WO2020260426A1 - Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17 - Google Patents

Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17 Download PDF

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WO2020260426A1
WO2020260426A1 PCT/EP2020/067759 EP2020067759W WO2020260426A1 WO 2020260426 A1 WO2020260426 A1 WO 2020260426A1 EP 2020067759 W EP2020067759 W EP 2020067759W WO 2020260426 A1 WO2020260426 A1 WO 2020260426A1
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alkyl
compound
formula
optionally substituted
substituents
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Fabien Claude LECOMTE
James Thomas Reuberson
Richard David Taylor
Josep LLAVERIA CROS
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UCB Biopharma SRL
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted l//-imidazo[4,5-c]pyridin-4-one derivatives, and analogues thereof. These compounds act as modulators of IL-17 activity, and are accordingly of benefit as pharmaceutical agents for the treatment and/or prevention of pathological conditions, including adverse inflammatory and autoimmune disorders.
  • IL-17A (originally named CTLA-8 and also known as IL-17) is a pro- inflammatory cytokine and the founder member of the IL-17 family (Rouvier et al, ./. Immunol ., 1993, 150, 5445-5456). Subsequently, five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al. , Cytokine Growth Factor Rev., 2003, 14, 155-174).
  • IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Thl7, that also express IL-21 and IL-22 signature cytokines (Korn et al, Ann. Rev. Immunol., 2009, 27, 485-517).
  • IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al, J. Immunol., 2008, 181, 2799- 2805).
  • IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.
  • the compounds in accordance with the present invention being potent modulators of human IL-17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active
  • WO 2013/116682 and WO 2014/066726 relate to separate classes of chemical compounds that are stated to modulate the activity of IL-17 and to be useful in the treatment of medical conditions, including inflammatory diseases.
  • WO 2018/229079 describes a class of spirocyclic oxoindoline derivatives, and analogues thereof, that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders.
  • the present invention provides a compound of formula (I) or an N- oxide thereof, or a pharmaceutically acceptable salt thereof:
  • D represents C-R 3 or N
  • E represents C-R 4 or N
  • Z represents -CH(R 5 )N(H)C(0)R 6 , -CH(R 5 )N(H)S(0) 2 R 6 ,
  • R 1 represents hydrogen or Ci- 6 alkyl
  • R 2 , R 3 and R 4 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -S0 2 R a , -NR b R c , -NR c COR d ,
  • R 5 represents hydrogen; or R 5 represents Ci-6 alkyl, C 3 -9 cycloalkyl, C 3 -9 cycloalkyl(Ci-6)alkyl, C4-9 cycloalkenyl, C4-12 bicycloalkyl, C5-9 spirocycloalkyl, C5-9 spirocycloalkyl(Ci-6)alkyl, Cs-n tricycloalkyl, Cs-n tricycloalkyl(Ci-6)alkyl, C7-1 3 dispirocycloalkyl, C7-1 3 dispirocycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, C 3 -7
  • heterocycloalkyl C 3 -7 heterocycloalkyl(Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R 5a represents C 3 -7 cycloalkyl, C4-9 bicycloalkyl, aryl, C 3 -7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, represent C 3 -7 cycloalkyl, C4-9 bicycloalkyl or C 3 -7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;
  • R 6 represents -OR 6a or -NR 6b R 6c ; or R 6 represents Ci-6 alkyl, C 3 -9 cycloalkyl, C 3 -9 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl- (Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R 6a represents C i-6 alkyl; or R 6a represents C 3 -9 cycloalkyl, which group may be optionally substituted by one or more substituents;
  • R 6b represents hydrogen or Ci-6 alkyl
  • R 6C represents hydrogen or Ci-6 alkyl
  • R 7 represents aryl, heteroaryl or spiro[(C3-7)heterocycloalkyl] [heteroaryl], any of which groups may be optionally substituted by one or more substituents;
  • R a represents trifluorom ethyl; or R a represents Ci-6 alkyl, C 3 -9 cycloalkyl, C 3 -9 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl- (Ci-6)alkyl, heteroaryl or heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R b and R c independently represent hydrogen or trifluorom ethyl; or Ci-6 alkyl, C 3 -9 cycloalkyl, C 3 -9 cycloalkyl(Ci-6)alkyl, aryl, aryl(Ci-6)alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci- 6 )alkyl, heteroaryl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents;
  • R d represents hydrogen; or R d represents Ci- 6 alkyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
  • R e represents Ci- 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention also provides a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.
  • the present invention also provides the use of a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.
  • the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N- oxide thereof, or a
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one, two or three substituents. Suitably, such groups will be unsubstituted, or substituted by one or two substituents.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid.
  • the present invention also includes within its scope co-crystals of the compounds of formula (I) above.
  • co-crystal is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio.
  • the preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals , ed. J. Wouters & L. Quere, RSC Publishing, 2012).
  • Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched Ci- 6 alkyl groups, for example Ci-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n- propyl, isopropyl, «-butyl, sec-butyl, isobutyl, /c/7-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as“Ci- 6 alkoxy”,“Ci- 6 alkylthio”,“Ci- 6 alkyl sulphonyl” and“Ci- 6 alkylamino” are to be construed accordingly.
  • Suitable C2-6 alkenyl groups include vinyl and allyl.
  • Suitable C2-6 alkynyl groups include ethynyl and propargyl.
  • C3-9 cycloalkyl refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo- fused analogues thereof.
  • Suitable C3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononanyl.
  • C4-9 cycloalkenyl refers to monovalent groups of 4 to 9 carbon atoms derived from an unsaturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof.
  • Suitable C4-9 cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • C4-12 bicycloalkyl refers to monovalent groups of 4 to 12 carbon atoms derived from a saturated bicyclic hydrocarbon.
  • Typical bicycloalkyl groups include bicyclo[l. l.l]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.
  • C5-9 spirocycloalkyl refers to saturated bicyclic ring systems containing 5 to 9 carbon atoms, in which the two rings are linked by a common atom.
  • Suitable spirocycloalkyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl and spiro[4.4]nonanyl.
  • Cs-n tri cycloalkyl refers to monovalent groups of 8 to 11 carbon atoms derived from a saturated tricyclic hydrocarbon. Typical tricycloalkyl groups include adamantanyl.
  • C7-13 di spirocycloalkyl refers to saturated tricyclic ring systems containing 7 to 13 carbon atoms, in which the three rings incorporate two spiro linkages.
  • Suitable di spirocycloalkyl groups include dispiro[2.0.24.13]heptanyl.
  • aryl refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci- 6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • C3-7 heterocycloalkyl refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo- furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro- thiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[l,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, benzoxaziny
  • C3-7 heterocycloalkenyl refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkenyl groups include 2,5-dihydropyrrolyl, thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl, 1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 2,3-dihydro-l,4-oxazinyl and 6,7- dihydro-5//- 1 ,4-oxazepinyl .
  • C4-9 heterobicycloalkyl corresponds to C4-9 bicycloalkyl wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Typical heterobicycloalkyl groups include 6- oxabicyclo[3.1.OJhexanyl, 3-azabicyclo[3.1.OJhexanyl, 2-oxa-5-azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.2.0]heptanyl, 6-oxabicyclo[3.1. ljheptanyl, 3 -azabicyclo[3.1.
  • heteroaryl refers to monovalent aromatic groups containing at least 5 atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-Z>][l,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrol o[2, 3 -/>]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrol o[3,4-/>]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4- ]pyrimidinyl, pyrazolo[l,5-a]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl,
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 'H, 2 H (deuterium) or 3 H (tritium) atom, preferably 'H
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • D represents C-R 3 . In another embodiment, D represents N.
  • E represents C-R 4 . In another embodiment, E represents N.
  • D represents C-R 3 and E represents C-R 4 .
  • the present invention provides a compound of formula (1-1) or an L -oxide thereof, or a pharmaceutically acceptable salt thereof:
  • R 1 represents hydrogen or methyl.
  • R 1 represents hydrogen. In another embodiment, R 1 represents Ci- 6 alkyl, especially methyl.
  • R 2 , R 3 and R 4 independently represent hydrogen; or Ci- 6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 2 , R 3 and R 4 independently represent hydrogen; or ethyl, which group may be optionally substituted by one or more substituents.
  • optional substituents which may be present on R 2 , R 3 or R 4 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluorom ethyl, difluoroethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, (Ci-6)alkyl- oxadiazolyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, Ci-6 alkoxy, difluoromethoxy, trifluoro- methoxy, pentafluorothio, Ci-6 alkylthio, Ci-6 alkylsulfmyl, (Ci-6)alkyl(imino)sulfmyl,
  • Ci-6 alkylsulfonyl amino, amino(Ci-6)alkyl, Ci-6 alkylamino, di(Ci-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkyl carbonylamino(Ci-6)alkyl, C2-6 alkoxycarbonylamino, Ci-6 alkyl sulfonylamino, formyl, C2-6 alkylcarbonyl, hydroxy(Ci-6)alkyl carbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, chloro(Ci-6)alkylamino- carbonyl, di(Ci-6)alkylaminocarbonyl, azetidinylcarbonyl, hydroxyazetidinylcarbonyl, difluoroazetidinylcarbonyl, (hydroxy)(trifluoromethyl)azetidinylcarbonyl, (hydroxy
  • Typical examples of optional substituents which may be present on R 2 , R 3 or R 4 include one, two or three substituents independently selected from di(Ci-6)alkylamino- carbonyl.
  • substituents which may be present on R 2 , R 3 or R 4 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, /ert-butyl, trifluoromethyl, difluoroethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, methyloxadiazolyl, hydroxy, hydroxymethyl, hydroxyisopropyl, oxo, methoxy, te/V-butoxy, difluoromethoxy, trifluoromethoxy, pentafluorothio, methylthio, methylsulfmyl, (imino)(methyl)sulfmyl, methylsulfonyl, amino, amino
  • Typical examples of particular substituents on R 2 , R 3 or R 4 include one, two or three substituents independently selected from dimethylaminocarbonyl.
  • piperazinylmethyl methylpiperazinylmethyl, oxetanylpiperazinylmethyl, methylsulfonyl- piperazinylmethyl, acetylpiperazinylmethyl, /c/7-butoxy carbonyl pi perazi ny 1 m ethyl , (acetyl )( /c/7-butoxy carbonyl )pi perazi ny 1 m ethyl , morpholinylmethyl, (/c/7-butoxy- carbonyl)(difluoroazetidinylcarbonyl)-2,5-dihydropyrrolyl, 3,6-dihydro-2//-pyranyl, ethoxy carbonyl-3, 6-dihydro-2iT-pyranyl, di methyl ami nocarbonyl -3, 6-dihydro-2//- pyranyl, /c/7-butoxy carbonyl - 1 ,2,3 ,4
  • Suitable values of R 2 , R 3 or R 4 include hydrogen and dimethylaminocarbonylethyl.
  • R 2 represents Ci- 6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 2 represents ethyl, which group may be optionally substituted by one or more substituents.
  • optional substituents on R 2 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluoro- methyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, (Ci- 6 )alkyloxadiazolyl, hydroxy, hydroxy(Ci- 6 )alkyl, oxo, Ci- 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci- 6 alkylthio, Ci- 6 alkylsulfmyl, (Ci- 6 )alkyl- (imino)sulfmyl, Ci- 6 alkylsulfonyl, amino, amino(Ci- 6 )alkyl, Ci- 6 alkylamino, di(Ci- 6 )- alkyl, Ci-
  • Typical examples of optional substituents on R 2 include one, two or three substituents independently selected from di(Ci- 6 )alkylaminocarbonyl.
  • substituents on R 2 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, fer/-butyl, trifluoromethyl, phenyl, fluorophenyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, oxadiazolyl, methyloxadiazolyl, hydroxy, hydroxymethyl, oxo, methoxy, /c/7-butoxy, difluoromethoxy, trifluoromethoxy, methyl- thio, methylsulfmyl, (imino)(methyl)sulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, /c/T-butylamino, dimethylamino, acetyla
  • Typical examples of particular substituents on R 2 include one, two or three substituents independently selected from dimethylaminocarbonyl.
  • R 2 Illustrative values of R 2 include hydrogen, cyano, -OR a , -SOR a , -NR b R c ,
  • R 2 examples include dimethylaminocarbonyl ethyl.
  • R 3 represents hydrogen, halogen or -NR b R c ; or R 3 represents Ci- 6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci- 6 )alkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents hydrogen, fluoro or -NR b R c ; or R 3 represents ethyl, phenyl, morpholinyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 3 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluoro- methyl, hydroxy, hydroxy(Ci- 6 )alkyl, oxo, Ci- 6 alkoxy, difluoromethoxy, trifluoro- methoxy, Ci- 6 alkylthio, Ci- 6 alkylsulfmyl, Ci- 6 alkylsulfonyl, amino, amino(Ci- 6 )alkyl, Ci- 6 alkylamino, di(Ci- 6 )alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci- 6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci- 6 alkylaminocarbonyl, di(Ci- 6
  • substituents on R 3 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, fer/-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, /c/V-butylamino, dimethylamino, acetylamino, methoxy carbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, difluoromethylhydroxy
  • R 3 include hydrogen, fluoro, -NR b R c , /er/-butoxy carbonyl- ethyl, dimethylaminocarbonylphenyl, morpholinyl, methylsulfonylpiperidinylmethyl, methylsulfonylpiperazinylmethyl, acetylpiperazinylmethyl, morpholinylmethyl and difluoroazeti diny 1 carb ony lpy ri diny 1.
  • R 3 represents hydrogen
  • R 4 represents hydrogen, halogen or -OR a .
  • R 4 represents hydrogen. In a second embodiment, R 4 represents halogen. In one aspect of that embodiment, R 4 represents fluoro. In another aspect of that embodiment, R 4 represents chloro. In a third embodiment, R 4 represents -OR a . Typical values of R 4 include hydrogen, fluoro and -OR a .
  • Z represents -CH(R 5 )N(H)C(0)R 6 .
  • Z represents -CH(R 5 )N(H)S(0)2R 6 .
  • Z represents -CH(R 5 )R 7 .
  • Z represents -CH(R 5 )N(H)R 7 .
  • Z represents -CH(R 5 )C(0)N(H)R 7 .
  • a first sub-class of compounds according to the invention is represented by the compounds of formula (IA), and pharmaceutically acceptable salts thereof:
  • a second sub-class of compounds according to the invention is represented by the compounds of formula (IB), and pharmaceutically acceptable salts thereof:
  • a third sub-class of compounds according to the invention is represented by the compounds of formula (IC), and pharmaceutically acceptable salts thereof:
  • a fourth sub-class of compounds according to the invention is represented by the compounds of formula (ID), and pharmaceutically acceptable salts thereof:
  • a fifth sub-class of compounds according to the invention is represented by the compounds of formula (IE), and pharmaceutically acceptable salts thereof:
  • a sixth sub-class of compounds according to the invention is represented by the compounds of formula (IF), and pharmaceutically acceptable salts thereof:
  • Z represents -CH(R 5 )N(H)C(0)R 6 .
  • R 5 represents Ci- 6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(Ci- 6 )alkyl, C4-9 cycloalkenyl, C4-12 bicycloalkyl, C5-9 spirocycloalkyl, C5-9 spirocycloalkyl(Ci-5)alkyl,
  • Cs-n tricycloalkyl Cs-n tricycloalkyl(Ci- 6 )alkyl, C7-13 dispirocycloalkyl, aryl, aryl- (Ci- 6 )alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci- 6 )alkyl, heteroaryl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 5 represents C3-9 cycloalkyl, C4-12 bicycloalkyl, C5-9 spirocycloalkyl or C7-13 dispirocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 5 represents C3-9 cycloalkyl, which group may be optionally substituted by one or more substituents.
  • R 5 represents hydrogen. In a second embodiment, R 5 represents optionally substituted Ci- 6 alkyl. In a third embodiment, R 5 represents optionally substituted C3-9 cycloalkyl. In a fourth embodiment, R 5 represents optionally substituted C3-9 cycloalkyl(Ci- 6 )alkyl. In a fifth embodiment, R 5 represents optionally substituted C4-9 cycloalkenyl. In a sixth embodiment, R 5 represents optionally substituted C4-9 bicycloalkyl. In a seventh embodiment, R 5 represents optionally substituted C5-9 spirocycloalkyl.
  • R 5 represents optionally substituted C5-9 spirocycloalkyl(Ci- 6 )alkyl. In a ninth embodiment, R 5 represents optionally substituted C8-11 tri cycloalkyl. In a tenth embodiment, R 5 represents optionally substituted Cx-i 1 tricycloalkyl(Ci- 6 )alkyl. In an eleventh embodiment, R 5 represents optionally substituted aryl. In a twelfth embodiment, R 5 represents optionally substituted aryl(Ci- 6 )alkyl. In a thirteenth embodiment, R 5 represents optionally substituted C3-7 heterocycloalkyl.
  • R 5 represents optionally substituted C3-7 heterocycloalkyl(Ci- 6 )- alkyl. In a fifteenth embodiment, R 5 represents optionally substituted heteroaryl. In a sixteenth embodiment, R 5 represents optionally substituted heteroaryl(Ci- 6 )alkyl. In a seventeenth embodiment, R 5 represents optionally substituted C7-13 dispirocycloalkyl. In an eighteenth embodiment, R 5 represents optionally substituted C7-13 dispirocycloalkyl- (Ci- 6 )alkyl.
  • R 5 is other than hydrogen.
  • Typical values of R 5 include methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexylmethyl, cyclooctenyl, bicyclo[4.1.0]heptanyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[3.3]- heptanylmethyl, adamantanyl, adamantanylmethyl, dispiro[2.0.24.13]heptanyl, phenyl, benzyl, phenylethyl, naphthylmethyl, thienyl, indolyl, pyridinyl, thienylmethyl, indolyl- methyl and pyridinylmethyl, any of which groups may be optionally substituted by one or more
  • R 5 Illustrative values of R 5 include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptanyl, spiro[2.5]octanyl and dispiro[2.0.24.13]heptanyl, any of which groups may be optionally substituted by one or more substituents.
  • Suitable values of R 5 include cyclohexyl and cyclooctyl, either of which groups may be optionally substituted by one or more substituents.
  • Apposite values of R 5 include cyclohexyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 5 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluoro- methyl, phenyl, hydroxy, oxo, Ci- 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci- 6 alkylthio, Ci- 6 alkylsulfmyl, Ci- 6 alkylsulfonyl, amino, Ci- 6 alkylamino, di(Ci- 6 )alkyl- amino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci- 6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci- 6 alkyl- aminocarbonyl, di(Ci- 6 )alkylaminocarbonyl, aminosulfonyl, Ci- 6 al
  • Suitable examples of optional substituents on R 5 include one, two or three substituents independently selected from halogen, cyano, Ci- 6 alkyl, trifluoromethyl, phenyl, hydroxy, Ci- 6 alkoxy and aminocarbonyl, especially Ci- 6 alkyl.
  • substituents on R 5 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, fer/-butyl, trifluoromethyl, phenyl, hydroxy, oxo, methoxy, /er/-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methyl sulfmyl, methylsulfonyl, amino, methylamino, /er/-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, amino sulfonyl,
  • Suitable examples of particular substituents on R 5 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, methyl, trifluoro methyl, phenyl, hydroxy, methoxy, /er/-butoxy and aminocarbonyl, especially methyl.
  • R 5 Illustrative examples of specific values of R 5 include hydrogen, methyl, isopropyl, 1-methylpropyl, 2-methylpropyl, cyclopropyl, cyclopentyl, indanyl, cyclohexyl, methyl- cyclohexyl, trifluoromethylcyclohexyl, difluorocyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, cyclohexylmethyl, cyclooctenyl, bicyclo[4.1.0]heptanyl, spiro- [3.3]heptanyl, spiro[2.5]octanyl, dispiro[2.0.24.13]heptanyl, phenyl, chlorophenyl, benzyl, fluorobenzyl, chlorobenzyl, (chloro)(fluoro)benzyl, dichlorobenzyl, bromobenzyl, cyan
  • Apposite examples of particular values of R 5 include cyclopentyl, cyclohexyl, methylcyclohexyl, difluorocyclohexyl, dimethylcyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.1.0]heptanyl, spiro[2.5]octanyl and dispiro[2.0.24.13]heptanyl.
  • R 5 Representative examples of specific values of R 5 include methylcyclohexyl and cyclooctyl.
  • R 5 represents methylcyclohexyl, especially 4-methyl- cyclohexyl. In a second embodiment, R 5 represents cyclooctyl.
  • R 5a represents optionally substituted C3-7 cycloalkyl. In a second embodiment, R 5a represents optionally substituted C4-9 bicycloalkyl. In a third embodiment, R 5a represents optionally substituted aryl. In a fourth embodiment, R 5a represents optionally substituted C3-7 heterocycloalkyl. In a fifth embodiment, R 5a represents optionally substituted heteroaryl.
  • Typical values of R 5a include cyclobutyl, cyclopentyl, bicyclo[l. l.l]pentanyl, phenyl, dihydrobenzofuranyl and pyrrolyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 5a include Ci- 6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, Ci- 6 alkoxy, Ci- 6 alkylthio, Ci- 6 alkyl- sulfmyl, Ci- 6 alkyl sulfonyl, C2-6 alkylcarbonyl, amino, Ci- 6 alkylamino and di(Ci- 6 )alkyl- amino.
  • R 5a Selected examples of optional substituents on R 5a include Ci- 6 alkyl and halogen.
  • Typical examples of particular substituents on R 5a include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, methoxy, methylthio, methylsulfmyl, methylsulfonyl, acetyl, amino, methylamino and dimethylamino.
  • R 5a Selected examples of particular substituents on R 5a include methyl and chloro.
  • Selected values ofR 5a include cyclobutyl, cyclopentyl, bicyclo[l.l. l]pentanyl, phenyl, chlorophenyl, dihydrobenzofuranyl and methylpyrrolyl.
  • R 5b represents hydrogen, methyl or ethyl.
  • R 5b represents hydrogen.
  • R 5b represents Ci- 6 alkyl, especially methyl or ethyl.
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, may represent C3-7 cycloalkyl, C4-9 bicycloalkyl or C3-7 hetero cycloalkyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C3-7 cycloalkyl.
  • examples include cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, tetrahydronaphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl and
  • cyclononanyl any of which groups may be optionally substituted by one or more substituents.
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C4-9
  • bicycloalkyl examples include bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl and bicyclo[3.2.1]octanyl, any of which groups may be optionally substituted by one or more substituents.
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C3-7 hetero cycloalkyl.
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, may suitably represent optionally substituted C3-7 hetero cycloalkyl. Examples include tetrahydropyranyl and piperidinyl, either of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on such groups include Ci- 6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, Ci- 6 alkoxy, Ci- 6 alkyl- thio, Ci- 6 alkylsulfmyl, Ci- 6 alkylsulfonyl, C2-6 alkylcarbonyl, amino, Ci- 6 alkylamino and di(Ci- 6 )alkylamino.
  • Selected examples of optional substituents on such groups include Ci- 6 alkyl, halogen, trifluoromethyl, trifluoroethyl, phenyl and Ci- 6 alkoxy.
  • Typical examples of particular substituents on such groups include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, phenyl, hydroxy, methoxy, methylthio, methylsulfmyl, methylsulfonyl, acetyl, amino, methylamino and
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, include methylcyclobutyl, dimethylcyclobutyl, phenylcyclobutyl, benzocyclobutenyl, methylbenzocyclobutenyl, chlorobenzocyclobutenyl, methoxy- benzocyclobutenyl, cyclopentyl, methylcyclopentyl, indanyl, chloroindanyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, trifluoromethylcyclohexyl, tetrahydro- naphthalenyl, cycloheptanyl, benzocycloheptenyl, cyclooctanyl, cyclononanyl,
  • R 6 represents -OR 6a or -NR 6b R 6c ; or R 6 represents Ci- 6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(Ci- 6 )alkyl, aryl, aryl(Ci- 6 )alkyl, heteroaryl or heteroaryl- (Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents -OR 6a ; or R 6 represents Ci- 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents -OR 6a ; or R 6 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 6 represents optionally substituted Ci- 6 alkyl. In a second embodiment, R 6 represents optionally substituted C3-9 cycloalkyl. In a third embodiment, R 6 represents optionally substituted C3-9 cycloalkyl(Ci- 6 )alkyl. In a fourth embodiment,
  • R 6 represents optionally substituted aryl. In a fifth embodiment, R 6 represents optionally substituted aryl(Ci- 6 )alkyl. In a sixth embodiment, R 6 represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, R 6 represents optionally substituted C3-7 heterocycloalkyl(Ci- 6 )alkyl. In an eighth embodiment, R 6 represents optionally substituted heteroaryl. In a ninth embodiment, R 6 represents optionally substituted heteroaryl(Ci- 6 )alkyl. In a tenth embodiment, R 6 represents -OR 6a . In an eleventh embodiment, R 6 represents -NR 6a R 6b .
  • R 6 examples include -OR 6a or -NR 6a R 6b ; and methyl, ethyl, propyl, 2- methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • Illustrative values of R 6 include -OR 6a ; and methyl, phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Suitable values of R 6 include pyrazolyl, isoxazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 include isoxazolyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 6 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluoro- methyl, phenyl, fluorophenyl, hydroxy, hydroxy(Ci- 6 )alkyl, oxo, Ci- 6 alkoxy, difluoro- methoxy, trifluoromethoxy, Ci- 6 alkylthio, Ci- 6 alkyl sulfinyl, Ci- 6 alkylsulfonyl, amino, amino(Ci- 6 )alkyl, Ci- 6 alkylamino, di(Ci- 6 )alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C2- 6 alkylcarbonylamino, C2- 6 alkylcarbonylamino(Ci- 6 )alkyl,
  • Suitable examples of optional substituents on R 6 include one, two or three substituents independently selected from Ci- 6 alkyl.
  • substituents on R 6 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, te/V-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy,
  • Suitable examples of particular substituents on R 6 include one, two or three substituents independently selected from methyl.
  • R 6 Illustrative examples of particular values of R 6 include methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl- cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl,
  • hydroxymethylbenzyl benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxy- benzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylamino- benzyl, pyrrolidinylbenzyl, (dimethyl)(pyrrolidinyl)benzyl, morpholinylbenzyl,
  • Favoured values of R 6 include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyl oxadiazolyl.
  • R 6 is methylisoxazolyl.
  • R 6a represents Ci-6 alkyl.
  • R 6a represents Ci-6 alkyl. In a second embodiment, R 6a represents optionally substituted C3-9 cycloalkyl.
  • R 6a represents Ci-6 alkyl; or R 6a represents cyclobutyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 6a include one, two or three substituents independently selected from halogen, cyano, nitro, Ci-6 alkyl, trifluoro- methyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, Ci-6 alkoxy, difluoromethoxy, trifluoro- methoxy, Ci-6 alkylthio, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, amino, amino(Ci-6)alkyl,
  • Suitable examples of optional substituents on R 6a include one, two or three substituents independently selected from halogen.
  • Typical examples of specific substituents on R 6a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, fer/-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, /c/V-butylamino, dimethylamino, acetylamino, methoxy carbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-
  • Suitable examples of specific substituents on R 6a include one, two or three substituents independently selected from fluoro.
  • R 6a Illustrative examples of specific values of R 6a include methyl, ethyl, «-propyl, isopropyl, «-butyl, /c/ -butyl and difluorocyclobutyl.
  • Suitable examples of specific values of R 6a include /er/-butyl and difluoro cyclobutyl.
  • R 6a represents /er/-butyl.
  • R 6b represents hydrogen or methyl.
  • R 6b represents hydrogen. In a second embodiment, R 6b represents Ci-6 alkyl, especially methyl.
  • R 6c represents hydrogen or methyl.
  • R 6c represents hydrogen. In a second embodiment, R 6c represents Ci-6 alkyl, especially methyl.
  • R 7 represents aryl, which group may be optionally substituted by one or more substituents.
  • R 7 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 7 represents spiro[(C3-7)heterocycloalkyl] [heteroaryl], which group may be optionally substituted by one or more substituents.
  • Typical values of R 7 include phenyl, pyrazolo[l,5-a]pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, imidazo[l,2-Z>]pyridazinyl, imidazo[l,2-c]pyrimidinyl, purinyl, pyridinyl, pyridazinyl, cinnolinyl, pyrimidinyl, pyrazinyl and spiro[tetrahydro- pyranyl] [indole], any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 7 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci-6 alkyl, difluoromethyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci-6 alkylthio, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, amino, amino(Ci-6)alkyl, Ci-6 alkylamino, di(Ci-6)alkylamino, pyrrolidinyl, morpholinyl, piperazinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylamino(Ci-6)alkyl, C2-6
  • Ci-6 alkylsulfonylamino formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulfonyl, Ci-6 alkylaminosulfonyl and di(Ci-6)alkylaminosulfonyl.
  • substituents on R 7 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, fer/-butyl, difluoromethyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, isopropoxy, /c/V-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, /c/T-butylamino, dimethylamino, pyrrolidinyl, morpholinyl, piperazinyl, acetylamino, acetyl aminoethyl, methoxycarbonylamino, methylsulfonyl- amino, formyl, acet
  • R 7 Illustrative values of R 7 include phenyl, pyrazolo[l,5-a]pyrazinyl, benzoxazolyl, fluorobenzoxazolyl, methylbenzoxazolyl, benzothiazolyl, benzimidazolyl, fluoro- benzimidazolyl, imidazo[l,2-Z>]pyridazinyl, imidazo[l,2-c]pyrimidinyl, purinyl, pyridinyl, cyanopyridinyl, methylpyridinyl, methoxypyridinyl, pyridazinyl, chloropyridazinyl, cyanopyridazinyl, methylpyridazinyl, ethylpyridazinyl, isopropylpyridazinyl, difluoro- methylpyridazinyl, trifluoromethylpyridazinyl, methoxy
  • Suitable substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include halogen, Ci-6 alkyl, Ci-6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci-6 alkoxy(Ci-6)alkyl, Ci-6 alkylthio, Ci-6 alkylsulphinyl, Ci-6 alkylsulphonyl, hydroxy, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano, trifluoromethyl, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, C2-6 alkylcarbonyloxy, amino, Ci-6 alkylamino, di(Ci-6)alkylamino, phenylamino, pyridinylamino, C2-6 alkylcarbonylamino, C2-6 alkyl
  • Typical examples of particular substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydroxymethyl, hydroxyethyl, aminomethyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl,
  • ethoxycarbonyl tert- butoxycarbonyl, acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, /c/T-butoxycarbonylamino, acetylaminomethyl, methylsulphonylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl.
  • R a represents Ci- 6 alkyl, C3-9 cycloalkyl, aryl, aryl(Ci- 6 )alkyl, C3-7 heterocycloalkyl, heteroaryl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a represents Ci- 6 alkyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more
  • R a represents Ci- 6 alkyl, aryl(Ci- 6 )alkyl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Illustrative values of R a include methyl, ethyl, cyclopropyl, phenyl, benzyl, oxetanyl, tetrahydropyranyl, piperidinyl, pyridinyl, pyridazinyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Representative values of R a include methyl, cyclopentyl, phenyl, oxetanyl, tetrahydropyranyl, piperidinyl, pyridinyl and pyridazinyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected examples of suitable substituents on R a include Ci- 6 alkoxy, oxo and Ci- 6 alkyl sulfonyl.
  • R a Selected examples of specific substituents on R a include methoxy, oxo and methyl- sulfonyl.
  • R a represents optionally substituted Ci- 6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted Ci- 6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted Ci- 6 alkyl, e.g.
  • R a represents optionally substituted aryl.
  • R a represents unsubstituted aryl, especially phenyl.
  • R a represents monosub stituted aryl, especially methylphenyl.
  • R a represents optionally substituted aryl(Ci- 6 )alkyl, ideally unsubstituted aryl(Ci- 6 )alkyl, especially benzyl.
  • R a represents optionally substituted heteroaryl.
  • R a represents optionally substituted heteroaryl(Ci- 6 )alkyl, e.g. dioxoisoindolylpropyl.
  • R a represents optionally substituted C3-9 cycloalkyl, e.g. cyclopentyl.
  • R a represents optionally substituted C3-7 heterocycloalkyl.
  • R a Particular values include methyl, methoxyethyl, cyclopentyl, phenyl, benzyl, oxetanyl, tetrahydropyranyl, methylsulfonylpiperidinyl, dioxoisoindolylpropyl, pyridinyl and pyridazinyl.
  • R b represents hydrogen or trifluorom ethyl; or Ci- 6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci- 6 )alkyl, aryl, aryl(Ci- 6 )alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci- 6 )alkyl, heteroaryl or heteroaryl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or Ci- 6 alkyl, aryl(Ci- 6 )alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical values of R b include hydrogen and Ci- 6 alkyl.
  • R b represents hydrogen or trifluorom ethyl; or methyl, ethyl, «-propyl, isopropyl, «-butyl, 2-methylpropyl, /er/-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl,
  • pyrrolidinylpropyl thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolyl ethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or methyl, ethyl, «-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R b Selected examples of suitable substituents on R b include Ci- 6 alkoxy, Ci- 6 alkylthio, Ci- 6 alkylsulphinyl, Ci- 6 alkylsulphonyl, hydroxy, cyano, C2-6 alkoxycarbonyl, di- (Ci- 6 )alkylamino and C2-6 alkoxy carbonylamino.
  • R b Selected examples of specific substituents on R b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, /cvV-butoxy carbonyl, dimethylamino and /c/V-butoxycarbonylamino.
  • R b include hydrogen, methyl, methoxy ethyl, methylthioethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino- ethyl, /f/V-butoxycarbonyl ami noethyl, dihydroxy propyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.
  • R b represents hydrogen. In another embodiment, R b represents Ci- 6 alkyl, especially methyl.
  • R c include hydrogen; or Ci- 6 alkyl, C3-7 cycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R c represents C3-7 heterocycloalkyl, which group may be optionally substituted by one or more substituents.
  • R c represents hydrogen, Ci- 6 alkyl or C3-7 cycloalkyl.
  • R c include hydrogen; or methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R c include tetrahydropyranyl and piperidinyl, either of which groups may be optionally substituted by one or more substituents.
  • R c Selected examples of suitable substituents on R c include Ci- 6 alkyl sulfonyl, C2-6 alkylcarbonyl and C2-6 alkoxycarbonyl.
  • R c Selected examples of specific substituents on R c include methylsulfonyl, acetyl and tert- butoxycarbonyl .
  • R c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, methylsulfonylpiperidinyl, acetylpiperidinyl and tert- butoxycarbonylpiperidinyl.
  • Particular values of R c include tetrahydropyranyl and methylsulfonylpiperidinyl.
  • R c represents hydrogen or Ci-6 alkyl.
  • R c is hydrogen.
  • R c represents Ci-6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents C3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the moiety -NR b R c may suitably represent azetidin-l-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl,
  • homomorpholin-4-yl or homopiperazin-l-yl any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable substituents on the heterocyclic moiety -NR b R c include Ci-6 alkyl, Ci-6 alkylsulphonyl, hydroxy, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, amino, C2-6 alkylcarbonyl- amino, C2-6 alkylcarbonylamino(Ci-6)alkyl, C2-6 alkoxycarbonylamino, Ci-6 alkyl- sulphonylamino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR b R c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, /c/7-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.
  • R c Specific values of the moiety -NR b R c include azetidin-l-yl, hydroxyazetidin-l-yl, hydroxymethylazetidin- 1 -yl, (hydroxy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin-l-yl, cyanoazetidin-l-yl, carboxyazetidin-l-yl, aminoazetidin-l-yl,
  • R d represents hydrogen; or Ci-6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable values for R d include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert- butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R d Selected examples of suitable substituents on R d include halogen, Ci- 6 alkyl, Ci- 6 alkoxy, oxo, C2-6 alkylcarbonyloxy and di(Ci- 6 )alkylamino.
  • R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
  • R d represents hydrogen. In another embodiment, R d represents optionally substituted Ci- 6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted Ci- 6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, R d ideally represents substituted Ci- 6 alkyl, e.g. substituted methyl or substituted ethyl, including
  • R d represents optionally substituted aryl.
  • R d represents unsubstituted aryl, especially phenyl.
  • R d represents monosub stituted aryl, especially methylphenyl.
  • R d represents disubstituted aryl, e.g. dimethoxyphenyl.
  • R d represents optionally substituted heteroaryl, e.g. thienyl, chlorothienyl, methylthienyl, methylimidazolyl or thiazolyl.
  • R d represents optionally substituted C3-7 cycloalkyl, e.g. cyclopropyl or cyclobutyl.
  • R d represents optionally substituted C3-7 heterocycloalkyl, e.g. thiazolidinyl or oxo- thiazolidinyl.
  • R d selected examples include hydrogen, methyl, acetoxy methyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, /er/-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
  • R e represents Ci- 6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
  • R e Selected examples of suitable substituents on R e include Ci- 6 alkyl, especially methyl.
  • R e represents optionally substituted Ci- 6 alkyl, ideally unsubstituted Ci- 6 alkyl, e.g. methyl or propyl, especially methyl.
  • R e represents optionally substituted aryl.
  • R e represents unsubstituted aryl, especially phenyl.
  • R e represents monosub stituted aryl, especially methylphenyl.
  • R e represents optionally substituted heteroaryl.
  • Selected values of R e include methyl, propyl and methylphenyl.
  • R 16 represents methyl or ethyl
  • R 2 and R 5 are as defined above.
  • R 16 represents methyl. In a second embodiment, R 16 represents ethyl.
  • the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
  • the compounds according to the present invention are useful in the treatment and/or prophylaxis of a pathological disorder that is mediated by a pro-inflammatory IL-17 cytokine or is associated with an increased level of a pro-inflammatory IL-17 cytokine.
  • the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer’s Disease, Crohn’s disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman’s disease, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie’s Disease, coeliac disease, gall bladder disease, Pilonidal disease, peritonitis, psoriasis,
  • WO 2009/089036 reveals that modulators of IL-17 activity may be administered to inhibit or reduce the severity of ocular inflammatory disorders, in particular ocular surface inflammatory disorders including Dry Eye Syndrome (DES). Consequently, the compounds in accordance with the present invention are useful in the treatment and/or prevention of an IL-17-mediated ocular inflammatory disorder, in particular an IL-17- mediated ocular surface inflammatory disorder including Dry Eye Syndrome.
  • a IL-17-mediated ocular inflammatory disorder in particular an IL-17- mediated ocular surface inflammatory disorder including Dry Eye Syndrome.
  • Ocular surface inflammatory disorders include Dry Eye Syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, Pemphigoid syndrome, Stevens- Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis.
  • Dry Eye Syndrome include keratoconjunctivitis sicca (KCS), Sjogren syndrome,
  • Sjogren syndrome-associated keratoconjunctivitis sicca Sjogren syndrome-associated keratoconjunctivitis sicca, non-Sjogren syndrome- associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.
  • ATD aqueous tear deficiency
  • the compounds of the present invention may be useful in the treatment and/or prophylaxis of a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, scleroderma, systemic sclerosis, lung fibrosis, inflammatory bowel diseases (including Crohn’s disease and ulcerative colitis), ankylosing spondylitis and other spondylo arthropathies, cancer and pain (particularly pain associated with inflammation).
  • a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic l
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis or ankylosing spondylitis.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • wetting agents e.g. sodium lauryl sulphate.
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds according to the present invention may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds according to the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol,
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzyl alkonium chloride or chlorhexidine acetate.
  • a bactericidal or fungicidal agent for example phenylmercuric nitrate, benzyl alkonium chloride or chlorhexidine acetate.
  • the compounds according to the present invention may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • a compound in accordance with the present invention may be co administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.
  • the compounds of formula (IA) above may be prepared by a process which comprises reacting a carboxylic acid of formula R 6 -C02H with a compound of formula (III):
  • Suitable coupling agents include l-[bis(dimethylamino)methylene]-liT-l,2,3- triazolo[4,5-Z>]pyridinium 3-oxid hexafluorophosphate (HATU); and 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.
  • Suitable bases include organic amines, e.g. a trialkylamine such as A f , A f -di i sopropy 1 ethyl a i ne.
  • the reaction is conveniently performed at ambient or elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or a dipolar aprotic solvent such as A f ,A-di methyl form amide, or a chlorinated solvent such as dichloromethane.
  • R 6 represents Ci-6 alkyl, e.g. methyl
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula R 6 -COCl, e.g. acetyl chloride, with a compound of formula (III) as defined above.
  • the reaction is conveniently accomplished in the presence of a base.
  • Suitable bases include organic amines, e.g. a trialkylamine such as A f ,A-di isopropyl ethyl amine.
  • the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • R 6 represents -OR 6a
  • the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R 6a -OH with A f , A f '-di sued ni m i dyl carbonate, ideally in the presence of a base, e.g. an organic amine such as triethylamine; and (ii) reacting the resulting material with a compound of formula (III) as defined above.
  • Steps (i) and (ii) are conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • the compounds of formula (IB) above may be prepared by a process which comprises reacting a compound of formula (III) as defined above with a compound of formula L 1 -S(0)2R 6 , wherein R 6 is as defined above, and L 1 represents a suitable leaving group.
  • the leaving group L 1 is suitably a halogen atom, e.g. chloro.
  • reaction is conveniently carried out at ambient temperature in the presence of pyridine.
  • reaction may be carried out at ambient temperature in the presence of a base, e.g. an organic amine such as N,N-d ⁇ i sopropy 1 ethyl a i ne, in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • a base e.g. an organic amine such as N,N-d ⁇ i sopropy 1 ethyl a i ne
  • suitable solvent e.g. a chlorinated solvent such as dichloromethane.
  • the compounds of formula (IC) above may be prepared by a process which comprises reacting a compound of formula (III) as defined above with a compound of formula L 2 -R 7 , wherein R 7 is as defined above, and L 2 represents a suitable leaving group.
  • the leaving group L 2 is suitably a halogen atom, e.g. chloro or bromo.
  • Suitable bases include organic amines, e.g. a trialkylamine such as A,/V-diisopropylethylamine.
  • the reaction is typically performed at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane, or a cyclic amide such as l-methyl-2-pyrrolidinone, or an organic sulfoxide such as dimethyl sulfoxide.
  • the reaction may be performed in the presence of a transition metal catalyst.
  • Suitable transition metal catalysts of use in this procedure include [(2-di-/er/- butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l,r-biphenyl)-2-(2'-amino-l, r- biphenyl)]palladium(II) methanesulfonate (tBuBrettPhos Pd G3).
  • the reaction is conveniently carried out at an elevated temperature in the presence of a base, e.g. an inorganic base such as potassium /cvV-but oxide, in a suitable solvent or solvent mixture.
  • the solvent or solvents may suitably be selected from a cyclic ether such as 1,4-dioxane, and a sulfoxide solvent such as dimethyl sulfoxide.
  • the compounds of formula (IA) above wherein R 1 represents hydrogen may be prepared by a process which comprises cyclising a compound of formula (IV):
  • Cyclisation of compound (IV) is conveniently effected by heating in a suitable medium, e.g. polyphosphoric acid, or acetic acid.
  • the intermediates of formula (IV) above may be prepared by reacting a compound of formula (V) with a carboxylic acid of formula (VI) or a salt thereof, e.g. a lithium salt thereof:
  • the intermediates of formula (VI) may be prepared by a two-step procedure which comprises: (i) reacting a carboxylic acid of formula R 6 -C02H with a compound of formula (VII): wherein Aik 1 represents Ci-4 alkyl, e.g. methyl, and R 5 and R 6 are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C02H; and (ii) saponification of the resulting material by treatment with a base.
  • step (i) Alternative coupling agents that may usefully be employed in step (i) include N- (3 -dimethyl ami nopropyl )-A"-ethylcarbodii mi de hydrochloride (EDC.HC1) and ()- (benzotriazol-1 -yl)-A f ,A f ,A f ',A"-tetramethyluronium hexafluorophosphate (HBTU).
  • EDC.HC1 N- (3 -dimethyl ami nopropyl )-A"-ethylcarbodii mi de hydrochloride
  • HBTU hexafluorophosphate
  • the saponification reaction in step (ii) will generally be effected by treatment with a base.
  • Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide.
  • the product may be the lithium salt of the carboxylic acid of formula (VI).
  • Step (ii) is conveniently effected at ambient temperature in water and a suitable organic solvent, e.g. a cyclic ether such as tetrahydrofuran, optionally in admixture with a Ci-4 alkanol such as methanol.
  • a suitable organic solvent e.g. a cyclic ether such as tetrahydrofuran, optionally in admixture with a Ci-4 alkanol such as methanol.
  • R 5 is as defined above, and R p represents a L -protecting group; under conditions analogous to those described above for the reaction between compounds (V) and (VI);
  • the L -protecting group R p will suitably be /c/7-butoxycarbonyl (BOC), in which case the removal thereof in step (iii) may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as
  • steps (ii) and (iii) may be accomplished simultaneously.
  • the L -protecting group R q will suitably be 2-(trimethylsilyl)ethoxymethyl.
  • Step (i) is suitably effected by treatment of compound (IX) with a base, e.g. an organic base such as //-butyllithium, followed by reaction with compound (X).
  • a base e.g. an organic base such as //-butyllithium
  • the reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • step (ii) removal of the /c/V-butylsulfinyl group and the A f -protecting group R q from compound (XI) in step (ii) may both be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.
  • an acid e.g. a mineral acid such as hydrochloric acid.
  • Step (i) is conveniently carried out at an elevated temperature.
  • Step (ii) is suitably effected by treating the reactants with a base, e.g. an inorganic base such as sodium hydride.
  • a base e.g. an inorganic base such as sodium hydride.
  • the intermediates of formula (X) above may be prepared by reacting an aldehyde derivative of formula R 5 -CHO with 2-methyl-2-propanesulfmamide.
  • the reaction is suitably effected in the presence of pyridinium / oluenesulfonate and magnesium sulfate.
  • the reaction is conveniently carried out at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • the compounds of formula (ID) above may be prepared by a process which comprises reacting a compound of formula R 7 -NH2 with a compound of formula (XII):
  • the intermediates of formula (XII) above may be prepared by a three-step procedure which comprises: (i) reacting a compound of formula (V) as defined above with a compound of formula (XIII), or a salt thereof, e.g. a lithium salt thereof:
  • R 5 is as defined above, and Aik 1 represents Ci-4 alkyl, e.g. methyl; under conditions analogous to those described above for the reaction between compounds (V) and (VI); (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (IV); and (ii) saponification of the resulting material by treatment with a base.
  • the saponification reaction in step (iii) will generally be effected by treatment with a base.
  • Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide.
  • the product may be the lithium salt of the carboxylic acid of formula (XII).
  • Step (iii) is conveniently effected at ambient temperature in water and a suitable organic solvent, e.g. a Ci-4 alkanol such as ethanol.
  • a suitable organic solvent e.g. a Ci-4 alkanol such as ethanol.
  • the compounds of formula (IE) above may be prepared by a two-step procedure which comprises: (i) reacting a compound of formula (V) as defined above with a compound of formula (XIV):
  • R 5 and R 7 are as defined above; under conditions analogous to those described above for the reaction between compounds (V) and (VI); and (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (IV).
  • the compounds of formula (IF) above may be prepared by a process which comprises reacting a compound of formula (V) as defined above with a compound of formula (XV):
  • R 5a , R 5b and R 6 are as defined above.
  • the reaction will generally be performed in the presence of acetic acid.
  • the reaction is conveniently carried out at an elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • R 5a , R 5b and R 6 are as defined above.
  • the reaction is conveniently effected by treating the reagents with titanium tetrachloride; followed by treatment of the resulting material with pyridine.
  • the starting materials of formula (V), (VII), (VIII), (XIII), (XIV) and (XVI) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • a compound of formula (I) comprising a N-BOC moiety (wherein BOC is an abbreviation for tert- butoxycarbonyl) may be converted into the corresponding compound comprising a N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • a compound of formula (I) comprising a N-H functionality may be alkylated, e.g. methylated, by treatment with a suitable alkyl halide, e.g. iodomethane, typically in the presence of a base, e.g. an inorganic carbonate such as sodium carbonate.
  • a suitable alkyl halide e.g. iodomethane
  • a base e.g. an inorganic carbonate such as sodium carbonate.
  • a compound of formula (I) comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl halide, e.g. acetyl chloride, typically in the presence of a base, e.g. an organic base such as /V,/V-di i sopropy 1 ethyl a i ne or triethyl- amine.
  • a compound of formula (I) comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl anhydride, e.g. acetic anhydride, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a compound of formula (I) comprising a N-H functionality may be converted into the corresponding compound comprising a N-S(0)2Alk 1 functionality (wherein Aik 1 is as defined above) by treatment with the appropriate Ci-4 alkylsulfonyl chloride reagent, e.g. methyl sulfonyl chloride, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • Ci-4 alkylsulfonyl chloride reagent e.g. methyl sulfonyl chloride
  • a base e.g. an organic base such as triethylamine.
  • a compound of formula (I) comprising a N-H functionality may be converted into the corresponding compound comprising a carbamate or urea moiety respectively by treatment with the appropriate chloroformate or carbamoyl chloride reagent, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a compound of formula (I) comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety by treatment with the appropriate amine-substituted (3-methylimidazol-3-ium-l-yl)methanone iodide derivative, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a base e.g. an organic base such as triethyl amine.
  • a compound of formula (I) comprising a N-H functionality may be converted into the corresponding compound comprising a N-C(H) functionality by treatment with the appropriate aldehyde or ketone in the presence of a reducing agent such as sodium tri ac etoxy b orohy dri de .
  • a compound of formula (I) comprising a Ci-4 alkoxycarbonyl moiety -CCbAlk 1 may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as lithium hydroxide.
  • a compound of formula (I) comprising a /er/-butoxy carbonyl moiety may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with trifluoroacetic acid.
  • a compound of formula (I) comprising a carboxylic acid (-CO2H) moiety may be converted into the corresponding compound comprising an amide moiety by treatment with the appropriate amine, under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C02H.
  • a compound of formula (I) comprising a Ci-4 alkoxycarbonyl moiety -CCkAlk 1 may be converted into the corresponding compound comprising a hydroxymethyl (-CH2OH) moiety by treatment with a reducing agent such as lithium aluminium hydride.
  • a compound of formula (I) comprising a Ci-4 alkylcarbonyloxy moiety
  • -OC(0)Alk 1 (wherein Aik 1 is as defined above), e.g. acetoxy, may be converted into the corresponding compound comprising a hydroxy (-OH) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as sodium hydroxide.
  • a base e.g. an alkali metal hydroxide salt such as sodium hydroxide.
  • a compound of formula (I) comprising a halogen atom, e.g. bromo may be converted into the corresponding compound comprising an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety by treatment with the appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3 -propanediol or neopentyl glycol.
  • the reaction is typically effected in the presence of a transition metal catalyst, and a base.
  • the transition metal catalyst may be [l,T-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may advantageously be employed in conjunction with 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (XPhos).
  • the base may be an inorganic base such as sodium carbonate or potassium carbonate.
  • a compound of formula (I) comprising a halogen atom may be converted into the corresponding compound comprising an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety via a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriate bromoaryl, heterocycloalkenyl or bromoheteroaryl derivative substituted with a suitable leaving group, e.g. a halogen atom such as bromo, or a sulfonyloxy moiety such as trifluoromethylsulfonyloxy.
  • Step (i) is conveniently effected in the presence of a transition metal catalyst, and a base such as potassium acetate.
  • the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may advantageously be employed in conjunction with 2-dicyclohexylphosphino- 2',4',6'-triisopropylbiphenyl (XPhos).
  • the transition metal catalyst may be [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II).
  • Step (ii) is conveniently effected in the presence of a transition metal catalyst such as [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II), and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a compound of formula (I) comprising a cyano (-CN) moiety may be converted into the corresponding compound comprising a 1-aminoethyl moiety by a two-step process which comprises: (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(IV) isopropoxide; and (ii) treatment of the resulting material with a reducing agent such as sodium borohydride. If an excess of methylmagnesium chloride is employed in step (i), the corresponding compound comprising a 1 -amino- 1-methylethyl moiety may be obtained.
  • a compound of formula (I) comprising the moiety -S- may be converted into the corresponding compound comprising the moiety -S(0)(NH)- by treatment with
  • a hydrogenation catalyst e.g. palladium on charcoal.
  • a compound of formula (I) comprising an aromatic nitrogen atom may be converted into the corresponding compound comprising an A-oxide moiety by treatment with a suitable oxidising agent, e.g. 3-chloroperbenzoic acid.
  • a suitable oxidising agent e.g. 3-chloroperbenzoic acid.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Greene’s Protective Groups in Organic Synthesis , ed. P.G.M. Wuts, John Wiley & Sons, 5 th edition, 2014.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit the ability of IL-17A to bind to IL-17RA.
  • compounds of the present invention exhibit an ICso value of 10 mM or less, generally of 5 mM or less, usually of 1 pM or less, typically of 500 nM or less, suitably of 100 nM or less, ideally of 50 nM or less, and preferably of 25 nM or less (the skilled person will appreciate that a lower ICso figure denotes a more active compound).
  • certain compounds in accordance with this invention potently inhibit IL-17 induced IL-6 release from human dermal fibroblasts.
  • compounds of the present invention exhibit an ICso value of 10 pM or less, generally of 5 pM or less, usually of 1 pM or less, typically of 500 nM or less, suitably of 100 nM or less, ideally of 50 nM or less, and preferably of 25 nM or less (as before, the skilled person will appreciate that a lower ICso figure denotes a more active compound).
  • this assay is to test the ability of compounds to disrupt the interaction between IL-17A and soluble IL-17 Receptor A (IL-17RA). The ability of a compound to inhibit IL-17A binding to IL-17RA is measured in this assay.
  • Soluble IL-17RA (33-317)-HKH-TEV-Fc was expressed in an Expi HEK293 cell system and purified by protein A chromatography and size exclusion.
  • the Fc tag was cleaved by TEV, producing IL-17RA (33-317)-HKH, and the protein was labelled with amine reactive terbium (Thermo Fisher #PV3581).
  • IL-17A (10 pL) was added to a black low volume assay plate (Costar #4511) and diluted compound (5 pL) was transferred from the aqueous dilution plate. The cytokine and compound were allowed to incubate for 1 h, then IL-17RA (10 pL) was added. The plates were wrapped in foil and incubated at room temperature for 18-20 h with gentle shaking ( ⁇ 400 rpm) before being read on a Perkin Elmer Envision plate reader
  • the final assay concentrations were IL-17A-AF647 2 nM and IL-17RA-Tb 2 nM, 5% DMSO.
  • the compound of the accompanying Example When tested in the IL-17 FRET assay, the compound of the accompanying Example was found to exhibit an ICso value of 10 pM or better.
  • the compound of the accompanying Example When tested in the IL-17 FRET assay, the compound of the accompanying Example exhibits ICso an value generally in the range of about 0.01 nM to about 10 pM, usually in the range of about 0.01 nM to about 5 mM, typically in the range of about 0.01 nM to about 1 mM, suitably in the range of about 0.01 nM to about 500 nM, appositely in the range of about 0.01 nM to about 100 nM, ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM.
  • This assay is to test the neutralising ability to IL-17 proteins, in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone produces only a very weak signal but in combination with certain other cytokines, such as TNFa, a synergistic effect can be seen in the production of
  • IL-6 inflammatory cytokines
  • HDFs were stimulated with IL-17A (50 pM) in combination with TNF-a (25 pM).
  • the resultant IL-6 response was then measured using a homogenous time-resolved FRET kit from Cisbio.
  • the kit utilises two monoclonal antibodies, one labelled with Eu- Cryptate (Donor) and the second with d2 or XL665 (Acceptor).
  • the intensity of the signal is proportional to the concentration of IL-6 present in the sample (Ratio is calculated by 665/620 x 104).
  • the ability of a compound to inhibit IL-17 induced IL-6 release from human dermal fibroblasts is measured in this assay.
  • HDF cells (Sigma #106-05n) were cultured in complete media (DMEM + 10% FCS + 2 mM L-glutamine) and maintained in a tissue culture flask using standard techniques. Cells were harvested from the tissue culture flask on the morning of the assay using TrypLE (Invitrogen #12605036). The TrypLE was neutralised using complete medium (45 mL) and the cells were centrifuged at 300 x g for 3 minutes. The cells were re-suspended in complete media (5 mL) counted and adjusted to a concentration of 3.125 x 10 4 cells/mL before being added to the 384 well assay plate (Coming #3701) at 40 pL per well. The cells were left for a minimum of three hours, at 37°C/5% CO2, to adhere to the plate.
  • complete media DMEM + 10% FCS + 2 mM L-glutamine
  • Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1 : 1, as per kit insert.
  • a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 pL), then supernatant (10 pL) was transferred from the assay plate to Greiner reagent plate. The mixture was incubated at room temperature for 3 h with gentle shaking ( ⁇ 400 rpm) before being read on a Synergy Neo 2 plate reader (Excitation: 330 nm; Emission: 615/645 nm).
  • compounds of the accompanying Examples exhibit IC50 values generally in the range of about 0.01 nM to about 10 pM, usually in the range of about 0.01 nM to about 5 pM, typically in the range of about 0.01 nM to about 1 pM, suitably in the range of about 0.01 nM to about 500 nM, appositely in the range of about 0.01 nM to about 100 nM, ideally in the range of about 0.01 nM to about 50 nM, and preferably in the range of about 0.01 nM to about 25 nM.
  • DIPEA A f , A -di isopropyl ethyl amine
  • T3P 1-propanephosphonic anhydride
  • TFA trifluoroacetic acid
  • HATU 1 - [bi s(di methyl ami no)m ethylene]- 1//- 1 ,2,3-triazolo[4,5-/ ]pyridinium 3-oxid hexafluorophosphate
  • NMR spectra were recorded on a Bruker Avance III HD 500 MHz, 400 MHz, 300 MHz or 250 MHz spectrometer.
  • HPLC-MS was performed on a Shimadzu LCMS-2010EV system coupled to SPD- M20A PDA and Softa Model 400 ELS detectors.

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Abstract

La présente invention concerne une série de dérivés d'imidazole bicycliques fusionnés substitués de formule (I), comprenant des dérivés de 1H-imidazo[4,5-c]pyridin-4-one et des analogues de ceux-ci, qui sont des modulateurs puissants de l'activité de l'IL-17 humaine, et sont donc utiles dans le traitement et/ou la prévention de diverses maladies humaines, notamment des troubles inflammatoires et auto-immuns. Formule (I) dans laquelle, D représente C-R3 ou N ; E représente C-R4 ou N ; Z représente -CH(R5)N(H)C(0)R6, -CH(R5)N(H)S(0)2R6, -C(=CR5aR5b) N(H)C(0)R6, -CH(R5)R7, -CH(R5)N(H)R7 ou -CH(R5)C(0)N(H)R7 ; R1 représente hydrogène ou alkyle en C1-6.
PCT/EP2020/067759 2019-06-26 2020-06-24 Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17 WO2020260426A1 (fr)

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WO2021170627A1 (fr) 2020-02-25 2021-09-02 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021170631A1 (fr) 2020-02-25 2021-09-02 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021204801A1 (fr) 2020-04-07 2021-10-14 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il -17
WO2021204800A1 (fr) 2020-04-07 2021-10-14 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021250194A1 (fr) 2020-06-12 2021-12-16 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255085A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255174A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255086A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2022096411A1 (fr) 2020-11-09 2022-05-12 UCB Biopharma SRL Dérivés de dicyclopropylméthyle en tant que modulateurs d'il-17
WO2022096412A1 (fr) 2020-11-09 2022-05-12 UCB Biopharma SRL Dérivés de dicyclopropylméthyle en tant que modulateurs d'il-17
WO2022128584A1 (fr) 2020-12-14 2022-06-23 UCB Biopharma SRL Dérivés d'imidazopyridazine utilisés en tant que modulateurs d'il-17
US11377425B1 (en) 2018-12-19 2022-07-05 Leo Pharma A/S Small molecule modulators of IL-17
WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
US11691979B2 (en) 2020-04-30 2023-07-04 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11377425B1 (en) 2018-12-19 2022-07-05 Leo Pharma A/S Small molecule modulators of IL-17
WO2021170631A1 (fr) 2020-02-25 2021-09-02 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021170627A1 (fr) 2020-02-25 2021-09-02 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
WO2021204801A1 (fr) 2020-04-07 2021-10-14 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il -17
WO2021204800A1 (fr) 2020-04-07 2021-10-14 UCB Biopharma SRL Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17
US11702422B2 (en) 2020-04-30 2023-07-18 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
US11691979B2 (en) 2020-04-30 2023-07-04 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
WO2021250194A1 (fr) 2020-06-12 2021-12-16 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255085A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255174A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2021255086A1 (fr) 2020-06-18 2021-12-23 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2022096411A1 (fr) 2020-11-09 2022-05-12 UCB Biopharma SRL Dérivés de dicyclopropylméthyle en tant que modulateurs d'il-17
WO2022096412A1 (fr) 2020-11-09 2022-05-12 UCB Biopharma SRL Dérivés de dicyclopropylméthyle en tant que modulateurs d'il-17
WO2022128584A1 (fr) 2020-12-14 2022-06-23 UCB Biopharma SRL Dérivés d'imidazopyridazine utilisés en tant que modulateurs d'il-17
WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17

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