New pyrazol-3-one compounds are hypoxia-inducible transcription factor-prolyl-4-hydroxylase inhibitors useful e.g. to treat and/or prophylaxis heart-circulation diseases, heart failure, anemia, chronic kidney diseases and renal failure

摘要

Pyrazol-3-one compounds (I) and their salts, solvates and solvate of the salts, are new, where (I) excludes 3-methyl-1-(pyridin-2-yl)-4-(1-pyridin-2-yl-3-methyl-1H-pyrazol-5-yl)-2H-3-pyrazolin-5(1H)-one. Pyrazol-3-one compounds of formula (I) and their salts, solvates and solvate of the salts, are new, where (I) excludes 3-methyl-1-(pyridin-2-yl)-4-(1-pyridin-2-yl-3-methyl-1H-pyrazol-5-yl)-2H-3-pyrazolin-5(1H)-one. R 1 : nitrogen containing aryl group of formula (a)-(d); A : C-R 4 or N, where maximum two ring members of A are simultaneously N; E : O, S or N-R 5; R 2 : nitrogen containing heteroaryl-group of formula (e)-(q); a1, a2 : point of attachment with the dihydropyrazolone ring; G : C-R 6 or N, where maximum two ring members of G are simultaneously N; J : O, S or N-R 7; L : C-R 8 or N, where maximum two ring members of L are simultaneously N; R 4, R 6, R 8 : H, halo, cyano, NO 2, (1-6C)-alkyl (substituted with 1-3 of T), (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl (where the (hetero)cycloalkyl, phenyl and heteroaryl are substituted with 1-3 of T 1), -C(=O)-R 9, -C(=O)-R 1 0, -C(=O)-NR 1 1R 1 2, -O-C(=O) -R 1 3, -O-C(=O)-NR 1 4R 1 5, -NR 1 6-C(=O)-R 1 7, -NR 1 8-C(=O)-OR 1 9, -NR 2 0-C(=O) -NR 2 1R 2 2, -NR 2 3-SO 2-R 2 4, -SO 2-R 2 5, -SO 2-NR 2 6R 2 7, -OR 2 8, -SR 2 9 or -NR 3 0R 3 1; T : halo, CN, oxo, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C(=O)-R 9, -C(=O)-OR 1 0, -C(=O)-NR 1 1R 1 2, -O-C(=O)-R 1 3, -O-C(=O)-NR 1 4R 1 5, -NR 1 6-C(=O)-R 1 7, -NR 1 8-C(=O)-OR 1 9, -NR 2 0-C(=O)-NR 2 1R 2 2, -NR 2 3-SO 2-R 2 4, -SO 2-R 2 5, -SO 2-NR 2 6R 2 7, -OR 2 8, -SR 2 9 or -NR 3 0R 3 1, where the cycloalkyl-, heterocycloalkyl-, phenyl- and heteroaryl are substituted by 1-3 of halo, CN, (1-4C)-alkyl, trifluoromethyl, OH, (1-4C)-alkoxy, trifluoromethoxy, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl and/or (1-4C)-alkoxycarbonyl; T 1 : (1-6C)-alkyl, halo, CN, oxo, -C(=O)-R 9, -C(=O)-OR 1 0, -C(=O)-NR 1 1R 1 2, -O-C(=O)-R 1 3, -O-C(=O)-NR 1 4R 1 5 -NR 1 6-C(=O) -R 1 7, -NR 1 8-C(=O)-OR 1 9, -NR 2 0-C(=O)-NR 2 1R 2 2, -NR 2 3-SO 2-R 2 4, -SO 2-R 2 5, -SO 2-NR 2 6R 2 7, -OR 2 8, -SR 2 9 or -NR 3 0R 3 1, where the alkyl is substituted with 1-3 of halo, CN, OH, trifluoromethoxy, (1-4C) -alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl; either R 9-R 1 1, R 1 3, R 1 4, R 1 7, R 1 9, R 2 1, R 2 4, R 2 5, R 2 6, R 2 8-R 3 0 : H, (1-6C)-alkyl (substituted with 1-3 of halo, cyano, OH, trifluoromethoxy, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5- or 6-membered heteroaryl), (where the (hetero)cycloalkyl, phenyl and heteroaryl are substituted with 1-3 of halo, cyano, (1-4C)-alkyl, trifluoromethyl, OH, (1-4C)-alkoxy, trifluoromethoxy, oxo, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl or (1-4C)-alkoxycarbonyl); and R 1 2, R 1 5, R 1 6, R 1 8, R 2 0, R 2 2, R 2 3, R 2 7, R 3 1 : H or (1-6C)-alkyl, which is optionally substituted with halo, CN, OH, trifluoromethoxy, (1-4C)-alkoxy, amino, mono-(1-4C)-alkylamino, di-(1-4C)-alkylamino, hydroxycarbonyl or (1-4C)-alkoxycarbonyl; or R 1 1R 1 2, R 1 4R 1 5, R 1 6R 1 7, R 1 8R 1 9, R 2 0R 2 1, R 2 1R 2 2, R 2 3R 2 4, R 2 6R 2 7, R 3 0R 3 1 : 5- or 6-membered heterocycloalkyl ring; R 5, R 7 : H, (1-6C)-alkyl (substituted by T), (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl (where the (hetero)cycloalkyl, phenyl and heteroaryl are substituted with 1-3 of T 1); and R 3 : H, (1-6C)-alkyl or (3-7C)-cycloalkyl. Independent claims are included for: (1) preparations of (I); and (2) a medicament comprising (I) and inert, non-toxic auxiliary material. [Image] [Image] [Image] [Image] ACTIVITY : Cardiant; Antianemic; Nephrotropic; Antianginal; Cerebroprotective; Vasotropic; Antiarteriosclerotic; Hypotensive; Dermatological; Antimicrobial; Antiinflammatory; Gastrointestinal-Gen; Antiarthritic; Antirheumatic; Ophthalmological; Antiparkinsonian; Neuroprotective; Nootropic; Analgesic; Vulnerary; Anabolic; Endocrine-Gen; Antidiabetic. MECHANISM OF ACTION : Hypoxia-inducible transcription factor (HIF)-prolyl-4-hydroxylase inhibitor.