Inhibitors of human aldosterone synthetase (CYP11B2)

Abstract

The present invention relates to organic chemistry, pharmacology, medicine, in particular to compounds for inhibiting human cytochrome 11B2 (CYP11B2) activity and their use in the treatment and / or prevention of various diseases and conditions mediated or maintained by aldosterone hormone activity. The compound has a structure as shown in a general formula (I), wherein R1, R2, R3, R4 and R5 are defined in the specification. The invention also relates to a pharmaceutical composition containing the compound and a preparation method thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to organic chemistry, pharmacology, and medicine. Specifically, the present invention relates to compounds for inhibiting the activity of human cytochrome 11B2 (CYP11B2), and the use of these compounds in the treatment and / or prevention of various diseases and disorders mediated or supported by aldosterone hormone activity. The present invention also relates to pharmaceutical compositions containing these compounds and methods for preparing the same. Background Art

[0002] Aldosterone is a steroid hormone whose main physiological function is to maintain the balance of sodium and potassium by regulating cation exchange (reabsorption of Na+ and secretion of K+) in the distal nephron, thereby causing an increase in blood pressure. In addition to its physiological effects, aldosterone is also involved in the pathogenesis of diseases or pathological conditions caused by excessive aldosterone synthesis (primary aldosteronism) and / or accompanied by excessive aldosterone synthesis (secondary aldosteronism), including various diseases such as the cardiovascular system, kidneys, and metabolic syndrome.

[0003] Modern treatment methods for conditions caused by and / or associated with excessive aldosterone synthesis involve interventions at different levels of the renin-angiotensin-aldosterone system (RAAS). Current medical standards include the following drug classes: renin inhibitors (IRs), angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEIs), and mineralocorticoid receptor (MR) blockers. However, in 25-50% of patients treated with IRs, ARBs, and ACE inhibitors either alone or in combination, serum aldosterone levels eventually return to pre-treatment levels or higher (the aldosterone breakthrough phenomenon) (Bomback et al., 2007, Nature Clinical Practice Nephrology, Vol. 3, pp. 486-492; Bomback et al., 2012, Journal of the American Society of Hypertension, Vol. 6, No. 5, pp. 338-45), while the use of MR blockers leads to a compensatory increase in serum aldosterone levels (Pitt et al., 2013, European Heart Journal, Vol. 34, pp. 2453-2463; Calhoun et al., 2011, Circulation, Vol. 124, pp. 1945-1955). Therefore, it has not been possible to completely eliminate all the pathological effects of aldosterone in the human body, including MR-mediated and non-MR-mediated actions. The latter include the following aspects: a) Through the action of GPCR receptors, aldosterone has a so-called "rapid effect", leading to apoptosis and preventing the proliferation of vascular endothelial and smooth muscle cells [Namsolleck et al., 2014, Nephrology, Dialysis, Transplantation, 29 (Suppl. 1), i62-i68], impaired vasoconstriction (Feldman et al., 2013, Clinical and Experimental Pharmacology and Physiology, 40, 916-921), and endothelial inflammation [Ziwei Tang et al., 2021, International Journal of Endocrinology, 2021, Article ID 5575927].In addition, recent in vitro and ex vivo studies have shown that aldosterone also enhances CYP11B2 gene expression through GPCR activation, thereby enhancing its own biosynthesis and release (Caroccia et al., 2019, Journal of Clinical Endocrinology and Metabolism, Vol. 104, No. 12, 6316 - 6324); b) pancreatic β-cell injury (Luther et al., 2011, Diabetologia 54, 2152 - 2163; Fang Chen et al., 2015, Scientific Reports Vol. 5, Article number: 13215 (2015)), which can lead to glucose intolerance; c) interaction with the IGF-I receptor in vascular smooth muscle cells, promoting vascular remodeling by stimulating fibroblast elastin production (Mitts et al., 2010, The Journal of Investigative Dermatology Vol. 130, No. 10, 2396 - 2406), suggesting that aldosterone may accelerate the development of atherosclerosis through this mechanism (Cascella et al., 2010, Endocrinology 151(12):5851 - 64); d) inducing vasoconstriction through a protein kinase C-dependent pathway (possibly through membrane receptors), leading to deterioration of the contractile and metabolic functions of the ischemic heart, so elevated plasma or cardiac tissue aldosterone levels may have an adverse effect on coronary heart disease (Fujita et al., 2005, Hypertension 46(1):113 - 7); e) aldosterone has been shown to be the main mechanism explaining the increased ventricular arrhythmias and sudden cardiac death associated with high aldosterone levels during ST-segment elevation myocardial infarction (STEMI) by non-MR-dependent activation of the potassium current (IK1) (Alexandre et al., 2015, PLoS One Vol. 10, No. 7); f) the dimerization effect of aldosterone on the angiotensin II receptor (AT1) may play an important role in pathological conditions such as hypertension and atherosclerosis (Sinphitukkul et al., 2019, Archives of Medical Science 15(6):1589 - 1598). In addition, aldosterone also mediates a non-genomic endothelium-independent vasoconstrictor effect through the AT1 receptor (Yamada et al., 2008, Cardiovascular Research 79(1):169 - 78).

[0004] Based on the above, inhibiting aldosterone synthesis would have therapeutic advantages compared to existing therapies and could overcome the limitations of existing treatment standards.

[0005] Aldosterone is synthesized by a single enzyme, CYP11B2 (aldosterone synthase), which catalyzes the conversion of 11-deoxycorticosterone (11-DOC) to aldosterone in three steps (via corticosterone and 18-hydroxycorticosterone). Therefore, CYP11B2 is a potential therapeutic target for inhibiting aldosterone synthesis and may have excellent pharmacodynamic properties (different from those observed with other RAAS modulators).

[0006] In summary, it is clear that drugs capable of inhibiting CYP11B2 (aldosterone synthase) can be used to treat and / or prevent diseases or conditions mediated or maintained by excessive aldosterone synthesis. Studies in rodents and primates have shown that at least 7 compounds with different chemical structures have shown effects of inhibiting aldosterone synthase in in vitro and in vivo experiments, and 3 of them have shown the effect of reducing aldosterone in clinical trials: LCI699 (Novartis), RO6836191 (Roche), and LY3045697 (Eli Lilly) [Comprehensive Review of Aldosterone Synthase Inhibitors in Cardiovascular Diseases: Preclinical, Clinical, and Computational Data, Lenzini L et al., Pharmaceutical Research 2021; 163:105332. doi:10.1016 / j.phrs.2020.105332; PMID: 33271294]; [Aldosterone Synthase Inhibitors, Weldon SM, Brown NF, Vitamins and Hormones 2019; 109:211-239. doi:10.1016 / bs.vh.2018.10.002; PMID: 30678857; Clinical Trials: NCT00817635, NCT01995383, NCT01821703]. Therefore, the inhibition of aldosterone synthase activity observed under in vitro conditions will also be observed in vivo.

[0007] In addition, CYP11B2-specific molecules have been shown to be useful as diagnostic markers for a variety of diseases associated with CYP11B2 overexpression. [Development of [18F]AldoView as the First Highly Selective Aldosterone Synthase PET Tracer for Primary Aldosteronism Imaging. Sander K et al., Journal of Medicinal Chemistry 2021; 8; 64(13):9321-9329. doi:10.1021 / acs.jmedchem.1c00539. PMID: 34137616]. Summary of the Invention

[0008] Brief Description of the Invention

[0009] In various embodiments of the present invention, the present invention provides novel chemical substances capable of inhibiting the activity of human CYP11B2 enzyme, and the biological activities of these substances have been studied. Therefore, the present invention relates to compounds, pharmaceutical compositions containing the compounds, uses of the compounds, methods of using them in the treatment of various diseases and conditions, and methods of preparing the compounds.

[0010] Detailed Description of the Invention

[0011] The compounds disclosed in the present invention inhibit the activity of human CYP11B2 enzyme, and the biological activities of these compounds have been studied.

[0012] Accordingly, the present invention relates to compounds, pharmaceutical compositions comprising said compounds, uses of said compounds, methods of using them in the treatment of various diseases and disorders, and methods of preparing said compounds.

[0013] The present invention discloses a compound of formula (I) as defined hereinafter or a pharmaceutically acceptable salt thereof.

[0014] The present invention discloses a compound of formula (I) as defined hereinafter or a pharmaceutically acceptable salt thereof for use as a medicament.

[0015] The present invention further discloses a compound of formula (I) as defined hereinafter for reducing the aldosterone level in a subject.

[0016] The present invention further discloses a compound of formula (I) as defined hereinafter for treating and / or preventing a disease or disorder mediated or maintained by overproduction of aldosterone.

[0017] The present invention further discloses a compound of formula (I) as defined herein for treating a disease selected from the group consisting of: primary aldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, and insulin resistance.

[0018] The present invention further discloses a compound of formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof,

[0019]

[0020] wherein,

[0021] R1 is a 5- or 6-membered heteroaryl containing 0-1 oxygen, 0-1 sulfur and / or 0-4 nitrogens, optionally substituted by 1-5 substituents R1a;

[0022] Each R1a is independently selected from the group consisting of: 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;

[0023] R2, R3, R4 and R5 are each independently selected from the group consisting of:

[0024] -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3) alkyl; or

[0025] -(ii) -OH, -SH; or

[0026] -(iii) (C1-C3)-alkoxy, a 3-7 membered heterocyclic group containing 0-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, wherein each of the above groups is optionally partially or fully substituted by substituents selected from the group consisting of: -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, -NH2, a 3-7 membered heterocyclic group containing one oxygen atom, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3-7 membered heterocyclic group containing one nitrogen atom and optionally 1-2 oxygen and / or sulfur heteroatoms; or

[0027] -(iv) a 4-7 membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which must be substituted by 1-4 substituents selected from the group consisting of: oxo, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and is also optionally substituted by 1-3 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl, and (C1-C3) alkoxy; or

[0028] -(v) -NRaRb, wherein each Ra and Rb:

[0029] - each independently is hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7-membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 5-7-membered heteroaryl containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, and the heteroaryl is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl;

[0030] Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-7-membered heterocyclic group containing 1-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-4 substituents selected from the group consisting of: 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

[0031] Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14-membered bicyclic heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-4 substituents selected from the group consisting of: 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;

[0032] D / S represents the presence of a double bond or a single bond;

[0033] The dashed bond indicates that the ring is aromatic.

[0034] In another preferred embodiment, the present invention includes a compound of formula (I) as defined above, wherein at least two of R2, R3, R4, R5 are not hydrogen.

[0035] In another preferred embodiment, the present invention includes a compound of formula (I) as defined above, wherein at least three of R2, R3, R4 and R5 are not hydrogen.

[0036] In another preferred embodiment, the present invention includes a compound of formula (I) as defined above, wherein R2, R3, R4 and R5 are not hydrogen.

[0037] In another preferred embodiment, the present invention comprises a compound of formula (I) as defined above, wherein R2, R3, R4 and R5 are each independently selected from the group consisting of:

[0038] -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3)-alkyl;

[0039] -(ii) a group selected from the group consisting of (C1-C3)-alkoxy, (C3-C7) cycloalkyl, halogenated (C1-C3) alkoxy containing 1-4 halogen atoms;

[0040] -(iii) -NRaRb, wherein each Ra and Rb:

[0041] - are each independently hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7 membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, optionally substituted with 1-2 substituents selected from the group consisting of (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 5-7 membered heteroaryl containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, optionally substituted with 1-2 substituents selected from the group consisting of (C1-C3)-alkyl, or partially or fully halogenated (C1-C3)-alkyl;

[0042] - alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-2 nitrogen atoms, and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted with 1-2 substituents selected from the group consisting of (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, or

[0043] - alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted with 1-4 substituents selected from the group consisting of deuterium, halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl or (C1-C3) alkoxy.

[0044] In another preferred embodiment, in the compound of formula (I) defined above, at least one of R2, R3, R4 and R5 is in the para position and is each independently selected from the group consisting of:

[0045] -OH, -SH, (C1-C3)-alkoxy, a 3-7-membered heterocyclic group containing 0-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, (C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, wherein each of the above groups is optionally partially or completely substituted by substituents selected from the group consisting of: -OH, 1-4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, a 3-7-membered heterocyclic group containing one oxygen atom, -NH2, (C1-C3)-alkylamino, di(C1-C3)-alkylamino or a 3-7-membered heterocyclic group containing one nitrogen atom and optionally 1-2 oxygen and sulfur heteroatoms; or

[0046] -NRaRb, wherein each Ra and Rb:

[0047] - are each independently hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or completely halogenated (C1-C3)-alkyl, a 3-7-membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and 1-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl or partially or completely halogenated (C1-C3) alkyl, a 5-7-membered heteroaryl containing 1-2 nitrogen atoms, said heteroaryl being optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl or partially or completely halogenated (C1-C3) alkyl;

[0048] Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-7-membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3) alkyl, partially or completely halogenated (C1-C3) alkyl; or

[0049] Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14-membered bicyclic heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-4 substituents selected from the group consisting of: halogen, (C1-C3)-alkyl, partially or completely halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3) alkynyl, or (C1-C3) alkoxy.

[0050] In another preferred embodiment, in the compound of formula (I) as defined above, wherein each R1 is independently selected from the group consisting of: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, R1 is optionally substituted by a group selected from the group consisting of: methyl, methanesulfonyl, halogen, methylamino, cyano, and cyclopropyl.

[0051] In another preferred embodiment, in the compound of formula (I) as defined above, two of R2, R3, R4, R5 are in the meta position and are groups selected from the group consisting of: methyl or halogen, one of R2, R3, R4, R5 is hydrogen, and one of R2, R3, R4, R5 is in the para position and is a group selected from the group consisting of: methoxy, isopropyloxy, cyclopropylmethoxy, difluoroethoxy, -NH2, -N(CH3)2, cyclopropylamino, -N(CH3)-cyclobutyl, -N(CH3)-methylthiazolyl, methylpiperidinylamino, -NH-(C1-C3)-alkyl-N(CH3)2, morpholinyl, methylpiperazinyl, azetidinyl optionally substituted with methyl, thiomorpholinyl, hexahydropyrrolopyrrolyl optionally substituted with methyl, diazaspiro[nonane], octahydropyrrolopyridine optionally substituted with methyl.

[0052] In another preferred embodiment, the present invention includes a compound of formula (Ia), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0053]

[0054] wherein,

[0055] R1 is as defined above;

[0056] R6 are each independently selected from the group consisting of:

[0057] --OH, -SH, -(C1-C3)-alkoxy, 3-7 membered heterocyclic group containing 0-1 oxygen atom and / or 0-1 sulfur atom, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, (C3-C7)-cycloalkyl-S-(C1-C3)-alkyl; wherein each of the above groups is optionally partially or fully substituted with a substituent selected from the group consisting of: -OH, 1-4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, 3-7 membered heterocyclic group containing one oxygen atom, -NH2, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or 3-7 membered heterocyclic group containing one nitrogen atom and optionally 1-2 heteroatoms selected from oxygen and sulfur, or

[0058] -NRaRb, wherein each Ra and Rb:

[0059] - each independently is hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7-membered heterocyclic group containing 0-1 oxygen, 0-1 sulfur and / or 1-4 nitrogens, optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, or partially or fully halogenated (C1-C3)-alkyl, a 5-7-membered heteroaryl containing 0-1 oxygen, 0-1 sulfur and / or 1-4 nitrogens, said heteroaryl optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, or partially or fully halogenated (C1-C3)-alkyl;

[0060] Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-7-membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)alkyl, partially or fully halogenated (C1-C3)alkyl; or

[0061] Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 6-14-membered bicyclic heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted by 1-4 substituents selected from the group consisting of: halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)alkynyl, or (C1-C3)alkoxy.

[0062] In another preferred embodiment, the present invention includes a compound of formula (IIa), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0063]

[0064] wherein,

[0065] R1 and R6 are as defined above.

[0066] In another preferred embodiment, the present invention includes a compound of formula (Ib), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0067]

[0068] wherein,

[0069] Q1, Q2, Q3, Q4, Q5 are each independently selected from nitrogen or carbon, where no more than two of Q1, Q2, Q3, Q4 and Q5 are nitrogen, and said carbon is optionally substituted by 1-5 substituents R1a;

[0070] R2, R3, R4, R5 and R1a are as defined above;

[0071] The dashed bond indicates that the ring is aromatic.

[0072] In another preferred embodiment, the present invention includes a compound of formula (Ic), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0073]

[0074] wherein,

[0075] Q6, Q7, Q8, Q9 are each independently selected from oxygen, carbon or nitrogen, where no more than two of Q6, Q7, Q8 and Q9 are nitrogen or oxygen, and the carbon is optionally substituted with 1-2 substituents R1a;

[0076] R2, R3, R4, R5 and R1a are as defined above;

[0077] The dashed bond indicates that the ring is aromatic.

[0078] In another preferred embodiment, the present invention includes a compound of formula (Id), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0079]

[0080] wherein,

[0081] Q1, Q2, Q3, Q4, Q5 and R6 are as defined above.

[0082] In another preferred embodiment, the present invention includes a compound of formula (Ie), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0083]

[0084] wherein,

[0085] Q6, Q7, Q8, Q9 and R6 are as defined above.

[0086] In another preferred embodiment, the present invention includes a compound of formula (If), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0087]

[0088] wherein,

[0089] R1 and R6 are as defined above.

[0090] In another preferred embodiment, the present invention includes a compound of formula (IIb), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0091]

[0092] Wherein,

[0093] Q1, Q2, Q3, Q4, Q5, R2, R3, R4 and R5 are as defined above;

[0094] The dashed bond indicates that the ring is aromatic.

[0095] In another preferred embodiment, the present invention includes a compound of formula (IId), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0096]

[0097] Wherein,

[0098] Q1, Q2, Q3, Q4, Q5 and R6 are as defined above.

[0099] In another preferred embodiment, the present invention includes a compound of formula (IIId), or a pharmaceutically acceptable salt, solvate or hydrate thereof:

[0100]

[0101] Wherein,

[0102] Q1, Q2, Q3, Q4 are each independently nitrogen or carbon;

[0103] - If each R'1 is independently 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, then each R'2 is independently a 4-7 membered heterocyclic group containing 1-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, which must be substituted by 1-2 substituents selected from the group consisting of oxo group, or -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and is further optionally substituted by 1-3 substituents selected from the group consisting of deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl and (C1-C3)alkoxy; or

[0104] - If each R'1 is independently -C(=O)-NH-(C1-C5)-alkyl; then each R2 is independently:

[0105] -NRсRd, wherein each Rc and Rd:

[0106] - Each is independently hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7 membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, a 5-7 membered heteroaryl containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, said heteroaryl optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl;

[0107] Alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted by 1-4 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, oxo group, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl or (C1-C3) alkoxy, or

[0108] Alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted by 1-4 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, oxo, (C1-C3)-alkyl-(C3-C6)-cycloalkyl, or (C1-C3)-alkoxy.

[0109] In one specific embodiment, the present invention includes compounds (according to IUPAC nomenclature) selected from the group consisting of:

[0110] 1_01 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridyl)pyrrolo[2,3-c]pyridine;

[0111] 1_02 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0112] 1_03 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0113] 1_04 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(6-methylpyridazin-3-yl)pyrrolo[2,3-c]pyridine;

[0114] 1_05 1-(4-Methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methylsulfonyl-2-pyridyl)pyrrolo[2,3-c]pyridine;

[0115] 1_06 1-((3,5-Difluoro-4-isopropoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0116] 1_07 1-((4-(Cyclopropylmethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0117] 1_08 1-((4-(2,2-Difluoroethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0118] 1_09 2,6-Difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline;

[0119] 1_10 4-(2,6-Difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)morpholine;

[0120] 1_11 2,6-Difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline;

[0121] 1_12 1-((3,5-Difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0122] 1_13 N-Cyclopropyl-2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline;

[0123] 1_14 N-Cyclobutyl-2,6-difluoro-N-methyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline;

[0124] 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;

[0125] 1_16 2,6-Difluoro-4-((4-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenol;

[0126] 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;

[0127] 1_18 1-((3,5-Difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0128] 1_19 1-((3,5-Difluoro-4-(3-methylazetidin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0129] 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;

[0130] 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;

[0131] 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;

[0132] 1_23 4-(2,6-Difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)thiomorpholine;

[0133] 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;

[0134] 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;

[0135] 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;

[0136] 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;

[0137] 1_28 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridinecarbonitrile;

[0138] 1_29 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(5-fluoropyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0139] 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;

[0140] 1_31 4-(5-cyclopropylpyridin-2-yl)-1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridine;

[0141] 1_32 2,6-difluoro-4-((4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline;

[0142] 1_33 2,6-difluoro-N,N-dimethyl-4-((4-(5-methylpyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline;

[0143] 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;

[0144] 2_02 1-((4-(4-(Cyclopropylmethyl)piperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0145] 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)pyridinecarboxamide;

[0146] 3_01 1-((3,5-Difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0147] 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;

[0148] 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;

[0149] 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;

[0150] 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;

[0151] 3_06 6-(1-((3,5-Difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)nicotinonitrile;

[0152] 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;

[0153] 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;

[0154] 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;

[0155] 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;

[0156] 3_11 1-((3,5-Difluoro-4-(4-isopropylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0157] 3_12 1-((4-(4-Cyclopropylpiperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0158] 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;

[0159] 3_14 1-((4-(1,4-Diazepan-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine;

[0160] 3_15 1-(2,6-Difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)piperidin-4-amine;

[0161] 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;

[0162] 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;

[0163] 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;

[0164] 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;

[0165] 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;

[0166] 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;

[0167] 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;

[0168] 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;

[0169] 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)pyridinecarbonitrile;

[0170] 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 (hydrochloride);

[0171] 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

[0172] 3_27 1-((3,5-Difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (hydrochloride);

[0173] 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)pyridinecarbonitrile;

[0174] 4_01 1-((3,5-Difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (hydrochloride).

[0175] The compounds of the present invention may exist in the form of various stereoisomers, diastereoisomers or enantiomers or mixtures thereof. All such forms are part of the present invention.

[0176] The present invention also relates to the use of the compounds of the present invention for inhibiting CYP11B2.

[0177] The present invention also relates to the use of the compounds of the present invention for reducing the aldosterone level in a subject.

[0178] In a specific embodiment of the present invention, the subject is a human.

[0179] The present invention also relates to the use of the compounds of the present invention in the preparation of CYP11B2 inhibitors.

[0180] The present invention also relates to the use of the compounds of the present invention in the preparation of a preparation for reducing the aldosterone level in a subject.

[0181] The present invention also relates to the use of the compounds of the present invention in the preparation of a pharmaceutical composition for treating and / or preventing a disease or disorder mediated or maintained by CYP11B2 activity, said composition comprising a therapeutically or prophylactically effective amount of the compound of the present invention and at least one pharmaceutically acceptable excipient.

[0182] The present invention also includes a pharmaceutical composition for treating and / or preventing a disease or disorder mediated or maintained by CYP11B2 activity, said composition comprising a therapeutically or prophylactically effective amount of the compound of the present invention and at least one pharmaceutically acceptable excipient.

[0183] In a specific embodiment of the present invention, the pharmaceutically acceptable excipient is a carrier, adjuvant and / or solvent.

[0184] In a specific embodiment of the present invention, the disease is selected from the group consisting of: primary aldosteronism (Conn syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction cardiocirrhosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.

[0185] In a specific embodiment of the present invention, the primary aldosteronism is Conn syndrome, including the following diseases or conditions: aldosterone adenoma, idiopathic aldosteronism, unilateral or bilateral adrenal hyperplasia, type I and type II familial aldosteronism, aldosterone carcinoma, and aldosterone ectopia.

[0186] The present invention also relates to a method for reducing the aldosterone level in a subject, comprising administering a therapeutically effective amount of a compound of the present invention to the subject.

[0187] 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.

[0188] In a specific embodiment of the present invention, the disease or condition is selected from the group consisting of: primary aldosteronism (Conn syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction cardiocirrhosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.

[0189] In a specific embodiment of the present invention, the primary aldosteronism is Conn syndrome, including the following diseases or conditions: aldosterone adenoma, idiopathic aldosteronism, unilateral or bilateral adrenal hyperplasia, type I and type II familial aldosteronism, aldosterone carcinoma, and aldosterone ectopia.

[0190] In a specific embodiment of the present invention, the subject is a human.

[0191] The technical achievement of the present invention is to develop compounds that can efficiently inhibit the activity of human cytochrome 11B2 (CYP11B2). These compounds are expected to be used for the prevention and / or treatment of diseases or pathological conditions or disorders mediated or maintained by excessive aldosterone synthesis.

[0192] Detailed Embodiments of the Present Invention

[0193] Definitions (Terms)

[0194] For a better understanding of the present invention, the following are some terms used in the description of the present invention. Unless otherwise specified, the following definitions apply herein. In addition, unless otherwise specified, all occurrences of functional groups are independently selected and can be represented by a slash to indicate that two occurrences of a functional group can be the same or different (such as R2, etc.). In the description of the present invention, the terms "comprising" and "including" are construed as "including, among other things". These terms are not intended to be construed as "consisting only of...".

[0195] As used herein, the term "alkyl", by itself or as part of another substituent, refers to a straight-chain or branched-chain saturated hydrocarbon group, including hydrocarbon groups having a specified number of carbon atoms, and typically refers to groups having one to ten carbon atoms. For example, the term "(C1-C3)-alkyl" refers to methyl, ethyl, propyl, etc.

[0196] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon aliphatic group which, unless otherwise specified, contains 1 to 6 carbon atoms and at least one degree of unsaturation. By way of example, and without limitation, include vinyl, etc.

[0197] As used herein, the term "alkynyl" refers to a linear or branched-chain hydrocarbon aliphatic group which, unless otherwise specified, contains 1 to 6 carbon atoms and at least one triple bond. By way of example, and without limitation, include ethynyl, etc.

[0198] The term "partially or fully halogenated" includes a branched or straight-chain hydrocarbon chain in which one or more hydrogen atoms are replaced by a halogen. Examples of haloalkyl groups include, but are not limited to, the following groups: trifluoromethyl, trichloromethyl, -C(CF3)2CH3, etc.

[0199] The term "(C1-C3)-alkylsulfonyl" refers to -SO2-alkyl, where alkyl is as defined above. By way of example, and without limitation, include SO2CH3, SO2CH2CH3, etc.;

[0200] The term "halogen", by itself or as part of another term, refers to a fluorine, chlorine, bromine, or iodine atom.

[0201] The term "aryl", unless otherwise specified, refers to a monocyclic or bicyclic aromatic ring containing 5 - 12 carbon atoms and conforming to Hückel's aromatic rule: a cyclic planar molecule having 4n + 2π (Pi) electrons. Specific examples of aryl include phenyl and naphthyl.

[0202] The term "alkoxy" refers to an alkyl group as defined above attached to a molecule through a bridging oxygen atom. For example, the term "alkoxy" refers to -O-alkyl, where the alkyl group contains 1 to 3 carbon atoms and is in linear (straight-chain) or branched form. By way of example, alkoxy groups include, but are not limited to, the following groups: methoxy, ethoxy, n-propoxy, etc.

[0203] The term "alkylamino" refers to an alkyl group as defined above attached to a molecule through 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 and is in linear (straight-chain) or branched form. By way of example, alkylamino groups include, but are not limited to, the following groups: methylamino, N,N-dimethylamino, ethylamino, etc.

[0204] As used herein, the term "bicyclic" or "bicyclo" refers to a bridged, fused or spiro bicyclic system. The bicyclic heterocycle contains 6 to 14 atoms, preferably 7 to 10 atoms. The bicyclic ring may contain one to four heteroatoms selected from the group consisting of nitrogen, oxygen and / or sulfur. In bicyclic compounds, examples include phenyl rings fused to five-membered heterocycles.

[0205] Examples of bicyclic structures include, but are not limited to:

[0206]

[0207] As used herein, the term "heteroaryl" refers to a 5- or 7-membered aromatic ring that complies with Hückel's aromaticity rule: a cyclic planar molecule having 4n + 2π (Pi) electrons and containing 1 to 5 heteroatoms selected from nitrogen atoms, oxygen and / or sulfur. Examples of heteroaryl groups include pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, triazinyl, thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, etc.

[0208] As used herein, the term "heterocycle" refers to 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 azepane, pyrrolidine, piperidine, ethylene oxide, tetrahydrofuran, tetrahydropyran, oxepane, piperazine, morpholine, thiomorpholine, diazepane, oxazepane, thiazepane, homopiperazine, homomorpholine, etc. "Heterocycle", "heterocyclic group" or "heterocyclic" also refers to a saturated or partially unsaturated, optionally substituted ring.

[0209] The present invention only encompasses combinations of substituents and derivatives that can form stable or chemically possible compounds. A stable or chemically possible compound is a compound whose stability is sufficient to meet the requirements of synthesis and analytical detection. The preferred compounds of the present invention have sufficient stability and will not decompose for at least one week at temperatures up to 40 °C under non-reaction conditions.

[0210] Unless otherwise indicated, the compound structures given in the materials of this application also mean all stereoisomers, i.e., the R- and S-isomers of each asymmetric center. In addition, the individual stereochemical isomers of the compounds of the present invention, as well as enantiomeric and diastereomeric mixtures, are also the subject of the present invention. Accordingly, the present invention includes diastereoisomers or enantiomers that are substantially free of other isomers (molar purity > 90%; more preferably > 95%), as well as mixtures of such isomers.

[0211] Specific optical isomers can be obtained by separating racemic mixtures according to standard procedures, for example, treating with an optically active acid or base to obtain diastereomeric salts, then separating the diastereomeric mixture by crystallization, and then separating the optically active base from these salts. Suitable acids include tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, xylenesulfonic acid, and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method is to react the compounds of the present invention with an activated form of an optically pure acid or an optically pure isocyanate to synthesize covalently bonded diastereomeric molecules. The resulting diastereoisomers can be separated by conventional methods such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain enantiomerically pure compounds.

[0212] The optically active compounds of the present invention can be obtained from optically active starting materials. These isomers can be in the form of free acids, free bases, esters, or salts.

[0213] The term "solvate" refers to an aggregate or complex of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0214] The term "hydrate" refers to a complex in which the solvent molecule is water.

[0215] The compounds of the present invention may exist in radiolabeled form, i.e., these compounds may contain one or more atoms whose atomic mass or mass number is different from that of the most common natural isotope. Radioactive isotopes of hydrogen, carbon, phosphorus, and chlorine include 3 H, 14 C, 32 P, 35 S, and 36 Cl. Compounds of the present invention containing these radioactive isotopes and / or other radioactive isotopes of atoms are within the scope of the present invention. Tritium (i.e., 3 H) and carbon (i.e., 14 C) radioactive isotopes are particularly favored because they are easy to prepare and detect.

[0216] The compounds of the present invention labeled with radioactive isotopes can be obtained by methods well known to those skilled in the art. The labeled compounds can be prepared using the methods described herein by simply replacing the unlabeled reagent with an appropriate labeling reagent.

[0217] The compounds of the present invention can exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or another derivative. As used herein, the term "pharmaceutically acceptable salt" refers to salts that are within the scope of medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, etc., and that meet a reasonable ratio of benefits and risks. Medicinal salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in medicine. The salts can be obtained directly during the process of isolating or purifying 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 acid 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 amino acid salts obtained by other methods used in the art (such as using ion exchange methods). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc. Typical alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. In addition, if desired, pharmaceutically acceptable salts can also contain non-toxic ammonium, quaternary ammonium, and amine cations, which are derived from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0218] The term "therapeutically effective amount" refers to the amount of the compound administered or delivered to a patient that is most likely to produce the desired response to the treatment (prevention). The exact amount required may vary from patient to patient depending on factors such as the patient's age, weight, and general condition, the severity of the disease, the method of administration, and combination therapy with other drugs.

[0219] The term "patient" (or "subject") includes all mammals, preferably humans, that use the compounds of the present invention, and are treated and / or prevented from diseases or disorders by self - administration and / or administration to the patient by others.

[0220] The terms "treatment", "therapy" include the treatment of a pathological condition in a mammal (preferably a human), and include: a) blocking (halting) the course of the disease; b) reducing the severity of the disease, i.e., inducing the regression of the disease.

[0221] The terms "prevention", "preventive treatment" include eliminating risk factors and preventive treatment of sub - clinical stage diseases in humans, aiming to reduce the likelihood of the clinical stage of the disease. According to known data, factors for patients selected to receive preventive treatment increase the risk of the clinical stage of the disease compared to the general population. Preventive treatment includes a) primary prevention and b) secondary prevention. Primary prevention refers to preventive treatment of patients who have not reached the clinical stage of the disease. Secondary prevention refers to preventing the recurrence of the same or similar clinical symptoms of the disease.

[0222] The term "risk reduction" includes treatment that reduces the incidence of the clinical stage of a disease. Examples of reducing the risk of a disease include primary and secondary disease prevention.

[0223] Embodiments of the present invention Examples

[0224] The specific compounds disclosed in the present invention are for the purpose of explaining the present invention to more comprehensively understand the present invention. Table 1 shows specific examples of the compounds of the present invention, and these compounds can be prepared by the methods described in the general synthetic scheme, examples and methods known in the art. The methods are not exhaustive and can be reasonably modified. These reactions must be carried out using appropriate solvents and materials. When synthesizing specific compounds using these conventional steps, the functional groups present in the compound and their influence on the reaction process must be considered. In order to obtain certain compounds, it is necessary to change the order of the steps or preferentially adopt one of several alternative synthetic schemes. The following compounds should not be regarded as the only examples within the scope of the present invention, nor are they in any way a limitation of the present invention.

[0225] In a specific embodiment of the present invention, the compound of formula I is the compound of №1_01 - 4_01 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0226] In a specific embodiment of the present invention, the compound of formula Ia is the compound of №1_06 - 1_14, 1_18 - 4_01 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0227] In a specific embodiment of the present invention, the compound of formula IIa is the compound of №1_15 - 1_17 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0228] In a specific embodiment of the present invention, the compound of formula IIb is the compound of №1_15 - 1_17 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0229] In a specific embodiment of the present invention, the compound of formula IId is the compound of №1_15 - 1_17 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0230] In a specific embodiment of the present invention, the compound of formula Ia is the compound of №1_06 - 1_14, 1_18 - 1_26, and 1_28 - 1_33 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0231] In a specific embodiment of the present invention, the compound of formula Ic is the compound of №1_27 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0232] In a specific embodiment of the present invention, the compound of formula Ie is the compound of №1_06 - 1_14, 1_18 - 1_26, and 1_28 - 1_33 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0233] In a specific embodiment of the present invention, the compound of formula Ic is the compound of №1_27 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0234] In a specific embodiment of the present invention, the compound of formula 1f is the compound of №1_1 - 1_5 listed in Table 1 below, and its pharmaceutically acceptable salts and / or stereoisomers.

[0235] Table 1

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] Conventional synthesis method

[0244] The optimal reaction conditions and reaction time may vary depending on the reagents used. Unless otherwise specified, those skilled in the art are free to select solvents, temperature, pressure and other reaction conditions.

[0245] General formula for the synthesis of the intermediate (R1, R2, R3, R4 and R5 are defined as above):

[0246]

[0247] The intermediate X (conventional structure) for synthesis, bromine derivative (intermediate Y) and sulfonyl chloride derivative (intermediate Z) can be obtained commercially or can be easily prepared by methods known to those skilled in the art.

[0248] Synthesis of the Compounds of the Present Invention

[0249]

[0250] Route 1. General synthetic route for the intermediate of the target compound synthesized in the present invention.

[0251] Preparation of intermediate BB-a

[0252] DMAP (4-(dimethylamino)pyridine) (0.1 equivalent), triethylamine (2 equivalents) and intermediate Z (1.3 equivalents) were added to a solution of intermediate X (1 equivalent) in DCM (dichloromethane). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was neutralized with water and extracted with dichloromethane (DCM). The organic phase was washed with brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain intermediate BB-a.

[0253] Obtaining intermediate BB-b

[0254] B2pin2 (bis(pinacolato)diboron) (1.5 equivalents) and potassium acetate (3 equivalents) were added to a 1,4-dioxane solution of intermediate BB-a (1 equivalent), and then degassed in the presence of PdCl2(dppf) (bis(diphenylphosphino)ferrocene] palladium(II) dichloride) (0.5 equivalent). The reaction mixture was heated at 100 °C for 6 hours under microwave conditions. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. 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 to obtain intermediate BB-b, which can be used in the next step without further purification.

[0255]

[0256] Route 2. General synthetic route of the target compound of the present invention.

[0257] Preparation of the compounds of the present invention

[0258] To a solution of intermediate BB-b (1 equiv) in a THF (tetrahydrofuran) / water (10 / 1) mixture was added intermediate Y (1.2 equiv), cesium carbonate (2 equiv), and then degassed in the presence of PdCl2(dppf) (bis(diphenylphosphino)ferrocene palladium(II) dichloride) (0.5 equiv). The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. 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 silica gel column chromatography.

[0259]

[0260] Route 3. Synthetic route of the intermediate for synthesizing target compound 1 of the present invention.

[0261] Preparation of 4-bromo-1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)pyrrolo[2,3-c]pyridine (BB-a1)

[0262] To a solution of 4-bromo-1H-pyrrolo[2,3-c]pyridine (500 mg, 2.54 mmol) in DCM (dichloromethane) (8.0 ml) was added 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). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was neutralized with water and extracted with dichloromethane (DCM). The organic phase was washed with brine and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using cyclohexane / ethyl acetate from 100 / 0 to 90 / 10 as the 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.

[0263] Preparation of [1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)pyrrolo[2,3-c]pyridin-4-yl]boronic acid (BB-b1)

[0264] 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 B2pin2 (bis(pinacolato)diboron) (963 mg, 3.80 mmol), potassium acetate (744 mg, 7.59 mmol), and then degassed in the presence of PdCl2(dppf) (bis(diphenylphosphino)ferrocene]palladium(II) dichloride) (370 mg, 0.51 mmol). Under microwave conditions, the reaction mixture was heated at 100 °C for 6 hours. The reaction mixture was cooled to room temperature and filtered through 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 to give a brown oil, (1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)boronic acid (BB-b1) (1.99 g, 99% yield), which was used in the next step without further purification.

[0265]

[0266] Route 4. Synthetic route of the target compound 1_01 of the present invention.

[0267] Preparation of 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridyl)pyrrolo[2,3-c]pyridine (Compound 1_01)

[0268] To 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 2-bromo-5-methylpyridine (53.7 mg, 0.31 mmol) and cesium carbonate (163 mg, 0.50 mmol), and then degassed in the presence of PdCl2(dppf) (bis(diphenylphosphino)ferrocene)palladium(II) dichloride (9.14 mg, 0.13 mmol). The reaction mixture was stirred at 80 °C for 6 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. 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 silica gel column chromatography using cyclohexane / ethyl acetate from 100 / 0 to 60 / 40 as the eluent. The resulting solid was slurried in 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, yield 9.7%) as a white solid.

[0269] The preparation methods of Compounds 1_02 - 1_33 were similar to the above steps, but using the characteristic bromo derivatives of Intermediate Y and the sulfonyl chloride derivatives of Intermediate Z.

[0270] Common methods for synthesizing Compounds 2_01 - 4_01 in the present invention.

[0271] General formula of the intermediate for synthesis (R1, R2 are defined as above):

[0272]

[0273] Intermediate

[0274] Intermediate 2X (general structure) and Intermediate 2Y for synthesis are commercially available or can be easily prepared by methods known to those skilled in the art.

[0275] General Synthetic Route of Compounds 2_01 - 4_01 of the Present Invention

[0276]

[0277] Route 5. General synthetic route of the target compounds 2_01 - 4_01 of the present invention.

[0278] To a mixture of intermediate 2Y (1 equiv) in DMSO was added Cs2CO3 (502 mg, 2.67 equiv). After 15 minutes at room temperature, intermediate 2X (0.67 equiv) was added to the reaction mixture, and the reaction mixture was stirred at room temperature for 18 hours. The mixture was purified directly by preparative high performance liquid chromatography to give the compound of the present invention.

[0279] Some specific compounds of the present invention were obtained.

[0280] Prepare 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)

[0281] 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 purified directly by preparative high performance liquid chromatography 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, yield 26%) as a white solid.

[0282]

[0283] Route 6. Synthetic route of the target compound 2_02 of the present invention

[0284] Prepare 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)

[0285] To a mixture of 1,4-diazabicyclo[3.2.1]octane dihydrochloride (107 mg, 578 μmol) in dimethyl sulfoxide (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 (Intermediate 2, 150 mg, 385 μmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was purified directly 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.

[0286]

[0287] Route 7. Synthetic route of the target compound 3_20 of the present invention

[0288] The preparation methods of compounds 2_01, 2_03 - 3_19 and 3_21 - 4_01 are similar to the above steps, but the characteristic intermediates are used.

[0289] Experimental analysis

[0290] LC-MS analysis of the compounds of the present invention.

[0291] HPLC analysis was performed on an X-Select CSH C18 XP column (2.5 μm 30 x 4.6 mm id), eluting with 0.1% formic acid aqueous solution (solvent A) and 0.1% formic acid acetonitrile solution (solvent B), using the following elution gradient: 0 - 3 minutes: 5% - 100% B, 3 - 4 minutes 100% B, flow rate 1.8 mL / min, temperature 40 °C. Mass spectrometry (MS) was recorded on a Waters ZQ mass spectrometer (scanning 200 - 900 uma), using electrospray positive ion [ES+, to obtain [M + H+] molecular ion] or electrospray negative ion [ES-, to obtain [M - H]- molecular ion] mode, with a cone voltage of 20 V.

[0292] Example 1.

[0293] Compound 1_01: 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methyl-2-pyridinyl)pyrrolo[2,3-c]pyridine; molecular weight = 407.49; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 408.4 [M + H]+.

[0294] Example 2.

[0295] Compound 1_02: 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 408.47; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 409.4 [M+H]+.

[0296] Example 3.

[0297] Compound 1_03: 1-((4-methoxy-3,5-dimethylphenyl)sulfonyl)-4-(5-methylpyrimidin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 408.47; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 409.4 [M+H]+.

[0298] Example 4.

[0299] Compound 1_04: 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(6-methylpyridazin-3-yl)pyrrolo[2,3-c]pyridine; molecular weight = 409.3; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 395.2 [M+H]+.

[0300] Example 5.

[0301] Compound 1_05: 1-(4-methoxy-3,5-dimethylphenyl)sulfonyl-4-(5-methylsulfonyl-2-pyridyl)pyrrolo[2,3-c]pyridine; molecular weight = 471.55; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 472.1 [M+H]+.

[0302] Example 6.

[0303] Compound 1_06: 1-((3,5-difluoro-4-isopropoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 429.44; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 430.1 [M+H]+.

[0304] Example 7.

[0305] Compound 1_07: 1-((4-(cyclopropylmethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 441.45; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 442.3 [M+H]+.

[0306] Example 8.

[0307] Compound 1_08: 1-((4-(2,2-difluoroethoxy)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; Molecular weight = 451.4; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 452.0 [M+H]+.

[0308] Example 9.

[0309] Compound 1_09: 2,6-difluoro-N,N-dimethyl-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; Molecular weight = 414.43; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 415.1 [M+H]+.

[0310] Example 10.

[0311] Compound 1_10: 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)morpholine; Molecular weight = 456.47; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 457.1 [M+H]+.

[0312] Example 11.

[0313] Compound 1_11: 2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; Molecular weight = 386.38; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 387.3 [M+H]+.

[0314] Example 12.

[0315] Compound 1_12: 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; Molecular weight = 469.51; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 470.2 [M+H]+.

[0316] Example 13.

[0317] Compound 1_13: N-cyclopropyl-2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; Molecular weight = 426.44; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 427.4 [M+H]+.

[0318] Example 14.

[0319] 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; Molecular weight = 454.5; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 455.3 [M+H]+.

[0320] Example 15.

[0321] 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; Molecular weight = 416.45; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 417.4 [M+H]+.

[0322] Example 16.

[0323] Compound 1_16: 2,6-difluoro-4-((4-(pyridin-2-yl)-2,3-dihydro-H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenol; Molecular weight = 389.38; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z *** [M+H]+.

[0324] Example 17.

[0325] 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; Molecular weight = 471.53; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 472.4 [M+H]+.

[0326] Example 18.

[0327] Compound 1_18: 1-((3,5-difluoro-4-methoxyphenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; Molecular weight = 401.39; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z ** [M+H]+.

[0328] Example 19.

[0329] Compound 1_19: 1-((3,5-difluoro-4-(3-methylazetidin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; Molecular weight = 440.47; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 441.1 [M+H]+.

[0330] Example 20.

[0331] 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; Molecular weight = 497.54; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 498.3 [M+H]+.

[0332] Example 21.

[0333] 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; Molecular weight = 483.54; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 484.1 [M+H]+.

[0334] Example 22.

[0335] 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; Molecular weight = 457.5; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 458.4 [M+H]+.

[0336] Example 23.

[0337] Compound 1_23: 4-(2,6-difluoro-4-((4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)phenyl)thiomorpholine; Molecular weight = 472.53; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 473.3 [M+H]+.

[0338] Example 24.

[0339] 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; molecular weight = 495.55; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 496.4 [M+H]+.

[0340] Example 25.

[0341] 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; molecular weight = 495.55; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 496.2 [M+H]+.

[0342] Example 26.

[0343] 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; molecular weight = 509.58; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 510.2 [M+H]+.

[0344] Example 27.

[0345] 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; molecular weight = 484.48; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 485.4 [M+H]+.

[0346] Example 28.

[0347] Compound 1_28: 5-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridinecarbonitrile; molecular weight = 494.52; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 495.4 [M+H]+.

[0348] Example 29.

[0349] 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; molecular weight = 488.49; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 489.1 [M+H]+.

[0350] Example 30.

[0351] Compound 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; molecular weight = 499.54; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 500.2 [M+H]+.

[0352] Example 31.

[0353] 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; molecular weight = 509.58; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 510.4 [M+H]+.

[0354] Example 32.

[0355] Compound 1_32: 2,6-difluoro-4-((4-(5-methylpyrazin-2-yl)-1H-pyrrolo[2,3-c]pyridin-1-yl)sulfonyl)aniline; molecular weight = 401.39; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 402.1 [M+H]+.

[0356] Example 33.

[0357] 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; molecular weight = 428.46; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 429.1 [M+H]+.

[0358] Example 34.

[0359] 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; molecular weight = 483.49; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 484.1 [M+H]+.

[0360] Example 35.

[0361] Compound 2_02: 1-((4-(4-(cyclopropylmethyl)piperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 509.58; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 510.4 [M+H]+.

[0362] Example 36.

[0363] 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)pyridinecarboxamide; molecular weight = 594.68; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 595.5 [M+H]+.

[0364] Example 37.

[0365] Compound 3_01: 1-((3,5-difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 455.48; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 456.1 [M+H]+.

[0366] Example 38.

[0367] 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; molecular weight = 498.55; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 499.4 [M+H]+.

[0368] Example 39.

[0369] 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; molecular weight = 498.55; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 499.1 [M+H]+.

[0370] Example 40.

[0371] 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; molecular weight = 512.58; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 513.4 [M+H]+.

[0372] Example 41.

[0373] 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; molecular weight = 495.51; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 496.3 [M+H]+.

[0374] Example 42.

[0375] Compound 3_06: 6-(1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)nicotinonitrile; molecular weight = 494.52; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 495.3 [M+H]+.

[0376] Example 43.

[0377] 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; molecular weight = 499.54; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 500.4 [M+H]+.

[0378] Example 44.

[0379] 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; molecular weight = 499.54; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 500.4 [M+H]+.

[0380] Example 45.

[0381] 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; molecular weight = 495.51; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 496.3 [M+H]+.

[0382] Example 46.

[0383] 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; molecular weight = 495.51; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 496.3 [M+H]+.

[0384] Example 47.

[0385] Compound 3_11: 1-((3,5-difluoro-4-(4-isopropylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 497.56; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 498.4 [M+H]+.

[0386] Example 48.

[0387] Compound 3_12: 1-((4-(4-cyclopropylpiperazin-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 495.55; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 496.4 [M+H]+.

[0388] Example 49.

[0389] 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; molecular weight = 483.54; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 484.1 [M+H]+.

[0390] Example 50.

[0391] Compound 3_14: 1-((4-(1,4-diazepan-1-yl)-3,5-difluorophenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine; molecular weight = 469.51; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 470.1 [M+H]+.

[0392] Example 51.

[0393] 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; molecular weight = 469.51; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 470.4 [M+H]+.

[0394] Example 52.

[0395] 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; molecular weight = 481.52; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 482.4 [M+H]+.

[0396] Example 53.

[0397] 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; molecular weight = 481.52; purity (HPLC) > 95%, mass spectrometry (ESI+), m / z 482.2 [M+H]+.

[0398] Example 54.

[0399] 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; Molecular weight = 481.52; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 482.3 [M+H]+.

[0400] Example 55.

[0401] 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; Molecular weight = 495.55; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 496.4 [M+H]+.

[0402] Example 56.

[0403] 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; Molecular weight = 481.52; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 482.3 [M+H]+.

[0404] Example 57.

[0405] 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; Molecular weight = 467.49; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 468.4 [M+H]+.

[0406] Example 58.

[0407] 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; Molecular weight = 525.58; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 526.4 [M+H]+.

[0408] Example 59.

[0409] 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; Molecular weight = 521.55; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 522.4 [M+H]+.

[0410] Example 60.

[0411] 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)picolinitrile; Molecular weight = 520.56; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 521.4 [M+H]+.

[0412] Example 61.

[0413] 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 (hydrochloride); Molecular weight = 467.49; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 468.2 [M+H]+.

[0414] Example 62.

[0415] 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; Molecular weight = 481.52; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 482.2 [M+H]+.

[0416] Example 63.

[0417] Compound 3_27: 1-((3,5-difluoro-4-(piperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (hydrochloride); Molecular weight = 455.48; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 456.2 [M+H]+.

[0418] Example 64.

[0419] 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; Molecular weight = 506.53; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 507.4 [M+H]+.

[0420] Example 65.

[0421] Compound 4_01: 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (hydrochloride); Molecular weight = 469.51; Purity (HPLC) > 95%, Mass spectrometry (ESI+), m / z 470.2 [M+H]+.

[0422] Biological activity characteristics of the compounds of the present invention

[0423] The inventors of the present invention studied the activity of the compounds of the present invention as CYP11B2 inhibitors. The analysis was carried out in a reconstituted system containing 0.5 μM recombinant CYP11B2, 0.3 μM human adrenodoxin reductase, and 2 μM human adrenalin. 100 μM corticosterone was used as a control reaction. The formation of the product was detected using an HPLC system with an ultraviolet detector. The test compound was added to the reaction mixture to a final concentration ≤ 2 μM. The concentrated protein mixture was diluted to a final volume of 0.5 ml with buffer and pre-incubated at 37 °C for 10 minutes, and then the substrate was added. The reaction was initiated by adding NADPH (nicotinamide adenine dinucleotide phosphate) at a final concentration of 0.25 mM and a regeneration system (glucose-6-phosphate and glucose-6-phosphate dehydrogenase) in 25 mM potassium phosphate buffer (pH 7.4) containing 0.1 mM DTT (dithiothreitol), 0.1% Tween-20, and 4 mM MgCl2, and incubated at 37 °C. After incubation for 30 minutes, the reaction was stopped by adding 5 ml of dichloromethane. The organic phase was separated by centrifugation, evaporation, and dissolution in ethanol and transferred to a vial for HPLC study. A C18 Luna 250x4.6 mm chromatographic column was used on an Agilent Technologies 1200 series instrument (USA), and the mobile phase was ethanol. The activity (a) was calculated as the amount of product (nmol) per 1 nmol of CYP per minute.

[0424]

[0425]

[0426] ​Wherein, k is a correction coefficient (k = 1 when the molar extinction coefficients of the steroid substrate and product are similar at a detection wavelength of 254 nm), As is the peak area of the substrate, cs is the concentration of the substrate, Ap is the peak area of the product, ce is the concentration of CYP (cytochrome P450), and t is the reaction time.

[0427] The inhibition level of CYP11B2 activity is expressed as a percentage, where 0% means no inhibition in the reaction without the test compound and 100% means the test compound has complete inhibition. Compounds of all embodiments of the present invention are suitable for inhibiting CYP11B2 activity. Preferred subgroups include compounds with an inhibition rate of CYP11B2 activity in the range of 1 - 100% (+). In this subgroup, there is another subgroup of more preferred compounds with an inhibition rate of CYP11B2 activity in the range of 20 - 100% (++). Among the latter, compounds 2.1 - 2.4 and 3.1 - 3.6 with an inhibition rate of CYP11B2 activity of 35 - 100% (+++) or compounds 1.1 - 1.18 with an inhibition rate of CYP11B2 activity of 50 - 100% (+++) belong to another subgroup of more preferred compounds. See Table 2. The connection numbers correspond to the earlier numbers given in Table 1.

[0428] Table 2

[0429]

[0430]

[0431]

[0432] Pharmaceutical composition

[0433] The present invention also relates to a pharmaceutical composition, which contains compounds of general formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId (or prodrugs, pharmaceutically acceptable salts or other pharmaceutically acceptable derivatives) and one or more pharmaceutically acceptable carriers, adjuvants, diluents and / or excipients, which can enter the patient's body together with the compounds that are the essence of the present invention, will not destroy the pharmacological activity of the compounds of the present invention, and are non-toxic when the administered dose is sufficient to provide a therapeutic amount of the compound.

[0434] The pharmaceutical composition of the present invention comprises the compound of the present invention and a pharmaceutically acceptable carrier, which may include any solvent, diluent, dispersant or suspending agent, surfactant, isotonic agent, thickening agent and emulsifier, preservative, binder, lubricant, etc. suitable for a specific dosage form. Materials that can be used 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 oil, cottonseed oil, sesame oil, olive oil, corn oil and soybean oil, etc.; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering substances such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic solutions, Ringer's solution; alcohol and phosphate buffer solutions. Other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, film-forming agents, sweeteners, flavors and fragrances, preservatives and antioxidants can also be added to the composition.

[0435] The subject matter of the present invention is also dosage forms - a class of pharmaceutical compositions whose structures are optimized to be suitable for administration in a certain method at a therapeutically effective dose, for example, intravenous injection, intramuscular injection, oral administration, subcutaneous injection, intraocular injection, inhalation, intranasal injection and sublingual administration at the recommended dose.

[0436] The dosage forms of the present invention may comprise structures obtained by liposome methods, microencapsulation methods, methods for obtaining drug nano-forms or other methods known in pharmaceutical technology.

[0437] When preparing a composition (such as a tablet), the active ingredient is mixed with one or more pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, silica, gum arabic, mannitol, microcrystalline cellulose, hydroxypropyl methylcellulose or similar compounds.

[0438] Tablets can be coated with sucrose, cellulose derivatives or other suitable coating agents. There are various methods for preparing tablets, such as direct compression, dry or wet granulation or hot doping.

[0439] A pharmaceutical composition in the form of gelatin capsules can be obtained by mixing the active ingredient with a solvent and filling the resulting mixture into soft or hard capsules.

[0440] For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injection solutions can be used, and the compatibilizer therein contains pharmaceutical agents such as propylene glycol or butylene glycol.

[0441] Although the present invention has been described with reference to the disclosed embodiments, those skilled in the art should clearly understand that the specific experiments described in detail are only for illustrating the present invention and should not be construed as limiting the scope of the present invention in any way. It should be clear that various modifications can be made without departing from the essence of the present invention.

[0442] Therapeutic methods

[0443] The compounds of the present invention are inhibitors of CYP11B2 (aldosterone synthase), and thus they are effective agents for treating and / or preventing diseases or disorders that can be alleviated by reducing aldosterone levels. Due to their ability to inhibit aldosterone synthase, the compounds of the present invention can be used to treat and / or reduce the risk of developing the following diseases: primary aldosteronism (Conn's syndrome), chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, and insulin resistance.

[0444] The characteristics of these diseases are very evident in humans, but similar etiologies also exist in other mammals and can be treated with the pharmaceutical compositions of the present invention.

[0445] For therapeutic use, the compounds of the present invention can be administered as a pharmaceutical composition in any dosage form by any route of administration. The dosage form generally includes a pharmaceutically acceptable carrier suitable for the selected specific dosage form. In particular, the compounds of the present invention can be administered daily for a period of time required for treating and / or preventing diseases related to the patient, including courses lasting for several days, months, years, or the lifetime of the patient. Routes of administration include, but are not limited to, intravenous injection, intramuscular injection, oral administration, subcutaneous injection, intraocular injection, inhalation, intranasal injection, and sublingual administration. Preferred routes of administration are oral and intravenous injection.

[0446] The present invention also relates to a pharmaceutical composition containing a daily dose of the compound in the form of a fixed dosage unit, and a combined preparation containing the pharmaceutical composition or the compound. In a preferred embodiment, the composition used according to the present invention is administered once a day at a dose of 1 mg or more of the selected compound of the present invention. The preferred dose is 1 - 500 mg. The most preferred dose is 10 - 200 mg.

[0447] One or more other pharmacological active agents can be administered in combination with the compounds of formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId. Generally speaking, in addition to the compounds of formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId, any other single or multiple active agents, including but not limited to antihypertensive drugs, antidiabetic drugs and / or anti-obesity drugs, can be used in combination with the compounds of formula I, Ia, IIa, Ib, IIb, Ic, Id, IId, Ie, If, IIId in a single or separate dosage form, so that the active agents play a therapeutic role simultaneously or sequentially.

Claims

1. A compound defined by the following formula (I), or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein, R1 is a 5- or 6-membered heteroaryl containing 0-1 oxygen, 0-1 sulfur and / or 0-4 nitrogens, optionally substituted by 1-5 substituents R1a; Each R1a is independently selected from the group consisting of: 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; R2, R3, R4 and R5 are each independently selected from the group consisting of: -(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, a 3- to 7-membered heterocyclic group containing 0-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, wherein each of the above groups is optionally partially or fully substituted by a substituent selected from the group consisting of: -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, -NH2, a 3- to 7-membered heterocyclic group containing one oxygen atom, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3- to 7-membered heterocyclic group containing one nitrogen atom and optionally 1-2 oxygen and / or sulfur heteroatoms; or -(iv) a 4- to 7-membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which must be substituted by 1-4 substituents selected from the group consisting of: oxo, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and is also optionally substituted by 1-3 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)alkyl, (C2-C3)alkenyl, (C2-C3)alkynyl, (C1-C3)alkoxy; or -(v) -NRaRb, wherein each Ra and Rb: - Each independently is hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3- to 7-membered heterocyclic group containing 0 to 1 oxygen atom, 0 to 1 sulfur atom, and / or 0 to 4 nitrogen atoms, which is optionally substituted with 1 to 2 substituents selected from the group consisting of: (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 5- to 7-membered heteroaryl group containing 0 to 1 oxygen atom, 0 to 1 sulfur atom, and / or 0 to 4 nitrogen atoms, and the heteroaryl group is optionally substituted with 1 to 2 substituents selected from the group consisting of: 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- to 7-membered heterocyclic group containing 1 to 2 nitrogen atoms, 0 to 1 oxygen atom, and / or 0 to 1 sulfur atom, which is optionally substituted with 1 to 4 substituents selected from the group consisting of: (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, oxo, -(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- to 14-membered bicyclic heterocyclic group containing 1 to 2 nitrogen atoms, 0 to 1 oxygen atom, and / or 0 to 1 sulfur atom, which is optionally substituted with 1 to 4 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, oxo, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, (C1-C3)-alkoxy; D / S represents the presence of a double bond or a single bond; The dashed bond indicates that the ring is aromatic.

2. The compound according to claim 1, characterized in that, At least two of R2, R3, R4, and R5 are not hydrogen.

3. The compound according to claim 2, wherein At least three of R2, R3, R4, and R5 are not hydrogen.

4. The compound according to claim 1, wherein R2, R3, R4, and R5 are each independently selected from the group consisting of: -(i) hydrogen, deuterium, halogen, (C1-C3)-alkyl, (C3-C5)-cycloalkyl, -C(=O)-CH3, partially or fully halogenated (C1-C3) alkyl; -(ii) groups selected from the group consisting of: (C1-C3)-alkoxy, (C3-C7) cycloalkyl, halogenated (C1-C3) alkoxy containing 1 to 4 halogen atoms; -(iii) -NRaRb, wherein each Ra and Rb: - each independently is hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7-membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 5-7-membered heteroaryl containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (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 heterocyclic group containing 1-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-2 substituents selected from the group consisting of: (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 heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-4 substituents selected from the group consisting of: deuterium, halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, or (C1-C3)-alkoxy.

5. The compound according to claim 1, characterized in that, At least one of the groups R2, R3, R4, R5 is in the para position and each independently is selected from the group consisting of: -OH, -SH, (C1-C3)-alkoxy, a 3-7-membered heterocyclic group containing 0-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, (C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, wherein each of the above groups is optionally partially or fully substituted by a substituent selected from the group consisting of: -OH, 1-4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, a 3-7-membered heterocyclic group containing one oxygen atom, -NH2, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3-7-membered heterocyclic group containing one nitrogen atom and optionally 1-2 oxygen and sulfur heteroatoms; or -NRaRb, wherein each Ra and Rb: - each independently is hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7-membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and 1-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 5-7-membered heteroaryl containing 1-2 nitrogen atoms, wherein the heteroaryl is optionally substituted by 1-2 substituents selected from the group consisting of: (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 heterocyclic group containing 1-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-2 substituents selected from the group consisting of: (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 heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-4 substituents selected from the group consisting of: halogen, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, or (C1-C3)-alkoxy.

6. The compound according to claim 1, wherein R1 are each independently selected from the group consisting of: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, wherein R1 is optionally substituted by substituents selected from the group consisting of: methyl, methanesulfonyl, halogen, methylamino, cyano and cyclopropyl.

7. The compound according to claim 1, characterized in that, Two of R2, R3, R4, R5 are in the meta position and are groups selected from the group consisting of: methyl, halogen, one of R2, R3, R4, R5 is hydrogen, and one of R2, R3, R4, R5 is in the para position and is a group selected from the group consisting of: methoxy, isopropyloxy, cyclopropylmethoxy, difluoroethoxy, -NH2, -N(CH3)2, cyclopropylamino, -N(CH3)-cyclobutyl, -N(CH3)-methylthiazolyl, methylpiperidinylamino, -NH-(C1-C3)-alkyl-N(CH3)2, morpholinyl, methylpiperazinyl, azetidinyl optionally substituted by methyl, thiomorpholinyl, hexahydropyrrolopyrrolyl optionally substituted by methyl, diazaspiro[5.5]undecanyl, octahydropyrrolopyridyl optionally substituted by methyl.

8. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound of the structure shown in formula (Ia), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, R1 is as defined in claim 1, R6 are each independently selected from the group consisting of: --OH, -SH, -(C1-C3)-alkoxy, a 3-7-membered heterocyclic group containing 0-1 oxygen atom and / or 0-1 sulfur atom, (C3-C7)-cycloalkyl, -S-(C1-C3)-alkyl, -(C3-C7)-cycloalkyl-S-(C1-C3)-alkyl, wherein each of the above groups is optionally partially or completely substituted by a substituent selected from the group consisting of: -OH, 1-4 halogen atoms, (C1-C3)-alkoxy, (C3-C7)-cycloalkyl, a 3-7-membered heterocyclic group containing one oxygen atom, -NH2, (C1-C3)-alkylamino, di(C1-C3)-alkylamino, or a 3-7-membered heterocyclic group containing one nitrogen atom and optionally 1-2 heteroatoms selected from oxygen and sulfur; -NRaRb, wherein each Ra and Rb: - are each independently hydrogen, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, a partially or completely halogenated (C1-C3)-alkyl, a 3-7-membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and / or 1-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, a partially or completely halogenated (C1-C3)-alkyl, a 5-7-membered heteroaryl containing 0-1 oxygen atom, 0-1 sulfur atom and / or 1-4 nitrogen atoms, and the heteroaryl is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, or a partially or completely halogenated (C1-C3)-alkyl; alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-7-membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, a partially or completely 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 heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, which is optionally substituted by 1-4 substituents selected from the group consisting of: halogen, (C1-C3)-alkyl, a partially or completely halogenated (C1-C3)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl or (C1-C3) alkoxy.

9. The compound according to claim 1, wherein The compound of formula (I) is a compound of the structure shown in formula (IIa), or a pharmaceutically acceptable salt, solvate or hydrate thereof: R1 and R6 are as defined in claim 8.

10. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound of the structure shown in formula (Ib), or a pharmaceutically acceptable salt, solvate or hydrate thereof: wherein Q1, Q2, Q3, Q4 and Q5 are each independently selected from the group consisting of: nitrogen or carbon, wherein no more than two of Q1, Q2, Q3, Q4 and Q5 are nitrogen, and the carbon is optionally substituted by 1-5 substituents R1a; R2, R3, R4, R5 and R1a are as defined in claim 1; The dashed line indicates that the ring is aromatic.

11. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound having the structure of formula (Ic), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, Q6, Q7, Q8 and Q9 are each independently selected from the group consisting of: oxygen, carbon or nitrogen, wherein no more than two of Q6, Q7, Q8 and Q9 are nitrogen or oxygen, and the carbon is optionally substituted by 1-2 substituents R1a; R2, R3, R4, R5 and R1a are as defined in claim 1; The dashed line indicates that the ring is aromatic.

12. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound having the structure of formula (Id), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, Q1, Q2, Q3, Q4 and Q5 are as defined in claim 10; R6 is as defined in claim 8.

13. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound having the structure of formula (Ie), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, Q6, Q7, Q8 and Q9 are as defined in claim 11; R6 is as defined in claim 8.

14. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound having the structure of formula (If), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, R1 is as defined in claim 1; R6 is as defined in claim 8.

15. The compound according to claim 1, wherein, The compound of formula (I) is a compound having the structure of formula (IIb), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, Q1, Q2, Q3, Q4 and Q5 are as defined in claim 10; R2, R3, R4 and R5 are as defined in claim 1; The dashed line indicates that the ring is aromatic.

16. The compound according to claim 1, characterized in that, The compound of formula (I) is a compound having the structure of formula (IId), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, Q1, Q2, Q3, Q4 and Q5 are as defined in claim 10; R6 is as defined in claim 8.

17. The compound according to claim 1, wherein, The compound of formula (I) is a compound having the structure of formula (IIId), or a pharmaceutically acceptable salt, solvate or hydrate thereof: Wherein, Q1, Q2, Q3, Q4 are each independently selected from the group consisting of: nitrogen, carbon; - If each R'1 is independently selected from the group consisting of: 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, then each R'2 is independently a 4-7 membered heterocyclic group containing 1-2 nitrogen atoms, 0-1 oxygen atom and / or 0-1 sulfur atom, which must be substituted by 1-2 substituents selected from the group consisting of: oxo, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, and is also optionally substituted by 1-3 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5) alkyl, (C2-C3) alkenyl, (C2-C3) alkynyl and (C1-C3) alkoxy; or - If each R'1 is independently -C(=O)-NH-(C1-C5)-alkyl; then each R2 is independently: -NRсRd, wherein each Rc and Rd: - each independently is hydrogen, deuterium, (C3-C7)-cycloalkyl, -(C1-C3)-alkyl-N(CH3)2, (C1-C3)-alkyl, partially or fully halogenated (C1-C3)-alkyl, a 3-7 membered heterocyclic group containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, which is optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl or partially or fully halogenated (C1-C3)-alkyl, a 5-7 membered heteroaryl containing 0-1 oxygen atom, 0-1 sulfur atom and / or 0-4 nitrogen atoms, said heteroaryl being optionally substituted by 1-2 substituents selected from the group consisting of: (C1-C3)-alkyl, or partially or fully halogenated (C1-C3)-alkyl; Alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted by 1-4 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, oxo, -(C1-C3)-alkyl-(C3-C6)-cycloalkyl, or (C1-C3)-alkoxy; or Alternatively, Rc and Rd together with the nitrogen atom to which they are attached form a 6-14 membered bicyclic heterocyclic group containing 1-2 nitrogen atoms and 0-1 oxygen atom and / or 0-1 sulfur atom, optionally substituted by 1-4 substituents selected from the group consisting of: deuterium, halogen, (C1-C5)-alkyl, partially or fully halogenated (C1-C5)-alkyl, (C2-C3)-alkenyl, (C2-C3)-alkynyl, oxo, (C1-C3)-alkyl-(C3-C6)-cycloalkyl, or (C1-C3)-alkoxy.

18. The compound according to claim 1, wherein the compound is 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-dihydro-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)pyridinecarbonitrile; 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)pyridinecarboxamide; 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)picolinitrile; 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 (hydrochloride); 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 (hydrochloride); 5-(1-((3,5-difluoro-4-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)sulfonyl)-1H-pyrrolo[2,3-c]pyridin-4-yl)picolinitrile; 1-((3,5-difluoro-4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-4-(pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine (hydrochloride).

19. Use of a compound according to any one of claims 1-18 for inhibiting CYP11B2.

20. Use of a compound according to any one of claims 1-18 for reducing the aldosterone level in a subject.

21. The use according to claim 20, wherein, The subject is a human.

22. A pharmaceutical composition for treating and / or preventing a disease or disorder mediated or maintained by CYP11B2 activity, comprising a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 to 18 and at least one pharmaceutically acceptable excipient.

23. The pharmaceutical composition according to claim 22, wherein The pharmaceutically acceptable excipient is a carrier, adjuvant and / or solvent.

24. The pharmaceutical composition according to claim 22, wherein, The disease is selected from the group consisting of: primary aldosteronism, chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia, or insulin resistance.

25. The pharmaceutical composition according to claim 24, wherein, The primary aldosteronism is Conn syndrome, including diseases or disorders selected from the group consisting of: aldosterone adenoma, idiopathic aldosteronism, unilateral or bilateral adrenal hyperplasia, type I and type II familial aldosteronism, aldosterone carcinoma, and aldosterone ectopia.

26. A method for treating and / or preventing a disease or disorder mediated or maintained by CYP11B2 activity in a subject, comprising administering a therapeutically or prophylactically effective amount of a compound according to any one of claims 1 - 18.

27. The method according to claim 26, wherein The disease is selected from the group consisting of: primary aldosteronism, chronic heart failure, chronic heart failure with preserved ejection fraction, left ventricular dysfunction, left ventricular hypertrophy, arterial hypertension, resistant arterial hypertension, pulmonary arterial hypertension, coronary heart disease, cirrhosis, metabolic syndrome, chronic kidney disease, glomerulosclerosis, glomerulonephritis, nephritic syndrome, focal segmental glomerulosclerosis, diabetic nephropathy, cardiac and vascular remodeling, post-infarction cardiosclerosis, atherosclerosis, increased collagen formation, endothelial dysfunction, hypokalemia or insulin resistance.

28. The method according to claim 26, wherein The primary aldosteronism is Conn syndrome, including diseases or disorders selected from the group consisting of: aldosterone adenoma, idiopathic aldosteronism, unilateral or bilateral adrenal hyperplasia, type I and type II familial aldosteronism, aldosterone carcinoma, and aldosterone ectopia.

29. The method according to claim 24, wherein The subject is a human.

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