WO2021204800A1 - Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17 - Google Patents

Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17 Download PDF

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WO2021204800A1
WO2021204800A1 PCT/EP2021/058937 EP2021058937W WO2021204800A1 WO 2021204800 A1 WO2021204800 A1 WO 2021204800A1 EP 2021058937 W EP2021058937 W EP 2021058937W WO 2021204800 A1 WO2021204800 A1 WO 2021204800A1
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mmol
compound
formula
minutes
alkyl
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PCT/EP2021/058937
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Prafulkumar Tulshibhai CHOVATIA
Gregory William HASLETT
Fabien Claude LECOMTE
James Madden
Nathaniel Julius Thomas Monck
Timothy John Norman
Konstantinos RAMPALAKOS
Adam Peter SMALLEY
Robert Straker
Selvaratnam SUGANTHAN
Mengyang XUAN
Zeshan YOUSUF
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UCB Biopharma SRL
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Priority claimed from GBGB2005151.2A external-priority patent/GB202005151D0/en
Priority claimed from GBGB2009912.3A external-priority patent/GB202009912D0/en
Application filed by UCB Biopharma SRL filed Critical UCB Biopharma SRL
Publication of WO2021204800A1 publication Critical patent/WO2021204800A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • 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.
  • WO 2019/138017 describes a class of fused bicyclic imidazole derivatives, including benzimidazole 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:
  • R 1 represents hydrogen or fluoro
  • R 3 represents -COR 3a , -CO 2 R 3a or -SCkR 3® ; or R 3 represents hydrogen; or R 3 represents C 1-6 alkyl or C 3-9 cycloalkyl, either of which groups may be optionally substituted by one or more fluorine atoms;
  • R 3a represents C 1-6 alkyl, optionally substituted by one or more fluorine atoms
  • R 4a represents hydrogen, fluoro or hydroxy
  • R 4® represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents
  • R 4b represents hydrogen, fluoro or C 1-6 alkyl
  • 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.
  • 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).
  • C 3-7 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.
  • 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[3,4-6]-
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • the present invention provides a compound of formula (1-1) or (1-2) or an TV-oxide thereof, or a pharmaceutically acceptable salt thereof:
  • Y represents -0-, -N(R 3 >, -C(R 4a XR 4b > or -S-, wherein R 3 , R 48 and R 4b are as defined above.
  • Z represents imidazolyl, imidazo[l,2-a]pyridinyl, triazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyrazinyl or tetrazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, difluoromethyl, trifluoro(C 1-6 )alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[l.l.l]pentanyl, cyano- bicyclo[l .1.
  • optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, difluoroethyl, trifluoro- (C i-6)alkyl, difluorocyclobutyl, cyclopropylmethyl and cy anobicyclo[ 1.1.1 ]pentanyl .
  • Additional examples include cyano.
  • Selected examples of particular substituents on Z include one, two or (where possible) three substituents independently selected from fluoro, cyano, difluoroethyl, trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl and cyanobicyclo[l.l.l]pentanyl.
  • Typical values of Z include trifluoroethylpyrazolyl, (methylXtrifluoroethyl)- pyrazolyl, pyrazolo[l,5-a]pyridinyl, methylindazolyl, trifluoroethylisoxazolyl, (methyl)- (trifluoroethyl)isoxazolyl, trifluoroethylisothiazolyl, trifluoroethylimidazolyl, cyclopropylmethylimidazolyl, (methylXtrifluoroethyl)imidazolyl, imidazo[ 1 ,2 -a ⁇ - pyridinyl, trifluoroethyltriazolyl, difluorocyclopropyltriazolyl, difluorocyclobutyl- triazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[l.l.l]pentanyltriazolyl
  • Selected values of Z include cyclopropylmethylimidazolyl, fluoroimidazo[l,2-a]- pyridinyl, difluoroethyltriazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicy clo[ 1.1.1 ]pentanyltriazolyl, fluoro[ 1 ,2,4]triazolo- [4,3 -a]pyridinyl, cy ano[ 1 ,2,4]triazolo[4,3 -a]pyridinyl, cy ano[ 1 ,2,4]triazolo[4,3 -a]- pyrazinyl and trifluoroethyltetrazolyl.
  • Illustrative values of Z include cyclopropylmethylimidazolyl, difluoroethyl- triazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[l.l.l]pentanyltriazolyl, fluoro[l,2,4]triazolo[4,3-a]pyridinyl and trifluoroethyltetrazolyl.
  • R 2z represents hydrogen, halogen, cyano, nitro, C 1-6 alkyl, difluoromethyl, trifluoro(Ci-6)alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[l.l.l]pentanyl, cyanobicyclo[l.l.l]- pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(Ci-6)alkyl, C 1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C
  • Suitable values of Z include the groups of formula (Zk), (Zl), (Zn), (Zp), (Zs),
  • Z include the groups of formula (Zk), (Zn), (Zp), (Zs), (Zt), (Zu) and (Zv) as defined above.
  • R 2z represents hydrogen, halogen or cyano. More particularly, R 2z represents hydrogen or halogen. In a first embodiment, R 2z represents hydrogen. In a second embodiment, R 2z represents halogen, especially fluoro. In a third embodiment,
  • R 2z represents cyano
  • Typical values of R 2z include hydrogen, fluoro, methyl, difluoromethyl, trifluoro- ethyl, trifluoropropyl, 2-methyl-3 ,3 ,3 -trifluoropropyl, cyclopropylmethyl, difluoro- cyclopropylmethyl and methylamino. Additional values include cyano.
  • R 3 represents -COR 3a , -COaR 38 or -SOaR 3® ; or R 3 represents hydrogen; or R 3 represents C 1-6 alkyl, which group may be optionally substituted by one or more fluorine atoms, generally by one, two or three fluorine atoms, typically by three fluorine atoms.
  • R 3a represents C 1-6 alkyl or trifluoro(C i-e)alkyl .
  • R 3a represents C 1-6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R 3a represents methyl. In a second aspect of that embodiment, R 3a represents ethyl. In a second embodiment, R 3a represents trifluoro(Ci ⁇ )- alkyl, especially trifluoroethyl.
  • R 4a represents hydrogen or fluoro; or R 4a represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 4a represents hydrogen; or R 4a represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 4a represents hydrogen or C 1-6 alkyl.
  • Typical examples of optional substituents on R 4a include one, two or three substituents independently selected from halogen, cyano, nitro, hydroxy, C 1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, Ci-6 alkylthio, Ci-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C i-6)alkylamino, C 2-6 alkyl- carbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkyl- carbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di- (C i-6)alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulfony
  • substituents on R 4a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoro- ethoxy, methylthio, methylsulfmyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, m ethoxy carbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxy carbonyl, ethoxy carbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino- sulfonyl and dimethylsulfoxi
  • Apposite examples of particular substituents on R 4a include one, two or three substituents independently selected from fluoro and ethylsulfonyl.
  • Suitable examples of particular substituents on R 4a include one, two or three substituents independently selected from fluoro.
  • Typical values of R 4a include hydrogen, methyl, difluoroethyl, trifluoroethyl and ethylsulfonylethyl .
  • R 4a particularly values include hydrogen, methyl, difluoroethyl and trifluoroethyl. Suitable values of R 4a include hydrogen and methyl.
  • R 4b represents hydrogen.
  • R* represents fluoro.
  • R 4b represents C 1-6 alkyl, especially methyl or ethyl.
  • R* represents methyl.
  • R* represents ethyl.
  • R 4a and R* may together form an optionally substituted spiro linkage.
  • R 4a and R 46 when taken together with the carbon atom to which they are both attached, may represent C 3-7 cycloalkyl or C 3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent a cyclopentyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent a cyclohexyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent C 3-7 heterocycloalkyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent an oxetanyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R* when taken together with the carbon atom to which they are both attached, may suitably represent a pyrrolidinyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may suitably represent a tetrahydropyranyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 46 when taken together with the carbon atom to which they are both attached, may represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • R 4a and R 4b when taken together with the carbon atom to which they are both attached, may represent cyclobutyl, cyclohexyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • Apposite examples of optional substituents on the spirocycle formed by R 4a and R 4b include C 1-6 alkyl, halogen, trifluoroethyl and C 2-6 alkoxycarbonyl, especially halogen.
  • Suitable examples of optional substituents on the spirocycle formed by R 4a and R* include halogen and C 2-6 alkoxycarbonyl.
  • Typical examples of particular substituents on the spirocycle formed by R 4® and R 4b include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, m ethoxy carbonyl, ethoxy- carbonyl, amino, methylamino and dimethylamino.
  • Apposite examples of particular substituents on the spirocycle formed by R 4a and R 4b include methyl, fluoro, trifluoroethyl and methoxycarbonyl, especially fluoro.
  • Suitable examples of particular substituents on the spirocycle formed by R 4a and R 4b include fluoro and methoxycarbonyl.
  • Selected examples of the spirocycle formed by R 4a and R 4b include cyclopropyl and difluorocyclohexyl.
  • R 5 represents methyl or ethyl. In a first embodiment, R 5 represents methyl. In a second embodiment, R 5 represents ethyl.
  • R 6 represents -OR 6® ; or R 6 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 6 represents optionally substituted C 1-6 alkyl. In a second embodiment, R 6 represents optionally substituted C 3-9 cycloalkyl. In a third embodiment, R 6 represents optionally substituted C 3-9 cycloalkyl(C i-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 C 3-7 heterocycloalkyl. In a seventh embodiment, R 6 represents optionally substituted C 3-7 heterocycloalkyl(Ci-6)alkyl. In an eighth embodiment, R 6 represents optionally substituted heteroaryl.
  • R 6 represents optionally substituted heteroary 1(C i-e)alkyl .
  • R 6 represents -OR 6® .
  • R 6 represents -NR 6a R 6b .
  • R 6 examples include -OR 6® or -NR ⁇ R 66 ; 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.
  • R 6 examples include -OR 6® ; and 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.
  • Apposite values of R 6 include pyrazolyl and oxadiazolyl, either of which groups may be optionally substituted by one or more substituents.
  • R 6 include oxadiazolyl, 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, C 1-6 alkyl, trifluoro- methyl, phenyl, fluorophenyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, C 1-6 alkoxy, difluoro- methoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, amino(Ci-6)alkyl, C 1-6 alkylamino, di(C i-6)alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C 2-6 alkylcarbonylamino, C 2-6 alkyl carbonyl amino(Ci-6)alkyl, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulf
  • Suitable examples of optional substituents on R 6 include one, two or three substituents independently selected from C 1-6 alkyl.
  • substituents on R 6 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, m ethoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl- amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, m ethoxy carbonylamino, methylsulfonyl- amino, formyl, ace
  • Suitable examples of particular substituents on R 6 include one, two or three substituents independently selected from methyl and ethyl.
  • R 6 Illustrative examples of particular values of R 6 include methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxy ethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl- cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chloro- phenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethyl-
  • Favoured values of R 6 include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl.
  • R 6 include methyloxadiazolyl and ethyloxadiazolyl.
  • R 6® represents C 1-6 alkyl. In a second embodiment, R 6® represents optionally substituted C 3-9 cycloalkyl. Typically, R 6® represents C 1-6 alkyl; or R 6a represents cyclobutyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 6® include one, two or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoro- methyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoro- methoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, amino(Ci-6)alkyl, Ci-6 alkylamino, di(C i-6)alkyl amino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbon
  • substituents on R 6® include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetyl amino, m ethoxy carbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxy carbonyl, tert-butoxy carbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl,
  • R 66 represents hydrogen or methyl.
  • R 66 represents hydrogen. In a second embodiment, R 66 represents C 1-6 alkyl, especially methyl.
  • R 60 represents hydrogen or methyl.
  • R 60 represents hydrogen. In a second embodiment, R 60 represents C 1-6 alkyl, especially methyl.
  • the moiety -NR ⁇ R 60 may suitably 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.
  • Selected examples of suitable substituents on the heterocyclic moiety -NR 6 ⁇ 66 include C 1-6 alkyl, C 1-6 alkylsulfonyl, hydroxy, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonyl- amino, C 2-6 alkyl carbonylamino(C i-6)alkyl, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonyl- amino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR 6 ⁇ 66 include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxy carbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulfonylamino and aminocarbonyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and A-oxides thereof, and pharmaceutically acceptable salts thereof: wherein
  • R 16 represents methyl or ethyl; and A, E, Z and R 4a are as defined above. In a first embodiment, R 16 represents methyl. In a second embodiment, R 16 represents ethyl.
  • A, E, Z, R 4a and R 16 are as defined above.
  • 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, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie’s Disease, coeliac disease, gall bladder disease, Pilonidal disease, periton
  • 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, comeal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, comeal neovascularization, keratoprosthesis surgery, comeal 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 includes keratoconjunctivitis sicca (KCS), Sjogren syndrome, 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.
  • KCS keratoconjunctivitis sicca
  • Sjogren syndrome Sjogren syndrome-associated keratoconjunctivitis sicca
  • non-Sjogren syndrome- associated keratoconjunctivitis sicca keratitis sicca
  • sicca syndrome xerophthalmia
  • tear film disorder decreased tear production
  • ATD aqueous tear deficiency
  • meibomian gland dysfunction meibomian gland dysfunction
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondyloarthritis 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.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as 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); or wetting agents (e.g. sodium lauryl sulphate).
  • 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
  • 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.
  • 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 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, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • 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, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium 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 coadministered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.
  • Suitable coupling agents include 1 -[bis(dimethylamino)methylene]- 1/f- 1,2,3- triazolo[4,5-6]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 N,N-diisopropylethylamine, or pyridine.
  • the reaction is conveniently performed at ambient or elevated temperature in a suitable solvent, e.g.
  • the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R ⁇ -OH with N,N-disuccinimidyl 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 ( ⁇ ) 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, or an organic nitrile solvent such as acetonitrile.
  • a suitable solvent e.g. a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.
  • the intermediates of formula ( ⁇ ) above may be prepared by removal of the N- protecting group R p from a compound of formula (TV): wherein A, E, Y and Z are as defined above, and R p represents a /V-protecting group.
  • the A-protecting group R p may be benzyloxycarbonyl, in which case the removal thereof may conveniently be effected by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst, e.g. palladium on charcoal, or palladium hydroxide on charcoal.
  • a hydrogenation catalyst e.g. palladium on charcoal, or palladium hydroxide on charcoal.
  • the compounds of formula (I) above wherein Y represents -N(R 3 )-, in which R 3 represents -COR 3a may be prepared by a process which comprises reacting a carboxylic acid of formula R 3a -C02H, wherein R 3a is as defined above, with the appropriate compound of formula (I) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen; under conditions analogous to those described above for the reaction between compound ( ⁇ ) and a carboxylic acid of formula R 6 -C02H.
  • the intermediates of formula (TV) above wherein Y represents -N(R 3 )-, in which R 3 represents -COR 3a may be prepared by reacting a carboxylic acid of formula R 3a -C02H, wherein R 3a is as defined above, with the appropriate compound of formula (TV) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C02H.
  • the compounds of formula (I) above wherein Y represents -N(R 3 )-, in which R 3 represents -COaR 38 may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen, with a compound of formula L 1a -C02R 3a , wherein L 1a represents a suitable leaving group, and R 3a is as defined above.
  • the leaving group L 1a is suitably a halogen atom, e.g. chloro.
  • the leaving group L 1a may suitably be 2,5-dioxopyrrolidin-l-yloxy.
  • the compounds of formula (I) above wherein Y represents -N(R 3 )-, in which R 3 represents -SO 2 R 3a may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen, with a compound of formula L 1b -S02R 3a , wherein L 1b represents a suitable leaving group, and R 3a is as defined above.
  • the leaving group L 1b is suitably a halogen atom, e.g. chloro.
  • Suitable bases include organic amines, e.g. a trialkylamine such as ⁇ A-diisopropylethylamine or triethylamine.
  • the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • the compounds of formula (I) above wherein Y represents -N(R 3 )-, in which R 3 represents C 1-6 alkyl, optionally substituted by one or more fluorine atoms may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen, with a compound of formula L 2 -R 3b , wherein L 2 represents a suitable leaving group, and R 3b represents C 1-6 alkyl, optionally substituted by one or more fluorine atoms.
  • the intermediates of formula (TV) above wherein Y represents -N(R 3 )-, in which R 3 represents C 1-6 alkyl, optionally substituted by one or more fluorine atoms may be prepared by reacting the appropriate compound of formula (TV) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen, with a compound of formula L 2 -R 3b , wherein L 2 and R 3b are as defined above.
  • the leaving group L 2 may suitably be a sulfonyloxy derivative, e.g. trifluoro- methanesulfonyloxy.
  • the reaction is conveniently accomplished in the presence of a base.
  • bases include organic amines, e.g. a trialkylamine such as triethylamine.
  • the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • the compounds of formula (I) above wherein Y represents -N(R 3 )-, in which R 3 represents C 3-9 cycloalkyl, optionally substituted by one or more fluorine atoms (e.g. 3,3- difluorocyclobutyl), may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen, with the appropriate cycloalkanone, optionally substituted by one or more fluorine atoms (e.g. 3,3-difluorocyclobutanone), in the presence of a reducing agent.
  • the reducing agent is suitably sodium triacetoxyborohydride.
  • the reaction is conveniently performed in the presence of acetic acid.
  • the compounds of formula (I) above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen, may conveniently be prepared by reacting the corresponding compound of formula (I) wherein Y represents -N(R 3 )-, in which R 3 represents -SO 2 R 3a and R 3a represents fert-butyl, with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the intermediates of formula (TV) above wherein Y represents -N(R 3 )-, in which R 3 represents hydrogen may conveniently be prepared by reacting the corresponding compound of formula (TV) wherein Y represents -N(R 3 )-, in which R 3 represents -SO 2 R 3a and R 3a represents tert-butyl, with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the compounds of formula (I) above may be prepared by a process which comprises cyclising a compound of formula (VA) or (VB): wherein A, E, Y, Z and R 6 are as defined above.
  • Cyclisation of compound (VA) or (VB) is conveniently effected by heating in the presence of a suitable medium, e.g. an acid such as acetic acid, or trifluoroacetic acid.
  • a suitable medium e.g. an acid such as acetic acid, or trifluoroacetic acid.
  • the intermediates of formula (VA) or (VB) above may be prepared by reacting a compound of formula (VI) with a carboxylic acid of formula (VII) or a salt thereof, e.g. a lithium salt thereof:
  • step (i) Alternative coupling agents that may usefully be employed in step (i) include N- (3-dimethylaminopropyl)-/V , -ethylcarbodiimide hydrochloride (EDC.HC1) and O- (benzotriazol- 1 -ylJ-V ⁇ A ⁇ /VV/V-tetramethyluronium hexafluorophosphate (HBTU).
  • EDC.HC1 -ethylcarbodiimide hydrochloride
  • HBTU benzotriazol- 1 -ylJ-V ⁇ A ⁇ /VV/V-tetramethyluronium 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 (VII).
  • 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 C 1-6 alkanol such as methanol.
  • a suitable organic solvent e.g. a cyclic ether such as tetrahydrofuran, optionally in admixture with a C 1-6 alkanol such as methanol.
  • the intermediates of formula (TV) above may be prepared by a two-step procedure which comprises the following steps:
  • the W-protecting group R q will suitably be 2-(trimethylsilyl)ethoxymethyl.
  • Step (i) is suitably effected by treatment of compound (X) with a base, e.g. an organic base such as w-butyllithium, followed by reaction with compound (XI).
  • a base e.g. an organic base such as w-butyllithium
  • the reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • step (ii) removal of the tert-butylsulfinyl group and the W-protecting group R q from compound ( ⁇ ) in step (ii) may both be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic 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, or an organic amine such as N,N-diisopropylethylamine.
  • a base e.g. an inorganic base such as sodium hydride, or an organic amine such as N,N-diisopropylethylamine.
  • the intermediate of formula (XI) above may be prepared by reacting 4,4- difluorocyclohexyl carboxaldehyde with 2-methyl-2-propanesulfinamide.
  • the reaction is suitably effected in the presence of pyridinium /7-toluenesulfonate and magnesium sulfate.
  • reaction is conveniently carried out at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • a suitable solvent e.g. a chlorinated solvent such as dichloromethane.
  • the compounds of formula (I) wherein Z represents a group of formula (Zs) as defined above, in which R 2z is hydrogen may be prepared by a process which comprises reacting a compound of formula R lz -NI1 ⁇ 2 and a trialkyl orthoformate HCCO-Alk 1 ⁇ with a compound of formula (XIII): wherein A, E, Y, R 6 , R lz and Aik 1 are as defined above.
  • the reaction is conveniently performed at an elevated temperature in the presence of acetic acid.
  • the reaction may typically be carried out in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane.
  • reaction is conveniently performed at an elevated temperature in a suitable solvent, e.g. a C 1-6 alkanol such as ethanol.
  • a suitable solvent e.g. a C 1-6 alkanol such as ethanol.
  • the saponification reaction in step (i) will generally be effected by treatment with a base.
  • Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide.
  • Suitable bases of use in step (iii) include organic amines, e.g. a trialkylamine such as triethylamine.
  • the reaction is conveniently performed at ambient temperature in the presence of hexachloroethane and a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a compound 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 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 ( ⁇ ) and a carboxylic acid of formula R 6 -C02H.
  • a compound comprising a halogen atom 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 [1,1 '-bis(diphenylphosphino)fenOcene]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 comprising a halogen atom e.g. bromo
  • a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately substituted bromoaryl or bromoheteroaryl derivative.
  • Step (i) is conveniently effected in the presence of a transition metal catalyst such as [l,l'-bis(diphenylphosphino)fenOcene]- dichloropalladium(n), and potassium acetate.
  • a compound comprising a cyano (-CN) moiety may be converted into the corresponding compound comprising a 1 -ami noethyl moiety by a two-step process which comprises: (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(TV) 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.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • 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. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
  • 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 IL-17 induced IL-6 release from human dermal fibroblasts. Indeed, when tested in the HDF cell line assay described below, compounds of the present invention exhibit an ICso value of 1500 nM or less, generally of 500 nM or less, usually of 100 nM or less, typically of 50 nM or less, suitably of 25 nM or less, ideally of 20 nM or less, and preferably of 15 nM or less (the skilled person will appreciate that a lower ICso figure denotes a more active compound).
  • 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 TNFo, a synergistic effect can be seen in the production of inflammatory cytokines, i.e. IL-6.
  • HDF normal human dermal fibroblasts
  • 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 ⁇ L 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
  • 10 ⁇ L from the aqueous dilution plate was transferred to the reagent plate containing 30 ⁇ L of the diluted cytokines, to give a 2.5% DMSO solution.
  • the compounds were incubated with the cytokine mixtures for 1 h or 5 h at 37°C (incubation times for specific test compounds are indicated in the Table below). After the incubation, 10 ⁇ L was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C/5% CO2.
  • HATU l-[bis(dimethylamino)methylene]-l/f-l,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate
  • XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
  • Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
  • h hour r.t: room temperature
  • M mass RT: retention time
  • PDA spectrum range: 210-420 nm; step: 1 nm
  • the mixture was stirred at 45°C for 16 h, then washed with water (75 mL) and saturated aqueous sodium bicarbonate solution (2 x 75 mL). The combined aqueous washings were extracted with DCM (100 mL). The organic fractions were combined, dried over sodium sulfate and concentrated.
  • Tebbe reagent (1.7 mL, 0.85 mmol) was added to a solution of Intermediate 37 (266 mg, 0.42 mmol) in THF (10 mL) under nitrogen. The mixture was heated at 80°C for 3 h, then allowed to cool to room temperature. The mixture was quenched with saturated aqueous NH4CI solution (10 mL) and diluted with EtOAc (20 mL). The layers were separated. The aqueous layer was further diluted with brine (25 mL) and water (50 mL), and extracted with EtOAc (30 mL). The combined organic extracts were dried (Na2S04) and concentrated in vacuo.
  • the mixture was retreated with 2- azido- 1,1,1 -trifluoroethane in TBME (0.5M, 0.12 mL, 0.058 mmol) and chloro(l,2,3,4,5- pentamethylcyclopenta-2,4-dien- 1 -yl)bis(triphenylphosphine)ruthenium (5.0 mg, 6.28 pmol), then stirred at 60°C for 30 minutes.
  • the mixture was concentrated, then purified by flash column chromatography, eluting with a gradient of 15-35% EtOAc in heptanes, to afford the title compound (297 mg, 67%, 85% purity) as a dark yellow gum.
  • the ice bath was removed, and the reaction mixture was stirred for 18 h.
  • the reaction mixture was cooled to 0°C and re-treated with pyridine (0.95 mL, 11.8 mmol) and acetyl chloride (0.72 mL, 10.1 mmol).
  • the ice bath was removed and the reaction mixture was stirred for 2 h, then diluted with saturated aqueous ammonium chloride solution (25 mL).
  • the organic layer was separated and washed with brine (20 mL), then dried (MgSCh).
  • the residue was purified by silica column chromatography, eluting with a gradient of ethyl acetate in heptane (0-100%).
  • the material was further purified by sonicating in a mixture of diethyl ether (10 mL) and heptane (60 mL). The solid was filtered off, then washed with heptane (30 mL) and dried, to afford the title compound (7.48 g, 58% yield corrected for a purity of 88%) as a white solid.
  • HATU (1.24 g, 3.26 mmol) was added to a solution of 4-methyl- 1 ,2,5-oxadiazole- 3-carboxylic acid (0.42 g, 3.26 mmol) and DIPEA (1.4 mL, 8.15 mmol) in DCM (50 mL) at r.t.
  • the resulting material was sonicated for 5 minutes and stirred for 10 minutes at r.t, then a solution of Intermediate 107 (95%, 1.20 g, 2.72 mmol) in DCM (10 mL) was added.
  • the reaction mixture was stirred at r.t.
  • Aqueous HC1 (2M, 4.0 mL) was added to a stirred solution of Intermediate 120 (270 mg, 0.32 mmol) in ethanol (8 mL). The reaction mixture was stirred at 65°C for 5 h, then additional 2M aqueous HC1 (1 mL) was added. The resulting solution was stirred at 65°C overnight, then concentrated, diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 x 10 mL).
  • HATU 51 mg, 0.13 mmol was added to a stirred solution of DIPEA (117 ⁇ L , 0.67 mmol), Intermediate 47 (86% purity, 60 mg, 0.11 mmol) and 4-methyl-l,2,5- oxadiazole-3 -carboxylic acid (16 mg, 0.12 mmol) in DCM (1.5 mL) at r.t. The mixture was stirred for 2 h, then washed with water (5 mL). The organic fraction was passed through a phase separator, then concentrated. The residue was dissolved in 1:1 DMSO: MeOH (2 mL) and purified via acidic, reverse-phase HPLC (Separation Method 3), then freeze-dried, to afford a white powder (31.5 mg). Chiral separation of the diastereomers
  • Example 11 ⁇ H (400 MHz, CD 3 OD) 7.90 (s, 1H), 7.37 (d, 78.1 Hz, 1H), 7.03 (dd, 78.4, 6.6 Hz, 1H), 5.28 (d, 78.7 Hz, 1H), 5.25-5.16 (m, 1H), 4.84-4.74 (m, 2H), 2.55 (s, 3H),
  • Example 15 chiral LC RT 3.36 minutes
  • Example 16 chiral LC RT 4.08 minutes
  • Example 16 ⁇ H (400 MHz, DMSO-de) 8.08 (s, 1H), 7.86 (dd, J 10.0, 5.1 Hz, 1H), 7.43 (ddd, J 10.1, 7.9, 2.2 Hz, 1H), 7.12 (s, 1H), 6.59 (s, 1H), 5.06 (dd, .734.9, 7.5 Hz, 2H), 2.49 (s, 3H), 2.20 (s, 1H), 2.10-1.92 (m, 2H), 1.83 (d, .77.0 Hz, 5H), 1.45 (d, J 13.3 Hz, 1H), 1.25 (d, 78.0 Hz, 2H).
  • LCMS Methodhod 5 5): [M+H] + m/z 557, [M-H] + m/z 555, RT 1.64 minutes.
  • Example 17 ⁇ ⁇ H (400 MHz, DMSO-de) 12.77 (s, 1H), 9.64 (s, 1H), 8.14 (s, 1H), 7.31 (s, 1H), 7.19-7.03 (m, 1H), 6.15-5.76 (m, 1H), 5.45 (dt, J 18.3, 9.1 Hz, 1H), 5.24-4.96 (m,
  • Example 18 ⁇ H (400 MHz, DMSO-de) 12.77 (s, 1H), 9.65 (s, 1H), 8.14 (s, 1H), 7.30 (s, 1H), 7.18-7.03 (m, 1H), 6.15-5.76 (m, 1H), 5.46 (dq, J 17.8, 8.9 Hz, 1H), 5.26-4.97 (m, 2H), 4.84 (t, Jin Hz, 1H), 2.84-2.64 (m, 2H), 2.47 (s, 3H), 2.35-2.24 (m, 1H), 2.02 (d, J 39.7 Hz, 3H), 1.91-1.68 (m, 2H), 1.61-1.47 (m, 1H), 1.43-1.16 (m, 2H).
  • Example 19 ⁇ H (400 MHz, CD 3 OD) 7.99 (s, 1H), 7.36 (d, J8.4 Hz, 1H), 7.08 (dd, J8.4, 6.6 Hz, 1H), 6.26-5.94 (m, 1H), 5.94-5.62 (m, 1H), 5.24 (d, 78.7 Hz, 1H), 4.95-4.88 (m, 1H), 4.77-4.62 (m, 1H), 4.59-4.42 (m, 1H), 2.83-2.63 (m, 2H), 2.51 (s, 3H), 2.40-2.24 (m, 1H), 2.16-1.96 (m, 3H), 1.96-1.66 (m, 2H), 1.61-1.35 (m, 3H).
  • Example 23 ⁇ H (500 MHz, DMSO-de) 12.78 (s, 1H), 9.78-9.52 (m, 1H), 8.12 (s, 1H), 7.46-7.26 (m, 1H), 7.10 (dd, 78.3, 6.7 Hz, 1H), 6.44-6.18 (m, 1H), 5.24-5.12 (m, 1H), 4.93 (t, 77.4 Hz, 1H), 4.91-4.77 (m, 1H), 4.60-4.44 (m, 1H), 3.30-3.17 (m, 2H), 2.47 (s, 3H), 2.35-2.23 (m, 1H), 2.10-1.91 (m, 3H), 1.88-1.71 (m, 2H), 1.59-1.51 (m, 1H), 1.46- 1.22 (m, 2H).
  • Example 23 ⁇ H (500 MHz, DMSO-de) 13.19-12.67 (m, 1H), 9.76-9.49 (m, 1H), 8.12 (s, 1H), 7.46-7.26 (m, 1H), 7.10 (dd, 78.3, 6.7 Hz, 1H), 6.32 (tt, 754.2, 3.2 Hz, 1H), 5.18 (t, 77.7 Hz, 1H), 4.93 (t, 77.4 Hz, 1H), 4.85 (qd, 715.9, 2.7 Hz, 1H), 4.59-4.45 (m, 1H), 3.24 (dd, 718.4, 10.8 Hz, 2H), 2.47 (s, 3H), 2.35-2.25 (m, 1H), 2.10-1.91 (m, 3H), 1.90-
  • Example 26 The resulting impure yellow oil (200 mg) was purified by basic Cl 8 reverse-phase HPLC, followed by chiral SFC (Chiralpak IH, 10% methanol + 0.1% NH4OH) to afford Example 26 (3.7 mg, 2.9%) and Example 27 (5.0 mg, 4.0%).
  • Example 26 LCMS (Method 2): [M+H] + m/z 632, RT 1.86 minutes.
  • LCMS (Method 6) [M+H] + m/z 632, RT 1.85 minutes.
  • Analytical chiral LC (Chiralpak IH, 4.6 x 150 mm, 35°C, 15% MeOH (+ 0.1% NH 4 OH), 3 mL/minute) RT 1.92 minutes.
  • Example 31 (10.1 mg) and Example 32 (8.1 mg).
  • Example 31 ⁇ H (400 MHz, CD3OD) 8.01-7.93 (m, 1H), 7.83 (s, 1H), 7.58 (dd, 79.8, 5.0 Hz, 1H), 7.34-7.20 (m, 2H), 7.09-7.01 (m, 1H), 6.09-5.69 (m, 1H), 5.24 (d, 78.7 Hz, 1H), 5.06-4.95 (m, 1H), 3.01-2.71 (m, 2H), 2.51 (s, 3H), 2.38-2.25 (m, 1H), 2.17-1.97 (m, 3H), 1.93-1.68 (m, 2H), 1.65-1.35 (m, 3H).
  • Example 32 ⁇ H (400 MHz, CD3OD) 8.02-7.98 (m, 1H), 7.85 (s, 1H), 7.61 (dd, 79.9, 4.8 Hz, 1H), 7.37-7.23 (m, 2H), 7.12-7.03 (m, 1H), 6.13-5.65 (m, 1H), 5.26 (d, 78.7 Hz, 1H), 5.08-4.97 (m, 1H), 3.01-2.71 (m, 2H), 2.52 (s, 3H), 2.41-2.26 (m, 1H), 2.20-1.99 (m, 3H), 1.94-1.71 (m, 2H), 1.66-1.39 (m, 3H).

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Abstract

L'invention concerne une série de dérivés de 4,4-difluorocyclohexyl substitués tels que définis dans la description, étant de puissants modulateurs de l'activité d'IL -17 humaine, étant par conséquent utiles dans le traitement et/ou la prévention de diverses maladies humaines, y compris des troubles inflammatoires et auto-immuns.
PCT/EP2021/058937 2020-04-07 2021-04-06 Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17 WO2021204800A1 (fr)

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CN115260167A (zh) * 2022-08-01 2022-11-01 陕西盘龙药业集团股份有限公司 一种3-四唑基甲基-1,3,5-三嗪-2,4-二酮类化合物及其制备方法和应用
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
WO2024017880A1 (fr) 2022-07-22 2024-01-25 UCB Biopharma SRL Dérivés d'imidazotriazine utilisés comme modulateurs de l'il-17

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11691979B2 (en) 2020-04-30 2023-07-04 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
US11702422B2 (en) 2020-04-30 2023-07-18 Janssen Pharmaceutica Nv Imidazopyridazines as 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
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2024017880A1 (fr) 2022-07-22 2024-01-25 UCB Biopharma SRL Dérivés d'imidazotriazine utilisés comme modulateurs de l'il-17
CN115260167A (zh) * 2022-08-01 2022-11-01 陕西盘龙药业集团股份有限公司 一种3-四唑基甲基-1,3,5-三嗪-2,4-二酮类化合物及其制备方法和应用

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