WO2021170631A1 - 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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WO2021170631A1
WO2021170631A1 PCT/EP2021/054523 EP2021054523W WO2021170631A1 WO 2021170631 A1 WO2021170631 A1 WO 2021170631A1 EP 2021054523 W EP2021054523 W EP 2021054523W WO 2021170631 A1 WO2021170631 A1 WO 2021170631A1
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formula
compound
mmol
alkyl
optionally substituted
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PCT/EP2021/054523
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Gareth Neil BRACE
Rose Elizabeth CHAPPELL
Prafulkumar Tulshibhai CHOVATIA
Ellen Olivia GALLIMORE
Helen Tracey Horsley
James Andrew Johnson
Joanna Rachel Quincey
James Thomas Reuberson
Giancarlo Trani
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UCB Biopharma SRL
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Priority claimed from GBGB2002636.5A external-priority patent/GB202002636D0/en
Priority claimed from GBGB2009184.9A external-priority patent/GB202009184D0/en
Application filed by UCB Biopharma SRL filed Critical UCB Biopharma SRL
Publication of WO2021170631A1 publication Critical patent/WO2021170631A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted 4,4-difluorocyclohexyl derivatives. 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).
  • IL-17B to IL-17F 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 compounds.
  • 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 and WO 2020/011731 describe spirocyclic molecules 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.
  • 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.
  • WO 2019/223718 describes heterocyclic compounds, including benzimidazole derivatives, that are stated to inhibit IL-17A and to be useful as immunomodulators.
  • PCT/EP2019/082779 both published on 18 June 2020 as WO 2020/120140 and WO 2020/120141 respectively
  • co-pending international patent applications PCT/IB2020/055970, PCT/EP2020/067758 and PCT/EP2020/067759 all published on 30 December 2020 as WO 2020/261141, WO 2020/260425 and WO 2020/260426 respectively, claiming priority from United Kingdom patent applications 1909190.9,
  • the compounds in accordance with the present invention also possess other notable advantages.
  • the compounds of the invention display valuable metabolic stability, as determined in either microsomal or hepatocyte incubations.
  • the present invention provides a compound of formula (I) or an A-oxide thereof, or a pharmaceutically acceptable salt thereof: wherein
  • A represents C-R 1 or N
  • E represents C-R 2 or N
  • Z represents a group of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg) or (Zh):
  • R 1 represents hydrogen or fluoro
  • R 2 represents hydrogen or fluoro
  • R 3 represents -NR 3a R 3b ; or R 3 represents a group of formula (Wa): the asterisk (*) represents the point of attachment to the remainder of the molecule;
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 3 to 6 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom; or
  • W represents the residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom; or
  • W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5 to 10 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom;
  • R 3a represents hydrogen or Ci- 6 alkyl;
  • R 3b represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms;
  • R 4 represents -COR 4a , -C02R 4a or -S02R 4b ; or R 4 represents hydrogen; or R 4 represents Ci- 6 alkyl or C3-9 cycloalkyl, either of which groups may be optionally substituted by one or more fluorine atoms; R 4a represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms;
  • R 4b represents Ci- 6 alkyl
  • R 5a represents hydrogen or fluoro
  • R 5b represents hydrogen or fluoro
  • 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, 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 a represents Ci- 6 alkyl; or R 6a represents C3-9 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 Ci- 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.
  • 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 pharmaceutically acceptable salt thereof.
  • 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. Generally, such groups will be unsubstituted, or substituted by one, two, three or four 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.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of formula (I) or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use , ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002.
  • 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, «-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, /e/V-butyl, 2,2-dimethylpropyl and 3- methylbutyl.
  • 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.
  • 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, benzoxa
  • 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, pyrrolo[2,3-Z>]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, thiazo
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
  • 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 3 ⁇ 4.
  • 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.
  • A represents C-R 1 . In another embodiment, A represents N.
  • E represents C-R 2 . In another embodiment, E represents N.
  • A represents C-R 1 or N; and E represents C-R 2 .
  • A represents C-R 1 ; and E represents C-R 2 .
  • the present invention provides a compound of formula (1-1) or (1-2) or an
  • Z represents a group of formula (Za).
  • Z represents a group of formula (Zb).
  • Z represents a group of formula (Zc).
  • Z represents a group of formula (Zd).
  • Z represents a group of formula (Ze).
  • Z represents a group of formula (Zf).
  • Z represents a group of formula (Zg).
  • Z represents a group of formula (Zh).
  • Z represents a group of formula (Zb), (Zc), (Zd) or (Zf).
  • Y represents O, N-R 4 or S(0)2, wherein R 4 is as defined above.
  • Y represents N-R 4 .
  • Y represents O. In a second embodiment, Y represents N-R 4 . In a third embodiment, Y represents CR 5a R 5b . In a fourth embodiment, Y represents S. In a fifth embodiment, Y represents S(O). In a sixth embodiment, Y represents S(0)2. In a seventh embodiment, Y represents S(0)(N-R 7 ).
  • R 1 represents hydrogen. In a second embodiment, R 1 represents fluoro.
  • R 2 represents hydrogen. In a second embodiment, R 2 represents fluoro.
  • R 3 represents -NR 3a R 3b .
  • R 3 represents a group of formula (Wa) as defined above.
  • R 3a represents hydrogen.
  • R 3a represents Ci- 6 alkyl, especially methyl or ethyl.
  • R 3a represents methyl.
  • R 3a represents ethyl.
  • R 3b represents unsubstituted Ci- 6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R 3b represents methyl. In a second aspect of that embodiment, R 3b represents ethyl. In a second embodiment, R 3b represents Ci- 6 alkyl substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms.
  • R 3b represents Ci- 6 alkyl substituted by three fluorine atoms. Examples of that aspect include l,l,l-trifluoroprop-2-yl.
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 3 to 6 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
  • W represents the residue of an optionally substituted saturated bicyclic ring system containing 4 to 10 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
  • W represents the residue of an optionally substituted saturated bicyclic ring system containing 5, 6 or 7 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
  • W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5 to 10 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
  • W represents the residue of an optionally substituted saturated spirocyclic ring system containing 5, 6 or 7 carbon atoms, one nitrogen atom, and 0, 1, 2 or 3 additional heteroatoms independently selected from N, O and S, but containing no more than one O or S atom.
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms, one nitrogen atom, and 0 or 1 oxygen atom(s).
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms and one nitrogen atom.
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 3 carbon atoms and one nitrogen atom.
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms and one nitrogen atom.
  • W represents the residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms, one nitrogen atom, and one oxygen atom.
  • the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and no additional heteroatoms (i.e. it is an optionally substituted azetidin-l-yl, pyrrolidin-l-yl, piperidin-l-yl or hexahydroazepin-1- yl ring).
  • the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and one additional heteroatom selected from N, O and S.
  • the group of formula (Wa) is an optionally substituted morpholin-4-yl moiety.
  • the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and two additional heteroatoms selected from N, O and S, of which not more than one is O or S.
  • the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and three additional heteroatoms selected from N, O and S, of which not more than one is O or S.
  • Typical values of the group of formula (Wa) include azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, thiazolidin-3-yl, isothiazolidin-2-yl, imidazolidin-l-yl, piperidin-l-yl, piperazin-l-yl, homopiperazin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-l-yl, [l,4]oxazepan-4-yl, [l,4]diazepan-l-yl, [l,4]thiadiazepan-4-yl, azocan-l-yl, 3-azabicyclo- [3.1.0]hexan-3-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, 6-azabicyclo[3.2.0]heptan-6-yl,
  • the group of formula (Wa) is unsubstituted.
  • the group of formula (Wa) is substituted by one or more substituents, typically by one to six substituents, suitably by two to four substituents.
  • the group of formula (Wa) is substituted by one substituent.
  • the group of formula (Wa) is substituted by two substituents.
  • the group of formula (Wa) is substituted by three substituents.
  • the group of formula (Wa) is substituted by four substituents.
  • the group of formula (Wa) is substituted by five substituents.
  • the group of formula (Wa) is substituted by six substituents.
  • Typical examples of optional substituents on the group of formula (Wa) include halogen, Ci- 6 alkyl, trifluoromethyl, hydroxy, hydroxy(Ci- 6 )alkyl, Ci- 6 alkoxy, difluoro- methoxy, trifluoromethoxy, Ci- 6 alkoxy(Ci- 6 )alkyl, Ci- 6 alkylthio, Ci- 6 alkylsulfonyl, cyano, oxo, formyl, C2-6 alkylcarbonyl, carboxy, carboxy(Ci- 6 )alkyl, C2-6 alkoxy carbonyl, C2-6 alkoxycarbonyl(Ci- 6 )alkyl, amino, amino(Ci- 6 )alkyl, Ci- 6 alkylamino, di(Ci- 6 )alkyl- amino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci- 6 alkylsulfony
  • Typical examples of particular substituents on the group of formula (Wa) include fluoro, chloro, bromo, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulfonyl, cyano, oxo, formyl, acetyl, ethyl carbonyl, tert- butylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, /c/V-butoxy- carbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methyl- amino, ethylamino, dimethylamino, acetylamino, /er/-butoxycarbonylamino, methyl-
  • Suitable examples of particular substituents on the group of formula (Wa) include fluoro.
  • Typical values of the group of formula (Wa) include difluoroazetidin-l-yl, tetrafluoropyrrolidin-l-yl and tetrafluoromorpholin-4-yl.
  • R 4 represents -COR 4a , -CCER 43 or -S02R 4b ; or R 4 represents hydrogen; or R 4 represents Ci- 6 alkyl, which group may be optionally substituted by one or more fluorine atoms, generally by one, two or three fluorine atoms, typically by two fluorine atoms.
  • R 4 represents -COR 4a .
  • R 4 represents -CCER 43
  • R 4 represents -CCER 43
  • R 4 represents hydrogen.
  • R 4 represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms.
  • R 4 represents unsubstituted Ci- 6 alkyl, especially methyl or ethyl.
  • R 4 represents Ci- 6 alkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms.
  • R 4 represents C3-9 cycloalkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms.
  • R 4 represents unsubstituted C3-9 cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 4 represents C3-9 cycloalkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms. Examples of that aspect include difluorocyclobutyl .
  • R 4 represents -COR 4a , -CCER 43 or -S02R 4b ; or R 4 represents hydrogen; or R 4 represents difluoroethyl.
  • R 4a represents Ci- 6 alkyl, optionally substituted by one, two or three fluorine atoms.
  • R 4a represents Ci- 6 alkyl or difluoro(Ci- 6 )alkyl.
  • R 4a represents Ci- 6 alkyl, especially methyl or ethyl.
  • R 4a represents methyl.
  • R 4a represents ethyl.
  • R 4a represents difluoro(Ci- 6 )- alkyl, especially difluoroethyl.
  • Particular values of R 4a include methyl and difluoroethyl.
  • R 4b represents methyl or ethyl. In a first embodiment, R 4b represents methyl. In a second embodiment, R 4b represents ethyl.
  • R 5a represents hydrogen. In a second embodiment, R 5a represents fluoro.
  • R 5b represents hydrogen. In a second embodiment, R 5b represents fluoro.
  • 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 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.
  • R 6 represents optionally substituted heteroaryl(Ci- 6 )alkyl.
  • R 6 represents -OR 6a .
  • 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.
  • R 6 examples include -OR 6a ; and pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 include -OR 6a ; and oxadiazolyl, which group may be optionally substituted. 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 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, 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, C2- 6 alkoxycarbonylamino,
  • 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, hydroxymethyl, oxo, methoxy, /er/-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl- amino, fer/-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetyl aminoethyl, methoxycarbonylamino, methylsulfonyl- amino, formyl, acetyl,
  • 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, carboxyethyl, 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- s
  • Favoured values of R 6 include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl.
  • R 6 include methyloxadiazolyl and ethyloxadiazolyl.
  • 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, 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)alkylaminocarbonyl, aminosulfon
  • Suitable examples of optional substituents on R 6a include one, two or three substituents independently selected from halogen.
  • 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, fe/7-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminos
  • 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, /er/-butyl, cyclobutyl and difluorocyclobutyl.
  • R 6a represents cyclobutyl
  • R 6b represents hydrogen or methyl.
  • R 6b represents hydrogen.
  • 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 methyl or ethyl.
  • R 7 represents methyl.
  • R 7 represents ethyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and L -ox ides thereof, and pharmaceutically acceptable salts thereof:
  • R 16 represents methyl or ethyl; and A, E, Y and R 3 are as defined above.
  • R 16 represents methyl. In a second embodiment, R 16 represents ethyl.
  • A, E, Y, R 3 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, 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, hidradenitis suppurativa, scleroderma, systemic sclerosis, lung fibrosis, inflammatory bowel diseases (including Crohn’s disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).
  • a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, ps
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo 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.
  • 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.
  • 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, 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. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
  • 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.
  • Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
  • the quantity of a compound according to the present invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g.
  • 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 (I) above may be prepared by a process which comprises reacting a carboxylic acid of formula R 6 -C02H with a compound of formula (III): wherein Z, A, E and R 6 are as defined above.
  • Suitable coupling agents include l-[bis(dimethylamino)methylene]-li7-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/ 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/A f -di methyl form amide or A/A- dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.
  • 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 f -di i sopropyl ethyl a i ne .
  • the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • 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, or an organic nitrile solvent such as acetonitrile.
  • the intermediates of formula (III) above may be prepared by removal of the N- protecting group R p from a compound of formula (IV): wherein Z, A and E are as defined above, and R p represents a V-protecting group.
  • the A -protecting group R p will suitably be /c/ -butoxycarbonyl (BOC), in which case the removal thereof may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the L -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.
  • Z 1 represents a group of formula (Za-1), (Zb-1), (Zc-1), (Zd-1), (Ze-1), (Zf-1), (Zg-1) or (Zh-1):
  • A, E, R 3 , R 4a 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.
  • the intermediates of formula (IV) above wherein Y represents N-R 4 , in which R 4 represents -COR 4a may be prepared by reacting a carboxylic acid of formula R 4a -C02H with a compound of formula (VI):
  • the compounds of formula (I) above wherein Y represents N-R 4 , in which R 4 represents -C0 2 R 4a , may be prepared by a process which comprises reacting a compound of formula (V) as defined above with a compound of formula L la -C0 2 R 4a , wherein L la represents a suitable leaving group, and R 4a is as defined above.
  • the intermediates of formula (IV) above wherein Y represents N-R 4 , in which R 4 represents -C0 2 R 4a may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula L la -C0 2 R 4a , wherein L la and R 4a are as defined above.
  • the leaving group L la is suitably a halogen atom, e.g. chloro.
  • the leaving group L la may suitably be 2,5-dioxopyrrolidin-l-yloxy.
  • Suitable bases include organic amines, e.g. a trialkylamine such as V,A-di isopropyl ethyl amine 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 4 , in which R 4 represents -S0 2 R 4b , may be prepared by a process which comprises reacting a compound of formula (V) as defined above with a compound of formula L lb -S0 2 R 4b , wherein L lb represents a suitable leaving group, and R 4b is as defined above.
  • the intermediates of formula (IV) above wherein Y represents N-R 4 , in which R 4 represents -S0 2 R 4b may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula L lb -S02R 4b , wherein L lb and R 4b are as defined above.
  • the leaving group L lb is suitably a halogen atom, e.g. chloro.
  • the reaction is conveniently accomplished in the presence of a base.
  • bases include organic amines, e.g. a trialkylamine such as A f , A -di isopropyl ethyl amine 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 4 , in which R 4 represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms may be prepared by a process which comprises reacting a compound of formula (V) as defined above with a compound of formula L 2 -R 4c , wherein L 2 represents a suitable leaving group, and R 4c represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms.
  • the intermediates of formula (IV) above wherein Y represents N-R 4 , in which R 4 represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula L 2 -R 4c , wherein L 2 and R 4c 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 4 , in which R 4 represents C3-9 cycloalkyl, optionally substituted by one or more fluorine atoms (e.g. 3,3- difluorocyclobutyl), may be prepared by a process which comprises reacting a compound of formula (V) as defined above 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 intermediates of formula (IV) above wherein Y represents N-R 4 , in which R 4 represents C3-9 cycloalkyl, optionally substituted by one or more fluorine atoms (e.g. 3, 3 -difluorocyclobutyl), may be prepared by reacting a compound of formula (VI) as defined above 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 (V) above may conveniently be prepared by reacting the corresponding compound of formula (I) wherein Y represents N-R 4 , in which R 4 represents -CChR 43 and R 4a represents tert- butyl, with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the intermediates of formula (VI) above may conveniently be prepared by reacting the corresponding compound of formula (IV) wherein Y represents N-R 4 , in which R 4 represents -CCkR 43 and R 4a represents /er/-butyl, with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • Z 2 represents a group of formula (Za-2), (Zb-2), (Zc-2), (Zd-2), (Ze-2), (Zf-2), (Zg-2) or (Zh-2): the asterisk (*) represents the point of attachment to the remainder of the molecule;
  • Aik 1 represents Ci-4 alkyl, e.g. methyl or ethyl; and A, E, Y and R p are as defined above; and
  • 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 or sodium hydroxide.
  • Step (i) is conveniently effected at ambient or elevated temperature in water and/or a suitable organic solvent, e.g. a cyclic ether such as tetrahydrofuran, or a Ci-4 alkanol such as methanol.
  • Alternative coupling agents that may usefully be employed in step (ii) include 2- chloro-l-methylpyridinium iodide.
  • the intermediates of formula (VII) above may be prepared by reacting a compound of formula Z 2 -L 3 with a compound of formula (VIII): wherein M 1 represents -B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3 -propanediol or neopentyl glycol, L 3 represents a suitable leaving group, and Z 2 , A, E and R p are as defined above; in the presence of a transition metal catalyst.
  • M 1 represents -B(OH)2 or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3 -propanediol or neopentyl glycol
  • L 3 represents a suitable leaving group
  • Z 2 , A, E and R p are as defined above; in the presence of a transition metal catalyst.
  • the leaving group L 3 is suitably a halogen atom, e.g. bromo.
  • the leaving group L 3 may suitably be a sulfonyloxy derivative, e.g. methanesulfonyloxy or trifluoromethanesulfonyloxy.
  • the transition metal catalyst may suitably be tris(dibenzylideneacetone)- palladium(O), which may typically be employed in conjunction with 2-dicyclohexyl- phosphino-2',4',6'-triisopropylbiphenyl (XPhos).
  • XPhos 2-dicyclohexyl- phosphino-2',4',6'-triisopropylbiphenyl
  • the reaction will be performed at an elevated temperature in the presence of potassium phosphate.
  • the transition metal catalyst may be [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium(II).
  • the reaction may conveniently be performed at an elevated temperature in the presence of potassium carbonate.
  • the intermediates of formula (VII) above may alternatively be prepared by reacting a compound of formula Z 2 -M' with a compound of formula (IX): wherein Z 2 , A, E, L 3 , M 1 and R p are as defined above; in the presence of a transition metal catalyst; under conditions analogous to those described above for the reaction between compound (VIII) and a compound of formula Z 2 -L 3 .
  • the intermediates of formula (VIII) above wherein M 1 represents a cyclic ester of -B(OH)2 formed with pinacol may be prepared by reacting bis(pinacolato)diboron with a compound of formula (IX) as defined above; in the presence of a transition metal catalyst.
  • the transition metal catalyst may suitably be tris(dibenzylideneacetone)- palladium(O), which may typically be employed in conjunction with 2-dicyclohexyl- phosphino-2',4',6'-triisopropylbiphenyl (XPhos).
  • the reaction will be performed at an elevated temperature in the presence of potassium acetate.
  • the compounds of formula (I) above may be prepared by a process which comprises cyclising a compound of formula (XA) or (XB):
  • Cyclisation of compound (XA) or (XB) is conveniently effected by heating in a suitable medium, e.g. acetic acid, or trifluoroacetic acid.
  • a suitable medium e.g. acetic acid, or trifluoroacetic acid.
  • the intermediates of formula (XA) or (XB) above may be prepared by reacting a compound of formula (XI) with a carboxylic acid of formula (XII) or a salt thereof, e.g. a lithium salt thereof:
  • the intermediates of formula (XII) 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 (XIII): wherein Aik 1 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).
  • 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. Where lithium hydroxide is employed in step (ii) of the above procedure, the product may be the lithium salt of the carboxylic acid of formula (XII).
  • 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.
  • the intermediates of formula (III) above may be prepared by a procedure which comprises the following steps: (i) reacting a compound of formula (XVII) with the compound of formula
  • the L -protecting group R q will suitably be 2-(trimethylsilyl)ethoxymethyl.
  • Step (i) is suitably effected by treatment of compound (XVII) with a base, e.g. an organic base such as //-butyllithium, followed by reaction with compound (XVIII).
  • 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-protecting group R q from compound (XIX) 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 intermediate of formula (XVIII) above may be prepared by reacting 4,4- difluorocyclohexyl carboxaldehyde 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 starting materials of formula (XI), (XIII), (XIV), (XV) and (XVI) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art. It will be understood that 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 comprising aN-BOC moiety (wherein BOC is an abbreviation for /er/-butoxy- carbonyl) 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 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 compound 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,A-diisopropylethyl a ine or triethylamine.
  • a compound 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 suitable acyl anhydride e.g. acetic anhydride
  • a base e.g. an organic base such as triethylamine.
  • a compound 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 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 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 compound 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 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 comprising a /c77-butoxy- carbonyl moiety may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with trifluoroacetic acid.
  • 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 (III) and a carboxylic acid of formula R 6 -C02H.
  • a compound comprising a Ci-4 alkoxycarbonyl moiety -CCbAlk 1 (wherein Aik 1 is as defined above) 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 comprising a Ci-4 alkylcarbonyloxy moiety -0C(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 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 [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 comprising a halogen atom e.g.
  • bromo may be converted into the corresponding compound comprising an optionally substituted aryl 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 appropriately substituted bromo- aryl or bromoheteroaryl derivative.
  • Step (i) is conveniently effected in the presence of a transition metal catalyst such as [l,T-bis(diphenylphosphino)ferrocene]dichloro- palladium(II), and potassium acetate.
  • Step (ii) is conveniently effected in the presence of a transition metal catalyst such as [l,T-bis(diphenylphosphino)ferrocene]dichloro- palladium(II), and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a transition metal catalyst such as [l,T-bis(diphenylphosphino)ferrocene]dichloro- palladium(II)
  • a base e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a compound 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
  • a compound comprising the moiety -S- may be converted into the corresponding compound comprising the moiety -S(0)(NH)- by treatment with (diacetoxyiodo)benzene and ammonium carbamate.
  • a hydrogenation catalyst e.g. palladium on charcoal.
  • a compound comprising an aromatic nitrogen atom may be converted into the corresponding compound comprising an L -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.
  • 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.
  • compounds in accordance with this invention potently inhibit the ability of IL-17A to bind to IL-17RA.
  • compounds of the present invention exhibit a pICso value of 5.0 or more, generally of 6.0 or more, usually of 7.0 or more, typically of 7.2 or more, suitably of 7.5 or more, ideally of 7.8 or more, and preferably of 8.0 or more (pICso equals -logiofICso], in which IC50 is expressed as a molar concentration, so the skilled person will appreciate that a higher pICso 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 a pICso value of 5.0 or more, generally of 6.0 or more, usually of 7.0 or more, typically of 7.2 or more, suitably of 7.5 or more, ideally of 7.8 or more, and preferably of 8.0 or more (as before, the skilled person will appreciate that a higher pICso 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).
  • IL-17RA soluble IL-17 Receptor A
  • An ⁇ L-17AA-TEV-Human Fc construct was expressed in a CHO SXE cell system and purified by protein A chromatography and size exclusion.
  • the protein was labelled with an amine reactive AlexaFluor 647 dye (Thermo Fisher #A20006), as per manufacturer’s instruction.
  • 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).
  • Assay buffer [Dulbecco’s PBS (Sigma #14190-094), 0.05% P20 (Thermo
  • 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 (Excitation: 330 nm; Emission 615/645 nm).
  • the final assay concentrations were IL-17A-AF6472 nM and IL-17RA-Tb 2 nM, 5% DMSO.
  • 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 inflammatory cytokines, i.e. IL-6.
  • HDF normal human dermal fibroblasts
  • 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
  • TNFa and IL-17 cytokine were prepared in complete media to final concentrations of TNFa 25 pM/IL-17A 50 pM, then 30 pL of the solution was added to a 384 well reagent plate (Greiner #781281).
  • 10 pL from the aqueous dilution plate was transferred to the reagent plate containing 30 pL 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 pL was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C/5% CO2.
  • 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).
  • T3P® propylphosphonic anhydride solution
  • HATU 1 - [bi s(di methyl ami no)m ethylene]- 1//- 1 ,2,3-triazolo[4,5-/ ]pyridinium 3-oxid hexafluorophosphate
  • MSDXT, pH 10 Stationary Phase Waters Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 pm column)
  • Mobile Phase A 10 mM ammonium formate in water + 0.1% ammonia solution
  • Mobile Phase B acetonitrile + 5% water + 0.1% ammonia solution
  • the reaction mixture was heated at 100 °C for 20 h.
  • the mixture was re-treated twice with Pd2(dba)3 (0.05 g, 0.20 mmol), XPhos (0.05 g, 0.40 mmol) and l-/er/-butyl 3-ethyl 4-(trifluoromethanesulfonyloxy)-2, 5-dihydro- l //-pyrrol e- 1 , 3 -di carboxyl ate (0.41 g, 1.05 mmol), and once with 2M aqueous K3PO4 solution (1.25 mL, 2.52 mmol).
  • the reaction mixture was heated at 100°C for 5.5 h, then cooled to r.t., diluted with EtOAc (50 mL) and washed with brine (50 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography, eluting with a gradient of EtOAc-heptane (0-100%), to afford the title compound (1.73 g, 59%) as a yellow oil.
  • Lithium hydroxide (0.93 g, 37.40 mmol) in water (16 mL) was added to a solution of Intermediate 3 (90%, 6.82 g, 9.35 mmol) in THF (64 mL).
  • the reaction mixture was stirred for 25 h at r.t., then for 22 h at 50°C, then cooled to r.t.
  • Lithium hydroxide (0.25 g, 10.30 mmol) in water (8 mL) was added.
  • the reaction mixture was heated at 50°C for a further 3 h, then cooled to r.t. and concentrated in vacuo.
  • the pH of the aqueous layer was adjusted to 4 using 10% aqueous citric acid.
  • Methyl chloroformate (33 mL, 0.428 mmol) in DCM (8 mL) was added dropwise to an ice-cooled (0°C) solution of Intermediate 6 (96%, 368 mg, 0.563 mmol) and DIPEA (197 pL, 1.13 mmol) in DCM (8 mL).
  • the reaction mixture was stirred at 0°C for 20 minutes, then allowed to warm to r.t. and stirred for 0.5 h.
  • the reaction mixture was quenched with water (8 mL) and stirred vigorously for 15 minutes.
  • Saturated aqueous ammonium chloride solution (8 mL) was added.
  • the mixture was stirred vigorously for 15 minutes, then filtered through a phase separation frit, washing with DCM (3 x 5 mL).
  • the combined organic layers were concentrated in vacuo.
  • the resulting brown oil was purified by flash column chromatography, eluting with a gradient of EtO Ac-heptane (0- 75%), to afford the title compound (366 mg, 85%) as a beige solid.
  • the resulting brown/green oil was purified by flash column chromatography on silica (Biotage SNAP 25g; gradient elution with 100% isohexane to 100% EtOAc).
  • the resulting green oil was taken up in acetic acid (5 mL) and heated at 70°C for 3 h. The reaction mixture was allowed to cool, and concentrated in vacuo.
  • the resulting brown oil was purified by flash column chromatography on silica, with a gradient elution of 100% isohexane to 100% EtOAc.
  • the crude isolated material was dissolved in water (1 mL) and EtOH (5 mL), then lithium hydroxide monohydrate (80.1 mg, 1.07 mmol) was added. The reaction mixture was stirred at room temperature overnight.
  • the reaction mixture was stirred at 20°C for 9 days. Additional ammonium formate (8.41 g, 135.60 mmol) in water (20 mL) and 10% palladium on carbon (50% wet with water, 5.0%, 3.65 g, 1.71 mmol) were added, in 3 and 5 portions respectively, at regular intervals over the 9 day period.
  • the reaction mixture was filtered through Celite®, washing thoroughly with MeOH and EtOH, then the solvent was concentrated in vacuo. The residue was dissolved in EtOAc, and washed with saturated aqueous NaHC03 solution. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgS04 and filtered.
  • Tris(dibenzylideneacetone)dipalladium(0) (240 mg, 0.26 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (250 mg, 0.52 mmol) were added. The reaction mixture was stirred at 100°C for 3 h. An additional aliquot of bis(pinacolato)diboron (1.50 g, 5.90 mmol) was added, and reaction mixture was stirred at 100°C for 1 h.
  • Ammonium formate (5.25 g, 83.3 mmol) was added to a solution of Intermediate 44 (3.14 g, 4.15 mmol) in ethanol (120 mL). The mixture was degassed with three cycles of vacuum and nitrogen, then 10% palladium on charcoal, 50% wet (5.0%, 0.44 g, 0.208 mmol) was added at 20°C. The reaction mixture was stirred at 20°C for 1 h. Additional ammonium formate (5.25 g, 83.3 mmol) and 10% palladium on charcoal, 50% wet (5.0%, 0.44 g, 0.208 mmol) were added at 20°C. The reaction mixture was stirred at 20°C for 18 h, then filtered through Celite® and washed with EtOH.
  • HATU (135 mg, 0.454 mmol) was added to a solution of Intermediate 8 (253 mg, 0.42 mmol), 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (65 mg, 0.51 mmol) and DIPEA (222 pL, 1.27 mmol).
  • the reaction mixture was stirred at 20°C for 3 h, then diluted with DCM (5 mL) and saturated aqueous NaHCCh solution (5 mL). The mixture was stirred vigorously for 10 minutes, then filtered through a phase separation frit. The aqueous layer was washed with DCM (3 x 5 mL). The combined organic layers were concentrated in vacuo.
  • Example 7 (118 mg) was subjected to chiral HPLC (Waters SFC80 equipped with a Chiralcel OD-H, 10 x 250 mm, 5 pm column, flow rate 15 mL/minute, eluting with 20% 2-propanol, 80% CO2) to afford, after freeze-drying, the title compounds (Peak 1, 32 mg, 12%; and Peak 2, 39 mg, 15%) as white solids.
  • chiral HPLC Waters SFC80 equipped with a Chiralcel OD-H, 10 x 250 mm, 5 pm column, flow rate 15 mL/minute, eluting with 20% 2-propanol, 80% CO2
  • Peak 1 (arbitrarily assigned 37?, 47? at pyrrolidine): 5H (400 MHz, DMSO-dr,) 12.70 (s,
  • Peak 2 (arbitrarily assigned 3.V,4k at pyrrolidine): 5H (400 MHz, DMSO-dr,) 12.74 (s, 1H), 9.64 (s, 1H), 7.29 (d, 74.5 Hz, 1H), 6.92 (t, 76.0 Hz, 1H), 5.18 (d, 78.1 Hz, 1H), 4.38 (q, 713.3 Hz, 1H), 4.18 (p, 77.8, 7.2 Hz, 1H), 3.86 (q, 714.4 Hz, 1H), 3.77-3.70 (m, 2H),
  • Example 4 5H (400 MHz, CDsOD) 7.39 (dd, 78.4, 2.4 Hz, 1H), 7.24-7.15 (m, 1H), 5.27 (d, 78.6 Hz, 1H), 4.79-4.72 (m, 2H), 4.60-4.53 (m, 2H), 4.20-4.06 (m, 2H), 3.95-3.83 (m, 2H), 3.79 (s, 3H), 2.68 (s, 1H), 2.54 (s, 3H), 2.42-2.26 (m, 1H), 2.21-1.97 (m, 3H), 1.95- 1.69 (m, 1H), 1.64-1.28 (m, 3H).
  • Example 5 (49 mg) was subjected to chiral SFC HPLC (Lux Cellulose-4, 250 x 21.2 mm, 5 pm column, flow rate 100 mL/minute, eluting with a 10-25% MeOH (+0.1% MLOH) method (ABPR 120 bar), using a 7.5 minute run time on a Waters Prep 100 Fractionlynx system, in tandem with a Waters SQD2 mass spectrometer) to afford, after freeze-drying, the title compounds (Peak 1, 11 mg, 22%; and Peak 2, 13 mg, 27%) as white solids.
  • Peak 1 (arbitrarily assigned 3S,4S at pyrrolidine): 5H (400 MHz, DMSO-de) 13.04-12.47 (m, 1H), 9.86-9.21 (m, 1H), 7.27-7.18 (m, 1H), 6.83 (br s, 1H), 5.17 (d, J 7.8 Hz, 1H), 4.77-4.59 (m, 1H), 4.38-4.23 (m, 1H), 4.17-4.05 (m, 1H), 4.03-3.91 (m, 1H), 3.86-3.50 (m, 8H), 2.54-2.48 (m, 3H), 2.48 (s, 3H), 2.31-2.18 (m, 1H), 2.10-1.95 (m, 1H), 1.96-1.85 (m, 1H), 1.84-1.64 (m, 1H), 1.62-1.52 (m, 1H), 1.49-1.34 (m, 1H), 1.33-1.19 (m, 1H). LCMS (Method 3):
  • Peak 2 (arbitrarily assigned R,4R at pyrrolidine): 5H (400 MHz, DMSO-de) 12.65 (s,
  • the resulting yellow oil was purified by flash column chromatography on silica (Biotage, SNAP lOg; gradient elution with 100% isohexane to 100% EtOAc, followed by 100% DCM to 30% MeOH/DCM).
  • the resulting oil was further purified by chiral preparative HPLC to yield, after freeze-drying, the title compounds (Peak 1, 8 mg, 6.9%; Peak 2, 8 mg, 6.9%; Peak 3, 9 mg, 7.8%; and Peak 4, 8 mg, 6.4%) as white solids.
  • Peak 1 (assigned as the 3R,4S cis isomer): 5H (400 MHz, CD3OD) 7.36 (d, J8.5 Hz, 1H), 7.20-7.10 (m, 1H), 5.27 (d, J8.7 Hz, 1H), 4.37 (q, J 11.6 Hz, 1H), 4.22-4.08 (m, 1H), 4.08-3.85 (m, 4H), 3.73 (s, 3H), 3.60 (dt, J 10.1, 4.8 Hz, 1H), 3.05 (q, J 4.6 Hz, 1H), 2.54 (s, 3H), 2.33 (q, J 10.5 Hz, 1H), 2.21-1.67 (m, 8H), 1.63-1.26 (m, 4H).
  • Peak 3 (assigned as the 3S,4R cis isomer): 5H (400 MHz, CD3OD) 7.36 (d, 78.4 Hz, 1H), 7.14 (dd, 78.5, 6.3 Hz, 1H), 5.27 (d, 78.7 Hz, 1H), 4.38 (q, 711.5 Hz, lH), 4.15 (q, 7 12.2 Hz, 1H), 4.08-3.79 (m, 5H), 3.73 (s, 3H), 3.60 (dt, 79.9, 4.8 Hz, 1H), 3.05 (q, 74.5 Hz, 1H), 2.54 (s, 3H), 2.38-2.25 (m, 1H), 2.22-1.98 (m, 3H), 1.98-1.69 (m, 4H), 1.61-1.25 (m, 4H).
  • LCMS (Method 3): [M+H] + m/z 654.4, RT 1.728 minutes.
  • Chiral analysis (Method
  • Peak 4 (assigned as the 3R, 4R trans isomer): 5H (400 MHz, CD3OD) 7.38 (d, 78.3 Hz, 1H), 7.23 (dd, 78.4, 6.2 Hz, 1H), 5.26 (d, 78.7 Hz, 1H), 4.60 (q, 711.6 Hz, 2H), 4.37- 4.04 (m, 4H), 3.89 (q, 711.9 Hz, 1H), 3.74 (s, 3H), 3.06 (td, 711.4, 3.8 Hz, 2H), 2.54 (s, 3H), 2.39-2.25 (m, 1H), 2.21-2.00 (m, 3H), 1.98-1.71 (m, 4H), 1.63-1.28 (m, 4H).
  • Example 12 was subjected to chiral HPLC (Method 10) to afford, after freeze- drying, the title compounds (Peak 1, 2 mg; and Peak 2, 4 mg) as white solids.
  • Peak 1 (arbitrarily assigned 37?, 47? at pyrrolidine): 5H (500 MHz, DMSO-de) 13.03-12.47 (m, 1H), 9.76-9.46 (m, 1H), 7.36-7.19 (m, 1H), 7.16-7.06 (m, 1H), 6.15 (tt, 755.8, 4.3 Hz, 1H), 5.17 (t, 77.0 Hz, 1H), 4.45-4.31 (m, 1H), 4.17-4.05 (m, 1H), 3.82-3.68 (m, 1H), 3.66-3.53 (m, 2H), 3.23-3.06 (m, 4H), 3.07-2.95 (m, 2H), 2.84 (t, 78.8 Hz, 1H), 2.44 (s, 3H), 2.33-2.18 (m, 1H), 2.12-1.87 (m, 3H), 1.87-1.68 (m, 2H), 1.57-1.45 (m, 1H), 1.41- 1.34 (m, 1H), 1.30
  • Peak 2 (arbitrarily assigned 3S,4S at pyrrolidine): 5H (500 MHz, DMSO-de) 12.99-12.52 (m, 1H), 9.78-9.45 (m, 1H), 7.36-7.19 (m, 1H), 7.14-7.04 (m, 1H), 6.15 (tt, 755.6, 4.1 Hz, 1H), 5.25-5.10 (m, 1H), 4.45-4.32 (m, 1H), 4.16-4.06 (m, 1H), 3.80-3.66 (m, 1H), 3.64-3.50 (m, 2H), 3.23-3.07 (m, 4H), 3.06-2.95 (m, 2H), 2.84 (t, 78.8 Hz, 1H), 2.47 (s, 3H), 2.33-2.19 (m, 1H), 2.09-1.88 (m, 3H), 1.87-1.65 (m, 2H), 1.55-1.43 (m, 1H), 1.43- 1.32 (m, 1H), 1.30-1.
  • HATU (175 mg, 0.46 mmol) in DMF (1 mL) was added to a stirred solution of Intermediate 21 (242 mg, 0.38 mmol), 2,2-difluoropropanoic acid (51 mg, 0.46 mmol) and DIPEA (0.2 mL, 1.15 mmol) in DMF (10 mL) at r.t. After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting orange oil was dissolved in EtOAc (50 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and brine (3 x 10 mL), then dried over MgSCL, filtered and concentrated in vacuo.
  • Example 15 (258 mg) was subjected to chiral HPLC (Method 12) to afford, after freeze-drying, the title compounds (Peak 1, 86 mg, 31%; and Peak 2, 70 mg, 25%) as white solids.
  • Peak 1 (arbitrarily assigned 3R,4R at pyrrolidine): 5H (500 MHz, CD3OD) 7.34 (br s, 1H), 7.07 (dd, 78.4, 6.5 Hz, 1H), 5.24 (d, J8.8 Hz, 1H), 4.42-4.29 (m, 1H), 4.28-4.12 (m, 2.5H), 4.07-3.93 (m, 2H), 3.88-3.78 (m, 1.5H), 3.78-3.68 (m, 1H), 3.57-3.46 (m, 1H), 3.43-3.32 (m, 1H), 2.51 (d, J 0.7 Hz, 3H), 2.37-2.23 (m, 1H), 2.16-1.97 (m, 3H), 1.92- 1.81 (m, 4H), 1.80-1.68 (m, 1H), 1.58-1.46 (m, 2H), 1.44-1.35 (m, 1H).
  • uPLC-MS Method 5H (500 MHz, CD3OD) 7.
  • Peak 2 (arbitrarily assigned 3L',4L' at pyrrolidine): 5H (500 MHz, CD3OD) 7.33 (br s, 1H), 7.07 (dd, 78.4, 6.5 Hz, 1H), 5.24 (dd, 78.8, 1.8 Hz, 1H), 4.43-4.29 (m, 1H), 4.28-4.13 (m, 2.5H), 4.06-3.93 (m, 2H), 3.88-3.78 (m, 1.5H), 3.78-3.68 (m, 1H), 3.58-3.47 (m, 1H), 3.42-3.32 (m, 1H), 2.51 (d, J0.6 Hz, 3H), 2.35-2.24 (m, 1H), 2.16-1.95 (m, 3H), 1.92- 1.80 (m, 4H), 1.80-1.68 (m, 1H), 1.56-1.45 (m, 2H), 1.44-1.34 (m, 1H).
  • uPLC-MS Method 5H (500 MHz, CD
  • Example 18 (242 mg) was subjected to chiral HPLC (Method 14) to afford, after freeze-drying, the title compounds (Peak 1, 93 mg, 23%; and Peak 2, 88 mg, 22%) as white solids.
  • Peak 1 (arbitrarily assigned 3R,4R at pyrrolidine): 5H (500 MHz, DMSO-dr,) 12.51 (br s, 1H), 7.77 (d, 78.6 Hz, 1H), 7.24 (d, 78.3 Hz, 1H), 6.94-6.84 (m, 1H), 4.85-4.73 (m, 1H), 4.70-4.60 (m, 1H), 4.44-4.29 (m, 1H), 4.22-4.11 (m, 1H), 3.94-3.79 (m, 1H), 3.77-3.68 (m, 2H), 3.68-3.61 (m, 5H), 3.61-3.55 (m, 1H), 3.55-3.42 (m, 2H), 2.28-2.12 (m, 2H),
  • Peak 2 (arbitrarily assigned 37,47 at pyrrolidine): 5H (500 MHz, DMSO-dr,) 12.54 (br s, 1H), 7.78 (d, 78.2 Hz, 1H), 7.25 (d, 77.8 Hz, 1H), 6.97-6.81 (m, 1H), 4.87-4.74 (m, 1H),
  • Peak 1 (assigned 3R,4R at pyrrolidine): 5H (400 MHz, CD3OD) 6.83 (dd, J 11.2, 4.7 Hz, 1H), 5.26 (d, J8.8 Hz, 1H), 4.54 (q, J 11.7 Hz, 1H), 4.19 (ddd, J24.3, 12.7, 9.1 Hz, 2H), 4.07-3.72 (m, 8H), 3.67 (dd, J 11.2, 7.1 Hz, 1H), 3.57-3.48 (m, 1H), 2.97 (qd, J7.6, 2.1 Hz, 2H), 2.30 (d, J 10.8 Hz, 1H), 2.16-1.98 (m, 3H), 1.92-1.69 (m, 2H), 1.56-1.35 (m, 3H), 1.29 (t, J 7.5 Hz, 3H).
  • LC-MS Method 1 16: [M+H] + m/z 672.2, RT 2.62 minutes,
  • Peak 2 (assigned 3S,4S at pyrrolidine): 5H (400 MHz, CD3OD) 6.83 (dd, J 11.2, 4.7 Hz, 1H), 5.25 (d, J8.7 Hz, 1H), 4.54 (q, J 11.6 Hz, 1H), 4.27-4.12 (m, 2H), 4.08-3.71 (m,
  • Peak 1 (arbitrarily assigned R,R at pyrrolidine): 5H (400 MHz, CD3OD) 7.36 (d, J 8.5 Hz, 1H), 7.12 (dd, J8.5, 6.5 Hz, 1H), 5.25 (d, J8.9 Hz, 1H), 4.49 (q, J 11.5 Hz, 1H), 4.30- 4.20 (m, 1H), 4.13 (q, J 12.1 Hz, 1H), 3.94-3.72 (m, 5H), 3.75 (d, J2.5 Hz, 3H), 3.71- 3.63 (m, 1H), 3.55-3.47 (m, 1H), 2.97 (qd, 77.5, 1.9 Hz, 2H), 2.37-2.25 (m, 1H), 2.18- 1.96 (m, 3H), 1.94-1.67 (m, 2H), 1.60-1.34 (m, 3H), 1.29 (t, J1.5 Hz, 3H). Chiral analysis (Method 19): RT 3.53 minutes (100%).
  • Peak 2 (arbitrarily assigned S,S at pyrrolidine): 5H (400 MHz, CD3OD) 7.36 (d, J8.5 Hz, 1H), 7.12 (dd, J8.5, 6.5 Hz, 1H), 5.25 (d, J8.9 Hz, 1H), 4.49 (q, J 11.5 Hz, 1H), 4.30- 4.20 (m, 1H), 4.13 (q, J 12.1 Hz, 1H), 3.94-3.72 (m, 5H), 3.75 (d, J2.5 Hz, 3H), 3.71- 3.63 (m, 1H), 3.55-3.47 (m, 1H), 2.97 (qd, 77.5, 1.9 Hz, 2H), 2.37-2.25 (m, 1H), 2.18- 1.96 (m, 3H), 1.94-1.67 (m, 2H), 1.60-1.34 (m, 3H), 1.29 (t, J1.5 Hz, 3H). Chiral analysis (Method 19): RT 4.05 minutes (99%).

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Abstract

L'invention concerne une série de dérivés de 4,4-difluorocyclohexyl substitués tels que définis dans la description, qui sont de puissants modulateurs de l'activité de l'IL-17 humaine, et qui sont par conséquent utiles dans le traitement et/ou la prévention de diverses maladies humaines, y compris des troubles inflammatoires et auto-immuns.
PCT/EP2021/054523 2020-02-25 2021-02-24 Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17 WO2021170631A1 (fr)

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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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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

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