WO2021170627A1 - Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17 - Google Patents

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

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WO2021170627A1
WO2021170627A1 PCT/EP2021/054519 EP2021054519W WO2021170627A1 WO 2021170627 A1 WO2021170627 A1 WO 2021170627A1 EP 2021054519 W EP2021054519 W EP 2021054519W WO 2021170627 A1 WO2021170627 A1 WO 2021170627A1
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mmol
minutes
compound
mixture
formula
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Rickki Lee CONNELLY
James Richard FROST
Ellen Olivia GALLIMORE
Gregory William HASLETT
Helen Tracey Horsley
Joanna Rachel Quincey
James Thomas Reuberson
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UCB Biopharma SRL
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Priority claimed from GBGB2002635.7A external-priority patent/GB202002635D0/en
Priority claimed from GBGB2012481.4A external-priority patent/GB202012481D0/en
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Publication of WO2021170627A1 publication Critical patent/WO2021170627A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted 4,4-difluorocyclohexyl derivatives. These compounds act as modulators of IL-17 activity, and are accordingly of benefit as pharmaceutical agents for the treatment and/or prevention of pathological conditions, including adverse inflammatory and autoimmune disorders.
  • IL-17A (originally named CTLA-8 and also known as IL-17) is a pro- inflammatory cytokine and the founder member of the IL-17 family (Rouvier et al, ./. Immunol ., 1993, 150, 5445-5456).
  • IL-17B to IL-17F five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al, Cytokine Growth Factor Rev., 2003, 14, 155-174).
  • IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Thl7, that also express IL-21 and IL-22 signature cytokines (Korn et al, Ann. Rev. Immunol., 2009, 27, 485-517).
  • IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al, J. Immunol., 2008, 181, 2799- 2805).
  • IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.
  • the compounds in accordance with the present invention being potent modulators of human IL-17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
  • WO 2013/116682 and WO 2014/066726 relate to separate classes of chemical compounds that are stated to modulate the activity of IL-17 and to be useful in the treatment of medical conditions, including inflammatory diseases.
  • WO 2018/229079 and WO 2020/011731 describe spirocyclic molecules that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders.
  • WO 2019/138017 describes a class of fused bicyclic imidazole derivatives, including benzimidazole derivatives and analogues thereof, that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders.
  • WO 2019/223718 describes heterocyclic compounds, including benzimidazole derivatives, that are stated to inhibit IL-17A and to be useful as immunomodulators.
  • PCT/EP2019/082779 both published on 18 June 2020 as WO 2020/120140 and WO 2020/120141 respectively
  • co-pending international patent applications PCT/IB2020/055970, PCT/EP2020/067758 and PCT/EP2020/067759 all published on 30 December 2020 as WO 2020/261141, WO 2020/260425 and WO 2020/260426 respectively, claiming priority from United Kingdom patent applications 1909190.9,
  • the compounds in accordance with the present invention also possess other notable advantages.
  • the compounds of the invention display valuable metabolic stability, as determined in either microsomal or hepatocyte incubations.
  • the present invention provides a compound of formula (I) or an A-oxide thereof, or a pharmaceutically acceptable salt thereof: wherein
  • A represents C-R 1 or N
  • E represents C-R 2 or N
  • Z represents a group of formula (Za), (Zb), (Zc), (Zd), (Ze) or (Zf):
  • Y represents O, N-R 4 , CR 5a R 5b , S, S(0), S(0) 2 or S(0)(N-R 7 );
  • R 1 represents hydrogen or fluoro;
  • R 2 represents hydrogen or fluoro
  • R 3 represents -OR 3a ; or R 3 represents C3-9 cycloalkyl, C4-12 bicycloalkyl, C3-7 heterocycloalkyl or C4-9 heterobicycloalkyl, any of which groups may be optionally substituted by one or more substituents;
  • R 3a represents Ci- 6 alkyl; or R 3a represents C3-9 cycloalkyl, which group may be optionally substituted by one or more substituents;
  • R 4 represents -COR 4a , -CCkR 43 or -S02R 4b ; or R 4 represents hydrogen; or R 4 represents Ci- 6 alkyl or C3-9 cycloalkyl, either of which groups may be optionally substituted by one or more fluorine atoms;
  • R 4a represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms
  • R 4b represents Ci- 6 alkyl
  • R 5a represents hydrogen, fluoro, methyl, difluoromethyl or trifluoromethyl
  • R 5b represents hydrogen, fluoro, methyl or hydroxy; or R 5a and R 5b , when taken together with the carbon atom to which they are both attached, represent cyclopropyl;
  • R 6 represents -OR 6a or -NR 6b R 6c ; or R 6 represents Ci- 6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(Ci- 6 )alkyl, aryl, aryl(Ci- 6 )alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl- (Ci- 6 )alkyl, heteroaryl or heteroaryl (Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R a represents Ci- 6 alkyl; or R 6a represents C3-9 cycloalkyl, which group may be optionally substituted by one or more substituents;
  • R 6b represents hydrogen or Ci- 6 alkyl
  • R 6C represents hydrogen or Ci- 6 alkyl
  • R 7 represents Ci- 6 alkyl
  • the present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.
  • the present invention also provides a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.
  • the present invention also provides the use of a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.
  • the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt thereof.
  • 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.
  • such groups will be unsubstituted, or substituted by one, two or three substituents.
  • such groups will be unsubstituted, or substituted by one or two substituents.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of formula (I) or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use , ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002.
  • Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid.
  • the present invention also includes within its scope co-crystals of the compounds of formula (I) above.
  • co-crystal is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio.
  • the preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals , ed. J. Wouters & L. Quere, RSC Publishing, 2012).
  • Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched Ci- 6 alkyl groups, for example Ci-4 alkyl groups.
  • Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups.
  • Particular alkyl groups include methyl, ethyl, «-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, /f/V-butyl, 2,2-dimethylpropyl and 3- methylbutyl.
  • Derived expressions such as “Ci- 6 alkoxy”, “Ci- 6 alkylthio”, “Ci- 6 alkyl sulphonyl” and “Ci- 6 alkylamino” are to be construed accordingly.
  • C3-9 cycloalkyl refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof.
  • Suitable C3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononanyl.
  • C4-12 bicycloalkyl refers to monovalent groups of 4 to 12 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[l.l.l]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl.
  • aryl refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl. Suitable aryl(Ci- 6 )alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • C3-7 heterocycloalkyl refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo- furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro- thiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[l,2,5]thiadiazolo[2,3-a]- pyrazinyl, homopiperazinyl, morpholinyl, benzoxa
  • C4-9 heterobicycloalkyl corresponds to C4-9 bicycloalkyl wherein one or more of the carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Typical heterobicycloalkyl groups include 6- oxabicyclo[3.1.OJhexanyl, 3-azabicyclo[3.1.OJhexanyl, 2-oxa-5-azabicyclo[2.2.1J- heptanyl, 6-azabicyclo[3.2.0]heptanyl, 6-oxabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1J- heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa- 5-azabicyclo[2.2.2]octanyl, 8-oxabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]
  • heteroaryl refers to monovalent aromatic groups containing at least 5 atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-Z>]- [l,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-Z>]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrrol o[3,4-/>]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4- J- pyrimidinyl, pyrazolo[l,5-a]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazoly
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
  • Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
  • each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 'H, 2 H (deuterium) or 3 H (tritium) atom, preferably 3 ⁇ 4.
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • A represents C-R 1 . In another embodiment, A represents N. In one embodiment, E represents C-R 2 . In another embodiment, E represents N.
  • A represents C-R 1 or N; and E represents C-R 2 .
  • the present invention provides a compound of formula (1-1) or (1-2) or an L -oxide thereof, or a pharmaceutically acceptable salt thereof: wherein Z, R 1 , R 2 and R 6 are as defined above.
  • Z represents a group of formula (Za), (Zb), (Zc), (Ze) or (Zf) as defined above.
  • Z represents a group of formula (Za).
  • Z represents a group of formula (Zb).
  • Z represents a group of formula (Zc).
  • Z represents a group of formula (Zd).
  • Z represents a group of formula (Ze).
  • Z represents a group of formula (Zf).
  • Z represents a group of formula (Zc) or (Zd).
  • Z represents a group of formula (Zc).
  • Y represents O. In a second embodiment, Y represents N-R 4 . In a third embodiment, Y represents CR 5a R 5b . In a fourth embodiment, Y represents S. In a fifth embodiment, Y represents S(O). In a sixth embodiment, Y represents S(0)2. In a seventh embodiment, Y represents S(0)(N-R 7 ).
  • Y represents O, N-R 4 , CR 5a R 5b or S(0)2, wherein R 4 , R 5a and R 5b are as defined above.
  • Y represents O, N-R 4 or S(0)2, wherein R 4 is as defined above.
  • R 1 represents hydrogen. In a second embodiment, R 1 represents fluoro.
  • R 2 represents hydrogen. In another embodiment, R 2 represents fluoro.
  • R 3 represents C3-9 cycloalkyl, C4-12 bicycloalkyl, C3-7 heterocycloalkyl or C4-9 heterobicycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents -OR 3a ; or R 3 represents C3-9 cycloalkyl, C4-12 bicycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents C3-9 cycloalkyl, C4-12 bicycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents cyclobutyl, bicyclo[l.l.l]pentanyl, azetidinyl, pyrrolidinyl, tetrahydropyranyl or morpholinyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R 3 may represent -OR 3a .
  • R 3 represents -OR 3a ; orR 3 represents cyclobutyl, bicyclo[l.l.l]pentanyl, pyrrolidinyl or tetrahydropyranyl, any of which groups may be optionally substituted by one or more substituents.
  • R 3 represents cyclobutyl, bicyclo[l.l.l]pentanyl, pyrrolidinyl or tetrahydropyranyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 3 include one, two, three or four substituents independently selected from halogen.
  • Typical examples of particular substituents on R 3 include one, two, three or four substituents independently selected from fluoro.
  • Typical values of R 3 include difluorocyclobutyl, fluorobicyclo[l.l.l]pentanyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, difluorotetrahydropyranyl and tetrafluoromorpholinyl. Additional values of R 3 include -OR 3a .
  • R 3 includes -OR 3a , difluorocyclobutyl, fluorobicyclo[ 1.1.1 ]- pentanyl, difluoropyrrolidinyl and difluorotetrahydropyranyl.
  • R 3 examples include difluorocyclobutyl, fluorobicyclo[l.l.l]pentanyl, difluoropyrrolidinyl and difluorotetrahydropyranyl.
  • R 3a represents Ci- 6 alkyl.
  • R 3a represents optionally substituted C3-9 cycloalkyl.
  • R 3a represents Ci- 6 alkyl; or R 3a represents cyclopropyl or cyclobutyl, either of which groups may be optionally substituted by one or more substituents.
  • R 3a represents cyclopropyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 3a include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluoro- methyl, hydroxy, hydroxy(Ci- 6 )alkyl, oxo, Ci- 6 alkoxy, difluoromethoxy, trifluoro- methoxy, Ci- 6 alkylthio, Ci- 6 alkylsulfmyl, Ci- 6 alkylsulfonyl, amino, amino(Ci- 6 )alkyl, Ci- 6 alkylamino, di(Ci- 6 )alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci- 6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci- 6 alkylaminocarbonyl, di(Ci- 6
  • Suitable examples of optional substituents on R 3a include one, two or three substituents independently selected from halogen.
  • substituents on R 3a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, te/V-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, fe/7-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl,
  • Suitable examples of specific substituents on R 3a include one, two or three substituents independently selected from fluoro.
  • R 3a Illustrative examples of specific values of R 3a include methyl, ethyl, «-propyl, isopropyl, «-butyl, /er/-butyl, cyclopropyl, fluorocyclopropyl, cyclobutyl and difluoro- cyclobutyl.
  • a selected value of R 3a is cyclopropyl.
  • R 4 represents -COR 4a , -CCER 43 or -S02R 4b ; or R 4 represents hydrogen; or R 4 represents Ci- 6 alkyl, which group may be optionally substituted by one or more fluorine atoms, generally by one, two or three fluorine atoms, typically by two fluorine atoms.
  • R 4 represents -CCER 43
  • R 4 represents -COR 4a .
  • R 4 represents -CCER 43
  • R 4 represents -CCER 43
  • R 4 represents hydrogen.
  • R 4 represents Ci- 6 alkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms.
  • R 4 represents unsubstituted Ci- 6 alkyl, especially methyl or ethyl.
  • R 4 represents Ci- 6 alkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms. Examples of that aspect include difluoroethyl.
  • R 4 represents C3-9 cycloalkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms.
  • R 4 represents unsubstituted C3-9 cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 4 represents C3-9 cycloalkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms. Examples of that aspect include difluorocyclobutyl .
  • R 4a represents Ci- 6 alkyl, optionally substituted by one, two or three fluorine atoms.
  • R 4a represents Ci- 6 alkyl or difluoro(Ci- 6 )alkyl.
  • R 4a represents Ci- 6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R 4a represents methyl. In a second aspect of that embodiment, R 4a represents ethyl. In a second embodiment, R 4a represents difluoro(Ci- 6 )- alkyl, especially difluoroethyl.
  • R 4a include methyl and difluoroethyl.
  • R 4b represents methyl or ethyl. In a first embodiment, R 4b represents methyl. In a second embodiment, R 4b represents ethyl.
  • R 5a represents hydrogen or fluoro. In a first embodiment, R 5a represents hydrogen. In a second embodiment, R 5a represents fluoro. In a third embodiment, R 5a represents methyl. In a fourth embodiment, R 5a represents difluorom ethyl. In a fifth embodiment, R 5a represents trifluorom ethyl.
  • R 5a represents fluoro, methyl, difluorom ethyl or trifluorom ethyl.
  • R 5a represents fluoro or methyl.
  • R 5b represents hydrogen, fluoro or methyl.
  • R 5b represents hydrogen or fluoro.
  • R 5b represents hydrogen. In a second embodiment, R 5b represents fluoro. In a third embodiment, R 5b represents methyl. In a fourth embodiment, R 5b represents hydroxy. Suitably, R 5b represents hydrogen, fluoro or hydroxy.
  • R 5b represents fluoro or methyl, especially fluoro.
  • R 5a and R 5b may together form a spiro linkage.
  • R 5a and R 5b when taken together with the carbon atom to which they are both attached, may represent cyclopropyl.
  • R 6 represents -OR 6a or -NR 6b R 6c ; or R 6 represents Ci- 6 alkyl, C3-9 cycloalkyl, C3-9 cycloalkyl(Ci- 6 )alkyl, aryl, aryl(Ci- 6 )alkyl, heteroaryl or heteroaryl- (Ci- 6 )alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents -OR 6a ; or R 6 represents C3-9 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 represents -OR 6a ; or R 6 represents heteroaryl, which group may be optionally substituted by one or more substituents.
  • R 6 represents optionally substituted Ci- 6 alkyl.
  • R 6 represents optionally substituted C3-9 cycloalkyl.
  • R 6 represents optionally substituted C3-9 cycloalkyl(Ci- 6 )alkyl.
  • R 6 represents optionally substituted aryl.
  • R 6 represents optionally substituted aryl(Ci- 6 )alkyl.
  • R 6 represents optionally substituted C3-7 heterocycloalkyl.
  • R 6 represents optionally substituted C3-7 heterocycloalkyl(Ci- 6 )alkyl. In an eighth embodiment, R 6 represents optionally substituted heteroaryl. In a ninth embodiment, R 6 represents optionally substituted heteroaryl(Ci- 6 )alkyl. In a tenth embodiment, R 6 represents -OR 6a . In an eleventh embodiment, R 6 represents -NR 6a R 6b .
  • R 6 examples include -OR 6a or -NR 6a R 6b ; and methyl, ethyl, propyl, 2- methylpropyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, pyrazolyl, isoxazolyl, oxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl or pyridinylmethyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 includes -OR 6a ; and cyclopropyl, phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 include -OR 6a ; and cyclopropyl, phenyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R 6 examples include -OR 6a ; and pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • Suitable values of R 6 include pyrazolyl, isoxazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. Particular values of R 6 include oxadiazolyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 6 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci- 6 alkyl, trifluoro- methyl, phenyl, fluorophenyl, hydroxy, hydroxy(Ci- 6 )alkyl, oxo, Ci- 6 alkoxy, difluoro- methoxy, trifluoromethoxy, Ci- 6 alkylthio, Ci- 6 alkylsulfmyl, Ci- 6 alkylsulfonyl, amino, amino(Ci- 6 )alkyl, Ci- 6 alkylamino, di(Ci- 6 )alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C2-6 alkylcarbonylamino, C2-6 alkylcarbonylamino(Ci- 6 )alkyl, C2-6 alkoxycarbonylamino, Ci-
  • R 6 Apposite examples of optional substituents on R 6 include one, two or three substituents independently selected from halogen, Ci- 6 alkyl and trifluorom ethyl.
  • Suitable examples of optional substituents on R 6 include one, two or three substituents independently selected from Ci- 6 alkyl.
  • substituents on R 6 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, fer/-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, methoxy, /er/-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl- amino, fe/V-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetyl aminoethyl, methoxycarbonylamino, methylsulfonyl- amino, formyl, acetyl,
  • Apposite examples of particular substituents on R 6 include one, two or three substituents independently selected from fluoro, methyl, ethyl and trifluoromethyl.
  • Suitable examples of particular substituents on R 6 include one, two or three substituents independently selected from methyl and ethyl.
  • R 6 Illustrative examples of particular values of R 6 include methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl- cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chloro- phenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethyl- s
  • R 6 includes -OR 6a , fluorocyclopropyl, trifluorom ethyl- cyclopropyl, fluorophenyl, methyloxadiazolyl and ethyloxadiazolyl.
  • Apposite values of R 6 include -OR 6a , trifluorom ethylcyclopropyl, fluorophenyl, methyloxadiazolyl and ethyloxadiazolyl.
  • Favoured values of R 6 include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl.
  • R 6 include methyloxadiazolyl and ethyloxadiazolyl.
  • R 6a represents Ci-6 alkyl. In a second embodiment, R 6a represents optionally substituted C3-9 cycloalkyl.
  • R 6a represents Ci-6 alkyl; or R 6a represents cyclobutyl, which group may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 6a include one, two or three substituents independently selected from halogen, cyano, nitro, Ci-6 alkyl, trifluoro- methyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, Ci-6 alkoxy, difluoromethoxy, trifluoro- methoxy, Ci-6 alkylthio, Ci-6 alkylsulfmyl, Ci-6 alkylsulfonyl, amino, amino(Ci-6)alkyl, Ci-6 alkylamino, di(Ci-6)alkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, Ci-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulfon
  • Suitable examples of optional substituents on R 6a include one, two or three substituents independently selected from halogen.
  • substituents on R 6a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, te/V-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, fe/V-butylamino, dimethylamino, acetylamino, methoxycarbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl
  • R 6a Illustrative examples of specific values of R 6a include methyl, ethyl, «-propyl, isopropyl, «-butyl, /er/-butyl, cyclobutyl and difluorocyclobutyl.
  • R 6a represents isopropyl.
  • R 6a represents cyclobutyl.
  • R 6b represents hydrogen or methyl.
  • R 6b represents hydrogen. In a second embodiment, R 6b represents Ci- 6 alkyl, especially methyl.
  • R 6c represents hydrogen or methyl. In a first embodiment, R 6c represents hydrogen. In a second embodiment, R 6c represents Ci- 6 alkyl, especially methyl.
  • R 7 represents methyl or ethyl. In a first embodiment, R 7 represents methyl. In a second embodiment, R 7 represents ethyl.
  • R 16 represents methyl or ethyl
  • R 16 represents methyl. In a second embodiment, R 16 represents ethyl.
  • A, Y, R 3 and R 16 are as defined above.
  • 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), Sjogren syndrome, Sjogren syndrome-associated keratoconjunctivitis sicca, non-Sjogren syndrome- associated keratoconjunctivitis sicca, keratitis sicca, sicca syndrome, xerophthalmia, tear film disorder, decreased tear production, aqueous tear deficiency (ATD), meibomian gland dysfunction and evaporative loss.
  • KCS keratoconjunctivitis sicca
  • Sjogren syndrome Sjogren syndrome-associated keratoconjunctivitis sicca
  • non-Sjogren syndrome- associated keratoconjunctivitis sicca keratitis sicca
  • sicca syndrome xerophthalmia
  • tear film disorder decreased tear production
  • ATD aqueous tear deficiency
  • meibomian gland dysfunction meibomian gland dysfunction
  • the compounds of the present invention may be useful in the treatment and/or prophylaxis of a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, lung fibrosis, inflammatory bowel diseases (including Crohn’s disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).
  • a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, ps
  • the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo arthritis or ankylosing spondylitis.
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • compositions 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.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.
  • the compounds according to the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • the compounds according to the present invention may be formulated in an ointment such as petrolatum.
  • the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non-irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • a compound in accordance with the present invention may be co administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule.
  • Another pharmaceutically active agent e.g. an anti-inflammatory molecule.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a carboxylic acid of formula R 6 -C02H with a compound of formula (III): wherein Z, A, E and R 6 are as defined above.
  • Suitable coupling agents include l-[bis(dimethylamino)methylene]-li7-l,2,3- triazolo[4,5-/>]pyridinium 3-oxid hexafluorophosphate (HATU); and 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide.
  • Suitable bases include organic amines, e.g. a trialkylamine such as A f , A f -di i sopropy 1 ethyl a i ne, and 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 A f ,A-dimethyl- formamide or A f , A f -di ethyl acetam i de; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran; or a dipolar aprotic solvent such as A f ,A-dimethyl- formamide or A f , A f -di ethyl acetam i de; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.
  • a suitable solvent e.g. a cyclic ether such as
  • 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, or 2- fluorobenzoyl chloride, or isopropyl chloroformate, with a compound of formula (III) as defined above.
  • the reaction is conveniently accomplished in the presence of a base.
  • Suitable bases include organic amines, e.g. a trialkylamine such as A,A-diisopropylethyl- amine.
  • the reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or a cyclic ether such as tetrahydrofuran.
  • the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R 6a -OH with A f , A f '-di sued ni m i dyl carbonate, ideally in the presence of a base, e.g. an organic amine such as triethylamine; and (ii) reacting the resulting material with a compound of formula (III) as defined above.
  • Steps (i) and (ii) are conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a carboxylic acid of formula R 3 -C02H with a compound of formula (IV): wherein
  • Z 1 represents a group of formula (Za-1), (Zb-1), (Zc-1), (Zd-1), (Ze-1) or (Zf-1): in which the asterisk (*) represents the point of attachment to the remainder of the molecule; and
  • A, E, Y, R 3 and R 6 are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C02H.
  • the compounds of formula (I) above may be prepared by a process which comprises cyclising a compound of formula (VA) or (VB): wherein Z, A, E and R 6 are as defined above.
  • Cyclisation of compound (VA) or (VB) is conveniently effected by heating in a suitable medium, e.g. acetic acid, or trifluoroacetic acid.
  • a suitable medium e.g. acetic acid, or trifluoroacetic acid.
  • the intermediates of formula (VA) or (VB) above may be prepared by reacting a compound of formula (VI) with a carboxylic acid of formula (VII) or a salt thereof, e.g. a lithium salt thereof: (VI) (VII) wherein Z, A, E and R 6 are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C0 2 H.
  • the intermediates of formula (VII) may be prepared by a two-step procedure which comprises: (i) reacting a carboxylic acid of formula R 6 -C0 2 H with a compound of formula (VIII): wherein Aik 1 represents Ci-4 alkyl, e.g. methyl or ethyl, and R 6 is as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C0 2 H; and (ii) saponification of the resulting material by treatment with a base.
  • step (i) Alternative coupling agents that may usefully be employed in step (i) include N- (3 -dimethyl ami nopropyl )-A"-ethylcarbodii mi de hydrochloride (EDC.HC1) and ()- (benzotriazol-1 -yl)-A f ,A f ,A f ',A"-tetramethyluronium hexafluorophosphate (HBTU).
  • EDC.HC1 N- (3 -dimethyl ami nopropyl )-A"-ethylcarbodii mi de hydrochloride
  • HBTU hexafluorophosphate
  • the saponification reaction in step (ii) will generally be effected by treatment with a base.
  • Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide.
  • the product may be the lithium salt of the carboxylic acid of formula (VII).
  • Step (ii) is conveniently effected at ambient temperature in water and a suitable organic solvent, e.g. a cyclic ether such as tetrahydrofuran, optionally in admixture with a Ci-4 alkanol such as methanol.
  • a suitable organic solvent e.g. a cyclic ether such as tetrahydrofuran, optionally in admixture with a Ci-4 alkanol such as methanol.
  • the L -protecting group R p will suitably be /c/7-butoxycarbonyl (BOC), in which case the removal thereof in step (iii) may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the L -protecting group R p may be benzyloxycarbonyl, in which case the removal thereof may conveniently be effected by catalytic hydrogenation, typically by treatment with hydrogen gas, or ammonium formate, 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.
  • Z 2 represents a group of formula (Za-2), (Zb-2), (Zc-2), (Zd-2), (Ze-2) or (Zf-2):
  • R z represents a L -protecting group; and A, E, Y and R 6 are as defined above.
  • the L -protecting group R z will suitably be /c/7-butoxycarbonyl (BOC), in which case the removal thereof may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • the L -protecting group R q will suitably be 2-(trimethylsilyl)ethoxymethyl.
  • Step (i) is suitably effected by treatment of compound (XII) with a base, e.g. an organic base such as //-butyllithium, followed by reaction with compound (XIII).
  • a base e.g. an organic base such as //-butyllithium
  • the reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • step (ii) removal of the /c/V-butylsulfinyl group and the A-protecting group R q from compound (XIV) in step (ii) may both be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid.
  • an acid e.g. a mineral acid such as hydrochloric acid.
  • the L -protecting group R q is 2-(trimethylsilyl)ethoxymethyl
  • the intermediates of formula (XII) above may be prepared by a procedure which comprises the following steps:
  • 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 potassium carbonate.
  • a base e.g. an inorganic base such as sodium hydride or potassium carbonate.
  • the intermediate of formula (XIII) above may be prepared by reacting 4,4- difluorocyclohexyl carboxaldehyde with 2-methyl-2-propanesulfmamide. The reaction is suitably effected in the presence of pyridinium / oluenesulfonate and magnesium sulfate. The reaction is conveniently carried out at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • the intermediates of formula (IV) above may be prepared by a procedure which comprises the following steps:
  • Z 2 , A, E, R p and R q are as defined above; under conditions analogous to those described above; (ii) reaction of the material thereby obtained with a carboxylic acid of formula R 6 -C02H, under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C02H; and
  • step (iii) may both be accomplished 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 intermediates of formula (III) above may be prepared by a procedure which comprises the following steps:
  • step (i) removal of the A-protecting groups R p and R q in step (i) may both be accomplished 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 intermediates of formula (III) above wherein R 3 represents -OR 3a may be prepared by a procedure which comprises the following steps:
  • Step (ii) is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.
  • a suitable solvent e.g. a chlorinated solvent such as dichloromethane.
  • the reaction may suitably be accomplished in the presence of a base.
  • Suitable bases include organic amines, e.g. a trialkylamine such as A( A -di i sopropy 1 ethyl am i ne.
  • Z 2 , A, E, R p and R q are as defined above, and L 1 represents a suitable leaving group; in the presence of a transition metal catalyst.
  • the leaving group L 1 is suitably a halogen atom, e.g. bromo.
  • Suitable transition metal catalysts of use in the reaction include [4,4'-bis(l,l- dimethylethyl)-2,2'-bipyridine-M,M']bis- ⁇ 3,5-difluoro-2-[5-(trifluoromethyl)-2- pyridinyl -A/] phenyl -C ⁇ iridium(III) hexafluorophosphate.
  • the reaction will generally be performed in the presence of nickel(II) chloride ethylene glycol dimethyl ether complex and 4,4'-di-/er/-butyl-2,2'-dipyridyl.
  • the reaction will suitably be effected in the presence of a base, e.g.
  • a suitable bright light source will typically comprise the ‘integrated photoreactor’ described in ACS Cent. Sci ., 2017, 3, 647-653.
  • Alternative bright light sources include the Penn M2 photoreactor.
  • the reaction will conveniently be carried out at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as A(A-di methyl form amide.
  • the intermediates of formula (XVI) above may be prepared by a procedure which comprises the following steps: (i) reacting a compound of formula (IX) as defined above with a compound of formula (XVII): wherein A, E and L 1 are as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (IX);
  • Step (iii) is suitably effected by treating the reactants with a base, e.g. an inorganic base such as sodium hydride or potassium carbonate.
  • a base e.g. an inorganic base such as sodium hydride or potassium carbonate.
  • the intermediates of formula (III) above may be prepared by a procedure which comprises the following steps:
  • any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • a compound comprising aN-BOC moiety (wherein BOC is an abbreviation for /c/7-butoxy- carbonyl) may be converted into the corresponding compound comprising a N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • a compound comprising a N-H functionality may be alkylated, e.g. methylated, by treatment with a suitable alkyl halide, e.g. iodomethane, typically in the presence of a base, e.g. an inorganic carbonate such as sodium carbonate.
  • a compound comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl halide, e.g. acetyl chloride, typically in the presence of a base, e.g. an organic base such as V,V-diisopropylethyl a ine or triethylamine.
  • a compound comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl anhydride, e.g. acetic anhydride, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-S(0)2Alk 1 functionality (wherein Aik 1 is as defined above) by treatment with the appropriate Ci-4 alkylsulfonyl chloride reagent, e.g. methyl sulfonyl chloride, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • Ci-4 alkylsulfonyl chloride reagent e.g. methyl sulfonyl chloride
  • a base e.g. an organic base such as triethylamine.
  • a compound comprising a N-H functionality may be converted into the corresponding compound comprising a carbamate or urea moiety respectively by treatment with the appropriate chloroformate or carbamoyl chloride reagent, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a compound comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety by treatment with the appropriate amine-substituted (3-methyl-imidazol-3-ium-l-yl)methanone iodide derivative, typically in the presence of a base, e.g. an organic base such as triethylamine.
  • a base e.g. an organic base such as triethylamine.
  • a compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-C(H) functionality by treatment with the appropriate aldehyde or ketone in the presence of a reducing agent such as sodium tri ac etoxy b orohy dri de .
  • a reducing agent such as sodium tri ac etoxy b orohy dri de .
  • a compound comprising a Ci-4 alkoxycarbonyl moiety -CCbAlk 1 may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as lithium hydroxide.
  • a compound comprising a /c/7-butoxy- carbonyl moiety may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with trifluoroacetic acid.
  • a compound comprising a carboxylic acid (-CO2H) moiety may be converted into the corresponding compound comprising an amide moiety by treatment with the appropriate amine, under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R 6 -C02H.
  • a compound comprising a Ci-4 alkoxycarbonyl moiety -CCkAlk 1 may be converted into the corresponding compound comprising a hydroxymethyl (-CH2OH) moiety by treatment with a reducing agent such as lithium aluminium hydride.
  • a compound comprising a Ci-4 alkylcarbonyloxy moiety -0C(0)Alk 1 (wherein Aik 1 is as defined above), e.g. acetoxy, may be converted into the corresponding compound comprising a hydroxy (-OH) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as sodium hydroxide.
  • a base e.g. an alkali metal hydroxide salt such as sodium hydroxide.
  • a compound comprising a halogen atom may be converted into the corresponding compound comprising an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety by treatment with the appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3 -propanediol or neopentyl glycol.
  • the reaction is typically effected in the presence of a transition metal catalyst, and a base.
  • the transition metal catalyst may be [l,l'-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
  • a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately substituted bromoaryl or bromoheteroaryl derivative.
  • Step (i) is conveniently effected in the presence of a transition metal catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), and potassium acetate.
  • Step (ii) is conveniently effected in the presence of a transition metal catalyst such as [l,l'-bis(diphenylphosphino)ferrocene]- dichloropalladium(II), and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a transition metal catalyst such as [l,l'-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. 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(0)(NH)- by treatment with (diacetoxyiodo)benzene and ammonium carbamate.
  • a hydrogenation catalyst e.g. palladium on charcoal.
  • a compound comprising an aromatic nitrogen atom may be converted into the corresponding compound comprising an L -oxide moiety by treatment with a suitable oxidising agent, e.g. 3-chloroperbenzoic acid.
  • a suitable oxidising agent e.g. 3-chloroperbenzoic acid.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. 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.
  • compounds in accordance with this invention potently inhibit the ability of IL-17A to bind to IL-17RA.
  • compounds of the present invention exhibit a pICso value of 5.0 or more, generally of 6.0 or more, usually of 7.0 or more, typically of 7.2 or more, suitably of 7.5 or more, ideally of 7.8 or more, and preferably of 8.0 or more (pICso equals -logiofICso], in which IC5 0 is expressed as a molar concentration, so the skilled person will appreciate that a higher pICso figure denotes a more active compound).
  • certain compounds in accordance with this invention potently inhibit IL-17 induced IL-6 release from human dermal fibroblasts.
  • compounds of the present invention exhibit a pICso value of 5.0 or more, generally of 6.0 or more, usually of 7.0 or more, typically of 7.2 or more, suitably of 7.5 or more, ideally of 7.8 or more, and preferably of 8.0 or more (as before, the skilled person will appreciate that a higher pICso figure denotes a more active compound).
  • this assay is to test the ability of compounds to disrupt the interaction between IL-17A and soluble IL-17 Receptor A (IL-17RA). The ability of a compound to inhibit IL-17A binding to IL-17RA is measured in this assay.
  • An ⁇ L-17AA-TEV-Human Fc construct was expressed in a CHO SXE cell system and purified by protein A chromatography and size exclusion.
  • the protein was labelled with an amine reactive AlexaFluor 647 dye (Thermo Fisher #A20006), as per manufacturer’s instruction.
  • Soluble IL-17RA (33-317)-HKH-TEV-Fc was expressed in an Expi HEK293 cell system and purified by protein A chromatography and size exclusion.
  • the Fc tag was cleaved by TEV, producing IL-17RA (33-317)-HKH, and the protein was labelled with amine reactive terbium (Thermo Fisher #PV3581).
  • IL-17A (10 pL) was added to a black low volume assay plate (Costar #4511) and diluted compound (5 pL) was transferred from the aqueous dilution plate. The cytokine and compound were allowed to incubate for 1 h, then IL-17RA (10 pL) was added. The plates were wrapped in foil and incubated at room temperature for 18-20 h with gentle shaking ( ⁇ 400 rpm) before being read on a Perkin Elmer Envision plate reader (Excitation: 330 nm; Emission 615/645 nm).
  • the final assay concentrations were IL-17A-AF6472 nM and IL-17RA-Tb 2 nM, 5% DMSO.
  • This assay is to test the neutralising ability to IL-17 proteins, in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone produces only a very weak signal but in combination with certain other cytokines, such as TNFa, a synergistic effect can be seen in the production of inflammatory cytokines, i.e. IL-6.
  • HDF normal human dermal fibroblasts
  • HDFs were stimulated with IL-17A (50 pM) in combination with TNF-a (25 pM).
  • the resultant IL-6 response was then measured using a homogenous time-resolved FRET kit from Cisbio.
  • the kit utilises two monoclonal antibodies, one labelled with Eu- Cryptate (Donor) and the second with d2 or XL665 (Acceptor).
  • the intensity of the signal is proportional to the concentration of IL-6 present in the sample (Ratio is calculated by 665/620 x 104).
  • HDF cells (Sigma #106-05n) were cultured in complete media (DMEM + 10%
  • FCS + 2 mM L-glutamine FCS + 2 mM L-glutamine
  • FCS + 2 mM L-glutamine FCS + 2 mM L-glutamine
  • Cells were harvested from the tissue culture flask on the morning of the assay using TrypLE (Invitrogen #12605036). The TrypLE was neutralised using complete medium (45 mL) and the cells were centrifuged at 300 x g for 3 minutes. The cells were re-suspended in complete media (5 mL) counted and adjusted to a concentration of 3.125 x 10 4 cells/mL before being added to the 384 well assay plate (Coming #3701) at 40 pL per well. The cells were left for a minimum of three hours, at 37°C/5% CO2, to adhere to the plate.
  • TNFa and IL-17 cytokine were prepared in complete media to final concentrations of TNFa 25 pM/IL-17A 50 pM, then 30 pL of the solution was added to a 384 well reagent plate (Greiner #781281).
  • 10 pL from the aqueous dilution plate was transferred to the reagent plate containing 30 pL of the diluted cytokines, to give a 2.5% DMSO solution.
  • the compounds were incubated with the cytokine mixtures for 1 h or 5 h at 37°C (incubation times for specific test compounds are indicated in the Table below). After the incubation, 10 pL was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C/5% CO2.
  • Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1 : 1, as per kit insert.
  • a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 pL), then supernatant (10 pL) was transferred from the assay plate to Greiner reagent plate.
  • the mixture was incubated at room temperature for 3 h with gentle shaking ( ⁇ 400 rpm) before being read on a Synergy Neo 2 plate reader (Excitation: 330 nm; Emission: 615/645 nm).
  • the compounds of the accompanying Examples were found to exhibit the following pICso values.
  • the following Examples illustrate the preparation of compounds according to the invention.
  • TMED A A f ,A f ,A", A f -tetramethyl e ⁇ y
  • T3P® propylphosphonic anhydride solution
  • HATU 1 - [bi s(di methyl ami no)m ethylene]- 1//- 1 ,2,3-triazolo[4,5-/]pyridinium 3-oxid hexafluorophosphate
  • Fmoc-OSu A-(9//-fluoren-9-ylmethoxycarbonyloxy)succinimide
  • Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
  • Pd(dppf)Cl2 [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • NiCh glyme nickel(II) chloride ethylene glycol dimethyl ether complex ⁇ Ir[dF(CF3)ppy]2(dtbpy) ⁇ PF 6 : [4,4'-bis(l,l-dimethylethyl)-2,2'-bipyridine- ,M']bis- 13,5-difluoro-2-[5-(trifluoro ethyl)-2-pyridinyl-A']phenyl-C [iridiu (III) hexafluoro phosphate h: hour r.t.: room temperature
  • Chiral analysis was performed using a Chiralpak IC 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 60 bar), using a 6.5 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • Chiral analysis was performed using a Chiralpak IC 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method with a hold gradient embedded in the method from 8% MeOH (+ 0.1% NH4OH) at 1 minute to 12% at 6 minutes (ABPR 120 bar), using a 10 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • Chiral analysis was performed using a Chiralpak IC 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with an isocratic 10% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 20 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • Chiral analysis was performed using a Waters analytical SFC with a gradient of 30% methanol:70% CO2, on a Pirkle (R,R) Whelk-01 5 pm, 250 x 4.6 mm column with a flow rate of 2.4 mL/minute.
  • Method 23 Chiral analysis was performed using a Chiralpak IC 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 6.5 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • Method 24 was performed using a Chiralpak IC 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 6.5 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • Solvent B acetonitrile + 5% water + 0.% ammonia aolution Gradient:
  • Method 27 Purification was performed using a Lux Cellulose- 1, 250 x 21.2 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with an isocratic 10% MeOH (+ 0.1% NH4OH) method (ABPR 60 bar), using a 7.5 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.
  • Method 28 Purification was performed using a Lux Cellulose- 1, 250 x 21.2 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with an isocratic 10% MeOH (+ 0.1% NH4OH) method (ABPR 60 bar), using a 7.5 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.
  • Chiral HPLC was performed using Waters 2795 (detected with Waters 2998 PDA) with a gradient of 95:5 heptane:EtOH with a Chiralcel OD-H, 20 x 250 mm, 5 pm column and a flow rate of 18 mL/minute.
  • Chiral analysis was performed using a gradient of 95:5 heptane:EtOH on a Chiralcel OD-H, 4.6 x 250 mm, 5 pm column with a flow rate of 1 mL/minute.
  • Reverse-phase HPLC was carried out using a Gilson Prep system with UV215 detection. Stationary phase: Waters Sunfire C18, 30 x 100 mm, 10 pm
  • Chiral HPLC was performed using a Waters 2795 (detected with Waters 2998 PDA) with a gradient of 85: 15 heptane:IPA on a Chiralcel AD-H, 20 x 250 mm, 5 pm column with a flow rate of 9 mL/minute.
  • Chiral analysis was performed using a gradient of 85: 15 heptaneTPA on a Chiralcel AD-H, 4.6 x 250 mm, 5 pm column with a flow rate of 0.5 mL/minute.
  • Method 38 Chiral purification was performed using a Chiralpak IB, 250 x 20 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with an isocratic 5% MeOH (+ 0.1% NFLOH) method (ABPR 120 bar), using a 30 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.
  • Method 39 Chiral purification was performed using a Chiralpak IB, 250 x 20 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with an isocratic 5% MeOH (+ 0.1% NFLOH) method (ABPR 120 bar), using a 30 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.
  • Chiral analysis was performed using a Chiralpak IB, 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with an isocratic 5% MeOH (+ 0.1% MLOH) method (ABPR 120 bar), using a 30 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters QDa mass spectrometer.
  • Chiral purification was performed using a Chiralpak IB, 250 x 20 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 60 bar), using a 10 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.
  • Method 41 Chiral analysis was performed using a Chiralpak IB, 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 6.5 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters SQD2 mass spectrometer.
  • Method 42 Chiral analysis was performed using a Chiralpak IB, 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient of 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 6.5 minute run time on a Waters UPC 2 Acquity system, in tandem with a Waters SQD2 mass spectrometer.
  • Chiral purification was performed using a Regis (R,R)-Whelk-1, 250 x 21.1 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with a gradient of 3- 40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 7.5 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.
  • Chiral purification was performed using a Waters 2795 (detected with Waters 2998 PDA) prep system with a 100% MeOH gradient on a Cellulose-4, 21.2 x 250 mm, 5 pm column with a flow rate of 9 mL/minute.
  • the reactor was purged three times with nitrogen, followed by three purges of hydrogen.
  • the reaction mixture was stirred at 800 rpm, with a gas entrainment impeller, for 16 h at 90°C, under a constant 8 bar pressure of hydrogen.
  • additional diacetato[(i?)-(+)-5,5'-bis(diphenylphosphino)-4,4'-bi-l,3-benzodioxole]ruthenium(II) (1.11 g, 1.32 mmol) was added to the reaction mixture, and heating at 90°C under a constant 8 bar pressure of hydrogen was continued for a further 20 h.
  • the reaction mixture was cooled to 20°C and purged three times with nitrogen.
  • the aqueous layer was extracted with EtOAc (20 mL) and the combined organic extracts were washed with half-saturated aqueous NaHC03 solution (2 x 50 mL), followed by brine (20 mL).
  • the material was extracted from the organic layer with 1M aqueous HC1 (2 x 50 mL), and the combined acidic aqueous extracts were basified with saturated aqueous K2CO3 solution.
  • the material was extracted with EtOAc (2 x 50 mL).
  • the combined organic extracts were dried over MgS04, then filtered and concentrated under reduced pressure, to give the title compound (2.06 g, 85%).
  • the vial was capped and the mixture was purged with N2 for 10 minutes, then the cap was sealed with parafilm and irradiated (450 nm) using an ‘integrated photoreactor’ ⁇ ACS Cent. Sci., 2017, 3, 647-653) (settings: Fan, 1612 rpm; Stir, 392 rpm; LED, 100%) for 16 h.
  • the mixture was diluted with EtOAc (30 mL) and washed with water (2 x 20 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo.
  • DBU (1.10 mL, 7.38 mmol) was divided equally and added to each vial.
  • the solutions were purged by bubbling through N2 with sonication for 10 minutes.
  • the mixtures were sealed under nitrogen with parafilm and irradiated with 2 x blue LED lamp (40 W, Kessil A160WE LED Aquarium Light - Tuna Blue) with stirring for 20 h (a fan was used to maintain the temperature at approximately 21°C; the vials were positioned approximately 5 cm from the nearest light; the light was set at maximum intensity and greater blue colour setting).
  • the mixtures were combined and diluted with EtOAc (150 mL), then washed with water (2 x 100 mL).
  • the vial was capped, and the mixture was purged with N2 for 10 minutes, then the cap was sealed with parafilm and irradiated (450 nm) using an ‘integrated photoreactor’ (ACS Cent. Sci., 2017, 3, 647-653) (settings: Fan, 1612 rpm; Stir, 392 rpm; LED, 100%) for 16 h.
  • the mixture was diluted with EtOAc (30 mL) and washed with water (2 x 20 mL). The combined organic layers were dried (FteSCri) and concentrated in vacuo.
  • the vial was capped and the mixture was purged with N2 for 10 minutes, then the cap was sealed with parafilm and irradiated (450 nm) using an ‘integrated photoreactor’ (ACS Cent. Sci., 2017, 3, 647-653) (settings: Fan, 1612 rpm;
  • the capped vials were sealed with parafilm and irradiated separately at 450 nm in a Penn M2 photoreactor for 30 h.
  • the combined mixtures were diluted with EtOAc (50 mL), then washed with water (2 x 50 mL) and brine (25 mL).
  • the organic layer was dried over MgSCri, then filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with a gradient of EtOAc in heptane, gave the title compound (2: 1 mixture of regio- isomers) (1.48 g, 59%).
  • Peak 1 5H (400 MHz, 373K, DMSO-de) 7.40-7.29 (m, 2H), 5.66 (s, 1H), 5.26 (d, J 8.0 Hz, 1H), 4.53-4.46 (m, 1H), 4.25 (d, J 11.8 Hz, 1H), 4.00 (d, J 13.7 Hz, 1H), 3.94 (dd, J 11.4, 3.8 Hz, 1H), 3.90-3.70 (m, 3H), 3.59 (td, J 11.5, 3.2 Hz, 1H), 3.40 (br t, J 12.7 Hz, 1H), 2.93 (q, J1.5 Hz, 2H), 2.37-2.16 (m, 2H), 2.15-1.70 (m, 9H), 1.70-1.60 (m, 1H), 1.54-1.42 (m, 1H), 1.43-1.31 (m, 1H), 1.26 (t, J1.5 Hz, 3H).
  • Peak 2 5H (400 MHz, 373K, DMSO-de) 7.35-7.26 (m, 2H), 5.66 (s, 1H), 5.24 (d, J7.8 Hz, 1H), 4.51 (dd, J9.1, 3.3 Hz, 1H), 4.25 (d, J 11.9 Hz, 1H), 4.01-3.90 (m, 2H), 3.90- 3.81 (m, 2H), 3.69 (q, J 13.6 Hz, 1H), 3.58 (td, J 11.4, 3.1 Hz, 1H), 3.43 (br t, J 12.4 Hz, 1H), 2.93 (q, 77.4 Hz, 2H), 2.35-2.18 (m, 2H), 2.18-1.70 (m, 9H), 1.70-1.60 (m, 1H), 1.55-1.42 (m, 1H), 1.42-1.31 (m, 1H), 1.26 (t, 77.5 Hz, 3H).
  • Example 6 (48 mg) was subjected to chiral SFC using Waters Prep SFC80 with a gradient of 10% IP A, 90% CO2, Chiralcel OD-H, 10 x 250 mm, 5 pm, flow rate 15 mL/minute to give, after lyophilisation, the title compounds (Peak 1, 13 mg, 16% yield, 96% ee; and Peak 2, 12 mg, 15% yield, 86% ee).
  • Peak 1 5H (500 MHz, DMSO-de) 13.31-12.46 (m, 1H), 9.89-9.41 (m, 1H), 8.11-7.84 (m, 1H), 7.20 (d, 78.2 Hz, 1H, rotamer A), 7.06 (d, 78.1 Hz, 1H, rotamer B), 5.52-5.12 (m, 2H), 4.60 (t, 712.7 Hz, 1H), 4.15 (d, 713.2 Hz, 1H, rotamer A), 3.95-3.41 (m, 4H), 3.13-
  • Peak 2 5H (500 MHz, DMSO-de) 13.43-12.31 (m, 1H), 9.81-9.44 (m, 1H), 8.11-7.82 (m, 1H), 7.19 (d, 77.2 Hz, 1H, rotamer A), 7.06 (d, 78.3 Hz, 1H, rotamer B), 5.49-5.13 (m, 2H), 4.67-4.54 (m, 1H), 4.15 (d, 712.9 Hz, 1H, rotamer A), 3.32 (m, 4H), 3.08 (t, 711.5 Hz, 1H, rotamer B), 2.91 (q, 77.4 Hz, 2H), 2.48-2.41 (m, 2H), 2.34-2.14 (m, 5H), 2.12- 1.90 (m, 3H), 1.89-1.70 (m, 2H), 1.66-1.54 (m, 1H), 1.49-1.26 (m, 2H), 1.23 (t, 77.5 Hz, 3H). Approximately
  • Example 9 (30 mg) was subject to chiral HPLC (Waters Prep 100-SQD2 equipped with a Chiralcel OD-H 20 x 250 mm, 5 pm column, eluting with 9: 1 heptane/EtOH) to afford, after freeze-drying, the title compounds ( Example 10, 6 mg, 20%; and Example 11, 6 mg, 20%) as white powders.
  • chiral HPLC Waters Prep 100-SQD2 equipped with a Chiralcel OD-H 20 x 250 mm, 5 pm column, eluting with 9: 1 heptane/EtOH
  • Example 10 5H (400 MHz, DMSO-de) 12.57 (s, 1H), 9.20 (s, 1H), 7.30 (d, 78.3 Hz, 1H), 7.09-7.00 (m, 1H), 5.59 (s, 1H), 5.24 (d, 78.0 Hz, 1H), 4.11-3.92 (m, 2H), 3.76-3.66 (m, 2H), 3.56 (s, 4H), 3.37-3.15 (m, 3H), 2.93 (q, 77.5 Hz, 2H), 2.87-2.69 (m, 3H), 2.31-2.25 (m, 1H), 2.13-1.94 (m, 3H), 1.90-1.70 (m, 2H), 1.67-1.60 (m, 1H), 1.52-1.41 (m, 1H), 1.41-1.31 (m, 1H), 1.25 (t, 77.5 Hz, 3H). LCMS (Method 8): [M+H] + m/z 668, RT 3.42 minutes. Chiral analysis (
  • Example 11 5H (400 MHz, DMSO-de) 12.55 (s, 1H), 9.22 (s, 1H), 7.30 (d, 78.2 Hz, 1H), 7.07-7.01 (m, 1H), 5.59 (s, 1H), 5.24 (d, 78.0 Hz, 1H), 4.08-3.97 (m, 2H), 3.76-3.67 (m, 2H), 3.55 (s, 4H), 3.39-3.22 (m, 3H), 2.96-2.90 (m, 2H), 2.84-2.69 (m, 3H), 2.31-2.25 (m, 1H), 2.10-2.00 (m, 2H), 1.99-1.94 (m, 1H), 1.86-1.71 (m, 2H), 1.68-1.59 (m, 1H), 1.51- 1.43 (m, 1H), 1.40-1.34 (m, 1H), 1.25 (t, 77.5 Hz, 3H). LCMS (Method 8): [M+H] + m/z 668,
  • Peaks 1 and 3 5H (400 MHz, 373K, DMSO-de) 12.57 (s, 1H), 9.05 (s, 1H), 7.88 (d, 78.3 Hz, 1H), 7.04 (d, 78.3 Hz, 1H), 5.70-5.49 (s, 1H), 5.27 (d, 77.7 Hz, 1H), 4.39-4.09 (m, 1H), 3.56-3.26 (m, 1H), 2.57-2.46 (obscured s, 3H), 2.43-2.26 (m, 8H), 2.19-1.92 (m,
  • Peak 1 5H (400 MHz, DMSO-de) 12.98 (s, 1H), 8.98-8.65 (m, 1H), 8.08-7.85 (m, 1H), 7.72-7.60 (m, 1H), 7.60-7.49 (m, 1H), 7.34-7.21 (m, 2H), 7.20-6.97 (m, 1H), 6.06-5.49 (m, 1H), 5.23 (t, J8.0 Hz, 1H), 4.74-4.02 (m, 1H), 3.61-2.93 (m, 2H), 2.61-2.51 (obscured m, 3H), 2.43-2.11 (m, 5H), 2.12-1.90 (m, 5H), 1.89-1.68 (m, 2H), 1.66-1.51 (m, 1H), 1.50-1.26 (m, 2H).
  • Peak 2 5H (400 MHz, DMSO-de) 13.28-12.43 (m, 1H), 8.95-8.59 (m, 1H), 8.07-7.80 (m, 1H), 7.72-7.60 (m, 1H), 7.60-7.47 (m, 1H), 7.36-7.24 (m, 2H), 7.19-6.97 (m, 1H), 6.06- 5.53 (m, 1H), 5.24 (t, J8.1 Hz, 1H), 4.72-4.05 (m, 1H), 3.64-2.94 (m, 2H), 2.62-2.51
  • Peak 1 5H (400 MHz, DMSO-de) 13.27-12.32 (m, 1H), 8.30-8.05 (m, 1H), 8.03-7.79 (m, 1H), 7.21-6.89 (m, 1H), 6.08-5.46 (m, 1H), 5.03 (t, 78.2 Hz, 1H), 4.73-3.95 (m, 1H),
  • Example 31 (arbitrarily assigned as anti isomer 27,47) (29 mg, 5.5%) and Example 32 (arbitrarily assigned as anti isomer 27, 47) (29 mg, 5.5%).
  • Example 33 (84 mg) was separated by chiral SFC (Method 31) to give only the two major anti diastereomers:
  • Example 34 (arbitrarily assigned 2L',4L') (28 mg, 98% d.e.); and
  • Example 35 (arbitrarily assigned 2R,4R) (21 mg, 96% d.e.).
  • Example 34 5H (400 MHz, DMSO-de) 13.44-12.43 (m, 1H), 9.79-9.40 (m, 1H), 8.08-7.87 (m, 1H), 7.14-6.97 (m, 1H), 6.11-5.15 (m, 3H), 4.49-3.90 (m, 1H), 3.16-2.73 (m, 1H), 2.71-2.58 (m, 1H), 2.49-2.45 (m, 6H), 2.41-2.25 (m, 4H), 2.13-1.91 (m, 4H), 1.90-1.53
  • Example 35 d H (400 MHz, DMSO-de) 13.32-12.58 (m, 1H), 9.88-9.42 (m, 1H), 8.07-7.87 (m, 1H), 7.16-6.97 (m, 1H), 6.11-5.13 (m, 3H), 4.49-3.89 (m, 1H), 3.15-2.72 (m, 1H), 2.72-2.60 (m, 1H), 2.48-2.44 (m, 6H), 2.41-2.24 (m, 4H), 2.14-1.91 (m, 4H), 1.91-1.53 (m, 5H), 1.49-1.18 (m, 3H).
  • EXAMPLE 36 4.4-Ditluorocvclohexyl )i 5-r4-(difluoromethyl )- 1 -O-fluorobicvcloPl .1.1 lpentane- l-carbonyllpiperi din-2 -yll-H7-imidazor4.5-/>lpyridin-2- l-fluoro- cvclopropanecarboxamide
  • N- G bSV (4.4-DifluorocvclohexyD( 5-r(2i?.4i?)-4-(difluorom ethyl)- 1 -(3 -fluorobicvclo- ri.l.l1pentane-l-carbonvnpiperidin-2-yl1-li7-imidazor4.5-/>1pyridin-2- l- fluorocvclopropanecarboxamide
  • Example 3d (130 mg) was separated by chiral LC (Method 33) to give only the two major anti diastereomers: Example 37 (arbitrarily assigned 25) 45) (36.7 mg, 100% d.e.); and Example 38 (arbitrarily assigned 2R,4R) (38.6 mg, 98% d.e.).
  • Example 37 5H (400 MHz, DMSO-de) 13.07 (s, 1H), 8.80-8.59 (m, 1H), 8.04-7.88 (m, 1H), 7.13-6.99 (m, 1H), 6.10-5.44 (m, 2H), 5.13-4.99 (m, 1H), 4.50-3.92 (m, 1H), 3.17- 2.58 (m, 2H), 2.48-2.45 (m, 2H), 2.45-2.15 (m, 5H), 2.14-1.54 (m, 8H), 1.54-1.43 (m, 1H), 1.42-1.10 (m, 7H).
  • Example 38 5H (400 MHz, DMSO-de) 13.03 (s, 1H), 8.81-8.54 (m, 1H), 8.07-7.85 (m, 1H), 7.15-6.97 (m, 1H), 6.12-5.46 (m, 2H), 5.15-5.01 (m, 1H), 4.49-3.91 (m, 1H), 3.16- 2.60 (m, 2H), 2.48-2.46 (m, 2H), 2.45-2.16 (m, 5H), 2.12-1.44 (m, 9H), 1.42-1.09 (m,
  • Example 39 (25 mg) was separated by chiral LC (Method 36) to give only the two major anti diastereomers: Example 40 (arbitrarily assigned 27,47) (5.8 mg, 100% d.e.); and Example 41 (arbitrarily assigned 2R,4R ) (7.0 mg, 96% d.e.).
  • Example 40 5H (400 MHz, CDsOD) 7.94 (d, 78.3 Hz, 1H), 7.26-7.14 (m, 1H), 5.85-5.47 (m, 2H), 5.26 (d, 78.5 Hz, 1H), 4.26-3.97 (m, 2H), 3.15-3.04 (m, 1H), 2.80-2.65 (m, 1H), 2.52 (s, 3H), 2.41-2.28 (m, 1H), 2.28-1.98 (m, 4H), 1.96-1.35 (m, 8H), 0.79-0.50 (m, 4H). Two exchangeable proton signals not observed.
  • Chiral analysis (Method 37): RT 26.02 minutes.
  • Example 41 5H (400 MHz, DMSO-de) 13.00 (s, 1H), 9.54 (s, 1H), 8.02-7.87 (m, 1H), 7.16-7.00 (m, 1H), 6.08-5.71 (m, 1H), 5.63-5.32 (m, 1H), 5.20 (d, 77.9 Hz, 1H), 4.16- 3.85 (m, 2H), 3.29-3.17 (m, 1H), 3.08-2.92 (m, 1H), 2.48 (s, 3H), 2.32-1.90 (m, 5H), 1.90-1.56 (m, 5H), 1.52-1.26 (m, 3H), 0.90-0.41 (m, 4H).
  • Example 44 (arbitrarily assigned R,R : 5H (400 MHz, 373K, DMSO-dr,) 12.59 (br s, 1H), 9.08 (br s, 1H), 7.89 (d, J8.2 Hz, 1H), 7.11 (d, J 8.4 Hz, 1H), 5.85 (s, 1H), 5.27 (d, J7.7 Hz, 1H), 4.69-4.63 (m, 1H), 4.33 (br s, 1H), 3.94-3.60 (m, 2H), 3.44 (s, 1H), 3.24-3.11 (m, 1H), 2.53-2.49 (obscured s, 3H), 2.49-2.20 (m, 3H), 2.18-1.93 (m, 8H), 1.92-1.75 (m,
  • Example 46 (arbitrarily assigned R,K : 5H (400 MHz, 373K, DMSO-dr,) 12.59 (br s, 1H), 8.20 (d, J8.8 Hz, 1H), 7.92 (d, J8.3 Hz, 1H), 7.10 (d, J 8.3 Hz, 1H), 5.90-5.84 (m, 1H), 5.16 (t, 78.1 Hz, 1H), 4.53 (br s, 1H), 4.38 (br s, 1H), 3.98-3.89 (m, 1H), 3.88-3.78 (m, 1H), 3.39 (br s, 1H), 3.27-3.14 (m, 1H), 2.49-2.34 (m, 1H), 2.31-2.19 (m, 2H), 2.15-1.98 (m, 6H), 1.96-1.70 (m, 4H), 1.66-1.58 (m, 1H), 1.48-1.17 (m, 6H).
  • Example 48 (arbitrarily assigned S,R): 5H (400 MHz, 373K, DMSO-de) 13.02-12.48 (br s, 1H), 9.40-8.48 (br s, 1H), 7.98 (d, J8.3-Hz, 1H), 7.22 (d, J8.3-Hz, 1H), 6.33-5.41 (v br s, 1H), 5.28 (t, J7.6-Hz, 1H), 4.63-3.78 (v br s, 1H), 3.46-3.10 (br s, 1H), 2.80-2.57 (br s,
  • Example 49 (arbitrarily assigned R,S): 5H (400 MHz, 373K, DMSO-de) 13.02-12.48 (br m, 1H), 9.36-8.96 (br m, 1H), 7.98 (d, J8.3 Hz, 1H), 7.37-7.08 (br s, 1H), 6.33-5.41 (v br s, 1H), 5.28 (t, J1.6 Hz, 1H), 4.63-3.78 (v br s, 1H), 3.46-3.10 (br s, 1H), 2.80-2.57 (br s, 1H), 2.56-2.47 (obscured s, 3H), 2.47-2.28 (m, 7H), 2.16 (dd, J 14.5, 7.4 Hz, 1H), 2.12- 1.94 (m, 3H), 1.93-1.66 (m, 5H), 1.57-1.34 (m, 2H).
  • Example 50 (arbitrarily assigned S,S): 5H (400 MHz, 373K, DMSO-de) 9.10 (d, 78.6 Hz, 1H), 7.91 (d, 78.2 Hz, 1H), 7.15 (d, 78.2 Hz, 1H), 6.01-5.66 (br s, 1H), 5.42 (t, J 8.3 Hz, 1H), 5.27 (t, 78.2 Hz, 1H), 4.13 (ddd, J 14.0, 6.7, 3.2 Hz, 1H), 3.52 (ddd, J 14.1, 10.4, 5.7
  • Example 51 (arbitrarily assigned R,K : 5H (400 MHz, 373K, DMSO-de) 12.93-12.25 (m, 1H), 9.28-8.97 (m, 1H), 8.02-7.78 (m, 1H), 7.15 (d, 78.2 Hz, 1H), 5.85 (s, 1H), 5.42 (t, 7 8.3 Hz, 1H), 5.27 (t, 78.1 Hz, 1H), 4.19-4.06 (m, 1H), 3.61-3.42 (m, 1H), 2.59-2.46 (obscured s, 3H), 2.40-2.24 (m, 9H), 2.15-1.93 (m, 4H), 1.92-1.65 (m, 4H), 1.56-1.33 (m, 2H). 19 F NMR (282 MHz, DMSO-de) d -82.40 (s, 3F), -90.11 (dd, 7233.1, 16.0 Hz, IF),
  • Example 52 (arbitrarily assigned S,R ): 5H (400 MHz, 373K, DMSO-de) 12.91-12.59 (br s, 1H), 9.30-9.02 (br s, 1H), 7.98 (d, 78.2 Hz, 1H), 7.23 (d, 78.3 Hz, 1H), 5.63 (d, 77.2 Hz,
  • Example 53 (arbitrarily assigned R, S): 5H (400 MHz, 373K, DMSO-de) 12.91-12.59 (br s, 1H), 9.30-9.02 (br s, 1H), 7.98 (d, 78.2 Hz, 1H), 7.23 (d, 78.3 Hz, 1H), 5.63 (d, 77.2 Hz, 1H), 5.28 (d, 77.6 Hz, 1H), 4.14-4.06 (m, 1H), 4.04-3.89 (m, 1H), 3.29-3.13 (m, 1H), 2.63-2.41 (obscured s and m, 4H), 2.40-2.27 (m, 1H), 2.20 (dd, 714.4, 7.5 Hz, 1H), 2.15- 1.93 (m, 3H), 1.92-1.65 (m, 5H), 1.57-1.33 (m, 2H), 0.73-0.55 (m, 4H). The OH proton signal was not observed. LCMS
  • Example 54 (33 mg) was separated by chiral LC (Method 44) to give Example 55 (arbitrarily assigned 3 K) (6.0 mg, 100% d.e.); and Example 56 (arbitrarily assigned 3ri)

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Abstract

L'invention concerne une série de dérivés de 4,4-difluorocyclohexyl substitués tels que définis dans la description, qui sont de puissants modulateurs de l'activité de l'IL-17 humaine, et qui sont par conséquent utiles dans le traitement et/ou la prévention de diverses maladies humaines, notamment des troubles inflammatoires et auto-immuns.
PCT/EP2021/054519 2020-02-25 2021-02-24 Dérivés de difluorocyclohexyle utilisés en tant que modulateurs d'il-17 WO2021170627A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
US11691979B2 (en) 2020-04-30 2023-07-04 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2024017880A1 (fr) 2022-07-22 2024-01-25 UCB Biopharma SRL Dérivés d'imidazotriazine utilisés comme modulateurs de l'il-17

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089036A2 (fr) 2008-01-09 2009-07-16 Schepens Eye Research Institute Compositions thérapeutiques utilisées pour le traitement des affections inflammatoires oculaires
WO2013116682A1 (fr) 2012-02-02 2013-08-08 Ensemble Therapeutics Corporation Composés macrocycliques pour une modulation d'il-17
WO2014066726A2 (fr) 2012-10-26 2014-05-01 Ensemble Therapeutics Corporation Composés pour la modulation d'il-17
WO2018229079A1 (fr) 2017-06-14 2018-12-20 Ucb Biopharma Sprl Indolines spirocycliques utilisées comme modulateurs d'il-17
WO2019138017A1 (fr) 2018-01-15 2019-07-18 Ucb Biopharma Sprl Dérivés d'imidazole fusionnés utilisés en tant qu'inhibiteurs d'il-17
WO2019223718A1 (fr) 2018-05-22 2019-11-28 成都先导药物开发股份有限公司 Immunomodulateur
WO2020011731A1 (fr) 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020120140A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés de benzimidazolone, et analogues de ceux-ci, en tant que modulateurs d'il-17
WO2020120141A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés d'amine fonctionnalisés utiles en tant que modulateurs d'il-17
WO2020261141A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazopyridine en tant que modulateurs d'il-17
WO2020260426A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
WO2020260425A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009089036A2 (fr) 2008-01-09 2009-07-16 Schepens Eye Research Institute Compositions thérapeutiques utilisées pour le traitement des affections inflammatoires oculaires
WO2013116682A1 (fr) 2012-02-02 2013-08-08 Ensemble Therapeutics Corporation Composés macrocycliques pour une modulation d'il-17
WO2014066726A2 (fr) 2012-10-26 2014-05-01 Ensemble Therapeutics Corporation Composés pour la modulation d'il-17
WO2018229079A1 (fr) 2017-06-14 2018-12-20 Ucb Biopharma Sprl Indolines spirocycliques utilisées comme modulateurs d'il-17
WO2019138017A1 (fr) 2018-01-15 2019-07-18 Ucb Biopharma Sprl Dérivés d'imidazole fusionnés utilisés en tant qu'inhibiteurs d'il-17
WO2019223718A1 (fr) 2018-05-22 2019-11-28 成都先导药物开发股份有限公司 Immunomodulateur
WO2020011731A1 (fr) 2018-07-12 2020-01-16 UCB Biopharma SRL Analogues d'indanes spirocycliques utilisés comme modulateurs d'il-17
WO2020120140A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés de benzimidazolone, et analogues de ceux-ci, en tant que modulateurs d'il-17
WO2020120141A1 (fr) 2018-12-11 2020-06-18 UCB Biopharma SRL Dérivés d'amine fonctionnalisés utiles en tant que modulateurs d'il-17
WO2020261141A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazopyridine en tant que modulateurs d'il-17
WO2020260426A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17
WO2020260425A1 (fr) 2019-06-26 2020-12-30 UCB Biopharma SRL Dérivés d'imidazole fusionnés utilisés en tant que modulateurs d'il-17

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
"Greene's Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS
"Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH
"Pharmaceutical Salts and Co-crystals", 2012, RSC PUBLISHING
ACS CENT. SCI., vol. 3, 2017, pages 647 - 653
ARKIN M R ET AL: "SMALL-MOLECULE INHIBITORS OF PROTEIN-PROTEIN INTERACTIONS: PROGRESSING TOWARDS THE DREAM", NATURE REVIEWS. DRUG DISCOVERY, NATURE PUBLISHING GROUP, GB, vol. 3, no. 4, 1 April 2004 (2004-04-01), pages 301 - 317, XP009047669, ISSN: 1474-1784, DOI: 10.1038/NRD1343 *
GAFFEN, CYTOKINE, vol. 43, 2008, pages 402 - 407
KORN ET AL., ANN. REV. IMMUNOL., vol. 27, 2009, pages 485 - 517
MOSELEY ET AL., CYTOKINE GROWTH FACTOR REV., vol. 14, 2003, pages 155 - 174
ROUVIER ET AL., J. IMMUNOL., vol. 150, 1993, pages 5445 - 5456
WRIGHT ET AL., J. IMMUNOL., vol. 181, 2008, pages 2799 - 2805

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11691979B2 (en) 2020-04-30 2023-07-04 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
US11702422B2 (en) 2020-04-30 2023-07-18 Janssen Pharmaceutica Nv Imidazopyridazines as modulators of IL-17
WO2023275301A1 (fr) 2021-07-01 2023-01-05 UCB Biopharma SRL Dérivés d'imidazotriazine utiles comme modulateurs de l'il-17
WO2023025783A1 (fr) 2021-08-23 2023-03-02 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023111181A1 (fr) 2021-12-16 2023-06-22 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2023166172A1 (fr) 2022-03-04 2023-09-07 Leo Pharma A/S Modulateurs à petites molécules d'il-17
WO2024017880A1 (fr) 2022-07-22 2024-01-25 UCB Biopharma SRL Dérivés d'imidazotriazine utilisés comme modulateurs de l'il-17

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