WO2022096411A1 - Dicyclopropylmethyl derivatives as il-17 modulators - Google Patents

Dicyclopropylmethyl derivatives as il-17 modulators Download PDF

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Publication number
WO2022096411A1
WO2022096411A1 PCT/EP2021/080250 EP2021080250W WO2022096411A1 WO 2022096411 A1 WO2022096411 A1 WO 2022096411A1 EP 2021080250 W EP2021080250 W EP 2021080250W WO 2022096411 A1 WO2022096411 A1 WO 2022096411A1
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alkyl
compound
substituents
formula
optionally substituted
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PCT/EP2021/080250
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French (fr)
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Anne Marie Foley
James Thomas Reuberson
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UCB Biopharma SRL
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Priority claimed from GBGB2017641.8A external-priority patent/GB202017641D0/en
Priority claimed from GBGB2112860.8A external-priority patent/GB202112860D0/en
Application filed by UCB Biopharma SRL filed Critical UCB Biopharma SRL
Publication of WO2022096411A1 publication Critical patent/WO2022096411A1/en

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    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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 dicyclopropylmethyl 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., J. Immunol., 1993, 150, 5445-5456). Subsequently, five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174).
  • IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Thl7, that also express IL-21 and IL-22 signature cytokines (Korn et al., Ann. Rev. Immunol., 2009, 27, 485-517).
  • IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al., J. Immunol. , 2008, 181, 2799- 2805).
  • IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.
  • the compounds in accordance with the present invention being potent modulators of human IL- 17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active 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.
  • Heterocyclic compounds stated to be capable of modulating IL- 17 activity are also described in WO 2020/127685, WO 2020/146194 and WO 2020/182666.
  • WO 2020/120140 and WO 2020/120141 describe discrete classes of chemical compounds 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 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:
  • A represents C-R 1 or N
  • E represents C-R 2 or N
  • 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): in which 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 C 1-6 alkyl;
  • R 3b represents C 1-6 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, C 3-7 heterocycloalkyl, C 3-7 heterocycloalkyl(C 1-6 )alkyl, heteroaryl or heteroaryl(C 1-6 )alkyl, any of
  • 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.
  • 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.
  • 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.
  • Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched C 1-6 alkyl groups, for example C 1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl.
  • Derived expressions such as “C 1-6 alkoxy”, “C 1-6 alkylthio”, “C 1-6 alkylsulphonyl” and “C 1-6 alkylamino” are to be construed accordingly.
  • C 3-9 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 C 3-9 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(C 1-6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • 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.
  • 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-[1,2,5]thiadiazolo[2,3-a]- pyrazinyl, homopiperazinyl, morpholinyl, benzoxazin
  • 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-b]- [1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]- pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, ox
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
  • compounds of formula (I) may accordingly exist as enantiomers.
  • compounds in accordance with the invention possess two or more asymmetric centres, they may additionally exist as diastereomers.
  • the invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. It is to be understood that 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 1 H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1 H.
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • A represents C-R 1 .
  • A represents N.
  • E represents C-R 2 .
  • 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 (I-1) or (I-2) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof: wherein R 1 , R 2 , R 3 , R 4a , R 4b and R 6 are as defined above.
  • R 1 represents hydrogen.
  • R 1 represents fluoro.
  • R 2 represents hydrogen.
  • 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 C 1-6 alkyl, especially methyl or ethyl.
  • R 3a represents methyl.
  • R 3a represents ethyl.
  • R 3b represents C 1-6 alkyl or C 3-7 cycloalkyl(C 1-6 )alkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3b represents C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 3b represents optionally substituted C 1-6 alkyl.
  • R 3b represents optionally substituted C 3-7 cycloalkyl.
  • R 3b represents optionally substituted C 3-7 cycloalkyl(C 1-6 )alkyl.
  • R 3b represents optionally substituted aryl.
  • R 3b represents optionally substituted aryl(C 1-6 )alkyl.
  • R 3b represents optionally substituted C 3-7 heterocycloalkyl.
  • R 3b represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl.
  • R 3b represents optionally substituted heteroaryl.
  • R 3b represents optionally substituted heteroaryl(C 1-6 )alkyl.
  • Typical examples of R 3b include ethyl, n-propyl, isopropyl, 2-methylpropyl and cyclopropylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • Apposite examples of R 3b include ethyl and n-propyl, either of which groups may be optionally substituted by one or more substituents.
  • Suitable examples of R 3b include ethyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 3b include one, two or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoro- methyl, hydroxy, C 1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkyl- amino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino- carbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 )alkylaminocarbonyl, aminosulfon
  • Suitable examples of optional substituents on R 3b include one, two or three substituents independently selected from halogen.
  • Typical examples of particular substituents on R 3b include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethyl- sulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamin
  • Suitable examples of particular substituents on R 3b include one, two or three substituents independently selected from fluoro.
  • Typical values of R 3b include difluoroethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, (cyclopropyl)(trifluoromethyl)methyl and difluorocyclopropylmethyl. Additional values include difluoropropyl.
  • Apposite values of R 3b include trifluoroethyl and difluoropropyl. Suitable values of R 3b include trifluoroethyl.
  • 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-1-yl, pyrrolidin-1-yl, piperidin-1-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-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, isothiazolidin-2-yl, imidazolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-1-yl, [1,4]oxazepan-4-yl, [1,4]diazepan-1-yl, [1,4]thiadiazepan-4-yl, azocan-1-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, 3-azabicyclo[3.1.1]heptan-3-yl, 6-ox
  • 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, C 1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, difluoro- methoxy, trifluoromethoxy, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 alkylthio, C 1-6 alkylsulfonyl, cyano, oxo, formyl, C 2-6 alkylcarbonyl, carboxy, carboxy(C 1-6 )alkyl, C 2-6 alkoxycarbonyl, C 2-6 alkoxycarbonyl(C 1-6 )alkyl, amino, amino(C 1-6 )alkyl, C 1-6 alkylamino, di(C
  • Suitable examples of optional substituents on the group of formula (Wa) include halogen.
  • 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, ethylcarbonyl, tert- butylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methyl- amino, ethylamino, dimethylamino, acet
  • 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 C 1-6 alkyl, which group may be optionally substituted by one or more substituents.
  • R 4a represents hydrogen.
  • R 4a represents fluoro.
  • R 4a represents hydroxy.
  • R 4a represents C 1-6 alkyl, especially methyl or ethyl, which group may be optionally substituted by one or more substituents. In a first aspect of that embodiment, R 4a represents optionally substituted methyl. In a second aspect of that embodiment, R 4a represents optionally substituted ethyl.
  • 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, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, C 1-6 alkylamino, di(C 1-6 )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 1-6 )alkylaminocarbonyl, aminosulfonyl, C 1-6 alkylaminosulf
  • Suitable examples of optional substituents on R 4a include one, two or three substituents independently selected from halogen.
  • Typical examples of particular 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, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulfonyl,
  • Suitable examples of particular substituents on R 4a include one, two or three substituents independently selected from fluoro.
  • Illustrative values of R 4a include hydrogen, fluoro, hydroxy, methyl, difluoroethyl and trifluoroethyl.
  • Typical values of R 4a include methyl, difluoroethyl and trifluoroethyl.
  • Suitable values of R 4a include difluoroethyl.
  • R 4b represents hydrogen.
  • R 4b represents fluoro.
  • R 4b represents C 1-6 alkyl, especially methyl or ethyl.
  • R 4b represents methyl.
  • R 4b represents ethyl. Typical values of R 4b include hydrogen and fluoro. Alternatively, R 4a and R 4b may together form an optionally substituted cyclic moiety. Thus, R 4a and R 4b , 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 C 3-7 cycloalkyl, 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 cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, 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 cyclobutyl or cyclohexyl, 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 cyclopropyl 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 cyclobutyl 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 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 4b 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 4b when taken together with the carbon atom to which they are both attached, may suitably represent a piperidinyl 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 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 cyclohexyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.
  • Typical examples of optional substituents on the cyclic moiety formed by R 4a and R 4b include one, two or three substituents independently selected from C 1-6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkyl- sulfinyl, C 1-6 alkylsulfonyl, C 2-6 alkylcarbonyl, C 2-6 alkoxycarbonyl, amino, C 1-6 alkyl- amino and di(C 1-6 )alkylamino.
  • Suitable examples of optional substituents on the cyclic moiety formed by R 4a and R 4b include one, two or three substituents independently selected from halogen.
  • Typical examples of particular substituents on the cyclic moiety formed by R 4a and R 4b include one, two or three substituents independently selected from methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl, amino, methyl- amino and dimethylamino.
  • Suitable examples of particular substituents on the cyclic moiety formed by R 4a and R 4b include one, two or three substituents independently selected from fluoro.
  • Typical examples of the cyclic moiety formed by R 4a and R 4b include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonyl- pyrrolidinyl, tetrahydropyranyl, piperidinyl and methoxycarbonylpiperidinyl.
  • Suitable examples of the cyclic moiety formed by R 4a and R 4b include difluoro- cyclohexyl.
  • R 6 represents -OR 6a or -NR 6b R 6c ; or R 6 represents C 1-6 alkyl, C 3-9 cycloalkyl, C 3-9 cycloalkyl(C 1-6 )alkyl, aryl, aryl(C 1-6 )alkyl, heteroaryl or heteroaryl- (C 1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents -OR 6a or -NR 6b R 6c ; or R 6 represents aryl or heteroaryl, either 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 C 1-6 alkyl.
  • R 6 represents optionally substituted C 3-9 cycloalkyl.
  • R 6 represents optionally substituted C 3-9 cycloalkyl(C 1-6 )alkyl.
  • R 6 represents optionally substituted aryl.
  • R 6 represents optionally substituted aryl(C 1-6 )alkyl.
  • R 6 represents optionally substituted C 3-7 heterocycloalkyl.
  • R 6 represents optionally substituted C 3-7 heterocycloalkyl(C 1-6 )alkyl. In an eighth embodiment, R 6 represents optionally substituted heteroaryl. In a ninth embodiment, R 6 represents optionally substituted heteroaryl(C 1-6 )alkyl. In a tenth embodiment, R 6 represents -OR 6a . In an eleventh embodiment, R 6 represents -NR 6a R 6b .
  • R 6 examples include -OR 6a or -NR 6a R 6b ; and methyl, ethyl, propyl, 2- methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents. Additional values of R 6 include triazolyl, which group may be optionally substituted by one or more substituents.
  • R 6 include -OR 6a or -NR 6a R 6b ; and phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Illustrative values of R 6 include -OR 6a ; and pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Apt values of R 6 include phenyl, pyrazolyl, isoxazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 More apt values of R 6 include phenyl, pyrazolyl and 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. Typical examples of R 6 include oxadiazolyl and triazolyl, 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.
  • 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(C 1-6 )alkyl, oxo, C 1-6 alkoxy, difluoro- methoxy, trifluoromethoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, amino(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C 2-6 alkylcarbonylamino, C 2-6 alkylcarbonyla
  • Apposite examples of optional substituents on R 6 include one, two or three substituents independently selected from halogen and C 1-6 alkyl. 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, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl- amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl- amino, formyl, acetyl, carb
  • Apposite examples of particular substituents on R 6 include one, two or three substituents independently selected from fluoro, methyl and ethyl. Suitable examples of particular substituents on R 6 include one, two or three substituents independently selected from methyl and ethyl. Favoured examples of particular substituents on R 6 include one, two or three substituents independently selected from methyl and isopropyl.
  • 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
  • R 6 Favoured values of R 6 include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl. Selected values of R 6 include methylpyrazolyl, ethylpyrazolyl, methyloxadiazolyl and ethyloxadiazolyl. Typical examples of particular values of R 6 include methyloxadiazolyl, ethyl- oxadiazolyl and isopropyltriazolyl.
  • Suitable examples of particular values of R 6 include methyloxadiazolyl and isopropyltriazolyl. Particular examples of selected values of R 6 include methyloxadiazolyl and ethyloxadiazolyl. In a first embodiment, R 6 represents methyloxadiazolyl. In a second embodiment, R 6 represents ethyloxadiazolyl. In a third embodiment, R 6 represents isopropyltriazolyl. In a first embodiment, R 6a represents C 1-6 alkyl. In a second embodiment, R 6a represents optionally substituted C 3-9 cycloalkyl.
  • R 6a represents C 1-6 alkyl; or R 6a represents cyclobutyl, which group may be optionally substituted by one or more substituents.
  • substituents on R 6a include one, two or three substituents independently selected from halogen, cyano, nitro, C 1-6 alkyl, trifluoro- methyl, hydroxy, hydroxy(C 1-6 )alkyl, oxo, C 1-6 alkoxy, difluoromethoxy, trifluoro- methoxy, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, amino, amino(C 1-6 )alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonylamino, formyl, C 2-6 alkylcarbon
  • Suitable examples of optional substituents on R 6a include one, two or three substituents independently selected from halogen.
  • Typical examples of specific substituents on R 6a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxy
  • Suitable examples of specific substituents on R 6a include one, two or three substituents independently selected from fluoro.
  • Illustrative examples of specific values of R 6a include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl and difluorocyclobutyl.
  • R 6a represents cyclobutyl.
  • R 6b represents hydrogen or methyl.
  • R 6b represents hydrogen.
  • R 6b represents C 1-6 alkyl, especially methyl.
  • R 6c represents hydrogen or methyl.
  • R 6c represents hydrogen.
  • R 6c represents C 1-6 alkyl, especially methyl.
  • the moiety -NR 6b R 6c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
  • R 6c Selected examples of suitable substituents on the heterocyclic moiety -NR 6b R 6c include C 1-6 alkyl, C 1-6 alkylsulfonyl, hydroxy, hydroxy(C 1-6 )alkyl, amino(C 1-6 )alkyl, cyano, oxo, C 2-6 alkylcarbonyl, carboxy, C 2-6 alkoxycarbonyl, amino, C 2-6 alkylcarbonyl- amino, C 2-6 alkylcarbonylamino(C 1-6 )alkyl, C 2-6 alkoxycarbonylamino, C 1-6 alkylsulfonyl- amino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR 6b R 6c include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulfonylamino and aminocarbonyl.
  • R 16 represents methyl, ethyl or isopropyl; and A, E, R 3 , R 4a and R 4b are as defined above.
  • R 16 represents methyl or ethyl.
  • R 16 represents methyl.
  • R 16 represents ethyl.
  • R 16 represents isopropyl.
  • Another sub-class of compounds according to the invention is represented by the compounds of formula (IIB) and N-oxides thereof, and pharmaceutically acceptable salts thereof: wherein X represents CH or N; and A, E, R 3 , R 4a , R 4b and R 16 are as defined above.
  • X represents CH or N
  • A, E, R 3 , R 4a , R 4b and R 16 are as defined above.
  • X represents CH.
  • X represents N.
  • Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
  • 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 includes keratoconjunctivitis sicca (KCS), Sjögren syndrome, Sjögren syndrome-associated keratoconjunctivitis sicca, non-Sjögren 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
  • Sjögren syndrome Sjögren syndrome-associated keratoconjunctivitis sicca
  • non-Sjögren 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 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.
  • Pharmaceutical 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 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.
  • the 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.
  • 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.
  • 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 -CO 2 H or a salt thereof, e.g.
  • an alkali metal salt such as the lithium salt thereof, with a compound of formula (III): wherein A, E, R 3 , R 4a , R 4b and R 6 are as defined above.
  • the reaction is conveniently accomplished in the presence of a coupling agent and a base.
  • Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU); and 2,4,6-tripropyl- 1,3,5,2,4,6-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. a cyclic ether such as tetrahydrofuran; or a dipolar aprotic solvent such as N,N-dimethyl- formamide or N,N-dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.
  • a coupling agent such as N-(3-dimethylaminopropyl)-N ⁇ -ethylcarbodiimide (EDC).
  • the reaction is suitably performed at an appropriate temperature, e.g. a temperature in the region of 0°C, in a suitable solvent, e.g. an organic nitrile solvent such as acetonitrile.
  • a suitable solvent e.g. an organic nitrile solvent such as acetonitrile.
  • R 6 represents C 1-6 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 N,N-diisopropylethylamine.
  • the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran.
  • R 6 represents -OR 6a
  • the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R 6a -OH with 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 (III) as defined above. Steps (i) and (ii) are conveniently performed at ambient temperature in a suitable solvent, e.g.
  • 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 A, E, R 3 , R 4a and R 4b are as defined above, and R p represents a N-protecting group.
  • the N-protecting group R p will suitably be tert-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 N-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 or triethylsilane 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 may be prepared by a two-step process which comprises: (i) saponifying a compound of formula (V): wherein A, E, R 4a , R 4b and R 6 are as defined above, and Alk 1 represents C 1-4 alkyl, e.g.
  • step (i) reaction of the carboxylic acid derivative thereby obtained with a compound of formula R 3 -H; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -CO 2 H.
  • a base include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide.
  • the reaction is conveniently performed at ambient or elevated temperature in water and a suitable organic solvent, e.g.
  • step (i) may generally be effected by treatment with an acid, e.g. an organic acid such as trifluoroacetic acid.
  • an acid e.g. an organic acid such as trifluoroacetic acid.
  • the reaction is conveniently performed at ambient temperature in a suitable organic solvent, e.g. a chlorinated solvent such as dichloromethane.
  • Alternative coupling agents that may usefully be employed in step (ii) include 2- chloro-1-methylpyridinium iodide.
  • the compounds of formula (I) above may be prepared by a process which comprises cyclising a compound of formula (VIA) or (VIB):
  • step (i) illustrates that alternative coupling agents that may usefully be employed in step (i) include O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU).
  • HBTU O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • the intermediates of formula (IV) above may be prepared by a two-step procedure which comprises the following steps: (i) reacting a compound of formula (VII) as defined above with a compound of formula (X): wherein R p is as defined above; under conditions analogous to those described above for the reaction between compounds (VII) and (VIII); and (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VIA) or (VIB).
  • the intermediates of formula (III) above may be prepared by a procedure which comprises the following steps: (i) reacting a compound of formula (XI) with the compound of formula (XII): wherein A, E, R 3 , R 4a and R 4b are as defined above, and R q represents a N-protecting group; to provide a compound of formula (XIII): wherein A, E, R 3 , R 4a , R 4b and R q are as defined above; and (ii) removal of the tert-butylsulfinyl group and the N-protecting group R q from compound (XIII).
  • the N-protecting group R q will suitably be 2-(trimethylsilyl)ethoxymethyl.
  • Step (i) is suitably effected by treatment of compound (XI) with a base, e.g. an organic base such as n-butyllithium, followed by reaction with compound (XII).
  • a base e.g. an organic base such as n-butyllithium
  • the reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the intermediates of formula (XI) above may be prepared by a procedure which comprises the following steps: (i) reaction of a compound of formula (VII) as defined above with formic acid; and (ii) reaction of the material thereby obtained with 2-(trimethylsilyl)ethoxymethyl chloride. 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 (XII) above may be prepared by reacting 2,2- dicyclopropylacetaldehyde with 2-methyl-2-propanesulfinamide.
  • the reaction is suitably effected in the presence of pyridinium p-toluenesulfonate 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 intermediates of formula (V) above may be prepared by reacting a carboxylic acid of formula R 6 -CO 2 H with a compound of formula (XIV): wherein A, E, R 4a , R 4b and Alk 1 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 -CO 2 H.
  • the intermediates of formula (XIV) above may be prepared by a three-step procedure which comprises the following steps: (i) reacting a compound of formula (X) as defined above with a compound of formula (XV): wherein A, E, R 4a , R 4b and Alk 1 are as defined above; under conditions analogous to those described above for the reaction between compounds (VII) and (VIII); (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VIA) or (VIB); and (iii) removal of the N-protecting group R p from the material thereby obtained; under conditions analogous to those described above for the removal of the N-protecting group R p from compound (IV).
  • the intermediates of formula (IV) above may be prepared by a four-step procedure which comprises the following steps: (i) reacting a compound of formula (X) as defined above with a compound of formula (XV) as defined above under conditions analogous to those described above for the reaction between compounds (VII) and (VIII); (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VIA) or (VIB); (iii) saponification of the resulting material under conditions analogous to those described above for the saponification of compound (V); and (iv) reaction of the carboxylic acid derivative thereby obtained with a compound of formula R 3 -H; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -CO 2 H.
  • the starting materials of formula (VII), (IX), (X) and (XV) 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 a N-BOC moiety (wherein BOC is an abbreviation for tert-butoxy- carbonyl) may be converted into the corresponding compound comprising a N-H moiety by treatment with an acid, e.g.
  • 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.
  • 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 compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-S(O)2Alk 1 functionality (wherein Alk 1 is as defined above) by treatment with the appropriate C 1-4 alkylsulfonyl chloride reagent, e.g.
  • methylsulfonyl chloride 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 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 or N,N-diisopropylethyl- amine.
  • 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-1-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 triacetoxyborohydride.
  • a compound comprising a C1-4 alkoxycarbonyl moiety -CO 2 Alk 1 (wherein Alk 1 is as defined above) may be converted into the corresponding compound comprising a carboxylic acid (-CO 2 H) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as lithium hydroxide.
  • a compound comprising a tert-butoxy- carbonyl moiety may be converted into the corresponding compound comprising a carboxylic acid (-CO 2 H) moiety by treatment with trifluoroacetic acid.
  • a compound comprising a carboxylic acid (-CO 2 H) 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 -CO 2 H.
  • a compound comprising a C 1-4 alkoxycarbonyl moiety -CO 2 Alk 1 may be converted into the corresponding compound comprising a hydroxymethyl (-CH 2 OH) moiety by treatment with a reducing agent such as lithium aluminium hydride.
  • a compound comprising a C 1-4 alkylcarbonyloxy moiety -OC(O)Alk 1 (wherein Alk 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 compound comprising a halogen atom e.g.
  • bromo may be converted into the corresponding compound comprising an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety by treatment with the appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol.
  • the reaction is typically effected in the presence of a transition metal catalyst, and a base.
  • the transition metal catalyst may be [1,1′-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 bromoaryl or bromoheteroaryl derivative.
  • Step (i) is conveniently effected in the presence of a transition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), and potassium acetate.
  • Step (ii) is conveniently effected in the presence of a transition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a transition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]- dichloropalladium(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.
  • step (i) If an excess of methylmagnesium chloride is employed in step (i), the corresponding compound comprising a 1-amino-1-methylethyl moiety may be obtained.
  • a compound comprising the moiety -S- may be converted into the corresponding compound comprising the moiety -S(O)(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 N-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.
  • these isomers may be separated by conventional techniques.
  • diastereomeric derivatives e.g. salts
  • a mixture of enantiomers of formula (I) e.g. a racemate
  • an appropriate chiral compound e.g. a chiral base.
  • 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.
  • compounds of the present invention exhibit a pIC50 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 (pIC 50 equals -log 10 [IC 50 ], in which IC50 is expressed as a molar concentration, so the skilled person will appreciate that a higher pIC50 figure denotes a more active compound).
  • pIC 50 equals -log 10 [IC 50 ]
  • IC50 is expressed as a molar concentration
  • HDF normal human dermal fibroblasts
  • IL-17A 50 pM
  • TNF- ⁇ 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 (Corning #3701) at 40 ⁇ L per well. The cells were left for a minimum of three hours, at 37°C/5% CO 2 , to adhere to the plate. Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 ⁇ L from the titration plate was transferred to 45 ⁇ L of complete media and mixed to give a solution containing 10% DMSO.
  • TNF ⁇ and IL-17 cytokine were prepared in complete media to final concentrations of TNF ⁇ 25 pM/IL-17A 50 pM, then 30 ⁇ L of the solution was added to a 384 well reagent plate (Greiner #781281). 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 5 h at 37°C. 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% CO 2 .
  • 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 ⁇ L), then supernatant (10 ⁇ L) 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).
  • the crude residue was re-dissolved in DCM (50 mL), then aqueous NaOH solution (1M, 50 mL) was added and the layers were separated.
  • DCM (50 mL) and aqueous hydrochloric acid (2M, 50 mL) were added to the basic aqueous layer, then the layers were separated and the aqueous layer was re-extracted with DCM (2 x 30 mL).
  • the combined DCM layers were passed through a phase separator and concentrated in vacuo to give the crude title compound (90% purity) (1.69 g, 46%) as a yellow oil, which was utilised without further purification.
  • reaction mixture was stirred at r.t. for 2 h, then diluted with DCM (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of EtOAc/heptane (0-20%), to afford the title compound (7.01 g, 90% yield, corrected for solvent content) as an orange oil.
  • the pH of the aqueous layer was adjusted to pH 3 using 6N HCl ( ⁇ 4 mL). Crystals from a previous batch were seeded, then the flask was externally cooled and left to stand for 2 h. The contents were filtered off, then washed with water (2 x 10 mL) and dried, to afford the title compound (719 mg, 49%) as a white solid.
  • the reaction mixture was stirred at r.t. for 16 h, then poured into water (400 mL). The resulting suspension was stirred for a further 15 minutes.
  • the solid was collected by filtration, rinsing the filter cake with water (2 x 100 mL), diethyl ether/heptane (1:1, 150 mL) and heptane (200 mL), then dried under a flow of nitrogen for 1.5 h.
  • the solid was further dried in a vacuum oven for 2 h at 40°C to afford the title compound ( ⁇ 9:1 mixture of regioisomers by NMR) (8.79 g, 81% yield corrected for 94% purity) as a pale purple solid.
  • reaction mixture was stirred for a further 30 minutes.
  • the catalyst was removed by filtration over micro glass fibre paper (double layer), rinsing the pad with MeOH (2 x 50 mL). The filtrates were combined, and the solvent was removed in vacuo, to afford the title compound (1:1 mixture of diastereoisomers) (7.35 g, 96%) as a pale brown foamy solid, which was utilised without further purification.
  • Peak 1 (Example 2, arbitrarily assigned R,S) LCMS (Method 3): [M+H] + 573.4, RT 2.03 minutes.
  • Chiral Analysis (Method 11): RT 1.89 minutes, 100%.
  • Peak 2 (Example 3, arbitrarily assigned S,S) LCMS (Method 3): [M+H] + 573.4, RT 2.03 minutes.
  • Chiral Analysis (Method 11): RT 2.22 minutes, 95.8%.
  • Peak 1 (Example 5, arbitrarily assigned R) LCMS (Method 3): [M+H] + 596, RT 2.10 minutes.
  • Chiral Analysis (Method 11): RT 2.09 minutes, 100%.
  • Peak 2 (Example 6, arbitrarily assigned S) LCMS (Method 3): [M+H] + 596, RT 2.10 minutes.
  • Chiral Analysis (Method 11): RT 2.28 minutes, 95.5%.
  • the reaction mixture was stirred at r.t. for 1.5 h., then poured into water (300 mL) and brine (50 mL). The resulting suspension was stirred for a further 15 minutes to give a sticky residue. The aqueous phase was decanted off (discarded), and the sticky solid was dissolved in EtOAc (150 mL). The solution was washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography (Isolera 4, 350 g SFAR Duo column), eluting with a gradient of EtOAc in heptane (10-70%).
  • Peak 1 (arbitrarily assigned R): ⁇ H (400 MHz, DMSO-d6) 12.74 (s, 1H), 8.78 (dd, J 16.6, 9.3 Hz, 1H), 8.68 (t, J 6.1 Hz, 1H), 8.16 (s, 1H), 7.29 (d, J 8.5 Hz, 1H), 7.21 (dd, J 8.5, 6.3 Hz, 1H), 5.59 (hept, J 6.5 Hz, 1H), 5.46 (dd, J 9.2, 6.3 Hz, 1H), 4.32 (dd, J 8.5, 5.2 Hz, 1H), 3.58-3.44 (m, 1H), 3.50 (s, 1H), 3.20-3.06 (m, 1H), 1.48 (s, 1H), 1.46-1.36 (m, 9H), 1.04-0.91 (m, 1H), 0.73 (dq, J 13.7, 5.4 Hz, 2H), 0.46-0.35 (m, 2H), 0.32-0.14 (m, 2H

Abstract

k series of substituted dicyclopropylmethyl derivatives as defined herein, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

Description

DICYCLOPROPYLMETHYL DERIVATIVES AS IL-17 MODULATORS
The present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted dicyclopropylmethyl 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., J. Immunol., 1993, 150, 5445-5456). Subsequently, five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al., Cytokine Growth Factor Rev., 2003, 14, 155-174). IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Thl7, that also express IL-21 and IL-22 signature cytokines (Korn et al., Ann. Rev. Immunol., 2009, 27, 485-517). IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al., J. Immunol. , 2008, 181, 2799- 2805). IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.
The compounds in accordance with the present invention, being potent modulators of human IL- 17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
Furthermore, 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. Thus, 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.
Heterocyclic compounds stated to be capable of modulating IL- 17 activity are also described in WO 2020/127685, WO 2020/146194 and WO 2020/182666.
WO 2020/120140 and WO 2020/120141, and 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), describe discrete classes of chemical compounds 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.
None of the prior art available to date, however, discloses or suggests the precise structural class of substituted dicyclopropylmethyl derivatives as provided by the present invention.
As well as being potent modulators of human IL- 17 activity, the compounds in accordance with the present invention also possess other notable advantages. In particular, 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:
Figure imgf000004_0001
wherein
A represents C-R1 or N;
E represents C-R2 or N;
R1 represents hydrogen or fluoro;
R2 represents hydrogen or fluoro;
R3 represents -NR3aR3b; or R3 represents a group of formula (Wa):
Figure imgf000004_0002
in which 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; R3a represents hydrogen or C1-6 alkyl; R3b represents C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R4a represents hydrogen, fluoro or hydroxy; or R4a represents C1-6 alkyl, which group may be optionally substituted by one or more substituents; and R4b represents hydrogen, fluoro or C1-6 alkyl; or R4a and R4b, when taken together with the carbon atom to which they are both attached, represent C3-9 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; R6 represents -OR6a or -NR6bR6c; or R6 represents C1-6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl- (C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R6a represents C1-6 alkyl; or R6a represents C3-9 cycloalkyl, which group may be optionally substituted by one or more substituents; R6b represents hydrogen or C1-6 alkyl; and R6c represents hydrogen or C1-6 alkyl; or R6b and R6c, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents. The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. The present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy. The present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated. The present invention also provides the use of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated. The present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt thereof. Where 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. For use in medicine, 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. The technical term “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 C1-6 alkyl groups, for example C1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as “C1-6 alkoxy”, “C1-6 alkylthio”, “C1-6 alkylsulphonyl” and “C1-6 alkylamino” are to be construed accordingly. The term “C3-9 cycloalkyl” as used herein 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. The term “aryl” as used herein 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(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl. The term “C3-7 heterocycloalkyl” as used herein 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-[1,2,5]thiadiazolo[2,3-a]- pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl. The term “heteroaryl” as used herein 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-b]- [1,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]- pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]- thiazolyl, imidazo[1,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, imidazo- [4,5-b]pyridinyl, imidazo[1,2-b]pyridazinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo- [1,2-c]pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]- triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, 5,6,7,8-tetrahydro[1,2,4]triazolo- [4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]- pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups. The term “halogen” as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine. Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds in accordance with the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C=O)↔enol (CH=CHOH) tautomers or amide (NHC=O)↔hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise. It is to be understood that 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. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 12C, 13C or 14C atom, preferably 12C. In one embodiment, A represents C-R1. In another embodiment, A represents N. In one embodiment, E represents C-R2. In another embodiment, E represents N. In a particular embodiment, A represents C-R1 or N; and E represents C-R2. In one aspect of that embodiment, A represents C-R1; and E represents C-R2. Suitably, the present invention provides a compound of formula (I-1) or (I-2) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000009_0001
wherein R1, R2, R3, R4a, R4b and R6 are as defined above. In a first embodiment, R1 represents hydrogen. In a second embodiment, R1 represents fluoro. In a first embodiment, R2 represents hydrogen. In a second embodiment, R2 represents fluoro. In a first embodiment, R3 represents -NR3aR3b. In a second embodiment, R3 represents a group of formula (Wa) as defined above. In a first embodiment, R3a represents hydrogen. In a second embodiment, R3a represents C1-6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R3a represents methyl. In a second aspect of that embodiment, R3a represents ethyl. Typically, R3b represents C1-6 alkyl or C3-7 cycloalkyl(C1-6)alkyl, either of which groups may be optionally substituted by one or more substituents. Suitably, R3b represents C1-6 alkyl, which group may be optionally substituted by one or more substituents. In a first embodiment, R3b represents optionally substituted C1-6 alkyl. In a second embodiment, R3b represents optionally substituted C3-7 cycloalkyl. In a third embodiment, R3b represents optionally substituted C3-7 cycloalkyl(C1-6)alkyl. In a fourth embodiment, R3b represents optionally substituted aryl. In a fifth embodiment, R3b represents optionally substituted aryl(C1-6)alkyl. In a sixth embodiment, R3b represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, R3b represents optionally substituted C3-7 heterocycloalkyl(C1-6)alkyl. In an eighth embodiment, R3b represents optionally substituted heteroaryl. In a ninth embodiment, R3b represents optionally substituted heteroaryl(C1-6)alkyl. Typical examples of R3b include ethyl, n-propyl, isopropyl, 2-methylpropyl and cyclopropylmethyl, any of which groups may be optionally substituted by one or more substituents. Apposite examples of R3b include ethyl and n-propyl, either of which groups may be optionally substituted by one or more substituents. Suitable examples of R3b include ethyl, which group may be optionally substituted by one or more substituents. Typical examples of optional substituents on R3b include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro- methyl, hydroxy, C1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkyl- amino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, amino- carbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6)alkylaminosulfonyl and di(C1-6)alkylsulfoximino. Suitable examples of optional substituents on R3b include one, two or three substituents independently selected from halogen. Typical examples of particular substituents on R3b include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethyl- sulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximino. Suitable examples of particular substituents on R3b include one, two or three substituents independently selected from fluoro. Typical values of R3b include difluoroethyl, trifluoroethyl, trifluoropropyl, trifluoroisopropyl, (cyclopropyl)(trifluoromethyl)methyl and difluorocyclopropylmethyl. Additional values include difluoropropyl. Apposite values of R3b include trifluoroethyl and difluoropropyl. Suitable values of R3b include trifluoroethyl. In a first embodiment, 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. In a first aspect of that embodiment, 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. In a second embodiment, 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. In a first aspect of that embodiment, 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. In a third embodiment, 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. In a first aspect of that embodiment, 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. Suitably, 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). In a first embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 or 4 carbon atoms and one nitrogen atom. In a first aspect of that embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 3 carbon atoms and one nitrogen atom. In a second aspect of that embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms and one nitrogen atom. In a second embodiment, W represents the residue of an optionally substituted saturated monocyclic ring containing 4 carbon atoms, one nitrogen atom, and one oxygen atom. In a first embodiment, 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-1-yl, pyrrolidin-1-yl, piperidin-1-yl or hexahydroazepin-1- yl ring). In a second embodiment, the group of formula (Wa) represents a saturated monocyclic ring containing one nitrogen atom and one additional heteroatom selected from N, O and S. In a first aspect of that embodiment, the group of formula (Wa) is an optionally substituted morpholin-4-yl moiety. In a third embodiment, 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. In a fourth embodiment, 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-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, isothiazolidin-2-yl, imidazolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, azepan-1-yl, [1,4]oxazepan-4-yl, [1,4]diazepan-1-yl, [1,4]thiadiazepan-4-yl, azocan-1-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, 3-azabicyclo[3.1.1]heptan-3-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo- [4.1.0]heptan-3-yl, 2-oxa-5-azabicyclo[2.2.2]octan-5-yl, 3-azabicyclo[3.2.1]octan-3-yl, 8- azabicyclo[3.2.1]octan-8-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 3,8-diazabicyclo- [3.2.1]octan-3-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 3,6-diazabicyclo[3.2.2]nonan-3-yl, 3,6-diazabicyclo[3.2.2]nonan-6-yl, 3-oxa-7-azabicyclo[3.3.1]nonan-7-yl, 3,7-dioxa-9- azabicyclo[3.3.1]nonan-9-yl, 3,9-diazabicyclo[4.2.1]nonan-3-yl, 3,9-diazabicyclo[4.2.1]- nonan-9-yl, 5-azaspiro[2.3]hexan-5-yl, 5-azaspiro[2.4]heptan-5-yl, 2-azaspiro[3.3]heptan- 2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 3-oxa-6-azaspiro[3.3]heptan-6-yl, 6-thia-2-aza- spiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 2-oxa-6-azaspiro[3.5]nonan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 2-oxa-7-azaspiro[3.5]nonan-7-yl, 2,4,8-triazaspiro[4.5]- decan-2-yl, 2,4,8-triazaspiro[4.5]decan-4-yl and 2,4,8-triazaspiro[4.5]decan-8-yl, any of which groups may be optionally substituted by one or more substituents. In a first embodiment, the group of formula (Wa) is unsubstituted. In a second embodiment, the group of formula (Wa) is substituted by one or more substituents, typically by one to six substituents, suitably by two to four substituents. In a first aspect of that embodiment, the group of formula (Wa) is substituted by one substituent. In a second aspect of that embodiment, the group of formula (Wa) is substituted by two substituents. In a third aspect of that embodiment, the group of formula (Wa) is substituted by three substituents. In a fourth aspect of that embodiment, the group of formula (Wa) is substituted by four substituents. In a fifth aspect of that embodiment, the group of formula (Wa) is substituted by five substituents. In a sixth aspect of that embodiment, the group of formula (Wa) is substituted by six substituents. Typical examples of optional substituents on the group of formula (Wa) include halogen, C1-6 alkyl, trifluoromethyl, hydroxy, hydroxy(C1-6)alkyl, C1-6 alkoxy, difluoro- methoxy, trifluoromethoxy, C1-6 alkoxy(C1-6)alkyl, C1-6 alkylthio, C1-6 alkylsulfonyl, cyano, oxo, formyl, C2-6 alkylcarbonyl, carboxy, carboxy(C1-6)alkyl, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(C1-6)alkyl, amino, amino(C1-6)alkyl, C1-6 alkylamino, di(C1-6)alkyl- amino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, aminocarbonyl, C1-6 alkylaminocarbonyl and di(C1-6)alkylaminocarbonyl. Suitable examples of optional substituents on the group of formula (Wa) include halogen. 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, ethylcarbonyl, tert- butylcarbonyl, carboxy, carboxymethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, amino, aminomethyl, methyl- amino, ethylamino, dimethylamino, acetylamino, tert-butoxycarbonylamino, methyl- sulfonylamino, aminocarbonyl, methylaminocarbonyl and dimethylaminocarbonyl. Suitable examples of particular substituents on the group of formula (Wa) include fluoro. Generally, R4a represents hydrogen or fluoro; or R4a represents C1-6 alkyl, which group may be optionally substituted by one or more substituents. Typically, R4a represents hydrogen; or R4a represents C1-6 alkyl, which group may be optionally substituted by one or more substituents. Suitably, R4a represents C1-6 alkyl, which group may be optionally substituted by one or more substituents. In a first embodiment, R4a represents hydrogen. In a second embodiment, R4a represents fluoro. In a third embodiment, R4a represents hydroxy. In a fourth embodiment, R4a represents C1-6 alkyl, especially methyl or ethyl, which group may be optionally substituted by one or more substituents. In a first aspect of that embodiment, R4a represents optionally substituted methyl. In a second aspect of that embodiment, R4a represents optionally substituted ethyl. Typical examples of optional substituents on R4a include one, two or three substituents independently selected from halogen, cyano, nitro, hydroxy, C1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkyl- carbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkyl- carbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di- (C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6)alkylamino- sulfonyl and di(C1-6)alkylsulfoximino. Suitable examples of optional substituents on R4a include one, two or three substituents independently selected from halogen. Typical examples of particular substituents on R4a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoro- ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino- sulfonyl and dimethylsulfoximino. Suitable examples of particular substituents on R4a include one, two or three substituents independently selected from fluoro. Illustrative values of R4a include hydrogen, fluoro, hydroxy, methyl, difluoroethyl and trifluoroethyl. Typical values of R4a include methyl, difluoroethyl and trifluoroethyl. Suitable values of R4a include difluoroethyl. In a first embodiment, R4b represents hydrogen. In a second embodiment, R4b represents fluoro. In a third embodiment, R4b represents C1-6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R4b represents methyl. In a second aspect of that embodiment, R4b represents ethyl. Typical values of R4b include hydrogen and fluoro. Alternatively, R4a and R4b may together form an optionally substituted cyclic moiety. Thus, R4a and R4b, when taken together with the carbon atom to which they are both attached, may represent C3-7 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a first embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent C3-7 cycloalkyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a general illustration of that embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a particular illustration of that embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent cyclobutyl or cyclohexyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a first aspect of that embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent a cyclopropyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a second aspect of that embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent a cyclobutyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a third aspect of that embodiment, R4a and R4b, 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. In a fourth aspect of that embodiment, R4a and R4b, 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. In a second embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent C3-7 heterocycloalkyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a general illustration of that embodiment, R4a and R4b, 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. As a particular illustration of that embodiment, R4a and R4b, 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. In a first aspect of that embodiment, R4a and R4b, 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. In a second aspect of that embodiment, R4a and R4b, 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. In a third aspect of that embodiment, R4a and R4b, 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. In a fourth aspect of that embodiment, R4a and R4b, when taken together with the carbon atom to which they are both attached, may suitably represent a piperidinyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. Typically, R4a and R4b, 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. Suitably, R4a and R4b, when taken together with the carbon atom to which they are both attached, may represent cyclohexyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. Typical examples of optional substituents on the cyclic moiety formed by R4a and R4b include one, two or three substituents independently selected from C1-6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl- sulfinyl, C1-6 alkylsulfonyl, C2-6 alkylcarbonyl, C2-6 alkoxycarbonyl, amino, C1-6 alkyl- amino and di(C1-6)alkylamino. Suitable examples of optional substituents on the cyclic moiety formed by R4a and R4b include one, two or three substituents independently selected from halogen. Typical examples of particular substituents on the cyclic moiety formed by R4a and R4b include one, two or three substituents independently selected from methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, methoxycarbonyl, ethoxycarbonyl, amino, methyl- amino and dimethylamino. Suitable examples of particular substituents on the cyclic moiety formed by R4a and R4b include one, two or three substituents independently selected from fluoro. Typical examples of the cyclic moiety formed by R4a and R4b include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonyl- pyrrolidinyl, tetrahydropyranyl, piperidinyl and methoxycarbonylpiperidinyl. Suitable examples of the cyclic moiety formed by R4a and R4b include difluoro- cyclohexyl. Typically, R6 represents -OR6a or -NR6bR6c; or R6 represents C1-6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, heteroaryl or heteroaryl- (C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents. Appositely, R6 represents -OR6a or -NR6bR6c; or R6 represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents. Suitably, R6 represents -OR6a; or R6 represents heteroaryl, which group may be optionally substituted by one or more substituents. In a first embodiment, R6 represents optionally substituted C1-6 alkyl. In a second embodiment, R6 represents optionally substituted C3-9 cycloalkyl. In a third embodiment, R6 represents optionally substituted C3-9 cycloalkyl(C1-6)alkyl. In a fourth embodiment, R6 represents optionally substituted aryl. In a fifth embodiment, R6 represents optionally substituted aryl(C1-6)alkyl. In a sixth embodiment, R6 represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, R6 represents optionally substituted C3-7 heterocycloalkyl(C1-6)alkyl. In an eighth embodiment, R6 represents optionally substituted heteroaryl. In a ninth embodiment, R6 represents optionally substituted heteroaryl(C1-6)alkyl. In a tenth embodiment, R6 represents -OR6a. In an eleventh embodiment, R6 represents -NR6aR6b. Typical values of R6 include -OR6a or -NR6aR6b; 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. Additional values of R6 include triazolyl, which group may be optionally substituted by one or more substituents. Representative values of R6 include -OR6a or -NR6aR6b; and phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. Illustrative values of R6 include -OR6a; and pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. Apt values of R6 include phenyl, pyrazolyl, isoxazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. More apt values of R6 include phenyl, pyrazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. Suitable values of R6 include pyrazolyl, isoxazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. Apposite values of R6 include pyrazolyl and oxadiazolyl, either of which groups may be optionally substituted by one or more substituents. Typical examples of R6 include oxadiazolyl and triazolyl, either of which groups may be optionally substituted by one or more substituents. Particular values of R6 include oxadiazolyl, which group may be optionally substituted by one or more substituents. Typical examples of optional substituents on R6 include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro- methyl, phenyl, fluorophenyl, hydroxy, hydroxy(C1-6)alkyl, oxo, C1-6 alkoxy, difluoro- methoxy, trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, amino(C1-6)alkyl, C1-6 alkylamino, di(C1-6)alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylamino(C1-6)alkyl, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylamino- carbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl, di(C1-6)alkylaminosulfonyl and di- (C1-6)alkylsulfoximinyl. Apposite examples of optional substituents on R6 include one, two or three substituents independently selected from halogen and C1-6 alkyl. Suitable examples of optional substituents on R6 include one, two or three substituents independently selected from C1-6 alkyl. Typical examples of particular substituents on R6 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, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl- amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, methoxycarbonylamino, methylsulfonyl- amino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximinyl. Apposite examples of particular substituents on R6 include one, two or three substituents independently selected from fluoro, methyl and ethyl. Suitable examples of particular substituents on R6 include one, two or three substituents independently selected from methyl and ethyl. Favoured examples of particular substituents on R6 include one, two or three substituents independently selected from methyl and isopropyl. Illustrative examples of particular values of R6 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- sulfoximinylphenyl, benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)- benzyl, dichlorobenzyl, (chloro)(difluoro)benzyl, bromobenzyl, cyanobenzyl, methyl- benzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxy- benzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylamino- benzyl, pyrrolidinylbenzyl, (dimethyl)(pyrrolidinyl)benzyl, morpholinylbenzyl, (dimethyl)(morpholinyl)benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, ethylpyrazolyl, (methyl)(tetrahydropyranyl)- pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl and aminopyridinyl- methyl. Additional examples include isopropyltriazolyl. Favoured values of R6 include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl. Selected values of R6 include methylpyrazolyl, ethylpyrazolyl, methyloxadiazolyl and ethyloxadiazolyl. Typical examples of particular values of R6 include methyloxadiazolyl, ethyl- oxadiazolyl and isopropyltriazolyl. Suitable examples of particular values of R6 include methyloxadiazolyl and isopropyltriazolyl. Particular examples of selected values of R6 include methyloxadiazolyl and ethyloxadiazolyl. In a first embodiment, R6 represents methyloxadiazolyl. In a second embodiment, R6 represents ethyloxadiazolyl. In a third embodiment, R6 represents isopropyltriazolyl. In a first embodiment, R6a represents C1-6 alkyl. In a second embodiment, R6a represents optionally substituted C3-9 cycloalkyl. Typically, R6a represents C1-6 alkyl; or R6a represents cyclobutyl, which group may be optionally substituted by one or more substituents. Typical examples of optional substituents on R6a include one, two or three substituents independently selected from halogen, cyano, nitro, C1-6 alkyl, trifluoro- methyl, hydroxy, hydroxy(C1-6)alkyl, oxo, C1-6 alkoxy, difluoromethoxy, trifluoro- methoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, amino(C1-6)alkyl, C1-6 alkylamino, di(C1-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(C1-6)alkylaminocarbonyl, aminosulfonyl, C1-6 alkylaminosulfonyl and di(C1-6)alkylaminosulfonyl. Suitable examples of optional substituents on R6a include one, two or three substituents independently selected from halogen. Typical examples of specific substituents on R6a 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, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethyl- aminosulfonyl. Suitable examples of specific substituents on R6a include one, two or three substituents independently selected from fluoro. Illustrative examples of specific values of R6a include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclobutyl and difluorocyclobutyl. Typically, R6a represents cyclobutyl. Typically, R6b represents hydrogen or methyl. In a first embodiment, R6b represents hydrogen. In a second embodiment, R6b represents C1-6 alkyl, especially methyl. Typically, R6c represents hydrogen or methyl. In a first embodiment, R6c represents hydrogen. In a second embodiment, R6c represents C1-6 alkyl, especially methyl. Alternatively, the moiety -NR6bR6c may suitably represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents. Selected examples of suitable substituents on the heterocyclic moiety -NR6bR6c include C1-6 alkyl, C1-6 alkylsulfonyl, hydroxy, hydroxy(C1-6)alkyl, amino(C1-6)alkyl, cyano, oxo, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, amino, C2-6 alkylcarbonyl- amino, C2-6 alkylcarbonylamino(C1-6)alkyl, C2-6 alkoxycarbonylamino, C1-6 alkylsulfonyl- amino and aminocarbonyl. Selected examples of specific substituents on the heterocyclic moiety -NR6bR6c include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, 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 N-oxides thereof, and pharmaceutically acceptable salts thereof:
Figure imgf000022_0001
wherein R16 represents methyl, ethyl or isopropyl; and A, E, R3, R4a and R4b are as defined above. Generally, R16 represents methyl or ethyl. In a first embodiment, R16 represents methyl. In a second embodiment, R16 represents ethyl. In a third embodiment, R16 represents isopropyl. Another sub-class of compounds according to the invention is represented by the compounds of formula (IIB) and N-oxides thereof, and pharmaceutically acceptable salts thereof:
Figure imgf000023_0001
wherein X represents CH or N; and A, E, R3, R4a, R4b and R16 are as defined above. In a first embodiment, X represents CH. In a second embodiment, X represents N. Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof. 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. Generally, 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, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, Type I Diabetes, lyme arthritis, meningoencephalitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrosing disorders including pulmonary fibrosis, liver fibrosis, renal fibrosis, scleroderma or systemic sclerosis, cancer (both solid tumours such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies and in particular acute myelogenous leukaemia, chronic myelogenous leukemia, chronic lymphatic leukemia, gastric cancer and colon cancer), heart disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydia and pain (particularly pain associated with inflammation). 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. 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. Particular categories of Dry Eye Syndrome include keratoconjunctivitis sicca (KCS), Sjögren syndrome, Sjögren syndrome-associated keratoconjunctivitis sicca, non-Sjögren 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. Illustratively, 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). Suitably, 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. Pharmaceutical 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. For oral administration, 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). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration, the 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. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. In addition to the formulations described above, 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. For nasal administration or administration by inhalation, 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. The 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. For topical 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. Alternatively, 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. For ophthalmic administration 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. Alternatively, for ophthalmic administration the compounds according to the present invention may be formulated in an ointment such as petrolatum. For rectal administration 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. 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. 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. If desired, 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 R6-CO2H or a salt thereof, e.g. an alkali metal salt such as the lithium salt thereof, with a compound of formula (III):
Figure imgf000028_0001
wherein A, E, R3, R4a, R4b and R6 are as defined above. The reaction is conveniently accomplished in the presence of a coupling agent and a base. Suitable coupling agents include 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU); and 2,4,6-tripropyl- 1,3,5,2,4,6-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. a cyclic ether such as tetrahydrofuran; or a dipolar aprotic solvent such as N,N-dimethyl- formamide or N,N-dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate. Alternatively, the reaction may conveniently be accomplished in the presence of a coupling agent such as N-(3-dimethylaminopropyl)-Nʹ-ethylcarbodiimide (EDC). The reaction is suitably performed at an appropriate temperature, e.g. a temperature in the region of 0°C, in a suitable solvent, e.g. an organic nitrile solvent such as acetonitrile. Where R6 represents C1-6 alkyl, e.g. methyl, the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula R6-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 N,N-diisopropylethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran. Where R6 represents -OR6a, the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R6a-OH with N,Nʹ-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 (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 Rp from a compound of formula (IV):
Figure imgf000029_0001
wherein A, E, R3, R4a and R4b are as defined above, and Rp represents a N-protecting group. The N-protecting group Rp will suitably be tert-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. Alternatively, the N-protecting group Rp 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 or triethylsilane in the presence of a hydrogenation catalyst, e.g. palladium on charcoal, or palladium hydroxide on charcoal. In an alternative procedure, the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) saponifying a compound of formula (V):
Figure imgf000030_0001
wherein A, E, R4a, R4b and R6 are as defined above, and Alk1 represents C1-4 alkyl, e.g. methyl, ethyl or tert-butyl; and (ii) reaction of the carboxylic acid derivative thereby obtained with a compound of formula R3-H; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R6-CO2H. Where Alk1 represents methyl or ethyl, 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. The reaction is conveniently performed at ambient or elevated temperature in water and a suitable organic solvent, e.g. a cyclic ether such as tetrahydrofuran, or a C1-4 alkanol such as methanol. Alternatively, where Alk1 represents tert-butyl, the saponification reaction in step (i) may generally be effected by treatment with an acid, e.g. an organic acid such as trifluoroacetic acid. The reaction is conveniently performed at ambient temperature in a suitable organic solvent, e.g. a chlorinated solvent such as dichloromethane. Alternative coupling agents that may usefully be employed in step (ii) include 2- chloro-1-methylpyridinium iodide. In another procedure, the compounds of formula (I) above may be prepared by a process which comprises cyclising a compound of formula (VIA) or (VIB):
Figure imgf000031_0001
wherein A, E, R3, R4a, R4b and R6 are as defined above. Cyclisation of compound (VIA) or (VIB) is conveniently effected by heating in a suitable medium, e.g. acetic acid, or trifluoroacetic acid. The intermediates of formula (VIA) or (VIB) above may be prepared by reacting a compound of formula (VII) with a carboxylic acid of formula (VIII) or a salt thereof, e.g. a lithium salt thereof:
Figure imgf000031_0002
wherein A, E, R3, R4a, R4b and R6 are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R6-CO2H. The intermediates of formula (VIII) may be prepared by a two-step procedure which comprises: (i) reacting a carboxylic acid of formula R6-CO2H with a compound of formula (IX):
Figure imgf000032_0001
wherein R6 and Alk1 are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R6-CO2H; and (ii) saponification of the resulting material under conditions analogous to those described above for the saponification of compound (V). Alternative coupling agents that may usefully be employed in step (i) include O- (benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU). The intermediates of formula (IV) above may be prepared by a two-step procedure which comprises the following steps: (i) reacting a compound of formula (VII) as defined above with a compound of formula (X):
Figure imgf000032_0002
wherein Rp is as defined above; under conditions analogous to those described above for the reaction between compounds (VII) and (VIII); and (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VIA) or (VIB). In the alternative, the intermediates of formula (III) above may be prepared by a procedure which comprises the following steps: (i) reacting a compound of formula (XI) with the compound of formula (XII):
Figure imgf000033_0001
wherein A, E, R3, R4a and R4b are as defined above, and Rq represents a N-protecting group; to provide a compound of formula (XIII):
Figure imgf000033_0002
wherein A, E, R3, R4a, R4b and Rq are as defined above; and (ii) removal of the tert-butylsulfinyl group and the N-protecting group Rq from compound (XIII). The N-protecting group Rq will suitably be 2-(trimethylsilyl)ethoxymethyl. Step (i) is suitably effected by treatment of compound (XI) with a base, e.g. an organic base such as n-butyllithium, followed by reaction with compound (XII). The reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran. Where the N-protecting group Rq is 2-(trimethylsilyl)ethoxymethyl, removal of the tert-butylsulfinyl group and the N-protecting group Rq from compound (XIII) 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. Where the N-protecting group Rq is 2-(trimethylsilyl)ethoxymethyl, the intermediates of formula (XI) above may be prepared by a procedure which comprises the following steps: (i) reaction of a compound of formula (VII) as defined above with formic acid; and (ii) reaction of the material thereby obtained with 2-(trimethylsilyl)ethoxymethyl chloride. 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. The intermediate of formula (XII) above may be prepared by reacting 2,2- dicyclopropylacetaldehyde with 2-methyl-2-propanesulfinamide. The reaction is suitably effected in the presence of pyridinium p-toluenesulfonate 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 intermediates of formula (V) above may be prepared by reacting a carboxylic acid of formula R6-CO2H with a compound of formula (XIV):
Figure imgf000034_0001
wherein A, E, R4a, R4b and Alk1 are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R6-CO2H. The intermediates of formula (XIV) above may be prepared by a three-step procedure which comprises the following steps: (i) reacting a compound of formula (X) as defined above with a compound of formula (XV):
Figure imgf000035_0001
wherein A, E, R4a, R4b and Alk1 are as defined above; under conditions analogous to those described above for the reaction between compounds (VII) and (VIII); (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VIA) or (VIB); and (iii) removal of the N-protecting group Rp from the material thereby obtained; under conditions analogous to those described above for the removal of the N-protecting group Rp from compound (IV). In an alternative method, the intermediates of formula (IV) above may be prepared by a four-step procedure which comprises the following steps: (i) reacting a compound of formula (X) as defined above with a compound of formula (XV) as defined above under conditions analogous to those described above for the reaction between compounds (VII) and (VIII); (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VIA) or (VIB); (iii) saponification of the resulting material under conditions analogous to those described above for the saponification of compound (V); and (iv) reaction of the carboxylic acid derivative thereby obtained with a compound of formula R3-H; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R6-CO2H. Where they are not commercially available, the starting materials of formula (VII), (IX), (X) and (XV) 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. By way of example, a compound comprising a N-BOC moiety (wherein BOC is an abbreviation for tert-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 N,N-diisopropylethylamine or triethylamine. Similarly, 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. Simlarly, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-S(O)2Alk1 functionality (wherein Alk1 is as defined above) by treatment with the appropriate C1-4 alkylsulfonyl chloride reagent, e.g. methylsulfonyl chloride, typically in the presence of a base, e.g. an organic base such as triethylamine. Simlarly, 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 or N,N-diisopropylethyl- amine. Alternatively, 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-1-yl)methanone iodide derivative, typically in the presence of a base, e.g. an organic base such as triethylamine. Alternatively, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety N-C(O)N(H)Alk1 (wherein Alk1 is as defined above) by treatment with the appropriate isocyanate derivative Alk1-N=C=O, 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 triacetoxyborohydride. A compound comprising a C1-4 alkoxycarbonyl moiety -CO2Alk1 (wherein Alk1 is as defined above) 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. Alternatively, a compound comprising a tert-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 R6-CO2H. A compound comprising a C1-4 alkoxycarbonyl moiety -CO2Alk1 (wherein Alk1 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 C1-4 alkylcarbonyloxy moiety -OC(O)Alk1 (wherein Alk1 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 compound comprising a halogen atom, e.g. bromo, may be converted into the corresponding compound comprising an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety by treatment with the appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3-propanediol or neopentyl glycol. The reaction is typically effected in the presence of a transition metal catalyst, and a base. The transition metal catalyst may be [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In the alternative, 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). Suitably, 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 bromoaryl or bromoheteroaryl derivative. Step (i) is conveniently effected in the presence of a transition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), and potassium acetate. Step (ii) is conveniently effected in the presence of a transition metal catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), and 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 methylmagnesium chloride is employed in step (i), the corresponding compound comprising a 1-amino-1-methylethyl moiety may be obtained. A compound comprising the moiety -S- may be converted into the corresponding compound comprising the moiety -S(O)(NH)- by treatment with (diacetoxyiodo)benzene and ammonium carbamate. A compound comprising a C=C double bond may be converted into the corresponding compound comprising a CH-CH single bond by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal. A compound comprising an aromatic nitrogen atom may be converted into the corresponding compound comprising an N-oxide moiety by treatment with a suitable oxidising agent, e.g.3-chloroperbenzoic acid. Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, 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. Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. 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. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, 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. During 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, 5th 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. Thus, when tested in the HDF cell line assay described below, compounds of the present invention exhibit a pIC50 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 (pIC50 equals -log10[IC50], in which IC50 is expressed as a molar concentration, so the skilled person will appreciate that a higher pIC50 figure denotes a more active compound). Inhibition of IL-17A induced IL-6 release from Dermal Fibroblast Cell Line The purpose of 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 TNFα, a synergistic effect can be seen in the production of inflammatory cytokines, i.e. IL-6. HDFs were stimulated with IL-17A (50 pM) in combination with TNF-α (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 104 cells/mL before being added to the 384 well assay plate (Corning #3701) at 40 μL per well. The cells were left for a minimum of three hours, at 37°C/5% CO2, to adhere to the plate. Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 μL from the titration plate was transferred to 45 μL of complete media and mixed to give a solution containing 10% DMSO. Mixtures of TNFα and IL-17 cytokine were prepared in complete media to final concentrations of TNFα 25 pM/IL-17A 50 pM, then 30 μL of the solution was added to a 384 well reagent plate (Greiner #781281). 10 μL from the aqueous dilution plate was transferred to the reagent plate containing 30 μL of the diluted cytokines, to give a 2.5% DMSO solution. The compounds were incubated with the cytokine mixtures for 5 h at 37°C. After the incubation, 10 μL was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C/5% CO2. From the 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. To a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 μL), then supernatant (10 μL) 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). When tested in the HDF cell line assay as described above, the compounds of the accompanying Examples were found to exhibit the following pIC50 values.
Figure imgf000041_0003
Figure imgf000041_0002
Figure imgf000041_0001
The following Examples illustrate the preparation of compounds according to the invention. EXAMPLES Abbreviations DCM: dichloromethane THF: tetrahydrofuran MeOH: methanol EtOH: ethanol DMSO: dimethyl sulfoxide DIPEA: N,N-diisopropylethylamine DMF: N,N-dimethylformamide AcOH: acetic acid EtOAc: ethyl acetate TFA: trifluoroacetic acid TBME: tert-butyl methyl ether IPA: isopropanol T3P®: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate EDC: N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide h: hour r.t.: room temperature M: mass RT: retention time HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry SFC: Supercritical Fluid Chromatography Analytical and Preparative Methods Method 1 Short pH 3. Stationary Phase: Phenomenex Gemini NX-C18 (2 x 20 mm, 3 μm column) Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00 Method 2 Long pH 10. Stationary Phase: Phenomenex Gemini NX-C18 (2 x 20 mm, 3 μm column) Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Method 3 MSDXT, pH 10. Stationary Phase: Waters Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 μm column) Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1.5 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00 0.10 95.00 5.00 3.50 5.00 95.00 4.00 5.00 95.00 4.05 95.00 5.00 Method 4 Agilent, pH 3, 6 minute run. Stationary Phase: X-Bridge C18 Waters (2.1 x 20 mm, 2.5 μm column) Column Temperature: 40°C Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Method 5 Agilent, pH 3, 3 minute run. Stationary Phase: X-Bridge C18 Waters (2.1 x 20 mm, 2.5 μm column) Column Temperature: 40°C Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid Flow rate: 1 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00 Method 6 Purification was performed on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer. Stationary Phase: Regis (R,R)-Whelk-1 (250 x 21.1 mm, 5 µm column) Column Temperature: 40°C Flow rate: 100 mL/minute Method: 3-40% EtOH ABPR: 120 bar Run time: 7.5 minutes Method 7 SFC Chiral Analysis. Stationary Phase: Regis (R,R)-Whelk-1 (150 x 4.6 mm, 5 µm column) Column Temperature: 35°C Flow rate: 3 mL/minute Method: 3-40% EtOH gradient Run time: 6.5 minutes Method 8 Waters Acquity-QDA. Stationary Phase: Waters Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 μm column) Column Temperature: 40°C PDA Wavelength Range: 210-400 nm Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 0.7 mL/minute Gradient program: Time A%
Figure imgf000045_0001
0.00 95.00 5.00 0.50 95.00 5.00 4.00 5.00 95.00 5.00 5.00 95.00 5.10 95.00 5.00 Method 9 pH 10. Stationary Phase: Phenomenex Gemini NmX-C18 (2 x 20 mm, 3 μm column) Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00 1.50 5.00 95.00 2.25 5.00 95.00 2.50 95.00 5.00 Method 10 Purification was performed on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer. Stationary Phase: Chiralpak IH (250 x 20 mm, 5 µm column) Column Temperature: 40°C Flow rate: 100 mL/minute Method: 3-40% MeOH (+ 0.1% NH4OH) ABPR: 60 bar Run time: 7.75 minutes Method 11 Chiral analysis method. Stationary Phase: Chiralpak ID (150 x 4.6 mm, 3 µm column) Column Temperature: 35°C Flow rate: 3 mL/minute Method: 3-40% MeOH + 0.1% NH4OH over 6.5 minutes Method 12 Purification was performed on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer. Stationary Phase: Chiralpak IH (250 x 20 mm, 5 µm column) Column Temperature: 40°C Flow rate: 100 mL/minute Method: 3-25% MeOH (+ 0.1% NH4OH) ABPR: 60 bar Run time: 10 minutes Method 13 Stationary Phase: Phenomenex, Kinetex-XB C18, 2.1 mm x 100 mm, 1.7 μm Column Temperature: 40°C Mobile Phase A: 0.1% formic acid in water Mobile Phase B: 0.1% formic acid in acetonitrile Flow rate: 0.6 mL/minute Gradient program: Time A% B% 0.00 95 55 5.30 0 100 5.80 0 100 5.82 95 5 7.00 95 5 Method 14 Stationary Phase: Chiralpak AD-3, 100 x 4.6 mm, 3 μm Column Temperature: 35°C Mobile Phase A: CO2 Mobile Phase B: IPA (+ 0.05% isopropylamine) Flow rate: 3.4 mL/minute Gradient program: Time A% B% 0.00 95 5 2.00 60 40 3.00 60 40 3.60 95 5 4.00 95 5 Method 15 Separation performed using SFC, on a Whelk-O1(R,R) 227 x 50 mm, 20 µm column, flow rate 360 mL/minute, column temperature 30°C, eluting with a 20% MeOH isocratic method (ABPR 150 bar), using a 2.5 minute cycle time (4.5 minute separation time) on a PIC Solution Prep 700 system UV triggered. Method 16 Chiral analysis performed using UHPLC, on a Whelk-O1(R,R) 150 x 4.6 mm, 3 µm column, flow rate 1.5 mL/minute, column temperature 30°C, eluting with a 50/50 ethanol/ n-heptane isocratic method, using an 8 minute run on a 1290 Agilent system UV triggered. Method 17 Stationary Phase: Waters Acquity UPLC BEH C181.7 µm (2.1 x 100 mm) column Column Temperature: 45°C Mobile Phase A: H2O/acetonitrile/ammonium formate (95/5/63 mg/L) + 100 µL/L NH4OH Mobile Phase B: acetonitrile/H2O/ammonium formate (95/5/63 mg/L) + 100 µL/L NH4OH Flow rate: 0.4 mL/minute to 0.5 mL/minute Gradient program: Time A% B% 0 99 1 0.8 99 1 5.30 0 100 5.35 0 100 7.30 0 100 7.35 99 1 9 90 1 INTERMEDIATE 1 2-Amino-3,3-dicyclopropylpropanoic acid hydrochloride 2,2-Dicyclopropylacetaldehyde (5.00 g, 40.3 mmol) in THF (16 mL) was added to a suspension of ammonium carbonate (9.67 g, 101 mmol) and potassium cyanide (3.28 g, 50.4 mmol) in water (16 mL) in a sealed pressure flask. The mixture was heated at 60°C for 18 h, then cooled using an ice bath. Aqueous hydrochloric acid (6M) was added carefully to adjust the pH to <5. The resultant white solid was filtered, washed with water and dried in vacuo. The resulting crude 5-(dicyclopropylmethyl)imidazolidine-2,4-dione (colourless solid) (6.42 g) was suspended in aqueous NaOH solution (5M, 45 mL) and heated at reflux temperature for 18 h. The mixture was cooled to room temperature, then placed in an ice bath and acidified with concentrated aqueous hydrochloric acid (20 mL) to adjust the pH <5, whereupon a precipitate formed. The mixture was extracted with EtOAc (100 mL, then 30 mL). The aqueous layer was concentrated in vacuo and freeze- dried (acetonitrile/water), then extracted with warm ethanol (100 mL) and filtered. The ethanol layer was concentrated in vacuo to give the title compound (containing 15% w/w NH4Cl) (3.5 g, 51%) as a light pink solid. δH (400 MHz, D2O) 4.01 (d, J 3.5 Hz, 1H), 0.89-0.65 (m, 3H), 0.65-0.22 (m, 6H), 0.22-0.04 (m, 2H). INTERMEDIATE 2 2-(Benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid To a suspension of Intermediate 1 (2.5 g, 12.0 mmol) and triethylamine (5.9 mL, 42 mmol) in DCM (60 mL) at 0°C (cooled in an ice/water bath) was added N-(benzyloxy- carbonyloxy)succinimide (2.9 g, 11.4 mmol) in portions. The reaction mixture was stirred at r.t. for 21 h, then diluted and washed with aqueous hydrochloric acid solution (1M, 3 x 50 mL). The resulting mixture was passed through a phase separator and concentrated in vacuo. The crude residue was re-dissolved in DCM (50 mL), then aqueous NaOH solution (1M, 50 mL) was added and the layers were separated. DCM (50 mL) and aqueous hydrochloric acid (2M, 50 mL) were added to the basic aqueous layer, then the layers were separated and the aqueous layer was re-extracted with DCM (2 x 30 mL). The combined DCM layers were passed through a phase separator and concentrated in vacuo to give the crude title compound (90% purity) (1.69 g, 46%) as a yellow oil, which was utilised without further purification. δH (400 MHz, DMSO-d6) 12.53 (s, 1H), 7.48 (d, J 8.9 Hz, 1H), 7.42-7.28 (m, 5H), 5.09 (d, J 12.7 Hz, 1H), 5.04 (d, J 12.7 Hz, 1H), 4.20 (dd, J 8.9 and 4.4 Hz, 1H), 1.06-0.91 (m, 1H), 0.85-0.74 (m, 1H), 0.58-0.43 (m, 2H), 0.42-0.21 (m, 4H), 0.20-0.00 (m, 3H). LCMS (Method 1): [M+H]+ m/z 304.0, RT 1.18 minutes. INTERMEDIATE 3 N,N-Dibenzyl-2,3-difluoro-6-nitroaniline To a stirred solution of 2,3,4-trifluoronitrobenzene (200 g, 1.13 mol) in aceto- nitrile (2 L) were added DIPEA (296 g, 2.29 mol) and dibenzylamine (245 g, 1.20 mol). The reaction mixture was stirred at 65°C for 18 h, then TBME (2 L) and water (1 L) were added. The phases were separated, and the organic fractions were washed with water (1 L), 5% HCl solution (1.6 L), 50% brine (1 L) and brine (600 mL). The organic fraction was dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in TBME (500 mL) with heating, and isohexane (700 mL) was added. The mixture was allowed to cool to r.t., and crystallisation afforded the title compound (310 g, 77%). δH (300 MHz, DMSO-d6) 7.69 (m, 1H), 7.45-7.20 (m, 11H), 4.20 (s, 4H). LCMS (Method 2): [M+H]+ m/z 355.0, RT 3.03 minutes. INTERMEDIATE 4 Methyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]acetate To a solution of Intermediate 3 (15.0 g, 42.3 mmol) and dimethyl malonate (7.4 mL, 63 mmol) in DMF (85 mL) was added K2CO3 (14.6 g, 106 mmol). The mixture was heated at 60°C for 24 h, then diluted with TBME (450 mL) and water (300 mL). The pH was adjusted to ~7 with 10% aqueous HCl. The organic layer was washed with water (2 x 300 mL), separated and concentrated in vacuo. The residue was dissolved in a mixture of DMSO (170 mL) and water (17 mL). Lithium chloride (5.4 g, 130 mmol) was added to the solution, and the mixture was heated at 115°C for 20 h. Water (400 mL) was added to the mixture. The resulting yellow suspension was extracted with TBME (2 x 300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over Na2SO4 and concentrated. The residue was recrystallised from TBME and isohexane to give the title compound (11.26 g, 65%). LCMS (Method 3): [M+H]+ m/z 409, RT 2.95 minutes. INTERMEDIATE 5 Methyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorobutanoate To a stirred solution of Intermediate 4 (10.60 g, 26.0 mmol) in THF was added NaH (60%, 1.15 g, 28.6 mmol) in one portion at -10°C. The mixture was stirred for 15 minutes, then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (3.6 mL, 27.2 mmol) was added dropwise. The reaction mixture allowed to warm to r.t. and stirred for 18 h, then quenched with saturated aqueous NH4Cl solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (2 x 50 mL) and dried over MgSO4, then filtered and concentrated in vacuo. The resulting crude material was separated by flash column chromatography, eluting with EtOAc/heptane (0- 100% gradient), to afford the title compound (7.4 g, 59%) as a yellow-orange solid. δH (500 MHz, DMSO-d6) 7.53 (dd, J 8.4, 0.9 Hz, 1H), 7.38-7.13 (m, 11H), 5.97 (tt, J 56.1, 4.4 Hz, 1H), 4.21-4.06 (m, 5H), 3.63 (s, 3H), 2.77-2.55 (m, 1H), 2.23 (dtdd, J 19.2, 15.2, 8.2, 4.4 Hz, 1H). LCMS (Method 4): [M+H]+ m/z 473, RT 3.66 minutes. INTERMEDIATE 6 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluorobutanoic acid To a stirred solution of Intermediate 5 (10.00 g, 21.2 mmol) in THF (100 mL) was added a solution of LiOH.H2O (2.20 g, 51.2 mmol) in water (25 mL) portionwise at r.t. The reaction mixture was stirred for 16 h, then cooled with an ice bath. HCl solution (6M, 10 mL) was added dropwise. The resulting solution was diluted with water (20 mL) and extracted with EtOAc (200 mL). The organic layer was washed with water (2 x 50 mL) and brine (50 mL), then dried over anhydrous Na2SO4 and filtered. The solvent was concentrated in vacuo to afford the title compound (9.77 g, 96%) as a yellow solid, which was utilised without further purification. δH (400 MHz, CDCl3) 7.35 (dd, J 8.4, 1.1 Hz, 1H), 7.29-7.20 (m, 10H), 7.06 (dd, J 8.3, 6.7 Hz, 1H), 5.64 (tt, J 56.1, 4.5 Hz, 1H), 4.21 (s, 4H), 4.10 (t, J 7.4 Hz, 1H), 2.76-2.60 (m, 1H), 2.28-2.10 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -116.37 (d, J 287.0 Hz), -117.47, -118.00 (d, J 287.0 Hz). LCMS (Method 5): [M+H]+ m/z 459, RT 2.05 minutes (95% UV purity). INTERMEDIATE 7 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4-difluoro-N-(2,2,2-trifluoroethyl)- butanamide To a stirred solution of Intermediate 6 (6.50 g, 14.2 mmol) and 2,2,2-trifluoro- ethanamine (1.3 mL, 17.0 mmol) in DCM (65 mL) was added HATU (6.47 g, 17.0 mmol), followed by DIPEA (5.0 mL, 28.6 mmol). The reaction mixture was stirred at r.t. for 2 h, then diluted with DCM (100 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of EtOAc/heptane (0-20%), to afford the title compound (7.01 g, 90% yield, corrected for solvent content) as an orange oil. δH (400 MHz, CDCl3) 7.37 (dd, J 8.5, 1.5 Hz, 1H), 7.31-7.20 (m, 10H), 7.11 (dd, J 8.5, 6.7 Hz, 1H), 5.70 (tt, J 56.3, 4.4 Hz, 1H), 5.60 (t, J 6.3 Hz, 1H), 4.26-4.19 (m, 4H), 3.94 (t, J 7.3 Hz, 1H), 3.92-3.76 (m, 2H), 2.83-2.63 (m, 1H), 2.21-2.06 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -72.50, -115.87 (d, J 286.3 Hz), -118.29 (d, J 286.3 Hz), -119.00. LCMS (Method 4): [M+H]+ m/z 540, RT 3.64 minutes (100%). INTERMEDIATES 8 & 9 (2S)-2-(3,4-Diamino-2-fluorophenyl)-4,4-difluoro-N-(2,2,2-trifluoroethyl)butanamide and (2R)-2-(3,4-diamino-2-fluorophenyl)-4,4-difluoro-N-(2,2,2-trifluoroethyl)butanamide To a solution of Intermediate 7 (1.5 g, 2.78 mmol) in EtOH (20 mL) at r.t. was added 10% palladium on charcoal (592 mg, 0.56 mmol). The reaction mixture was evacuated and purged three times with nitrogen gas, then placed under an atmosphere of hydrogen gas. The reaction mixture was stirred under 1 atmosphere of hydrogen gas (balloon) at ambient temperature for 20 h, then filtered over a pad of Celite®, rinsing the filter cake with EtOH (2 x 5 mL). The filtrates were combined, and the solvent was removed in vacuo. The crude residue was purified by flash column chromatography, eluting with a gradient of EtOAc/hexanes (0-60%). The resulting brown oil was subjected to chiral preparative SFC (Method 6) to afford the title compounds (Peak 1, 270 mg; and Peak 2, 270 mg) as white solids. Peak 1 (Intermediate 8, arbitrarily assigned S): Chiral Analysis (Method 7) RT 3.96 minutes (100%). LCMS (Method 8): [M]+ m/z 329, RT 1.82 minutes. Peak 2 (Intermediate 9, arbitrarily assigned R): Chiral Analysis (Method 7) RT 4.93 minutes (100%). LCMS (Method 8): [M]+ m/z 329, RT 1.82 minutes. INTERMEDIATE 10 Benzyl N-(2,2-dicyclopropyl-1-{5-[( 3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)-
Figure imgf000052_0001
propyl]-4-fluoro-1H-benzimidazol-2-yl}ethyl)carbamate To a solution of Intermediate 8 (210 mg, 0.64 mmol) and Intermediate 2 (232 mg, 0.77 mmol) in DCM (5 mL) was added DIPEA (335 μL, 1.9266 mmol), followed by HATU (313 mg, 0.80 mmol). The reaction mixture was stirred for 18 h at ambient temperature. Additional Intermediate 2 (100 mg, 0.33 mmol), DIPEA (150 μL, 0.86 mmol) and HATU (150 mg, 0.38 mmol) were added at ambient temperature, and the reaction mixture was stirred for a further 18 h. Additional Intermediate 2 (50 mg, 0.17 mmol), DIPEA (100 μL, 0.57 mmol) and HATU (100 mg, 0.25 mmol) were added at ambient temperature, and the mixture was stirred for a further 4 h. The reaction mixture was diluted with DCM (20 mL), water was added, and the material was passed through a phase separator. The aqueous layer was washed with DCM (20 mL), and the combined organic layers were concentrated in vacuo. The resulting crude clear oil was stirred in AcOH (10 mL) at 60°C for 18 h, then the mixture was concentrated in vacuo. The resulting brown oil was purified by flash column chromatography, eluting with EtOAc/ hexanes (0-100% gradient), to give the title compound (90% purity) (311 mg, 82%) as a clear oil. LCMS (Method 9): [M+H]+ m/z 597, RT 1.42 minutes. INTERMEDIATE 11 (2S)-2-[2-(1-Amino-2,2-dicyclopropylethyl)-4-fluoro-1H-benzimidazol-5-yl]-4,4- difluoro-N-(2,2,2-trifluoroethyl)butanamide To a suspension of Intermediate 10 (310 mg, 0.52 mmol) in EtOH (25 mL) at r.t. was added 10% palladium on charcoal (10 mass %, 110.6 mg, 0.1043 mmol). The reaction mixture was evacuated and purged three times with nitrogen gas, then placed under an atmosphere of hydrogen gas. The reaction mixture was stirred under 1 atmosphere of hydrogen gas (balloon) at ambient temperature for 20 h, then filtered over a pad of Celite®, rinsing the filter cake with EtOH (2 x 5 mL). The filtrates were combined, and the solvent was removed in vacuo, to give the title compound (170 mg, 71%) as a clear film, which was utilised without further purification. LCMS (Method 9): [M+H]+ m/z 463.2, RT 1.17 minutes. INTERMEDIATE 12 N,N-Dibenzyl-6-chloro-3-nitropyridin-2-amine To a solution of 2,6-dichloro-3-nitropyridine (50 g, 251 mmol) in DCM (500 mL) were added dibenzylamine (52 mL, 262 mmol) and triethylamine (70 mL, 502 mmol). The reaction mixture was stirred at 45°C for 23 h, then cooled to r.t., diluted with DCM (500 mL) and washed with water (500 mL). The aqueous layer was re-extracted with DCM (200 mL). The combined organic extracts were washed with water (500 mL), and the washings were re-extracted with DCM (200 mL). The combined organic extracts were dried over Na2SO4, then filtered and concentrated in vacuo, to afford the title compound (96.2 g, quantitative) as a dark orange viscous oil, which was utilised without further purification. LCMS (Method 2): [M+H]+ m/z 354, RT 3.03 minutes. INTERMEDIATE 13   O1-tert-Butyl O3-ethyl 2-[6-(dibenzylamino)-5-nitropyridin-2-yl]propanedioate To a solution of Intermediate 12 (96.2 g, 262 mmol) in DMF (520 mL) were added K2CO3 (90.4 g, 654 mmol) and tert-butyl ethyl malonate (77 mL, 390 mmol). The resulting mixture was stirred at 75°C for 3 days, then cooled to r.t. and poured into water (1.5 L). The dark brown mixture was slowly acidified with 1N HCl solution until pH 3-4 was achieved, then the aqueous mixture was extracted with TBME (2 x 1 L). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SNAP 1500 g, 0-25% EtOAc in hexanes) to afford the title compound (65.4 g, 37%) as an orange oil. LCMS (Method 2): [M+H]+ m/z 506, RT 3.23 minutes. INTERMEDIATE 14 Ethyl 2-[6-(dibenzylamino)-5-nitropyridin-2-yl]acetate To a solution of Intermediate 13 (65.4 g, 97.6 mmol) in DCM (100 mL) was added TFA (100 mL, 1323 mmol). The resulting mixture was stirred at r.t. for 24 h, then concentrated in vacuo. The residue was taken up in water (1 L) and basified with 4N aqueous NaOH solution to pH 9-10, then extracted with TBME (2 x 1 L). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SNAP 750 g, 0-25% EtOAc in hexanes) to afford the title compound (43.3 g, 94%) as an orange oil. LCMS (Method 2): [M+H]+ m/z 406, RT 2.90 minutes. INTERMEDIATE 15 Ethyl 1-[6-(dibenzylamino)-5-nitropyridin-2-yl]-4,4-difluorocyclohexanecarboxylate Intermediate 14 (2.6 g, 6.5 mmol) was placed in a 150 mL flask, and the vessel was purged with nitrogen. DMF (33 mL) was added. The clear dark green solution was purged with nitrogen, then 3,3-difluoro-1,5-diiodopentane (2.34 g, 6.50 mmol) was added in one portion. The resulting clear orange solution was purged with nitrogen and Cs2CO3 (5.09 g, 15.6 mmol) was added in one portion. The vessel was purged with nitrogen, and the dark green, opaque reaction mixture was stirred at r.t. for 18 h, then poured onto water (120 mL) and brine (10 mL). The layers were separated. The aqueous layer was re- extracted with EtOAc (100 mL and 50 mL). The combined organic layers were washed with water (50 mL) and brine (30 mL), then dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by NP flash chromatography (100g Sfar Duo HC, DCM in hexanes) to afford the title compound (1.88 g, 55%) as an orange oil. LCMS (Method 9): [M+H]+ m/z 510, RT 1.55 minutes. INTERMEDIATE 16 Ethyl 1-(5,6-diaminopyridin-2-yl)-4,4-difluorocyclohexanecarboxylate To a solution of Intermediate 15 (2.45 g, 4.41 mmol) in EtOH (19 mL) under nitrogen was added palladium on carbon (10% w/w, 245 mg). The mixture was evacuated three times and backfilled with hydrogen, then stirred at r.t. under 1 bar of hydrogen for 7 days. The reaction mixture was filtered through a pad of Celite® and washed with EtOH (2 x 50 mL). The combined filtrates were concentrated in vacuo. The residue was re-dissolved in EtOH (19 mL) and stirred at r.t. under nitrogen, then palladium on carbon (10% w/w, 245 mg) was added. The mixture was evacuated three times and backfilled with hydrogen, then stirred at r.t. under 1 bar of hydrogen for 3 days. The reaction mixture was filtered through Celite®, and the filter cake was washed with EtOH (2 x 50 mL). The filtrates were concentrated in vacuo to afford the title compound (1.46 g, 99%) as a crude purple oil, which was utilised without further purification. LCMS (Method 2): [M+H]+ m/z 300, RT 1.67 minutes. INTERMEDIATE 17 Ethyl 1-[6-amino-5-(tert-butoxycarbonylamino)pyridin-2-yl]-4,4-difluorocyclohexane- carboxylate A solution of di-tert-butyl dicarbonate (1.05 g, 4.76 mmol) in EtOH (4.5 mL) was added to Intermediate 16 (1.46 g, 4.35 mmol), then guanidine hydrochloride (63 mg, 0.66 mmol) was added. The resulting mixture was stirred at 50°C for 24 h, and left standing at r.t. for 2 days, then concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was passed through a hydrophobic frit and concentrated in vacuo. The crude residue was purified by flash chromatography (SNAP 50 g, 0-25% EtOAc in hexane) to afford the title compound (1.37 g, 76%) as a colourless oil which solidified upon standing. LCMS (Method 2): [M+H]+ m/z 400, RT 2.40 minutes. INTERMEDIATE 18 Ethyl 1-[6-{[2-(benzyloxycarbonylamino)-3,3-dicyclopropylpropanoyl]amino}-5-(tert- butoxycarbonylamino)pyridin-2-yl]-4,4-difluorocyclohexanecarboxylate To a solution of Intermediate 17 (1.4 g, 3.4 mmol) in EtOAc (10 mL) were added Intermediate 2 (1.1 g, 3.7 mmol) and pyridine (1.2 mL, 15 mmol). The mixture was cooled to 4°C, then a solution of T3P® in EtOAc (50% w/w, 5 mL, 8.5 mmol) was added over 3 minutes. The resulting mixture was allowed to warm to r.t. and stirred for 19 h, then poured onto ice. The mixture was diluted with EtOAc (50 mL) and partitioned. The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. The crude residue was purified by flash chromatography (SNAP 50 g, 0-50% EtOAc in hexane) to afford the title compound (2.07 g, 89%) as an off-white solid. LCMS (Method 9): [M+H]+ m/z 685, RT 1.77 minutes. INTERMEDIATE 19 Ethyl 1-{2-[1-(benzyloxycarbonylamino)-2,2-dicyclopropylethyl]-1H-imidazo[4,5-b]- pyridin-5-yl}-4,4-difluorocyclohexanecarboxylate To a solution of Intermediate 18 (2.07 g, 3.02 mmol) in DCM (10 mL) was added TFA (2.3 mL, 30 mmol). The resulting mixture was stirred at 43°C for 24 h. The solvent was removed in vacuo. The residue was dissolved in water (50 mL), then treated with 2N aqueous NaOH solution until pH 9-10 was achieved. The resulting suspension was extracted with EtOAc (2 x 50 mL), and the organic extracts were concentrated in vacuo. The resulting crude light pink oil was purified by flash chromatography (SNAP 25 g, 0- 100% EtOAc in hexane) to afford the title compound (1.6 g, 92%) as a clear oil. LCMS (Method 9): [M+H]+ m/z 567, RT 1.53 minutes. INTERMEDIATE 20 1-{2-[1-(Benzyloxycarbonylamino)-2,2-dicyclopropylethyl]-1H-imidazo[4,5-b]pyridin-5- yl}-4,4-difluorocyclohexanecarboxylic acid To a solution of Intermediate 19 (510 mg, 0.9 mmol) in DCM (9 mL) was added NaOH (3M solution in MeOH, 1.3 mL, 3.9 mmol). The resulting mixture was stirred at r.t. for 2 days, then poured into water (50 mL). The organic layer was separated, and the aqueous layer was acidified to pH 2 with 6M aqueous HCl solution. The resulting precipitate was filtered and dried under vacuum to afford the title compound (550 mg, 96.4%) as a beige solid. LCMS (Method 9): [M+H]+ m/z 539, RT 1.04 minutes. INTERMEDIATE 21 Benzyl N-(2,2-dicyclopropyl-1-{5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)- cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}ethyl)carbamate To a cooled solution (0°C) of Intermediate 20 (550 mg, 0.90 mmol) in dry acetonitrile (4.5 mL) under nitrogen was added 2,2,2-trifluoroethylamine (290 μL, 3.61 mmol), followed by EDC (211 mg, 1.08 mmol). The resulting mixture was stirred at 0°C for 1 h, and warmed to ambient temperature, then diluted with EtOAc (20 mL) and water (20 mL). The layers were separated, and the organic layer was washed with water (20 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (25g SFar cartridge, eluting with a gradient of 0-100% EtOAc in isohexane) to afford the title compound (350 mg, 59%) as a solid. LCMS (Method 9): [M+H]+ 620, RT 1.48 minutes. INTERMEDIATE 22 1-[2-(1-Amino-2,2-dicyclopropylethyl)-1H-imidazo[4,5-b]pyridin-5-yl]-4,4-difluoro-N- (2,2,2-trifluoroethyl)cyclohexanecarboxamide To a solution of Intermediate 21 (350 mg, 0.56 mmol) in EtOH (6 mL) was added palladium on carbon (10% w/w, 120 mg, 0.113 mmol). The resulting mixture was evacuated and backfilled with hydrogen (using a balloon), then stirred under 1 bar of hydrogen for 16 h. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with MeOH (50 mL). The combined filtrates were concentrated in vacuo to afford the title compound (300 mg, quantitative) as a brown oil, which was utilised without further purification. LCMS (Method 9): [M+H]+ 486, RT 1.24 minutes. INTERMEDIATE 23 N,N-Dibenzyl-2,3-difluoro-6-nitroaniline To a solution of 2,3,4-trifluoronitrobenzene (13 mL, 113 mmol) and DIPEA (40 mL, 229 mmol) in THF (225 mL) was added dibenzylamine (27 mL, 136 mmol). The yellow solution was heated at 75°C 48 h. After cooling, the reaction mixture was diluted with water (200 mL) and EtOAc (200 mL). The organic layer was separated and washed with 10% HCl solution, water (2 x 200 mL) and saturated aqueous NaHCO3 solution (200 mL), then brine (200 mL). The yellow organic layer was concentrated in vacuo. The resultant yellow oil was flashed through a plug of silica, eluting with 20% EtOAc in hexanes. To the resulting lighter-coloured yellow oil were added hexanes (250 mL) to induce rapid crystallisation. After stirring the solution at r.t. for 1 h, the crystals were collected, then washed with hexanes (20 mL) and dried, to yield the title compound (22.95 g, 57.3%). δH (300 MHz, DMSO-d6) 7.69 (ddd, J 9.2, 5.4, 2.2 Hz, 1H), 7.45-7.35 (m, 1H), 7.35-7.19 (m, 10H), 4.20 (d, J 1.3 Hz, 4H). INTERMEDIATE 24 Diethyl 2-(2,2,2-trifluoroethyl)propanedioate To a cooled (0°C) solution of diethyl malonate (5 g, 30.9 mmol) in THF (62 mL) was added potassium tert-butoxide (4.25 g, 37.0 mmol) in small portions over 5 minutes (internal temperature maintained below 3°C), then 2,2,2-trifluoroethyl trifluoromethane- sulfonate (13.5 mL, 92.7 mmol) was added dropwise over 6 minutes (internal temperature maintained below 1.5°C). The resulting mixture was warmed to 40°C and stirred. After 20 h, the reaction mixture was cooled to r.t. and poured into water. The mixture was neutralized with 6N HCl and extracted with TBME (250 mL, then 100 mL). The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography (SNAP 100 g, 0-35% EtOAc in hexane) afforded the title compound (5.66 g, 75.6%) as a colourless liquid. δH (300 MHz, DMSO-d6) 4.28-4.20 (m, 4H), 3.65-3.60 (m, 1H), 2.87-2.75 (m, 4H), 1.30-1.24 (m, 6H). INTERMEDIATE 25 Diethyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-2-(2,2,2-trifluoroethyl)propane- dioate To a solution of Intermediate 23 (3.66 g, 10.34 mmol) and Intermediate 24 (6.26 g, 25.8 mmol) in DMF (21 mL, 271 mmol) was added K2CO3 (7.15 g, 51.7 mmol). The resulting mixture was stirred at 85°C for 72 h, then cooled to r.t., poured into water (250 mL) and extracted with TBME (250 mL, then 100 mL). The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography (SNAP 100 g, 0-10% EtOAc in hexanes; isocratic at 10%) afforded the title compound (5.76 g, 91.4%) as a thick yellow oil. LCMS (Method 2): [M+H]+ 577, RT 3.39 minutes. INTERMEDIATE 26 Ethyl 2-[3-(dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4,4-trifluorobutanoate To a solution of Intermediate 25 (797 mg, 1.307 mmol) in THF (6 mL, 73.7 mmol) were added water (0.6 mL, 30 mmol) and LiOH.H2O (232 mg, 5.53 mmol). The resulting mixture was stirred at r.t. for 2 h, then heated to 60°C. After 3 h of heating at 60°C, the temperature was lowered to 40°C and stirring was continued for another 21 h. The mixture was cooled to r.t., then diluted with water (50 mL) and extracted with EtOAc (50 mL). The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. The residue was taken up in EtOH (10 mL), and concentrated sulfuric acid (0.3 mL, 5 mmol) was added. The resulting mixture was stirred under reflux temperature for 2.5 h, then cooled to r.t. and concentrated in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (50 mL). The organic extracts were passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography (SNAP 25 g, 5% EtOAc in hexane) afforded the title compound (451 mg, 64.3%) as a yellow oil which solidified upon prolonged standing. LCMS (Method 2): [M+H]+ 505, RT 3.30 minutes. INTERMEDIATE 27 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-4,4,4-trifluorobutanoic acid To a solution of Intermediate 26 (10 g, 19.82 mmol) in THF (80 mL) and water (8 mL) was added LiOH.H2O (1.7 g, 40 mmol). The resulting mixture was stirred at r.t. for 24 h, then diluted with water (250 mL) and EtOAc (350 mL), and neutralized with 1M HCl. The organic extracts were separated, then passed through a hydrophobic frit and concentrated in vacuo, to afford the title compound (10 g, quantitative) as an orange/ brownish solid. INTERMEDIATE 28 2-[3-(Dibenzylamino)-2-fluoro-4-nitrophenyl]-N-(2,2-difluoropropyl)-4,4,4-trifluoro- butanamide To a stirred solution of Intermediate 27 (90.00 g, 0.19 mol) and 2,2-difluoro- propan-1-amine hydrochloride (1:1) (26.20 g, 0.20 mol) in dry DMF (1.0 L) was added DIPEA (66 mL, 0.38 mol) in a single portion. HATU (76.00 g, 0.20 mol) was added portionwise over 2 minutes. The reaction mixture was stirred at r.t. for 1 h, then diluted with water (2.5 L) and brine (0.5 L). The resulting solution was extracted with EtOAc (3 x 1 L). The organic extracts were combined and washed with brine (2 x 1 L), then dried over anhydrous sodium sulfate (500 g) and filtered. The solvent was removed in vacuo. The resulting viscous brown oil was purified by dry flash chromatography (1 kg silica pad), eluting with a gradient of EtOAc in heptane (0-30%), to afford the title compound (100.0 g, 96%) as a yellow solid. δH (400 MHz, CDCl3) 7.37 (dd, J 8.6, 1.6 Hz, 1H), 7.31-7.20 (m, 10H), 7.13 (dd, J 8.5, 6.7 Hz, 1H), 5.65 (t, J 6.1 Hz, 1H), 4.23-4.19 (m, 4H), 3.99 (t, J 6.8 Hz, 1H), 3.72-3.49 (m, 2H), 3.24-3.08 (m, 1H), 2.46-2.31 (m, 1H), 1.54 (t, J 18.6 Hz, 3H). INTERMEDIATE 29 2-(3,4-Diamino-2-fluorophenyl)-N-(2,2-difluoropropyl)-4,4,4-trifluorobutanamide To a stirred solution of Intermediate 28 (9.60 g, 17.4 mmol) in EtOH (170 mL) was added 10% Pd/C (50% wet) (5.0%, 2.60 g, 1.22 mmol). The reaction mixture was evacuated three times with nitrogen gas, then placed under an atmosphere of hydrogen gas. The reaction mixture was stirred under 1 atmosphere of hydrogen gas (balloon) at r.t. for 16 h, then filtered over a double layer of glass microfibre filter paper, rinsing the filter cake with EtOH (2 x 50 mL). The filtrates were combined, then the solvent was removed in vacuo, to afford the title compound (6.20 g, 94% yield corrected for estimated 90% purity) as a purple semi-solid, which was utilised without further purification. δH (500 MHz, DMSO-d6) 8.46 (t, J 6.3 Hz, 1H), 6.35 (t, J 8.0 Hz, 1H), 6.28 (dd, J 8.2, 1.1 Hz, 1H), 4.76 (s, 2H), 4.41 (s, 2H), 3.99 (dd, J 9.0, 4.5 Hz, 1H), 3.57-3.46 (m, 2H), 3.08- 2.95 (m, 1H), 2.44-2.33 (m, 1H), 1.45 (t, J 19.0 Hz, 3H). INTERMEDIATE 30 5-(Dicyclopropylmethyl)imidazolidine-2,4-dione A stirred mixture of diammonium carbonate (47.10 g, 0.501 mol), 2,2- dicyclopropylacetaldehyde (95%, 26.10 g, 0.200 mol) and potassium cyanide (13.09 g, 0.201 mol) in a mixture of ethanol (140 mL) and water (140 mL) was heated at 60°C for 18 h. To the cooled reaction mixture were added 2N HCl (200 mL), then 6N HCl (100 mL) partwise. Additional 2N HCl (60 mL) was added, and the mixture was stirred at r.t. for 1 h. Additional 2N HCl (50 mL) was added to the mixture and the solid was filtered off, then washed with water (2 x 200 mL) and dried, to afford the title compound (95% purity) (32.81 g, 80%) as a white solid. δH (500 MHz, DMSO-d6) 10.58 (s, 1H), 8.04 (s, 1H), 4.05 (d, J 1.5 Hz, 1H), 0.91-0.81 (m, 1H), 0.82-0.73 (m, 1H), 0.52-0.36 (m, 3H), 0.36-0.23 (m, 3H), 0.23-0.17 (m, 1H), 0.13-0.07 (m, 1H), 0.06-0.00 (m, 1H). LCMS (Method 13): [M+H]+ m/z 195, RT 1.72 minutes. INTERMEDIATE 31 2-(Benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid To a stirred solution of Intermediate 30 (95%, 1.00 g, 4.89 mmol) in 1,4-dioxane (6 mL) was added 5M aqueous sodium hydroxide solution (6.0 mL, 30.0 mmol). The mixture was heated at 100°C for 18 h, then 1,4-dioxane (6 mL) and water (6 mL) were added, and the mixture was heated at 120°C for two days. To the cooled reaction mixture were added TBME (10 mL) and water (10 mL). The two-phase mixture was filtered. To the filtrate were added 6N HCl (6 mL) and TBME (10 mL). The undissolved solid was filtered off. To the filtrate was added TBME (10 mL). The layers were separated, and the aqueous layer was washed with TBME (3 x 10 mL). To the aqueous layer was added 5N aqueous NaOH solution (0.5 mL), and the pH of the solution was adjusted to pH 7 using 6N HCl/5M aqueous NaOH solution. To the aqueous solution (~40 mL) were added THF (20 mL), then NaHCO3 (1.01 g), then disodium carbonate (1.01 g, 9.53 mmol), then 1-(benzyloxycarbonyloxy)pyrrolidine-2,5-dione (0.90 g, 3.61 mmol) at r.t. The mixture was stirred at r.t. for 2.5 days, then TBME (20 mL) was added, followed by water (30 mL). The organic layer was separated off. To the aqueous layer was added water (10 mL). The aqueous layer was washed with TBME (10 mL), then filtered and washed with TBME (10 mL). The pH of the aqueous layer was adjusted to pH 3 using 6N HCl (~4 mL). Crystals from a previous batch were seeded, then the flask was externally cooled and left to stand for 2 h. The contents were filtered off, then washed with water (2 x 10 mL) and dried, to afford the title compound (719 mg, 49%) as a white solid. δH (500 MHz, DMSO-d6) 12.53 (s, 1H), 7.47 (d, J 8.9 Hz, 1H), 7.41-7.28 (m, 5H), 5.11-5.01 (m, 2H), 4.19 (dd, J 8.9, 4.4 Hz, 1H), 1.03-0.92 (m, 1H), 0.85-0.74 (m, 1H), 0.57-0.49 (m, 1H), 0.49-0.43 (m, 1H), 0.41-0.20 (m, 4H), 0.19-0.01 (m, 3H). LCMS (Method 13): [M+H]+ m/z 304, RT 3.13 minutes. INTERMEDIATES 32 & 33 (2S)-2-(Benzyloxycarbonylamino)-3,3-dicyclopropylpropanoic acid (Intermediate 32) (2R)-2-(Benzyloxycarbonylamino)-3,3-dicyclopropyl propanoic acid (Intermediate 33) Intermediate 31 (100% purity) (850 g, 2.80 mol) was subjected to separation by prep-SFC (column: Daicel Chiralpak AD, 250 mm x 50 mm, 10 μm; mobile phase: [Neu- IPA]; B%: 45%-45%, 6 minutes), and the fractions were concentrated in vacuo at 45°C, to provide the title compounds (Peak 1, 324 g, 1.07 mol, 100% purity; and Peak 2, 351 g, 1.16 mol, 100% purity) as white solids. 1H NMR and LCMS matched those for Intermediate 31. Chiral analysis (Method 14): Peak 1, RT 1.97 minutes; Peak 2, RT 2.29 minutes. INTERMEDIATE 34 Benzyl N-[(1S)-1-({2-amino-4-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoropropyl]-3- fluorophenyl}carbamoyl)-2,2-dicyclopropylethyl]carbamate To a stirred solution of Intermediate 29 (90%, 6.20 g, 16.3 mmol) and Intermediate 32 (4.93 g, 16.3 mmol) in DMF (60 mL) was added HATU (6.81 g, 17.9 mmol) portionwise, followed by DIPEA (5.7 mL, 32.6 mmol). The reaction mixture was stirred at r.t. for 16 h, then poured into water (400 mL). The resulting suspension was stirred for a further 15 minutes. The solid was collected by filtration, rinsing the filter cake with water (2 x 100 mL), diethyl ether/heptane (1:1, 150 mL) and heptane (200 mL), then dried under a flow of nitrogen for 1.5 h. The solid was further dried in a vacuum oven for 2 h at 40°C to afford the title compound (~9:1 mixture of regioisomers by NMR) (8.79 g, 81% yield corrected for 94% purity) as a pale purple solid. δH (400 MHz, DMSO-d6) 9.35 (d, J 3.2 Hz, 1H), 8.64 (t, J 6.2 Hz, 1H), 7.50 (d, J 8.7 Hz, 1H), 7.42-7.27 (m, 5H), 7.03 (d, J 8.4 Hz, 1H), 6.56 (t, J 8.0 Hz, 1H), 5.11-5.02 (m, 2H), 4.91 (s, 2H), 4.42-4.33 (m, 1H), 4.14 (dd, J 8.9, 4.6 Hz, 1H), 3.57-3.46 (m, 2H), 3.16-2.99 (m, 1H), 2.60-2.52 (m, 1H), 1.47 (t, J 19.0 Hz, 3H), 0.96-0.84 (m, 1H), 0.84-0.72 (m, 1H), 0.68- 0.52 (m, 1H), 0.52-0.41 (m, 1H), 0.40-0.07 (m, 7H). INTERMEDIATE 35 Benzyl N-[(1S)-2,2-dicyclopropyl-1-{5-[1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro- propyl]-4-fluoro-1H-benzimidazol-2-yl}ethyl]carbamate To a stirred solution of Intermediate 34 (8.79 g, 14.0 mmol) in DCM (250 mL) was added TFA (4.2 mL, 56.5 mmol) portionwise. The reaction mixture was stirred at 40°C for 16 h, then cooled to ambient temperature and 1M aqueous NaOH solution (60 mL) was added portionwise. Saturated aqueous NaHCO3 solution (20 mL) was then added portionwise with care (potential frothing). The organic phase was collected and washed with water (100 mL), then dried over anhydrous sodium sulfate and filtered. Heptane (100 mL) was added to the filtrate, and the solvent was concentrated in vacuo, to afford the title compound (9.0 g, 98%) as a pale pink solid. δH (500 MHz, CD3OD) 7.42- 7.23 (m, 6H), 7.20-6.94 (m, 1H), 5.20-4.97 (m, 3H), 4.40 (dd, J 8.8, 5.0 Hz, 1H), 3.68- 3.42 (m, 2H), 3.27-3.14 (m, 1H), 2.62-2.48 (m, 1H), 1.42 (t, J 18.6 Hz, 3H), 0.86-0.73 (m, 3H), 0.55-0.38 (m, 2H), 0.31-0.13 (m, 4H), 0.07 to -0.05 (m, 1H), -0.22 to -0.33 (m, 1H). Three NH signals not observed. INTERMEDIATE 36 2-{2-[(1S)-1-Amino-2,2-dicyclopropylethyl]-4-fluoro-1H-benzimidazol-5-yl}-N-(2,2- difluoropropyl)-4,4,4-trifluorobutanamide To a stirred solution of Intermediate 35 (9.00 g, 14.7 mmol) in MeOH (90 mL) was added 10% Pd/C (50% wet) (5.0%, 1.50 g, 0.705 mmol), followed by the dropwise addition of triethylsilane (4.7 mL, 29.5 mmol) over 15 minutes at r.t. (small exotherm up to 28°C observed). The reaction mixture was stirred for a further 30 minutes. The catalyst was removed by filtration over micro glass fibre paper (double layer), rinsing the pad with MeOH (2 x 50 mL). The filtrates were combined, and the solvent was removed in vacuo, to afford the title compound (1:1 mixture of diastereoisomers) (7.35 g, 96%) as a pale brown foamy solid, which was utilised without further purification. δH (500 MHz, CD3OD) 7.31 (d, J 8.4 Hz, 1H), 7.28-7.23 (m, 1H), 4.40 (dd, J 8.7, 5.1 Hz, 1H), 4.32 (d, J 5.0 Hz, 1H), 3.61 (q, J 13.6 Hz, 1H), 3.50 (q, J 13.6 Hz, 1H), 3.28-3.15 (m, 1H), 2.62- 2.49 (m, 1H), 1.41 (t, J 18.6 Hz, 3H), 0.88-0.81 (m, 1H), 0.80-0.72 (m, 1H), 0.66-0.55 (m, 1H), 0.54-0.48 (m, 1H), 0.48-0.43 (m, 1H), 0.37-0.27 (m, 2H), 0.27-0.16 (m, 2H), 0.08 to -0.02 (m, 1H), -0.15 to -0.28 (m, 1H). Four NH signals not observed. EXAMPLE 1
Figure imgf000065_0001
N-(2,2-Dicyclopropyl-1-{5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)propyl]-4- fluoro-1H-benzimidazol-2-yl}ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a solution of Intermediate 11 (170 mg, 0.37 mmol) in DCM (10 mL) at r.t. were added 4-methyl-1,2,5-oxadiazole-3-carboxylic acid (47 mg, 0.37 mmol), DIPEA (260 μL, 1.50 mmol) and HATU (159 mg, 0.40 mmol) sequentially. The reaction mixture was stirred for 3 h, then diluted with DCM (20 mL). Water was added, and the material was passed through a phase separator. The aqueous layer was washed with DCM (20 mL), and the combined organic layers were concentrated in vacuo. The resulting crude clear oil was purified by flash column chromatography, eluting with a gradient of EtOAc/ hexanes (0-100%), to give the title compound (110 mg, 52%) as an off-white solid. δH (300 MHz, DMSO-d6) 13.09-12.43 (m, 1H), 9.40 (dd, J 9.0, 4.1 Hz, 1H), 8.99-8.51 (m, 1H), 7.35 (dd, J 28.1, 8.4 Hz, 1H), 7.24-7.04 (m, 1H), 6.27-5.64 (m, 1H), 5.50 (dd, J 9.1, 6.8 Hz, 1H), 4.36-4.11 (m, 1H), 3.89 (dtq, J 15.2, 10.1, 5.6, 5.2 Hz, 2H), 3.33 (br s, 1H), 2.82-2.52 (m, 2H), 2.39-1.94 (m, 1H), 1.36-0.90 (m, 2H), 0.91-0.58 (m, 2H), 0.41 (dt, J 8.6, 4.8 Hz, 2H), 0.33-0.05 (m, 5H), -0.05 (d, J 35.8 Hz, 1H). LCMS (Method 3): [M+H]+ 573.4, RT 2.03 minutes.
Figure imgf000066_0001
N-[(1R)-2,2-Dicyclopropyl-1-{5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)- propyl]-4-fluoro-1H-benzimidazol-2-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide N-[(1S)-2,2-Dicyclopropyl-1-{5-[(1S)-3,3-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)- propyl]-4-fluoro-1H-benzimidazol-2-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3-carboxamide Example 1 (110 mg, 0.19 mmol) was subjected to chiral preparative SFC (Method 10) to afford the title compounds (Peak 1, 18 mg; and Peak 2, 22 mg) as white solids. Peak 1 (Example 2, arbitrarily assigned R,S) LCMS (Method 3): [M+H]+ 573.4, RT 2.03 minutes. Chiral Analysis (Method 11): RT 1.89 minutes, 100%. Peak 2 (Example 3, arbitrarily assigned S,S) LCMS (Method 3): [M+H]+ 573.4, RT 2.03 minutes. Chiral Analysis (Method 11): RT 2.22 minutes, 95.8%.
Figure imgf000066_0002
N-(2,2-Dicyclopropyl-1-{5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)cyclohexyl]- 1H-imidazo[4,5-b]pyridin-2-yl}ethyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide To a cooled (0°C) solution of Intermediate 22 (300 mg, 0.62 mmol) and 4-methyl- 1,2,5-oxadiazole-3-carboxylic acid (89 mg, 0.69 mmol) in acetonitrile (5 mL) was added EDC (133 mg, 0.69 mmol). The reaction mixture was stirred at 0°C for 1 h, then water (1.5 mL) was added to the suspension. The resulting white precipitate was filtered and washed with water (10 mL), then dried under vacuum, to afford the title compound (270 mg, 70%) as a white solid. δH (400 MHz, DMSO-d6) 12.87 (d, J 173.2 Hz, 1H), 9.23 (s, 1H), 8.26 (t, J 6.2 Hz, 1H), 7.95 (s, 1H), 7.21 (d, J 8.4 Hz, 1H), 5.52 (dd, J 8.9, 6.2 Hz, 1H), 3.85 (dt, J 16.4, 7.9 Hz, 2H), 2.67-2.46 (m, 5H), 2.38-2.15 (m, 2H), 2.14-1.80 (m, 4H), 1.01 (d, J 7.6 Hz, 1H), 0.95-0.63 (m, 2H), 0.61-0.34 (m, 2H), 0.22 (dp, J 13.2, 4.7 Hz, 4H), 0.12 to -0.20 (m, 2H). LCMS (Method 3): [M+H]+ 596, RT 2.10 minutes.
Figure imgf000067_0001
N-[(1R)-2,2-Dicyclopropyl-1-{5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)- cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3- carboxamide N-[(1S)-2,2-Dicyclopropyl-1-{5-[4,4-difluoro-1-(2,2,2-trifluoroethylcarbamoyl)- cyclohexyl]-1H-imidazo[4,5-b]pyridin-2-yl}ethyl]-4-methyl-1,2,5-oxadiazole-3- carboxamide Example 4 (20 mg, 0.44 mmol) was subjected to chiral preparative SFC (Method 12) to afford the title compounds (Peak 1, 4 mg; and Peak 2, 4 mg) as white solids. Peak 1 (Example 5, arbitrarily assigned R) LCMS (Method 3): [M+H]+ 596, RT 2.10 minutes. Chiral Analysis (Method 11): RT 2.09 minutes, 100%. Peak 2 (Example 6, arbitrarily assigned S) LCMS (Method 3): [M+H]+ 596, RT 2.10 minutes. Chiral Analysis (Method 11): RT 2.28 minutes, 95.5%.
Figure imgf000068_0001
N-[(1S)-2,2-Dicyclopropyl-1-{5-[(1R)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro- propyl]-4-fluoro-1H-benzimidazol-2-yl}ethyl]-2-isopropyl-1,2,4-triazole-3-carboxamide N-[(1S)-2,2-Dicyclopropyl-1-{5-[(1S)-1-(2,2-difluoropropylcarbamoyl)-3,3,3-trifluoro- propyl]-4-fluoro-1H-benzimidazol-2-yl}ethyl]-2-isopropyl-1,2,4-triazole-3-carboxamide To a stirred solution of Intermediate 36 (7.30 g, 13.8 mmol) and lithium 2- isopropyl-1,2,4-triazole-3-carboxylate (2.35 g, 14.6 mmol) in DMF (49 mL) was added HATU (5.78 g, 15.2 mmol) portionwise, followed by DIPEA (4.8 mL, 27.5 mmol) dropwise. The reaction mixture was stirred at r.t. for 1.5 h., then poured into water (300 mL) and brine (50 mL). The resulting suspension was stirred for a further 15 minutes to give a sticky residue. The aqueous phase was decanted off (discarded), and the sticky solid was dissolved in EtOAc (150 mL). The solution was washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo. The residue was purified using automated chromatography (Isolera 4, 350 g SFAR Duo column), eluting with a gradient of EtOAc in heptane (10-70%). The resulting beige solid (mixture of diastereomers) (6.28 g) was further purified using chiral SFC (Method 15) to yield the title compounds (Peak 1, 1.46 g, 17%; and Peak 2, 2.16 g, 25.5%). Peak 1 (arbitrarily assigned R): δH (400 MHz, DMSO-d6) 12.74 (s, 1H), 8.78 (dd, J 16.6, 9.3 Hz, 1H), 8.68 (t, J 6.1 Hz, 1H), 8.16 (s, 1H), 7.29 (d, J 8.5 Hz, 1H), 7.21 (dd, J 8.5, 6.3 Hz, 1H), 5.59 (hept, J 6.5 Hz, 1H), 5.46 (dd, J 9.2, 6.3 Hz, 1H), 4.32 (dd, J 8.5, 5.2 Hz, 1H), 3.58-3.44 (m, 1H), 3.50 (s, 1H), 3.20-3.06 (m, 1H), 1.48 (s, 1H), 1.46-1.36 (m, 9H), 1.04-0.91 (m, 1H), 0.73 (dq, J 13.7, 5.4 Hz, 2H), 0.46-0.35 (m, 2H), 0.32-0.14 (m, 2H), -0.09 (q, J 5.4 Hz, 1H). LCMS (Method 17): [M+H]+ m/z 614, RT 4.85 minutes. Chiral analysis (Method 16): RT 1.375 minutes (100%). Peak 2 (arbitrarily assigned S): δH (400 MHz, DMSO-d6) 13.18-12.54 (m, 1H), 8.87-8.71 (m, 1H), 8.65 (t, J 6.3 Hz, 1H), 7.46-7.25 (m, 1H), 7.25-7.10 (m, 1H), 5.59 (p, J 6.6 Hz, 1H), 5.46 (dd, J 9.1, 6.4 Hz, 1H), 4.31 (dd, J 8.4, 5.3 Hz, 1H), 3.50 (td, J 13.6, 7.2 Hz, 2H), 3.23-3.03 (m, 1H), 2.61 (ddd, J 15.6, 11.1, 5.1 Hz, 1H), 0.99 (q, J 8.5 Hz, 1H), 0.72 (d, J 4.8 Hz, 2H), 0.42 (d, J 7.7 Hz, 2H), 0.33-0.13 (m, 4H), 0.08 (d, J 5.3 Hz, 2H), -0.04 to -0.21 (m, 1H). LCMS (Method 17): [M+H]+ m/z 614, RT 4.87 minutes. Chiral analysis (Method 16): RT 1.719 minutes (99%).

Claims

Claims: 1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000070_0001
wherein A represents C-R1 or N; E represents C-R2 or N; R1 represents hydrogen or fluoro; R2 represents hydrogen or fluoro; R3 represents -NR3aR3b; or R3 represents a group of formula (Wa):
Figure imgf000070_0002
in which 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; R3a represents hydrogen or C1-6 alkyl; R3b represents C1-6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R4a represents hydrogen, fluoro or hydroxy; or R4a represents C1-6 alkyl, which group may be optionally substituted by one or more substituents; and R4b represents hydrogen, fluoro or C1-6 alkyl; or R4a and R4b, when taken together with the carbon atom to which they are both attached, represent C3-9 cycloalkyl or C3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; R6 represents -OR6a or -NR6bR6c; or R6 represents C1-6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(C1-6)alkyl, aryl, aryl(C1-6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl- (C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R6a represents C1-6 alkyl; or R6a represents C3-9 cycloalkyl, which group may be optionally substituted by one or more substituents; R6b represents hydrogen or C1-6 alkyl; and R6c represents hydrogen or C1-6 alkyl; or R6b and R6c, when taken together with the nitrogen atom to which they are both attached, represent azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-1-yl, homopiperidin-1-yl, homomorpholin-4-yl or homopiperazin-1-yl, any of which groups may be optionally substituted by one or more substituents.
2. A compound as claimed in claim 1 represented by formula (I-1) or (I-2) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000072_0001
wherein R1, R2, R3, R4a, R4b and R6 are as defined in claim 1.
3. A compound as claimed in claim 1 or claim 2 wherein R6 represents heteroaryl, which group may be optionally substituted by one or more substituents.
4. A compound as claimed in claim 1 represented by formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000072_0002
wherein R16 represents methyl, ethyl or isopropyl; and A, E, R3, R4a and R4b are as defined in claim 1.
5. A compound as claimed in claim 1 represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt thereof:
Figure imgf000073_0001
wherein X represents CH or N; A, E, R3, R4a and R4b are as defined in claim 1; and R16 is as defined in claim 4.
6. A compound as claimed in any one of the preceding claims wherein R3 represents -NR3aR3b, in which R3a is as defined in claim 1; and R3b represents C1-6 alkyl or C3-7 cycloalkyl(C1-6)alkyl, either of which groups may be optionally substituted by one or more substituents.
7. A compound as claimed in any one of the preceding claims wherein R4a represents C1-6 alkyl, which group may be optionally substituted by one, two or three substituents independently selected from halogen.
8. A compound as claimed in any one of claims 1 to 6 wherein R4a and R4b, when taken together with the carbon atom to which they are both attached, represent cyclohexyl, which group may be unsubstituted, or substituted by one or more substituents.
9. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.
10. A compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.
11. A compound of formula (I) as defined in claim 1 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.
12. A compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder.
13. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
14. A pharmaceutical composition as claimed in claim 16 further comprising an additional pharmaceutically active ingredient.
15. The use of a compound of formula (I) as defined in claim 1 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.
16. The use of a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of an inflammatory or autoimmune disorder.
17. 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 in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt thereof.
18. A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an N- oxide thereof, or a pharmaceutically acceptable salt thereof.
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