WO2017207534A1 - Composés hétéroarylbenzimidazole substitués - Google Patents

Composés hétéroarylbenzimidazole substitués Download PDF

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WO2017207534A1
WO2017207534A1 PCT/EP2017/062978 EP2017062978W WO2017207534A1 WO 2017207534 A1 WO2017207534 A1 WO 2017207534A1 EP 2017062978 W EP2017062978 W EP 2017062978W WO 2017207534 A1 WO2017207534 A1 WO 2017207534A1
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group
methyl
hydrogen atom
group selected
alkyl
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Julien LEFRANC
Anne Mengel
Volker Schulze
Clara CHRIST
Florian PRINZ
Antje Margret Wengner
Detlef STÖCKIGT
Ulf Bömer
Benjamin Bader
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Bayer Pharma AG
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Bayer Pharma AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention covers substituted heteroarylbenzimidazole compounds of general formula (I) as described and defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative and/or inflammatory disorders, as a sole agent or in combination with other active ingredients.
  • the present invention covers heteroarylbenzimidazole compounds of general formula (I) which inhibit Tank-binding kinase 1 (TBK1 ) and/or ⁇ kinase epsilon ( ⁇ ).
  • Tank-binding kinase 1 (TBK1 ) and ⁇ kinase epsilon ( ⁇ ) are two non-canonical ⁇ kinases (IKKs). They play crucial roles in interferon regulatory factor (IRF) and nuclear factor kappaB (N F-KB) signaling cascades.
  • IRF interferon regulatory factor
  • N F-KB nuclear factor kappaB
  • TBK1 and ⁇ share 49% identity and 65% similarity with each other and the kinase domains are 27% identical to IKKa and ⁇ (Shen RR & Hahn WC (201 1 ) Emerging roles for the non-canonical IKKs in cancer. Oncogene 30(6):631 -641 ).
  • Both ⁇ and TBK1 are comprised of an N-terminal kinase domain, an ubiquitin-like domain, a C- terminal LZ and a HLH motif (Larabi A, et al. (2013) Crystal structure and mechanism of activation of TANK-binding kinase 1 . Cell reports 3(3):734-746).
  • TBK1 and ⁇ exhibit differential expression patterns.
  • TBK1 like IKKa and ⁇ , is ubiquitously expressed. In contrast, ⁇ expression is restricted to particular tissue compartments, with highest levels detected in lymphoid tissues, peripheral blood lymphocytes and the pancreas.
  • TBK1 was originally identified as an IKK-related Serine/Threonine kinase which, in complex with ⁇ , induces the transcription of IFN-I genes as part of the anti-viral innate immune response.
  • TBK1 resides downstream of Toll-like receptors and has as natural substrates the transcription factors IRF3 and IRF7 which, upon phosphorylation by TBK1 , translocate to the nucleus and trigger IFN-I gene transcription (Han KJ, et al. (2004) Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways.
  • IRF3 and IRF7 transcription factors
  • TBK1 and ⁇ are not a part of the classical ⁇ / ⁇ / ⁇ signaling complex, these kinases were originally characterized as activators of N F- ⁇ and target multiple N F-KB members and effectors. Both IKK-related kinases phosphorylate ⁇ at one of the two-serine residues typically targeted on ⁇ (Shen RR & Hahn WC (201 1 ) Emerging roles for the non- canonical IKKs in cancer. Oncogene 30(6):631 -641 ).
  • TBK1 and ⁇ have been linked to the pathophysiology of several diseases and represent promising potential targets for drug development as is demonstrated by several drug finding projects, both from academia and from the pharmaceutical industry as reviewed recently by Yu and colleagues (Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (201 1 - 2014). Expert opinion on therapeutic paienis:1 -12).
  • ⁇ was found to be amplified in breast cancer lines and breast carcinomas. Subsequent experiments identified ⁇ as a breast cancer oncogene (Boehm JS, et ai. (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129(6):1065-1079). Work by other groups further confirmed the role of ⁇ (and TBK1 ) in breast cancer (e.g. Barbie TU, et ai. (2014) Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth.
  • TBK1 is up-regulated under hypoxic conditions and was shown to behave as a pro-angiogenic factor (Korherr C, et al. (2006) Identification of proangiogenic genes and pathways by high- throughput functional genomics: TBK1 and the IRF3 pathway. Proceedings of the National Academy of Sciences of the United States of America 103(1 1 ):4240-4245). Moreover, TBK1 over-expression in HUVEC cells induces the secretion of pro-angiogenic factors via the activation of IRF3 (Korherr C, et al. (2006) Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway.
  • TBK1 has been identified as a key factor linking innate immune signaling to tumor cell survival via the small GTPase and Ras effector RalB (Chien Y, et al. (2006) RalB GTPase- mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival.
  • Ras-transformed cancer cells are addicted to TBK1 -induced survival signals, and TBK1 kinase inhibition may therefore constitute a tumor cell-specific approach to cancer treatment.
  • TBK1 was shown to be essential for cell lines with activated KRas. This links RalB mediated activation of TBK1 to the generation of specific NF-KB-regulated survival signals downstream of oncogenic KRas (Barbie DA, et al. (2009) Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462(7269):108-1 12).
  • TBK1 has been proposed as a target for the treatment of autoimmune diseases, inflammation and other diseases.
  • TBK1 is involved in regulating rheumatoid synovitis and also acts as a key regulator in neuroinflammation, microvascular inflammation and gastritis. Additional potential indications include obesity and type 2 diabetes.
  • TBK1 signaling has also been shown to be involved in mediating normal tension glaucoma, familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia diseases.
  • ALS familial amyotrophic lateral sclerosis
  • ALS familial amyotrophic lateral sclerosis
  • frontotemporal dementia diseases In the field of cancer, there are an increasing number of reports demonstrating that TBK1 mediates cell apoptosis and proliferation in cancer cell lines, especially those that depend on oncogenic KRAS expression.
  • TBK1 plays a key role in maintaining drug resistance in prostate cancer (PCa) cells by interaction with mammalian target of rapamycin and inhibiting its function, which can induce cell-cycle arrest in PCa cells.
  • PCa prostate cancer
  • TBK1 silencing decreased the expression of epithelial markers and increased the expression of mesenchymal markers in ERa (estrogen receptor)-positive breast cancer cells.
  • TBK1 plays a significant role in radiation-induced epithelial— mesenchymal transition.
  • TBK1 -dependent mechanism for NF- ⁇ signaling pathway contributes to autophagy addiction in K-Ras-driven non-small-cell lung cancer cells (reviewed in Yu T, et al. (2015) TBK1 inhibitors: a review of patent literature (201 1 - 2014). Expert opinion on therapeutic patents: 1 -12).
  • WO 2010127754 discloses 3-([1 ,2,3]-triazol-4-yl-pyrrolo[2.3-b]pyridine derivatives as inhibitors of PDK1 , ⁇ and TBK 1.
  • WO 201 1046970 discloses amino-pyrimidine compounds as inhibitors of TBK1 and/or ⁇ .
  • WO 2012010826 discloses pyrimidine compounds as inhibitors of TBK1 and/or ⁇ .
  • WO 2012104007 discloses 7-azaindole derivatives as inhibitors or PDK1 , ⁇ , ⁇ 1 and TGF-beta..
  • WO 2012161877 discloses pyridine and pyrazine derivatives as inhibitors of TBK1 and ⁇ .
  • WO 2012161879 discloses thiazole derivatives as inhibitors of TBK1 and ⁇ .
  • CN 103251600 discloses a 2-amino-4-(3'-cyano-4'-pyyrolidyl)phenyl pyrimidine compound inter alia as inhibitor of TBK-1 .
  • WO 2013024282 discloses an inhibitor of one or both of TBK1 and ⁇ , or a down-regulator of the expression of one or both TBK1 and ⁇ , for use in a method of treating a cancer that is dependent on the PI3kinase pathway, and cites multiple further patent applications and scientific publications disclosing further inhibitors of TBK1 and ⁇ .
  • WO 2013034238 discloses benzonitrile derivatives as inhibitors of TBK1 and ⁇ .
  • WO 2013075785 discloses 3-cyanaryl-1 H-pyrazolo[2.3-b]pyridine derivatives as inhibitors of TBK1 and ⁇ .
  • WO 20131 17285 discloses furo-[3,2b] and thieno-[3.2-b]pyridine derivatives as inhibitors of TBK1 and ⁇ .
  • WO 2014004863 discloses heteroaromatic compounds as inhibitors of TBK1 and/or ⁇ .
  • US 20150344473 discloses fused heteroaromatic compounds of TBK1 and ⁇ .
  • WO 1998056376 discloses heteroaryl compounds for the modulation of protein tyrosine kinase related signal transduction.
  • WO 2002076438 discloses ligands of the Flt-1 receptor.
  • WO 2004058762 discloses inhibitors of Mitogen Activated Protein Kinase-activated Protein Kinase-2 (MK-2).
  • WO 2004085425 discloses fused azole derivatives as Kinase inhibitors.
  • WO 2005020921 discloses c-Kit modulators and method of use.
  • US 2005038023 discloses pyrazole compounds as Protein Kinase inhibitors.
  • WO 2006099379 discloses benzazole derivatives as beta-Secretase inhibitors.
  • WO 2007084390 discloses organic compounds as HDAC inhibitors.
  • WO 2007089512 discloses heterocyclic compounds as activators of Glucokinase.
  • WO 2007100646 discloses multicyclic compounds as modulators of various protein kinase receptor enzymes, such as Tie-2 and Aurora kinase.
  • WO 2008057280 discloses multicyclic compounds as modulators of various protein kinase receptors, such as Tie-2 and Aurora kinase.
  • WO 2010034797 discloses 1 H-benzimidazole-5-carboxamides as anti-inflammatory agents.
  • WO 20101 15736 discloses heterocyclic compounds as inhibitors of dihydroorotate dehydrogenase.
  • WO 201 1 161 159 discloses heterocyclic compounds as Kinase inhibitors.
  • WO 2012068546 discloses heterocycle amines as inhibitors of IRAK-1 and IRAK-4.
  • WO 2015031564 discloses substituted 1 H-benzo[d]imidazole series compounds as lysine specific demethylase (LSD-1 ) inhibitors.
  • the compounds of the present invention have surprisingly been found to effectively inhibit TBK1 and/or ⁇ and may therefore be used for the treatment or prophylaxis of hyperproliferative and/or inflammatory disorders, such as cancer, for example. DESCRIPTION of the INVENTION
  • the present invention covers compounds of general formula (I):
  • pyrazolyl imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R 7 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R 8 group, represents a group selected from
  • R 1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R 9 group;
  • R 2 represents a group selected from
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy;
  • R 4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy; represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl; represents a hydrogen atom, a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-haloalkyl, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom; represents a hydrogen atom, a halogen atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom; represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-
  • said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group; represents a halogen atom or a group selected from d-Ce-alkyl, Ci-C 6 -haloalkyl, Ci-C 6 -hydroxyalkyl, (Ci-C 3 -alkoxy)-(Ci-C 3 -alkyl)-, C2-C6-alkenyl, C2-C6-alkynyl, Cs-Cs-cycloalkyl, C4-C8-cycloalkenyl, (Cs-Cs-cycloalkyl)- (Ci-C3-alkyl)-, (phenyl)-Ci-C3-alkyl-, 4- to 7-
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; and R 12a , independently from each other, represent a hydrogen atom or a group selected from Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C3-C6-cycloalkyl and benzyl,
  • said 5- to 6-membered heteroaryl group and said phenyl group being optionally substituted one, two or three times, identically or differently, with a halogen atom or a group selected from -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy and Ci-C3-haloalkoxy; represents a group selected from Ci-C 4 -alkyl and benzyl; and R 15a , independently from each other, represent a hydrogen atom or a group selected from Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C3-C6-cycloalkyl and benzyl,
  • R 15a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a halogen atom or a group selected from hydroxy, -CN, Ci-C3-alkyl, Ci-C3-haloalkyl, Ci-C3-alkoxy, Ci-C3-haloalkoxy and (Ci-C3-alkoxy)- (Ci-C 3 -alkyl)-;
  • R 16 represents a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkyl)-, 4- to 7-membered heterocycloalkyl, 5- to 6-membered heteroaryl and phenyl,
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or sulphur atom. Commonly, it is possible for the number of optional substituents, when present, to be 1 , 2, 3, 4 or 5, in particular 1 , 2 or 3.
  • the term "one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2".
  • a composite substituent be composed of more than one parts, e.g. (Ci-C4-alkoxy)-(Ci-C4-alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e. the Ci-C4-alkoxy part can be attached to any carbon atom of the Ci-C4-alkyl part of said (Ci-C4-alkoxy)-(Ci-C4-alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent
  • substituent it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • halogen atom means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
  • an oxo substituent represents an oxygen atom, which is bound to a carbon atom or to a sulfur atom via a double bond.
  • Ci-C6-alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, ie f-butyl, pentyl, isopentyl, 2-methylbutyl, 1 -methylbutyl, 1 -ethylpropyl,
  • said group has 1 , 2, 3 or 4 carbon atoms ("Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or ie f-butyl group, more particularly 1 , 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.
  • C2-C6-alkylene means a linear or branched, saturated, divalent hydrocarbon chain (or “tether”) having 2, 3, 4, 5 or 6 carbon atoms, e.g. -CH2-CH2- ("ethylene” or “C2-alkylene”), -CH2-CH2-CH2-, -C(H)(CH 3 )-CH 2 - or -C(CH 3 ) 2 -) ("propylene” or "C 3 -alkylene”), or, for example -CH 2 -C(H)(CH 3 )-CH 2 -, -CH 2 -C(CH 3 ) 2 -), -CH2-CH2-CH2-CH2- ("butylene” or "C 4 -alkylene”), "Cs-alkylene", e.g.
  • n-pentylene or "-C 6 -alkylene-", e.g. -CH2-CH2-CH2-CH2-CH2-CH2- ("n-hexylene") or -C(CH 3 )2-C(CH 3 )2- group.
  • alkylene is a -C(CH3)2-C(CH3)2- group.
  • Ci-C6-hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term “Ci-C6-alkyl” is defined supra, and in which 1 , 2 or 3 hydrogen atoms are replaced with a hydroxy group, e.g. a hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl,
  • Ci-C6-alkylsulfanyl means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-S-, in which the term "Ci-C6-alkyl” is as defined supra, e.g.
  • Ci-C6-haloalkyl means a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C6-alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom, to give rise to a "Ci-C6-fluoroalkyl” group, particularly a "Ci-C4-fluoroalkyl” group, more particularly, a "Ci-C3-fluoroalkyl” group.
  • Ci-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2 ,2 ,2-trif luoroethy I , pentafluoroethyl, 3,3,3-trifluoropropyl or
  • Ci-C6-alkoxy means a linear or branched, saturated, monovalent group of formula (Ci-C6-alkyl)-0-, in which the term "Ci-C6-alkyl” is as defined supra, e.g. a methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, ie f-butoxy, pentyloxy, isopentyloxy or n-hexyloxy group, or an isomer thereof.
  • Ci-C6-haloalkoxy means a linear or branched, saturated, monovalent Ci-C6-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom, to give rise to a "Ci-C6-fluoroalkoxy” group, particularly a "Ci-C4-fluoroalkoxy” group, more particularly, a "Ci-C3-fluoroalkoxy” group.
  • Said Ci-C6-haloalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy.
  • Ci-C6-haloalkylsulfanyl means a linear or branched, saturated, monovalent C1-C6- alkylsulfanyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom.
  • said halogen atom is a fluorine atom to give rise to a "Ci-C6-fluoroalkylsulfanyl” group, particularly a "Ci-C4-fluoroalkylsulfanyl” group, more particularly, a "Ci-C3-fluoroalkylsulfanyl” group.
  • Ci-C6-haloalkylsulfanyl group is, for example, fluoromethylsulfanyl, difluoromethylsulfanyl, trifluoromethylsulfanyl, 2,2,2-trifluoroethylsulfanyl or pentafluoroethylsulfanyl.
  • C2-C6-alkenyl means a linear or branched, monovalent hydrocarbon group, which contains one double bond, and which has 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”).
  • Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1 -yl (or “allyl”), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, pent-4-enyl, pent-3-enyl, pent-2-enyl, pent-1 -enyl, hex-5-enyl, hex-4-enyl, hex-3-enyl, hex-2-enyl, hex-1 -enyl, prop-1 -en-2-yl (or “isopropenyl”), 2-methylprop-2-enyl, 1 -methylprop-2-enyl,
  • C2-C6-alkynyl means a linear or branched, monovalent hydrocarbon group which contains one triple bond, and which contains 2, 3, 4, 5 or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkynyl").
  • Said C2-C6-alkynyl group is, for example, ethynyl, prop-1 -ynyl, prop-2-ynyl (or “propargyl"), but-1 -ynyl, but-2-ynyl, but-3-ynyl, pent-1 -ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1 -ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1 -methylprop-2-ynyl, 2-methylbut-3-ynyl, 1 -methylbut-3-ynyl, 1 -methylbut-2-ynyl,
  • Cs-Cs-cycloalkyl means a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4, 5, 6, 7 or 8 carbon atoms ("Cs-Cs-cycloalkyl”). Particularly, said group is monocyclic and has 3, 4, 5 or 6 carbon atoms ("C3-C6-cycloalkyl”).
  • Said Cs-Cs-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[4.2.0]octyl or octahydropentalenyl.
  • C4-C8-cycloalkenyl means a monovalent, mono- or bicyclic hydrocarbon ring which contains 4, 5, 6, 7 or 8 carbon atoms and one double bond. Particularly, said ring contains 4, 5 or 6 carbon atoms ("C4-C6-cycloalkenyl").
  • Said C4-C8-cycloalkenyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl group, or a bicyclic hydrocarbon ring, e.g. a bicyclo[2.2.1]hept-2-enyl or bicyclo[2.2.2]oct-2-enyl.
  • Cs-Cs-cycloalkoxy means a saturated, monovalent, mono- or bicyclic group of formula (C3-C8-cycloalkyl)-0-, which contains 3, 4, 5, 6, 7 or 8 carbon atoms, in which the term "Cs-Cs-cycloalkyl” is defined supra, e.g. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy group.
  • spirocycloalkyl means a saturated, monovalent bicyclic hydrocarbon group in which the two rings share one common ring carbon atom, and wherein said bicyclic hydrocarbon group contains 5, 6, 7, 8, 9, 10 or 1 1 carbon atoms, it being possible for said spirocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms except the spiro carbon atom.
  • Said spirocycloalkyl group is, for example, spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[2.4]heptyl, spiro[2.5]octyl, spiro[2.6]nonyl, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[4.6]undecyl or spiro[5.5]undecyl.
  • heterocycloalkyi and “4- to 6-membered heterocycloalkyi” mean a monocyclic, saturated heterocycle with 4, 5, 6 or 7 or, respectively, 4, 5 or 6 ring atoms in total, which contains one or two identical or different ring heteroatoms from the series N, O and S, it being possible for said heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkyi group can be a 4-membered ring, such as azetidinyl, oxetanyl or thietanyl, for example; or a 5-membered ring, such as tetrahydrofuranyl, 1 ,3-dioxolanyl, thiolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1 ,2-oxazolidinyl, 1 ,3-oxazolidinyl or 1 ,3-thiazolidinyl, for example; or a 6-membered ring, such as tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl or 1 ,
  • 4- to 6-membered heterocycloalkyi means a 4- to 6-membered heterocycloalkyi as defined supra containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O, S.
  • 5- or 6-membered heterocycloalkyi means a monocyclic, saturated heterocycle with 5 or 6 ring atoms in total, containing one ring nitrogen atom and optionally one further ring heteroatom from the series: N, O.
  • heterocycloalkenyl means a monocyclic, unsaturated, non- aromatic heterocycle with 5, 6 or 7 ring atoms in total, which contains one or two double bonds and one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterocycloalkenyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said heterocycloalkenyl group is, for example, 4/-/-pyranyl, 2/-/-pyranyl, 2,5-dihydro-1 /-/-pyrrolyl, [1 ,3]dioxolyl, 4/-/-[1 ,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrothio- phenyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl or 4H-[1 ,4]thiazinyl.
  • heterospirocycloalkyi means a bicyclic, saturated heterocycle with 6, 7, 8, 9, 10 or 1 1 ring atoms in total, in which the two rings share one common ring carbon atom, which "heterospirocycloalkyi" contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said heterospirocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said heterospirocycloalkyi group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxaazaspiro[3.3]heptyl, thiaazaspiro[3.3]heptyl, oxaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, azaspiro[4,5]decyl, oxazaspiro [5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl, azaspiro[5.5]undecyl, or one of the further homologous scaffolds such as spiro[3.4]-, spiro[4.4]-, spiro[2.4]-, spiro[2.5]-,
  • fused heterocycloalkyl means a bicyclic, saturated heterocycle with 6, 7, 8, 9 or 10 ring atoms in total, in which the two rings share two adjacent ring atoms, which "fused heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said fused heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, a nitrogen atom.
  • Said fused heterocycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]- nonyl or azabicyclo[4.4.0]decyl.
  • bridged heterocycloalkyl means a bicyclic, saturated heterocycle with 7, 8, 9 or 10 ring atoms in total, in which the two rings share two common ring atoms which are not adjacent, which "bridged heterocycloalkyl” contains one or two identical or different ring heteroatoms from the series: N, O, S; it being possible for said bridged heterocycloalkyl group to be attached to the rest of the molecule via any one of the carbon atoms, except the spiro carbon atom, or, if present, a nitrogen atom.
  • Said bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1 ]heptyl, thiazabicyclo[2.2.1 ]heptyl, diazabicyclo[2.2.1 ]heptyl, azabicyclo- [2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabi- cyclo[3.2.1 ]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1 ]octyl, azabicyclo[3.3.1 ]nonyl, diazabicyclo[3.3.1 ]nonyl, oxazabicyclo[3.3.1 ]non
  • heteroaryl means a monovalent, monocyclic, bicyclic or tricyclic aromatic ring having 5, 6, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5, 6, 9 or 10 ring atoms, which contains at least one ring heteroatom and optionally one, two or three further ring heteroatoms from the series: N, O and/or S, and which is bound via a ring carbon atom or optionally via a ring nitrogen atom (if allowed by valency).
  • Said heteroaryl group can be a 5-membered heteroaryl group, such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl or tetrazolyl; or a 6-membered heteroaryl group, such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl; or a tricyclic heteroaryl group, such as, for example, carbazolyl, acridinyl or phenazinyl; or a 9-membered heteroaryl group, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl,
  • heteroaryl or heteroarylene groups include all possible isomeric forms thereof, e.g.: tautomers and positional isomers with respect to the point of linkage to the rest of the molecule.
  • pyridinyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.
  • the heteroaryl group is a a 5- or 6-membered heteroaryl group.
  • heteroaryloxy means a monovalent, monocyclic, bicyclic or tricyclic aromatic group of the formula (heteroaryl)-O-, in which the term “heterorayl is as defined supra, e.g. thienyloxy, thiazolyloxy, pyridinyloxy, pyrimidinyloxy, benzofuranyloxy, for example.
  • phenyloxy means a group of the formula (phenyl)-O.
  • ⁇ - ⁇ - ⁇ as used in the present text, e.g. in the context of the definition of "Ci-C6-alkyl", “Ci-C6-haloalkyl", “Ci-C6-hydroxyalkyl", “Ci-C6-alkoxy” or “Ci-C6-haloalkoxy” means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • C3-C8 as used in the present text, e.g. in the context of the definition of "Cs-Cs-cycloalkyl" means a cycloalkyl group having a finite number of carbon atoms of 3 to 8, i.e. 3, 4, 5, 6, 7 or 8 carbon atoms.
  • C1-C6 encompasses Ci , C2, C3, C 4 , C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • C1-C4 encompasses Ci , C 2 , C 3 , C 4 , C1-C4, C1-C3, C1-C2, C2-C4, C2-C3 and C 3 -C 4 ;
  • C1-C3 encompasses Ci , C 2 , C 3 , C1-C3, C1-C2 and C2-C3;
  • C2-C6 encompasses C2, C3, C 4 , C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6;
  • C3-C10 encompasses C3, C 4 , C5, C6, C7, Ce, Cg, C10, C3-C10, C3-Cg, C3-C8, C3-C7,
  • C3-C8 encompasses C3, C 4 , C5, C6, C7, Ce, C3-C8, C3-C7, C3-C6, C3-C5, C3-C4, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Ce, C5-C7, C5-C6, C6-Ce, C6-C7 and C7-C8;
  • C 3 -C 6 encompasses C 3 , C 4 , C 5 , C 6 , C 3 -C 6 , C3-C5, C3-C4, C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C4-C8 encompasses C 4 , C5, C6, C7, Ce, C4-C8, C4-C7, C4-C6, C4-C5, Cs-Ce, C5-C7, C5-C6, C6-Ce, C6-C7 and C7-C8;
  • C4-C7 encompasses C 4 , C 5 , C 6 , C 7 , C 4 -C 7 , C 4 -C 6 , C 4 -C 5 , C5-C7, C 5 -C 6 and C 6 -C 7 ;
  • C4-C6 encompasses C 4 , C5, C6, C4-C6, C4-C5 and C5-C6;
  • C5-C10 encompasses C5, C6, C7, Ce, Cg, C10, C5-C10, Cs-Cg, C5-C8, C5-C7, C5-C6, C6-C10, C6- Cg, C6-Ce, C6-C7, C7-C10, C7-Cg, C7-C8, Ce-Cio, Ce-Cg and Cg-Cio!
  • C6-C10 encompasses C6, C7, C8, Cg, C10, C6-C10, C6-Cg, C6-Ce, C6-C7, C7-C10, C7-Cg, C7-C8, Ce-Cio, Ce-Cg and Cg-Cio-
  • the term "leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
  • protecting group is a protective group attached to an oxygen or nitrogen atom in intermediates used for the preparation of compounds of the general formula (I). Such groups are introduced e.g. by chemical modification of the respective hydroxy or amino group in order to obtain chemoselectivity in a subsequent chemical reaction. Protective groups for hydroxy and amino groups are descibed for example in P.G.M.
  • protective groups for amino groups can be selected from substituted sulfonyl groups, such as mesyl-, tosyl- or phenylsulfonyl-, acyl groups such as benzoyl, acetyl or tetrahydropyranoyl, or carbamate based groups, such as ie f.-butoxycarbonyl (Boc).
  • Protective groups for hydroxy groups can be selected from acyl groups such as benzoyl, acetyl, pivaloyl or tetrahydropyranoyl, or can include silicon, as in e.g. tert-butyldimethylsilyl, tert- butyldiphenylsilyl, triethylsilyl or triisopropylsilyl.
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • Isotopic variant of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • Isotopic variant of the compound of general formula (I) is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • unnatural proportion means a proportion of such isotope which is higher than its natural abundance.
  • the natural abundances of isotopes to be applied in this context are described in "Isotopic Compositions of the Elements 1997", Pure Appl. Chem., 70(1 ), 217-235, 1998.
  • isotopes examples include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 125 l, 129 l and 131 1, respectively.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 0, 18 0, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 CI, 82 Br, 123 l, 124 l, 125 l
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium ("deuterium- containing compounds of general formula (I)").
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I).
  • These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium-containing and 13 C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D2O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules. Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e.
  • deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%.
  • the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s). It is understood that the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005, 127, 9641 ], lipophilicity [B. Testa et al., Int. J. Pharm., 1984, 19(3), 271 ]) and/or the metabolic profile of the molecule and may result in changes in the ratio of parent compound to metabolites or in the amounts of metabolites formed.
  • physicochemical properties such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc, 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc, 2005,
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism.
  • deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P450.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable.
  • Enzymatic separations, with or without derivatisation are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. (R)- or (S)- isomers, in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • any compound of the present invention can exist, as shown below, as a tautomer 1 , or tautomer 2 or tautomer 3, in which " * " represents the point of attachment to the rest of the molecule, or even a mixture in any amount of the three tautomers, namely : tautomer 1 tautomer 2 tautomer 3
  • the present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised.
  • the present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio.
  • polar solvents in particular water
  • stoichiometric solvates e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1 -19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or "mineral acid", such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy;
  • R 4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl;
  • R 5 represents a hydrogen atom
  • R 6i represents a hydrogen atom, a halogen atom or a group selected from Ci-C3-alkyl and trifluoromethyl, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6 represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,
  • said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group;
  • R 7 and R 8 when being attached to adjacent ring atoms of the group R 1 , together form a group selected from:
  • R 9 represents a hydrogen atom or a group selected from methoxy and ethoxy
  • R 10 represents a hydrogen atom or a methyl or ethyl group
  • phenyl group being optionally substituted one or two times, identically or differently, with a fluorine atom, chlorine atom or bromine atom, or a group selected from -CN, methyl, trifluoromethyl and methoxy;
  • R 12 and R 12a independently from each other, represent a hydrogen atom or a group selected from Ci-C 4 -alkyl, Ci-C 4 -fluoroalkyl and benzyl,
  • R 12 and R 12a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyi group, said group being optionally substituted once with a methyl group;
  • R 13 represents a group selected from Ci-C 4 -alkyl, Ci-C 4 -fluoroalkyl, C3-C6-cycloalkyl and (C 3 -C 6 -cycloalkyl)-(Ci-C 2 -alkyl)-;
  • R 14 represents a group selected from Ci-C 4 -alkyl and benzyl
  • R 15 and R 15a independently from each other, represent a hydrogen atom or a group selected from Ci-C3-alkyl, trifluoromethyl and cyclopropyl,
  • R 15 and R 15a together with the nitrogen atom they are attached to, represent a 4- to 7- membered heterocycloalkyi group, said group being optionally substituted one or two times, identically or differently, with a group selected from Ci-C3-alkyl and C1-C3- fluoroalkyl;
  • R 16 represents a group selected from Ci-C 4 -alkyl, Ci-C 4 -fluoroalkyl and C3-C6-cycloalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 2 represents a group selected from
  • R 3 represents a hydrogen atom, a fluorine atom, a chlorine atom, or a group selected from methyl, ethyl, methoxy and ethoxy;
  • R 4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a Ci-C2-alkyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl ,
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group;
  • R 8 represents a fluorine, atom, a chlorine atom, or a group selected from Ci-C6-alkyl, Ci-C 4 -fluoroalkyl, (Ci-C 2 -alkoxy)-(Ci-C 2 -alkyl)-, (C 3 -C 4 -cycloalkyl)-(methyl)-, -N(R 12 )R 12a ,
  • R 9 represents a hydrogen atom or a methoxy group
  • R 10 represents a hydrogen atom or a methyl group
  • R 12 and R 12a independently from each other, represent a hydrogen atom or a group selected from Ci-C 2 -fluoroalkyl, methyl and ethyl;
  • R 13 represents a group selected from Ci-C4-alkyl, Ci-C3-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)-(methyl)-;
  • R 14 represents a Ci-C4-alkyl group
  • R 15 and R 15a independently from each other, represent a hydrogen atom or a group selected from methyl and ethyl,
  • R 15 and R 15a together with the nitrogen atom they are attached to, represent a 5- to 6- membered heterocycloalkyl group selected from pyrrolidinyl, piperidinyl and morpholinyl, said group being optionally substituted once with a methyl group;
  • R 16 represents a group selected from methyl, ethyl and trifluoromethyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 3 represents represents a hydrogen atom or a fluorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents a represents a (C3-C4-cycloalkyl)-(methyl)- group
  • R 8 represents a fluorine atom or a group selected from Ci-C3-alkyl, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, -N(R 12 )R 12a , Ci-C 3 -alkoxy and (cyclopropyl)-(methoxy)-;
  • R 10 represents a methyl group
  • R 13 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
  • R 14 represents a tert-butyl group
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • R 8 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;
  • R 10 represents a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • R 8 represents a group selected from methyl and methoxy
  • R 10 represents a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group in which "*" represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • R 10 represents a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from in which "*" represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 8 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;
  • R 10 represents a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 2 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups
  • R 6a and R 6b is different from a hydrogen atom
  • R 8 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;
  • R 10 represents a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl, cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from
  • R 2 represents a group
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a fluorine atom, a chlorine atom or a methyl group
  • R 6b represents a hydrogen atom
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • R 8 represents a group selected from methyl and methoxy
  • R 10 represents a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl and cyclopropyl;
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 3 represents represents a hydrogen atom or a fluorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents a represents a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group;
  • R 8 represents a fluorine atom or a group selected from Ci-C3-alkyl, (Ci-C2-alkoxy)-(Ci-C2- alkyl)-, -N(R 12 )R 12a , Ci-C3-alkoxy and (cyclopropyl)-(methoxy)-;
  • R 10 represents a hydrogen atom or a methyl group
  • R 12 and R 12a independently from each other, represent a group selected from methyl and ethyl;
  • R 13 represents a group selected from Ci-C2-fluoroalkyl, C3-C4-cycloalkyl and (cyclopropyl)- (methyl)-;
  • R 14 represents a tert-butyl group
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 6a and R 6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
  • R 8 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;
  • R 10 represents a hydrogen atom or a methyl group
  • R 13 represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
  • R 8 represents a group selected from methyl, methoxy, (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-;
  • R 10 represents a hydrogen atom or a methyl group
  • R 13 represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom or a fluorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
  • R 10 represents a hydrogen atom or a methyl group
  • R 13 represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups
  • R 6a and R 6b is different from a hydrogen atom
  • R 8 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;
  • R 10 represents a methyl group
  • R 13 represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from in which "*" represents the point of attachment to the rest of the molecule, the ring of said group being optionally substituted, identically or differently, with one or two R 8 groups;
  • R 2 represents a group
  • R 3 represents a hydrogen atom or a fluorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 8 represents a group selected from methyl, trifluoromethyl, (methoxy)-(methyl)-, dimethylamino, diethylamino, methoxy, ethoxy, iso-propoxy and (cyclopropyl)- (methoxy)-;
  • R 10 represents a hydrogen atom or a methyl group
  • R 13 represents a group selected from 2 ,2 ,2-trif luoroethy I , cyclopropyl, cyclobutyl and (cyclopropyl)-(methyl)-;
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 3 represents a hydrogen atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom;
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups
  • R 6a and R 6b is different from a hydrogen atom
  • R 8 represents a group selected from methyl, (methoxy)-(methyl)- and (cyclopropyl)- (methoxy)-;
  • R 10 represents a methyl group
  • R 13 represents a group selected from 2,2,2-trifluoroethyl and cyclopropyl
  • the present invention covers compounds of general formula (I), supra, in which:
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups;
  • R 2 represents a group
  • R 3 represents a hydrogen atom or a fluorine atom
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom
  • R 6a represents a fluorine atom, a chlorine atom or a methyl group
  • R 6b represents a hydrogen atom
  • R 7 represents represents a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom;
  • R 8 represents a group selected from methyl, methoxy, (methoxy)-(methyl)- and (cyclopropyl)-(methoxy)-;
  • R 10 represents a hydrogen atom or a methyl group
  • R 13 represents a group selected from a group selected from 2,2,2-trifluoroethyl and cyclopropyl;
  • R 1 represents a group selected from
  • pyrazolyl imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R 7 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R 8 group,
  • R 1 represents a group selected from
  • R 1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R 9 group,
  • R 1 represents a group selected from
  • pyrazolyl imidazolyl, oxadiazolyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidinyl and pyrazinyl, said group being optionally substituted with one R 7 group, and said group being, additionally, optionally substituted one or two times, differently or identically, with a R 8 group,
  • the present invention covers compounds of formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 1 represents a group selected from pyridine-3-yl or pyridazin-3-yl, optionally substituted with one R 9 group,
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • the present invention covers compounds of formula (I), supra, in which:
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 1 represents a group selected from
  • the ring of said group being, besides R 7 , optionally substituted, identically or differently, with one or two further R 8 groups, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule;
  • the ring of said group being optionally substituted, identically or differently, with one or two R 8 groups,
  • R 1 represents a group selected from
  • R 1 represents a group selected from
  • the present invention covers compounds of formula (I), supra, in which: R 1 represents a group selected from
  • R 1 represents a group selected from
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • the present invention covers compounds of formula (I), supra, in which:
  • R 1 represents a group in which "*" represents the point of attachment to the rest of the molecule
  • R 1 represents a group in which "*" represents the point of attachment to the rest of the molecule
  • R 1 represents a group in which "*" represents the point of attachment to the rest of the molecule
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 7 represents a hydrogen atom or a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom or a methyl group
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 7 represents a hydrogen atom or a (C3-C4-cycloalkyl)-(methyl)- group
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 7 represents a hydrogen atom or a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 7 represents a group selected from (cyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)-, said (cyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,
  • the present invention covers compounds of formula (I), supra, in which: R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule;
  • R 7 represents a group selected from (cyclopropyl)-(methyl)- and (cyclobutyl)-(methyl)-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • the ring of said group being optionally substituted, identically or differently, with one or two R 8 groups,
  • the present invention covers compounds of formula (I), supra, in which:
  • R 1 represents a group
  • R 1 represents a group
  • R 8 is selected from methyl, (methoxy)-(methyl)- and (cyclopropyl)- (methoxy)-;
  • R 1 represents a group
  • R 1 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • said group being optionally substituted, identically or differently, with one or two R 8 groups,
  • R 1 represents a group
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group in which " * " represents the point of attachment to the rest of the molecule
  • R 2 represents a group
  • R 2 represents a group
  • the present invention covers compounds of formula (I), supra, in which:
  • R 2 represents a group
  • R 2 represents a group
  • R 11 represents a Ci-C2-fluoroalkyl group
  • the present invention covers compounds of formula (I), supra, in which: R 2 represents a group
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group selected from in which " * " represents the point of attachment to the rest of the molecule
  • R 2 represents a group
  • R 2 represents a group
  • the present invention covers compounds of formula (I), supra, in which:
  • R 2 represents a group
  • R 2 represents a group
  • R 2 represents a group
  • R 2 represents a group
  • R 11 represents a Ci-C2-fluoroalkyl group
  • R 2 represents a group
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • the present invention covers compounds of formula (I), supra, in which: R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group
  • the present invention covers compounds of formula (I), supra, in which:
  • R 2 represents a group
  • R 2 represents a group
  • the present invention covers compounds of formula (I), supra, in which:
  • R 2 represents a group
  • R 2 represents a group
  • R 11 represents a Ci-C2-fluoroalkyl group
  • R 2 represents a group
  • the present invention covers compounds of formula (I), supra, in which:
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group selected from
  • R 2 represents a group
  • R 2 represents a group
  • R 2 represents a group C H 3
  • R 2 represents a group
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C6-alkoxy,
  • R 3 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-alkoxy,
  • R 3 represents a hydrogen atom, a fluorine atom, a chlorine atom, or a group selected from methyl, ethyl, methoxy and ethoxy,
  • R 3 represents a hydrogen atom, a fluorine atom, or a group selected from methyl and methoxy,
  • the present invention covers compounds of formula (I), supra, in which:
  • R 3 represents a hydrogen atom or a fluorine atom
  • R 3 represents a hydrogen atom
  • R 3 represents a fluorine atom
  • R 4 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy and Ci-C4-haloalkoxy,
  • R 4 represents a hydrogen atom or a group selected from Ci-C3-alkyl and Ci-C3-fluoroalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of formula (I), supra, in which:
  • R 4 represents a hydrogen atom, or a group selected from methyl and trifluoromethyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 4 represents a hydrogen atom or a methyl group
  • R 4 represents a hydrogen atom
  • R 5 represents a hydrogen atom or a halogen atom or a group selected from Ci-C4-alkyl, Ci-C4-haloalkyl and C3-C6-cycloalkyl,
  • R 5 represents a hydrogen atom or a fluorine atom or a chlorine atom a group selected from methyl, trifluoromethyl and cyclopropyl,
  • the present invention covers compounds of formula (I), supra, in which:
  • R 5 represents a hydrogen atom
  • R 6a represents a hydrogen atom, a halogen atom or a group selected from Ci-C4-alkyl and Ci-C4-haloalkyl, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6a represents a hydrogen atom, a halogen atom or a group selected from Ci-C3-alkyl and trifluoromethyl, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a Ci-C2-alkyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • the present invention covers compounds of formula (I), supra, in which:
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6a represents a fluorine atom, a chlorine atom or a methyl group
  • R 6a represents a fluorine atom, a chlorine atom or a methyl group, with the proviso that R 6b represents a hydrogen atom,
  • R 6a represents a hydrogen atom, with the proviso that the group R 6b is different from a hydrogen atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 6a represents a fluorine atom or a chlorine atom
  • R 6a represents a chlorine atom
  • R 6a represents a fluorine atom
  • R 6a represents a methyl group
  • R 6b represents a hydrogen atom, a halogen atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 6b represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that at least one of the groups R 6a and R 6b is different from a hydrogen atom,
  • the present invention covers compounds of formula (I), supra, in which:
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups
  • R 6a and R 6b is different from a hydrogen atom
  • R 6b represents a hydrogen atom, with the proviso that the group R 6a is different from a hydrogen atom,
  • R 6b represents a fluorine atom
  • R 6b represents a chlorine atom
  • the present invention covers compounds of formula (I), supra, in which: R 6a represents a hydrogen atom, a halogen atom or a group selected from
  • Ci-C4-alkyl and Ci-C4-haloalkyl are Ci-C4-alkyl and Ci-C4-haloalkyl, and in which
  • R 6b represents a hydrogen atom, a halogen atom or a methyl group
  • one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom
  • R 6a represents a hydrogen atom, a halogen atom or a group selected from
  • Ci-C3-alkyl and trifluoromethyl and in which
  • R 6b represents a hydrogen atom, a fluorine atom, a chlorine atom or a bromine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom or a
  • Ci-C2-alkyl group and in which
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom
  • one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom
  • R 6a represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group, and in which
  • R 6b represents a hydrogen atom, a fluorine atom or a chlorine atom, with the proviso that one of the groups R 6a and R 6b represents a hydrogen atom and the other of the groups R 6a and R 6b is different from a hydrogen atom,
  • R 7 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C6-haloalkyl, C3- Ce-cycloalkyl and (C 3 -C 6 -cycloalkyl)-(Ci-C 3 -alkyl)-,
  • said C3-C6-cycloalkyl and said (C3-C6-cycloalkyl)-(Ci-C3-alkyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a Ci-C3-alkyl group,
  • R 7 represents a hydrogen atom or a group selected from Ci-C6-alkyl, Ci-C4-fluoroalkyl, C3-C4-cycloalkyl and (C3-C4-cycloalkyl)-(methyl)-,
  • said C3-C4-cycloalkyl and said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one, two or three times, identically or differently, with a fluorine atom, a chlorine atom or with a methyl group,
  • R 7 represents a group selected from C2-C4-alkyl, C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)- (methyl)-,
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 7 represents a group selected from C2-C4-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
  • R 7 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl,
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group,
  • R 7 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C 2 -C 4 -fluoroalkyl,
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom
  • the present invention covers compounds of formula (I), supra, in which: R 7 represents a hydrogen atom or a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl,
  • R 7 represents a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,
  • R 7 represents a group selected from (C3-C4-cycloalkyl)-(methyl)- and C2-C4-fluoroalkyl, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 7 represents a group selected from C2-C4-fluoroalkyl and (cyclopropyl)-(methyl)-,
  • R 7 represents a group selected from C2-C4-fluoroalkyl and (cyclopropyl)-(methyl)-,
  • said (cyclopropyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 7 represents a group selected from C2-C4-fluoroalkyl and (cyclobutyl)-(methyl)-,
  • said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group
  • R 7 represents a group selected from C2-C4-fluoroalkyl and (cyclobutyl)-(methyl)-,
  • R 7 represents a group selected from C2-C3-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
  • R 7 represents a group selected from C2-C3-fluoroalkyl and (C3-C4-cycloalkyl)-(methyl)-, said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,
  • R 7 represents a group selected from C2-C3-fluoroalkyl and (cyclopropyl)-(methyl)-,
  • R 7 represents a group selected from C2-C3-fluoroalkyl and (cyclopropyl)-(methyl)-,
  • R 7 represents a group selected from C2-C3-fluoroalkyl and (cyclobutyl)-(methyl)-,
  • said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group
  • R 7 represents a group selected from C2-C3-fluoroalkyl and (cyclobutyl)-(methyl)-, said (cyclobutyl)-(methyl)- group being optionally substituted one or two times with a fluorine atom,
  • R 7 represents a (C3-C4-cycloalkyl)-(methyl)- group
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group,
  • R 7 represents a (cyclopropyl)-(methyl)- group
  • said (cyclopropyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 7 represents a (cyclobutyl)-(methyl)- group
  • said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a chlorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention covers compounds of formula (I), supra, in which: R 7 represents a (C3-C4-cycloalkyl)-(methyl)- group,
  • said (C3-C4-cycloalkyl)-(methyl)- group being optionally substituted one or two times, identically or differently, with a fluorine atom or a methyl group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 7 represents a (cyclopropyl)-(methyl)- group
  • R 7 represents a (cyclobutyl)-(methyl)- group
  • said (cyclobutyl)-(methyl)- group being optionally substituted one or two times, , identically or differently, with a fluorine atom or a methyl group,

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  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés hétéroarylbenzimidazole substitués de formule générale (I) : dans lesquels R1, R2, R3, R4, R5, R6a et R6b sont tels que définis ici, des procédés de préparation desdits composés, des composés intermédiaires utiles pour préparer lesdits composés, des compositions pharmaceutiques et des combinaisons comprenant lesdits composés et l'utilisation desdits composés pour fabriquer des compositions pharmaceutiques pour le traitement ou la prophylaxie de maladies, en particulier de troubles hyperprolifératifs et/ou inflammatoires, en monothérapie ou en association avec d'autres principes actifs.
PCT/EP2017/062978 2016-06-03 2017-05-30 Composés hétéroarylbenzimidazole substitués Ceased WO2017207534A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018130537A1 (fr) * 2017-01-10 2018-07-19 ETH Zürich Composés protecteurs de cellules et leur utilisation
WO2019133022A1 (fr) * 2017-12-30 2019-07-04 Aiviva Biopharma Inc. Inhibiteurs de multikinases et leurs utilisations dans l'hyperplasie de la prostate et les maladies des voies urinaires

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Cited By (6)

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WO2018130537A1 (fr) * 2017-01-10 2018-07-19 ETH Zürich Composés protecteurs de cellules et leur utilisation
US11628159B2 (en) 2017-01-10 2023-04-18 Eth Zurich Cell-protective compounds and their use
WO2019133022A1 (fr) * 2017-12-30 2019-07-04 Aiviva Biopharma Inc. Inhibiteurs de multikinases et leurs utilisations dans l'hyperplasie de la prostate et les maladies des voies urinaires
KR20200105874A (ko) * 2017-12-30 2020-09-09 아이비바 바이오파마, 인크. 멀티키나제 억제제 및 전립선 비대증 및 요로 질환에서의 용도
US11376252B2 (en) 2017-12-30 2022-07-05 Aiviva Biopharma, Inc. Multikinase inhibitors and uses in prostatic hyperplasia and urinary track diseases
KR102542751B1 (ko) 2017-12-30 2023-06-12 아이비바 바이오파마, 인크. 멀티키나제 억제제 및 전립선 비대증 및 요로 질환에서의 용도

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