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WO2018234353A1 - Novel substituted indole and indazole compounds as phosphodiesterase inhibitors - Google Patents

Novel substituted indole and indazole compounds as phosphodiesterase inhibitors Download PDF

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Publication number
WO2018234353A1
WO2018234353A1 PCT/EP2018/066355 EP2018066355W WO2018234353A1 WO 2018234353 A1 WO2018234353 A1 WO 2018234353A1 EP 2018066355 W EP2018066355 W EP 2018066355W WO 2018234353 A1 WO2018234353 A1 WO 2018234353A1
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Prior art keywords
alkyl
group
alkylen
methanone
morpholino
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PCT/EP2018/066355
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French (fr)
Inventor
Ingo Konetzki
Markus Wagener
Torsten Dunkern
David Rider
André Welbers
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Grünenthal GmbH
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Publication of WO2018234353A1 publication Critical patent/WO2018234353A1/en

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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
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel substituted indole and indazole compounds that are useful as medicaments.
  • This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to humans in need of the treatments.
  • This invention also relates to the preparation of said novel compounds.
  • this invention relates to pharmaceutical compositions and kits comprising the compounds.
  • Phosphodiesterases (abbreviated as PDEs), or more accurately 3',5'-cyclonucleotide phosphor- diesterases, are enzymes that catalyse the hydrolysis of the second messengers cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) to 5'-AMP (5'-adenosine mono- phosphate)-and 5'-GMP (5'-guanosine monophosphate).
  • Phosphodiesterases are a group of enzymes encompassing 1 1 gene families (PDE1-1 1 ), which differ inter alia through their affinity to cAMP and cGMP. Inhibition of phosphodiesterases thus represents a mechanism for modulating cellular processes and can be used to alleviate or cure disease conditions. Inhibitors of specific PDEs are known.
  • PDE4 isoenzymes as targets for anti-asthma drugs. European Respiratory Journal 8, 1 179- 1 183), has led to the development of PDE4 inhibitors having an anti-inflammatory effect.
  • PDE4 inhibitor having an anti-inflammatory effect is roflumilast for example (trade name Daxas ® ), which was approved as a medicament for the treatment of COPD (chronic obstructive pulmonary disease).
  • PDE4 inhibtor is apremilast (Otezla ® ) that was recently approved for the treatment of psoriatic athritis and plaque psoriasis.
  • apremilast Otezla ®
  • side-effects such as nausea, diarrhoea and headaches are observed, which limit their dose in humans.
  • Undesired side-effects in humans were not only observed with roflumilast and apremilast but also with other PDE4 inhibitors, so that the therapeutic range (therapeutic window) of such medicaments is relatively narrow.
  • PDE4 inhibitors having less severe or fewer side-effects and a better therapeutic window would therefore be desirable.
  • Phosphodiesterase 4 (PDE4) is cAMP-specific and encompasses 4 different subtypes (PDE4A, PDE4B, PDE4C and PDE4D). As is described below, efforts are being made to find subtype-selective PDE4 inhibitors, above all PDE4B-selective inhibitors, that have less severe or no side-effects, thus increasing the therapeutic range for such compounds significantly.
  • PDE4D The inhibition of PDE4D is associated with the occurrence of undesired side-effects, such as for example diarrhoea, vomiting and nausea (see in this regard Mori, F. et al. (2010): The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D, Journal of Chemical Neuroanatomy 40, 36-42; Press, N.J.; Banner K. H (2009): PDE4 inhibitors - A review of the current field, Progress in Medicinal Chemistry 47, 37-74; Robichaud, A. et al.
  • novel substituted indole and indazole compounds that possess the desired inhibiting and PDE4B-selective properties. These indole and indazole compounds are therefore particularly suitable for the treatment of diseases and conditions in which inhibition of the PDE4 enzyme, in particular PDE4B, is advantageous.
  • the compounds according to the present invention do not contain a particular pyrimidine substituent.
  • the first aspect of the invention thus relates to a compound characterized in that the compound has the general formula (I)
  • A, B and C independently represent CH or N;
  • X 1 represents CH or N
  • X 2 represents CH or N
  • R is selected from
  • Ci-C6-alkyl unsubstituted or mono- or polysubstituted
  • R 2 is selected from H or Ci-C6-alkyl, unsubstituted or mono- or polysubstituted;
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl
  • said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and may be mono- or bicyclic and
  • 3- to 12-membered heterocycloalkyl is unsubstituted or mono- or polysubstituted
  • R 3 is selected from the group consisting of (Ci-Ce)-alkyl, (Ci-C6)-hydroxyalkyl, (C3-C6)-cycloalkyl and
  • G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said 5- or 6- membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z, wherein
  • Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N0 2 , Ci-Ce-alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, (Ci-C 6 )-hydroxyalkyl, (Ci-C 6 )-cyanoalkyl, Ci-C 6 - alkoxy, (Ci-C 6 )-thioalkyl, (Ci-C 6 )-haloalkyl, (Ci-C 6 -alkoxy)-(Ci-C 6 -alkylenyl), (Ci-C 6 -alkoxy)-Ci-C 6 - alkoxy, (Ci-C6)-thiohaloalkyl, (Ci-C6)-haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalky
  • single stereoisomer in the sense of the present invention preferably means an individual enantiomer or diastereomer.
  • mixture of stereoisomers means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
  • physiologically acceptable salt in the sense of this invention preferably comprises a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base.
  • a physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid or one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid or with at least one inorganic or organic base respectively which is physiologically acceptable - in particular when used in human beings and/or other mammals.
  • physiologically acceptable solvate in the sense of this invention preferably comprises an adduct of one compound according to the present invention and/or a physiologically acceptable salt of at least one compound according to the present invention with distinct molecular equivalents of one solvent or more solvents.
  • the invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound.
  • Preferred isotopes are 2 H (deuterium), 3 H (tritium), 3 C and 4 C.
  • Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art.
  • the term "halogen" represents the radicals F, CI, Br and I, preferably the radicals F and CI, particularly preferred F.
  • Ci-C6-alkyl or "(Ci-C6)-alkyl” is understood to mean branched and unbranched alkyl groups consisting of 1 to 6 carbon atoms.
  • Examples of Ci-C6-alkyl radicals are CH 3 , CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , n-pentyl, 1-methyl- butyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl.
  • Ci-C4-alkyl radicals are preferred, in particular CH 3 , CH 2 CH 3
  • Ci-C6-alkoxy or "(Ci-C6)-alkoxy” is understood to mean branched and unbranched alkoxy groups consisting of 1 to 6 carbon atoms.
  • Examples of Ci-C6-alkoxy radicals are OCH 3 , OCH 2 CH 3 , 0(CH 2 ) 2 CH 3 , OCH(CH 3 ) 2 , 0(CH 2 ) 3 CH 3 , OCH(CH 3 )CH 2 CH 3 , OCH 2 CH(CH 3 ) 2 , OC(CH 3 ) 3 , 0(CH 2 ) 4 CH 3 , 0(CH 2 ) 2 CH(CH 3 ) 2 , OCH 2 CH(CH 3 )CH 2 CH 3 , OCH(CH 3 )(CH 2 ) 2 CH 3 , OC(CH 3 ) 2 CH 2 CH 3 , OCH 2 C(CH 3 ) 3 , 0(CH 2 ) 5 CH 3 , 0(CH 2
  • Ci-C 4 -alkoxy radicals are preferred, in particular OCH 3 , OCH 2 CH 3 , 0(CH 2 ) 2 CH 3 or OCH(CH 3 ) 2 .
  • the term "(Ci-C6)-haloalkyl” is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F.
  • the haloalkyi can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-halo- alkyl radicals are (Ci-C 3 )-haloalkyl radicals, in particular CHF 2 , CH 2 F, CF 3 , CH 2 CH 2 F, CH 2 CHF 2 and CH 2 CF 3 .
  • (Ci-C6)-haloalkoxy is understood to be a Ci-C6-alkoxy in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F.
  • the haloalkoxy radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-haloalkoxy radicals are (Ci-C 3 )-haloalkoxy radicals, in particular OCHF 2 , OCH 2 F, OCF 3 , OCF 2 CH 3 , OCH 2 CH 2 F, OCH 2 CHF 2 and OCH 2 CF 3 .
  • (Ci-C6)-hydroxyalkyl is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a hydroxyl group.
  • the hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-hydroxyalkyl radicals are (C1-G3)- hydroxyalkyl radicals, in particular CH 2 OH, CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and CH 2 CH(OH)CH 2 OH.
  • (Ci-C6)-cyanoalkyl is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a cyano group.
  • the hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-Ce)-cyanoalkyl radicals are (C1-G3)- cyanoalkyl radicals, in particular CH 2 CN, CH 2 CH 2 CN and CH 2 CH 2 CH 2 CN.
  • (Ci-C6)-thioalkyl is understood to mean branched and unbranched thioalkyl groups consisting of 1 to 6 carbon atoms.
  • Examples of (Ci-C6)-thioalkyl radicals are SCh , SCH2CH3, S(CH 2 ) 2 CH3, SCH(CH 3 ) 2 , S(CH 2 ) 3 CH3, SCH(CH 3 )CH 2 CH 3 , SCH 2 CH(CH 3 ) 2 , SC(CH 3 ) 3 , S(CH 2 ) 4 CH 3 , S(CH 2 ) 2 CH(CH 3 ) 2 , SCH 2 CH(CH 3 )CH 2 CH 3 , SCH(CH 3 )(CH 2 ) 2 CH 3 , SC(CH 3 ) 2 CH 2 CH 3 , SCH 2 C(CH 3 ) 3 , S(CH 2 ) 5 CH 3 , S(CH 2 ) 3 CH(CH 3 ) 2 , S(CH 2 ) 2 CH(CH 3 )CH 2 CH 3 , SCH 2 CH(CH 3 )(CH 2 ) 2 CH 3 , SCH 2 C(CH 3 ) 2 CH 2 CH 3 ,
  • (Ci-C 4 )-thioalkyl radicals are preferred, in particular SCH 3 , SCH 2 CH 3 , SCH 2 CH 2 CH 3 or SCH(CH 3 ) 2 .
  • the term "(Ci-C6)-thiohaloalkyl” is understood to be a (Ci-C6)-thioalkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F.
  • the thiohaloalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted.
  • Preferred (Ci-C6)-thiohaloalkyl radicals are (Ci-C3)-thiohaloalkyl radicals, in particular SCHF 2 , SCH 2 F, SCF3, SCF 2 CH 3 , SCH 2 CH 2 F, SCH 2 CHF 2 and SCH 2 CF 3 .
  • Ci C3-alkylen or “(Ci-C3)-alkylen”and “Ci C6-alkylen” or “(Ci-C6)-alkylen” are understood to be an acyclic saturated hydrocarbon radicals having 1 , 2 or 3 carbon atoms or 1 , 2, 3, 4, 5 or 6 carbon atoms, which can be branched or unbranched and unsubstituted or substituted once or several times, for example 2, 3, 4 or 5 times, by identical or different substituents and which link a corresponding moiety to the main structure.
  • Alkylene groups can preferably be chosen from the group consisting of CH 2 , CH 2 CH 2 , CH(CH 3 ), CH 2 CH 2 CH 2 , CH(CH 3 )CH 2 , C(CH 3 ) 2 , CH(CH 2 CH 3 ).
  • the alkylene groups can particularly preferably be chosen from the group consisting of CH 2 , CH 2 CH 2 and CH 2 CH 2 CH 2 .
  • the term "C 2 -C6-alkenyl” is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one double bond.
  • C 2 -C6-alkenyls are ethenyl (also referred to as vinyl), prop-1-enyl, prop-2-enyl (also referred to as allyl), but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl and hex-1-enyl.
  • the designation C 2 -C6-alkenyl includes all possible isomers, i.e. structural isomers (constitutional isomers) and stereoisomers ((Z) and (E) isomers).
  • C 2 -C6-alkinyl is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one triple bond. Examples of C 2 -C6-alkinyls are ethinyl.
  • C3C6-cycloalkyl or "(C3-C6)-cycloalkyl” denotes cyclic saturated hydrocarbons having 3, 4, 5 or 6 carbon atoms respectively, which can be unsubstituted or substituted once or several times, for example by 2, 3, 4 or 5 identical or different radicals, on one or more ring members.
  • C3-6-cycloalkyl can preferably be chosen from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • 3- to 7-membered heterocycloalkyi and "3- to 12-membered heterocycloalkyi” are understood to mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7, or having 3 to 12, i.e.
  • the heterocycloalkyl residues may be mono- or bi- cyclic.
  • the term "5- or 6-membered heteroaryl” is understood to represent a 5- or 6- membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each preferably selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted, including the formation of N-oxides; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position of the heteroaryl.
  • the binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise.
  • the heteroaryl may be condensed with a 4-, 5-, 6- or 7- membered ring, being carbocyclic or heterocyclic, wherei the heteroatoms of the heterocyclic ring are each preferably selected independently of one another from the group S, N and O, and wherein said condensed ring may be saturated, partially unsaturated or aromatic and may be unsubstituted or mono- or polysubstituted; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position.
  • heteroaryl moieties are benzofuranyl, benzoimidazolyl, benzo-thienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazo-thiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl,
  • the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF 2 , CH 2 F, OCF3, OH, CN, (Ci-C 6 )-alkyl, (Ci-C 6 )-hydroxyalkyl, (Ci-C 6 )-alkoxy, (Ci-C 6 )-hydroxyalkoxy, C 3 -C 6 -cyclo- alkyl, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl)CO(Ci-C 6 -alkyl), NHCO(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -alkyl)- CO(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -alkyl) 2 , NH(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -alkyl)(Ci-C 6 -alkyl
  • substituents may be present either on different or on the same atoms or at different places, and may include identical or different substituents.
  • the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF 2 , CH 2 F, OCF3, OH, CN, (Ci-C 6 )-alkyl, (Ci-C 6 )-hydroxyalkyl, (Ci-C 6 )-alkoxy, Cs-Ce-cycloalkyl, NH 2 , NH(Ci-C 6 - alkyl), N(Ci-C 6 -alkyl) 2 , NHCO(Ci-C 6 -alkyl), NH-CONH(Ci-C 6 -alkyl), NHCON(Ci-C 6 -alkyl) 2 , NHS(0) 2 (Ci- Ce-alkyl), CONH2, CONH(Ci-C 6 -alkyl), CON(Ci-C 6 -alkyl) 2 , S(0)(Ci-C 6 -alkyl) and S(0) 2 (Ci-C 6 -alkyl,
  • residues containing two or more residues of the same type such as Ci-C6-alkyl in N(Ci-C6-alkyl) 2
  • the two or more residues may be identical or different from each other. If the residues may be substituted, then it is understood that each residue may be independently substituted.
  • N(Ci-C6-alkyl) 2 wherein Ci-C6-alkyl may be unsubstituted or substituted by OH, encompasses for example inter alia N(CH 3 ) 2 , N(CH 3 )(CH 2 CH 3 ), N(CH 2 CH 3 ) 2 , N(CH 3 )(CH 2 CH 2 OH) and N(CH 2 CH 2 OH) 2 .
  • the compound of formula (I) is characterized in that A, B and C represent CH or
  • a and B represent CH and C represents N or
  • a and C represent CH and B represents N or
  • B and C represent CH and A represents N.
  • the compound of formula (I) is characterized in that each of A and B represents CH and C represents N or CH.
  • the compound of formula (I) is characterized in that
  • X 1 is N and X 2 is N or
  • X 1 is N and X 2 is CH or
  • X 1 is CH and X 2 is N.
  • the compound of formula (I) is characterized in that at least 2 of C, X 1 and X 2 represent N.
  • the compound of formula (I) is characterized in that X 1 is N and X 2 is N.
  • the compound of formula (I) is characterized in that R 3 is selected from the group consisting of methyl, ethyl, propyl, i-propyl, n-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, SOCH 3 and S0 2 CH 3 ,
  • R 3 is selected from the group consisting of methyl, ethyl, hydroxymethyl, 1 -hydroxyethyl, 2- hydroxypropan-2-yl, cyclopropyl, SOCH 3 and S0 2 CH 3 . More preferably, R 3 is selected from the group consisting of ethyl, cyclopropyl, SOCH3 and SO2CH3.
  • the compound of formula (I) is characterized in that G is one of the following groups G1 to G44
  • R 2 is selected from the group consisting of H, Ch or CH2CH3;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OCHF2, OH, CN, Ci-Ce-alkyl, Ci-Ce-hydroxyalkyl, Ci-Ce-alkoxy, Cs-Ce-cycloalkyl, 3- to 7- membered heterocycloalkyl, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , NHCO(Ci-C 6 -alkyl), NHCONH(Ci-C 6 - alkyl), NHCON(Ci-C 6 -alkyl) 2 , (Ci-C 6 -alkylen)NH 2 , (Ci-C 6 -alkylen)NH(Ci-C 6 -alkyl), (Ci-C 6 -alkylen)N(Ci-C 6 - alkyl) 2
  • Ci-C6-alkyl, said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is un- substituted or mono- or polysubstituted.
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44, wherein
  • R 2 is selected from the group consisting of H, CH3 or CH2CH3;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2,
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44, wherein
  • R 2 is selected from the group consisting of H, CH3 or CH2CH3;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2CN, SOCH3, SO2CH3,
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH2CH 2 NH(CH 3 ), C(CH 3 )2NH(CH 3 ) 2
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44, wherein
  • R 2 is selected from the group consisting of H, CH3 or CH2CH3;
  • k at each occurrence is 0, 1 , 2, 3 or 4;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH 2
  • G is selected from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of
  • Ci-Ce-alkyl (Ci-C 6 )-hydroxyalkyl, Ci-Ce-alkoxy, Cs-Ce-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , NHCO(Ci-C 6 -alkyl), CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), NH-S(0) 2 (Ci-C 6 -alkyl), CONH2, CONH(Ci-C 6 - alkyl), CO-N(Ci-C 6 -alkyl) 2 , S(0) 2 NH 2 , S(0) 2 NH(Ci-C6-alkyl), S(0)2N(
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH 2
  • G is selected from G1 or G2, wherein k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of
  • Ci-Ce-alkyl (Ci-C 6 )-hydroxyalkyl, Ci-Ce-alkoxy, Cs-Ce-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , NHCO(Ci-C 6 -alkyl), CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), NH-S(0) 2 (Ci-C 6 -alkyl), CONH 2 , CONH(Ci-C 6 - alkyl), CO-N(Ci-C 6 -alkyl) 2 , S(0) 2 NH 2 , S(0) 2 NH(C
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCHs, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCHs, CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3 ) 2 NH 2 , CH(CH 3
  • k at each occurrence is 0, 1 or 2;
  • Z A is H or F
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF 2 , CH 2 F, OCF 3 , OH, OCH 3 , OC 2 H 5 , OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH 2 , CONHCHs, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCHs, CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 ,
  • the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
  • k at each occurrence is 0, 1 or 2;
  • Z A is H or F
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2,
  • the compound of formula (I) is characterized in that
  • R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and
  • R 2 is selected from H or Ci-C6-alkyl
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, Ci-C6-alkoxy and C3-C6-cycloalkyl;
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
  • heterocycloalkyl wherein said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • the compound of formula (I) is
  • R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and
  • R 2 is selected from H or Ci-C6-alkyl
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH , Ci-C6-alkoxy and C3-C6-cycloalkyl;
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
  • said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • R denotes Ci-6-alkyl
  • R 6 is H, (Ci-Ce-alkyl), (Ci-C 6 )-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, Cs-Ce-cycloalkyl, CO(Ci-C 6 -alkyl) or S0 2 (Ci-C6-alkyl);
  • m 0, 1 , 2, 3, 4 or 5
  • X 3 at each occurrence is independently selected from the group consisting of
  • OH 0, CN , F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , Ci-Ce-alkyl, Ci-Ce-alkoxy, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , NHCO(Ci-C 6 -alkyl), C0 2 H , COO(Ci-C 6 -alkyl), CONH 2 , CONH(Ci-C 6 -alkyl) and CON(Ci-C 6 -alkyl) 2 ,
  • R 2 is selected from H , Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl or (Ci-C6-alkoxy)-Ci-C6-alkyl, preferably R 2 is selected from H or CH 3 .
  • R 2 is selected from H, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl or (Ci-C6-alkoxy)-Ci-C6-alkyl,
  • R 2 is selected from H or Ch . Still preferably,
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocydoalkyi
  • R 5 is selected from the group consisting of H , Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, C3-C6- cycloalkyl, CO(Ci-Ce-alkyl) and S0 2 -(Ci-C 6 )-alkyl;
  • p is 0, 1 , 2, 3, 4 or 5;
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl
  • 3- to 12-membered heterocycloalkyl denotes one of the following groups Q'1 to Q'65:
  • the 3- to 12-membered heterocycloalkyi is selected from the qroup consisting of Q'8, Q'23, Q'32, Q'40 and Q'44.
  • the compound of formula (I) is characterized in that
  • R is selected from OH , CN , Ci-Ce-alkyl, NH 2 , N H(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3- to
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , Ci-C6-alkoxy, (Ci-Ce- alkoxy)-Ci-C 6 -alkoxy, (hydroxy)-Ci-C 6 -alkoxy, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , N H(Ci-Ce- hydroxyalkyl), N(Ci-C 6 -alkyl)(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -hydroxyalkyl) 2 , NHCO(Ci-C 6 -alkyl), N(Ci-Ce-alk l)CO(Ci-Ce-alkyl), NHCO(Ci-C 6 -hydroxyalkyl), N(Ci-Ce-al
  • said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • the compound of formula (I) is characterized in that
  • R is selected from OH , CN , Ci-Ce-alkyl, NH 2 , N H(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , NH 2 , Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl;
  • said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • the compound of formula (I) is characterized in that
  • R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , Ci-C6-alkoxy, (C1-C6- alkoxy)-Ci-C 6 -alkoxy, (hydroxy)-Ci-C 6 -alkoxy, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , N H(Ci-C 6 - hydroxyalkyl), N(Ci-C 6 -alkyl)(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -hydroxyalkyl) 2 , NHCO(Ci-C 6 -alkyl),
  • said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • R , R 3 , L and G are defined as before.
  • the compound of formula (I) is a compound according to formula (la), (lb), (lc) or (Id), wherein
  • R and R 2 together with the nitrogen atom to which they are attached form one of the following heterocycles Q19, Q23 or Q26,
  • R 5 is H, CHs, CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , cydopropyl, C(0)CH 3 , C(0)CH 2 CH 3 , C(0)CH 2 CH 2 CH3, C(0)CH(CH 3 ) 2 , C(0)-cyclopropyl, CH2CH2CN, CH2CH2OH or CH2CH2OCH3;
  • p is 0, 1 , 2 or 3;
  • each X 6 idependently represents H, CH 3 , CH2CH3, OH, OCH 3 , CH2OH, CH2CH2OH or CH2CH2OCH3.
  • R is CH2CH 2 NH(CH 3 ), CH2CH 2 N(CH 3 )2, CH2CH2CH2OH, CH 2 CH(CH 3 )OH, CH(CH 3 )CH 2 OH, CH 2 C(0)N(CH 3 )2, CH 2 C(0)NH(CH 3 ) or CH 2 C(0)NH 2 and
  • R 2 is H or CH 3 , preferably R 2 is CH 3 ;
  • R 3 is selected from the group consisting of CH 3 , CH2CH3, CH2OH, CH2CH2OH, 2-hydroxypropan-2-yl, cydopropyl, SOCH3 and SO2CH3;
  • G is selected from the group consisting of G1 to G44 as defined above,
  • R 2 at each occurrence is independently selected from the group consisting of H, CH3 and CH2CH3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH3), C(CH 3 )2NH
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH
  • the compound of formula (I) is a compound according to formula (la), (lb), (lc) or (Id), wherein
  • R is selected from the group consisting of CH 3 , CH2CH3, (CH 2 )2CH 3 , CH(CH 3 )2, (CH 2 )3CH 3 ,
  • R 3 is selected from the group consisting of CH 3 , CH2CH3, CH2OH, CH2CH2OH, 2-hydroxypropan-2-yl, cydopropyl, SOCH3 and SO2CH3; and G is selected from the group consisting of G1 to G44 as defined above,
  • R 2 at each occurrence is independently selected from the group consisting of H, Ch and CH2CH3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH3), C(CH 3 )2NH(CH 3 ), CH(CH 3
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH
  • the compound according to general formula (I) is selected from one of formula (la), (lb), (lc) or (Id), wherein
  • G is select from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH3), C(CH 3 )2NH
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH2, CH(CH 3 )NH 2
  • the compound according to formula (la), (lb), (lc) or (Id) is characterized in that
  • G is selected from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH 2 ) 2 CH3, CH(CH 3 ) 2 , (CH 2 ) 3 CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 ,
  • the compound according to general formula (I) has the general formula (la), (lb), (lc) or (Id), wherein
  • R and R 2 together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is Q19 and p is 0
  • R is CH 3 , CH2CH3, CH2CH2OH, CH2CH 2 NH(CH 3 ), CH2CH 2 N(CH 3 )2, CH2CH2CH2OH, CH 2 CH(CH 3 )OH, CH(CH 3 )CH 2 OH, CH 2 C(0)N(CH 3 )2 or CH 2 C(0)NH 2 and
  • R 2 is CH 3 ;
  • R 3 is CH 3 , CH2CH3, cyclopropyl, SOCH3 or SO2CH3;
  • G is select from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH2CH 2 NH(CH 3 ), C(CH 3 ) 2 NH(CH 3 ), CH
  • the compound according to general formula (I) is selected from one of formula (la), (lb), (lc) or (Id), wherein
  • R is selected from the group consisting of CH3 and CH2CH3;
  • R 3 is selected from the group consisting of CH3, CH2CH3, cyclopropyl, SOCH3 and SO2CH3; and G is select from G1 or G2, wherein
  • k at each occurrence is 0, 1 , 2 or 3;
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , CONH2, CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH2, CH(CH 3 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH3), C(CH 3 )2NH(CH 3 ), CH(CH 3
  • the invention relates to a compound selected from the group consisting of
  • the compounds according to the first aspect of the invention are suitable for the treatment of various diseases or conditions in which inhibition of the PDE4 enzyme is advantageous.
  • One of the advantages of the compounds according to the first aspect of the invention is that they are selective PDE4B inhibitors.
  • PDE4D is not inhibited or is only partly inhibited, and hence the use of such selective PDE4B inhibitors gives rise to no side-effects or to significantly reduced side-effects, such as emesis and nausea, in particular indisposition, vomiting and sickness.
  • the therapeutic range of the compounds according to the invention is therefore advantageous.
  • a second aspect of the invention is a pharmaceutical composition (medicament) containing at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id).
  • a third aspect of the invention is a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id) for the use as a medicament, in particular for the treatment of conditions or diseases that can be treated by inhibition of the PDE4 enzyme, in particular the PDE4B enzyme.
  • a fourth aspect of the invention is a compound according to the first aspect of the invention, in particular of the general structure of formulae (I), (la), (lb), (Ic) or (Id) for the use as a medicament for the treatment of inflammatory diseases of the joints; and/or inflammatory diseases of the skin; and/or inflammatory diseases of the eyes; gastrointestinal diseases and complaints; inflammatory diseases of the internal organs; and/or hyperplastic diseases; respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract; diseases of the fibrotic spectrum; cancers; metabolic diseases; psychological disorders; and/or diseases of the peripheral or central nervous system.
  • the invention therefore also provides a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) for the use as a medicament for the treatment of inflammatory diseases of the joints, the skin, of respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract,of metabolic diseases and/or cardiovascular diseases.
  • a fifth aspect of the invention is the use of a compound according to the first aspect of the invention, in particular according to the general structure of (I), (la), (lb), (lc) or (Id) for the preparation of a
  • a sixth aspect of the invention is a method for the treatment of the diseases and conditions according to the fourth aspect of the invention in a human, which is characterised in that a therapeutically effective amount of at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) is administered.
  • the amount of active ingredient to be administered to the person or patient varies and is dependent on the patient's weight, age and medical history and on the type of administration, the indication and the severity of the illness.
  • the medicaments, drugs and pharmaceutical compositions according to the invention can take the form of and be administered as liquid, semi-solid or solid dosage forms and as for example injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pastilles, pellets, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols and contain, in addition to at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) according to the pharmaceutical form and depending on the administration route, pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active substances, dyes, preservatives, disintegrants, slip additives, lubricants, flavourings and/or binders.
  • pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active
  • auxiliary substances and the amounts thereof depends on whether the medicament is administered by oral, subcutaneous, parenteral, intravenous, vaginal, pulmonary, intraperitoneal, transdermal, intramuscular, nasal, buccal or rectal means or locally, for example on the skin, mucous membranes and eyes, and whether the medicament is designed to deliver the active ingredient by immediate, sustained, delayed or extended release.
  • Preparation of the medicaments and pharmaceutical compositions according to the invention takes place using agents, equipment, methods and procedures that are well-known from the prior art, such as "Remington's Pharmaceutical Sciences", Ed . A.R.
  • the compounds according to the invention can be synthesized according to general knowledge in the field of organic chemistry and in a manner as described here (cf. reaction schemes below) or analogously.
  • the reaction conditions in the synthesis routes described herein are known to the skilled person and are for some cases exemplified in the synthesis examples herein.
  • the necessary starting materials are either commercially available or can also be obtained according to general knowledge in the field of organic chemistry.
  • (AtaPhos)2PdCl2 bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll);
  • APCI atmospheric pressure chemical ionization; calc.
  • Mass spectrometry conditions Instrument: API 2000 LC/MS/MS from Applied Biosystem; Ionization technique: ESI using API source; Declustering Potential: 10-70 V depending on the ionization of compound; Mass range: 100-800 amu; Scan type: Q1 ; Polarity: + Ve; Ion Source: Turbo spray; Ion spray voltage: +5500 for +Ve mode; Mass Source temperature: 200°C
  • Mobile phase A 0.05% formic acid in water
  • B acetonitrile
  • Mass spectrometry conditions Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer) Ionization technique: ESI; Mass range: 100 to 800 Da; Polarity: + Ve
  • Mass spectrometry conditions Instrument: API 2000 LC/MS/MS from Applied Biosystem; Ionization technique: ESI using API source; Declustering Potential: 10-70 V depending on the ionization of compound; Mass range: 100-800 amu; Scan type: Q1 ; Polarity: + Ve; Ion Source: Turbo spray; Ion spray voltage: +5500 for +Ve mode; Mass Source temperature: 200°C
  • Mass spectrometry conditions Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer); ionization technique: ESI; mass range: 100 to 800 Da; polarity: positive ions.
  • the compounds according to formula (I) may be prepared according to general reaction schemes 01 to 07.
  • R 3 (Ci-C6)-alkyl, (C3-C6)-cycloalkyl, (Ci-Ce)-thioalkyl, more preferably ethyl, cyclopropyl, SMe. eaction scheme 02
  • a compound of the general formula IV can be also directly converted into a compound of formula VI analogously to the general reaction scheme 4.
  • R x is (Ci-Ce) alkyl, preferably methyl.
  • a compound of the general formula XVI can be also directly converted into a compound of formula XVIII analogously to the general reaction scheme 4.
  • Example 1 (3-Ethyl-1-(4-(2-hvdroxypropan-2-yl)-[2,3'-bipyridinl-6'-yl)-1 H-indazol-6-yl)(morpholino) methanone
  • the racemate was prepared in three steps from compound 5a analogously to synthesis example 3 (yield: 0.3 g, white solid).
  • the two enantiomers were obtained from the racemic mixture through chiral HPLC utilizing a chiral pack-IA column (250 x 21.0 mm, 5 ⁇ ) and hexane/EtOAc/ethanol/diethylamine (50/25/25/0.1 ) as mobile phase.
  • Flow rate was 21 .0 ml/min.
  • the racemate was obtained from compound 3a analogously to synthesis example 3 (yield: 0.25 g, white solid). Subsequent chiral preparative SFC HPLC of the racemate afforded the two enantiomers (column: YMC Chiral Amylose-C 250 x 4.6 mm, 5 ⁇ ; mobile phase: 45% C0 2 / 55% MeOH with 0.5% isopropylamine; flow rate: 25.0 ml/min; temperature: 35°C, column pressure: 100 bar).
  • Example 1 1-(5-(2-Fluorophenyl)pyridin-2-yl)-N-methyl-N-(2-(methylamino)ethyl)-3-(methylsulfinyl)-1 H- indole-6-carboxamide
  • Dimethylsulfane (9.1 g, 14.7 mmol, 1.1 eq) was added drop wise at 0°C to a stirred suspension of N- chlorosuccinamide (19.5 g, 14.7 mmol, 1.1 eq) in DCM (50 mL).
  • a solution of methyl 1 H-indole-6- carboxylate (23.0 g, 13.3 mmol, 1.0 eq) in DCM (50 mL) was added drop wise at -20°C and the mixture was stirred at RT for 1 h. The solvent was evaporated and the residue was dissolved in xylene (50 mL) and refluxed for 16 h.
  • Me3SiOK (1.4 g, 1 1.02 mmol, 5.0 eq) was added to a solution of compound 1 1d (900 mg, 2.205 mmol, 1.0 eq) in THF/H20 (3:1 , 25 mL) and the mixture was stirred for 2 days at RT. The solution was brought to pH ⁇ 6 with 10% citric acid solution and the precipitating solid was filtered off. The filter was washed with water and dried. White solid. Yield: 0.50 g (57%).
  • ⁇ , ⁇ -Dimethyl-hydroxylamine hydrochloride (19 g, 0.195 mol), EDCxHCI (27.4 g, 0.143 mol) and HOBT (19.32 g, 0.143 mol) were added at 0°C to a stirred suspension of 2,6-dichloro-nicotinic acid (25 g, 0.13 mol) in DCM (450 ml).
  • the reaction mixture was stirred for 15 min, TEA (72 ml, 0.52 mol) was added drop wise at 0°C, and stirring was continued at RT for 16 h.
  • the reaction mixture was washed successively with water, saturated NaHCCh solution, saturated NH4CI solution and brine, dried over Na2S04 and concentrated.
  • PdCl2(dppf) (30 mg, 0.036 mmol) was added to a suspension of compound 12f (300 mg, 0.721 1 mmol), bis(pinacolato)diboron (293 mg, 1.1538 mmol) and KOAc (213 mg, 2.1634 mmol) in dioxane (10 ml) stirred under an inert atmosphere. The reaction mixture was heated for 5 h at 1 10°C and then cooled to 90°C.
  • PdCl2(dppf) 54 mg, 0.066 was added to a suspension of compound 19e (0.5 g, 1.33 mmol), bis(pinacolato)diboron (0.68 g, 2.67 mmol) and KOAc (0.39 g, 4.01 mmol) in dioxane (20 mL) stirred under Ar. The reaction mixture was heated at 1 10°C for 3 h and then cooled to RT.
  • Oxone (0.19 g, 0.31 mmol) was added portion wise at RT to a solution of compound 19f (0.45 g, 1.04 mmol) in THF (32 mL) and water (10 mL). The reaction mixture was stirred at RT for 1 h, quenched with sat. Na2S03 solution and extracted with EtOAc (3x 100 mL). The combined organic layers were washed with sat. NaHCCh solution, dried over Na2S04 and concentrated. The remnat was purified by combi flash column chromatography [silica; DCM with 0-15% MeOH]. White solid. Yield: 0.25 g (53%).
  • racemic sulfoxide thus obtained was submitted to preperative chiral SFC HPLC to afford the single enantiomers (column: YMC Chiral Amylose-C 250 x 20 mm; mobile phase: 50% C0 2 / 50% MeOH with 0.5% isopropylamine; flow rate: 20.0 g/min; temperature: 35°C, column pressure: 100 bar).
  • the effects of the compounds on the activity of the human PDE4B1 was quantified by measuring the production of 5 ⁇ from cAMP using a human recombinant enzyme expressed in Sf9 cells and the LANCE® Ultra cAMP kit, a TR-FRET detection method from PerkinElmer.
  • the human PDE4B1 enzyme was purchased from SignalChem Lifesciences (Catalog# P92-31 BG).
  • test compound reference compound or water (control) was mixed with the enzyme (0.96 U) in a reaction buffer containing 50 mM Tris-HCI, 50 mM MgCI ⁇ and 5 mM DTT (pH 8.5). Thereafter, the reaction was initiated by addition of 500 nM cAMP (substrate) and the mixture was incubated for 30 min at rt. For control basal measurements, the enzyme was omitted from the reaction mixture. After 30 min, the reaction was stopped and diluted by a factor of 100 with the reaction buffer supplemented with 500 ⁇ IBMX.
  • the fluorescence donor Europium chelate-labeled cAMP
  • the fluorescence acceptor anti- cAMP antibody labeled with the ULightTM dye
  • 500 ⁇ IBMX 500 ⁇ IBMX
  • Aenri 620 nm
  • Aenri 665 nm using a microplate reader (PHERAstar, BMG).
  • the enzyme activity was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio) multiplied by 10000.
  • the results were expressed as percent inhibition of the control enzyme activity.

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Abstract

The invention relates to novel indole and indazole compounds characterized in that the compound has general formula (I), in which the chemical groupings, substituents, variables and indices are as defined in the description, and to their use as medicaments, in particular as medicaments for the treatment of conditions and diseases that can be treated by inhibition of the PDE4 enzyme.

Description

Novel substituted Indole and Indazole compounds as Phosphodiesterase Inhibitors
FIELD OF THE INVENTION
The present invention relates to novel substituted indole and indazole compounds that are useful as medicaments. This invention also relates to uses of the compounds to make medicaments and treatments comprising the administration of the compounds to humans in need of the treatments. This invention also relates to the preparation of said novel compounds. Moreover this invention relates to pharmaceutical compositions and kits comprising the compounds. BACKGROUND OF THE INVENTION
Phosphodiesterases (abbreviated as PDEs), or more accurately 3',5'-cyclonucleotide phosphor- diesterases, are enzymes that catalyse the hydrolysis of the second messengers cAMP (cyclic adenosine monophosphate) and cGMP (cyclic guanosine monophosphate) to 5'-AMP (5'-adenosine mono- phosphate)-and 5'-GMP (5'-guanosine monophosphate). Phosphodiesterases are a group of enzymes encompassing 1 1 gene families (PDE1-1 1 ), which differ inter alia through their affinity to cAMP and cGMP. Inhibition of phosphodiesterases thus represents a mechanism for modulating cellular processes and can be used to alleviate or cure disease conditions. Inhibitors of specific PDEs are known.
The discovery that the second messenger cAMP plays an important role in many inflammatory processes and that PDE4 is strongly expressed in cells that control inflammation processes (see inter alia Schudt, C. et al. (1995). PDE isoenzymes as targets for anti-asthma drugs. European Respiratory Journal 8, 1 179- 1 183), has led to the development of PDE4 inhibitors having an anti-inflammatory effect. One such PDE4 inhibitor having an anti-inflammatory effect is roflumilast for example (trade name Daxas®), which was approved as a medicament for the treatment of COPD (chronic obstructive pulmonary disease). Another PDE4 inhibtor is apremilast (Otezla®) that was recently approved for the treatment of psoriatic athritis and plaque psoriasis. In addition to the desired anti-inflammatory effect of roflumilast and apremilast, however, side-effects such as nausea, diarrhoea and headaches are observed, which limit their dose in humans. Undesired side-effects in humans were not only observed with roflumilast and apremilast but also with other PDE4 inhibitors, so that the therapeutic range (therapeutic window) of such medicaments is relatively narrow. The provision of PDE4 inhibitors having less severe or fewer side-effects and a better therapeutic window would therefore be desirable. Phosphodiesterase 4 (PDE4) is cAMP-specific and encompasses 4 different subtypes (PDE4A, PDE4B, PDE4C and PDE4D). As is described below, efforts are being made to find subtype-selective PDE4 inhibitors, above all PDE4B-selective inhibitors, that have less severe or no side-effects, thus increasing the therapeutic range for such compounds significantly.
The inhibition of PDE4D is associated with the occurrence of undesired side-effects, such as for example diarrhoea, vomiting and nausea (see in this regard Mori, F. et al. (2010): The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D, Journal of Chemical Neuroanatomy 40, 36-42; Press, N.J.; Banner K. H (2009): PDE4 inhibitors - A review of the current field, Progress in Medicinal Chemistry 47, 37-74; Robichaud, A. et al. (2002): Deletion of PDE4D in mice shortens a2-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis, The Journal of Clinical Investigation 110, 1045-52; Lee et al., (2007): Dynamic regulation of CFTR by competitive interactions of molecular adaptors, Journal of Biological Chemistry 282, 10414-10422; Giembycz, M.A. (2002): 4D or not 4D - the emetogenic basis of PDE4 inhibitors uncovered?, Trends in Pharmacological Sciences 23, 548). Several compounds exhibiting PDE4B selectivity have been disclosed (Naganuma et al. US2006/0293343; Naganuma et al. Bioorg. Med. Chem. Lett. 19 (2009) 3174-3176; Goto et al. Bioorg. Med. Chem. Lett. 24 (2014) 893-899; Hagen et al. Bioorg. Med. Chem. Lett. 24 (2014) 4031-4034; Chappie et al. US 2014/0235612). Indole and indazole compounds as inhibitors of PDE4B are known from WO 2016/008593 A1 , WO 2016/008592 A1 and WO 2016/008590 A1. These compounds are characterized by a specific pyrimidine substituent.
Based on the above, there is a need for compounds (active ingredients) that are preferably PDE4B- selective (which means that with a given amount of active ingredient inhibit PDE4B but without inhibiting or only weakly inhibiting the PDE4D subtype). The advantage of such a PDE4B selectivity is that various side-effects do not occur or occur only to a small extent and that therefore a greater therapeutic range of the pharmaceutical active ingredient may be obtained. The therapeutic range of a pharmaceutical active ingredient describes the gap between its therapeutic dose and a dose that would lead to a toxic or an undesired effect. The greater the therapeutic range is, the rarer or more unlikely is the occurrence of certain toxic or undesired side-effects and hence the safer and more acceptable the pharmaceutical active ingredient or medicament. The therapeutic range is often also referred to as the therapeutic window or therapeutic index. These names are used synonymously in the present application. SUMMARY OF THE INVENTION
The inventors have now found novel substituted indole and indazole compounds that possess the desired inhibiting and PDE4B-selective properties. These indole and indazole compounds are therefore particularly suitable for the treatment of diseases and conditions in which inhibition of the PDE4 enzyme, in particular PDE4B, is advantageous. In contrast to the compounds known from WO 2016/008593 A1 , WO 2016/008592 A1 and WO 2016/008590 A1 , the compounds according to the present invention do not contain a particular pyrimidine substituent.
The first aspect of the invention thus relates to a compound characterized in that the compound has the general formula (I)
Figure imgf000004_0001
wherein
A, B and C independently represent CH or N;
X1 represents CH or N;
X2 represents CH or N;
L is selected from the group consisting of C(=0)NR2,S(=0), S(=0)2, S(=0)2NR2, P(=0)(R2), O or bond;
R is selected from
Ci-C6-alkyl, unsubstituted or mono- or polysubstituted;
or
C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted;
R2 is selected from H or Ci-C6-alkyl, unsubstituted or mono- or polysubstituted;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl,
wherein said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and may be mono- or bicyclic and
wherein said 3- to 12-membered heterocycloalkyl is unsubstituted or mono- or polysubstituted;
R3 is selected from the group consisting of (Ci-Ce)-alkyl, (Ci-C6)-hydroxyalkyl, (C3-C6)-cycloalkyl and
SOx-(Ci-C6)-alkyl, wherein x is 1 or 2;
G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said 5- or 6- membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z, wherein
Z at each occurcence is independently selected from the group consisting of halogen, OH, CN, SH, N02, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, Ci-C6- alkoxy, (Ci-C6)-thioalkyl, (Ci-C6)-haloalkyl, (Ci-C6-alkoxy)-(Ci-C6-alkylenyl), (Ci-C6-alkoxy)-Ci-C6- alkoxy, (Ci-C6)-thiohaloalkyl, (Ci-C6)-haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkylenyl), 3- to 7-membered heterocycloalkyl, (3- to 7-membered heterocycloalkyl)-(Ci-C3-alkylenyl), said C3-6-cycloalkyl and said 3- to 7-membered heterocycloalkyl being in each case unsubstituted or mono- or polysubstituted, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), NHC02(Ci-C6-alkyl), NHC(0)NH2, NHCONH(Ci-C6-alkyl), NHCON(Ci-C6-alkyl)2, (Ci-C6-alkylen)NH2, (Ci-C6-alkylen)NH(Ci-C6-alkyl), (Ci-C6-alkylen)N(Ci-C6-alkyl)2, (Ci-C6- alkylen)NHCO(Ci-C6-alkyl), (Ci-C6-alkylen)NHC02(Ci-C6-alkyl), (Ci-C6-alkylen)NHC(0)NH2, (C1-O alkylen)NHCONH(Ci-C6-alkyl), (Ci-C6-alkylen)NHCON(Ci-C6-alkyl)2, NH((Ci-C6-alkylen)-C02(Ci-C6- alkyl), NH(Ci-C6-alkylen)-CONH2, NH(Ci-C6-alkylen)-CONH(Ci-C6-alkyl), NH(Ci-C6-alkylen)- CON(Ci-C6-alkyl)2, NHS(0)2OH, NHS(0)2(Ci-C6-alkyl), NHS(0)20(Ci-C6-alkyl), NHS(0)2NH2, NHS(0)2NH(Ci-C6-alkyl), NHS(0)2N(Ci-C6-alkyl)2, NH(Ci-C6-alkylen)-S(0)2OH, NH(Ci-C6-alkylen)-
S(0)2(Ci-C6-alkyl), NH(Ci-C6-alkylen)-S(0)20(Ci-C6-alkyl), NH(Ci-C6-alkylen)-S(0)2NH2, NH(Ci-C6- alkylen)-S(0)2NH(Ci-C6-alkyl), C02H, CO(Ci-C6-alkyl), C02(Ci-C6-alkyl), 0-CO(Ci-C6-alkyl), O- C02(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, OCONH(Ci-C6-alkyl), OCON(Ci- C6-alkyl)2, OS(0)2(Ci-C6-alkyl), OS(0)2OH, OS(0)20(Ci-C6-alkyl), OS(0)2NH2, OS(0)2NH(Ci-C6- alkyl), OS(0)2N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl), S(0)2(Ci-C6-alkyl), S(0)2OH, S(0)20(Ci-C6-alkyl),
S(0)2NH2, S(0)2NH(Ci-C6-alkyl), and S(0)2N(Ci-C6-alkyl)2; optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
DETAILED DESCRIPTION
The term "single stereoisomer" in the sense of the present invention preferably means an individual enantiomer or diastereomer. The term "mixture of stereoisomers" means in the sense of this invention the racemate and mixtures of enantiomers and/or diastereomers in any mixing ratio.
The term "physiologically acceptable salt" in the sense of this invention preferably comprises a salt of at least one compound according to the present invention and at least one physiologically acceptable acid or base. A physiologically acceptable salt of at least one compound according to the present invention and at least one physiologically acceptable acid or one physiologically acceptable base preferably refers in the sense of this invention to a salt of at least one compound according to the present invention with at least one inorganic or organic acid or with at least one inorganic or organic base respectively which is physiologically acceptable - in particular when used in human beings and/or other mammals.
The term "physiologically acceptable solvate" in the sense of this invention preferably comprises an adduct of one compound according to the present invention and/or a physiologically acceptable salt of at least one compound according to the present invention with distinct molecular equivalents of one solvent or more solvents.
The invention also includes isotopic isomers of a compound of the invention, wherein at least one atom of the compound is replaced by an isotope of the respective atom which is different from the naturally predominantly occurring isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are 2H (deuterium), 3H (tritium), 3C and 4C. Isotopic isomers of a compound of the invention can generally be prepared by conventional procedures known to a person skilled in the art. In the context of the present invention, the term "halogen" represents the radicals F, CI, Br and I, preferably the radicals F and CI, particularly preferred F.
Unless otherwise specified, the term "Ci-C6-alkyl" or "(Ci-C6)-alkyl" is understood to mean branched and unbranched alkyl groups consisting of 1 to 6 carbon atoms. Examples of Ci-C6-alkyl radicals are CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, n-pentyl, 1-methyl- butyl, 2-methylbutyl, 3-methylbutyl, 1 ,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, n-hexyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl. Ci-C4-alkyl radicals are preferred, in particular CH3, CH2CH3, (CH2)2CH3 or CH(CH3)2.
Unless otherwise specified, the term "Ci-C6-alkoxy" or "(Ci-C6)-alkoxy" is understood to mean branched and unbranched alkoxy groups consisting of 1 to 6 carbon atoms. Examples of Ci-C6-alkoxy radicals are OCH3, OCH2CH3, 0(CH2)2CH3, OCH(CH3)2, 0(CH2)3CH3, OCH(CH3)CH2CH3, OCH2CH(CH3)2, OC(CH3)3, 0(CH2)4CH3, 0(CH2)2CH(CH3)2, OCH2CH(CH3)CH2CH3, OCH(CH3)(CH2)2CH3, OC(CH3)2CH2CH3, OCH2C(CH3)3, 0(CH2)5CH3, 0(CH2)3CH(CH3)2, 0(CH2)2CH(CH3)CH2CH3, OCH2CH(CH3)(CH2)2CH3, OCH2C(CH3)2CH2CH3, OCH2CH(CH3)(CH2)2CH3, OCH(CH3)(CH2)3CH3, OC(CH3)2(CH2)2CH3,
0(CH2)2C(CH3)3. Ci-C4-alkoxy radicals are preferred, in particular OCH3, OCH2CH3, 0(CH2)2CH3 or OCH(CH3)2. Unless otherwise specified, the term "(Ci-C6)-haloalkyl" is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The haloalkyi can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-C6)-halo- alkyl radicals are (Ci-C3)-haloalkyl radicals, in particular CHF2, CH2F, CF3, CH2CH2F, CH2CHF2 and CH2CF3.
Unless otherwise specified, the term "(Ci-C6)-haloalkoxy" is understood to be a Ci-C6-alkoxy in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The haloalkoxy radicals can be branched or unbranched and optionally mono- or polysubstituted.
Preferred (Ci-C6)-haloalkoxy radicals are (Ci-C3)-haloalkoxy radicals, in particular OCHF2, OCH2F, OCF3, OCF2CH3, OCH2CH2F, OCH2CHF2 and OCH2CF3.
Unless otherwise specified, the term "(Ci-C6)-hydroxyalkyl" is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a hydroxyl group. The hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-C6)-hydroxyalkyl radicals are (C1-G3)- hydroxyalkyl radicals, in particular CH2OH, CH2CH2OH, CH2CH2CH2OH and CH2CH(OH)CH2OH.
Unless otherwise specified, the term "(Ci-C6)-cyanoalkyl" is understood to be a Ci-C6-alkyl in which at least one hydrogen is exchanged for a cyano group. The hydroxyalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-Ce)-cyanoalkyl radicals are (C1-G3)- cyanoalkyl radicals, in particular CH2CN, CH2CH2CN and CH2CH2CH2CN. Unless otherwise specified, the term "(Ci-C6)-thioalkyl" is understood to mean branched and unbranched thioalkyl groups consisting of 1 to 6 carbon atoms. Examples of (Ci-C6)-thioalkyl radicals are SCh , SCH2CH3, S(CH2)2CH3, SCH(CH3)2, S(CH2)3CH3, SCH(CH3)CH2CH3, SCH2CH(CH3)2, SC(CH3)3, S(CH2)4CH3, S(CH2)2CH(CH3)2, SCH2CH(CH3)CH2CH3, SCH(CH3)(CH2)2CH3, SC(CH3)2CH2CH3, SCH2C(CH3)3, S(CH2)5CH3, S(CH2)3CH(CH3)2, S(CH2)2CH(CH3)CH2CH3, SCH2CH(CH3)(CH2)2CH3, SCH2C(CH3)2CH2CH3, SCH2CH(CH3)(CH2)2CH3, SCH(CH3)(CH2)3CH3, SC(CH3)2(CH2)2CH3,
S(CH2)2C(CH3)3. (Ci-C4)-thioalkyl radicals are preferred, in particular SCH3, SCH2CH3, SCH2CH2CH3 or SCH(CH3)2. Unless otherwise specified, the term "(Ci-C6)-thiohaloalkyl" is understood to be a (Ci-C6)-thioalkyl in which at least one hydrogen is exchanged for a halogen atom, preferably for F or CI, particularly preferably for F. The thiohaloalkyl radicals can be branched or unbranched and optionally mono- or polysubstituted. Preferred (Ci-C6)-thiohaloalkyl radicals are (Ci-C3)-thiohaloalkyl radicals, in particular SCHF2, SCH2F, SCF3, SCF2CH3, SCH2CH2F, SCH2CHF2 and SCH2CF3.
In the context of the present invention, the terms "Ci C3-alkylen" or "(Ci-C3)-alkylen"and "Ci C6-alkylen" or "(Ci-C6)-alkylen" are understood to be an acyclic saturated hydrocarbon radicals having 1 , 2 or 3 carbon atoms or 1 , 2, 3, 4, 5 or 6 carbon atoms, which can be branched or unbranched and unsubstituted or substituted once or several times, for example 2, 3, 4 or 5 times, by identical or different substituents and which link a corresponding moiety to the main structure. Alkylene groups can preferably be chosen from the group consisting of CH2, CH2CH2, CH(CH3), CH2CH2CH2, CH(CH3)CH2, C(CH3)2, CH(CH2CH3). The alkylene groups can particularly preferably be chosen from the group consisting of CH2, CH2CH2 and CH2CH2CH2. Unless otherwise specified, the term "C2-C6-alkenyl" is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one double bond.
Examples of C2-C6-alkenyls are ethenyl (also referred to as vinyl), prop-1-enyl, prop-2-enyl (also referred to as allyl), but-1-enyl, but-2-enyl, but-3-enyl, pent-1-enyl and hex-1-enyl. The designation C2-C6-alkenyl includes all possible isomers, i.e. structural isomers (constitutional isomers) and stereoisomers ((Z) and (E) isomers). Unless otherwise specified, the term "C2-C6-alkinyl" is understood to mean branched and unbranched unsaturated alkyl groups consisting of 2 to 6 carbon atoms and having at least one triple bond. Examples of C2-C6-alkinyls are ethinyl.
Unless otherwise specified, the term "C3C6-cycloalkyl" or "(C3-C6)-cycloalkyl" denotes cyclic saturated hydrocarbons having 3, 4, 5 or 6 carbon atoms respectively, which can be unsubstituted or substituted once or several times, for example by 2, 3, 4 or 5 identical or different radicals, on one or more ring members. C3-6-cycloalkyl can preferably be chosen from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, the term "3- to 7-membered heterocycloalkyi" and "3- to 12-membered heterocycloalkyi" are understood to mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having 3 to 7, i.e. 3, 4, 5, 6 or 7, or having 3 to 12, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12, ring members, in which in each case at least one, if appropriate also two or three carbon atoms are replaced by a heteroatom or a heteroatom group each selected independently of one another from the group consisting of O, S, S(=0), S(=0)2, N, NH and N(Ci-6-alkyl) such as N(CH3), wherein the ring members can be unsubstituted or mono- or polysubstituted. The heterocycloalkyl residues may be mono- or bi- cyclic.
Unless otherwise specified, the term "5- or 6-membered heteroaryl" is understood to represent a 5- or 6- membered cyclic aromatic residue containing at least 1 , if appropriate also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are each preferably selected independently of one another from the group S, N and O and the heteroaryl residue can be unsubstituted or mono- or polysubstituted, including the formation of N-oxides; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position of the heteroaryl. The binding to the superordinate general structure can be carried out via any desired and possible ring member of the heteroaryl residue if not indicated otherwise. The heteroaryl may be condensed with a 4-, 5-, 6- or 7- membered ring, being carbocyclic or heterocyclic, wherei the heteroatoms of the heterocyclic ring are each preferably selected independently of one another from the group S, N and O, and wherein said condensed ring may be saturated, partially unsaturated or aromatic and may be unsubstituted or mono- or polysubstituted; e.g. substituted by 2, 3, 4 or 5 substituents, whereby the substituents can be the same or different and be in any desired and possible position. Examples of such heteroaryl moieties are benzofuranyl, benzoimidazolyl, benzo-thienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, furyl (furanyl), imidazolyl, imidazo-thiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, isoxazoyl, isothiazolyl, indolyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pyrazolyl, pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, phenazinyl, thienyl (thiophenyl), triazolyl, tetrazolyl, thiazolyl, thiadiazolyl and triazinyl.
Unless otherwise specified, the term "substituted" in connection with the non-aromatic moieties "alkyl", "alkenyl", "alkinyl" and "alkylen", in the context of this invention is understood as meaning replacement of a hydrogen radical by a substituent selected from the group consisting of =0, OH, CN, halogen, SH, NO2, Ci-C6-alkoxy, (Ci-C6)-hydroxyalkoxy, (Ci-C6)-thioalkyl, (Ci-C6-alkoxy)-Ci-C6-alkoxy, (Ci-C6)-thiohaloalkyl, (Ci-C6)-haloalkoxy, C3-C6-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(Ci-C6-alkyl), N(Ci-Ce- alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-Ce- hydroxyalkyl)2, =NH,
Figure imgf000008_0001
Ce-alkyl), =N(OH), NHCO(Ci-C6-alkyl), N(Ci-Ce-alk l)CO(Ci-Ce-alk l), NHCO(Ci-C6-hydroxyalkyl), N(Ci- C6-alkyl)CO(Ci-C6-hydroxyalkyl), NHCOO(Ci-C6-alkyl), NH-C(0)NH2, NHCONH(Ci-C6-alkyl), NHCON(Ci- C6-alkyl)2, NH(Ci-C6-alkylen)-COO(Ci-C6-alkyl), NH(Ci-C6-alkylen)-CONH2, NH(Ci-C6-alkylen)-CONH(Ci- Ce-alkyl), NH(Ci-C6-alkylen)-CON(Ci-C6-alkyl)2, NHS(0)2OH, NHS(0)2(Ci-C6-alkyl), NHS(0)20(Ci-C6- alkyl), NHS(0)2NH2, NHS(0)2NH(Ci-C6-alkyl), NHS(0)2N(Ci-C6-alkyl)2, NH(Ci-C6-alkylen)-S(0)2OH, NH(Ci-C6-alkylen)-S(0)2(Ci-C6-alkyl), NH(Ci-C6-alkylen)-S(0)20(Ci-C6-alkyl), NH(Ci-C6-alkylen)- S(0)2NH2, NH(Ci-C6-alkylen)-S(0)2NH(Ci-C6-alkyl), C02H, CO(Ci-Ce-alk l), COO(Ci-Ce-alk l), OCO(Ci- Ce-alkyl), OCOO(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, OCONH(Ci-C6-alkyl), OCON(Ci-C6-alkyl)2, OS(0)2(Ci-C6-alkyl), OS(0)2OH, OS(0)2-(Ci-C6-alkoxy), OS(0)2NH2, OS(0)2NH(Ci- Ce-alkyl), 0-S(0)2-N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl), S(0)2(Ci-C6-alkyl), S(0)2OH, S(0)20(Ci-C6-alkyl), S(0)2NH2, S(0)2NH(Ci-C6-alkyl), and S(0)2N(Ci-C6-alkyl)2. If a moiety is substituted with more than 1 substituent (polysubstituted), e.g. by 2, 3, 4, or 5 substituents, these substituents may be present either on different or on the same atoms, e.g. as in the case of CF3 or CH2CF3, or at different places, as in the case of CH(CI)-CH=CH-CHCI2. Substitution with more than 1 substituent may include identical or different substituents, such as, for example, in the case of CH(OH)-CH=CH-CHCI2.
Preferably, the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OH, CN, (Ci-C6)-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-alkoxy, (Ci-C6)-hydroxyalkoxy, C3-C6-cyclo- alkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)CO(Ci-C6-alkyl), NHCO(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)- CO(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), NHCO(Ci-C6-alkyl), NH-CONH(Ci-C6-alkyl), NHCON(Ci-C6-alkyl)2, NHS(0)2(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl) and S(0)2(Ci-C6-alkyl).
Unless otherwise specified, the term "substituted" in connection with the moieties "cycloalkyl" and "heterocycloalkyl", in the context of this invention is understood as meaning replacement of a hydrogen radical by a substituent selected from the group consisting of =0, OH, CN, halogen, SH, N02, Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, Ci-C6-alkoxy, (Ci-C6)-thioalkyl, (Ci- C6)-haloalkyl, (Ci-C6-alkoxy)-(Ci-C6-alkylenyl), (Ci-C6-alkoxy)-Ci-C6-alkoxy, (Ci-C6)-thiohaloalkyl, (Ci-C6)- haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkylenyl), 3- to 7-membered heterocycloalkyl, (3- to 7-membered heterocycloalkyl)-(Ci-C3-alkylenyl), NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), NHCOO(Ci-C6-alkyl), NH-C(0)NH2, NHCONH(Ci-C6-alkyl), NHCON(Ci-C6-alkyl)2, , (Ci-C6-alkylen)NH2, (Ci-C6-alkylen)NH(Ci-C6-alkyl), (Ci-C6-alkylen)N(Ci-C6- alkyl)2, (Ci-C6-alkylen)NHCO(Ci-C6-alkyl), (Ci-C6-alkylen)NHC02(Ci-C6-alkyl), (Ci-C6-alkylen)NH- C(0)NH2, (Ci-C6-alkylen)NHCONH(Ci-C6-alkyl), (Ci-C6-alkylen)NHCON(Ci-C6-alkyl)2, NH(Ci-C6-alkylen)- COO(Ci-C6-alkyl), NH(Ci-C6-alkylen)-CONH2, NH(Ci-C6-alkylen)-CONH(Ci-C6-alkyl), NH(Ci-C6-alkylen)- CON(Ci-C6-alkyl)2, NHS(0)2OH, NHS(0)2(Ci-C6-alkyl), NHS(0)20(Ci-C6-alkyl), NHS(0)2NH2, NHS(0)2- NH(Ci-C6-alkyl), NHS(0)2N(Ci-C6-alkyl)2, NH(Ci-C6-alkylen)-S(0)2OH, NH(Ci-C6-alkylen)-S(0)2(Ci-C6- alkyl), NH(Ci-C6-alkylen)-S(0)20(Ci-C6-alkyl), NH(Ci-C6-alkylen)-S(0)2NH2, NH(Ci-C6-alkylen)-S(0)2NH- (Ci-Ce-alkyl), C02H, CO(Ci-C6-alkyl), COO(Ci-C6-alkyl), OCO(Ci-C6-alkyl), OCOO(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, OCONH(Ci-C6-alkyl), OCON(Ci-C6-alkyl)2, OS(0)2(Ci-C6-alkyl), OS(0)2OH, OS(0)2-(Ci-C6-alkoxy), OS(0)2NH2, OS(0)2NH(Ci-C6-alkyl), 0-S(0)2-N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl), S(0)2(Ci-C6-alkyl), S(0)2OH, S(0)20(Ci-C6-alkyl), S(0)2NH2, S(0)2NH(Ci-C6-alkyl), and S(0)2N(Ci-C6-alkyl)2. If a moiety is substituted with more than 1 substituent (polysubstituted), e.g. by 2, 3, 4, or 5 substituents, these substituents may be present either on different or on the same atoms or at different places, and may include identical or different substituents.
Preferably, the substituents may be selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OH, CN, (Ci-C6)-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-alkoxy, Cs-Ce-cycloalkyl, NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), NH-CONH(Ci-C6-alkyl), NHCON(Ci-C6-alkyl)2, NHS(0)2(Ci- Ce-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl) and S(0)2(Ci-C6-alkyl).
Unless otherwise specified, for superordinate residues containing two or more residues of the same type, such as Ci-C6-alkyl in N(Ci-C6-alkyl)2, it is understood that the two or more residues may be identical or different from each other. If the residues may be substituted, then it is understood that each residue may be independently substituted. As an example, N(Ci-C6-alkyl)2, wherein Ci-C6-alkyl may be unsubstituted or substituted by OH, encompasses for example inter alia N(CH3)2, N(CH3)(CH2CH3), N(CH2CH3)2, N(CH3)(CH2CH2OH) and N(CH2CH2OH)2.
Within the scope of the present invention, the symbols
Figure imgf000010_0001
used in the formulae denote a link of a corresponding residue to the respective superordinate general structure.
In one embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that A, B and C represent CH or
A and B represent CH and C represents N or
A and C represent CH and B represents N or
B and C represent CH and A represents N.
Preferably, the compound of formula (I) is characterized in that each of A and B represents CH and C represents N or CH. In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
X1 is N and X2 is N or
X1 is N and X2 is CH or
X1 is CH and X2 is N.
Preferably, the compound of formula (I) is characterized in that at least 2 of C, X1 and X2 represent N.
More preferably, the compound of formula (I) is characterized in that X1 is N and X2 is N. In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that R3 is selected from the group consisting of methyl, ethyl, propyl, i-propyl, n-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, SOCH3 and S02CH3,
preferably R3 is selected from the group consisting of methyl, ethyl, hydroxymethyl, 1 -hydroxyethyl, 2- hydroxypropan-2-yl, cyclopropyl, SOCH3 and S02CH3. More preferably, R3 is selected from the group consisting of ethyl, cyclopropyl, SOCH3 and SO2CH3.
In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that G is one of the following groups G1 to G44
Figure imgf000011_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
R 2 is selected from the group consisting of H, Ch or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, Br, CF3, CHF2, CH2F, OCF3, OCHF2, OH, CN, Ci-Ce-alkyl, Ci-Ce-hydroxyalkyl, Ci-Ce-alkoxy, Cs-Ce-cycloalkyl, 3- to 7- membered heterocycloalkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), NHCONH(Ci-C6- alkyl), NHCON(Ci-C6-alkyl)2, (Ci-C6-alkylen)NH2, (Ci-C6-alkylen)NH(Ci-C6-alkyl), (Ci-C6-alkylen)N(Ci-C6- alkyl)2, NHS(0)2(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, S(0)2NH2, S(0)2NH(Ci-C6- alkyl), S(0)2N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl) and S(0)2(Ci-C6-alkyl),
wherein said Ci-C6-alkyl, said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is un- substituted or mono- or polysubstituted.
In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the groups G1 to G44, wherein
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2,
CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN , SOCH3, SO2CH3, SOCH2CH3, SO2CH2CH3, SO2NH2, pyrrolidinyl, piperidinyl, aziridinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherein said pyrrolidinyl, piperidinyl, aziridinyl, oxetanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, and NHCOCH3.
In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the groups G1 to G44, wherein
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2CN, SOCH3, SO2CH3,
SOCH2CH3, SO2CH2CH3, SO2NH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-oxetanyl, 1- pyrrolidinyl, 1 -piperidinyl and 1-morpholinyl. Preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2,
CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN , SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3.
In a preferred embodiment, the compound of formula (I) is characterized in that G is one of the groups G1 to G44, wherein
R 2 is selected from the group consisting of H, CH3 or CH2CH3;
k at each occurrence is 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OCHF2, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3, SOCH2CH3, SO2CH2CH3, SO2NH2, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.
In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that G is selected from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3; and
Z at each occurcence is independently selected from the group consisting of
F, CI, CF3, CHF2, CH2F, OCF3, OH, CN, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, Ci-Ce-alkoxy, Cs-Ce-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), NH-S(0)2(Ci-C6-alkyl), CONH2, CONH(Ci-C6- alkyl), CO-N(Ci-C6-alkyl)2, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl) and S(0)2(Ci-C6-alkyl),
preferably, Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3 cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1- piperidinyl and 1-morpholinyl. In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that G is selected from G1 or G2, wherein k at each occurrence is 0, 1 , 2 or 3; and
Z at each occurcence is independently selected from the group consisting of
F, CI, CF3, CHF2, CH2F, OCF3, OH, CN, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, Ci-Ce-alkoxy, Cs-Ce-cycloalkyl, 3- to 7-membered heterocycloalkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), NH-S(0)2(Ci-C6-alkyl), CONH2, CONH(Ci-C6- alkyl), CO-N(Ci-C6-alkyl)2, S(0)2NH2, S(0)2NH(Ci-C6-alkyl), S(0)2N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl) and S(0)2(Ci-C6-alkyl),
preferably, Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCHs, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCHs, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, S02CH3 cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1- piperidinyl and 1-morpholinyl. In more preferred embodiment, the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
Figure imgf000014_0001
G45 G2 ,
wherein the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
k at each occurrence is 0, 1 or 2; and
ZA is H or F;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCHs, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCHs, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCHs, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCHs.
In more preferred embodiment, the compound of formula (I) is characterized in that G is one of the following groups G45 or G2
Figure imgf000015_0001
G45
wherein the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
k at each occurrence is 0, 1 or 2; and
ZA is H or F;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2,
CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1 -piperidinyl and 1-morpholinyl.
In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that L is selected from C(=0)NR2, S(=0), S(=0)2 , P(=0)(R2), S(=0)2NR2 or bond. In another embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is selected from C(=0)NR2, S(=0), S(=0)2, S(=0)2NR2 or bond; and
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, =NH, NH2, NH(Ci-C6-alkyl), N(Ci-C6- alkyl)2, Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)- haloalkyl and Ci-C6-alkoxy;
and
R2 is selected from H or Ci-C6-alkyl
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH, Ci-C6-alkoxy and C3-C6-cycloalkyl;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
heterocycloalkyl, wherein said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of of halogen, CN , OH , =0, NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce-alkoxy.
Preferably,
L is selected from C(=0)NR2, S(=0) or S(=0)2. In a preferred embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that
L is C(=0)NR2;
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, NH(Ci-Ce-alkyl), N(Ci-Ce-alkyl)2,
Ci-C6-alkoxy, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce-alkoxy ;
and
R2 is selected from H or Ci-C6-alkyl
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH , Ci-C6-alkoxy and C3-C6-cycloalkyl;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered
heterocycloalkyl,
wherein said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of of halogen, CN , OH , =0, NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce-alkoxy.
Preferably,
L is C(=0)NR2;
R denotes Ci-6-alkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , =0, OH , Ci-C6-alkoxy, (Ci-C6-alkoxy)-Ci-C6- alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NH(Ci-C6-hydroxyalkyl), N(Ci- C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(Ci-C6-alkyl), N(Ci-C6-alkyl)CO(Ci-C6- alkyl), NHCO(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)CO(Ci-C6-hydroxyalkyl), CONH2, CONH(Ci-Ce- alkyl), CON(Ci-C6-alkyl)2, CONH(Ci-C6-hydroxyalkyl), CON(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, C3-C6-cycloalkyl, and 3- to 7-membered heterocycloalkyl;
or
denotes one of the following groups U1 to U8
Figure imgf000017_0001
wherein at each occurrence X2 is independently selected from the group consisting of OH, =0, CN, F, CI, Br, CF3, CHF2, CH2F, OCF3, Ci-Ce-alkyl, Ci-Ce-alkoxy, NH2, NH(Ci-Ce-alkyl), N(Ci-Ce- alkyl)2, NHCO(Ci-C6-alkyl), CO2H, COO(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl) and CON(Ci- C6-alkyl)2, and
wherein said group U1 to U8 may be connected to L via a Ci-3-alkylen, which in turn is unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, CI, CF3, =0, OCF3 and OH,
or denotes one of the following groups V1 to V33:
Figure imgf000017_0002
R6 is H, (Ci-Ce-alkyl), (Ci-C6)-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, Cs-Ce-cycloalkyl, CO(Ci-C6-alkyl) or S02(Ci-C6-alkyl);
at each occurence m is 0, 1 , 2, 3, 4 or 5, and X3 at each occurrence is independently selected from the group consisting of
OH , =0, CN , F, CI, Br, CF3, CHF2, CH2F, OCF3, Ci-Ce-alkyl, Ci-Ce-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), C02H , COO(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl) and CON(Ci-C6-alkyl)2,
and wherein said group V1 to V13 may be connected to L via a Ci-3-alkylen, which in turn may be unsubstituted or substituted with at least one substituent independently selected from the group consisting of F, CI, CF3, =0, OCF3 and OH .
and
R2 is selected from H , Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl or (Ci-C6-alkoxy)-Ci-C6-alkyl, preferably R2 is selected from H or CH3.
More preferably,
L is C(=0)NR2;
R
Figure imgf000018_0001
Figure imgf000019_0001
and
R2 is selected from H, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl or (Ci-C6-alkoxy)-Ci-C6-alkyl,
preferably R2 is selected from H or Ch . Still preferably,
L is C(=0)NR2; and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and wherein said 3- to 12-membered heterocydoalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN, OH, =0, NH2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-C6-alkoxy. Still preferably,
L is C(=0)NR2; and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocydoalkyi,
wherein said 3- to 12-membered heterocydoalkyi denotes one of the following groups Q1 to Q34:
Figure imgf000020_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the carbonyl group of L;
R5 is selected from the group consisting of H , Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, C3-C6- cycloalkyl, CO(Ci-Ce-alkyl) and S02-(Ci-C6)-alkyl;
at each occurrence p is 0, 1 , 2, 3, 4 or 5; and
X6 at each occurrence is independently selected from the group consisting of OH , =0, CN, F, CI, Br, CF3, CHF2, CH2F, OCF3, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, (Ci-C6)-alkoxy, (C3-C6)- cycloalkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), CO2H, CO(Ci-C6-alkyl), COO(Ci- Ce-alkyl), CONH2, CONH(Ci-C6-alkyl) and CON(Ci-C6-alkyl)2.
More preferably,
L is C(=0)NR2; and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl,
wherein said 3- to 12-membered heterocycloalkyl denotes one of the following groups Q'1 to Q'65:
Figure imgf000021_0001
Figure imgf000022_0001
Preferably, the 3- to 12-membered heterocycloalkyi is selected from the qroup consisting of Q'8, Q'23, Q'32, Q'40 and Q'44.
In another preferred embodiment of the first aspect of the invention, the compound of formula (I) is characterized in that
L is S(=0) or S(=0)2 and
R is selected from OH , CN , Ci-Ce-alkyl, NH2, N H(Ci-C6-alkyl), N(Ci-C6-alkyl)2, C3-C6-cycloalkyl or 3- to
7-membered heterocycloalkyi,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , Ci-C6-alkoxy, (Ci-Ce- alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, N H(Ci-Ce- hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(Ci-C6-alkyl), N(Ci-Ce-alk l)CO(Ci-Ce-alkyl), NHCO(Ci-C6-hydroxyalkyl), N(Ci-Ce-alk l)CO(Ci-Ce- hydroxyalkyl); CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, CONH(Ci-C6-hydroxyalkyl), CON(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, Cs-Ce-cycloalkyl, and 3- to 7- membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce-alkoxy. Preferably, the compound of formula (I) is characterized in that
L is S(=0) or S(=0)2 and
R is selected from OH , CN , Ci-Ce-alkyl, NH2, N H(Ci-C6-alkyl), N(Ci-C6-alkyl)2, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , NH2, Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-C6-alkoxy.
Yet preferably, the compound of formula (I) is characterized in that
L is S(=0) or S(=0)2 and
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl,
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , Ci-C6-alkoxy, (C1-C6- alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, N H(Ci-C6- hydroxyalkyl), N(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), N(Ci-C6-hydroxyalkyl)2, NHCO(Ci-C6-alkyl),
N(Ci-C6-alkyl)CO(Ci-C6-alkyl), NHCO(Ci-C6-hydroxyalkyl), N(Ci-C6-alkyl)CO(Ci-C6- hydroxyalkyl); CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, CONH(Ci-C6-hydroxyalkyl), CON(Ci-C6-alkyl)(Ci-C6-hydroxyalkyl), CON(Ci-C6-hydroxyalkyl)2, Cs-Ce-cycloalkyl, and 3- to 7- membered heterocycloalkyl;
and
wherein said 3- to 7-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyl is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce-alkoxy. Preferably, L is S(=0) or S(=0)2 and R is selected from one of the above substructures M1 to M76. More preferably,
L is S(=0) or S(=0)2 and R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH,
CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3-oxetanyl.
Still more preferably,
L is S(=0) or S(=0)2 and R is selected from the group consisting of CH3 and CH2CH3.
In yet another embodiment of the first aspect of the invention, the compound of formula (I) is
characterized in that the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc) or (Id)
Figure imgf000024_0001
wherein R , R3, L and G are defined as before.
Preferably, the compound of formula (I) is a compound according to formula (la), (lb), (lc) or (Id), wherein
L is C(=0)NR2;
R and R2 together with the nitrogen atom to which they are attached form one of the following heterocycles Q19, Q23 or Q26,
Figure imgf000024_0002
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the carbonyl group of L; R5 is H, CHs, CH2CH3, CH2CH2CH3, CH(CH3)2, cydopropyl, C(0)CH3, C(0)CH2CH3, C(0)CH2CH2CH3, C(0)CH(CH3)2, C(0)-cyclopropyl, CH2CH2CN, CH2CH2OH or CH2CH2OCH3;
at each occurrence p is 0, 1 , 2 or 3; and
each X6 idependently represents H, CH3, CH2CH3, OH, OCH3, CH2OH, CH2CH2OH or CH2CH2OCH3. or
wherein
R is CH2CH2NH(CH3), CH2CH2N(CH3)2, CH2CH2CH2OH, CH2CH(CH3)OH, CH(CH3)CH2OH, CH2C(0)N(CH3)2, CH2C(0)NH(CH3) or CH2C(0)NH2 and
R2 is H or CH3, preferably R2 is CH3;
R3 is selected from the group consisting of CH3, CH2CH3, CH2OH, CH2CH2OH, 2-hydroxypropan-2-yl, cydopropyl, SOCH3 and SO2CH3;
and G is selected from the group consisting of G1 to G44 as defined above,
R 2 at each occurrence is independently selected from the group consisting of H, CH3 and CH2CH3;
k at each occurrence 0, 1 , 2, 3, 4 or 5; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cydopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cydopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3, cydopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.
Preferably, the compound of formula (I) is a compound according to formula (la), (lb), (lc) or (Id), wherein
L is S(=0) or S(=0)2;
R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3,
CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH, CH(CH3)CH2CH2OH, cydopropyl, cyclobutyl and 3- oxetanyl;
R3 is selected from the group consisting of CH3, CH2CH3, CH2OH, CH2CH2OH, 2-hydroxypropan-2-yl, cydopropyl, SOCH3 and SO2CH3; and G is selected from the group consisting of G1 to G44 as defined above,
R 2 at each occurrence is independently selected from the group consisting of H, Ch and CH2CH3;
k at each occurrence 0, 1 , 2, 3, 4 or 5; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cydopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cydopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3, cydopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.
More preferably,
the compound according to general formula (I) is selected from one of formula (la), (lb), (lc) or (Id), wherein
G is select from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cydopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cydopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3,
preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1 -piperidinyl and 1-morpholinyl.
More preferably, the compound according to formula (la), (lb), (lc) or (Id) is characterized in that
G is selected from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2,
NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2,
CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3, cyclopropyl and cyclobutyl.
Even more preferably, the compound according to general formula (I) has the general formula (la), (lb), (lc) or (Id), wherein
L is C(=0)NR2;
R and R2 together with the nitrogen atom to which they are attached form a heterocycle wherein said heterocycle is Q19 and p is 0
or
R is CH3, CH2CH3, CH2CH2OH, CH2CH2NH(CH3), CH2CH2N(CH3)2, CH2CH2CH2OH, CH2CH(CH3)OH, CH(CH3)CH2OH, CH2C(0)N(CH3)2 or CH2C(0)NH2 and
R2 is CH3;
R3 is CH3, CH2CH3, cyclopropyl, SOCH3 or SO2CH3;
and
G is select from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3, SO2CH3 and cyclopropyl, preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, , CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3 and cyclopropyl.
Even more preferably, the compound according to general formula (I) is selected from one of formula (la), (lb), (lc) or (Id), wherein
L is S(=0) or S(=0)2;
R is selected from the group consisting of CH3 and CH2CH3;
R3 is selected from the group consisting of CH3, CH2CH3, cyclopropyl, SOCH3 and SO2CH3; and G is select from G1 or G2, wherein
k at each occurrence is 0, 1 , 2 or 3;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3, SO2CH3 and cyclopropyl, preferably Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CN, SOCH3, SO2CH3 and cyclopropyl.
In yet another preferred embodiment, the invention relates to a compound selected from the group consisting of
1 (3-Ethyl-1-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1 H-indazol-6-yl)(morpholino) methanone
2 3-Ethyl-N-(2-hydroxyethyl)-1-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-N-methyl-1 H-indazole- 6-carboxamide
3 (1-(4-Methyl-[2,3'-bipyridin]-6'-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)(morpholino) methanone
4 (1-(4-Methyl-[2,3'-bipyridin]-6'-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)(morpholino) methanone g (1-(5-(2-Fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
g (1-(5-(2-Fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)(morpholino)
methanone
8 (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin]-6'-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
g (1-(5-(3-(2-Aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6- yl)(morpholino)methanone
^ 1-(5-(2-Fluorophenyl)pyridin-2-yl)-N-methyl-N-(2-(methylamino)ethyl)-3-(methylsulfinyl)-1 H-indole- 6-carboxamide
12 (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin]-6'-yl)-3-ethyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)
(morpholino)methanone
13 (3-Ethyl- 1 -(4-(2-hyd roxypropan-2-yl )-[2 , 3'-bi pyrid i n]-6'-yl)- 1 H-pyrazolo[3 ,4-b] pyrid in-6- yl)(morpholino)methanone
14 (1-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-3-ethyl-1 H-pyrazolo[3,4-b]pyridin-6- yl)(morpholino)methanone
(3-Ethyl-1-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[3,4-b]pyridin-6- yl)(morpholino)methanone
1g (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
Λ Π (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6- yl)(morpholino)methanone
19 2 "-( '6T'-(3-Cyclopropyl-6-(ethylsulfonyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-amine
20 2-(6 )''-(3-Cyclopropyl-6-(ethylsulfinyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-amine 22 2-(6 3-Ethyl-6-(ethylsulfonyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-am
23 2-(6 3-Ethyl-6-(ethylsulfinyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-ami
optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
Owing to their excellent pharmacological activity, the compounds according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id), are suitable for the treatment of various diseases or conditions in which inhibition of the PDE4 enzyme is advantageous.
Such conditions and diseases are inter alia
- inflammatory diseases of the joints;
- inflammatory diseases of the skin;
- gastrointestinal diseases and complaints;
- inflammatory diseases of the internal organs;
- hyperplastic diseases;
- respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract;
- diseases of the fibrotic spectrum;
- cancers;
- metabolic diseases;
- psychological disorders; and
- diseases of the peripheral or central nervous system.
One of the advantages of the compounds according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id), is that they are selective PDE4B inhibitors. Preferably, PDE4D is not inhibited or is only partly inhibited, and hence the use of such selective PDE4B inhibitors gives rise to no side-effects or to significantly reduced side-effects, such as emesis and nausea, in particular indisposition, vomiting and sickness. The therapeutic range of the compounds according to the invention is therefore advantageous.
A second aspect of the invention is a pharmaceutical composition (medicament) containing at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id).
A third aspect of the invention is a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (Ic) or (Id) for the use as a medicament, in particular for the treatment of conditions or diseases that can be treated by inhibition of the PDE4 enzyme, in particular the PDE4B enzyme.
A fourth aspect of the invention is a compound according to the first aspect of the invention, in particular of the general structure of formulae (I), (la), (lb), (Ic) or (Id) for the use as a medicament for the treatment of inflammatory diseases of the joints; and/or inflammatory diseases of the skin; and/or inflammatory diseases of the eyes; gastrointestinal diseases and complaints; inflammatory diseases of the internal organs; and/or hyperplastic diseases; respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract; diseases of the fibrotic spectrum; cancers; metabolic diseases; psychological disorders; and/or diseases of the peripheral or central nervous system.
In a preferred embodiment of the fourth aspect of the invention, the invention therefore also provides a compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) for the use as a medicament for the treatment of inflammatory diseases of the joints, the skin, of respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract,of metabolic diseases and/or cardiovascular diseases. A fifth aspect of the invention is the use of a compound according to the first aspect of the invention, in particular according to the general structure of (I), (la), (lb), (lc) or (Id) for the preparation of a
medicament for the treatment of the diseases and conditions according to the fourth aspect of the invention. A sixth aspect of the invention is a method for the treatment of the diseases and conditions according to the fourth aspect of the invention in a human, which is characterised in that a therapeutically effective amount of at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) is administered. The amount of active ingredient to be administered to the person or patient varies and is dependent on the patient's weight, age and medical history and on the type of administration, the indication and the severity of the illness. Conventionally 0.1 to 5000 mg/kg, in particular 0.5 to 500 mg/kg, preferably 1 to 250 mg/kg of body weight of at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) are administered.
All embodiments, in particular the preferred embodiments, of the first aspect of the invention apply mutatis mutandis to all other aspects of the invention.
The medicaments, drugs and pharmaceutical compositions according to the invention can take the form of and be administered as liquid, semi-solid or solid dosage forms and as for example injection solutions, drops, juices, syrups, sprays, suspensions, granules, tablets, pastilles, pellets, transdermal therapeutic systems, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions or aerosols and contain, in addition to at least one compound according to the first aspect of the invention, in particular according to the general structure of formulae (I), (la), (lb), (lc) or (Id) according to the pharmaceutical form and depending on the administration route, pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active substances, dyes, preservatives, disintegrants, slip additives, lubricants, flavourings and/or binders.
The choice of auxiliary substances and the amounts thereof depends on whether the medicament is administered by oral, subcutaneous, parenteral, intravenous, vaginal, pulmonary, intraperitoneal, transdermal, intramuscular, nasal, buccal or rectal means or locally, for example on the skin, mucous membranes and eyes, and whether the medicament is designed to deliver the active ingredient by immediate, sustained, delayed or extended release. Preparation of the medicaments and pharmaceutical compositions according to the invention takes place using agents, equipment, methods and procedures that are well-known from the prior art, such as "Remington's Pharmaceutical Sciences", Ed . A.R.
Gennaro, 17th edition, Mack Publishing Company, Easton PD (1985), in particular part 8, chapters 76 to 93.
Unless indicated otherwise the compounds according to the invention can be synthesized according to general knowledge in the field of organic chemistry and in a manner as described here (cf. reaction schemes below) or analogously. The reaction conditions in the synthesis routes described herein are known to the skilled person and are for some cases exemplified in the synthesis examples herein. The necessary starting materials are either commercially available or can also be obtained according to general knowledge in the field of organic chemistry.
If not stated otherwise, all chemical moieties; variables and indices in the compounds shown in the following reaction schemes are as defined in the context of the compound of formula (I) and the various embodiments thereof. Examples:
The compounds according to the invention are specified in the table below, without limiting the invention The following abbreviations are used in the descriptions of the experiments:
(AtaPhos)2PdCl2 = bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(ll); APCI = atmospheric pressure chemical ionization; calc. = calculated; d = day; dba = dibenzylidene-acetone; DCM = dichloromethane; DIPEA = diisopropylethylamine; DME = dimethoxyethane; DMF = N,N-dimethyl- formamide; DMSO = dimethylsulfoxide; dppp = 1 ,3-bis(diphenylphosphino)propane; EtOAc = ethyl acetate; EtOH = ethanol; EDCxHCI = 1 -[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; ES- MS = electrospray mass spectrometry (ES-MS); eq. = equivalent; h = hour(s); HOAt = 1 -hydroxy-7-aza- 1 H-benzotriazole; KOi-Bu = potassium tert-butoxide; LiHMDS = lithium bis(trimethylsilyl)amid; mCPBA = m-chloroperoxybenzoic acid; min = minute(s); MeOH = methanol; MMPP = magnesium mono- peroxyphthalate; MTBE = methyl-tert-butylether; PdCl2(dppf) = [1 , 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(l l) DCM complex; Pd2(dba)3(0) = tris(dibenzylideneacetone)dipalladium(0); PE = petroleum ether; rt = room temperature; Rt = retention time; SFC = supercritical fluid chromatography; TBDPS = tert-butyldiphenylsilyl; TBTU = 2-(1 H-benzotriazol-1 -yl)-1 , 1 ,3,3-tetramethyluronium tetrafluoro- borate; TCCA = trichloroisocyanuric acid; tert = tertiary; TEA = triethylamine; TFA = 2,2,2-trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TOFMS = time-of-f light mass spectrometer; Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
The following analytical HPLC methods were used:
Method 1 :
Column: Zorbax Extend C18 (4.6 x 50 mm, 5 μιτι); column temperature: 25°C; instrument: Shimadzu Prominence; flow rate: 1.2 mL/min; injection volume: 2 μΙ_; detection: 220 and 260 nm; mobile phase A: 10 mM ammonium acetate in water; mobile phase B: acetonitrile.
Mobile phase gradient:
Figure imgf000032_0001
Mass spectrometry conditions: Instrument: API 2000 LC/MS/MS from Applied Biosystem; Ionization technique: ESI using API source; Declustering Potential: 10-70 V depending on the ionization of compound; Mass range: 100-800 amu; Scan type: Q1 ; Polarity: + Ve; Ion Source: Turbo spray; Ion spray voltage: +5500 for +Ve mode; Mass Source temperature: 200°C
Method 2:
Column: Resteck (30 mm x 2.1 mm, 1.8 μιτι); Column temperature: 50°C; Instrument: Waters ACQUITY UPLC; Flow rate: 1.5 mL/min; Injection volume: 2 μΙ; Detection: 210 to 400 nm (DAD)
Mobile phase A: 0.05% formic acid in water; B: acetonitrile; mobile phase
Mobile phase gradient:
Figure imgf000032_0002
Mass spectrometry conditions: Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer) Ionization technique: ESI; Mass range: 100 to 800 Da; Polarity: + Ve
Method 3:
Column: Epic C18 (50 x 4.6 mm, 5u, 120A); column temperature: 25°C; instrument: Shimadzu Prominence; flow rate: 1.2 mL/min; injection volume: 2 μί; detection: 220 and 260 nm; mobile phase A: 10 mM ammonium acetate in water; mobile phase B: acetonitrile.
Mobile phase gradient:
Time in min % A % B
0 90 10 1.5 70 30
3.0 10 90
4.0 10 90
5.0 90 10
Mass spectrometry conditions: Instrument: API 2000 LC/MS/MS from Applied Biosystem; Ionization technique: ESI using API source; Declustering Potential: 10-70 V depending on the ionization of compound; Mass range: 100-800 amu; Scan type: Q1 ; Polarity: + Ve; Ion Source: Turbo spray; Ion spray voltage: +5500 for +Ve mode; Mass Source temperature: 200°C
Method 4:
Column: Zorbax Extend (4.6 x 50 mm, 5 μιτι); column temperature: 50°C; instrument: Waters
UPLC; flow rate: 1.5 mL/min; injection volume: 2 μΙ; detection: 210 to 400 nm (DAD);
mobile phase A: 0.05% ammonium acetate in water; B: acetonitrile.
Mobile phase gradient:
Figure imgf000033_0002
Mass spectrometry conditions: Instrument: ACQUITY SQD Mass Spectrometer from Waters (Single quadruple mass spectrometer); ionization technique: ESI; mass range: 100 to 800 Da; polarity: positive ions.
SYNTHESIS OF EXAMPLE COMPOUNDS
The compounds according to formula (I) may be prepared according to general reaction schemes 01 to 07.
If not given otherwise, in below reaction scheme all substituents, chemical groupings and indices are as defined here in the context of the compound of general formula (I) and Rx is (C1-C6) alkyl, preferably methyl.
Reaction scheme 01
Figure imgf000033_0001
with R3 = (Ci-C6)-alkyl, (C3-C6)-cycloalkyl, (Ci-Ce)-thioalkyl, more preferably ethyl, cyclopropyl, SMe. eaction scheme 02
Figure imgf000034_0001
(VII) (VIII)
A compound of the general formula IV can be also directly converted into a compound of formula VI analogously to the general reaction scheme 4.
Reaction scheme 03:
Figure imgf000034_0002
Reaction scheme 04
Figure imgf000035_0001
eaction scheme 05
Figure imgf000035_0002
(XII) (XIII) (XIV)
Rx is (Ci-Ce) alkyl, preferably methyl.
Figure imgf000035_0003
Figure imgf000036_0001
A compound of the general formula XVI can be also directly converted into a compound of formula XVIII analogously to the general reaction scheme 4.
Example 1 : (3-Ethyl-1-(4-(2-hvdroxypropan-2-yl)-[2,3'-bipyridinl-6'-yl)-1 H-indazol-6-yl)(morpholino) methanone
Figure imgf000036_0002
1a) Methyl 3-ethyl-1 H-indazole-6-carboxylate
TEA (1 .3 mL, 8.96 mmol), Pd(OAc)2 (0.3 g, 1.34 mmol) and dppp (0.664 g, 1.61 mmol) were added to a solution of 6-bromo-3-ethyl-1 H-indazole (1 g, 4.48 mmol) in MeOH (60 mL) stirred in a steal bomb. The reaction mixture was stirred for 16 h at 60°C under CO atmosphere at 90 psi. The reaction mixture was cooled to RT, filtered through a plug of celite and washed with MeOH. The organic layer was concentrated, diluted with water (25 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and evaporated under reduced pressure. The remnant was purified by flash column chromatography [silica; 10-15% EtOAc in hexane]. White solid. Yield: 0.6 g (65%). HPLC (method 1 ): Rt = 3.05 min, m/z: [M+H]+ = 205.4 (MW calc. 204.09).
1 b) Methyl 1-(5-bromopyridin-2-yl)-3-ethyl-1 H-indazole-6-carboxylate
Compound 1a (1.5 g, 7.35 mmol), 5-bromo-2-fluoropyridine (1.94 g, 1 1.02 mmol) and CS2CO3 (4.77 g, 14.7 mmol) in DMF (10 mL) were stirred at 80°C for 16 h. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (3 x 30 mL). The organic layer was separated, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica, hexane/EtOAc = 95:5]. White solid. Yield: 1.5 g (56%). HPLC (method 3): Rt = 2.13 min, m/z: [M+H]+ = 361.9 (MW calc. 359.03).
1 c) Methyl 3-ethyl- 1 -( 4-( 2-hyd roxypropan-2-yl )-[2 , 3'-bi pyrid inl-6'-yl )- 1 H-indazole-6-carboxylate Bis(pinacolato)diboron (1.1 12 g, 4.44 mmol) and KOAc (0.814 g, 8.31 mmol) were added at RT to a solution of compound 1 b (1 g, 2.77 mmol) in dry dioxane (30 mL). The reaction apparatus was flushed with Ar followed by the addition of PdCl2(dppf) (1 13 mg, 0.13 mmol). The reaction mixture was then heated at 1 10°C for 2 h. After cooling to RT, 2-(2-bromopyridin-4-yl)propan-2-ol (0.897 g, 4.15 mmol), aqueous 2M K2CO3 solution (5 mL) and tetrakis(triphenylphosphine) palladium(O) (160 mg, 0.13 mmol) were added successively. The reaction mixture was heated at 1 10°C for 16 h, cooled to RT and filtered through a plug of celite. The filtrate was concentrated and the raw product was purified by flash column chromatography [silica; DCM/MeOH = 98:2]. White solid. Yield: 0.7 g (60%). HPLC (method 1 ): Rt = 3.88 min, m/z: [M+H]+ = 417.3 (MW calc. 416.18).
1d) 3-Ethyl- 1 -(4-(2-hvd roxypropan-2-yl )-[2 , 3'-bi pyrid i nl-6'-yl)- 1 H-indazole-6-carboxylic acid
LiOH-hbO (0.35 mg, 8.41 mmol) was added at 0°C to a solution of compound 1 c (0.7 g, 1.68 mmol) in a blend of THF-water (2:1 , 30 mL). The reaction mixture was stirred at RT for 16 h, concentrated and acidified with saturated KHSC solution. The solid was filtered off and co-evaporated with toluene. White solid. Yield: 0.6 g (88%). HPLC (method 1 ): Rt = 2.50 min, m/z: [M+H]+ = 403.1 (MW calc. 402.17).
1 e) (3-Ethyl-1-(4-(2-hvdroxypropan-2-ylH2,3'-bipyridinl-6'-yl)-1 H-indazol-6-yl)(morpholino) methanone
Compound 1d (0.3 g, 0.74 mmol) in DCM (30 mL) was stirred at RT for 16 h with HATU (0.421 g, 1.1 1 mmol), DIPEA (0.4 mL, 2.22 mmol) and morpholine (78 mg, 0.89 mmol). The reaction mixture was poured onto ice-cold water, stirred for 15 min and then extracted with EtOAc (3x 20 mL). The combined organic layers were washed with water and brine, dried over Na2S04 and concentrated. The remnant was purified by column chromatography [silica; DCM with 1-2 % MeOH]. White solid. Yield: 150 mg (43%).
HPLC (method 2): Rt = 1 .68 min, m/z: [M+H]+ = 472.3 (MW calc. 471 .2). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.24 (s, 1 H), 8.84 (s, 1 H), 8.63 (s, 2H), 8.09 (d, 2H, J = 8.5 Hz), 7.94 (d, 1 H, J = 7.9 Hz),
7.47 (d, 1 H, J = 3.1 Hz), 7.35 (d, 1 H, J = 7.4 Hz), 4.98 (bs, 1 H), 3.66 (bs, 4H), 3.57 (bs, 4H), 3.10-3.09
(m, 2H), 1.54 (s, 6H), 1.47-1.45 (m, 3H).
Example 2: 3-Ethyl-N-(2-hvdroxyethyl)-1-(4-(2-hvdroxypropan-2-yl)-[2,3'-bipyridinl-6'-yl)-N-methyl-1 H- indazole-6-carboxamide
Figure imgf000037_0001
A solution of compound 1d (0.300 g, 0.74 mmol), HATU (0.421 g, 1.1 1 mmol), DIPEA (0.4 mL, 2.22 mmol) and 2-(methylamino)ethan-1-ol (68 mg, 0.89 mmol) in DCM (30 mL) was stirred at RT for 16 h. The reaction mixture was poured onto ice-cold water, stirred for 15 min and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with water and brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography [silica; DCM with 1-2 % MeOH]. White solid. Yield: 60 mg (17%). HPLC (method 2): Rt = 1.57 min, m/z: [M+H]+ = 460.4 (MW calc. 459.2). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 9.23 (s, 1 H), 8.81 (s, 1 H), 8.63-8.60 (m, 2H), 8.09 (d, 2H, J = 9.0 Hz), 7.92 (d, 1 H, J = 8.2 Hz), 7.47 (d, 1 H, J = 5.0 Hz), 7.34 (d, 1 H, J = 7.9 Hz), 4.97 (s, 1 H), 4.43 (bs, 1 H), 3.65 (d, 2H, J = 5.2 Hz), 3.48 (bs, 2H), 3.12-3.05 (m, 5H), 1.54 (s, 6H), 1.48-1.44 (m, 3H).
Example 3: (1-(4-Methyl-[2,3'-bipyridi -6'-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)(morpholino) methanone
Figure imgf000038_0001
3a) Methyl 1-(5-bromopyridin-2-yl)-3-(methylthio)-1 H-indazole-6-carboxylate
Methyl 3-(methylsulfanyl)-1 H-indazole-6-carboxylate (1.5 g, 6.75 mmol), CS2CO3 (5.5 g, 16.89 mmol) and 5-bromo-2-fluoropyridine (5.94 g, 33.78 mmol) in DMF (15 mL) were stirred for 10 h at 90°C. The reaction mixture was cooled to RT and quenched with crushed ice. The precipitating solid was filtered off through a sintered funnel and co-evaporated with toluene. The crude material was triturated with hexane affording the target compound as white solid. Yield: 1.9 g (74%). HPLC (method 1 ): Rt = 4.65 min, m/z: [M+H]+ = 378.0 (MW calc. 378.24).
3b) Methyl 1-(4-methyl-[2,3'-bipyridinl-6'-yl)-3-(methylthio)-1 H-indazole-6-carboxylate
Obtained from compound 3a (0.75 g, 1.98 mmol) and 2-bromo-4-methylpyridine (0.51 1 g, 2.97 mmol) analogously to procedure 1 c. White solid. Yield: 0.485 g (63%). HPLC (method 1 ): Rt = 4.62 min, m/z: [M+H]+ = 390.8 (MW calc. 390.46).
3c) 1-(4-Methyl-[2,3'-bipyridinl-6'-yl)-3-(methylthio)-1 H-indazole-6-carboxylic acid
Compound 3b (0.43 g, 1.1 mmol) was saponified using the conditions detailed in procedure 1d. White solid. Yield: 0.365 g (88%). HPLC (method 1 ): Rt = 2.72 min, m/z: [M+H]+ = 377.1 (MW calc. 376.43).
3d) (1-(4-Methyl-[2,3'-bipyridinl-6'-yl)-3-(methylthio)-1 H-indazol-6-yl)(morpholino)methanone
HATU coupling of compound 3c (0.365 g, 0.97 mmol) with morpholine (101 mg, 1.16 mmol) according to the procedure of example 2. Solid. Yield: 350 mg (81 %). HPLC (method 1 ): Rt = 3.60 min, m/z: [M+H]+ = 446.3 (MW calc. 445.54).
3e) (1-(4-Methyl-[2,3'-bipyridinl-6'-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)(morpholino) methanone m-CPBA (77%, 0.108 g, 0.629 mmol) was added to an ice-cooled solution of compound 3d (0.35 g, 0.786 mmol) in DCM (30 mL) and the resulting mixture was stirred at RT for 1 h. The mixture was quenched with aqueous Na2S03 solution (15 mL) and the organic layer was separated and successively washed with saturated NaHCCh solution (2 x 15 mL) and brine (15 mL). The organic phase was then dried over Na2S04 and evaporated. The remnant was purified by flash column chromatography [silica; DCM with 3% MeOH]. White solid. Yield: 0.18 g (50%). HPLC (method 1 ): Rt = 2.74 min, m/z: [M+H]+ = 462.3 (MW calc. 461.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.33 (s, 1 H), 8.93 (s, 1 H), 8.73-8.71 (m, 1 H), 8.58 (d, 1 H, J = 4.9 Hz), 8.30 (d, 1 H, J = 8.3 Hz), 8.15 (d, 1 H, J = 8.7 Hz), 7.99 (s, 1 H), 7.51 (d, 1 H, J = 8.4 Hz), 7.28 (d, 1 H, J = 4.8 Hz), 3.70-3.35 (m, 8H), 3.23 (s, 3H), 2.43 (s, 3H).
Example 4: (1-(4-Methyl-[2,3'-bipyridinl-6'-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)(morpholino) methanone
Figure imgf000039_0001
m-CPBA (70%, 0.442 g, 1.79 mmol) was added portion wise at 0°C to a solution of compound 3d (0.4 g, 0.89 mmol) in dry DCM (40 mL). The reaction mixture was stirred at RT for 2 h and then quenched with sat. NaHCCh solution (30 mL) and sat. Na2S03 solution (30 mL). The aqueous phase was separated and extracted with DCM (3x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica; DCM with 2% MeOH] and then triturated with DCM/pentane. White solid. Yield: 0.12 g (28%). HPLC (method 2): Rt = 1.58 min, m/z: [M+H]+ = 478.3 (MW calc. 477.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.36 (s, 1 H), 8.93 (s, 1 H), 8.78-8.76 (m, 1 H), 8.60 (d, 1 H, J = 4.8 Hz), 8.20-8.17 (m, 2H), 8.02 (s, 1 H), 7.59 (d, 1 H, J = 8 Hz), 7.29-7.28 (m, 1 H), 3.70-3.56 (m, 9H), 3.39 (bs, 2H), 2.43 (s, 3H).
Example 5: (1-(5-(2-Fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl) (morpholino)- methanone
Figure imgf000039_0002
5a) Methyl 1-(5-(2-fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylthio)-1 ^
K2CO3 (1.64 g, 1 1.89 mmol) and (AtaPhos)2PdCI2 (0.28 g, 0.396 mmol) were added to a solution of compound 3a (1.5 g, 3.96 mmol) and (2-fluoro-5-methylphenyl)boronic acid (1.22 g, 7.93 mmol) in tert- amyl alcohol (50 mL) and water (5 mL) stirred under Ar. The reaction mixture was heated at 1 10°C for 5 h, then cooled to RT and filtered through a plug of celite. The filtrate was evaporated and the remnant was first purified by flash column chromatography [silica; DCM with 1.5% MeOH] and afterwards washed with DCM/pentane. White solid. Yield: 1.2 g (74%). HPLC (method 1 ): Rt = 3.21 min, m/z: [M+H]+ = 408.2 (MW calc. 407.46).
Compound 5a was converted in three steps into example 5 analogously to example 4.
White solid. Yield: 0.05 g. HPLC (method 3): Rt = 3.81 min, m/z: [M+H]+ = 495.1 (MW calc. 494.54). 1 H NMR (400 MHz, DMSO-d6, 100 °C, δ ppm): 8.88-8.85 (m, 2H), 8.29-8.27 (m, 1 H), 8.21-8.16 (m, 2H), 7.57-7.55 (m, 1 H), 7.50-7.49 (m, 1 H), 7.29 (s, 1 H), 7.26-7.21 (m, 1 H), 3.66-3.65 (m, 4H), 3.56 (s, 4H), 3.51 (s, 3H), 2.40 (s, 3H).
Examples 6 and 7: (1-(5-(2-Fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)-
Figure imgf000040_0001
The racemate was prepared in three steps from compound 5a analogously to synthesis example 3 (yield: 0.3 g, white solid). The two enantiomers were obtained from the racemic mixture through chiral HPLC utilizing a chiral pack-IA column (250 x 21.0 mm, 5μιη) and hexane/EtOAc/ethanol/diethylamine (50/25/25/0.1 ) as mobile phase. Flow rate was 21 .0 ml/min.
Faster eluting enantiomer (example 6): Yield = 105 mg. White solid. Specific optical rotation: [a]s8925 = - 72.04° (c. 0.6330, CHCb). Enantiomer excess = 100%. HPLC (method 1 ): Rt = 3.36 min, m/z: [M+H]+ = 479.2 (MW calc. 478.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.90 (s, 1 H), 8.84 (s, 1 H), 8.30-8.26 (m, 2H), 8.14-8.12 (m, 1 H), 7.52-7.48 (m, 2H), 7.30-7.25 (m, 2H), 3.70-3.38 (m, 8H), 3.23 (s, 3H), 2.37 (s, 3H).
Slower eluting enantiomer (example 7): Yield = 80 mg. White solid. Specific optical rotation: [a]s8925 = +59.84° (c. 0.4846, CHCb). Enantiomer excess = 95.5%. HPLC (method 2): Rt = 1.76 min, m/z: [M+H]+ = 479.1 (MW calc. 478.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.90-8.84 (m, 2H), 8.30-8.25 (m, 2H), 8.14-8.12 (m, 1 H), 7.52-7.48 (m, 2H), 7.30-7.25 (m, 2H), 3.70-3.38 (m, 8H), 3.23 (s, 3H), 2.37 (s, 3H). Example 8: (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridinl-6^
(morpholino)methanone
Figure imgf000041_0001
Prepared from methyl methyl 1-(5-bromopyridin-2-yl)-3-(methylthio)-1 H-indazole-6-carboxylate 3a and 2- (2-bromopyridin-4-yl)propan-2-amine analogously to synthesis example 4. White solid. Yield: 0.08 g. HPLC (method 1 ): Rt = 2.66 min, m/z: [M+H]+ = 521.4 (MW calc. 520.60). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.41 (s, 1 H), 8.95 (s, 1 H), 8.82-8.79 (m, 1 H), 8.64 (d, 1 H, J = 5.2 Hz), 8.27 (s, 1 H), 8.21-8.18 (m, 2H), 7.60-7.56 (m, 2H), 3.71-3.56 (m, 9H), 3.40-3.35 (m, 2H), 2.13 (s, 2H), 1 .44 (s, 6H). Examples 9 and 10: (1-(5-(3-(2-Aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)- (morpholino)methanone (faster and slower elutinq enantiomer)
Figure imgf000041_0002
The racemate was obtained from compound 3a analogously to synthesis example 3 (yield: 0.25 g, white solid). Subsequent chiral preparative SFC HPLC of the racemate afforded the two enantiomers (column: YMC Chiral Amylose-C 250 x 4.6 mm, 5μηη; mobile phase: 45% C02 / 55% MeOH with 0.5% isopropylamine; flow rate: 25.0 ml/min; temperature: 35°C, column pressure: 100 bar).
Faster eluting enantiomer (example 9): Yield = 90 mg. White solid. Enantiomer excess = 100%. HPLC (method 3): Rt = 2.63 min, m/z: [M+H]+ = 505.1 (MW calc. 504.61 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 1 H), 8.94 (s, 1 H), 8.77-8.74 (m, 1 H), 8.63 (d, 1 H, J = 5.2 Hz), 8.31 (d, 1 H, J = 8.4 Hz), 8.25 (s, 1 H), 8.16 (d, 1 H, J = 8.8 Hz), 7.56-7.55 (m, 1 H), 7.51 (d, 1 H, J = 8.4 Hz), 3.70-3.57 (m, 6H), 3.40-3.35 (m, 2H), 3.23 (s, 3H), 2.1 1 (s, 2H), 1 .43 (s, 6H). Slower eluting enantiomer (example 10): Yield = 95 mg. White solid. Enantiomer excess = 100%. HPLC (method 4): Rt = 1.89 min, m/z: [M+H]+ = 505.27 (MW calc. 504.61 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.38 (s, 1 H), 8.94 (s, 1 H), 8.77-8.75 (m, 1 H), 8.65 (d, 1 H, J = 5.2 Hz), 8.31 (d, 1 H, J = 8 Hz), 8.25 (s, 1 H), 8.17 (d, 1 H, J = 8.4 Hz), 7.56-7.55 (m, 1 H), 7.51 (d, 1 H, J = 8.4 Hz), 3.70-3.57 (m, 6H), 3.40-3.35 (m, 2H), 3.23 (s, 3H), 1 .45 (s, 6H).
Example 1 1 : 1-(5-(2-Fluorophenyl)pyridin-2-yl)-N-methyl-N-(2-(methylamino)ethyl)-3-(methylsulfinyl)-1 H- indole-6-carboxamide
Figure imgf000042_0001
1 1a) Methyl 3-(methylthio)-1 H-indole-6-carboxylate
Dimethylsulfane (9.1 g, 14.7 mmol, 1.1 eq) was added drop wise at 0°C to a stirred suspension of N- chlorosuccinamide (19.5 g, 14.7 mmol, 1.1 eq) in DCM (50 mL). A solution of methyl 1 H-indole-6- carboxylate (23.0 g, 13.3 mmol, 1.0 eq) in DCM (50 mL) was added drop wise at -20°C and the mixture was stirred at RT for 1 h. The solvent was evaporated and the residue was dissolved in xylene (50 mL) and refluxed for 16 h. The xylene was removed under vacuum and with EtOAc (50 mL) was added. The solution was washed with water (100 mL), dried (Na2S04) and evaporated. The raw product was purified by silica gel column chromatography [100-200 mesh, 10% EtOAc/petrolether = 1 :9]. Yield: 20.0 g (67%). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 1 1.71 (s, 1 H), 8.08 (s, 1 H), 7.75-7.62 (m, 3H), 3.87 (s, 3H), 2.33 (s, 3H).
1 1 b) Methyl 1-(5-bromopyridin-2-yl)-3-(methylthio)-1 H-indole-6-carboxylate
Compound 1 1a (2.5 g, 1 1.312 mmol, 1.0 eq), 5-bromo-2-chloropyridine (2.6 g, 13.574 mmol, 1.2 eq) and KOtBu (1.9 g, 16.968 mmol, 1.5 eq) in DMF (10 mL) were stirred at 120°C for 16h. The mixture was diluted with EtOAc (50 mL) and filtered through a plug of celite. The filtrate was washed with water (2x 50 mL) and brine (25 mL), dried over Na2S04, and evaporated under vacuum. The remnant was purified by silica gel column chromatography [100-200 mesh, EtOAc/petrolether = 1 :9]. Yield: 1.8 g (43%). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.82 (d, J = 0.8 Hz, 1 H), 8.66-8.65 (m, 1 H), 7.99-7.96 (m, 2H), 7.86 (s, 1 H), 7.79 (dd, J = 8.4 and 0.4 Hz, 1 H), 7.44 (dd, J = 8.4 and 0.4 Hz, 1 H), 3.96 (s, 3H), 2.46 (s, 3H). 1 1 c) Methyl 1-(5-(2-fluorophenyl)pyridin-2-yl)-3-(methylthio)-1 H-indole-6-carboxylate
K2CO3 (1.98 g, 14.36 mmol, 3 eq), Pd2(dba)3 (438 mg, 0.478 mmol, 0.01 eq) and (tBu)3PHBF4 (69 mg, 0.239 mmol, 0.05 eq) were added to a solution of compound 1 1 b (1.8g, 4.787 mmol, 1.0 eq) and (2- fluorophenyl)boronic acid (1.4 g, 7.18 mmol, 1.5 eq) in THF/water (50 mL, 4:1 ) kept under Ar and the reaction mixture was stirred at 50°C for 2h. The mixture was cooled to RT, diluted with water (30 mL) and extracted with EtOAc (2x 50 mL). The combined organic layers were washed with brine, dried over Na2S04, and concentrated. The residue was purified by column chromatography [100-200 mesh, EtOAc/petrolether = 1 :9]. Yellow solid. Yield: 1.3 g, (69%). 1 H NMR (400 MHz, CDCIs, δ ppm): 8.93 (s, 1 H), 8.79 (s, 1 H), 8.09 (dd, J = 8.4, 4.8 Hz, 1 H), 8.07-7.99 (m, 2H), 7.82 (d, J = 8.4 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.54-7.49 (m, 1 H), 7.42-7.40 (m, 1 H), 7.32-7.25 (m, 1 H), 7.24-7.21 (m, 1 H), 3.97 (s, 3H), 2.48 (s, 3H).
1 1 d) Methyl 1-(5-(2-fluorophenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indole-6-carboxylate
mCPBA (0.652 g, 2.65 mmol, 0.8 eq) was added at -10°C to a solution of compound 1 1 c (1.3 g, 3.316 mmol, 1.0 eq) in DCM (50 mL) and the reaction mixture was stirred for 30 min at RT. The mixture was diluted with DCM (50 mL), washed with sat. NaHCCh solution and brine, dried over Na2S04, and evaporated under vacuum. The raw product was purified by silica gel column chromatography [100-200 mesh, EtOAc/petrolether = 2:3]. White solid. Yield: 0.900 g (64%). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.94 (s, 1 H), 8.82 (s, 1 H), 8.30 (s, 1 H), 8.15-8.12 (m, 1 H), 8.04-8.01 (dd, J = 8.4, 1.2 Hz, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.4 Hz, 1 H), 7.53-7.50 (m, 1 H), 7.48-7.37 (m, 1 H), 7.33-7.22 (m, 2H), 3.98 (s, 3H), 3.07 (s, 3H).
1 1 e) 1-(5-(2-Fluorophenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indole-6-carboxylic acid
Me3SiOK (1.4 g, 1 1.02 mmol, 5.0 eq) was added to a solution of compound 1 1d (900 mg, 2.205 mmol, 1.0 eq) in THF/H20 (3:1 , 25 mL) and the mixture was stirred for 2 days at RT. The solution was brought to pH ~6 with 10% citric acid solution and the precipitating solid was filtered off. The filter was washed with water and dried. White solid. Yield: 0.50 g (57%). 1 H NMR (400 MHz, CDCI3, δ ppm): 9.01 (s, 1 H), 8.83 (s, 1 H), 8.33 (s, 1 H), 8.15 (d, J = 8.8 Hz, 1 H), 8.08 (dd, J = 8.4, 1.2 Hz, 1 H), 8.00 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.54-7.50 (m, 1 H), 7.48-7.38 (m, 1 H), 7.33-7.29 (m, 1 H), 3.08 (s, 3H).
1 1f) 1-(5-(2-Fluorophenyl)pyridin-2-yl)-N-methyl-N-(2-(methylamino)ethyl)-3-(methylsulfinyl)-1 H- indole-6-carboxamide
To a stirred solution of compound 1 1 e (200 mg, 0.507 mmol, 1.0 eq) and N ,N2-dimethylethane-1 ,2- diamine (98 mg, 1.1 16 mmol, 2.2 eq) in dry DMF (5 mL) were added HATU (289 mg, 0.761 mmol, 1.5 eq) and DIPEA (0.3 mL, 1.52 mmol, 3.0 eq) and the reaction mixture was stirred for 1 h at RT. The mixture was diluted with ice water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organic layers were washed with water, dried over Na2S04 and evaporated. The raw product was purified by column chromatography [100-200 mesh, DCM/MeOH = 95:5]. White solid. Yield: 60 mg (12%). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.83 (s, 1 H), 8.68 (s, 1 H), 8.59 (s, 1 H), 8.29 (d, J = 9.2 Hz, 1 H), 8.07-8.01 (m, 2H), 7.74-7.69 (m, 1 H), 7.53-7.51 (m, 1 H), 7.43-7.37 (m, 3H), 4.10-3.40 (m, 3H), 3.25-2.80 (m, 9H), 2.62-2.40 (m, 2H).
Example 12: (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin1-6'-yl)-3-ethyl-1 H-pyrazolo[3,4-b1pyridin-6-yl) (morpholino)methanone
Figure imgf000044_0001
12a) 2,6-Dichloro-N-methoxy-N-methylnicotinamide
Ο,Ν-Dimethyl-hydroxylamine hydrochloride (19 g, 0.195 mol), EDCxHCI (27.4 g, 0.143 mol) and HOBT (19.32 g, 0.143 mol) were added at 0°C to a stirred suspension of 2,6-dichloro-nicotinic acid (25 g, 0.13 mol) in DCM (450 ml). The reaction mixture was stirred for 15 min, TEA (72 ml, 0.52 mol) was added drop wise at 0°C, and stirring was continued at RT for 16 h. The reaction mixture was washed successively with water, saturated NaHCCh solution, saturated NH4CI solution and brine, dried over Na2S04 and concentrated. The remnant was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 9: 1]. White solid. Yield: 25 g (81 %). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.1 1-8.09 (d, 1 H), 7.70-7.68 (d, 1 H), 3.65-3.47 (m, 3H), 3.30-3.12 (m, 3H).
12b) 1-(2,6-Dichloropyridin-3-yl)propan-1-one
Ethyl magnesium bromide (3 M in diethyl ether, 53.3 ml, 0.16 mol) was added drop wise at 0°C to a stirred solution of 2,6-dichloro-N-methoxy-N-methyl-nicotinamide (15 g, 0.064 mol) in THF (300 ml) and the resulting reaction mixture was stirred at RT for 2 h. The reaction mixture was poured into saturated NH4CI solution (150 ml) and extracted with EtOAc (2 x 150 ml). The combined organic layers were washed with brine (150 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure. The raw product was purified by column chromatography [100-200 mesh silica gel, hexane with 5% EtOAc]. Colorless liquid. Yield: 5 g (23%). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.22-8.20 (d, 1 H), 7.72-7.70 (d, 1 H), 3.00-2.94 (q, 2H), 1.06-1.05 (t, 3H).
12c) 6-Ch loro-3-ethyl- 1 H-pyrazolo[3 ,4-bl pyrid i ne
Hydrazine hydrate (6.9 ml, 0.1397 mol) was added at 0°C to a stirred solution of 1-(2-chloro-pyridin-3-yl)- propan-1-one (19 g, 0.0931 mol) in dimethylacetamide (250 ml) and the resulting reaction mixture was stirred at RT for 16 h. CS2CO3 (152 g, 0.4656 mol) was added and the mixture was heated to 120°C for 16 h. The reaction mixture was cooled to RT, poured into ice water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated. The residue was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 9: 1]. White solid. Yield: 5 g (19%). HPLC (method 2): Rt = 1.58 min, m/z: [M+H]+ = 182.1 (MW calc. 181.62). 1 H NMR (400 MHz, CDCI3, δ ppm): 10.74 (bs, 1 H), 8.00-7.98 (d, 1 H), 7.13-7.1 1 (d, 1 H), 3.01-2.95 (q, 2H), 1.40-1.38 (t, 3H).
12d) Methyl 3-ethyl-1 H-pyrazolo[3,4-b1pyridine-6-carboxylate A solution of compound 12c (5 g, 0.0276 mol) and TEA (7.68 ml, 0.0552 mol) in MeOH/DMF (2:1 , 120 mL) was flushed with Ar for 15 min, PdCl2(dppf) (2.02 g, 0.0027 mol) was added and the reaction mixture was heated in a Parr autoclave under an carbon monoxide atmosphere at 100 psi and 80°C for 2 h. The reaction mixture was cooled to RT and filtered through a plug of celite. The filter was rinsed with MeOH and the filtrate was concentrated under reduced pressure and then diluted with EtOAc. The organic phase was washed with water and brine, dried over Na2S04 and concentrated. The raw product was purified by column chromatography [silica 100-200 mesh, hexane/EtOAc = 4: 1]. Light brown solid. Yield: 850 mg (15%). HPLC (method 1 ): Rt = 2.66 min, m/z: [M+H]+ = 206 (MW calc. 205.21 ). 1 H NMR (400 MHz, CDCI3, δ ppm): 13.23 (s, 1 H), 8.23-8.21 (d, 1 H), 8.01-7.99 (d, 1 H), 4.20 (s, 3H), 3.01-2.94 (q, 2H), 1.45-1.43 (t, 3H).
12e) 1-(5-Bromopyridin-2-yl)-3-ethyl-1 H-pyrazolo[3,4-blpyridine-6-carboxylic acid
Compound 12d (700 mg, 3.4146 mmol), CS2CO3 (2.22 g, 6.8292 mmol) and 5-bromo-2-fluoro-pyridine (902 mg, 5.1219 mmol) in DMF (20 mL) were stirred at 80°C for 16 h. The reaction mixture was poured into ice water and washed with MTBE. The aqueous phase was acidified with 6 N hydrochloride solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04 and evaporated to dryness. White solid. Yield: 550 mg (46%). HPLC (method 2): Rt = 1.72 min, m/z: [M+H]+ = 349.0 (MW calc. 347.17). 12f ) (1-(5-Bromopyridin-2-yl)-3-ethyl-1 H-pyrazolo[3,4-blpyridin-6-yl)(morpholino)methanone
NMM (0.55 ml, 5.0287 mmol) and TBTU (1.29 g, 4.0229 mmol) were added at 0°C to a stirred suspension of compound 12e (700 mg, 2.01 14 mmol) in DMF (10 ml). 15 min later, morpholine (0.0.26 ml, 3.0172 mmol) was added drop wise and the reaction mixture was stirred at RT for 16 h. The mixture was washed successily with water, saturated NaHCCh solution, saturated NH4CI solution and brine, dried over Na2S04 and concentrated. The residues was triturated with MTBE affording the target compound as white solid. Yield: 530 mg (63%). HPLC (method 1 ): Rt = 3.0 min, m/z: [M+H]+ = 415.9 (MW calc. 416.27).
12g) (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridinl-6'-yl)-3-ethyl-1 H-pyrazolo[3,4-blpyridin-6-yl)
(morpholino)methanone
PdCl2(dppf) (30 mg, 0.036 mmol) was added to a suspension of compound 12f (300 mg, 0.721 1 mmol), bis(pinacolato)diboron (293 mg, 1.1538 mmol) and KOAc (213 mg, 2.1634 mmol) in dioxane (10 ml) stirred under an inert atmosphere. The reaction mixture was heated for 5 h at 1 10°C and then cooled to 90°C. 1-(2-Bromo-pyridin-4-yl)-1-methyl-ethylamine hydrochloride (272 mg, 1.0817 mmol), 2M aquoes K2CO3 solution (1 .44 ml) and tetrakis(triphenylphosphine) palladium(O) (42 mg, 0.036 mmol) were added at this temperature and stirring was continued at 90°C for 16 h. The mixture was filtered through a plug of celite and the filter was rinsed with MeOH/DCM (1 :9). The combined filtrates were concentrated and the residue was purified by column chromatography [silica 100-200 mesh, DCM with 2% MeOH]), followed by trituration in acetone/MTBE (20 ml). White solid. Yield: 70 mg, (20%). HPLC (method 2): Rt = 1.56 min, m/z: [M+H]+ = 473.2 (MW calc. 471.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.28 (m, 1 H), 8.73-8.70 (dd, 1 H), 8.65-8.64 (d, J = 5.1 Hz, 1 H), 8.57-8.55 (d, J = 8.2 Hz, 1 H), 8.32-8.30 (d, J = 8.6 Hz, 1 H), 8.12 (s, 1 H), 7.60-7.58 (d, J = 8.2 Hz, 1 H), 7.51-7.50 (dd, 1 H), 5.36 (s, 1 H), 3.72 (m, 4H), 3.65-3.63 (m, 4H), 3.12-3.06 (q, 2H), 1.51 (s, 6H), 1.43-1.39 (t, 3H).
Example 13: (3-Ethyl-1-(4-(2-hvdroxypropan-2-ylH2,3'-bipyridinl-6 I)-1 H-pyrazolo[3,4-blpyridin-6-ylV (morpholino)methanone
Figure imgf000046_0001
Prepared analogously to synthesis example 12. White solid. Yield: 1 10 mg. HPLC (method 2): Rt = 1.36 min, m/z: [M+H]+ = 472.3 (MW calc. 472.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.30-9.29 (m, 1 H), 8.73-8.70 (dd, 1 H), 8.64-8.62 (d, J = 5. 2 Hz, 1 H), 8.57-8.55 (d, J = 8.2 Hz, 1 H), 8.32-8.29 (d, J = 8.6 Hz, 1 H), 8.22 (s, 1 H), 7.60-7.58 (d, J = 8.2Hz, 1 H), 7.55-7.54 (dd, 1 H), 5.36 (s, 1 H), 3.72 (m, 4H), 3.64-3.63 (m, 4H), 3.10-3.08 (q, 2H), 1.44-1.39 (m, 9H).
Example 14: (1-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-3-ethyl-1 H-pyrazolo[3,4-blpyridin-6-yl)-
(morpholino)methanone
Figure imgf000046_0002
14a) 1-(4-Bromophenyl)-3-ethyl-1 H-pyrazolo[3,4-blpyridine
(4-Bromo-phenyl)-hydrazine hydrochloride (21.63 g, 0.0968 mol) was added at 0°C to a solution of 1-(2- chloro-pyridin-3-yl)-propan-1-one (7.5 g, 0.044 mol) in dimethylacetamide (150 ml) and the resulting reaction mixture was stirred at RT for 36 h. CS2CO3 (71.68 g, 0.22 mol) was added and the mixture was heated to 120°C for 6 h. The reaction mixture was then cooled to RT, poured into ice water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 9: 1]. White solid. Yield: 7.5 g (56%). HPLC (method 2): Rt = 1.89 min, m/z: [M+H]+ = 304.0 (MW calc. 302.17). 14b) 1-(4-Bromophenyl)-3-ethyl-1 H-pyrazolo[3,4-b1pyridine 7-oxide
m-CPBA (40.34 g, 0.18 mol) was added at 0°C to a stirred solution of compound 14a (1 1 g, 0.036 mol) in acetic acid (250 ml). The resulting reaction mixture was stirred at 60°C for 16 h, then cooled to RT and poured into ice water. The mixture was basified with saturated NaHCCh solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2S04 and concentrated. The remnant was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 9:1]. White solid. Yield: 5 g (43%). HPLC (method 2): Rt = 1.64 min, m/z: [M+H]+ = 320.0 (MW calc. 318.17). 14c) 1-(4-Bromophenyl)-3-ethyl-1 H-pyrazolo[3,4-blpyridine-6-carbonitrile
Dimethylcarbamoylchloride (6.4 ml, 0.048 mol) followed by trimethylsilyl cyanide (4.41 ml, 0.048 mol) were added at 0°C to a solution of compound 14b (5 g, 0.016 mol) in DCM (100 ml) and the resulting reaction mixture was stirred at RT for 42 h. The solvent was evaporated and the residue purified by column chromatography [100-200 mesh silica gel, hexane with 5% EtOAc]. Yellow solid. Yield: 3.4 g (66%). HPLC (method 1 ): Rt = 4.1 1 min, m/z: [M+H]+ = 327.0 (MW calc. 327.18).
14d) 1-(4-Bromophenyl)-3-ethyl-1 H-pyrazolo[3,4-blpyridine-6-carboxylic acid
NaOH (1.6 g, 0.039 mol) was added at RT to a solution of compound 14c (4.4 g, 0.013 mol) in THF/MeOH/water (180 ml, 4: 4: 1 ) and the resulting reaction mixture was refluxed for 42 h. The mixture was concentrated, diluted with water and washed with MTBE. The aqueous phase was acidified with 6 N hydrogen chloride solution and extracted with EtOAc. The combined organic layers were washed with water and brine, dried with Na2S04 and concentrated. The raw product was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 3:2]. Yellow solid. Yield: 3.3 g (70%). HPLC (method 2): Rt = 1.89 min, m/z: [M+H]+ = 347.9 (MW calc. 346.18). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 13.52 (s, 1 H), 8.57-8.55 (d, 1 H), 8.35-8.33 (d, 2H), 7.99-7.97 (d, 1 H), 7.78-7.75 (d, 2H), 3.10-3.04 (q, 2H), 1.39-1.37 (t, 3H).
14e) (1-(4-Bromophenyl)-3-ethyl-1 H-pyrazolo[3,4-b1pyridin-6-yl)(morpholino)methanone
Compound 14d (400 mg, 1.155 mmol), NMM (0.32 ml, 2.89 mmol) and TBTU (742.4 mg, 2.31 mmol) in DMF (5 ml) were stirred at 0°C for 15 min Morpholine (0.15 ml, 1.73 mmol) was added at this temperature drop wise and stirring was continued at RT for 16 h. The reaction mixture was washed successively with water, saturated NaHCCh solution, saturated NH4CI solution and brine, dried over Na2S04 and concentrated. The raw product was triturated with MTBE affording the target molecule as white solid. Yield: 400 mg (88%). HPLC (method 2): Rt = 1.78 min, m/z: [M+H]+ = 417.2 (MW calc. 415.28). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.55-8.53 (d, 1 H), 8.22-8.20 (d, 2H), 7.78-7.75 (d, 2H), 7.54-7.52 (d, 1 H), 3.71 (m, 4H), 3.60-3.52 (m, 4H), 3.08-3.03 (q, 2H), 1.39-1.37 (t, 3H).
14f) 1-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-3-ethyl-1 H-pyrazolo[3,4-b1pyridin-6- yl)(morpholino)methanone
PdCl2(dppf) (14.6 mg, 0.018 mmol) was added to compound 14e (150 mg, 0.36 mmol), bis(pinacolato)diboron (137.1 mg, 0.576 mmol) and KOAc (106 mg, 1.08 mmol) in dioxane (7.5 ml) stirred under Ar. The reaction mixture was stirred at 1 10°C for 5 h and then cooled to 90°C. 1-(2-Bromo-pyridin- 4-yl)-1-methyl-ethylamine (135.7 mg, 0.54 mmol), 2M K2CO3 solution (0.72 ml) and tetrakis(triphenylphosphine)palladium(0) (20.8 mg, 0.018 mmol) were added at this temperature and stirring was continued at 90°C for 16 h. The mixture was filtered through a plug of celite and the filter was rinsed with MeOH/DCM (1 :9). The filtrate was evaporated to dryness and the residue was purified by column chromatography [silica 100-200 mesh, DCM with 2% MeOH] followed by trituration with acetone/MTBE (20 ml). White solid. Yield: 80 mg (47%). HPLC (method 2): Rt = 2.73 min, m/z: [M+H]+ = 471.2 (MW calc. 470.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.58-8.54 (m, 2H), 8.38-8.36 (d, J = 8.9 Hz, 2H), 8.33-8.31 (d, J = 8.9 Hz, 2H), 8.15 (s, 1 H), 7.56-7.54 (d, J = 8.2 Hz, 1 H), 7.48-7.46 (dd, 1 H), 5.33 (s, 1 H), 3.73 (m, 4H), 3.64-3.59 (m, 4H), 3.12-3.06 (q, 2H), 2.13 (bs, 2H), 1.42-1.39 (m, 9H).
Example 15: (3-Ethyl-1-(4-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[3,4-blpyridin-6-yl)-
(morpholino)methanone
Figure imgf000048_0001
Prepared from compound 14e and 2-(2-bromo-pyridin-4-yl)-propan-2-ol in analogy to synthesis procedure 14f. White solid. Yield: 90 mg. HPLC (method 2): Rt = 1.52 min, m/z: [M+H]+ = 472.4 (MW calc. 471.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.60-8.59 (d, J = 5.1 Hz, 1 H), 8.56-8.54 (d, J = 8.2 Hz, 1 H), 8.39- 8.37 (d, J = 8.8 Hz, 2H), 8.31-8.29 (d, J = 8.8 Hz, 2H), 8.05 (s, 1 H), 7.56-7.54 (d, J = 8.2 Hz, 1 H), 7.44- 7.42 (dd, 1 H), 5.33 (s, 1 H), 3.73 (m, 4H), 3.65-3.59 (m, 4H), 3.1 1-3.06 (q, 2H), 1.50 (s, 6H), 1.41-1.39 (t, J = 7.5 Hz, 3H).
Example 16: (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
Figure imgf000048_0002
16a) n-(5-(2-Fluoro-5-qrifluoromethvO^
(morpholino)methanone
K2CO3 (1.24 g, 9 mmol) and (AtaPhos)2PdCI2 (0.212 g, 0.3 mmol) were added to a solution of (1-(5- bromopyridin-2-yl)-3-(methylthio)-1 H-indazol-6-yl)(morpholino)methanone (1.3 g, 3 mmol) and [2-fluoro-5- (trifluoromethyl)phenyl]boronic acid (1.24 g, 6 mmol) in tert-amylalcohol (40 mL) and water (4 mL) stirred under Ar. The reaction mixture was heated at 100°C for 5 h, then cooled and filtered over a plug of celite. The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography [silica; hexane with 0-50% EtOAc] and then washed with DCM/pentane (5 mL). White solid. Yield: 0.7 g (45%). HPLC (method 1 ): Rt = 4.02 min, m/z: [M+H]+ = 517.0 (MW calc. 516.51 ).
16b) (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
Compound 16a (0.2 g, 0.39 mmol) and oxone (0.95 g, 1 .55 mmol) in THF (15 mL) and water (5 mL) were stirred at RT for 2 h. The reaction mixture was quenched with sat. Na2S03 solution and extracted with EtOAc (3x 100 mL). The combined organic layers were washed with sat. NaHC03 solution, dried over Na2S04 and concentrated. The raw product was purified by flash column chromatography [silica; DCM with 2-5% MeOH]. White solid. Yield: 0.075 g (35%). HPLC (method 1 ): Rt = 1.74 min, m/z: [M+H]+ = 549.3 (MW calc. 548.51 ). 1 H NMR (400 MHz, DMSO-d6, 100°C, δ ppm): 8.93-8.89 (m, 2H), 8.39-8.37 (m, 1 H), 8.22-8.19 (m, 2H), 8.07-8.05 (m, 1 H), 7.87 (s, 1 H), 7.65-7.56 (m, 2H), 3.66-3.65 (m, 4H), 3.56 (s, 4H), 3.52 (s, 3H).
Examples 17 and 18: (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-
Figure imgf000049_0001
The racemate was obtained from compound 16a via m-CPBA oxidation in analogy to procedure 3e (yield: 0.35 g, white solid) and submitted for chiral preparative HPLC affording the single enantiomers (column: Chiralpack-IA column 250 x 21.0 mm, 5μιη; mobile phase: hexane/EtOAc/ ethanol/diethylamine = 50/25/25/0.1 ; flow rate: 21.0 ml/min). Faster eluting enantiomer (example 17): Yield = 100 mg. White solid. Specific optical rotation: [a]s8925 = - 64.45° (c. 0.6222, CHCI3). Enantiomer excess = 100%. HPLC (method 2): Rt = 1.77 min, m/z: [M+H]+ = 533.1 (MW calc. 532.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.93-8.91 (m, 2H), 8.38-8.35 (m, 1 H), 8.31 (d, 1 H, J = 8 Hz), 8.17 (d, 1 H, J = 8.4 Hz), 8.12-8.1 1 (m, 1 H), 7.91 (bs, 1 H), 7.69 (t, 1 H, J = 10 Hz), 7.51 (d, 1 H, J = 8.4 Hz), 3.70-3.57 (m, 6H), 3.39 (s, 2H), 3.23 (s, 3H).
Slower eluting enantiomer (example 18): Yield = 75 mg. White solid. Specific optical rotation: [a]58925 = +62.92° (c. 0.3608, CHCb). Enantiomer excess = 99.6%. HPLC (method 3): Rt = 3.74 min, m/z: [M+H]+ = 533.0 (MW calc. 532.51 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.93-8.91 (m, 2H), 8.38-8.29 (m, 2H), 8.18-8.1 1 (m, 2H), 7.91 (bs, 1 H), 7.69 (t, 1 H, J = 9.6 Hz), 7.51 (d, 1 H, J = 8.4 Hz), 3.70-3.57 (m, 6H), 3.50-3.38 (m, 2H), 3.23 (s, 3H).
Figure imgf000050_0001
19a) (4-Bromo-2-fluorophenyl)(cvclopropyl)methanol
Cyclopropyl magnesium bromide (0.7 M in THF, 27.4 mL, 19.21 mmol) was added drop wise at 0°C to a solution of 4-bromo-2-fluorobenzaldehyde (3 g, 14.77 mmol) in dry THF (80 mL). The reaction mixture was stirred at 0°C for 30 min, then slowly warmed to RT over 3 h and quenched with sat. NH4CI solution (50 mL). The mixture was extracted with EtOAc (3x 150 mL) and the combined organic layers were washed with brine, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica; hexane with 10% EtOAc]. Colorless oil. Yield: 2.3 g (63%). 19b) (4-Bromo-2-fluorophenyl)(cvclopropyl)methanone
(4-Bromo-2-fluorophenyl)(cyclopropyl)methanol (2.1 g, 8.56 mmol) and MnCte (2.98 g, 34.27 mmol) in DCM (120 mL) were stirred at 50°C for 18 h. The reaction mixture was cooled to RT and filtered through a plug of celite. The celite was rinsed with DCM (100 mL) and the filtrate was concentrated. The remnant was purified by flash column chromatography [silica; hexane with 10% EtOAc]. Colourless oil. Yield: 0.8 g (38%). HPLC (method 1 ): Rt = 3.62 min, m/z: [M+H]+ = 244.9 (MW calc. 243.07).
19c) 6-Bromo-3-cvclopropyl-1 H-indazole
Hydrazine hydrate solution (1 1.3 mL, 230.38 mmol) was added at RT to (4-bromo-2-fluoro- phenyl)(cyclopropyl)methanone (2.8 g, 1 1.52 mmol) in DMSO (5 mL) and the reaction mixture was heated at 130°C for 22 h. The mixture was cooled to RT and diluted with water. A precipitating solid was filtered off and dried. White solid. Yield: 2.5 g (92%) 19d) 3-Cvclopropyl-6-(ethylthio)-1 H-indazole
Xantphos (0.12 g, 0.21 mmol), Pd2(dba)3 (0.096 g, 0.105 mmol), DIPEA (0.75 mL, 4.22 mmol) and ethanethiol (0.16 mL, 2.1 1 mmol) were added at RT to a solution of 6-bromo-3-cyclopropyl-1 H-indazole (0.5 g, 2.1 1 mmol) in dioxane (30 mL) stirred under Ar and the reaction mixture was heated at 100°C for 18 h. The mixture was cooled to RT and filtered through a plug of celite. The filtrate was concentrated and the residue purified by flash column chromatography [silica; hexane/EtOAc = 4: 1]. Greenish solid. Yield: 0.45 g (98%).
19e) 1-(5-Bromopyridin-2-yl)-3-cvclopropyl-6-(ethylthio)-1 H-indazole
3-Cyclopropyl-6-(ethylsulfanyl)-1 H-indazole (1.8 g, 8.24 mmol), 5-bromo-2-fluoro-pyridine (2.17 g, 12.36 mmol) and Cs2C03 (6.7 g, 20.61 mmol) in dry DMF (12 mL) were stirred at 120°C for 3h. The reaction mixture was cooled to RT and poured into ice cold water. The precipitate was filtered off with a sintered funnel and the filter was dissolved in DCM (100 mL) and washed with brine. The organic layer was dried over Na2S04 and concentrated. White solid. Yield: 91 % (2.8 g, 7.48 mmol)
19f) 2-(6'-(3-Cvclopropyl-6-(ethylthio)-1 H-indazol-1-yl)-[2,3'-bipyridin1-4-yl)propan-2-amine
PdCl2(dppf) (54 mg, 0.066) was added to a suspension of compound 19e (0.5 g, 1.33 mmol), bis(pinacolato)diboron (0.68 g, 2.67 mmol) and KOAc (0.39 g, 4.01 mmol) in dioxane (20 mL) stirred under Ar. The reaction mixture was heated at 1 10°C for 3 h and then cooled to RT. 2-(2-Bromopyridin-4- yl)propan-2-amine (0.37 g,1 .47 mmol), 2M K2CO3 solution (2 mL) and tetrakis (triphenylphosphine)- palladium(O) (77 mg, 0.066 mmol) were added successively and the reaction mixture was stirred at 100°C for 16 h. The reaction mixture was again cooled to RT and filtered through a sintered funnel. The filtrate was concentrated and the residue purified by flash column chromatography [silica; DCM with 0-12 % MeOH]. Grey solid. Yield: 0.26 g (45%). HPLC (method 1 ): Rt = 4.47 min, m/z: [M+H]+ = 429.8 (MW calc. 429.58).
19g) 2-(6'-(3-Cvclopropyl-6-(ethylsulfonyl)-1 H-indazol-1-yl)-[2,3'-bipyridin1-4-yl)propan-2-amine
Compound 19f (0.18 g, 0.42 mmol) in THF (16 mL) and water (5.5 mL) was stirred in the presence of oxone (1.03 g, 1.67 mmol) at RT for 3 h. The mixture was quenched with sat. Na2S03 solution and extracted with EtOAc (3x 100 mL). The combined organic layers were washed with sat. NaHCCh solution, dried over Na2S04 and evaporated. The residue was purified by combi flash column chromatography [silica; DCM with 0-15% MeOH]. White solid. Yield: 0.06 g (31 %). HPLC (method 2): Rt = 1.53 min, m/z: [M+H]+ = 462.2 (MW calc. 461.58). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.36-9.33 (m, 2H), 8.72-8.69 (m, 1 H), 8.61 (d, 1 H, J = 5.2 Hz), 8.27-8.25 (m, 2H), 8.07-8.05 (m, 1 H), 7.82 (d, 1 H, J = 8.4 Hz), 7.53-7.52 (m, 1 H), 3.43-3.37 (m, 2H), 2.56-2.52 (m, 1 H), 1.43 (s, 6H), 1.19-1.13 (m, 7H).
Examples 20 and 21 : 2-(6'-(3-Cvclopropyl-6-(ethylsulfinyl)-1 H-indazol-1-yl)-[2,3'-bipyridin1-4-yl)propan-2- amine (faster and slower elutinq enantiomer)
Figure imgf000052_0001
Oxone (0.19 g, 0.31 mmol) was added portion wise at RT to a solution of compound 19f (0.45 g, 1.04 mmol) in THF (32 mL) and water (10 mL). The reaction mixture was stirred at RT for 1 h, quenched with sat. Na2S03 solution and extracted with EtOAc (3x 100 mL). The combined organic layers were washed with sat. NaHCCh solution, dried over Na2S04 and concentrated. The remnat was purified by combi flash column chromatography [silica; DCM with 0-15% MeOH]. White solid. Yield: 0.25 g (53%). The racemic sulfoxide thus obtained was submitted to preperative chiral SFC HPLC to afford the single enantiomers (column: YMC Chiral Amylose-C 250 x 20 mm; mobile phase: 50% C02 / 50% MeOH with 0.5% isopropylamine; flow rate: 20.0 g/min; temperature: 35°C, column pressure: 100 bar).
Faster eluting enantiomer (example 20): Yield = 45 mg. White solid. Enantiomer excess = 100%. HPLC (method 2): Rt = 1.51 min, m/z: [M+H]+ = 446.3 (MW calc. 445.58). 1 H NMR (400 MHz, MeOD, δ ppm): 9.20 (s, 1 H), 9.15-9.14 (m, 1 H), 8.60-8.59 (m, 1 H), 8.51-8.48 (m, 1 H), 8.10-8.07 (m, 3H), 7.54-7.51 (m, 2H), 3.16-3.10 (m, 1 H), 2.99-2.94 (m, 1 H), 2.43-2.39 (m, 1 H), 1.56 (s, 6H), 1.27-1.17 (m, 7H).
Slower eluting enantiomer (example 21 ): Yield = 46 mg. White solid. Enantiomer excess = 100%. HPLC (method 1 ): Rt = 2.97 min, m/z: [M+H]+ = 446.0 (MW calc. 445.58). 1 H NMR (400 MHz, MeOD, δ ppm): 9.19 (s, 1 H), 9.15-9.14 (m, 1 H), 8.61-8.59 (m, 1 H), 8.51-8.48 (m, 1 H), 8.10-8.09 (m, 1 H), 8.08-8.07 (m, 2H), 7.54-7.50 (m, 2H), 3.15-3.08 (m, 1 H), 2.99-2.94 (m, 1 H), 2.43-2.39 (m, 1 H), 1.56 (s, 6H), 1.27-1.14 (m, 7H).
Example 22: 2-(6'-(3-Ethyl-6-(ethylsulfonyl)-1 H-indazol-1-yl)-[2,3'-bipyridinl-4-yl)propan-2-amine
Figure imgf000052_0002
Prepared from 3-ethyl-6-(ethylthio)-1 H-indazole in three steps analogoulsy to example 19. White solid. Yield: 0.06 g. HPLC (method 2): Rt = 1.49 min, m/z: [M+H]+ = 450.2 (MW calc. 449.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.37-9.34 (m, 2H), 8.74-8.71 (m, 1 H), 8.61 (d, 1 H, J = 5.2 Hz), 8.28 (s, 1 H), 8.22 (d, 1 H, J = 8.4 Hz), 8.14 (d, 1 H, J = 8.8 Hz), 7.82-7.79 (m, 1 H), 7.53-7.52 (m, 1 H), 3.43-3.37 (m, 2H), 3.16-3.10 (m, 2H), 2.21 (bs, 2H), 1.45-1.41 (m, 9H), 1.17 (t, 3H, J = 7.6 Hz).
Examples 23 and 24: 2-(6'-(3-Ethyl-6-(ethylsulfinyl)-1 H-indazol-1-yl)-[2,3'-bipyridinl-4-yl)propan-2-amine
(faster and slower elutinq enantiomer)
Figure imgf000053_0001
The racemic sulfoxide (brown solid, 0.15 g) was obtained in analogy to example 20 and submitted to preperative chiral HPLC to afford the single enantiomers (column: Chiralpack-IA column 250 x 21 .0 mm, 5μιη; mobile phase: hexane/EtOAc/ethanol/diethylamine = 70/15/15/0.1 ; flow rate: 21.0 ml/min).
Faster eluting enantiomer (example 23): Yield = 44 mg. Brown solid. Enantiomer excess = 100%. HPLC (method 2): Rt = 1.50 min, m/z: [M+H]+ = 434.3 (MW calc. 433.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 1 H), 9.08 (s, 1 H), 8.71-8.69 (m, 1 H), 8.61 (d, 1 H, J = 5.2 Hz), 8.26 (s, 1 H), 8.1 1-8.08 (m, 2H), 7.53-7.51 (m, 2H), 3.14-3.07 (m, 3H), 2.88-2.85 (m, 1 H), 2.26 (bs, 2H), 1.44-1.40 (m, 9H), 1.08 (t, 3H, J = 7.2 Hz). Slower eluting enantiomer (example 24): Yield = 39 mg. Brown solid. Enantiomer excess = 99.2%. HPLC (method 2): Rt = 1.48 min, m/z: [M+H]+ = 434.3 (MW calc. 433.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.34 (s, 1 H), 9.08 (s, 1 H), 8.71-8.69 (m, 1 H), 8.62 (d, 1 H, J = 5.2 Hz), 8.26 (s, 1 H), 8.12-8.08 (m, 2H), 7.54-7.51 (m, 2H), 3.13-3.07 (m, 3H), 2.88-2.86 (m, 1 H), 1.44-1.40 (m, 9H), 1.08 (t, 3H, J = 7.2 Hz). Biological testing
TR-FRET assay using the LANCE® Ultra cAMP kit to determine the activity of hPDE4B1
The effects of the compounds on the activity of the human PDE4B1 was quantified by measuring the production of 5ΆΜΡ from cAMP using a human recombinant enzyme expressed in Sf9 cells and the LANCE® Ultra cAMP kit, a TR-FRET detection method from PerkinElmer. The human PDE4B1 enzyme was purchased from SignalChem Lifesciences (Catalog# P92-31 BG).
The test compound, reference compound or water (control) was mixed with the enzyme (0.96 U) in a reaction buffer containing 50 mM Tris-HCI, 50 mM MgCI∑ and 5 mM DTT (pH 8.5). Thereafter, the reaction was initiated by addition of 500 nM cAMP (substrate) and the mixture was incubated for 30 min at rt. For control basal measurements, the enzyme was omitted from the reaction mixture. After 30 min, the reaction was stopped and diluted by a factor of 100 with the reaction buffer supplemented with 500 μΜ IBMX. The fluorescence donor (Europium chelate-labeled cAMP) and the fluorescence acceptor (anti- cAMP antibody labeled with the ULight™ dye) were then added together with 500 μΜ IBMX to a 10 μΙ aliquot. After 60 min, the fluorescence transfer corresponding to the amount of residual cAMP was measured at Aex = 337 nm, Aenri = 620 nm and Aenri = 665 nm using a microplate reader (PHERAstar, BMG). The enzyme activity was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio) multiplied by 10000. The results were expressed as percent inhibition of the control enzyme activity. ICso values (ICso = concentration causing a half-maximal inhibition of control specific activity) were derived from dose response measurements with ten different concentrations (n = 3; N = 1- 3).
Several compounds according to the invention are tested in the above-described assay. The results are given in the tables below (ICso inhibition of PDE4B of Examples Nos.):
No. PDE4B ICso No. PDE4B ICso No. PDE4B ICso No. PDE4B ICso
[μΜ] (mean) [μΜ] (mean) [μΜ] (mean) [μΜ] (mean)
1 0.005 7 0.006 13 0.045 19 0.001
2 0.018 8 0.023 14 0.016 20 <0.001
3 0.025 9 0.004 15 0.018 21 0.006
4 0.016 10 0.146 16 0.002 22 <0.001
5 0.004 1 1 0.892 17 0.005 23 0.007
6 0.004 12 0.155 18 0.021 24 0.001

Claims

Claims
1. A compound of formula (I)
Figure imgf000055_0001
wherein
A, B and C independently represent CH or N;
X1 represents CH or N;
X2 represents CH or N;
L is selected from the group consisting of C(=0)NR2, S(=0), S(=0)2, S(=0)2NR2, P(=0)(R2), O or bond;
R is selected from
Ci-C 6-alkyl, unsubstituted or mono- or polysubstituted;
or
C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl, in each case unsubstituted or mono- or polysubstituted;
R2 is selected from H or Ci-C6-alkyl, unsubstituted or mono- or polysubstituted;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl,
wherein said 3- to 12-membered heterocycloalkyl may contain one or two additional heteroatoms selected from the group consisting of O, S and N and may be mono- or bicyclic and
wherein said 3- to 12-membered heterocycloalkyl is unsubstituted or mono- or polysubstituted; R3 is is selected from the group consisting of (Ci-Ce)-alkyl, (Ci-C6)-hydroxyalkyl, (C3-C6)-cycloalkyl and SOx-(Ci-C6)-alkyl,
wherein x is 1 or 2;
G represents a phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or said 5- or 6- membered heteroaryl is unsubstituted or substituted with one, two, three or four substituents Z, wherein
Z at each occurcence is independently selected from the group consisting of halogen, OH , CN, SH , N02, Ci-Ce-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, Ci-C6- alkoxy, (Ci-C6)-thioalkyl, (Ci-C6)-haloalkyl, (Ci-C6-alkoxy)-(Ci-C6-alkylenyl), (Ci-C6-alkoxy)-Ci-C6- alkoxy, (Ci-C6)-thiohaloalkyl, (Ci-C6)-haloalkoxy, (Ci-C6-thioalkyl)-(Ci-C6-alkylenyl), C3-C6-cycloalkyl, (C3-C6-cycloalkyl)-(Ci-C3-alkylenyl), 3- to 7-membered heterocycloalkyl, (3- to 7-membered heterocycloalkyl)-(Ci-C3-alkylenyl), said C3-6-cycloalkyl and said 3- to 7-membered heterocycloalkyl being in each case unsubstituted or mono- or polysubstituted, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), NHC02(Ci-C6-alkyl), NHC(0)NH2, NHCONH(Ci-C6-alkyl), NHCON(Ci-C6-alkyl)2, (Ci-C6-alkylen)NH2, (Ci-C6-alkylen)NH(Ci-C6-alkyl), (Ci-C6-alkylen)N(Ci-C6-alkyl)2, (Ci-C6- alkylen)NHCO(Ci-C6-alkyl), (Ci-C6-alkylen)NHC02(Ci-C6-alkyl), (Ci-C6-alkylen)NHC(0)NH2, (Ci-C6- alkylen)NHCONH(Ci-C6-alkyl), (Ci-C6-alkylen)NHCON(Ci-C6-alkyl)2, NH((Ci-C6-alkylen)-C02(Ci-C6- alkyl), NH(Ci-C6-alkylen)-CONH2, NH(Ci-C6-alkylen)-CONH(Ci-C6-alkyl), NH(Ci-C6-alkylen)- CON(Ci-C6-alkyl)2, NHS(0)2OH, NHS(0)2(Ci-C6-alkyl), NHS(0)20(Ci-C6-alkyl), NHS(0)2NH2, NHS(0)2NH(Ci-C6-alkyl), NHS(0)2N(Ci-C6-alkyl)2, NH(Ci-C6-alkylen)-S(0)2OH, NH(Ci-C6-alkylen)- S(0)2(Ci-C6-alkyl), NH(Ci-C6-alkylen)-S(0)20(Ci-C6-alkyl), NH(Ci-C6-alkylen)-S(0)2NH2, NH(Ci-C6- alkylen)-S(0)2NH(Ci-C6-alkyl), C02H, CO(Ci-C6-alkyl), C02(Ci-C6-alkyl), 0-CO(Ci-C6-alkyl), O- C02(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl), CON(Ci-C6-alkyl)2, OCONH(Ci-C6-alkyl), OCON(Ci- C6-alkyl)2, OS(0)2(Ci-C6-alkyl), OS(0)2OH, OS(0)20(Ci-C6-alkyl), OS(0)2NH2, OS(0)2NH(Ci-C6- alkyl), OS(0)2N(Ci-C6-alkyl)2, S(0)(Ci-C6-alkyl), S(0)2(Ci-C6-alkyl), S(0)2OH, S(0)20(Ci-C6-alkyl), S(0)2NH2, S(0)2NH(Ci-C6-alkyl), and S(0)2N(Ci-C6-alkyl)2;
optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof.
A compound according to claim 1 , characterized in that each characterized in that each of A and B represents CH and C represents N or CH.
A compound according to claims 1 or 2, characterized in that X1 is N and X2 is N.
A compound according to one or more of claims 1 to 3, characterized in that R3 is selected from the group consisting of methyl, ethyl, propyl, i-propyl, n-butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, cyclopropyl, SOCH3 and SCteCh ,
preferably R3 is selected from the group consisting of methyl, ethyl, hydroxymethyl, 1-hydroxyethyl, 2- hydroxypropan-2-yl, cyclopropyl, SOCH3 and SCteCh ;
more preferably R3 is selected from the group consisting of ethyl, cyclopropyl, SOCH3 and SCteCh .
5. A compound according to one or more of claims 1 to 4, wherein G is one of the following groups G1
Figure imgf000056_0001
Figure imgf000057_0001
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
R 2 is selected H, CH3 or CH2CH3;
k at each occurrence 0, 1 , 2, 3 or 4; and
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH, C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3, SO2CH3, SOCH2CH3, SO2CH2CH3, SO2NH2, pyrrolidinyl, piperidinyl, aziridinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,
wherein said pyrrolidinyl, piperidinyl, aziridinyl, oxetanyl, morpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, and NHCOCH3.
A compound according to one or more of claims 1 to 5, wherein G is one of the following groups G45 or G2
Figure imgf000058_0001
G45 G2
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the pyrimidine ring;
k at each occurrence 0, 1 or 2; and
ZA is H or F;
Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF2, CH2F, OCF3, OH, OCH3, OC2H5, OCOCH3, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), NH(CH2CH3), N(CH3)2, NHCOCH3, CH2OH, CH2CH2OH , C(CH3)2OH, CH(CH3)OH, CH2NH2, CH2CH2NH2, C(CH3)2NH2, CH(CH3)NH2, CH2NH(CH3), CH2CH2NH(CH3), C(CH3)2NH(CH3), CH(CH3)NH(CH3), CH2N(CH3)2, CH2CH2N(CH3)2, C(CH3)2N(CH3)2, CH(CH3)N(CH3)2, CH2CN, SOCH3,S02CH3, cyclopropyl, cyclobutyl, 3-oxetanyl, 2-aziridinyl, 3- aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl, wherein said cyclopropyl, cyclobutyl, 3- oxetanyl, 2-aziridinyl, 3-aziridinyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CI, CN, CF3, OCF3, OH, OCH3, CH3, CONH2, CONHCH3, CON(CH3)2, NH2, NH(CH3), N(CH3)2 and NHCOCH3.
A compound according to any of claims 1 to 6, characterized in that
L is selected from C(=0)NR2, S(=0), S(=0)2 , P(=0)(R2), S(=0)2NR2 or bond.
A compound according to any of claims 1 to 7, characterized in that
L is selected from C(=0)NR2, S(=0), S(=0)2, S(=0)2NR2 or bond; and
R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyl, wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, =N H , NH2, NH(Ci-C6- alkyl), N(Ci-C6-alkyl)2, Ci-C6-alkoxy, C3-C6-cycloalkyl and 3- to 7-membered heterocycloalkyi; and
wherein said 3- to 7-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, NH(Ci-Ce-alkyl), N(Ci-C6-alkyl)2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce-alkoxy;
and
R2 is selected from H or Ci-C6-alkyl
wherein said Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, OH , Ci-C6-alkoxy, and C3-C6- cycloalkyl;
or
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyi,
wherein said 3- to 12-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
wherein said 3- to 12-membered heterocycloalkyi is unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, CN , OH , =0, NH2, NH(Ci-Ce-alkyl), N(Ci-C6-alkyl)2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-haloalkyl and Ci-Ce- alkoxy.
9. A compound according to any of claims 1 to 8, characterized in that
L is C(=0)NR2 and
R is selected from one of the following substructures M1 to M76:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
and
R2 is selected from H or Ch .
A compound according to any of claims 1 to 9, characterized in that
L is C(=0)NR2 and
R and R2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocycloalkyl,
wherein said 3- to 12-membered heterocycloalkyl denotes one of the following groups Q1 to Q34:
Figure imgf000061_0002
Figure imgf000062_0001
Q31 Q32 Q33 Q34
in which the site marked with an asterisk (*) indicates the binding site, which is bonded to the carbonyl group of L;
R5 is selected from the group consisting of H, Ci-C6-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, Cs-Ce-cycloalkyl, CO(Ci-Ce-alkyl) and S02-(Ci-C6)-alkyl;
at each occurrence p is 0, 1 , 2, 3, 4 or 5; and
X6 at each occurrence is independently selected from the group consisting of OH, =0, CN , F, CI, Br, CF3, CHF2, CH2F, OCF3, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-C6)-cyanoalkyl, (Ci-C6)-alkoxy, (C3- C6)-cycloalkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NHCO(Ci-C6-alkyl), C02H, CO(Ci-C6-alkyl), COO(Ci-C6-alkyl), CONH2, CONH(Ci-C6-alkyl) and CON(Ci-C6-alkyl)2.
A compound according to any of claims 1 to 10, characterized in that
L is S(=0) or S(=0)2 and and R is selected from the group consisting of CH3, CH2CH3, (CH2)2CH3, CH(CH3)2, (CH2)3CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, CH2CONH2, CH2CON(CH3)2, CH2CH2OH, CH2CH2CH2OH, CH(CH3)CH2OH, CH2CH(CH3)OH, C(CH3)2CH2OH ,
CH(CH3)CH2CH2OH, cyclopropyl, cyclobutyl and 3-oxetanyl.
12. A compound according to any of claims 1 to 1 1 , characterized in that
L is S(=0) or S(=0)2 and R is selected from the group consisting of CH3, and CH2CH3.
A compound according to one or more of the preceding claims selected from the group consisting of
1 (3-Ethyl-1-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1 H-indazol-6-yl)(morpholino)
methanone
2 3-Ethyl-N-(2-hydroxyethyl)-1-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-N-methyl-1 H- indazole-6-carboxamide
3 (1-(4-Methyl-[2,3'-bipyridin]-6'-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)(morpholino) methanone
4 (1-(4-Methyl-[2,3'-bipyridin]-6'-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)(morpholino) methanone g (1-(5-(2-Fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
g (1-(5-(2-Fluoro-5-methylphenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6-yl)(morpholino) methanone
8 (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin]-6'-yl)-3-(methylsulfonyl)-1 H-indazol-6-yl)
(morpholino)methanone
g (1-(5-(3-(2-Aminopropan-2-yl)phenyl)pyridin-2-yl)-3-(methylsulfinyl)-1 H-indazol-6- yl)(morpholino)methanone
^ 1-(5-(2-Fluorophenyl)pyridin-2-yl)-N-methyl-N-(2-(methylamino)ethyl)-3-(methylsulfinyl)-1 H- indole-6-carboxamide
12 (1-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin]-6'-yl)-3-ethyl-1 H-pyrazolo[3,4-b]pyridin-6-^^
(morpholino)methanone 13 (3-Ethyl- 1 -(4-(2-hyd roxypropan-2-yl )-[2 , 3'-bi pyrid i n]-6'-yl)- 1 H-pyrazolo[3 ,4-b] pyrid in-6- yl)(morpholino)methanone
14 (1-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-3-ethyl-1 H-pyrazolo[3,4-b]p
yl)(morpholino)methanone
(3-Ethyl-1-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[3,4-b]pyridin^ yl)(morpholino)methanone
1g (1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2^
(morpholino)methanone
(1-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyridin-2-yl)-3-(methylsulfin
yl)(morpholino)methanone
19 2-(6 3-Cyclopropyl-6-(ethylsulfonyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-amin
20 2-(6 3-Cyclopropyl-6-(ethylsulfinyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-ami
22 2-(6 3-Ethyl-6-(ethylsulfonyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-amin
23 2-(6 3-Ethyl-6-(ethylsulfinyl)-1 H-indazol-1-yl)-[2,3'-bipyridin]-4-yl)propan-2-ami
optionally in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof. 14. Pharmaceutical composition comprising at least one compound as defined in one of claims 1 to 13.
15. A compound as defined in one of claims 1 to 13 in the presented form or in the form of a single stereoisomer or a mixture of stereoisomers, in the form of the free compound and/or a physiologically acceptable salt and/or a physiologically acceptable solvate thereof, for use as a medicament for the treatment of conditions or diseases that can be treated by inhibition of the PDE4 enzyme,
wherein the conditions or diseases that can be treated by inhibition of the PDE4 enzyme are selected from the following group: inflammatory diseases of the joints, skin and eyes, gastrointestinal diseases and complaints, inflammatory diseases of the internal organs; hyperplastic diseases, respiratory or lung diseases associated with elevated mucus production, inflammation and/or obstruction of the respiratory tract, diseases of the fibrotic spectrum, cancers, metabolic diseases, psychological disorders, and diseases of the peripheral or central nervous system.
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