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WO2018234354A1 - Nouveaux composés 3-indole et 3-indazole substitués utilisées en tant qu'inhibiteurs de phosphodiestérase - Google Patents

Nouveaux composés 3-indole et 3-indazole substitués utilisées en tant qu'inhibiteurs de phosphodiestérase 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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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

L'invention concerne de nouveaux composés de 3-indole et de 3-indazole, caractérisés en ce que le composé est représenté par la formule générale (I) dans laquelle les groupements chimiques, les substituants, les variables et les indices sont tels que définis dans la description, l'invention concerne également l'utilisation desdits nouveaux composés en tant que médicaments, en particulier en tant que médicaments pour le traitement d'affections et de maladies qui peuvent être traitées par inhibition de l'enzyme PDE4.
PCT/EP2018/066357 2017-06-20 2018-06-20 Nouveaux composés 3-indole et 3-indazole substitués utilisées en tant qu'inhibiteurs de phosphodiestérase Ceased WO2018234354A1 (fr)

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US10508113B2 (en) 2018-03-12 2019-12-17 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
WO2022231242A1 (fr) * 2021-04-26 2022-11-03 주식회사 스탠다임 Composé indazole ayant une activité inhibitrice de lrrk2
WO2022242697A1 (fr) * 2021-05-19 2022-11-24 南京药石科技股份有限公司 Inhibiteur sélectif de tyk2 et son utilisation
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
CN118994130A (zh) * 2024-07-02 2024-11-22 中国药科大学 一种吲唑酰胺类化合物及其用途
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

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US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10508113B2 (en) 2018-03-12 2019-12-17 Abbvie Inc. Inhibitors of tyrosine kinase 2 mediated signaling
US12473286B2 (en) 2018-05-04 2025-11-18 Incyte Corporation Salts of an FGFR inhibitor
US12024517B2 (en) 2018-05-04 2024-07-02 Incyte Corporation Salts of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12083124B2 (en) 2019-10-14 2024-09-10 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12168660B2 (en) 2019-12-04 2024-12-17 Incyte Corporation Derivatives of an FGFR inhibitor
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
KR102588242B1 (ko) 2021-04-26 2023-10-12 주식회사 스탠다임 Lrrk2 억제 활성을 갖는 인다졸 화합물
KR20230118694A (ko) * 2021-04-26 2023-08-11 주식회사 스탠다임 Lrrk2 억제 활성을 갖는 인다졸 화합물
WO2022231242A1 (fr) * 2021-04-26 2022-11-03 주식회사 스탠다임 Composé indazole ayant une activité inhibitrice de lrrk2
WO2022242697A1 (fr) * 2021-05-19 2022-11-24 南京药石科技股份有限公司 Inhibiteur sélectif de tyk2 et son utilisation
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
CN118994130A (zh) * 2024-07-02 2024-11-22 中国药科大学 一种吲唑酰胺类化合物及其用途

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