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WO2018234354A1 - NOVEL SUBSTITUTED 3-INDOLE AND 3-INDAZOLE COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS - Google Patents

NOVEL SUBSTITUTED 3-INDOLE AND 3-INDAZOLE COMPOUNDS AS PHOSPHODIESTERASE INHIBITORS Download PDF

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Publication number
WO2018234354A1
WO2018234354A1 PCT/EP2018/066357 EP2018066357W WO2018234354A1 WO 2018234354 A1 WO2018234354 A1 WO 2018234354A1 EP 2018066357 W EP2018066357 W EP 2018066357W WO 2018234354 A1 WO2018234354 A1 WO 2018234354A1
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Prior art keywords
alkyl
pyrimidin
indole
ethyl
carboxamide
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French (fr)
Inventor
Ingo Konetzki
Florian JAKOB
Markus Wagener
Torsten Dunkern
David Rider
André Welbers
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Gruenenthal GmbH
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Gruenenthal GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/10—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero 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

  • Novel substituted 3-lndole and 3-lndazole compounds as Phosphodiesterase Inhibitors
  • the present invention relates to novel substituted 3-indole and 3-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).
  • PDE4A, PDE4B, PDE4C and PDE4D are 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.
  • the inventors have now found novel substituted 3-indole and 3-indazole compounds that possess the desired inhibiting and PDE4B-selective properties. These 3-indole and 3-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 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 of each other represent CH or N;
  • X 1 , X 2 and W independently of each other represent CH or N;
  • R is selected from
  • 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 H, (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (C3-
  • 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, NO2, 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-cycloalkyl, (
  • 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. ln 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.
  • 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, di benzofuranyl, 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
  • 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 independently of each other represent CH or N and
  • X 1 , X 2 and W independently of each other represent CH or N;
  • 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 X 1 is N and X 2 is N.
  • the compound of formula (I) is characterized in that W is N or W is CH.
  • the compound of formula (I) is preferably characterized in that at least two of C, W, X 1 and X 2 represent N. More preferably,
  • W, X 1 , X 2 each represent N and C respresents CH or
  • C and W each represent N and X 1 and X 2 each represent CH or
  • X 1 and W each represent N and C and X 2 each represent CH or
  • C and X 1 each represent N and W and X 2 each represent CH.
  • the compound of formula (I) is characterized in that R 3 is selected from the group consisting of H, (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (C3- C6)-cycloalkyl and SOx-(Ci-C6)-alkyl, wherein x is 1 or 2.
  • R 3 is selected from the group consisting of H, (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (C 3 -C 6 )-cycloalkyl and S0 2 -(Ci-C 6 )-alkyl;
  • R 3 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH 3 )CH 2 CH3, CH 2 CH(CH 3 )2, C(CH 3 ) 3 , COCH3, COCH2CH3, COCH(CH 3 ) 2 , CF 3 , CHF2, CH2F, CH2CF3, cyclopropyl, SOCH3 and SO2CH3;
  • R 3 is selected from the group consisting of H, CH3, CH2CH3, COCH3, CH2CF3, cyclopropyl 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 heterocycloalkyi, NH 2 , NH(Ci-Ce-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-Ce-alk len)N(Ci-Ce- alkyl) 2 , NHS(0)
  • the compound of formula (I) is characterized in that G is one of the groups G1 to G44,
  • 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 , 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(CH 3 ) 2 NH(CH 3 ), CH(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, 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 ,
  • 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 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
  • 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, CF 3 , CHF2, CH2F, OCF 3 , OH, OCH 3 , OC2H5, OCOCH3, 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 , 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 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH 2 NH(
  • 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)2
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF2, CH2F, OCF 3 , OH, OCH 3 , OC2H5, OCOCH 3 , CH 3 , CH 2 CH 3 , (CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 ,
  • the compound of formula (I) is characterized in that G is one of the following groups G45 or G2 G45 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, 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 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, 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,
  • the compound of formula (I) is characterized in that
  • 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 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 heterocycloalkyi 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-Ce-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-Ce-alkyl), N(Ci-Ce-alkyl) 2 , NHCO(Ci-C 6 -alkyl), C0 2 H , COO(Ci-Ce-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 is selected from one of the following substructures M1 to M76:
  • 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 .
  • R and R 2 together with the nitrogen atom to which they are attached form a 3- to 12-membered heterocydoalkyi
  • said 3- to 12-membered heterocydoalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • 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, ON, Ci-Ce-alkyl, NH 2 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , Cs-Ce-cycloalkyl or 3- to 7-membered heterocycloalkyi,
  • Ci-C6-alkyl may be unsubstituted or substituted with one, two, three or four substituents selected from the group consisting of halogen, ON, 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 , NH(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-C 6 -alkyl)CO(Ci-C 6 -alkyl), NHCO(Ci-C 6 -hydroxyalkyl), N(Ci-Ce-alkyl
  • said 3- to 7-membered heterocycloalkyi 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 , NH(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl) 2 , C 3 -C 6 -cycloalkyl or 3- to 7-membered heterocycloalkyi,
  • 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 heterocycloalkyi;
  • the compound of formula (I) is characterized in that
  • R is selected from Ci-C6-alkyl, C3-C6-cycloalkyl or 3- to 7-membered heterocycloalkyi,
  • 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-Ce- hydroxyalkyl), N(Ci-C 6 -alkyl)(Ci-C 6 -hydroxyalkyl), N(Ci-C 6 -hydroxyalkyl) 2 , NHCO(Ci-C 6 -alkyl), N(Ci-C 6 -alkyl)CO(Ci-C 6 -alkyl), NHCO(Ci-C 6 -hydroxyalkyl), N(Ci-C 6
  • said 3- to 7-membered heterocycloalkyi may contain one or two additional heteroatoms selected from the group consisting of O, S and N and
  • the compound according to general formula (I) is selected from one of the general formula (la), (lb), (lc), (Id) or (le),
  • the compound of formula (I) is a compound according to formula (la), (lb), (Ic), (Id) or (le), 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, CH 3 , CH2CH3, CH2CH2CH3, CH(CH 3 ) 2 , cyclopropyl, C(0)CH 3 , C(0)CH 2 CH 3 , C(0)CH2CH 2 CH 3 , C(0)CH(CH 3 ) 2 , C(0)-cyclopropyl, CH2CH2CN, CH2CH2OH or CH 2 CH 2 OCH 3 ;
  • p is 0, 1 , 2 or 3;
  • each X 6 idependently represents H, CH 3 , CH 2 CH 3 , OH, OCH 3 , CH2OH, CH2CH2OH or CH 2 CH 2 OCH 3 . or
  • R is CH 2 CH 2 NH(CH 3 ), CH 2 CH 2 N(CH 3 )2, CH2CH2OH, 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 H, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH2CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , COCH 3 , COCH 2 CH 3 , COCH(CH 3 ) 2 , CF 3 , CHF2, CH2F, CH 2 CF 3 , cyclopropyl, SOCH 3 and S0 2 CH 3 ;
  • 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 3 and CH2CH 3 ; 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(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 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
  • 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 H, 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 , COCH3, COCH2CH3, COCH(CH 3 ) 2 , CF 3 , CHF2, CH2F, CH2CF3, 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 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 )NH 2 , CH 2 NH(CH 3 ), CH 2 CH 2 NH(CH3), C(CH 3 )
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF 3 , CHF2, CH2F, OCF 3 , OH, OCH 3 , OC2H5, OCOCH3, 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 , CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3
  • the compound according to general formula (I) is selected from one of formula (la), (lb), (Ic), (Id) or (le), 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, 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 , CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH 2 NH 2 , CH 2 CH 2 NH 2 , C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH
  • Z at each occurcence is independently selected from the group consisting of F, CI, CN, CF3, CHF 2 , CH 2 F, OCF3, OH, OCH3, OC 2 H 5 , OCOCH3, 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 , CONHCH3, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCH3, CH 2 OH, CH 2 CH 2 OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, 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
  • the compound according to formula (la), (lb), (Ic), (Id) or (le) 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, CHF 2 , CH 2 F, OCF3, OH, OCH3, OC 2 H 5 , OCOCH3, 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 , 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),
  • 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 H, CH 3 , CH 2 CH 3 , COCH 3 , CH 2 CF 3 , cyclopropyl and S0 2 CH 3 ;
  • 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, CF 3 , CHF2, CH2F, OCF 3 , OH, OCH 3 , OC2H5, OCOCHs, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH2CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH2, CONHCHs, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCHs, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH 2 NH
  • the compound according to general formula (I) is selected from one of formula (la),
  • R is selected from the group consisting of CH 3 and CH2CH 3 ;
  • R 3 is selected from the group consisting of H, CH 3 , CH2CH 3 , COCH 3 , CH2CF 3 , cyclopropyl and S02CH 3 ; 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, CF 3 , CHF2, CH2F, OCF 3 , OH, OCH 3 , OC2H5, OCOCH 3 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH2CH 2 CH 2 CH 3 , CH(CH 3 )CH 2 CH 3 , CH 2 CH(CH 3 ) 2 , C(CH 3 ) 3 , CONH2, CONHCHs, CON(CH 3 ) 2 , NH 2 , NH(CH 3 ), NH(CH 2 CH 3 ), N(CH 3 ) 2 , NHCOCHs, CH2OH, CH2CH2OH, C(CH 3 ) 2 OH, CH(CH 3 )OH, CH2NH2, CH2CH2NH2, C(CH 3 ) 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 )NH 2 , CH 2
  • 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 in particular according to the general structure of formulae (I), (la), (lb), (Ic), (Id) or (le) 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), (Id) or (le).
  • 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), (Id) or (le) 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), (Id) or (le) 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), (Ic), (Id) or (le) 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), (Ic), (Id) or (le) 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), (Ic), (Id) or (le) 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) or (lc) 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 bind
  • pharmaceutical auxiliary substances such as for example carrier materials, fillers, solvents, diluting agents, surface-active substances, dyes, pre
  • 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, 17 th edition, Mack Publishing Company, Easton PD (1985), in particular in part 8, chapters 76 to 93.
  • 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.
  • 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: positive ions; ion source: turbo spray; ion spray voltage: +5500 for positive ions; mass source temperature: 200°C Method 2:
  • 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: positive ions.
  • 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: positive ions; ion source: turbo spray; ion spray voltage: +5500 for positive ions; mass source temperature: 200°C
  • 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: positive ions; ion source: turbo spray; ion spray voltage: +5500 for positive ions; mass source temperature: 200°C 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 R x is (Ci-Ce) alkyl, preferably methyl.
  • Ts tosyl
  • Ms mesyl
  • PdCl2(dppf) 700 mg, 0.700 mmol, 0.05 eq was added to a solution of compound 1 b (6.5 g, 14.28 mmol, 1 eq), KOAc (3.5 g, 36.69 mmol, 2.5 eq) and bis(pinacolato)diboron (7.23 g, 28.58 mmol, 2 eq) in dioxane (70 ml) stirred under Ar.
  • the reaction mixture was refluxed for 16 h, then diluted with water (150 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na2S04 and evaporated under reduced pressure.
  • Synthesis example 1 (0.2 g, 0.55 mmol, 1 eq), TEA (0.153 ml, 1.1 1 mmol, 2 eq), acetic anhydride (0.104 ml, 1.1 1 mmol, 2 eq) and a catalytic amount of DMAP (0.006 g, 0.055 mmol, 0.1 eq) in dichloroethane (7.0 ml) were stirred at 90°C for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC. White solid. Yield: 0.07 g (32%).
  • Example 1 N,N-Dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole-5- carboxamide
  • Example 17 3-(5-(2-Fluoro-5-(2-hvdroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-
  • Methyl 1 H-indazole-5-carboxylate (1.5 g, 8.51 mmol) was added to a suspension of sodium hydride (442 mg, 1 1 .0 mmol, 1 .3 eq) in DMF (25 ml) cooled with an ice bath and the mixture was stirred under cooling for 1 h. Chloromethyl methyl ether (0.71 ml, 9.36 mmol, 1 .1 eq) was added and the mixture was stirred for 14 h upon warming to RT. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and evaporated. The residue was purified by flash chromatography [hexane with 7% EtOAc]. Yield: 1.2 g (64%).
  • Oxalylchloride (81 ⁇ , 0.93 mmol, 2.0 eq) and DMF as catalyst (0.05 ml) were added to a solution of compound 19f (200 mg, 0.46 mmol) in DCM (5 ml) and the resulting reaction mixture was stirred for 3 h at RT.
  • the solvent was distilled off under reduced pressure and a N2 atmosphere and the residue was dissolved in DCM (5 ml).
  • N-Methylaminoethanol (105 mg, 0.46 mmol, 3.0 eq) in DCM (2 ml) was added at 0°C and the mixture was stirred for 16 h at RT.
  • Example 22 1-Ethyl-N-(2-hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-
  • Tetrakis(triphenylphosphine) palladium(O) 35 mg, 0.03 mmol, 0.05 eq
  • a solution of compound 22b (0.15 g, 0.602 mmol, 1 eq) and 2-(2-(2-chloropyrimidin-5-yl)pyridin-4-yl)propan-2-ol (0.15 g, 0.602 mmol, 1.0 eq) in dioxane (3 ml) and aqueous K2CO3 solution (20%; 0.6 ml) that was degassed with Ar aforegoing.
  • Tetrakis(triphenylphosphine) palladium(O) (0.12 g, 0.10 mmol) was added at RT to a solution of compound 58c (0.50 g, 2.1 mmol) and 2-[2-(2-chloro-pyrimidin-5-yl)-pyridin-4-yl]-propan-2-ol (0.52 g, 2.1 mmol) in dioxane (25 mL) and 2M aqueous K2CO3 solution (3 mL) stirred under Ar. The reaction mixture was heated at 90°C for 2 h, cooled to RT and filtered through a plug of celite.
  • the racemate (0.4 g, white solid) was prepared analogously to example 60 but using only 0.5 equivalents of Oxone as oxidizing agent in the last step.
  • the pure enantiomers were obtained from this racemate via chiral preparative SFC (column: YMC Chiral Amylose-C, 250 x 20 mm; mobile phase: 55% carbon dioxide / 45% MeOH with 0.5% isopropylamine; flow rate: 25 g/min; temperature: 35°C; pressure: 85 bar).
  • Tetrakis(triphenylphosphine) palladium(O) (85.49 mg, 0.074 mmol) was added at RT to compound 63f (450 mg, 1.48 mmol) and 2,5-dibromo-benzene (349.07 mg, 1.48 mmol) in 1-4 dioxane (10 ml) and 2M aqueous K2CO3 solution (2 ml, 4.00 mmol) stirred under Ar.
  • the resulting reaction mixture was heated at 100°C for 16 h, cooled to RT and filtered through a plug of celite/Na2S04 (2: 1 ).
  • Example 65 (1-Ethyl-3-(4-(2-hvdroxypropan-2-ylH2,3'-bipyridinl-6'-vn-1 H-pyrazolo[4,3-blpyridin-5-vn-
  • Example 66 (3-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridinl-6'-yl)-1-ethyl-1 H-pyrazolo[4,3-blpyridin-5-yl) (morpholino)methanone
  • Example 68 1-Ethyl-N-(2-hvdroxyethyl)-3-(4-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)phenyl)-N-methyl-1 H- indazole-5-carboxamide
  • 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.
  • ICso values concentration causing a half-maximal inhibition of control specific activity

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Abstract

The invention relates to novel 3-indole and 3-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

- V-
Novel substituted 3-lndole and 3-lndazole compounds as Phosphodiesterase Inhibitors
FIELD OF THE INVENTION
The present invention relates to novel substituted 3-indole and 3-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). 1-lndole and 1-indazole compounds as inhibitors of PDE4B are known from WO 2016/008593 A1 , WO 2016/008592 A1 and WO 2016/008590 A1.
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 3-indole and 3-indazole compounds that possess the desired inhibiting and PDE4B-selective properties. These 3-indole and 3-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 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 of each other represent CH or N;
X1, X2 and W independently of each other represent 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 is selected from the group consisting of H, (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (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, NO2, 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. ln 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, di benzofuranyl, 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)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), COO(Ci-C6-alkyl), OCO(Ci-C6-alkyl), OCOO(Ci- Ce-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 independently of each other represent CH or N and
X1 , X2 and W independently of each other represent CH or N;
with the proviso that at least two of C, X1 , X2 and W represent N.
In another 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.
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 W is N or W is CH. The compound of formula (I) is preferably characterized in that at least two of C, W, X1 and X2 represent N. More preferably,
C, W, X1 and X2 each represent N or
C, W, X1 each represent N and X2 respresents CH or
W, X1, X2 each represent N and C respresents CH or
C, X1, X2 each represent N and W respresents CH or
C and W each represent N and X1 and X2 each represent CH or
X1 and W each represent N and C and X2 each represent CH or
C and X1 each represent N and W and X2 each represent CH.
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 H, (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (C3- C6)-cycloalkyl and SOx-(Ci-C6)-alkyl, wherein x is 1 or 2. Preferably, R3 is selected from the group consisting of H, (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (C3-C6)-cycloalkyl and S02-(Ci-C6)-alkyl;
more preferably R3 is selected from the group consisting of H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, COCH3, COCH2CH3, COCH(CH3)2, CF3, CHF2, CH2F, CH2CF3, cyclopropyl, SOCH3 and SO2CH3;
yet more preferably R3 is selected from the group consisting of H, CH3, CH2CH3, COCH3, CH2CF3, cyclopropyl 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
Figure imgf000012_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 heterocycloalkyi, NH2, NH(Ci-Ce-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-Ce-alk len)N(Ci-Ce- 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-Ce-alk l) and S(0)2(Ci-C6-alkyl),
wherein said Ci-C6-alkyl, said C3-C6-cycloalkyl and said 3- to 7-membered heterocycloalkyi 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, 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, SOCH2CH3, S02CH2CH3, 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,
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.
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, S02CH3 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, 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, 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, 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 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 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, (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-Ce-alkyl), N(Ci-Ce- 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-Ce-alkyl), N(Ci-C6-alkyl)2, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)- 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-C6-alkyl), N(Ci-C6-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
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 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-Ce-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 heterocycloalkyi;
or
denotes one of the following groups U 1 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, O-Ce-alk l, Ci-Ce-alkoxy, NH2, N H(Ci-Ce-alkyl), N(Ci-Ce- alkyl)2, NHCO(Ci-C6-alkyl), CO2H , COO(Ci-Ce-alk l), 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 imgf000018_0001
R6 is H , (Ci-Ce-alkyl), (Ci-C6)-hydroxyalkyl, (Ci-Ce)-cyanoalkyl, Cs-Ce-cycloalkyl, CO(Ci-Ce-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-Ce-alkyl), N(Ci-Ce-alkyl)2, NHCO(Ci-C6-alkyl), C02H , COO(Ci-Ce-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 is selected from one of the following substructures M1 to M76:
M1 M2 M3 Μ4 Μ5
M6 M7 Μ8 Μ9 Μ10
Η0^^
Figure imgf000019_0001
Figure imgf000020_0001
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 heterocydoalkyi,
wherein said 3- to 12-membered heterocydoalkyi 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_0002
Figure imgf000021_0001
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, ON, 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_0002
Figure imgf000022_0001
Figure imgf000023_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, ON, Ci-Ce-alkyl, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, Cs-Ce-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, ON, OH, Ci-C6-alkoxy, (Ci-Ce- alkoxy)-Ci-C6-alkoxy, (hydroxy)-Ci-C6-alkoxy, NH2, NH(Ci-C6-alkyl), N(Ci-C6-alkyl)2, NH(Ci-Ce- 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-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 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, 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, NH(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, NH2, 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 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, 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 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, (C1-C6- 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-C6-alkyl)CO(Ci-C6-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 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, Ci-Ce-alkyl, (Ci-C6)-hydroxyalkyl, (Ci-Ce)-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), (Id) or (le),
Figure imgf000025_0001
Preferably, the compound of formula (I) is a compound according to formula (la), (lb), (Ic), (Id) or (le), 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 imgf000025_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, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, 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, CH2CH2OH, 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 H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, COCH3, COCH2CH3, COCH(CH3)2, CF3, CHF2, CH2F, CH2CF3, cyclopropyl, SOCH3 and S02CH3;
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), (Id) or (le), 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 H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, COCH3, COCH2CH3, COCH(CH3)2, CF3, CHF2, CH2F, CH2CF3, 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, S02CH3, 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), (Ic), (Id) or (le), 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, S02CH3, cydopropyl, cyclobutyl, 3-oxetanyl, 1-pyrrolidinyl, 1-piperidinyl and 1-morpholinyl.
More preferably, the compound according to formula (la), (lb), (Ic), (Id) or (le) 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, S02CH3, cydopropyl and cyclobutyl. Even more preferably, the compound according to general formula (I) has the general formula (la), (lb),
(lc), (Id) or (le),
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 H, CH3, CH2CH3, COCH3, CH2CF3, cyclopropyl and S02CH3;
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, OCOCHs, 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 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, OCOCHs, 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, S02CH3 and cyclopropyl.
Even more preferably, the compound according to general formula (I) is selected from one of formula (la),
(lb), (lc), (Id) or (le),
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 H, CH3, CH2CH3, COCH3, CH2CF3, cyclopropyl and S02CH3; 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, 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 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, OCOCHs, 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, S02CH3 and cyclopropyl.
In yet another preferred embodiment, the invention relates to a compound selected from the group consisting of
1 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
2 1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
3 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1-(methylsulfonyl)-1 H-indole-5-carboxamide
4 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N,1-trimethyl-1 H-indole-5-carboxamide
5 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1 H-indole-5-carboxamide
6 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N,1-dimethyl-1 H-indole-5-carboxamide 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1-(methylsulfonyl)-1 H-indole-5- carboxamide
1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1 H-indole-5-
8
carboxamide
9 1-Acetyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
10 1-Acetyl-N,N-dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole-5-carboxamide
11 N,N-Dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole-5-carboxamide
12 (3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5-yl)(morpholino) methanone
13 1-(3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indol-1-yl)ethanone
14 (3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5-yl)(morpholino) methanone
15 1-(3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indol-1-yl)ethanone
3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1-(methyl-sulfonyl)-1 H-
16
indole-5-carboxamide
3-(5-(2-Fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1- 17
(methylsulfonyl)-1 H-indole-5-carboxamide
3-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1- 18
(methylsulfonyl)-1 H-indole-5-carboxamide
3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1-(methyl-sulfonyl)-1 H- 19
indazole-5-carboxamide
(3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazol-5-yl)
20
(morpholino)methanone
1-(3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indazol-1- 21
yl)ethanone
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1 H- 22
indazole-5-carboxamide
1-Ethyl-N-(2-hydroxyethyl)-3-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-N-methyl-1 H-indazole- 23
5-carboxamide
(1-Ethyl-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)
24
(morpholino)methanone
25 (1-Ethyl-3-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1 H-indazol-5-yl)(morpholino) methanone
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indazole-5- 26
carboxamide
27 1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1 H- indole-5-carboxamide
(1-Ethyl-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indo^
morpholino)methanone
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indole-5- carboxamide
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-(2,2,2- trifluoroethyl)-1 H-indazole-5-carboxamide
(3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-indazol-5- yl)(morpholino)methanone
N-(2-Hydroxyethyl)-3-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-N-methyl-1-(2,2,2- trifluoroethyl)-1 H-indazole-5-carboxamide
(3-(4-(2-Hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1-(2,2,2-trifluoroethyl)-1 H-indazol-5- yl)(morpholino)methanone
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-(2,2,2- trifluoroethyl)-1 H-indole-5-carboxamide
(3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)^
yl)(morpholino)methanone
(1-Methyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholi methanone (1-Ethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino) methanone
(3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazol-5-yl)(morpholino) methanone
(3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-1-methyl-1 H-indazol-5-yl)(morpholino)methanone
(3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-methyl-1 H-indazol-5-yl)(morpholino) methanone
N-(2-Hydroxyethyl)-N, 1-dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazole-5- carboxamide
(1-Methyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(pyrrolidin-1-yl) methanone 1-Ethyl-5-(ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
1-Ethyl-5-(ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
5-(Ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
5-(Ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole
5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole
1-(5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indol-1-yl)ethanone
2-(2-(2-(1-Ethyl-5-(ethylsulfinyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(1-Ethyl-5-(ethylsulfonyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-(methylsulfonyl)-1 H-indole-5- carboxamide
(3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5- yl)(morpholino)methanone
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1- (methylsulfonyl)-1 H-indole-5-carboxamide
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H- indole-5-carboxamide
2-(2-(2-(1-Ethyl-5-(ethylsulfinyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(1-Ethyl-5-(methylsulfinyl)-1 H-indazol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 59 2-(2-(2-(1-Ethyl-5-(methylsulfonyl)-1 H-indazol-3-yl)pyrimidin-5-y
60 2-(6 1-Ethyl-5-(ethylsulfonyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-ami
61 2-(6 1-Ethyl-5-(ethylsulfinyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-am
g2 (1-Ethyl-3-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[4,3-b]pyridin-5- yl)(morpholino)methanone
g4 (3-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-1-ethyl-1 H-pyrazolo[4,3-b]pyn
(morpholino)methanone
65 ( 1 -Ethyl-3-(4-(2-hyd roxypropan-2-yl )-[2 , 3'-bi pyrid i n]-6'-yl)- 1 H-pyrazolo[4 , 3-b] pyrid in-5- yl)(morpholino)methanone
66 (3-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1-ethyl-1 H-pyrazolo[4,3-b]pyrid
(morpholino)methanone
67 (1-Ethyl-3-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phen^ methanon
68 1-Ethyl-N-(2-hydroxyethyl)-3-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-N-methyl-1 H- indazole-5-carboxamide
69 2-(6 1-Ethyl-5-(ethylsulfinyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-ol
70 2-(6 1-Ethyl-5-(ethylsulfonyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-ol
71 4-(1-Cyclopropyl-3-(5-(2-fluorophenyl)py
72 (1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholin
73 (1-Cyclopropyl-3-(5-phenylpyrimidin-2-yl)-1 H-indazo
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), (Id) or (le) 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), (Id) or (le) 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), (Id) or (le). 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), (Id) or (le) 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), (Id) or (le) 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), (Ic), (Id) or (le) 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), (Ic), (Id) or (le) 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), (Ic), (Id) or (le) 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), (Id) or (le) 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) or (lc) 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 in 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:
APCI = atmospheric pressure chemical ionization; calc. = calculated; d = day; dba = dibenzylidene- acetone; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = Ν,Ν-dimethylformamide; DMSO = dimethylsulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; ES- MS = electrospray mass spectrometry (ES-MS); eq. = equivalent; HATU = 1-[Bis(dimethyl- amino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; h = hour(s); KOi-Bu = potassium tert-butoxide; mCPBA = m-chloroperoxybenzoic acid; min = minute(s); MeOH = methanol; MTBE = methyl-tert-butylether; NMM = N-methylmorpholine; NaOH = sodium hydroxide; PdCl2(dppf) = [1 , 1 '-bis(diphenylphosphino)ferrocene] dichloropalladium(ll) DCM complex; Pd2(dba)3(0) = tris(dibenzylideneacetone)dipalladium(0); PE = petroleum ether; RT = room temperature; Rt = retention time; SFC = supercritical fluid chromatography; TBTU = 2-(1 H-benzotriazol-1-yl)-1 , 1 ,3,3-tetramethyl- uronium tetrafluoroborate; tert = tertiary; TEA = triethylamine; TFA = 2,2,2-trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; TOFMS = time-of-flight mass spectrometer; Xantphos = 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
HPLC-Chromatoqraphy methods:
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 imgf000034_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: positive ions; ion source: turbo spray; ion spray voltage: +5500 for positive ions; mass source temperature: 200°C Method 2:
All parameters as described for method 1 with the only difference that the flow rate is 1.0 mL/min
Method 3:
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 gradient: Time in min % A % B
0 98 2
0.75 98 2
1.00 90 10
2.00 2 98
2.25 2 98
2.90 98 2
3.00 98 2
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.
Method 4:
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 imgf000035_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: positive ions; ion source: turbo spray; ion spray voltage: +5500 for positive ions; mass source temperature: 200°C
Method 5:
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 μΙ_; detection: 220 and 260 nm; mobile phase A: 10 mM ammonium acetate in water; mobile phase B: acetonitrile.
Mobile phase gradient:
Figure imgf000035_0002
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: positive ions; ion source: turbo spray; ion spray voltage: +5500 for positive ions; mass source temperature: 200°C 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 (Ci-Ce) alkyl, preferably methyl.
Reaction scheme 01 :
Figure imgf000036_0001
Hal stands for CI, Br, I.
Reaction scheme 02:
Figure imgf000036_0002
Hal stands for CI, Br, I.
Reaction scheme 03:
Figure imgf000036_0003
Figure imgf000037_0001
Instead of tosyl (Ts) other protecting groups like mesyl (Ms) can be used.
Reaction scheme 04:
Figure imgf000037_0002
(X) (XI) (Xii)
Hal stands for CI, Br, I.
Reaction scheme 05:
Figure imgf000037_0003
Hal stands for CI, Br, I.
Reaction scheme 06:
Figure imgf000038_0001
Figure imgf000038_0002
Hal stands for CI, Br, I.
Figure imgf000038_0003
(XXV)
Hal stands for CI, Br, I. Example 1 : 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl 1-1 H-indole-5-carboxamide
Figure imgf000039_0001
1a) Methyl 3-iodo-1 H-indole-5-carboxylate
K2CO3 (790.5 mg, 5.723 mmol, 2 eq) and iodine (395 mg, 3.142 mmol, 1.1 eq) were added to a solution of methyl 1 H-indole-5-carboxylate (500 mg, 2.831 mmol, 1 eq) in DMF (15 ml) and the mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice and Na2S∑03 solution. The aqueous phase was extracted with EtOAc (25 ml x2) and the combined organic layers were washed repeatedly with cold water (100 ml) and brine (100 ml), dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The raw product thus obtained was used in the next step without further purification. Yield: 400 mg (47%). Brown solid.
1 b) Methyl 3-iodo-1-tosyl-1 H-indole-5-carboxylate
NaH (9 mg, 0.361 mmol, 1.1 eq) was added to a solution of compound 1a (100 mg, 0.332 mmol, 1 eq) in THF (2 ml). The solution was cooled with an ice bath, tosyl chloride (69 mg. 0.361 mmol, 1.1 eq) was added portion wise and the reaction mixture was stirred at RT for 5 h. The mixture was quenched with ice and the organic solvent was evaporated. The precipitating solid was filtered off, washed repeatedly with cold water (100 ml) and dried to afford compound 1 b. White solid. Yield: 1 19 mg (79%).
1 c) Methyl 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-tosyl-1 H-indole-5-carboxylate
PdCl2(dppf) (700 mg, 0.700 mmol, 0.05 eq) was added to a solution of compound 1 b (6.5 g, 14.28 mmol, 1 eq), KOAc (3.5 g, 36.69 mmol, 2.5 eq) and bis(pinacolato)diboron (7.23 g, 28.58 mmol, 2 eq) in dioxane (70 ml) stirred under Ar. The reaction mixture was refluxed for 16 h, then diluted with water (150 ml) and extracted with EtOAc (3 x 60 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na2S04 and evaporated under reduced pressure.
1d) Methyl 3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1-tosyl-1 H-indole-5-carboxylate
K2CO3 (8 g, 54.19 mmol, 4 eq) and chloro-5-(2-fluorophenyl)pyrimidine (6 g, 28.65 mmol, 2 eq) were added to a solution of compound 1 c (6.5 g, 14.32 mmol, 1 eq) in dioxane (100 ml). The solution was degassed with Ar for 30 min and tetrakis(triphenylphosphine) palladium(O) (826 mg, 0.700 mmol, 0.05 eq) was added. The reaction mixture was refluxed for 16 h, then diluted with water (100 ml), and extracted with EtOAc (3 x 150 ml). The combined organic layers were washed with water (150 ml) and brine (200 ml), dried over anhydrous Na2S04 and evaporated under reduced pressure. The residue was purified by flash column chromatography [230-400 mesh silica gel; hexane/EtOAc = 4: 1]. White solid. Yield: 3.4 g, (20%). MS: m/z: [M+H]+ = 502.2 (MW calc. 501 .1 ). 1 e) 3-(5-(2-Fluorophenyl)pyrimidin-2-vn-1 H-indole-5-carboxylic acid
Lithium hydroxide monohydrate (1.362 g, 32.44 mmol, 5 eq) was added to a solution of compound 1d (3.5 g, 6.49 mmol, 1 eq) in MeOH (20 ml), THF (40 ml) and water (10 ml) cooled with an ice bath. The reaction mixture was stirred at RT for 16 h and then concentrated. The residue was acidified to pH 3 with 6N hydrogen chloride solution and the precipitating solid was filtered off, washed repeatedly with cold water (100 ml) and dried. Yellow solid. Yield: 1 .1 g (80%). MS: m/z: [M+H]+ = 334.0 (MW calc. 333.1 ).
1f) 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
TBTU (1.61g, 5.044 mmol, 1.8 eq), NMM (0.9 ml, 8.408 mmol, 1.6 eq) were added to a solution of compound 1 e (1.4 g, 4.204 mmol, 1 eq) in DMF (7 ml). After stirring at RT for 10 min dimethylamine hydrochloride (1.028 g, 12.612 mmol, 3 eq) was added and stirring was continued for 16 h. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (3 x 20 ml). The combined organic layers were washed with brine (50 ml), dried over Na2S04, filtered and evaporated under reduced pressure. The raw product was purified by column chromatography [100-200 silica gel, DCM/MeOH = 9.1 ]. White solid. Yield: 485 mg (74%).
Figure imgf000040_0001
A warm solution of copper(ll)acetate (100 mg, 0.554 mmol, 1 eq) and 2,2'-bipyridyl (86.6 mg, 0.55 mmol, 1 eq) in dichloroethane was added to a mixture of compound 1 (200 mg, 0.554 mmol, 1 eq), Na2C03 (1 16.6 mg, 1.1 mmol, 2 eq) and cyclopropylboronic acid (94.6 mg, 1.1 mmol, 2 eq) in dichloroethane (5 ml), that was stirred under Ar. The reaction mixture was heated at 90°C for 16 h, then cooled to RT and diluted with water. The aqueous phase was extracted with DCM and the combined organic layers were dried over anhydrous Na2S04, filtered and evaporated. The raw product was purified by column chromatography [230-400 mesh silica gel, hexane/EtOAc = 4.1]. White solid. Yield: 80 mg (36%). MS: m/z: [M+H]+ = 401 .1 (MW calc. 400.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.01 (s, 2H), 8.63 (s, 1 H), 8.29 (s, 1 H), 7.73-7.69 (m, 2H), 7.50 (bs, 1 H), 7.56-7.52 (m, 2H), 7.43-7.33 (m, 3H), 3.63 (bs, 1 H), 3.00 (s, 6H) 1.1 1 (m, 4H) Example 3: 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1-(methylsulfonyl)-1 H-indole-5- carboxamide
Figure imgf000041_0001
NaH (25 mg, 1.052 mmol, 1 eq) was added to an ice-cold solution of compound 1 (190 mg, 0.526 mmol, 1 eq) in THF (10 ml) and the mixture was stirred at 0°C for 1 h. Methanesulfonyl chloride (0.065 ml, 1.315 mmol, 2.5 eq) was added and stirring was continued for 16 h. The reaction mixture was quenched with water (100 ml) and extracted with DCM (100 ml x 2). The combined organic layers were dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The remnant was purified by column chromatography [100-200 silica gel, DCM/MeOH = 9:1]. White solid. Yield: 90 mg (39%). MS: m/z: [M+H]+ = 439.3 (MW calc. 438.1 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.15 (s, 2H), 8.75 (s, 1 H), 8.47 (s, 1 H), 7.98 (d, J = 8.6Hz, 1 H), 7.77 (t, J = 7.7Hz, 1 H), 7.56-7.52 (m, 2H), 7.46-7.39 (m, 2H), 3.69 (s, 6H), 2.99 (d, J = 25.1 Hz, 6H).
Example 4: 3-(5-(2-Fluorophenyl)pyri H-indole-5-carboxamide
Figure imgf000041_0002
Obtained from compound 1 (150 mg, 0.416 mmol) and methyl iodide (0.128 ml, 2.25 mmol) analogously to the procedure for example 3. White solid. Yield: 90 mg (80%). MS: m/z: [M+H]+ = 375 (MW calc. 374.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.00 (s, 2H), 8.63 (s, 1 H), 8.41 (s, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.52-7.49 (m, 1 H), 7.43-7.36 (m, 2H), 7.31 (d, J = 8.7 Hz, 1 H), 3.94 (s, 3H), 3.00 (s, 6H). Example 5: 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1 H-indole-5-carboxamide
Figure imgf000041_0003
Preprared from compound 1e (150 mg, 0.45 mmol) and 2-methylamino-ethanol (0.97 ml, 0.9 mmol) in analogy to procedure 1f. White solid. Yield: 120 mg (80%). MS: m/z: [M+H]+ = 391 (MW calc.390.4).1H NMR (400 MHz, DMSO-d6, δ ppm): 11.94 (s, 1H), 9.01 (s, 2H), 8.62 (s, 1H), 8.37 (s, 1H), 7.73 (t, J = 8.8 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.43-7.36 (m, 2H), 7.25 (d, J = 8.3 Hz, 1H), 4.75 (bs, 1H), 3.65 (s, 1H), 3.53 (bs, 2H), 3.36 (bs, 1 H), 3.02 (s, 3H).
Example 6: 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N,1-dimethyl-1H-indole-5- carboxamide
Figure imgf000042_0001
White solid. MS: m/z: [M+H]+ = 405 (MW calc.404.4). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.00 (s, 2H), 8.62 (s, 1H), 8.41 (s, 1H), 7.74-7.69 (t, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.50 (bs, 1H), 7.43- 7.38 (m, 2H), 7.32 (d, J = 8.4 Hz, 1H), 4.74 (bs,1H), 3.94 (s, 3H), 3.66 (bs,1H), 3.50 (bs, 3H), 3.17 (d, J = 5.2 Hz, 1H), 3.02 (s, 3H) Example 7: 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1-(methylsulfonyl)-1H- indole-5-carboxamide
Figure imgf000042_0002
Yield: 80 mg. White solid. MS: m/z: [M+H]+ = 469.2 (MW calc.468.1).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.15 (s, 2H), 8.75 (s, 1H), 8.46 (s, 1H), 7.97 (d, J = 7.3 Hz, 1H), 7.78 (t, J= 7.6 Hz, 1H), 7.53 (d, J = 8 Hz, 2H), 7.46-7.39 (m, 2H), 4.83-4.76 (m, 1H), 3.70 (s, 4H), 3.56-3.51 (m, 2H), 3.32 (s, 1H), 3.03 (s, 3H)
Example 8: 1-Cvclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1H-indole-5- carboxamide
Figure imgf000043_0001
Yield: 50 mg. White solid. MS: m/z: [M+H]+ = 431 (MW calc. 430.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.01 (s, 2H), 8.62 (s, 1 H), 8.29 (s, 1 H), 7.76-7.69 (m, 2H ), 7.50 (bs, 1 H), 7.43-7.34 (m, 3H), 4.74 (bs, 1 H), 3.63 (bs, 2H), 3.52 (bs, 2H), 3.37 (bs, 1 H), 3.02 (s, 3H), 1 .13-1.1 1 (m, 4H)
Example 9: 1-Acetyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxami^
Figure imgf000043_0002
Synthesis example 1 (0.2 g, 0.55 mmol, 1 eq), TEA (0.153 ml, 1.1 1 mmol, 2 eq), acetic anhydride (0.104 ml, 1.1 1 mmol, 2 eq) and a catalytic amount of DMAP (0.006 g, 0.055 mmol, 0.1 eq) in dichloroethane (7.0 ml) were stirred at 90°C for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried over Na2S04, filtered and evaporated under reduced pressure. The residue was purified by preparative HPLC. White solid. Yield: 0.07 g (32%). MS: m/z: [M+H]+ = 403.1 (MW calc. 404.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.15 (s, 2H), 8.74 (d, J = 8.8 Hz, 2H), 8.45 (d, J = 8.4 Hz, 1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.54-7.56 (m, 1 H), 7.39-7.48 (m, 3H), 3.00 (d, J = 25.6 Hz, 6H), 2.83 (s, 3H).
Example 10: 1-Acetyl-N,N-dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole-5-carboxamide
Figure imgf000043_0003
Prepared in analogy to synthesis example 9. White solid. Yield: 11 mg. MS: m/z: [M+H]+ = 400.0 (MW calc. 399.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.54 (s, 2H), 8.75 (d, J = 4.8 Hz, 2H), 8.61 (d, J = 4.8 Hz, 1 H), 8.46 (d, J = 8.4 Hz, 1 H), 8.04 (s, 1 H), 7.48 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 4.8 Hz, 3H), 2.98- 3.04 (m, 6H), 2.83 (s, 3H), 2.44 (s, 3H).
Example 1 1 : N,N-Dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole-5- carboxamide
Figure imgf000044_0001
Prepared in analogy to synthesis example 3. White solid. Yield: 0.07 g. MS: m/z: [M+H]+ = 436.1 (MW calc. 435.1 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.55 (s, 2H), 8.76 (s, 1 H), 8.61 (d, J = 5.2 Hz, 1 H), 8.48 (s, 1 H), 7.97-8.04 (m, 2H), 7.53 (d, J = 7.6 Hz, 1 H), 7.31 (d, J = 4.4 Hz, 3H), 3.69 (s, 3H), 3.02 (d, J = 22.4 Hz, 6H), 2.43 (s, 3H).
Example 12: (3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5-yl)(morpholino) methanone
Figure imgf000044_0002
Prepared from compound 1 e and morpholine in two steps in analogy to synthesis example 3. White solid. Yield: 0.07 g. MS: m/z: [M+H]+ = 480.8 (MW calc. 480.1 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.16 (s, 2H), 8.78 (s, 1 H), 8.47 (s, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.53-7.55 (m, 2H), 7.39- 7.46 (m, 2H), 3.31-3.69 (m, 1 1 H).
Example 13: 1-(3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indol-1-yl)ethanone
Figure imgf000045_0001
Prepared from compound 1 e and morpholine in two steps in analogy to synthesis example 9. White solid. Yield: 0.08 g. MS: m/z: [M+H]+ = 445.2 (MW calc. 444.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.15 (s, 2H), 8.76 (s, 2H), 8.47 (d, J = 8.4 Hz, 1 H), 7.78 (t, J = 7.2 Hz, 1 H), 7.50-7.55 (m, 1 H), 7.41-7.48 (m, 3H), 3.63 (bs, 8H), 2.83 (s, 3H).
Example 14: (3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5-yl)(morpholino) methanone
Figure imgf000045_0002
Prepared in analogy to synthesis example 3. White solid. Yield: 0.03 g. MS: m/z: [M+H]+ = 478.2 (MW calc. 477.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.56 (s, 2H), 8.79 (s, 1 H), 8.61 (d, J = 4.4 Hz, 1 H), 8.48 (s, 1 H), 8.05 (s, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 4.4 Hz, 1 H), 3.42- 3.70 (m, 1 1 H), 2.44 (s, 3H).
Example 15: 1-(3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indol-1- vDethanone
Figure imgf000045_0003
Prepared in analogy to synthesis example 9. White solid. Yield: 0.02 g. MS: m/z: [M+H]+ = 442.2 (MW calc. 441.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.55 (s, 2H), 8.77 (s, 2H), 8.61 (bs, 1 H), 8.47 (d, J = 8.4 Hz, 1 H), 8.05 (s, 1 H), 7.50 (d, J = 8.8 Hz, 1 H), 7.32 (bs, 1 H), 3.64 (bs, 8H), 2.83 (s, 3H), 2.44 (s, 3H).
Example 16: 3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1 -(methyl- sulfonyl)-1 H-indole-5-carboxamide
Figure imgf000046_0001
Prepared in analogy to synthesis example 3. White solid. Yield: 97 mg. MS: m/z: [M+H]+ = 483.0 (MW calc. 482.1 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.13 (s, 2H), 8.74 (d, J = 0.9 Hz, 1 H), 8.46 (s, 1 H), 7.97 (d, J = 8.3 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H), 7.53 (dd , J = 8.5, 1.3 Hz, 1 H), 7.35 (m, 2H), 4.79 (bs, 1 H), 3.69 (s, 4H), 3.53 (m, 2H), 3.35 (m, 1 H), 3.03 (s, 3H), 2.38 (s, 3H).
Example 17: 3-(5-(2-Fluoro-5-(2-hvdroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-
1-(methylsulfonyl)-1 H-indole-5-carboxamide
Figure imgf000046_0002
17a) tert-Butyl 3-iodo-1-(methylsulfonyl)-1 H-indole-5-carboxylate
Mesyl chloride (1.8 ml, 23.32 mmol, 2.0 eq) was added portion wise and under ice cooling to a mixture of compound 1 b (4.0 g, 1 1 .6 mmol, 1 eq) and NaH (60%, 746 mg, 18.65 mmol, 1.6eq) in THF (35 ml). The reaction mixture was stirred at RT for 2 h, quenched with ice and extracted with EtOAc (100 ml x 2). The combined organic layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The residue was purified by column chromatography [100-200 silica gel, hexane/ EtOAc = 4: 1]. Sticky solid. Yield: 2.4 g (49%). MS: m/z: [M+H]+ = 422.1 (MW calc. 421 .0). 17b) 3-lodo-1-(methylsulfonyl)-1 H-indole-5-carboxylic acid
Compound 17a (1.2 g, 2.85 mmol, 1 eq) in DCM (30 ml) was stirred in the presence of (5.7 ml) for 5h at RT. The reaction mixture was evaporated under reduced pressure and the raw product(1.0 g) thus obtained was used in the next step without further purification.
17c) N-(2-Hvdroxyethyl)-3-iodo-N-methyl-1-(methylsulfonyl)-1 H-indole-5-carboxamide
TBTU (1.05 g, 3.29 mmol, 1.2 eq) and NMM (0.75 ml, 6.86 mmol, 2.5 eq) were added at RT to a solution of compound 17b (1 .0 g, 2.74 mmol, 1 eq) in DMF (8 ml). After stirring for 10 min, 2-(methylamino)ethan- 1-ol (0.22 mg, 3.02 mmol, 1.1 eq) was added and stirring was continued for 16 h at RT. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na2S04 and filtered. The solvent were distilled off and the remnant was purified by column chromatography [100-200 silica gel, DCM with 5% MeOH]. White solid. Yield: 1.12 g, (97%). MS: m/z: [M+H]+ = 422.9 (MW calc. 422.0). 17d) 3-(5-(2-Fluoro-5-(2-hvdroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1- (methylsulfonyl)-1 H-indole-5-carboxamide
Compound 17c was transferred into a pinacol boronate that was subsequently reacted with 2-(3-(2- chloropyrimidin-5-yl)-4-fluorophenyl)propan-2-ol under Suzuki conditions in analogy to the procedures 1 c and 1d, respectively. White solid. Yield: 60 mg. MS: m/z: [M+H]+ = 527.2 (MW calc. 526.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.1 1 (s, 2H), 8.72 (s, 1 H), 8.45 (s, 1 H), 7.98 (d, J = 8.6 Hz, 1 H), 7.78 (d, J = 7.4 Hz, 1 H), 7.62 (s, 1 H), 7.52 (d , J = 8.4 Hz 1 H), 7.29 (t, J = 8.8 Hz 1 H), 4.8 (s, 1 H), 4.43 (s, 1 H), 3.6 (s, 3H), 3.64 (m, 2H), 3.5 (m, 2H), 3.06 (s, 3H), 1 .53 (s, 6H).
Example 18: 3-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1-
(methylsulfonyl)-1 H-indole-5-carboxamide
Figure imgf000047_0001
Prepared in analogy to synthesis example 17. White solid. Yield: 60 mg. MS: m/z: [M+H]+ = 537.1 (MW calc. 536.1 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.17 (s, 2H), 8.75 (s, 1 H), 8.48 (s, 1 H), 8.12 (d, J = 6.2 Hz, 1 H), 7.98 (d, J = 8.6 Hz, 1 H), 7.89 (s, 1 H), 7.63 (t, J = 9.6 Hz, 1 H), 7.52 (d , J = 8.3 Hz, 1 H), 4.42 (s, 1 H), 3.64 (m, 2H), 3.61 (s, 3H), 3.49 (m, 2H), 3.06 (s, 3H). Example 19: 3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)^^
sulfonyl)-1 H-indazole-5-carboxanriide
Figure imgf000048_0001
19a) Methyl 1-(methoxymethyl)-1 H-indazole-5-carboxylate
Methyl 1 H-indazole-5-carboxylate (1.5 g, 8.51 mmol) was added to a suspension of sodium hydride (442 mg, 1 1 .0 mmol, 1 .3 eq) in DMF (25 ml) cooled with an ice bath and the mixture was stirred under cooling for 1 h. Chloromethyl methyl ether (0.71 ml, 9.36 mmol, 1 .1 eq) was added and the mixture was stirred for 14 h upon warming to RT. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and evaporated. The residue was purified by flash chromatography [hexane with 7% EtOAc]. Yield: 1.2 g (64%).
19b) Methyl 1-(methoxymethyl)-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-5- carboxylate
Bis(1 ,5-cyclooctadiene)dimethoxydiiridium (150 mg, 0.22 mmol, 0.05 eq) and (4-tert-butyl-2-(4-tert- butylpyridin-2-yl)pyridine (121 mg, 0.45 mmol, 0.1 eq) were added to a suspension of compound 19a (1.0 g, 4.54 mmol) and bis(pinacolato)diboron (1.15 g, 4.54 mmol, 1.0 eq) in MTBE (30 ml) that was kept under Ar. The mixture was heated for 1 h in a microwave at 80°C and then filtered. The filtrate was concentrated and the product was used for the next step without further purification. 19c) Methyl 3-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-1-(methoxymethyl)-1 H-indazole-5-carboxylate PdCl2(dppf) (0.18 g, 0.26 mmol, 0.1 eq) was added to a mixture containing crude compound 19b (0.9 g, 2.6 mmol), 2-chloro-5-(2-fluoro-5-methylphenyl)pyrimidine (0.63 g, 2.86 mmol, 1.1 eq) and CS2CO3 (1.69 g, 5.2 mmol) in DMF (10 ml) stirred under Ar. The mixture was irradiated with microwaves at 100°C for 1 h, then diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2S04. The solvents were removed and the residue was purified by flash chromatography [hexane/EtOAc = 4: 1]. White solid. Yield: 0.9 g (86%). mg. MS: m/z: [M+H]+ = 406.9 (MW calc. 406.1 ).
19d) Methyl 3-(5-(2-fluoro-5-methylphenyl)pyrimidin-2-yl)-1 H-indazole-5-carboxylate
A solution of compound 19c (3.0 g, 7.34 mmol) and triflic acid (6 ml) in DCM (30 ml) was stirred overnight at RT. The reaction mixture was diluted with DCM and solid sodium bicarbonate was slowly added under cooling with an ice bath. After stirring for 30 min, the reaction mixture was filtered. The filtrate was evaporated and the residue was purified by flash chromatography [EtOAc /hexane = 1 : 1]. Yield: 1.2 g (45%). MS: m/z: [M+H]+ = 363.3 (MW calc. 363.4).
19e) 3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1 H-indazole-5-carboxylic acid
Aqueous NaOH solution (20%, 3 ml) was added to compound 19d (1 .2 g, 3.31 mmol) in methanol (6 ml), THF (4 ml) and water (2 ml) and the mixture was stirred at RT for 2 days. The volatiles were removed under reduced pressure and the residue was diluted with water, acidified with 1 N HCI solution and extracted with isopropyl amine / CHC (3:7). The organic phase was washed with brine, dried over Na2S04 and evaporated. Yield: 600 mg. MS: m/z: [M+H]+ = 349.1 (MW calc. 348.1 ).
19f) 3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazole-5-carboxylic acid NaH (248 mg, 10.34, mmol, 6 eq) was added at 0°C to compound 19e (600 mg, 1.72 mmol) in THF (10 ml). After stirring for 1 h at RT, mesyl chloride (400 μΙ_, 5.17 mmol, 3.0 eq) was added at 0°C and stirring was continued for 16 h at RT. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and evaporated. Yield: 250 mg. MS: m/z: [M+H]+ = 427.2 (MW calc. 426.1 ).
19g) 3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hvdroxyethyl)-N-methyl-1-(methyl-sulfonyl)- 1 H-indazole-5-carboxamide
Oxalylchloride (81 μΙ, 0.93 mmol, 2.0 eq) and DMF as catalyst (0.05 ml) were added to a solution of compound 19f (200 mg, 0.46 mmol) in DCM (5 ml) and the resulting reaction mixture was stirred for 3 h at RT. The solvent was distilled off under reduced pressure and a N2 atmosphere and the residue was dissolved in DCM (5 ml). N-Methylaminoethanol (105 mg, 0.46 mmol, 3.0 eq) in DCM (2 ml) was added at 0°C and the mixture was stirred for 16 h at RT. The reaction mixture was diluted with ice water and extracted with MeOH/DCM (1 :9, 2 x 100 ml). The combined organic extracts were washed with brine, dried over Na2S04, and concentrated. The raw product was purified by prep-HPLC chromatography. White solid. Yield: 11 mg (5%). MS: m/z: [M+H]+ = 484.1 (MW calc. 483.1 ). 1 H NMR (400 MHz, DMSO- d6, δ ppm): 9.29 (s, 2H), 8.75 (s, 1 H), 8.1 (s, 1 H), 7.75-7.78 (d, 1 H), 7.62-7.64 (d, 1 H), 7.31-7.38 (m, 2H), 4.81 (bs, 1 H), 3.31-3.68 (m, 7H), 2.4 (s, 3H).
Example 20: (3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazol-5-yl)
(morpholino)methanone
Figure imgf000049_0001
Prepared in analogy to example 19. White solid. Yield: 35 mg. MS: m/z: [M+H]+ = 496.0 (MW calc. 495.1 ). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.77 (s, 1 H), 8.12 (d, 1 H), 7.77 (d, 1 H), 7.63 (d, 1 H), 7.31-7.37 (m, 2H), 3.43-3.68 (m, 1 1 H), 2.4 (s, 3H). Example 21 : 1-(3-(5-(2-Fluoro-5-methylphenvnpyrimidin-2-vn-5-(morpholine-4-carbonvn-1 H-indazol-1- vDethanone
Figure imgf000050_0001
Prepared in analogy to example 19 with the difference that the reaction order was changed (→19e, 19g, 19d,19f). White solid. Yield: 80 mg. MS: m/z: [M+H]+ = 460.1 (MW calc. 459.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.29 (s, 2H), 8.75 (s, 1 H), 8.46 (d, 1 H), 7.76 (d, 1 H), 7.62 (d, 1 H), 7.33-7.36 (m, 2H), 3.42-3.64 (m, 8H), 2.86 (s, 3H), 2.4 (s, 3H).
Example 22: 1-Ethyl-N-(2-hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-
Figure imgf000050_0002
22a) Methyl 1-ethyl-1 H-indazole-5-carboxylate
NaH (1.24 g, 31 .21 mmol, 1.1 eq, 60% in mineral oil) was added portion wise to a solution of methyl 1 H- indazole-5-carboxylate (5.0 g, 28.38 mmol, 1 eq) in THF (50 ml) cooled with an ice bath. The mixture was stirred for 10 min, ethyliodide (2.51 ml, 31 .21 mmol, 1.1 eq) was added and stirring was continued at RT for 4 h. The mixture was quenched with ice and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04 and concentrated. The raw product was purified by flash chromatography [hexane/EtOAc = 85: 15]. White solid. Yield: 0.9 g (16%). MS: m/z: [M+H]+ = 205.1 (MW calc. 204.1 ). 22b) Methyl 1-ethyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indazole-5-carboxylate Bis(1 ,5-cyclooctadiene)dimethoxydiiridium (98 mg, 0.147 mmol, 0.03 eq) and (4-tert-butyl-2-(4-tert- butylpyridin-2-yl)pyridine (79 mg, 0.29 mmol, 0.06 eq) were added to a suspension of compound 22a (1.0 g, 4.9 mmol) and bis(pinacolato)diboron (1.2 g, 4.9 mmol, 1.0 eq) in MTBE (15 ml) stirred under Ar. The mixture was heated in a microwave for 2 h at 80°C, then cooled and filtered. The filtrate was evaporated and the raw product was used in the next step without further purification. MS: m/z: [M+H]+ = 331.1 (MW calc. 330.2).
22c) Methyl 1-ethyl-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indazole-5- carboxylate
Tetrakis(triphenylphosphine) palladium(O) (35 mg, 0.03 mmol, 0.05 eq) was added to a solution of compound 22b (0.15 g, 0.602 mmol, 1 eq) and 2-(2-(2-chloropyrimidin-5-yl)pyridin-4-yl)propan-2-ol (0.15 g, 0.602 mmol, 1.0 eq) in dioxane (3 ml) and aqueous K2CO3 solution (20%; 0.6 ml) that was degassed with Ar aforegoing. The reaction mixture was refluxed for 1 h, then diluted with water (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were washed with water (20 ml) and brine (20 ml), dried over anhydrous Na2S04 and concentrated under reduced pressure. The remnant was purified by flash column chromatography [230-400 mesh silica gel; EtOAc/hexane = 1 : 1]. White solid. Yield: 0.14 g (74%). MS: m/z: [M+H]+ = 418.0 (MW calc. 417.2).
22d) 1-Ethyl-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indazole-5-carboxylic acid Compound 22c (0.3 g, 0.719 mmol) in methanol (5 ml), THF (5 ml) and water (1.3 ml) was stirred in the presence of aqueous NaOH solution (20% 1.0 ml) at RT for 4 h. The organic solvent was removed and the mixture was diluted with water, acidified with 1 N HCI solution under cooling with an ice bath, and extracted with isopropylamine/CHC (3:7). The organic phase was washed with brine and dried over Na2S04. The solvents were evaporated under reduced pressure affording the target compound as white solid. Yield: 0.25 g (87%). MS: m/z: [M+H]+ = 404.1 (MW calc. 403.2).
22e) 1-Ethyl-N-(2-hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1 H- indazole-5-carboxamide
Compound 22d (0.1 g, 0.24 mmol), 2-(methylamino)ethan-1-ol (0.022 ml, 0.27 mmol, 1.1 eq), TBTU (96 mg, 0.297 mmol, 1.2 eq) and NMM (0.055 ml, 0.49 mmol, 2.0 eq) in DMF (2 ml) were stirred at RT for 1 h. The aqueous phase was separated and extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash column chromatography [230-400 mesh silica gel; EtOAc with 5% MeOH]. White Solid. Yield: 0.06 g (53%). MS: m/z: [M+H]+ = 461 .3 (MW calc. 460.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.6 (s, 2H), 8.69-8.66 (m, 2H), 8.19 (s, 1 H), 7.86 (d, J = 8.5 Hz, 1 H), 7.57-7.52(m, 2H), 5.38 (s, 1 H), 4.77 (brs, 1 H), 4.62 (m, 2H), 3.67-3.32 (4H), 3.03 (s, 3H), 1.51 (brs, 9H).
Example 23: 1-Ethyl-N-(2-hvdroxyethyl)-3-(4-(2-hvdroxypropan-2-yl)-[2,3'-bipyridin1-6'-yl)-N-methyl-1 H- indazole-5-carboxamide
Figure imgf000052_0001
Prepared in analogy to example 22. White solid. Yield: 0.09 g. MS: m/z: [M+H]+ = 460.0 (MW calc. 459.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.44 (s, 1 H), 8.7 (s, 1 H), 8.65 (d, J = 5.1 Hz, 1 H), 8.57 (dd, J = 8.4 Hz, J = 2.1 Hz, 1 H), 8.26 (d, J = 8.4 Hz, 1 H), 8.13 (s, 1 H), 7.81 (d, J = 8.7 Hz, 1 H), 7.53-7.5 (2H), 5.35 (s, 1 H), 4.78 (brs, 1 H), 4.58 (q, J = 7.1 Hz, 2H), 3.67-3.37 (4H), 3.03 (s, 3H), 1.52-1.48 (brs, 9H).
Example 24: (1-Ethyl-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)
(morpholino)methanone
Figure imgf000052_0002
Prepared in analogy to example 22. White solid. Yield: 0.07 g. MS: m/z: [M+H]+ = 473.3 (MW calc. 472.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.6 (s, 2H), 8.69 (s, 2H), 8.19 (s, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.58-7.53 (2H), 5.39 (s, 1 H), 4.63 (q, J = 7.0 Hz, 2H), 3.63 (brs, 8H), 1.52-1.49 (brs, 9H).
Example 25: (1-Ethyl-3-(4-(2-hvdroxypropan-2-yl)-[2,3'-bipyridinl-6'-yl)-1 H-indazol-5-yl)(morpholino) methanone
Figure imgf000052_0003
Prepared in analogy to example 22. White solid. Yield: 0.13 g. MS: m/z: [M+H]+ = 471 .8 (MW calc. 471.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.45 (s, 2H), 8.73 (s, 1 H), 8.65 (d, J = 5.0 Hz, 1 H), 8.57 (dd, J = 8.4 Hz, J = 2.2 Hz, 1 H), 8.26 (d, J = 8.4 Hz, 1 H), 8.13 (s, 1 H), 7.84 (d, J = 8.7 Hz, 1 H), 7.53-7.51 (m, 1 H), 5.35 (s, 1 H), 4.37 (q, J = 7.1 Hz, 2H), 3.63 (brs, 9H), 1.51-1.48 (9H).
Example 26: 1-Ethyl-N-(2-hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H- indazole-5-carboxamide
Figure imgf000053_0001
Prepared in analogy to example 22. White solid. Yield: 0.06 g. MS: m/z: [M+H]+ = 447.2 (MW calc. 446.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.63 (s, 2H), 9.12 (s, 1 H), 8.7 (d, J = 4.9 Hz, 1 H), 8.55 (brs, 1 H), 8.21 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 8.8 Hz, 1 H), 7.58 (d, J = 4.1 Hz, 1 H), 5.38 (s, 1 H), 4.76 (s, 1 H), 4.62 (q, J = 6.9 Hz, 2H), 3.56 (s, 2H), 3.39 (d, J = 5.6 Hz, 2H), 1.52-1.49 (brs, 9H). -Ethyl-N-(2-hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-
Figure imgf000053_0002
27a) Methyl 1-ethyl-3-iodo-1 H-indole-5-carboxylate
NaH (1.02 g, 25.58 mmol, 1.1 eq, 60% in mineral oil) was added portion wise and under ice cooling to a solution of methyl 3-iodo-1 H-indole-5-carboxylate (7.0 g, 23.25 mmol, 1 eq) in THF (70 ml). After stirring for 10 min, ethyliodide (2.07 ml, 25.38 mmol, 1.1 eq) was added and the reaction was stirred at RT for 4 h. The mixture was quenched with ice and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04 and concentrated. The residue was purified by flash chromatography [hexane/EtOAc = 85:15]. White solid. Yield: 6.1 g (80%). 27b) Methyl 1-ethyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-indole-5-carboxylate PdCl2(dppf) (370 mg, 0.455 mmol, 0.05 eq) was added to a solution of compound 27a (3.0 g, 9.1 1 mmol, 1 eq), TEA (5.8 ml, 41.94 mmol, 4.6 eq) and bis(pinacolato)diboron (8.6 ml, 59.27 mmol, 6.5 eq) in dioxane (50 ml) that was stirred under Ar. The reaction mixture was heated to 90°C for 40 min, diluted with EtOAc (200 ml) and filtered through a plug of celite. The filtrate was concentrated and the remnant purified by flash column chromatography [230-400 mesh silica gel; hexane/EtOAc = 4: 1]. Yield: 2.25 g (75%). White solid. MS: m/z: [M+H]+ = 329.8 (MW calc. 329.2).
Prepared from compound 27b following the synthetic procedures detailed for example 22. White solid. Yield: 0.08 g. MS: m/z: [M+H]+ = 460.3 (MW calc. 459.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.43 (s, 2H), 8.65 (m, 2H), 8.47 (s, 1 H), 8.1 (s, 1 H), 7.64 (d, J = 8.2 Hz, 1 H), 7.52 (d, J = 4.5 Hz, 1 H), 7.31 (d, J = 8.5 Hz, 1 H), 5.34 (s, 1 H), 4.76 (brs, 1 H), 4.37 (m, 2H), 3.65-3.32 (4H), 3.0 (s, 3H), 1 .5-1.43 (9H).
Example 28: (1-Ethyl-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indol-5-yl)
Figure imgf000054_0001
Prepared from compound 27b in analogy to example 22. Light yellow solid. Yield: 0.09 g. MS: m/z: [M+H]+ = 472.3 (MW calc. 471.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.44 (s, 2H), 8.7-8.64 (2H), 8.49 (s, 1 H), 8.1 1 (s, 1 H), 7.66 (d, J = 8.3 Hz, 1 H), 7.52 (s, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 5.35 (s, 1 H), 4.37 (m, 2H), 3.63 (brs, 8H), 1.52-1.43 (9H).
Example 29: 1-Ethyl-N-(2-hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H- indole-5-carboxamide
Figure imgf000054_0002
Prepared from compound 27b in analogy to example 22. Light yellow solid. Yield: 0.09 g. MS: m/z: [M+H]+ = 446.3 (MW calc. 445.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.63 (s, 2H), 9.12 (s, 1 H), 8.65 (d, J = 4.7 Hz, 1 H), 8.48 (s, 1 H), 8.36 (m, 1 H), 8.12 (s, 1 H), 7.77 (d, J = 8.4 Hz, 1 H), 7.65 (d, J = 8.5 Hz, 1 H), 7.52 (d, J = 4.2 Hz, 1 H), 5.35 (s, 1 H), 4.75 (t, J = 5.2 Hz, 1 H), 4.37 (m, 2H), 3.56 (d, J = 5.7 Hz, 2H), 3.38 (d, J = 5.4 Hz, 2H), 1.52-1.43 (9H). Example 30: N-(2-Hvdroxyethvn-3-(5-(4-(2-hvdroxypropan-2-vnpyridin-2-vnpyrimidin-2-vn-N-methyl-1-
Figure imgf000055_0001
30a) tert-Butyl 1-(2,2,2-trifluoroethyl)-1 H-indazole-5-carboxylate
1 , 1 , 1-Trifluoro-2-iodoethane (2.43 g, 1 1.6 mmol, 1.1 eq) was added drop wise to a solution of tert-butyl 1 H-indazole-5-carboxylate (2.3 g, 10.55 mmol, 1 eq) and Cs2C03 (5.15 g, 15.82 mmol, 1.5eq) in DMF (30 ml) and the reaction mixture was stirred at 100°C for 16 h in a sealed tube. The reaction mixture was cooled to RT, diluted with water and extracted with EtOAc (100 ml x 2). The combined organic layers were repeatedly washed with water (50 ml) and brine (50 ml), dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The raw product was purified by column chromatography [100-200 silica gel, hexane/EtOAc = 4: 1]. Solid. Yield: 0.58 g (18%). MS: m/z: [M+H]+ = 301 .2 (MW calc. 300.1 ).
Compound 30a was further converted into the target compound following the procedures described for example 22. White solid. Yield: 85 mg. MS: m/z: [M+H]+ = 515.3 (MW calc. 514.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.63 (s, 2H), 8.69 (s, 2H), 8.21 (s, 1 H), 7.97 (brs, 1 H), 7.64-7.57 (m, 2H), 5.7 (m, 2H), 5.39 (s, 1 H), 4.79 (brs, 1 H), 3.68-3.53 (3H), 3.03 (s, 3H), 1 .51 (brs, 6H).
Example 31 : (3-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-indazol- 5-yl)(morpholino)methanone
Figure imgf000055_0002
Synthesized from compound 30a in analogy to example 22. White solid. Yield: 0.08 g. MS: m/z: [M+H]+ = 527.3 (MW calc. 526.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.64 (s, 2H), 8.71 (m, 1 H), 8.21 (s, 1 H), 8.0 (d, J = 8.4 Hz, 1 H), 7.64 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 4.2 Hz, 1 H), 5.71 (m, 2H), 5.39 (s, 1 H), 3.64 (brs, 8H), 1.52 (brs, 6H).
Example 32: N-(2-Hvdroxyethyl)-3-(4-(2-hvdroxypropan-2-yl)-[2,3'-bipyridinl-6'-yl)-N-methyl-1-(2,2,2-
Figure imgf000056_0001
Synthesized from compound 30a in analogy to example 22. White solid. Yield: 105 mg. MS: m/z: [M+H]+ = 514.4 (MW calc. 513.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.47 (s, 1 H), 8.74 (s, 1 H), 8.66 (d, J = 5.1 Hz, 1 H), 8.61 (dd, J = 8.4 Hz, J = 2.1 Hz, 1 H), 8.27 (d, J = 8.4 Hz, 1 H), 8.14 (s, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.61 (d, J = 9.5 Hz, 1 H), 7.52 (dd, J = 5.1 Hz, J = 1.2 Hz, 1 H), 5.64 (q, J = 8.6 Hz, 2H), 5.35 (s, 1 H), 4.78 (brs, 1 H), 3.67-3.36 (4H), 3.03 (s, 3H), 1.51 (brs, 6H). Example 33: (3-(4-(2-Hvdroxypropan-2-yl)-[2,3'-bipyridinl-6'-yl)-1-(2,2,2-trifluoroethyl)-1 H-indazol-5-yl)-
(morpholino)methanone
Figure imgf000056_0002
Synthesized from compound 30a in analogy to example 22. White solid. Yield: 110 mg. MS: m/z: [M+H]+ = 526.2 (MW calc. 525.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.48 (s,1 H), 8.76 (s, 1 H), 8.66-8.6 (2H), 8.27 (d, J = 5.0 Hz, 1 H), 8.15 (s, 1 H), 7.96 (d, J = 8.6 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.52 (d, J = 5.0 Hz, 1 H), 5.65 (q, J = 8.7 Hz, 2H), 5.35 (s, 1 H), 3.64 (brs, 8H), 1.51 (brs, 6H).
Example 34: N-(2-Hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-
(2,2,2-trifluoroethyl)-1 H-indole-5-carboxamide
Figure imgf000057_0001
34a) tert-Butyl 3-iodo-1 H-indole-5-carboxylate
KOH (2.58 g, 46.08 mmol, 2.5 eq) followed by iodine (4.6 g, 36.86 mmol, 1.0 eq) were added to a solution of tert-butyl 1 H-indole-5-carboxylate (4.0 g, 18.43 mmol, 1 eq) in DMF (40 ml). The reaction mixture was stirred at RT for 3 h, then quenched with ice and Na2S203 solution and extracted with EtOAc (250 ml x 2). The combined organic layers were washed repeatedly with cold water (100 ml) and brine (100 ml), dried over anhydrous Na2S04, filtered and evaporated under reduced pressure. The product obtained was used in the next step without further purification. Brown solid. Yield: 5.0 g (79%). MS: m/z: [M+H]+ = 218.1 (MW calc. 217.1 ).
34b) tert-Butyl 3-iodo-1-(2,2,2-trifluoroethyl)-1 H-indole-5-carboxylate
1 , 1 , 1-Trifluoro-2-iodoethane (8.08 g, 38.47 mmol, 1.1 eq) was added drop wise to a mixture of compound 34a (12.0 g, 34.98 mmol, 1 eq) and Cs2C03 (17.1 g, 52.45 mmol, 1.5eq) in DMF (120 ml). The reaction mixture was stirred at 100°C for 16 h in a sealed tube, cooled to RT, diluted with water and extracted with EtOAc (200 ml x 2). The combined organic layers were washed repeatedly with water (50 ml) and brine (50 ml), dried over anhydrous Na2S04 and filtered. The solvents were distilled off and the residue was purified by column chromatography [100-200 silica gel; hexane/EtOAc = 4: 1]. Sticky solid. Yield: 3.0 g (20%). Compound 34b was further converted into example 34 following the synthesis protocols of example 22. White solid. Yield: 0.06 g. MS: m/z: [M+H]+ = 514.2 (MW calc. 513.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.48 (s, 2H), 8.69-8.65 (2H), 8.5 (s, 1 H), 8.13 (s, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 7.54 (d, J = 4.0 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 5.43 (m, 2H), 5.35 (s, 1 H), 4.78 (brs, 1 H), 3.55-3.32 (4H), 3.03 (s, 3H), 1.5 (brs, 6H).
Example 35: (3-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-indol-5- yl)(morpholino)methanone
Figure imgf000058_0001
Synthesized from compound 34b in analogy to example 22. White solid. Yield: 0.06 g. MS: m/z: [M+H]+ = 526.3 (MW calc. 525.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.48 (s, 2H), 8.73 (s, 1 H), 8.66 (d, J = 5.2 Hz, 1 H), 8.51 (s, 1 H), 8.13 (s, 1 H), 7.79 (d, J = 8.6 Hz, 1 H), 7.54 (dd, J = 5.1 Hz, J = 1.2 Hz, 1 H), 7.4 (d, J = 8.4 Hz, 1 H), 5.44 (q, J = 8.9 Hz, 2H), 5.35 (s, 1 H), 3.63-3.5 (brs, 8H), 1 .51 (brs, 6H).
(3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino)methanone used for the preparation of examples 36 to 38 was prepared in analogy to synthesis example 21. Example 36: (1-Methyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino) methanone
Figure imgf000058_0002
KOH (83.9 mg, 1.5 mmol) was added to a solution of (3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H- indazol-5-yl)(morpholino)methanone (200 mg, 0.5 mmol) in acetone (5 ml) and the mixture was stirred at RT for 30 min Methyl iodide (0.046 ml, 0.75 mmol) was added and stirring was continued until the starting material was consumed (LCMS). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography [DCM/MeOH = 9.1]. Yellow solid. Yield: 60 mg (29%). MS: m/z: [M+H]+ = 415.4 (MW calc. 414.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 2.44 (s, 3H), 3.55-3.64 (m, 8H), 4.23 (s, 3H), 7.32-7.33 (d, 1 H), 7.54-7.56 (d, 1 H), 7.83-7.85 (d, 1 H), 8.07 (s, 1 H), 8.61-8.63 (d, 1 H), 8.67 (s, 1 H)
Example 37: (1-Ethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino) methanone
Figure imgf000059_0001
Prepared in analogy to example 36. White solid. Yield: 75 mg. MS: m/z: [M+H]+ = 428.2 (MW calc. 429.4). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 1.49-1.53 (s, 3H), 2.32-2.66 (s, 3H), 3.64 (m, 8H), 4.59-4.64 (s, H), 7.32-7.33 (d, 1 H), 7.53-7.55 (d, 1 H), 7.87-7.89 (d, 1 H), 8.07 (s, 1 H), 8.62-8.63 (d, 1 H), 8.68 (s, 1 H), 9.59 (s, 2H)
Example 38: (3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazol-5-yl)(morpholi methanone
Figure imgf000059_0002
Prepared from (3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino)methanone in analogy to example 3. White solid. Yield: 73 mg. MS: m/z: [M+H]+ = 428.2 (MW calc. 429.4). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 2.46 (s, 3H), 3.68 (m, 1 1 H), 7.36-7.37 (d, 1 H), 7.77-7.79 (d, 1 H), 8.1 1-8.13 (t, 2H), 8.64-8.66 (d, 1 H), 8.78 (s, 1 H), 9.70 (s, 2H) Example 39: (3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-1-methyl-1 H-indazol-5-yl)(morpholino)methanone
Figure imgf000059_0003
Synthesis in analogy to example 36. Yellow solid. Yield: 82 mg. MS: m/z: [M+H]+ = 417.8 (MW calc. 417.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 3.62 (m, 8H), 7.40-7.47 (m, 2H), 7.63-7.64 (t, 2H), 7.78- 7.96 (m, 2H), 8.69 (s, 1 H), 9.18 (m, 2H) Example 40: (3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-^
methanone
Figure imgf000060_0001
Synthesis in analogy to example 36. Yellow solid. Yield: 45 mg. MS: m/z: [M+H]+ = 432.4 (MW calc. 431.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 2.32-2.39 (d, 3H), 3.63 (s, 8H), 4.23 (s, 3H), 7.31-7.33 (d, 2H), 7.53-7.61 (dd, 2H), 7.83-7.85 (d, 1 H), 8.65 (s, 1 H), 9.16 (s, 2H)
Example 41 : N-(2-Hvdroxyethvn-N, 1-dimethyl-3-(5-(4-methylpyridin-2-vnpyrimidin-2-vn-1 H-indazole-5- carboxamide
Figure imgf000060_0002
Synthesis in analogy to example 36. White solid. Yield: 38 mg. MS: m/z: [M+H]+ = 403.1 (MW calc. 402.2).
Example 42: (1-Methyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(pyrrolidin-1-yl) methanone
Figure imgf000060_0003
Synthesis in analogy to example 36. White solid. Yield: 60 mg. MS: m/z: [M+H]+ = 398.8 (MW calc. 398.2). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 1.83-1.91 (dd, 4H), 2.50 (s, 3H), 3.48-3.53 (dd, 4H), 4.23 (s, 3H), 7.32-7.33 (d, 1 H), 7.65-7.67 (t, 1 H), 7.80-7.82 (d, 1 H), 8.07 (s, 1 H), 8.61-8.62 (d, 1 H), 8.78 (s, 1 H), 9.55 (s, 2H) Example 43: 1-Ethyl-5-(ethylsulfinyl)-3-
Figure imgf000061_0001
43a) 5-(Ethylthio)-1 H-indole
A solution of 5-bromo-1 H-indole (10.0 g, 51.02 mmol), DIPEA (16.9 ml_, 102.04 mmol), ethane thiol (3.78 ml_, 51.02 mmol), xantphos (2.95 g, 5.1 mmol) and Pd2(dba)3 (2.33 g, 2.55 mmol) in dioxane (120 mL) was heated under Ar to 120°C for 16 h. The reaction mixture was cooled to RT and filtered through a sintered funnel. The filtrate was concentrated and the residue purified by flash column chromatography [silica, hexane with 10-25% EtOAc]. Light yellow sticky solid. Yield: 9.0 g (99%). HPLC (method 2): Rt = 3.30 min, m/z: [M+H]+ = 176.0 (MW calc. 177.27).
43b) 5-(Ethylthio)-3-iodo-1 H-indole
5-(Ethylthio)-1 H-indole (9.0 g, 50.83 mmol), K2CO3 (15.45 g, 1 12 mmol) and iodine (14.22 g, 1 12 mmol) in dry DMF (50 mL) were stirred at RT for 16 h. The reaction mixture was quenched with sat. Na2S203 solution and crushed ice and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2S04 and evaporated affording the title compound as brown oil that was used in the next step without further purification. Yield: 10.5 g (41 %)
43c) 5-(Ethylthio)-3-iodo-1-tosyl-1 H-indole
NaH (1.45 g, 36.30 mmol) was added portion wise at 0°C to a solution of compound 43b (10 g, 33.0 mmol) in dry THF (100 mL). The mixture was stirred at this temperature for 20 min p-Toluene sulfonyl chloride was then added at 0°C and stirring was continued at RT for 6 h. The reaction mixture was quenched at 0°C with sat. NaHCCh solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated. The raw product was purified by flash column chromatography [silica, hexane with 0-5% EtOAc]. White solid. Yield: 10.5 g (69%). HPLC (method 4): Rt = 4.92 min, m/z: [M-H]" = 456.0 (MW calc. 457.35).
43d) 5-(Ethylthio)-3-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2-yl)-1-tosyl-1 H-indole
PdCl2(dppf) (67 mg, 0.082 mmol) was added to compound 43c (0.75 g, 1.64 mmol), bis(pinacolato)diboron (0.83 g, 3.28 mmol) and dry KOAc (0.56 g, 5.74 mmol) in DMSO (15 mL) stirred at RT under Ar. The reaction mixture was stirred at 90°C for 30 min, then cooled to RT and filtered through a sintered funnel. The funnel was rinsed with EtOAc (100 mL) and the filtrate was washed with water and brine and dried over Na2S04. The solvents were removed in vacuo and the raw product thus obtained was used in the next step without further purification. White solid. Yield: 1.2 g (59%). HPLC (method 1 ): Rt = 4.44 min, m/z: [M+H]+ = 457.9 (MW calc. 457.42).
43e) 5-(Ethylthio)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-tosyl-1 H-indole
Tetrakis(triphenylphosphine) palladium(O) (0.12 g, 0.1 1 mmol) was added to a mixture of compound 43d (1.0 g, 2.19 mmol) and 2-chloro-5-(4-methyl-pyridin-2-yl)-pyrimidine (0.55 g, 2.63 mmol) in dioxane (40 mL) and 2M aqueous K2CO3 solution (4 mL) stirred at RT under Ar. The reaction mixture was heated at 100°C for 6 h, cooled to RT and filtered through a sintered funnel. The filtrate was concentrated and the remnant purified by flash column chromatography [silica; hexane /EtOAc = 4: 1]. Yellow sticky solid. Yield: 0.50 g (45%). HPLC (method 1 ): Rt = 2.69 min, m/z: [M+H]+ = 501.0 (MW calc. 500.64).
43f) 5-(Ethylthio)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
A solution of NaOH (0.15 g, 3.75 mmol) in water (4 mL) was added at 0°C to compound 43e (0.75 g, 1.5 mmol) in a blend of THF/MeOH (2:1 , 24 mL) and the reaction mixture was stirred at RT for 1.5 h. The mixture was concentrated, diluted with sat. NaHCCh solution and extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried over Na2S04 and evaporated. Yellow sticky solid. Yield: 0.45 g (87%). HPLC (method 1 ): Rt = 3.54 min, m/z: [M+H]+ = 347.2 (MW calc. 346.45).
43g) 1-Ethyl-5-(ethylthio)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
NaH (72 mg, 1.80 mmol) was added portion wise at 0°C to a solution of compound 43f (0.52 g, 1.50 mmol) in dry THF (20 mL) and the reaction mixture was stirred at RT for 20 min Ethyl iodide (0.13 mL, 1.65 mmol) was added at this temperature and stirring was continued at RT for 16 h. The mixture was quenched with sat. NH4CI solution under cooling with an ice bath and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2S04. The solvents were distilled off and the residue was purified by flash column chromatography [silica; DCM with 1 % MeOH]. Yellow solid. Yield: 0.25 g (44%). HPLC (method 1 ): Rt = 4.10 min, m/z: [M+H]+ = 375.2 (MW calc. 374.50).
43h) 1-Ethyl-5-(ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
mCPBA (58 mg, 0.25 mmol) dissolved in DCM was added drop wise at 0°C to a solution of compound 43g (0.1 1 g, 0.29 mmol) in DCM (20 mL). The reaction mixture was slowly brought to RT and stirred for 30 min The mixture was quenched with sat. Na2S03 solution at 0°C and extracted with DCM (3 x 30 mL). The combined organic layers were washed with sat. NaHCCh solution and brine, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica; DCM with 2.5% MeOH] followed by preparative thin layer choreography (acetone/DCM = 1 :4). White solid. Yield: 50 mg (44%). HPLC (method 1 ): Rt = 3.25 min, m/z: [M+H]+ = 391.1 (MW calc. 390.50). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.45 (s, 2H), 8.87 (s, 1 H), 8.59 (d, 1 H, J = 4.9 Hz), 8.55 (s, 1 H), 8.0 (s, 1 H), 7.83 (d, 1 H, J = 8.5 Hz), 7.51 (d, 1 H, J = 8.6 Hz), 7.28 (d, 1 H, J = 4.7 Hz), 4.42-4.37 (m, 2H), 3.02-2.95 (m, 1 H), 2.84-2.79 (m, 1 H), 2.42 (s, 3H), 1.46 (t, 3H, J = 7.2 Hz), 1.06 (t, 3H, J = 7.3 Hz) Example 44: 1-Ethyl-5-(ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
Figure imgf000063_0001
Prepared from compound 43g via oxidation with 2 equivalents mCPBA. White solid. Yield: 60 mg. HPLC (method 1): Rt = 3.30 min, m/z: [M+H]+ = 407.0 (MW calc. 406.50). 1H NMR (400 MHz, DMSO-d6, δ ppm): 9.48 (s, 2H), 9.14 (s, 1H), 8.65 (s, 1H), 8.59 (d, 1H, J = 4.9 Hz), 8.03 (s, 1H), 7.91 (d, 1H, J = 8.7 Hz), 7.75 (d, 1H, J = 8.6 Hz), 7.29 (d, 1H, J = 4.2 Hz), 4.44-4.42 (m, 2H), 3.29-3.26 (m, 2H), 2.42 (s, 3H), 1.47 (t, 3H, J = 7.1 Hz), 1.14 (t, 3H, J = 7.2 Hz)
Example 45: 5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
Figure imgf000063_0002
Prepared from compound 43e in two chemical steps comprising an oxidation (procedure 43h) and a removal of the protecting group (procedure 43f). Yellow solid. Yield: 30 mg. HPLC (method 1): Rt = 2.74 min, m/z: [M+H]+ = 363.1 (MW calc.362.45). 1H NMR (400 MHz, DMSO-d6, δ ppm): 12.11 (s, 1H), 9.43 (s, 2H), 8.83 (s, 1H), 8.57 (d, 1H, J = 4.7 Hz), 8.44 (s, 1H), 7.98 (s, 1H), 7.66 (d, 1H, J = 8.5 Hz), 7.43 (d, 1H, J = 8.3 Hz), 7.26 (d, 1H, J = 4.3 Hz), 3.02-2.95 (m, 1H), 2.84-2.79 (m, 1H), 2.39 (s, 3H), 1.03 (t, 3H, J = 7.3 Hz).
Example 46: 5-(Ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
Figure imgf000063_0003
Obtained from compound 43e via oxidation with 2 equivalents mCPBA (procedure 43h) followed by removal of the protecting group (procedure 43f). White solid. Yield: 48 mg. HPLC (method 3): Rt = 1.i min, m/z: [M+H]+ = 379.08 (MW calc. 378.45). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 12.33 (s, 1 H), 9.48 (s, 2H), 9.12 (s, 1 H), 8.59 (d, 1 H, J = 4.9 Hz), 8.55 (d, 1 H, J = 2.5 Hz), 8.03 (s, 1 H), 7.74-7.68 (m, 2H), 7.28 (d, 1 H, J = 4.7 Hz), 7.26 (d, 1 H, J = 4.3 Hz), 3.29-324 (m, 2H), 2.42 (s, 3H), 1.13 (t, 3H, J = 7.3 Hz). Example 47: 5-(Ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)p
Figure imgf000064_0001
Prepared from compound 43f in two chemical steps comprising a nucleophilic substitution with use of mesyl chloride (procedure 17a) and a mCPBA oxidation (procedure 43h). Yellow solid. Yield: 50 mg. HPLC (method 3): Rt = 1.67 min, m/z: [M+H]+ = 457.03 (MW calc. 456.54). 1 H NMR (400 MHz, DMSO- d6, δ ppm): 9.6 (s, 2H), 9.25 (s, 1 H), 8.62 (d, 2H, J = 4.7 Hz), 8.22 (d, 1 H, J = 8.8 Hz), 8.09 (s, 1 H), 8.01 - 7.98 (m, 1 H), 7.33 (d, 1 H, J = 4.9 Hz), 3.78 (s, 3H), 3.37-3.32 (m, 2H), 2.44 (s, 3H), 1.16 (t, 3H, J = 7.3 Hz).
Example 48: 5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole
Figure imgf000064_0002
Compound 43f was reacted with mesyl chloride (procedure 17a) followed by an oxidation with mCPBA (procedure 43h). White solid. Yield: 35 mg. HPLC (method 3): Rt = 1.64 min, m/z: [M+H]+ = 441.1 (MW calc. 440.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.57 (s, 2H), 8.99 (s, 1 H), 8.62 (d, 1 H, J = 4.7 Hz), 8.53 (s, 1 H), 8.13 (d, 1 H, J = 8.6 Hz), 8.07 (s, 1 H), 7.74 (d, 1 H, J = 8.2 Hz), 7.32-7.31 (m, 1 H), 3.73 (s, 3H), 3.06 (t, 1 H, J = 6.5 Hz), 2.85 (t, 1 H, J = 6.4 Hz), 2.43 (s, 3H), 1.08 (t, 3H, J = 7.2 Hz).
Example 49: 1-(5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indol-1-yl)ethanone
Figure imgf000065_0001
Compound 43f was reacted with acetyl chloride (procedure 17a) followed by an oxidation with mCPBA (procedure 43h). Light yellow solid. Yield: 45 mg. HPLC (method 1): Rt = 3.02 min, m/z: [M+H]+ = 405.2 (MW calc.404.49).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.57 (s, 2H), 8.97 (s, 1H), 8.82 (s, 1H), 8.61 (t, 2H, J = 5.5 Hz), 8.07 (s, 1H), 7.69 (d, 1H, J = 8.6 Hz), 7.32 (bs, 1H), 3.05 (t, 1H, J = 5.9 Hz), 2.85-2.80 (m, 4H), 2.44 (s, 3H), 1.06 (t, 3H, J = 7.1 Hz).
Figure imgf000065_0002
Prepared in analogy to example 43. Light yellow solid. Yield: 50 mg. HPLC (method 1): Rt = 2.89 min, m/z: [M+H]+ = 435.4 (MW calc.434.55).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.47 (s, 2H) 8.89 (s, 1H), 8.66 (d, 1H, J = 4.9 Hz), 8.55 (s, 1H), 8.13 (s, 1H), 7.84 (d, 1H, J = 8.5 Hz), 7.53-7.49 (m, 2H), 5.34 (s, 1H), 4.41-4.39 (m, 2H), 3.00-2.97 (m, 1 H), 2.84-2.81 (m, 1H), 1.48-1.44 (m, 9H), 1.08-1.05 (t, 3H, J = 7.1 Hz).
Example 51: 2-(2-(2-(1-Ethyl-5-(ethylsulfonyl)-1H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
Figure imgf000065_0003
Prepared in analogy to example 44. Yellow solid. Yield: 50 mg. HPLC (method 3): Rt = 1.64 min, m/z: [M+H]+ = 451.2 (MW calc. 450.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.51 (s, 2H), 9.16 (s, 1 H), 8.67 (d, 2H, J = 7.7 Hz), 8.15 (s, 1 H), 7.91 (d, 1 H, J = 8.6 Hz), 7.76 (d, 1 H, J = 8.5 Hz), 7.55 (d, 1 H, J = 4.6 Hz), 5.35 (s, 1 H), 4.44-4.41 (m, 2H), 3.29-3.26 (m, 2H), 1.51-1.45 (m, 9H), 1.15 (t, 3H, J = 7.2 Hz).
Example 52: 3-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-(methylsulfonyl)-1 H- indole-5-carboxamide
Figure imgf000066_0001
Prepared in analogy to example 3. White solid. Yield: 0.1 1 g. HPLC (method 1 ): Rt = 2.71 min, m/z: [M+H]+ = 466.0 (MW calc. 465.53). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.59 (s, 2H), 9.21 (s, 1 H), 8.69 (d, 1 H, J = 5.1 Hz), 8.55 (d, 1 H, J = 4.4 Hz), 8.47 (s, 1 H), 8.19 (s, 1 H), 7.99-7.92 (m, 2H), 7.57 (d, 1 H, J = 5.0 Hz), 5.36 (s, 1 H), 3.70 (s, 3H), 2.85 (d, 3H, J = 4.4 Hz), 1.51 (s, 6H).
Example 53: (3-(5-(4-(2-Hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5- yl)(morpholino)methanone
Figure imgf000066_0002
Prepared in analogy to example 3. White solid. Yield: 0.05 g. HPLC (method 3): Rt = 1.56 min, m/z: [M+H]+ = 522.2 (MW calc. 521.59). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.57 (s, 2H), 8.80 (s, 1 H), 8.69 (d, 1 H, J = 5.1 Hz), 8.48 (s, 1 H), 8.17 (s, 1 H), 8.01 (d, 1 H, J = 8.5 Hz), 7.57-7.56 (m, 2H), 5.37 (s, 1 H), 3.69-3.64 (m, 1 1 H), 1.51 (s, 6H).
Example 54: N-(2-Hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-
(methylsulfonyl)-1 H-indole-5-carboxamide
Figure imgf000067_0001
Prepared in analogy to example 3. White solid. Yield: 0.04 g. HPLC (method 3): Rt = 1.49 min, m/z: [M+H]+ = 510.2 (MW calc. 509.58). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.57 (s, 2H), 8.77 (s, 1 H), 8.68 (d, 1 H, J = 4.9 Hz), 8.47 (s, 1 H), 8.17 (s, 1 H), 7.98 (d, 1 H, J = 7.9 Hz), 7.57-7.52 (m, 2H), 5.37 (s, 1 H), 4.83-4.77 (m, 1 H), 3.70 (s, 4H), 3.57-3.35 (m, 3H), 3.04 (s, 3H), 1 .51 (s, 6H).
Example 55: N-(2-Hvdroxyethyl)-3-(5-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 -(methyl- sulfonyl)-1 H-indole-5-carboxamide
Figure imgf000067_0002
Prepared in analogy to example 3. White solid. Yield: 25 mg. HPLC (method 1 ): Rt = 2.62 min, m/z: [M+H]+ = 496.2 (MW calc. 495.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.59 (s, 2H), 9.22 (s, 1 H), 8.69 (d, 1 H, J = 4.8 Hz), 8.57-8.54 (m, 1 H), 8.48 (s, 1 H), 8.19 (s, 1 H), 7.97 (s, 2H), 7.57-7.56 (m, 1 H), 5.36 (s, 1 H), 4.77-4.74 (m, 1 H), 3.70 (s, 3H), 3.59-3.54 (m, 2H), 3.42-3.35 (m, 2H), 1.51 (s, 6H). Examples 56 and 57: 2-(2-(2-(1-Ethyl-5-(ethylsulfinyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
(faster and slower elutinq enantiomer)
Figure imgf000068_0001
The racemate was prepared in analogy to example 43 (yield: 0.80 g, light yellow solid) and then submitted for preparative chiral HPLC in order to obtain the pure enantiomers (HPLC method used: column: Chiralpak-IA 250 x 21.0 mm, 5μιη; mobile phase: hexane/EtOAc/EtOH/diethylamine = 50/25/25/0.1 ; flow rate: 21 .0 ml/min; run time: 15 min; detection: 340 nM).
Faster eluting enantiomer (example 56): Yield = 0.31 g. White solid. Specific optical rotation: [a]58925 = - 241.7° (c. 0.626, CHCIs). Enantiomeric excess = 100%. HPLC (method 3): Rt = 1.61 min, m/z: [M+H]+ = 435.1 (MW calc. 434.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.47 (s, 2H), 8.89 (s, 1 H), 8.66 (d, 1 H, J = 5.0 Hz), 8.55 (s, 1 H), 8.13 (s, 1 H), 7.83 (d, 1 H, J = 8.6 Hz), 7.53-7.49 (m, 2H), 5.34 (s, 1 H), 4.43-4.37 (m, 2H), 3.00-2.94 (m, 1 H), 2.86-2.77 (m, 1 H), 1.50-1.44 (m, 9H), 1.06 (t, 3H, J = 7.3 Hz).
Slower eluting enantiomer (example 57): Yield = 0.33 g. White solid. Specific optical rotation: [a]58925 = +224.68° (c. 0.6792, CHCI3). Enantiomeric excess = 99.6%. HPLC (method 5): Rt = 3.12 min, m/z: [M+H]+ = 435.2 (MW calc. 434.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.47 (s, 2H), 8.89 (s, 1 H), 8.66 (d, 1 H, J = 5.0 Hz), 8.55 (s, 1 H), 8.13 (s, 1 H), 7.83 (d, 1 H, J = 8.6 Hz), 7.53-7.48 (m, 2H), 5.34 (s, 1 H), 4.42-4.37 (m, 2H), 3.03-2.94 (m, 1 H), 2.83-2.76 (m, 1 H), 1.50-1.44 (m, 9H), 1.06 (t, 3H, J = 7.3 Hz).
Figure imgf000068_0002
58a) Methyl 3-((1-ethyl-1 H-indazol-5-yl)thio)propanoate
Xantphos (1 .02 g, 1.77 mmol), DIPEA (9.3 mL, 53.1 mmol), 3-mercapto-propionic acid methyl ester (1.97 mL, 17.7 mmol) and Pd2(dba)3(0) (0.81 g, 0.88 mmol) were added at RT to a solution of 5-bromo-1-ethyl- 1 H-indazole (4.0 g, 17.7 mmol) in dry dioxane (150 mL) that was previously degassed with Ar. 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 residue was purified by flash column chromatography [silica; hexane/EtOAc = 4: 1]. Yellow oil. Yield: 3.5 g (75%). HPLC (method 1 ): Rt = 3.34 min, m/z: [M+H]+ = 265.0 (MW calc. 264.34) 58b) 1-Ethyl-5-(methylthio)-1 H-indazole
Sodium metal pieces (2.3 g, 98.86 mmol) were added portion wise to MeOH (100 mL). After complete dissolution of sodium, 3-(1-ethyl-1 H-indazol-5-ylsulfanyl)-propionic acid methyl ester (3.0 g, 1 1.36 mmol) in MeOH (50 mL) was added drop wise and the reaction mixture was heated at 80°C for 1 h. The mixture was cooled to RT, methyl iodide (0.85 g, mmol) was added portion wise at 0°C and stirring was continued at RT for 1.5 h. The mixture was concentrated, diluted with EtOAc (100 mL) and washed with water. The organic phase was dried over Na2S04 and concentrated. The remnant was purified by flash column chromatography [silica; hexane/EtOAc = 7:3]. Colorless oil. Yield: 1.5 g (68%). HPLC (method 3): Rt = 1.62 min, m/z: [M+H]+ = 193.0 (MW calc. 192.07) 58c) ( 1 -Ethyl-5-( methylthio)-1 H-indazol-3-yl)boronic acid
Bis(pinacolato)diboron (0.95 mL, 6.5 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (21 mg, 0.078 mmol) and 1 ,5- cyclooctadiene)(methoxy)iridium(l)dimer (26 mg, 0.039 mmol) were added to a microwave vial with 1- ethyl-5-methylsulfanyl-1 H-indazole (0.25 g, 1.30 mmol) in MTBE (3 mL) under Ar. The reaction mixture was heated in a microwave at 90°C for 2 h, cooled to RT and filtered through a plug of celite. The filtrate was concentrated affording the target compound as brown sticky solid that was used in the next step without purification. Yield: 0.26 g (84%). HPLC (method 1 ): Rt = 2.89 min, m/z: [M+H]+ = 237.0 (MW calc. 236.10)
58d) 2-(2-(2-(1-Ethyl-5-(methylthio)-1 H-indazol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
Tetrakis(triphenylphosphine) palladium(O) (0.12 g, 0.10 mmol) was added at RT to a solution of compound 58c (0.50 g, 2.1 mmol) and 2-[2-(2-chloro-pyrimidin-5-yl)-pyridin-4-yl]-propan-2-ol (0.52 g, 2.1 mmol) in dioxane (25 mL) and 2M aqueous K2CO3 solution (3 mL) stirred under Ar. The reaction mixture was heated at 90°C for 2 h, cooled to RT and filtered through a plug of celite. The filtrate was concentrated and the residue purified by flash column chromatography [silica; DCM with 2 % MeOH]. Light yellow solid. Yield: 0.40 g (47%). HPLC (method 1 ): Rt = 3.36 min, m/z: [M+H]+ = 406.2 (MW calc. 405.52).
58e) 2-(2-(2-(1-Ethyl-5-(methylsulfinyl)-1 H-indazol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
mCPBA (77%, 0.10 g, 0.44 mmol) in water was added portion wise at 0°C to a solution of compound 58d (0.20 g, 0.49 mmol) in DCM (20 mL) and the reaction mixture was stirred at RT for 1 h. Sat. Na2S03 solution was added and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with sat. NaHC03 solution, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography [silica; DCM with 7.5% MeOH] followed by trituration with ether/pentane (1 :2). White solid. Yield: 0.10 g (48%). HPLC (method 1 ): Rt = 2.51 min, m/z: [M+H]+ = 421.8 (MW calc. 421.52). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.63 (s, 2H), 8.94 (s, 1 H), 8.70 (d, 1 H, J = 5.1 Hz), 8.21 (s, 1 H), 8.05 (d, 1 H, J = 8.8 Hz), 7.77 (d, 1 H, J = 8.8 Hz), 7.58 (d, 1 H, J = 4.7 Hz), 5.37 (s, 1 H), 4.68-4.63 (m, 2H), 2.81 (s, 3H), 1.53-1.50 (m, 9H).
Example 59: 2-(2-(2-(1-Ethyl-5-(methyls
Figure imgf000070_0001
Oxidation of compound 58d with 2 equivalents mCPBA. White solid. Yield: 65 mg. HPLC (method 1 ): Rt = 2.79 min, m/z: [M+H]+ = 437.9 (MW calc. 437.52). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.66 (s, 2H), 9.19 (s, 1 H), 8.71 (d, 1 H, J = 5.0 Hz), 8.23 (s, 1 H), 8.12 (d, 1 H, J = 8.9 Hz), 8.01 (d, 1 H, J = 8.9 Hz), 7.59 (d, 1 H, J 4 .8 Hz), 5.37 (s, 1 H), 4.71-4.66 (m, 2H), 3.29 (s, 3H), 1.54-1.50 (m, 9H).
Example 60: 2-(6'-(1-Ethyl-5-(ethylsulf '-bipyridinl-4-yl)propan-2-amine
Figure imgf000070_0002
Prepared in analogy to example 59 with the difference that the final oxidation was carried out with Oxone (2.5 equivalents) in THF and water. White solid. Yield: 45 mg (16%). HPLC (method 3): Rt = 1.40 min, m/z: [M+H]+ = 450.2 (MW calc. 449.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.18 (s, 1 H), 8.92-8.91 (m, 2H), 8.70 (d, 1 H, J= 5.2 Hz), 8.34 (s, 1 H), 8.14-8.12 (m, 1 H), 8.07-8.04 (m, 1 H), 7.92-7.90 (m, 1 H), 7.63-7.62 (m, 1 H), 4.69-4.64 (m, 2H), 3.37-3.31 (m, 2H), 2.24 (bs, 2H), 1.53 (t, 3H, J = 7.2 Hz), 1.44 (s, 6H), 1.16 (t, 3H, J = 7.6 Hz). Example 61 and 62: 2-(6'-(1-Ethyl-5-(ethylsulfinyl)-1 H-indazol-3-ylH2,3'-bipyridinl-4-yl)propan-2-amine
(faster and slower elutinq enantiomer)
Figure imgf000071_0001
The racemate (0.4 g, white solid) was prepared analogously to example 60 but using only 0.5 equivalents of Oxone as oxidizing agent in the last step. The pure enantiomers were obtained from this racemate via chiral preparative SFC (column: YMC Chiral Amylose-C, 250 x 20 mm; mobile phase: 55% carbon dioxide / 45% MeOH with 0.5% isopropylamine; flow rate: 25 g/min; temperature: 35°C; pressure: 85 bar).
Faster eluting enantiomer (example 61 ): Yield = 0.14 g. White solid. Specific optical rotation: [a]58925 = - 186.99° (c. 0.2674%, CHCb). Enantiomeric excess = 100%. HPLC (method 1 ): Rt = 2.65 min, m/z: [M+H]+ = 434.3 (MW calc. 433.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.51 (s, 1 H), 8.93 (s, 1 H), 8.63-8.60 (m, 2H), 8.28-8.26 (m, 2H), 7.99-7.97 (m, 1 H), 7.69-7.66 (m, 1 H), 7.53 (d, 1 H, J = 5.2 Hz), 4.64-4.58 (m, 2H), 3.09-3.02 (m, 1 H), 2.88-2.79 (m, 1 H), 2.26 (bs, 2H), 1.52 (t, 3H, J = 7.2 Hz), 1.43 (s, 6H), 1 .07 (t, 3H, J = 7.2 Hz).
Slower eluting enantiomer (example 62): Yield = 0.15 g. White solid. Specific optical rotation: [a]58925 = +181.00° (c. 0.3674%, CHCb). Enantiomeric excess = 100%. HPLC (method 5): Rt = 2.96 min, m/z: [M+H]+ = 434.2 (MW calc. 433.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.51 (s, 1 H), 8.93 (s, 1 H), 8.63-8.60 (m, 2H), 8.29-8.26 (m, 2H), 7.99-7.97 (m, 1 H), 7.69-7.66 (m, 1 H), 7.55-7.53 (m, 1 H), 4.64-4.58 (m, 2H), 3.09-3.02 (m, 1 H), 2.88-2.79 (m, 1 H), 2.33 (bs, 2H), 1.52 (t, 3H, J = 7.2 Hz), 1.43 (s, 6H), 1.07 (t, 3H, J = 7.2 Hz).
Example 63: (1-Ethyl-3-(4-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[4,3-blpyridin-5- yl)(morpholino)methanone
Figure imgf000071_0002
63a) 1-Ethyl-1 H-pyrazolo[4,3-blpyridine Ethyl hydrazine dihydrochloride (27.96 g, 210.23 mmol) was added at ice cold temperature to a stirred solution of 3-fluoro-pyridine-2-carbaldehyde (26.3 g, 210.23 mmol) in dimethylacetamide (520 ml). The reaction mixture was stirred for 3 h at RT, CS2CO3 (342.49 g, 1051.16 mmol) was added and stirring was continued at 120°C for 16 h. The reaction mixture was cooled to RT and poured into ice water that was extracted with EtOAc. The 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 = 4: 1]. Yield: 14 g (45%). Yellow liquid. HPLC (method 5): Rt = 2.62 min, m/z: [M+H]+ = 148 (MW calc.147.18). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.56-8.55 (d, 1 H), 8.21 (s, 1 H), 7.76-7.74 (d, 1 H), 7.28-7.26 (m, 1 H), 4.46-4.40 (q, 2H), 1.53-1.50 (t, 3H).
63b) 1-Ethyl-1 H-pyrazolo[4,3-blpyridine 4-oxide
mCPBA (30.09 g, 104.63 mmol) was added at 0°C to a stirred solution of compound 63a (14 g, 95.12 mmol) in DCM (300 ml) and the resulting reaction mixture was stirred at RT for 16 h. The mixture was quenched with saturated Na2S04 solution under cooling with an ice bath and extracted with DCM. The combined organic layers were washed with saturated Na2HC03 solution and brine, dried over Na2S04 and concentrated. The remnant was purified by column chromatography [DCM/MeOH = 9: 1]. Yield: 8 g (52%). Yellow solid. HPLC (method 5): Rt = 1.24 min, m/z: [M+H]+ = 163.6 (MW calc.163.18). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.34 (s, 1 H), 8.10-8.09 (d, 1 H), 7.36-7.34 (d, 1 H), 7.19-7.16 (m, 1 H), 4.43-4.37 (m, 2H), 1.53-1.50 (m, 3H).
63c) 1-Ethyl-1 H-pyrazolo[4,3-b1pyridine-5-carbonitrile
Dimethylcarbamoylchloride (13.5 ml, 147.12 mmol) followed by trimethylsilyl cyanide (19.6 ml, 147.12 mmol) was added at 0°C to a stirred solution of compound 63b (8 g, 49.04 mmol) in DCM (400 ml). The resulting reaction mixture was stirred at RT for 42 h, diluted with DCM and washed with brine. The organic phase was dried over Na2S04 and concentrated. The raw product was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 4: 1]. Yield: 7.5 g (75%). White solid. HPLC (method 5): Rt = 3.13 min, m/z: [M+H]+ = 173.2 (MW calc. 172.19). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.32 (s, 1 H), 7.87-7.85 (d, 1 H), 7.63-7.61 (d, 1 H), 4.49-4.41 (q, 2H), 1.56-1.52 (t, 3H). 63d) 1 -Ethyl- 1 H-pyrazolo[4 ,3-bl pyrid i ne-5-carboxylic acid
NaOH (3.95 g, 98.72 mmol) and compound 63c (4.25 g, 24.68 mmol) in MeOH/water (150 ml, 2: 1 ) were refluxed for 24 h. The reaction mixture was concentrated, then triturated with MTBE and acidified with 6 N HCI solution. The precipitate was filtered off and rinsed with MTBE to afford the target compound as white solid. Yield: 3.5 g (74%). HPLC (method 1 ): Rt = 0.81 min, m/z: [M+H]+ = 191.9 (MW calc.191.19). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 13.17 (s, 1 H), 8.46 (s, 1 H), 8.33-8.31 (d, 1 H), 8.08-8.05 (d, 1 H), 4.54- 4.49 (q, 2H), 1.44-1.40 (t, 3H).
63e) (1-Ethyl-1 H-pyrazolo[4,3-b1pyridin-5-yl)(morpholino)methanone
NMM (2.87 ml, 26.15 mmol) and TBTU (6.72 mg, 20.92 mmol) were added at 0°C to compound 63d (2 g, 10.46 mmol) in DMF (20 ml) and the mixture was stirred for 15 min Morpholine (1.35 ml, 15.69 mmol) was added at 0°C drop wise and the resulting reaction mixture was further stirred at RT for 16h. The mixture was subsequently washed with water, saturated solution of NaHCCh, saturated NhUCI solution and brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 2:3]. White solid. Yield: 2.4 g (88%). HPLC (method 3): Rt = 1.42 min, m/z: [M+H]+ = 261.1 (MW calc. 260.29). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.23 (s, 1 H), 7.85-7.82 (d, 1 H), 7.73-7.71 (d, 1 H), 4.47-4.44 (q, 2H), 3.84-3.78 (m, 6H), 3.71 (m, 1 H) 1.55-1.51 (q, 3H).
63f) (1-Ethyl-5-(morpholine-4-carbonyl)-1 H-pyrazolo[4,3-blpyridin-3-yl)boronic acid
Bis(1 ,5-cyclooctadiene)di^-methoxydiiridium(l) (164.45 mg, 0.248 mmol) and 4,4'-di-tert-butyl-2,2'- bipyridyl (133.16 mg, 0.496 mmol) were added at RT to a solution of compound 63e (2.15 g, 8.26 mmol) and bis(pinacolato)diboron (3.6 ml, 24.81 mmol) in MTBE (40 ml) stirred under Ar. The resulting reaction mixture was heated at 120°C for 16 h, cooled and filtered. The filtrate was evaporated and the raw product (2 g) thus obtained was used in the next step without further purification. HPLC (method 1 ): Rt = 1.67 min, m/z: [M+H]+ = 305.4 (MW calc. 304.1 1 ). 63g) (3-(4-Bromophenyl)-1-ethyl-1 H-pyrazolo[4,3-blpyridin-5-yl)(morpholino)methanone
Tetrakis(triphenylphosphine) palladium(O) (85.49 mg, 0.074 mmol) was added at RT to compound 63f (450 mg, 1.48 mmol) and 2,5-dibromo-benzene (349.07 mg, 1.48 mmol) in 1-4 dioxane (10 ml) and 2M aqueous K2CO3 solution (2 ml, 4.00 mmol) stirred under Ar. The resulting reaction mixture was heated at 100°C for 16 h, cooled to RT and filtered through a plug of celite/Na2S04 (2: 1 ). The filter was rinsed with MeOH/DCM (1 :9), the filtrate was evaporated and the residue was purified by column chromatography [100-200 mesh silica gel, hexane/EtOAc = 3:2]. White solid. Yield: 200 mg (33%). HPLC (method 1 ): Rt = 3.59 min, m/z: [M+H]+ = 417 (MW calc.417.28). 1 H NMR (400 MHz, CDCI3, δ ppm): 8.36 (d, 2H), 7.84- 7.83 (m, 2H), 7.62-7.60 (d, 2H), 4.48-4.54 (m, 2H), 3.90-3.77 (m, 8H), 1.59-1.54 (m, 3H). 63h) (1-Ethyl-3-(4-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[4,3-b1pyridin-5- yl)(morpholino)methanone
The phenyl bromide 63g was converted into the corresponding pinacol boronate in analogy to the protocol 43d. The product of this reaction was then reacted with 2-(2-bromo-pyridin-4-yl)-propan-2-ol to the target compound (see procedure 43e). White solid. Yield: 69 mg (37%). HPLC (method 1 ): Rt = 2.92 min, m/z: [M+H]+ = 472.1 (MW calc.471.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.61-8.55 (m, 3H), 8.40-8.38 (d, J = 8.7 Hz, 1 H), 8.28-8.26 (d, J = 8.2 Hz, 2H), 8.07 (s, 1 H), 7.75-7.73 (d, J = 8.7 Hz, 1 H), 7.44-7.43 (m, 1 H), 5.33 (s, 1 H), 4.59-4.58 (d, J = 7.2 Hz, 2H), 3.75-3.71 (m, 8H), 1.50 (s, 9H).
Example 64: (3-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-1-ethyl-1 H-pyrazolo[4,3-b1pyridin-5-yl) (morpholino)methanone
Figure imgf000074_0001
Prepared from compound 63g and 2-(2-bromopyridin-4-yl)propan-2-amine analogous to example 63. White solid. Yield: 80 mg. HPLC (method 3): Rt = 1.45 min, m/z: [M+H]+ = 471.32 (MW calc. 470.57). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.59-8.54 (m, 3H), 8.40-8.38 (d, J = 8.8 Hz, 1 H), 8.30-8.28 (d, J = 8.2 Hz, 2H), 8.17 (s, 1 H), 7.75-7.73 (d, J = 8.8 Hz, 1 H), 7.49-7.48 (d, J = 8.0 Hz, 1 H), 4.61-4.56 (q, 2H), 3.75- 3.71 (m, 8H), 2.90 (m, 2H), 1.51-1.48 (t, J = 7.2 Hz, 3H), 1.43 (s, 6H).
Example 65: (1-Ethyl-3-(4-(2-hvdroxypropan-2-ylH2,3'-bipyridinl-6'-vn-1 H-pyrazolo[4,3-blpyridin-5-vn-
(morpholino)methanone
Figure imgf000074_0002
Prepared in three steps from compound 63f analogously to example 63. White solid. Yield: 95 mg. HPLC (method 5): Rt = 2.85 min, MS m/z: [M+H]+ = 473.3 (MW calc. 472.54). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.42 (s, 1 H), 8.71-8.65 (m, 3H), 8.44-8.42 (d, J = 8.8 Hz, 1 H), 8.13 (s, 1 H), 7.76-7.74 (d, J = 8.7 Hz, 1 H), 7.51-7.50 (m, 1 H), 5.37 (s, 1 H), 4.63-4.61 (q, 2H), 3.74-3.70 (m, 8H), 1.51 (m, 9H).
Example 66: (3-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridinl-6'-yl)-1-ethyl-1 H-pyrazolo[4,3-blpyridin-5-yl) (morpholino)methanone
Figure imgf000075_0001
Prepared in three steps from compound 63f analogously to example 63. White solid. Yield: 80 mg. HPLC (method 5): Rt = 2.71 min, m/z: [M+H]+ = 472.3 (MW calc. 471.55). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.44 (s, 1 H), 8.71-8.64 (m, 3H), 8.44-8.42 (d, J = 8.8 Hz, 1 H), 8.23 (s, 1 H), 7.76-7.74 (d, J = 8.8 Hz, 1 H), 7.56-7.54 (d, J = 5.2 Hz, 1 H), 4.65-4.60 (q, 2H), 3.74-3.69 (m, 8H), 1.53-1.48 (m, 9H).
Example 67: (1-Ethyl-3-(4-(4-(2-hvdroxypropan-2-vnpyridin-2-vnphenvn-1 H-indazol-5-vn(morpholino) methanone
Figure imgf000075_0002
Prepared in analogy to synthesis example 22. White solid. Yield: 0.10 g. m/z: [M+H]+ = 471.2 (MW calc. 470.56). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 8.61 (d, J = 5.1 Hz, 1 H), 8.25 (d, J = 8.4 Hz, 1 H), 8.17 (s, 1 H), 8.1 1 (d, J = 8.4 Hz, 1 H), 8.06 (s, 1 H), 7.83 (d, J = 8.6 Hz, 1 H), 7.51 (d, J = 9.5 Hz, 1 H), 7.44 (dd, J = 1.3 and 5.2 Hz, 1 H), 5.34 (s, 1 H), 4.56 (q, J = 7.2 Hz, 2H), 3.62-3.57 (8H), 1.5-1.46 (9H). Example 68: 1-Ethyl-N-(2-hvdroxyethyl)-3-(4-(4-(2-hvdroxypropan-2-yl)pyridin-2-yl)phenyl)-N-methyl-1 H- indazole-5-carboxamide
Figure imgf000075_0003
Prepared in analogy to synthesis example 22. White solid. Yield: 0.10 g. MS: m/z: [M+H]+ = 459.2 (MW calc.458.55).1H NMR (400 MHz, DMSO-d6, δ ppm): 8.61 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 8.2 Hz, 3H), 8.11 (d, J = 8.2 Hz, 2H), 8.06 (s, 1H), 7.8 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 5.0 Hz, 1H), 5.34 (s, 1H), 4.88 (bs, 1H), 4.56 (q, J = 7.2 Hz, 2H), 3.56-3.32 (m, 4H), 3.02 (s, 3H), 1.48 (s, 9H).
Example 69: 2-(6'-(1-Ethyl-5-(ethylsulfi '-bipyridinl-4-vnpropan-2-ol
Figure imgf000076_0001
Prepared from 1-ethyl-5-(methylthio)-1H-indazole in analogy to synthesis example 58. White solid. Yield: 0.31 g. MS: m/z: [M+H]+ = 435.2 (MW calc.434.55).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.48 (d, J = 1.6 Hz, 1H), 8.92 (s, 1H), 8.65 (d, J = 5.1 Hz, 1H), 8.59 (dd, J = 2.3 and 8.4 Hz, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.68 (dd, J = 1.4 Hz and 8.8 Hz, 1H), 7.51 (dd, J = 1.3 and 5.0 Hz, 1H), 5.33 (s, 1H), 4.61 (q, J = 7.2 Hz, 2H), 3.06 (m, 1H), 2.84 (m, 1H), 1.53-1.49 (9H), 1.05 (t, J = 7.3 Hz, 3H). Example 70: 2-(6'-(1-Ethyl-5-(ethylsulf '-bipyridinl-4-yl)propan-2-ol
Figure imgf000076_0002
Prepared from 1-ethyl-5-(methylthio)-1H-indazole in analogy to synthesis example 59. White solid. Yield: 0.12 g. MS: m/z: [M+H]+ = 451.3 (MW calc.450.55).1H NMR (400 MHz, DMSO-d6, δ ppm): 9.51 (s, 1H), 9.20 (s, 1H), 8.66-8.61 (m, 2H), 8.30 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 4.5 Hz, 1H), 5.34 (s, 1H), 4.65 (q, 2H), 3.36 (2H), 1.51 (9H), 1.14 (t, J = 7.1 Hz, 3H).
Example 71: 4-(1-Cvclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1H-indazole-5-carbonyl)piperazin-2- one
Figure imgf000077_0001
71a) Methyl 3-iodo-1 H-indazole-5-carboxylate
NaOH (3.72 g, 93.0 mmol) was added to a solution of methyl 1 H-indazole-5-carboxylate (4.1 g, 23.3 mmol) in dry DMF (60 mL) and the solution was stirred for 5 min. A solution of iodide (13.0 g, 51 .2 mmol) in dry DMF (20 mL) was added and the mixture was stirred at RT for 1 h. Water, 10% aqueous Na2S203 solution and EtOAc were added, the layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water (3x), dried over Na2S04 and evaporated affording the target compound as white solid. Yield: 6.32 g (90%). MS: m/z: [M+H]+ = 303 (MW calc. 302.02)
71 b) Methyl 1-cyclopropyl-3-iodo-1 H-indazole-5-carboxylate
TEA (17.5 mL, 126 mmol) and pyridine (14.2 mL, 176 mmol) were added to a solution of cyclopropylboronic acid (6.48 g, 75 mmol), compound 71a (7.6 g, 25.2 mmol) and Cu(OAc)2 (9.14 g, 50.3 mmol) in dry THF (100 mL) / toluene (50 mL) and the mixture was heated to 75°C for 18 h. The solvents were evaporated and EtOAc was added to the residue. The suspension was filtered, the filter was rinsed with EtOAc and the organic layer was evaporated. Purification by column chromatography [silica, heptane with 5 to 50% EtOAc]. Upon dissolution in DCM/MeOH (10: 1 ), a solid appeared. Some Et.20 was added and the suspension was filtered. The residue was washed with Et.20 to give a first crop of the target indazol (1.53 g). The filtrate was partially evaporated and purified by column chromatography [silica, heptane with 5 to 50% EtOAc]. The product containing batches were combined and evaporated. The residue was triturated with Et.20 affording another 2.02 g. Total yield: 3.55 g (41 %). MS: m/z: [M+H]+ = 343 (MW calc. 342.13)
71 c) Methyl 1-cvclopropyl-3-(trimethylstannyl)-1 H-indazole-5-carboxylate
An argon-degassed solution of indazole 71 b (2.0 g, 5.85 mmol), hexamethylditin (4.79 g, 14.6 mmol) and tetrakis(triphenylphosphine) palladium(O) (0.68 g, 0.59 mmol) in dry 1 ,4-dioxane (50 mL) was stirred at 100°C for 18 h under Ar. The solution was cooled down to RT, 1 N aqueous KF solution (20 mL) and EtOAc (50 mL) were added and the mixture was stirred for 1 h. The suspension was filtered over Celite, the layers were separated and the organic phase was washed with water and brine, dried over Na2S04 and evaporated. Purification by column chromatography [silica, heptane with 2 to 20% EtOAc]. Total yield: 1.71 g (77%). MS: m/z: [M+H]+ = 380 (MW calc. 379.04)
71 d) Methyl 1-cvclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1 H-indazole-5-carboxylate Tetrakis(triphenylphosphine) palladium(O) (0.36 g, 0.31 mmol) was added to an argon-degassed solution of compound 71 c (1.17 g, 3.09 mmol) and 2-chloro-5-(2-fluorophenyl)pyrimidine (0.64 g, 3.09 mmol) in dry toluene (25 mL) and the mixture was stirred at 100°C for 72 h under Ar. After cooling to RT, the mixture was partitioned between saturated aqueous NhUCI solution and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2S04 and evaporated. Purification by column chromatography [silica, heptane with 5 to 50% EtOAc]. Orange solid. Yield: 960 mg (85% purity). Mass spectroscopy: m/z: [M+H]+ = 389 (MW calc. 388.13)
71 e) 1-Cvclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1 H-indazole-5-carboxylic acid
LiOH H20 (503 mg, 21.0 mmol) in water (5 mL) was added to a solution of compound 71d (960 mg, 2.10 mmol, 85% purity) in THF (15 mL) and the mixture was stirred at 40°C for 18 h. Extra LiOH H20 (503 mg, 21 .0 mmol) was added and stirring was continued at 60°C for 6 h, followed by 40°C for 18 h. After cooling to RT, EtOAc and water were added and the layers were separated. The aqueous phase was acidified to pH~3 by addition of 2N HCI solution and the precipitating white solid was filtered off, rinsed with water and air-dried. White solid. Yield: 560 mg (71 %). MS: m/z: [M+H]+ = 375 (MW calc. 374.34).
71f) 4-(1-Cvclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1 H-indazole-5-carbonyl)piperazin-2-one HATU (284 mg, 0.75 mmol) was added to a solution of carboxylic acid 71 e (280 mg, 0.75 mmol) and DIPEA (0.26 mL, 1.50 mmol) in dry DMF (4 mL) and the reaction mixture was stirred for 30 min. 2- oxopiperazine (75 mg, 0.75 mmol) was added and stirring was continued at RT for 5 min. The mixture was quenched with water and the precipitate was filtered off and washed thoroughly with water. Crystallisation from acetonitrile provided the final compound as white solid. Yield: 170 mg (50%). MS: m/z: [M+H]+ = 457.2 (MW calc. 456.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.19 (d, J = 1 .3 Hz, 2H), 8.69 (s, 1 H), 8.16 (s, 1 H), 7.92 (d, J = 8.7 Hz, 1 H), 7.80 (td, J = 7.9, 1.7 Hz, 1 H), 7.65-7.52 (m, 2H), 7.49- 7.38 (m, 2H), 4.25-3.95 (m, 2H), 4.06-4.00 (m, 1 H), 3.93-3.48 (m, 2H), 3.27 (br s, 2H), 1.31-1.20 (m, 4H).
Example 72: (1-Cvclopropyl-3-(5-(2-f H-indazol-5-yl)(morpholino) methanone
Figure imgf000078_0001
Prepared in analogy to example 71. White solid. Yield: 130 mg. MS: m/z: [M+H]+ = 444.2 (MW calc. 443.47). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.20 (d, J = 1.3 Hz, 2H), 8.66 (s, 1 H), 7.90 (d, J = 8.6 Hz, 1 H), 7.83-7.76 (m, 1 H), 7.61-7.53 (m, 2H), 7.49-7.39 (m, 2H), 4.06-3.98 (m, 1 H), 3.81-3.37 (m, 8H), 1.28-1.20 (m, 4H).
Example 73: (1-Cvclopropyl-3-(5-phenylpyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino)methanone
Figure imgf000079_0001
Prepared in analogy to example 71. White solid. Yield: 75 mg. MS: m/z: [M+H]+ = 426.2 (MW calc. 425.48). 1 H NMR (400 MHz, DMSO-d6, δ ppm): 9.31 (s, 2H), 8.68 (s, 1 H), 7.93-7.86 (m, 3H), 7.62-7.54 (m, 3H), 7.51 (t, J = 7.3 Hz, 1 H), 4.05-3.97 (m, 1 H), 3.81-3.39 (m, 8H), 1.30-1.20 (m, 4H).
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 (IC50 inhibition of PDE4B of Examples Nos.):
No. PDE4B IC50 No. PDE4B IC50 No. PDE4B IC50 No. PDE4B IC50
[μΜ] (mean) [μΜ] (mean) [μΜ] (mean) [μΜ] (mean)
1 0.084 20 0.019 39 0.179 58 0.020
2 0.068 21 0.033 40 0.071 59 0.013
3 0.004 22 0.063 41 0.221 60 0.188
4 0.021 23 0.034 42 0.141 61 0.102
5 0.676 24 0.013 43 0.007 62 0.007
6 0.024 25 0.010 44 0.003 63 0.004
7 0.023 26 0.200 45 0.274 64 0.106
8 0.093 27 0.026 46 0.095 65 0.086
9 0.264 28 0.017 47 0.004 66 0.179
10 0.294 29 0.194 48 0.01 1 67 0.127
1 1 0.005 30 0.134 49 1.130 68 0.275
12 0.002 31 0.079 50 0.005 69 0.016
13 0.028 32 0.142 51 0.002 70 0.008
14 O.001 33 0.020 52 0.033 71 0.016
15 0.164 34 0.081 53 0.001 72 0.016
16 0.002 35 0.041 54 0.064 73 0.050
17 0.182 36 0.267 55 0.013
18 0.058 37 0.015 56 0.013
19 0.315 38 0.151 57 0.008

Claims

Claims
1. A compound of formula (I)
Figure imgf000081_0001
wherein
A, B and C independently of each other represent CH or N;
X1 , X2 and W independently of each other represent 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 is selected from the group consisting of H , (Ci-Ce)-alkyl, (Ci-C6)-haloalkyl, CO(Ci-C6-alkyl), (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 , NO2, 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 either X1 is N and X2 is N or X1 is N and W 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 H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, C(CH3)3, COCH3, COCH2CH3, COCH(CH3)2, CF3, CHF2, CH2F, CH2CF3, cyclopropyl, SOCH3 and S02CH3,
more preferably R3 is selected from the group consisting of H, CH3, CH2CH3, COCH3, CH2CF3, cyclopropyl and S02CH3.
5. A compound according to one or more of claims 1 to 4, wherein G is one of the following groups G1 to G44
Figure imgf000082_0001
Figure imgf000083_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 imgf000084_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, N H(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, N H(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:
M1 M2 M3 Μ4 Μ5
M6 M7 Μ8 Μ9 Μ10
M1 1 M12 Μ13 Μ14 Μ15
I s Λ I
Figure imgf000086_0001
Figure imgf000087_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 imgf000087_0002
Figure imgf000088_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-C6-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. 13. A compound according to one or more of the preceding claims selected from the group consisting of
1 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
2 1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
3 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1-(methylsulfonyl)-1 H-indole-5-carboxamide
4 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N,N,1-trimethyl-1 H-indole-5-carboxamide
5 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1 H-indole-5-carboxamide g 3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N, 1-dimethyl-1 H-indole-5- carboxamide
3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1-(methylsulfonyl)-1 H- indole-5-carboxamide
g 1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1 H-indole-5- carboxamide
9 1-Acetyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-N,N-dimethyl-1 H-indole-5-carboxamide
10 1-Acetyl-N,N-dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole-5-carboxamide
^ N,N-Dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole-5- carboxamide
12 (3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5-yl)(morpholino) methanone
13 1-(3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indol-1-yl)ethanone (3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1-(me
methanone
1-(3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-5-(morpholine-4-carbonyl)-1 H-indo
3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1 -(methyl- 1 H-indole-5-carboxamide
3-(5-(2-Fluoro-5-(2-hydroxypropan-2-yl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1- (methylsulfonyl)-1 H-indole-5-carboxamide
3-(5-(2-Fluoro-5-(trifluoromethyl)phenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1- (methylsulfonyl)-1 H-indole-5-carboxamide
3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-N-(2-hydroxyethyl)-N-methyl-1-(methyl-sulfonyl)- 1 H-indazole-5-carboxamide
(3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazol-5-yl)
(morpholino)methanone
1-(3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-5-(m
yl)ethanone
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-m ethyl- 1 H-indazole-5-carboxamide
1-Ethyl-N-(2-hydroxyethyl)-3-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-N-methyl-1 H- indazole-5-carboxamide
(1-Ethyl-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)
(morpholino)methanone
(1-Ethyl-3-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1 H-indazol-5-yl)(morpholin methanone
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H- indazole-5-carboxamide
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl- 1 H-indole-5-carboxamide
(1-Ethyl-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H-indol-5-yl)
morpholino)methanone
1-Ethyl-N-(2-hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1 H- indole-5-carboxamide
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1- (2,2,2-trifluoroethyl)-1 H-indazole-5-carboxamide
(3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-indazol-5- yl)(morpholino)methanone
N-(2-Hydroxyethyl)-3-(4-(2-hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-N-methyl-1-(2,2,2- trifluoroethyl)-1 H-indazole-5-carboxamide
(3-(4-(2-Hydroxypropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1-(2,2,2-trifluoroethyl)-1 H-indazol-5- yl)(morpholino)methanone
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1- (2,2,2-trifluoroethyl)-1 H-indole-5-carboxamide
(3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(2,2,2-trifluoroethyl)-1 H-indo yl)(morpholino)methanone
(1-Methyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino) methanone (1-Ethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino) methanone
(3-(5-(4-Methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indazol-5-yl)(morpholino) methanone (3-(5-(2-Fluorophenyl)pyrimidin-2-yl)-1-m
(3-(5-(2-Fluoro-5-methylphenyl)pyrimidin-2-yl)-1-methyl-1 H-indazol-5-yl)(morphoH methanone
N-(2-Hydroxyethyl)-N, 1-dimethyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazole-5- carboxamide
(1-Methyl-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indazol-5-yl)(pyrrolidin-1-yl) methanone 1-Ethyl-5-(ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
1-Ethyl-5-(ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
5-(Ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indole
5-(Ethylsulfonyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole 5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indole 1-(5-(Ethylsulfinyl)-3-(5-(4-methylpyridin-2-yl)pyrimidin-2-yl)-1 H-indol-1-yl)ethanone
2-(2-(2-(1-Ethyl-5-(ethylsulfinyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(1-Ethyl-5-(ethylsulfonyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1-(methylsulfonyl)-1 H- indole-5-carboxamide
(3-(5-(4-(2-Hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1-(methylsulfonyl)-1 H-indol-5- yl)(morpholino)methanone
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-N-methyl-1- (methylsulfonyl)-1 H-indole-5-carboxamide
N-(2-Hydroxyethyl)-3-(5-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)pyrimidin-2-yl)-1- (methylsulfonyl)-1 H-indole-5-carboxamide
2-(2-(2-(1-Ethyl-5-(ethylsulfinyl)-1 H-indol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol
2-(2-(2-(1-Ethyl-5-(methylsulfinyl)-1 H-indazol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 2-(2-(2-(1-Ethyl-5-(methylsulfonyl)-1 H-indazol-3-yl)pyrimidin-5-yl)pyridin-4-yl)propan-2-ol 2-(6'-(1-Ethyl-5-(ethylsulfonyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-amine
2-(6'-(1-Ethyl-5-(ethylsulfinyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-amine
(1-Ethyl-3-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-pyrazolo[4,3-b]pyridin-5- yl)(morpholino)methanone
(3-(4-(4-(2-Aminopropan-2-yl)pyridin-2-yl)phenyl)-1-ethyl-1 H-pyrazolo[4,3-b]pyridin-5-yl) (morpholino)methanone
( 1 -Ethyl-3-(4-(2-hyd roxypropan-2-yl )-[2 , 3'-bi pyrid i n]-6'-yl)- 1 H-pyrazolo[4 , 3-b] pyrid in-5- yl)(morpholino)methanone
(3-(4-(2-Aminopropan-2-yl)-[2,3'-bipyridin]-6'-yl)-1-ethyl-1 H-pyrazolo[4,3-b]pyridin-5-yl) (morpholino)methanone
(1-Ethyl-3-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-1 H-indazol-5-yl)(morpholino) methanon
1-Ethyl-N-(2-hydroxyethyl)-3-(4-(4-(2-hydroxypropan-2-yl)pyridin-2-yl)phenyl)-N-methyl-1 H- indazole-5-carboxamide
2-(6'-(1-Ethyl-5-(ethylsulfinyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-ol
2-(6'-(1-Ethyl-5-(ethylsulfonyl)-1 H-indazol-3-yl)-[2,3'-bipyridin]-4-yl)propan-2-ol
4-(1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1 H-indazole-5-carbonyl)piperazin-2-one (1-Cyclopropyl-3-(5-(2-fluorophenyl)pyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino) methanone 73 (1-Cyclopropyl-3-(5-phenylpyrimidin-2-yl)-1 H-indazol-5-yl)(morpholino)m
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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