is selected from the following group: primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved systolic function, 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, nephrotic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction myocardial sclerosis, arteriosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia or insulin resistance.

[0064] In certain embodiments of the invention, primary hyperaldosteronism is Conn's syndrome, which includes the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, type 1 and type 2 familial aldosteronism, aldosterone-producing carcinoma, and ectopic aldosterone.

[0065] The present 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 present invention.

[0066] The present invention also includes a method for treating and / or preventing a disease or condition mediated or maintained by CYP11B2 activity in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound of the present invention.

[0067] In certain embodiments of the invention, the disease or condition is selected from the group consisting of primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved systolic function, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephrotic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction myocardial sclerosis, arteriosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia or insulin resistance.

[0068] In a particular embodiment of the invention, primary hyperaldosteronism is Conn's syndrome, which includes the following diseases or conditions: aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, type 1 and type 2 familial aldosteronism, aldosterone-producing carcinoma, and ectopic aldosterone.

[0069] In certain embodiments of the invention, the subject is a human.

[0070] The technical result of the present invention is the development of compounds that are highly effective in inhibiting the activity of human cytochrome 11B2 (CYP11B2). These compounds hold promise for the prevention and / or treatment of diseases or pathological conditions or disorders mediated or maintained by excessive synthesis of aldosterone.

[0071] Definition (term) To better understand the present invention, the following are some of the terms used in the description of the present invention. As used herein, the following definitions apply unless otherwise specified. Furthermore, unless otherwise indicated, all occurrences of a functional group are independently selected, which may be indicated by using a slash to specify that two occurrences can be the same or different (such as R). In describing the present invention, the terms "comprise" and "comprising" are to be interpreted as meaning "includes, among other things." The term is not intended to be interpreted as "consisting only of."

[0072] As used herein, the term "alkyl," by itself or as part of another substituent, refers to a straight- or branched-chain saturated hydrocarbon group, including hydrocarbon groups having the indicated number of carbon atoms, typically 1 to 10 carbon atoms. For example, the term (C1-C3)-alkyl refers to methyl, ethyl, propyl, etc.

[0073] The term "alkenyl," as used herein, unless otherwise specified, refers to a straight-chain or branched hydrocarbon-based aliphatic group containing 1 to 6 carbon atoms and at least one unsaturated atom. Examples include, but are not limited to, vinyl groups.

[0074] The term "alkynyl," as used herein, unless otherwise specified, refers to a straight-chain or branched hydrocarbon-based aliphatic group containing 1 to 6 carbon atoms and at least a triple bond. Examples include, but are not limited to, acetylenyl groups.

[0075] The term "partially or fully halogenated" includes branched or straight hydrocarbon chains in which one or more hydrogen atoms have been replaced with halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, -C(CF3)2CH3, and the like.

[0076] The term (C1-C3)-alkylsulfonyl means SO2-alkyl, wherein alkyl is as previously defined. By way of example, mention may be made of, but is not limited to, SO2CH2, SO2CH2CH2, etc.

[0077] The term "halogen" by itself or as part of another term refers to a fluorine, chlorine, bromine, or iodine atom.

[0078] The term "aryl," unless otherwise specified, refers to a monocyclic or bicyclic aromatic ring containing 5 to 12 carbon atoms according to the Hückel aromaticity rules. A cyclic, planar molecule has 4n + 2π (Pi) electrons. Examples of aryl include phenyl and naphthyl.

[0079] The term "alkoxy" refers to an alkyl group, as defined above, that is attached to a molecule via a bridging oxygen atom. For example, the term "alkoxy" refers to -O-alkyl, where the alkyl group contains 1 to 3 carbon atoms in the form of a straight (straight) or branched chain. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and the like.

[0080] The term "alkylamino" refers to an alkyl group, as defined above, attached to a molecule via a bridging nitrogen atom. For example, the term "alkylamino" refers to -NH-alkyl or -N(-alkyl)2, where the alkyl group contains 1 to 3 carbon atoms in the form of a straight (linear) or branched chain. Exemplary alkylamino groups include, but are not limited to, methylamino, N,N-dimethylamino, ethylamino, and the like.

[0081] The term "bicyclic ring" or "bicyclic" as used herein means a bridged, fused, or Spiroff bicyclic ring system. Bicyclic heterocycles contain 6 to 14 atoms, preferably 7 to 10 atoms. Bicyclic rings may contain 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and / or sulfur. Among bicyclic rings, mention may be made of a phenyl ring fused to a 5-membered heterocycle.

[0082] Examples of bicyclic structures include, but are not limited to, the following:

[0083] [ka] "Spiro" "Fusion" "Bridged Bicyclic"

[0084] The term "heteroaryl" as used herein refers to a 5- or 7-membered aromatic ring according to Hückel's aromaticity rules: a cyclic, planar molecule having 4n + 2π (Pi) electrons, containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and / or sulfur. Examples of heteroaryl include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazinyl, thiophenyl, furanyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isthiothiazolyl, triazolyl, tetrazolyl, and the like.

[0085] The term "heterocycle" in the sense of the invention as used herein means a 3- to 7-membered non-aromatic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms. This definition also includes partially saturated rings. Examples of heterocycles include azepine, pyrrolidinepiperidineoxirane, tetrahydrofuran, tetrahydropyran, oxepane, piperazinemorpholine, thiomorpholine, diazepine, oxazepane, thiazepine, homopiperazine, homomorpholine, etc. The terms "heterocyclic," "heterocyclyl," or "heterocyclic" also refer to saturated or partially unsaturated rings, which may be substituted.

[0086] The present invention includes only those combinations of substituents and derivatives that form stable or chemically feasible compounds. Stable or chemically feasible compounds are those whose stability is sufficient for their synthesis and analytical detection. Preferred compounds of the present invention are sufficiently stable that they do not decompose at temperatures up to 40° C. for at least one week in the absence of reaction conditions.

[0087] Unless otherwise specified, the structures of compounds depicted in the materials herein also include all stereoisomers, i.e., R and S isomers of each asymmetric center. Additionally, individual stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the compounds, are also contemplated by the present invention. Accordingly, the present invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%, more preferably >95% molar purity), as well as mixtures of such isomers.

[0088] Specific optical isomers can be obtained by separating the racemic mixture according to standard procedures, for example, by treating with an optically active acid or base to give diastereomeric salts, followed by separating the diastereomeric mixture by crystallization, and then isolating the optically active bases from these salts. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and camphorsulfonic acid. Another approach to separating optical isomers is to use a chiral chromatography column. Yet another separation method involves synthesizing covalently linked diastereomeric molecules by reacting the compounds of the present invention with activated forms of optically pure acids or optically pure isocyanates. The resulting diastereomers can be separated by conventional means, such as chromatography, distillation, crystallization, sublimation, and then hydrolyzed to give enantiomerically pure compounds.

[0089] The optically active compounds of the present invention can be obtained using optically active starting materials. Such isomers can be in the form of a free acid, a free base, an ester or a salt.

[0090] The term "solvate" refers to an association or complex of one or more solvent molecules with 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.

[0091] The term "hydrate" refers to the complex where the solvent molecule is water.

[0092] The compounds of the present invention may exist in radiolabeled form, i.e., they may contain one or more atoms whose atomic mass or mass number differs from that of the most common naturally occurring isotopes. Radioactive isotopes of hydrogen, carbon, phosphorus, and chlorine include: 3 H, 14 C. 32 P, 35 S, and 36 Compounds of the present invention that contain such radioisotopes and / or other radioisotopes of other atoms are within the scope of the present invention. 3 H and carbon, i.e. 14 C radioisotopes are particularly preferred because of their ease of preparation and detectability.

[0093] Radiolabeled compounds of the present invention can be obtained using methods well known to those skilled in the art. Labeled compounds can be prepared using the procedures described herein by simply substituting the appropriate labeled reagent for the unlabeled reagent.

[0094] The compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term "pharmaceutically acceptable salt" refers to a salt that, within the scope of medical judgment, is suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and that satisfies a reasonable benefit-risk ratio. 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 present invention, or they can be obtained separately by reacting the free acid or free base of the compounds of the present invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic acid salts include amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, succinic acid, or malonic acid, or obtained using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Examples of salts that can be used include 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, undecanoate, and valerate.Typical alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. In addition, pharmaceutically acceptable salts may, if desired, include non-toxic ammonium, quaternary ammonium, and amine cations derived from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0095] By "therapeutically effective amount" is meant the amount of 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, weight and general condition of the patient, severity of the disease, method of administration of the drug, co-treatment with other drugs, etc.

[0096] The term "patient" (or "subject") encompasses all mammalian, preferably human, species in which the compounds of the present invention are used to treat and / or prevent a disease or condition, either by self-administration and / or administration to the patient by a third party.

[0097] The terms "treatment" and "therapy" include the treatment of a pathological condition in a mammal, preferably a human, and include a) interrupting (halting) the course of the disease, and b) alleviating the severity of the disease, i.e., inducing regression of the disease.

[0098] The terms "prevention" and "prophylactic therapy" include the elimination of risk factors as well as preventative treatment during the asymptomatic stage of a disease in humans, with the aim of reducing the likelihood of the disease progressing to the clinical stage. Patients for preventative therapy are selected based on known data and factors that increase the risk of the disease progressing to the clinical stage compared to the general population. Preventative therapy includes a) primary prevention and b) secondary prevention. Primary prevention is defined as preventive treatment in patients who have not yet reached the clinical stage of the disease. Secondary prevention is the prevention of recurrence of a condition that is the same as or similar to the clinical state of the disease.

[0099] The term "risk reduction" encompasses therapies that decrease the occurrence of clinical stages of disease. Examples of disease risk reduction are primary and secondary disease prevention. [Example]

[0100] Specific compounds of the invention disclosed herein are provided for the purpose of illustrating the invention so that it may be more fully understood. Table 1 shows specific examples of compounds of the invention that can be prepared by the methods described in the general synthetic schemes, examples, and methods known in the art. The methods described are not exhaustive, and reasonable variations are possible. These reactions must be carried out using appropriate solvents and materials. When carrying out these general procedures for synthesizing specific substances, consideration must be given to the functional groups present in the substances and their influence on the course of the reaction. To obtain some substances, the order of steps may need to be changed or one of several alternative synthetic schemes may need to be prioritized. The following compounds should not be considered the only examples within the scope of the invention, and are not intended to limit the invention in any way.

[0101] In certain embodiments of the present invention, compounds of general formula I are compounds Nos. 1_01 to 4_01 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0102] In certain embodiments of the present invention, compounds of general formula Ia are compounds Nos. 1_06 to 1_14, 1_18 to 4_01 listed in Table 1 below, and pharmaceutically acceptable salts and / or stereoisomers thereof.

[0103] In a particular embodiment of the present invention, the compounds of general formula IIa are compounds Nos. 1_15 to 1_17 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0104] In a particular embodiment of the present invention, the compounds of general formula IIb are compounds Nos. 1_15 to 1_17 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0105] In a particular embodiment of the present invention, the compounds of general formula IId are compounds Nos. 1_15 to 1_17 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0106] In a particular embodiment of the present invention, the compounds of general formula Ia are compounds Nos. 1_06 to 1_14, 1_18 to 1_26 and 1_28 to 1_33 listed in Table 1 below, and pharmaceutically acceptable salts and / or stereoisomers thereof.

[0107] In a particular embodiment of the present invention, the compound of general formula Ic is compound No. 1_27 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0108] In a particular embodiment of the present invention, the compounds of general formula Ie are compounds Nos. 1_06 to 1_14, 1_18 to 1_26 and 1_28 to 1_33 listed in Table 1 below, and pharmaceutically acceptable salts and / or stereoisomers thereof.

[0109] In a particular embodiment of the present invention, the compound of general formula I is compound No. 1_27 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0110] In a particular embodiment of the present invention, the compounds of general formula If are compounds Nos. 1_1 to 1_5 listed in Table 1 below, as well as pharmaceutically acceptable salts and / or stereoisomers thereof.

[0111] [Table 1] TIFF2025538918000015.tif195120 TIFF2025538918000016.tif201124 TIFF2025538918000017.tif185125 TIFF2025538918000018.tif175127 TIFF2025538918000019.tif198121 TIFF2025538918000020.tif190125 TIFF2025538918000021.tif180121 TIFF2025538918000022.tif207128 TIFF2025538918000023.tif197122 TIFF2025538918000024.tif200123 TIFF2025538918000025.tif189124 TIFF2025538918000026.tif187122 TIFF2025538918000027.tif200122 TIFF2025538918000028.tif176122 TIFF2025538918000029.tif198122 TIFF2025538918000030.tif54119

[0112] General synthetic methods. Optimum reaction conditions and reaction times may vary depending on the reagents used. Unless otherwise specified, solvents, temperatures, pressures, and other reaction conditions can be freely selected by one skilled in the art.

[0113] General formula of intermediates for synthesis (R 1 , R 2 , R 3 , R 4 and R 5 are defined as above):

[0114] [ka] Intermediates

[0115] Intermediates X (general structure), bromine derivatives (intermediate Y) and sulfonyl chloride derivatives (intermediate Z) for the synthesis are either commercially available or readily prepared by methods known to those skilled in the art.

[0116] Synthesis of compounds according to the invention.

[0117] [ka] Scheme 1. General scheme for the synthesis of intermediates for the synthesis of target compounds according to the invention.

[0118] Preparation of Intermediate BB-a. To a solution of Intermediate X (1 equivalent) in DCM (dichloromethane) is added DMAP (4(dimethylamino)pyridine) (0.1 equivalent), triethylamine (2 equivalents), and Intermediate Z (1.3 equivalents). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is neutralized with water and extracted with DCM (dichloromethane). The organic phase is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give Intermediate BB-a.

[0119] Intermediate BB-b is obtained. To a solution of intermediate BB-a (1 equivalent) in 1,4-dioxane, B2pin2 (bis(pinacolato)diboron) (1.5 equivalents), potassium acetate (3 equivalents) are added, followed by degassing in the presence of PdCI2(dppf)(bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) (0.5 equivalents). The reaction mixture is heated at 100 °C for 6 hours under microwave conditions. The reaction mixture is cooled to room temperature and filtered through a pad of Celite. Ethyl acetate and water are added to the filtrate. The layers are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate BB-b, which is used in the next step without further purification.

[0120] [ka]

[0121] Scheme 2. General scheme for synthesizing target compounds according to the present invention. Preparation of compounds of the present invention. To a solution of intermediate BB-b (1 equivalent) in a THF (tetrahydrofuran) / water (10 / 1) mixture, intermediate Y (1.2 equivalents), cesium carbonate (2 equivalents) are added, and then degassed in the presence of PdCI2(dppf) (bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) (0.5 equivalents). The reaction mixture is stirred at 80°C for 6 hours. The reaction mixture is cooled to room temperature and filtered through a pad of Celite. Ethyl acetate and water are added to the filtrate.

[0122] The layers are separated and the aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography.

[0123] [ka]

[0124] Scheme 3. Scheme for synthesizing an intermediate for synthesizing target compound 1 according to the present invention. Preparation of 4-bromo-1-(4-methoxy-3,5-dimethylphenyl)sulfonylpyrrolo[2,3-c]pyridine (BB-a1). To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.54 mmol) in DCM (dichloromethane) (8.0 ml), DMAP (4(dimethylamino)pyridine) (31 mg, 0.25 mmol), triethylamine (707 μl, 5.08 mmol), and 4-methoxy-3,5-dimethylbenzenesulfonyl chloride (Intermediate Z1) (774 mg, 3.30 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with water and extracted with DCM (dichloromethane). The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 100 / 0 to 90 / 10 cyclohexane / ethyl acetate as eluent to give 4-bromo-1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine (BB-a1) (1.05 g, quantitative) as a colorless oil.

[0125] Preparation of 1-(4-methoxy-3,5-dimethylphenyl)sulfonylpyrrolo[2,3-c]pyridin-4-yl diboronic acid (BB-b1). To a solution of 4-bromo-1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine (BB-a1) (1.05 g, 2.53 mmol) in 1,4-dioxane (15.2 mL) was added B pin (bis(pinacolato)diboron) (963 mg, 3.80 mmol), potassium acetate (744 mg, 7.59 mmol), and then degassed in the presence of PdCI(dppf) (bis(diphenylphosphino)ferrocene]dichloropalladium(II)) (370 mg, 0.51 mmol). The reaction mixture was heated under microwave conditions at 100 °C for 6 h. The reaction mixture is cooled to room temperature and filtered through a pad of Celite. Ethyl acetate and water are added to the filtrate. The layers are separated and the aqueous phase is extracted with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)boronic acid (BB-b1) (1.99 g, 99% yield) as a brown oil, which is used in the next step without further purification.

[0126] [ka] Y1 BB-b1 Compound 1_01

[0127] Scheme 4. Scheme for synthesizing target compound 1_01 according to the present invention. Preparation of 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridyl)pyrrolo[2,3-c]pyridine (compound 1_01). A solution of (1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)boronic acid (BB-b1) (200 mg, 45 wt%, 0.25 mmol) in THF (tetrahydrofuran) (1.1 mL) and water (0.11 mL) was added to 2-bromo-5-methylpyridine (53.7 mg, 0.31 mmol), cesium carbonate (163 mg, 0.50 mmol), and then degassed in the presence of PdCl(dppf)(bis(diphenylphosphino)ferrocene]dichloropalladium(ll)) (9.14 mg, 0.13 mmol). The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. Ethyl acetate and water were added to the filtrate. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using 100 / 0 to 60 / 40 cyclohexane / ethyl acetate as the eluent. The resulting solid was triturated with diethyl ether, filtered, and dried to give 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (Compound 1_01) (10.4 mg, 9.7% yield) as a white solid.

[0128] Compounds 1_02-1_33 are prepared similarly to the procedure described above, but using the characteristic bromine derivative of intermediate Y and the sulfonyl chloride derivative of intermediate Z.

[0129] General approach for synthesizing compounds 2_01 to 4_01 according to the present invention. General formula of intermediates for synthesis (R 1 , R 2 are defined as above).

[0130] [ka] Intermediate 2X Intermediate 2Y Intermediates

[0131] Intermediates 2X (general structure) for the synthesis, and intermediate 2Y are either commercially available or readily prepared by methods known to those skilled in the art.

[0132] General scheme for synthesizing compounds 2_01 to 4_01 according to the present invention.

[0133] [ka] Intermediate 2X

[0134] Scheme 5. General scheme for synthesizing target compounds 2_01-4_01 according to the present invention. CS2CO3 (502 mg, 2.67 equivalents) is added to a mixture of intermediate 2Y (1 equivalent) in DMSO. After 15 minutes at room temperature, intermediate 2X (0.67 equivalents) is added to the reaction mixture, and the reaction mixture is stirred at room temperature for 18 hours. The mixture is directly purified by preparative HPLC to obtain the compounds of the present invention.

[0135] Some specific compounds according to the present invention are obtained. Preparation of 1-((3,5-difluoro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin)-2-yl)-1H-pyrrolo[2,3-c]pyridine (Compound 2_02). To a mixture of 1-cyclopropylmethylpiperazine (85.9 μL, 578 μmol) in DMSO (2.2 mL) was added CS2CO3 (502 mg, 1.54 mmol). After 15 minutes at room temperature, 4-(pyridin-2-yl)-1-((3,4,5-trifluorophenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine (150 mg, 385 μmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was directly purified by preparative HPLC to give 1-((4-(4-(cyclopropylmethyl)piperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (54 mg, 26% yield) as a white solid.

[0136] [ka] Intermediate 2X1 Compound 2_02

[0137] Scheme 6. Scheme for synthesizing target compound 2_02 according to the present invention. Preparation of 1-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (Compound 3_20): To a mixture of 1,4-diazabicyclo[3.2.1]octane dihydrochloride (107 mg, 578 μmol) in DMSO (2.2 mL) was added CS2CO3 (502 mg, 1.54 mmol). After 15 min at room temperature, 4-(pyridin-2-yl)-1-((3,4,5-trifluorophenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine (Intermediate 2, 150 mg, 385 μmol) was added, and the reaction mixture was stirred at room temperature for 3 h. The mixture was directly purified by preparative HPLC column chromatography to give 1-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (13 mg, 6.7% yield) as a white solid.

[0138] [ka] Intermediate 2X1 Compound 3_20

[0139] Scheme 7. Scheme for synthesizing target compound 3_20 according to the present invention. Compounds 2_01, 2_03 to 3_19, and 3_21 to 4_01 are obtained similarly to the above procedure, but using characteristic intermediates.

[0140] Experimental analysis LC-MS analysis of compounds according to the present invention. Analytical HPLC was performed on an X-Select CSHC18XP column (2.5 μm, 30 × 4.6 mm ID) eluted with 0.1% formic acid in water (solvent A) and 0.1% formic acid in acetonitrile (solvent B), using an elution gradient of 5% to 100% B from 0 to 3 min, 100% B from 3 to 4 min, at a flow rate of 1.8 mL / min at 40 °C. Mass spectra (MS) were recorded on a Waters ZQ mass spectrometer (scan 200–900 μm) using electrospray positive ionization [ES+] to obtain the [M+H+ molecular ion] or electrospray negative ionization [ES-] to obtain the [M-H- molecular ion] mode at 20 V cone voltage. [Example]

[0141] Compound 1_01: 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridyl)pyrrolo[2,3-c]pyridine; MW=407.49; Purity (by HPLC)>95%, MS(ESI+), m / z 408.4 [M+H]+. [Example]

[0142] Compound 1_02: 1-((4-Methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine MW=408.47; Purity (HPLC)>95%, MS(ESI+), m / z 409.4 [M+H]+. [Example]

[0143] Compound 1_03: 1-((4-Methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=408.47; Purity (HPLC)>95%, MS(ESI+), m / z 409.4 [M+H]+. [Example]

[0144] Compound 1_04: 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(6-methylpyridazin-3-yl)pyrrolo[2,3-c]pyridine; MW=409.3; Purity (HPLC)>95%, MS(ESI+), m / z 395.2 [M+H]+. [Example]

[0145] Compound 1_05: 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methylsulfonyl-2-pyridyl)pyrrolo[2,3-c]pyridine; MW=471.55; Purity (HPLC)>95%, MS(ESI+), m / z 472.1 [M+H]+. [Example]

[0146] Compound 1_06: 1-((3,5-difluoro-4-isopropoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=429.44; Purity (HPLC)>95%, MS(ESI+), m / z 430.1 [M+H]+. [Example]

[0147] Compound 1_07: 1-((4-(cyclopropylmethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=441.45; Purity (HPLC)>95%, MS(ESI+), m / z 442.3 [M+H]+. [Example]

[0148] Compound 1_08: 1-((4-(2,2-difluoroethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=451.4; Purity (HPLC)>95%, MS(ESI+), m / z 452.0 [M+H]+. [Example]

[0149] Compound 1_09: 2,6-difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW=414.43; Purity (HPLC)>95%, MS(ESI+), m / z 415.1 [M+H]+ [Example]

[0150] Compound 1_10: 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)morpholine MW=456.47; Purity (HPLC)>95%, MS(ESI+), m / z 457.1 [M+H]+. [Example]

[0151] Compound 1_11: 2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW = 386.38; Purity (HPLC) > 95%, MS (ESI+), m / z 387.3 [M+H]+. [Example]

[0152] Compound 1_12: 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=469.51; Purity (HPLC)>95%, MS(ESI+), m / z 470.2 [M+H]+. [Example]

[0153] Compound 1_13: N-cyclopropyl-2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW = 426.44; Purity (HPLC) > 95%, MS (ESI+), m / z 427.4 [M+H]+. [Example]

[0154] Compound 1_14: N-cyclobutyl-2,6-difluoro-N-methyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW = 454.5; Purity (HPLC) > 95%, MS (ESI+), m / z 455.3 [M+H]+. [Example]

[0155] Compound 1_15: 2,6-difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW=416.45; Purity (HPLC)>95%, MS(ESI+), m / z 417.4 [M+H]+. [Example]

[0156] Compound 1_16: 2,6-difluoro-4-((4-(pyridin-2-yl)-2,3-dehydro-H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenol; MW = 389.38; Purity (HPLC) > 95%, MS (ESI+), m / z [M+H]+. [Example]

[0157] Compound 1_17: 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; MW=471.53; Purity (HPLC)>95%, MS(ESI+), m / z 472.4 [M+H]+. [Example]

[0158] Compound 1_18: 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=401.39; Purity (HPLC)>95%, MS(ESI+), m / z ** [M+H]+. [Example]

[0159] Compound 1_19: 1-((3,5-difluoro-4-(3-methylazetidin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=440.47; Purity (HPLC)>95%, MS(ESI+), m / z 441.1 [M+H]+. [Example]

[0160] Compound 1_20: N-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-N,4-dimethylthiazol-2-amine; MW=497.54; Purity (HPLC)>95%, MS(ESI+), m / z 498.3 [M+H]+. [Example]

[0161] Compound 1_21: N-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-1-methylpiperidin-4-amine; MW=483.54; Purity (HPLC)>95%, MS(ESI+), m / z 484.1 [M+H]+. [Example]

[0162] Compound 1_22: N1-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-N2,N2-dimethylethane-1,2-diamine; MW=457.5; Purity (HPLC)>95%, MS(ESI+), m / z 458.4 [M+H]+. [Example]

[0163] Compound 1_23: 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)thiomorpholine; MW=472.53; Purity (HPLC)>95%, MS(ESI+), m / z 473.3 [M+H]+. [Example]

[0164] Compound 1_24: 1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-s]pyridine; MW=495.55; Purity (HPLC)>95%, MS(ESI+), m / z 496.4 [M+H]+. [Example]

[0165] Compound 1_25: 1-((3,5-difluoro-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=495.55; Purity (HPLC)>95%, MS(ESI+), m / z 496.2 [M+H]+. [Example]

[0166] Compound 1_26: 2-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-2,7-diazaspiro[4.4]nonane; MW=509.58; Purity (HPLC)>95%, MS(ESI+), m / z 510.2 [M+H]+. [Example]

[0167] Compound 1_27: 2-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)oxazole-4-carbonitrile; MW=484.48; Purity (HPLC)>95%, MS(ESI+), m / z 485.4 [M+H]+. [Example]

[0168] Compound 1_28: 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; MW=494.52; Purity (HPLC)>95%, MS(ESI+), m / z 495.4 [M+H]+. [Example]

[0169] Compound 1_29: 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(5-fluoropyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=488.49; Purity (HPLC)>95%, MS(ESI+), m / z 489.1 [M+H]+. [Example]

[0170] Compound 1_30: 55-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrazin-2-amine; MW=499.54; Purity (HPLC)>95%, MS(ESI+), m / z 500.2 [M+H]+. [Example]

[0171] Compound 1_31: 4-(5-cyclopropylpyridin-2-yl)-1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine; MW=509.58; Purity (HPLC)>95%, MS(ES1+), m / z 510.4 [M+H]+. [Example]

[0172] Compound 1_32: 2,6-difluoro-4-((4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW=401.39; Purity (HPLC)>95%, MS(ESI+), m / z 402.1 [M+H]+. [Example]

[0173] Compound 1_33: 2,6-difluoro-N,N-dimethyl-4-((4-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; MW=428.46; Purity (HPLC)>95%, MS(ESI+), m / z 429.1 [M+H]+. [Example]

[0174] Compound 2_01: 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-1-methylpiperazin-2-one; MW=483.49; Purity (HPLC)>95%, MS(ES1+), m / z 484.1 [M+H]+. [Example]

[0175] Compound 2_02: 1-((4-(4-(cyclopropylmethyl)piperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=509.58; Purity (HPLC)>95%, MS(ES1+), m / z 510.4 [M+H]+. [Example]

[0176] Compound 2_03: N-(tert-butyl)-5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolamide; MW = 594.68; Purity (HPLC) > 95%, MS (ESI+), m / z 595.5 [M+H]+. [Example]

[0177] Compound 3_01: 1-((3,5-Difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=455, 48; Purity (HPLC)>95%, MS(ES1+), m / z 456, 1 [M+H]+. [Example]

[0178] Compound 3_02: 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridin-3-amine; MW=498.55; Purity (HPLC)>95%, MS(ES1+), m / z 499.4 [M+H]+. [Example]

[0179] Compound 3_03: 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridin-2-amine; MW=498.55; Purity (HPLC)>95%, MS(ES1+), m / z 499.1 [M+H]+. [Example]

[0180] Compound 3_04: 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylpyridin-3-amine; MW=512.58; Purity (HPLC)>95%, MS(ES1+), m / z 513.4 [M+H]+. [Example]

[0181] Compound 3_05: 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazine-2-carbonitrile; MW=495.51; Purity (HPLC)>95%, MS(ES1+), m / z 496.3 [M+H]+. [Example]

[0182] Compound 3_06: 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)nicotinonitrile; MW=494.52; Purity (HPLC)>95%, MS(ES1+), m / z 495.3 [M+H]+. [Example]

[0183] Compound 3_07: 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridazin-3-amine; MW=499.54; Purity (HPLC)>95%, MS(ES1+), m / z 500, 4[M+H]+. [Example]

[0184] Compound 3_08: 2-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrimidin-5-amine; MW=499.54; Purity (HPLC)>95%, MS(ES1+), m / z 500, 4[M+H]+. [Example]

[0185] Compound 3_09: 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidine-2-carbonitrile; MW=495.51; Purity (HPLC)>95%, MS(ES1+), m / z 496.3 [M+H]+. [Example]

[0186] Compound 3_10: 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridazine-3-carbonitrile; MW=495.51; Purity (HPLC)>95%, MS(ES1+), m / z 496.3 [M+H]+. [Example]

[0187] Compound 3_11: 1-((3,5-difluoro-4-(4-isopropylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=497.56; Purity (HPLC)>95%, MS(ES1+), m / z 498.4 [M+H]+. [Example]

[0188] Compound 3_12: 1-((4-(4-cyclopropylpiperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=495.55; Purity (HPLC)>95%, MS(ES1+), m / z 496.4 [M+H]+. [Example]

[0189] Compound 3_13: 1-((3,5-difluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=483.54; Purity (HPLC)>95%, MS(ESI+), m / z 484.1 [M+H]+. [Example]

[0190] Compound 3_14: 1-((4-(1,4-diazepan-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=469.51; Purity (HPLC)>95%, MS(ESI+), m / z 470, 1 [M+H]+. [Example]

[0191] Compound 3_15: 1-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)piperidin-4-amine; MW=469.51; Purity (HPLC)>95%, MS(ES1+), m / z 470.4 [M+H]+. [Example]

[0192] Compound 3_16: 1-((3,5-difluoro-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=481.52; Purity (HPLC)>95%, MS(ESI+), m / z 482.4 [M+H]+. [Example]

[0193] Compound 3_17: 1-((3,5-difluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=481.52; Purity (HPLC)>95%, MS(ESI+), m / z 482.2 [M+H]+. [Example]

[0194] Compound 3_18: 6-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-3-methyl-3,6-diazabicyclo[3.1.1]heptane; MW = 481.52; Purity (HPLC) >95%, MS (ESI+), m / z 482.3 [M+H]+. [Example]

[0195] Compound 3_19: 1-((3,5-difluoro-4-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=495.55; Purity (HPLC)>95%, MS(ESI+), m / z 496.4 [M+H]+. [Example]

[0196] Compound 3_20: 1-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=481.52; Purity (HPLC)>95%, MS(ES1+), m / z 482.3 [M+H]+. [Example]

[0197] Compound 3_21: 1-((3,5-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=467.49; Purity (HPLC)>95%, MS(ES1+), m / z 468.4 [M+H]+. [Example]

[0198] Compound 3_22: 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrazin-2-amine; MW=525.58; Purity (HPLC)>95%, MS(ESI+), m / z 526.4 [M+H]+. [Example]

[0199] Compound 3_23: 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazine-2-carbonitrile; MW=521.55; Purity (HPLC)>95%, MS(ESI+), m / z 522.4 [M+H]+. [Example]

[0200] Compound 3_24: 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; MW = 520,56; Purity (HPLC) > 95%, MS (ESI+), m / z 521,4 [M+H]+. [Example]

[0201] Compound 3_25: 1-((4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt); MW = 467,49; Purity (HPLC) >95%, MS (ESI+), m / z 468, 2 [M+H]+. [Example]

[0202] Compound 3_26: 1-((4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; MW=481.52; Purity (HPLC)>95%, MS(ESI+), m / z 482.2 [M+H]+. [Example]

[0203] Compound 3_27: 1-((3,5-difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt); MW=455, 48; Purity (HPLC)>95%, MS(ES1+), m / z 456, 2[M+H]+. [Example]

[0204] Compound 3_28: 5-(1-((3,5-difluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; MW = 506.53; Purity (HPLC) > 95%, MS (ESI+), m / z 507.4 [M+H]+. [Example]

[0205] Compound 4_01: 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt); MW = 469.51; Purity (HPLC) > 95%, MS (ESI+), m / z 470.2 [M+H]+.

[0206] Characterization of the Biological Activity of Compounds of the Invention We investigated the activity of compounds of the invention as inhibitors of CYP11B2 when analyzed in a reconstituted system containing 0.5 μM recombinant CYP11B2, 0.3 μM human adrenodoxin reductase, 2 μM human adrenodoxin, and 100 μM corticosterone as a control reaction. Product formation was detected using an HPLC system equipped with a UV detector. Test compounds were 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 and preincubated at 37°C for 10 minutes before the addition of substrate. The reaction was initiated by adding NADPH (nicotinamide adenine dinucleotide phosphate) to a final concentration of 0.25 mM and incubated at 37°C using 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-2, 0.4 mM MgCl2. After 30 minutes of incubation, the reaction was stopped by adding 5 ml of dichloromethane. The organic phase was isolated by centrifugation, evaporation, and dissolution in ethanol and transferred to a vial for HPLC analysis. A C18 Luna 100A 250x4, 6 mm column was used on an Agilent Technologies 1200 Series instrument (USA) using ethanol as the mobile phase.

[0207] Activity (a) is calculated as the amount of product in nmol per minute per nmol of CYP.

[0208]

number

[0209] where k is a correction factor (k=1 is used as the molar extinction coefficient of the analogous steroid substrate and product at a detection wavelength of 254 nm). s is the peak area of ​​the substrate, and c s is the concentration of the substrate, and A p is the peak area of ​​the product, and c eis the concentration of CYP (cytochrome P450), and t is the reaction time.

[0210] The level of inhibition of CYP11B2 activity is expressed as a percentage, with 0% being defined as no inhibition in reactions without the test compound and 100% being absolute inhibition by the test compound. All embodiments of the compounds of the present invention are suitable for inhibiting CYP11B2 activity. A preferred subgroup includes compounds that inhibit CYP11B2 activity in the range of 1-100% (+). Within this subgroup, there is another subgroup of more preferred compounds that inhibit CYP11B2 activity in the range of 20-100% (++). Compounds 2.1-2.4 and 3.1-3.6 inhibit CYP11B2 activity in the range of 35-100% (+++), and compounds 1.1-1.18 inhibit CYP11B2 activity in the range of 50-100% (+++). See Table 2. The associated code numbers correspond to the previous codes shown in Table 1.

[0211] [Table 2] JPEG2025538918000042.jpg23191 JPEG2025538918000043.jpg8388

[0212] Pharmaceutical Composition The present invention also relates to pharmaceutical compositions comprising a compound of general formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId (or a prodrug, pharmaceutically acceptable salt, or other pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, diluents, and / or excipients, which can be introduced into the body of a patient together with the compound that is the essence of the present invention and which are non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound without destroying the pharmacological activity of the compound.

[0213] The pharmaceutical compositions of the present invention contain the compounds of the present invention together with a pharmaceutically acceptable carrier, which may include any solvent, diluent, dispersion or suspension, surfactant, isotonicity agent, thickener and emulsifier, preservative, binder, lubricant, etc., suitable for the particular dosage form. Materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, monosaccharides and oligosaccharides and their derivatives; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut, cottonseed, sesame, olive, corn, and soybean oil; 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; pyrogen-free water; isotonic solution, Ringer's solution; alcohol, and phosphate buffer. Other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, film-forming agents, sweeteners, flavors, and fragrances, preservatives, and antioxidants may also be included in the composition.

[0214] The subject of the present invention is a class of dosage forms-pharmaceutical compositions, the structure of which is optimized for administration into the body in therapeutically effective doses and in recommended dosage amounts for specific methods of administration, such as intravenous, intramuscular, oral, subcutaneous, intraocular, inhalation, intranasal and sublingual administration.

[0215] The dosage forms of the present invention may comprise structures obtained by liposomal methods, microencapsulation methods, methods for obtaining nanoforms of drugs, or other methods known in the pharmaceutical arts.

[0216] For preparing the compositions, e.g., in the form of tablets, the active ingredient is mixed with one or more pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silicon dioxide, gum arabic, mannitol, microcrystalline cellulose, hypromellose, or similar compounds.

[0217] Tablets may be coated with sucrose, cellulose derivatives, or other suitable coating agents. Tablets may be prepared in a variety of ways, including direct compression, dry or wet granulation, or hot doping.

[0218] A pharmaceutical composition in the form of a gelatin capsule can be obtained by mixing the active ingredient with a solvent and filling the resulting mixture into soft or hard capsules.

[0219] For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injection solutions are used, the compatibility of which includes pharmacological agents such as propylene glycol or butylene glycol.

[0220] Although the present invention has been described with reference to disclosed embodiments, it should be apparent to those skilled in the art that the specific experiments described in detail are for purposes of illustrating the invention only and should not be construed as limiting the scope of the invention in any way. It should be apparent that various modifications can be made without departing from the essence of the invention.

[0221] Treatment method The compounds of the present invention are inhibitors of CYP11B2 (aldosterone synthase) and are therefore useful agents for the treatment and / or prevention of diseases or conditions that can be alleviated by lowering aldosterone levels. Due to their ability to inhibit aldosterone synthase, the compounds of the present invention are useful in treating and / or reducing the risk of developing: primary hyperaldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved systolic function, 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, nephrotic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction myocardial sclerosis, arteriosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, and insulin resistance.

[0222] Although these disorders are well characterized in humans, they also exist in other mammals with similar etiologies and can be treated with the pharmaceutical compositions of the present invention.

[0223] For therapeutic use, the compounds of the present invention can be administered by pharmaceutical compositions in any pharmaceutical dosage form via any administration route. Dosage forms generally contain a pharmaceutically acceptable carrier suitable for the particular dosage form selected. In particular, the compounds of the present invention can be administered daily for the period necessary to treat and / or prevent the relevant disease in the patient, including a course of treatment for several days, several months, several years, or even 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 administration routes are oral and intravenous administration.

[0224] The present invention also relates to pharmaceutical compositions containing a daily dose of a compound in the form of a fixed dosage unit, and to combinations containing the pharmaceutical compositions or the compounds. In a preferred embodiment, the compositions for use according to the present invention are administered once daily at a dose of 1 mg or more of the selected compound of the present invention. A preferred dose is 1 to 500 mg. A most preferred dose is 10 to 200 mg. One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, or IIId. Generally, any additional single or multiple active agents other than the compounds of Formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId, such as, but not limited to, antihypertensive agents, antidiabetic agents, and / or antiobesity agents, may be used in any combination with the compounds of Formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId in single or separate dosage forms, thereby allowing for simultaneous or sequential therapeutic action of the active agents.

Claims

1. Compounds of general formula (I) as follows: 【Chemistry 1】 Formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R １ is a 5-6 membered heteroaryl containing 0-1 oxygen, 0-1 sulfur and / or 0-4 nitrogen, optionally substituted with 1-5 substituents R1a; R1a is independently selected from and is hydrogen, deuterium, halogen, (C1-C3) alkyl, (C3-C5) cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3) alkyl, (C1-C3) alkylsulfonyl, cyano, N,N-dimethylamine, N-methylamine, -C(=O)-NH-(C1-C5)-alkyl; R ２ , R ３ , R ４ , R ５ are each independently selected from the following: -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH ３ , partially or fully halogenated (C1-C3) alkyl, or -(ii) -OH, -SH, or -(iii) -(C1-C3)-alkoxy, 3- to 7-membered heterocyclyl containing 0 to 2 nitrogen atoms, 0 to 1 oxygen atoms, 0 to 1 sulfur atoms, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, each of the above groups optionally partially or fully substituted with substituents selected from: -OH, deuterium, 1 to 4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, (C1-C3)alkoxy, -NH , a 3- to 7-membered heterocycle containing one oxygen atom, (C1-C3)-alkylamino, di(C1-C3)-alkylamino or a 3- to 7-membered heterocycle containing one nitrogen atom and optionally 1 to 2 oxygen and / or sulfur heteroatoms; -(iv) necessarily substituted by 1 to 4 substituents selected from 4- to 7-membered heterocyclyl containing 1 to 2 nitrogen atoms, 0 to 1 oxygen atoms, 0 to 1 sulfur atoms, oxo group or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and optionally substituted by 1 to 3 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl and (C1-C3)alkoxy, or -(v) -NRaRb, wherein each Ra and Rb is: independently hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms and optionally substituted by 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms, said heteroaryl is optionally substituted with 1 to 2 substituents selected from deuterium, halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, optionally substituted by 1-4 substituents selected from (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, (C1-C3)alkoxy, or Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, optionally substituted by 1-4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)alkynyl, oxo group or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl or (C1-C3)alkoxy; R ２ , R ３ , R ４ , R ５ at least two of which are other than hydrogen; D / S - means that a double or single bond is present; A dashed bond means that the ring is aromatic.

2. R ２ , R ３ , R ４ and R ５ 2. The compound of claim 1, wherein at least three of are other than hydrogen.

3. R ２ , R ３ , R ４ , R ５ are each independently selected from the following and represent: -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH ３ , partially or fully halogenated (C1-C3) alkyl; -(ii) a group selected from (C1-C3)-alkoxy, (C3-C7)cycloalkyl, halogenated (C1-C3)alkoxy groups containing 1 to 4 halogen atoms, -(iii)-NRaRb, wherein each Ra and Rb is: independently hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms and optionally substituted by 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms, optionally 1 to 2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, or or Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, optionally substituted by 1-4 substituents selected from deuterium, halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl or (C1-C3)-alkoxy, R ２ , R ３ , R ４ , R ５ At least two of these are other than hydrogen.

4. 2. The compound of claim 1, wherein the radical R ２ , R ３ , R ４ , R ５ at least one of is in the para position, each is independently selected from the following and represents: -OH, -SH, -(C1-C3)-alkoxy, 0 to 2 nitrogen atoms, 0 to 1 oxygen atoms, 0 to 1 sulfur atoms, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, each of the above groups optionally partially or fully substituted with substituents selected from: -OH, 1 to 4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, 3- to 7-membered heterocycle containing 1 oxygen atom, -NH ２ , (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3- to 7-membered heterocycle containing one nitrogen atom and one to two oxygen and sulfur heteroatoms; or -NRaRb, where each Ra and Rb is: independently hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH ３ ) ２ , (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and 1-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 1-2 nitrogen atoms, wherein heteroaryl is optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, or Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, optionally substituted with 1-4 substituents selected from halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl or (C1-C3)-alkoxy.

5. R １ is independently selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, and oxazyl; R １ is optionally substituted with the group consisting of methyl, methylsulfonyl, halogen, methylamino, cyano, and cyclopropyl.

6. R ２ , R ３ , R ４ , R ５ two of which are in the meta position and are groups selected from methyl or halogen; R ２ , R ３ , R ４ , R ５ one of R is hydrogen; ２ , R ３ , R ４ , R ５ one of which is in the para position, and is methoxyisopropyloxy, cyclopropylmethoxy, difluoroethoxy, —NH ２ , -N(CH ３ ) ２ , cyclopropylamino, —N(CH ３ )-cyclobutyl, —N(CH ３ )-methylthiazolyl, methylpiperidylamino, —NH—(C1-C3)-alkyl-N(CH ３ ) ２ , morpholinyl, methylpiperazinyl, optionally methyl-substituted azetidinyl, thiomorpholinyl, optionally methyl-substituted hexahydropyrrolopyrrolyl, diazaspirononyl, and optionally substituted with methyloctahydropyrrolopyridinyl.

7. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (Ia): 【Chemistry 2】 Formula (Ia), or a pharmaceutically acceptable salt, or solvate or hydrate thereof, wherein: R １ is as defined in claim 1, R ６ is independently selected from the following: -OH, -SH, -(C1-C3)-alkoxy, 0 to 1 oxygen atoms, 0 to 1 sulfur atoms, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, each of the above groups optionally partially or fully substituted with substituents selected from: -OH, 1 to 4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, 3- to 7-membered heterocycle containing 1 oxygen atom, -NH ２ , (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3- to 7-membered heterocycle containing one nitrogen atom and optionally 1 to 2 heteroatoms selected from oxygen and sulfur; or -NRaRb, where each Ra and Rb is: independently hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH ３ ) ２ , (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3-7 membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and 1-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5-7 membered heteroaryl containing 0-1 oxygen, 0-1 nitrogen and / or 1-4 nitrogen, wherein heteroaryl is optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, or Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, optionally substituted with 1-4 substituents selected from halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl or (C1-C3)-alkoxy.

8. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IIa): Formula (IIa), 【Transformation 3】 or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R １ and R ６ is as set forth in claim 7.

9. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (Ib): 【Chemistry 4】 Formula (Ib), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q １ , Q ２ , Q ３ , Q ４ , Q ５ are each independently selected from nitrogen or carbon and are nitrogen or carbon, １ , Q ２ , Q ３ , Q ４ , and Q ５ wherein no more than two of are nitrogen, said carbons being optionally substituted with 1 to 5 substituents R1a; R ２ , R ３ , R ４ , R ５ and R1a is as defined in claim 1; A dotted bond means that the ring is aromatic.

10. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (Ic): 【Transformation 5】 Formula (Ic), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q ６ , Q ７ , Q ８ , Q ９ are each independently selected from oxygen, carbon, or nitrogen, and are oxygen, carbon, or nitrogen; Q ６ , Q ７ , Q ８ and Q ９ wherein no more than two of are nitrogen or oxygen, and the carbons are optionally substituted with 1-2 R groups; R ２ , R ３ , R ４ , R ５ and R1a are as defined in claim 1, A dotted bond means that the ring is aromatic.

11. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (Id): 【Transformation 6】 Formula (Id), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q １ , Q ２ , Q ３ , Q ４ , Q ５ is as claimed in claim 9; R ６ is as set forth in claim 7.

12. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (Ie): 【Transformation 7】 Formula (Ie), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q6, Q7, Q8, Q9 are as defined in claim 10; R ６ is as set forth in claim 7.

13. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (If): 【Transformation 8】 Formula (If), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: R １ is as defined in claim 1, R ６ is as set forth in claim 7.

14. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IIb): 【Chemistry 9】 Formula (IIb), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q １ , Q ２ , Q ３ , Q ４ , Q ５ is as claimed in claim 9; R ２ , R ３ , R ４ and R ５ is as claimed in claim 1; A dotted bond means that the ring is aromatic.

15. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IId): 【Chemistry 10】 Formula (IId), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q １ , Q ２ , Q ３ , Q ４ , Q ５ is as claimed in claim 9; R ６ is as set forth in claim 7.

16. 10. The compound of claim 1, wherein the compound of formula (I) is a compound whose structure is described by formula (IIId): 【Chemistry 11】 Formula (IIId), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein: Q １ , Q ２ , Q ３ , Q ４ each independently represents nitrogen or carbon; -R' is hydrogen, deuterium, halogen, (C1-C3) alkyl, (C3-C5) cycloalkyl, -C(=O)-CH , partially or fully halogenated (C1-C3) alkyl, (C1-C3) alkylsulfonyl, cyano, N,N-dimethylamine, N-methylamine; R' independently represents a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms, 0-1 oxygen atoms, and / or 0-1 sulfur atoms, which is necessarily substituted with 1-2 substituents selected from oxo groups or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and optionally substituted with 1-3 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, and (C1-C3) alkoxy; or When —R′ 1 independently represents —C(═O)—NH—(C1-C5)-alkyl, R 2 independently represents: -NRcRd, wherein each Rc and Rd is independently hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH ３ ) ２ , (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, 3- to 7-membered heterocyclyl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms and optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, 5- to 7-membered heteroaryl containing 0-1 oxygen atoms, 0-1 sulfur atoms and / or 0-4 nitrogen atoms, heteroaryl optionally substituted with 1-2 substituents selected from (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, or Rc and Rd together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen atoms and / or 0-1 sulfur atoms, optionally substituted by 1-4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C1-C3)alkoxy, or Alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclyl containing 1-2 nitrogen atoms and 0-1 oxygen and / or 0-1 sulfur atoms, optionally substituted by 1-4 substituents selected from deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)alkynyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl or (C1-C3)alkoxy.

17. The compound of claim 1 selected from the group consisting of: 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridyl)pyrrolo[2,3-c]pyridine; 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(6-methylpyridazin-3-yl)pyrrolo[2,3-c]pyridine; 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methylsulfonyl-2-pyridyl)pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-isopropoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((4-(cyclopropylmethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((4-(2,2-difluoroethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 2,6-difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)morpholine; 2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; N-cyclobutyl-2,6-difluoro-N-methyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 2,6-difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 2,6-difluoro-4-((4-(pyridin-2-yl)-2,3-dehydro-H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenol; 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-(3-methylazetidin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; N-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-N,4-dimethylthiazol-2-amine; N-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-1-methylpiperidin-4-amine; N1-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-N2,N2-dimethylethane-1,2-diamine; 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)thiomorpholine; 1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-s]pyridine; 1-((3,5-difluoro-4-(5-methyloctahydro-2H-pyrrolo[3,4-c]pyridin-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 2-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-2,7-diazaspiro[4.4]nonane; 2-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)oxazole-4-carbonitrile; 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(5-fluoropyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrazin-2-amine; 4-(5-cyclopropylpyridin-2-yl)-1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine; 2,6-difluoro-4-((4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 2,6-difluoro-N,N-dimethyl-4-((4-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-1-methylpiperazin-2-one; 1-((4-(4-(cyclopropylmethyl)piperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; N-(tert-butyl)-5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolamide; 1-((3,5-difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridin-3-amine; 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridin-2-amine; 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylpyridin-3-amine; 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazine-2-carbonitrile; 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)nicotinonitrile; 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyridazin-3-amine; 2-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrimidin-5-amine; 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrimidine-2-carbonitrile; 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridazine-3-carbonitrile; 1-((3,5-difluoro-4-(4-isopropylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((4-(4-cyclopropylpiperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((4-(1,4-diazepan-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)piperidin-4-amine; 1-((3,5-difluoro-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 6-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)-3-methyl-3,6-diazabicyclo[3.1.1]heptane; 1-((3,5-difluoro-4-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-(2,6-diazaspiro[3.3]heptan-2-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylpyrazin-2-amine; 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazine-2-carbonitrile; 5-(1-((3,5-difluoro-4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; 1-((4-(2,5-diazabicyclo[2.2.1]heptan-2-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt); 1-((4-(3,8-diazabicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; 1-((3,5-difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt) 5-(1-((3,5-difluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinonitrile; 1-((3,5-Difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (HCl salt).

18. 20. Use of a compound according to any one of claims 1 to 17 for inhibiting CYP11B2.

19. 20. Use of a compound according to any one of claims 1 to 17 in reducing aldosterone levels in a subject.

20. 20. The use of claim 19, wherein the subject is a human.

21. A pharmaceutical composition for treating and / or preventing a disease or condition mediated or maintained by CYP11B2 activity, comprising administering a therapeutically or prophylactically effective amount of a compound of the present invention described in any one of claims 1 to 17 and at least one pharmaceutically acceptable excipient.

22. 22. The pharmaceutical composition according to claim 21, characterized in that the pharmaceutically acceptable excipient is a carrier, adjuvant and / or solvent.

23. The pharmaceutical composition of claim 21, characterized in that the disease is selected from the following group: primary hyperaldosteronism, chronic heart failure, chronic heart failure with preserved systolic function, 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, nephrotic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction myocardial sclerosis, arteriosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia or insulin resistance.

24. The pharmaceutical composition of claim 23, characterized in that the primary hyperaldosteronism is Conn's syndrome, which includes diseases or conditions such as aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, type I and type II familial aldosteronism, aldosterone-producing cancer, and ectopic aldosterone.

25. A method for treating and / or preventing a disease or condition mediated or maintained by CYP11B2 activity in a subject, the method comprising administering a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 17.

26. 26. The method according to claim 25, characterized in that the disease is selected from the following group: primary hyperaldosteronism, chronic heart failure, chronic heart failure with preserved systolic function, 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, nephrotic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction myocardial sclerosis, arteriosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia or insulin resistance.

27. The method of claim 25, wherein the primary hyperaldosteronism is Conn's syndrome, which includes diseases or conditions such as aldosterone-producing adenoma, idiopathic hyperaldosteronism, unilateral or bilateral adrenal hyperplasia, type 1 and type 2 familial aldosteronism, aldosterone-producing cancer, and ectopic aldosterone.

28. 24. The method of claim 23, wherein the subject is a human.

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