WO2021170627A1

WO2021170627A1 - Difluorocyclohexyl derivatives as il-17 modulators

Info

Publication number: WO2021170627A1
Application number: PCT/EP2021/054519
Authority: WO
Inventors: Rickki Lee CONNELLY; James Richard FROST; Ellen Olivia GALLIMORE; Gregory William HASLETT; Helen Tracey Horsley; Joanna Rachel Quincey; James Thomas Reuberson
Original assignee: UCB Biopharma SRL
Current assignee: UCB Biopharma SRL
Priority date: 2020-02-25
Filing date: 2021-02-24
Publication date: 2021-09-02
Anticipated expiration: 2022-08-25

Abstract

A series of substituted 4,4-difluorocyclohexyl derivatives as defined herein, being potent modulators of human IL-17 activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

Description

DIFLUOROCYCLOHEXYL DERIVATIVES AS IL-17

MODULATORS

The present invention relates to heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted 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). Subsequently, five additional members of the family (IL-17B to IL-17F) have been identified, including the most closely related, IL-17F (ML-1), which shares approximately 55% amino acid sequence homology with IL-17A (Moseley et al, Cytokine Growth Factor Rev., 2003, 14, 155-174). IL-17A and IL-17F are expressed by the recently defined autoimmune related subset of T helper cells, Thl7, that also express IL-21 and IL-22 signature cytokines (Korn et al, Ann. Rev. Immunol., 2009, 27, 485-517). IL-17A and IL-17F are expressed as homodimers, but may also be expressed as the IL-17A/F heterodimer (Wright et al, J. Immunol., 2008, 181, 2799- 2805). IL-17A and F signal through the receptors IL-17R, IL-17RC or an IL-17RA/RC receptor complex (Gaffen, Cytokine, 2008, 43, 402-407). Both IL-17A and IL-17F have been associated with a number of autoimmune diseases.

The compounds in accordance with the present invention, being potent modulators of human IL-17 activity, are therefore beneficial in the treatment and/or prevention of various human ailments, including inflammatory and autoimmune disorders.

Furthermore, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.

WO 2013/116682 and WO 2014/066726 relate to separate classes of chemical compounds that are stated to modulate the activity of IL-17 and to be useful in the treatment of medical conditions, including inflammatory diseases. WO 2018/229079 and WO 2020/011731 describe spirocyclic molecules that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders.

WO 2019/138017 describes a class of fused bicyclic imidazole derivatives, including benzimidazole derivatives and analogues thereof, that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders.

WO 2019/223718 describes heterocyclic compounds, including benzimidazole derivatives, that are stated to inhibit IL-17A and to be useful as immunomodulators. Co-pending international patent applications PCT/EP2019/082774 and

PCT/EP2019/082779 (both published on 18 June 2020 as WO 2020/120140 and WO 2020/120141 respectively), and co-pending international patent applications PCT/IB2020/055970, PCT/EP2020/067758 and PCT/EP2020/067759 (all published on 30 December 2020 as WO 2020/261141, WO 2020/260425 and WO 2020/260426 respectively, claiming priority from United Kingdom patent applications 1909190.9,

1909191.7 and 1909194.1 respectively), describe discrete classes of chemical compounds that are stated to act as modulators of IL-17 activity, and thus to be of benefit in the treatment of pathological conditions including adverse inflammatory and autoimmune disorders. None of the prior art available to date, however, discloses or suggests the precise structural class of substituted 4,4-difluorocyclohexyl derivatives as provided by the present invention.

As well as being potent modulators of human IL-17 activity, the compounds in accordance with the present invention also possess other notable advantages. In particular, the compounds of the invention display valuable metabolic stability, as determined in either microsomal or hepatocyte incubations.

The present invention provides a compound of formula (I) or an A-oxide thereof, or a pharmaceutically acceptable salt thereof: wherein

A represents C-R¹ or N; E represents C-R² or N;

Z represents a group of formula (Za), (Zb), (Zc), (Zd), (Ze) or (Zf):

(Zd) (Ze) (Zf) in which the asterisk (*) represents the point of attachment to the remainder of the molecule;

Y represents O, N-R⁴, CR^5aR^5b, S, S(0), S(0)₂ or S(0)(N-R⁷); R¹ represents hydrogen or fluoro;

R² represents hydrogen or fluoro;

R³ represents -OR^3a; or R³ 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;

R⁴ represents -COR^4a, -CCkR⁴³ or -S02R^4b; or R⁴ represents hydrogen; or R⁴ 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; and

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;

R⁶ represents -OR^6a or -NR^6bR^6c; or R⁶ 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; and R⁷ 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. Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Generally, such groups will be unsubstituted, or substituted by one, two, three or four substituents. Typically, such groups will be unsubstituted, or substituted by one, two or three substituents. Suitably, such groups will be unsubstituted, or substituted by one or two substituents.

For use in medicine, the salts of the compounds of formula (I) will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula (I) or of their pharmaceutically acceptable salts. Standard principles underlying the selection and preparation of pharmaceutically acceptable salts are described, for example, in Handbook of Pharmaceutical Salts: Properties, Selection and Use , ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH, 2002. Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts which may, for example, be formed by mixing a solution of a compound of formula (I) with a solution of a pharmaceutically acceptable acid. The present invention also includes within its scope co-crystals of the compounds of formula (I) above. The technical term “co-crystal” is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals , ed. J. Wouters & L. Quere, RSC Publishing, 2012). Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched 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.

The term “C3-9 cycloalkyl” as used herein refers to monovalent groups of 3 to 9 carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof. Suitable C3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononanyl.

The term “C4-12 bicycloalkyl” as used herein 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.

The term “aryl” as used herein refers to monovalent carbocyclic aromatic groups derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl groups include phenyl and naphthyl, preferably phenyl. Suitable aryl(Ci-₆)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.

The term “C3-7 heterocycloalkyl” as used herein refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo- furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydro- thiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[l,2,5]thiadiazolo[2,3-a]- pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl.

The term “C4-9 heterobicycloalkyl” as used herein 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]octanyl, 8- azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1J- octanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9- azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo[4.2.1]nonanyl.

The term “heteroaryl” as used herein refers to monovalent aromatic groups containing at least 5 atoms derived from a single ring or multiple condensed rings, wherein one or more carbon atoms have been replaced by one or more heteroatoms selected from oxygen, sulphur and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-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, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,l-Z>]thiazolyl, imidazo[l,2-a]pyridinyl, imidazo[4,5-/>J- pyridinyl, imidazo[l,2-/>]pyridazinyl, purinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-c]- pyrimidinyl, imidazo[l,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [l,2,4]triazolo- [l,5-a]pyrimidinyl, 6,8-dihydro-5iT-[l,2,4]triazolo[4,3-a]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups.

The term “halogen” as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.

Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds in accordance with the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH₂C=0)< enol (CH=CHOH) tautomers or amide (NHC=0)< hydroxyimine (N=COH) tautomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.

It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 'H, ²H (deuterium) or ³H (tritium) atom, preferably ¾. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a ¹²C, ¹³C or ¹⁴C atom, preferably ¹²C.

In one embodiment, A represents C-R¹. In another embodiment, A represents N. In one embodiment, E represents C-R². In another embodiment, E represents N.

In a particular embodiment, A represents C-R¹ or N; and E represents C-R².

Suitably, 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, R¹, R² and R⁶ are as defined above.

Generally, Z represents a group of formula (Za), (Zb), (Zc), (Ze) or (Zf) as defined above. In a first embodiment, Z represents a group of formula (Za). In a second embodiment, Z represents a group of formula (Zb). In a third embodiment, Z represents a group of formula (Zc). In a fourth embodiment, Z represents a group of formula (Zd). In a fifth embodiment, Z represents a group of formula (Ze). In a sixth embodiment, Z represents a group of formula (Zf).

Suitably, Z represents a group of formula (Zc) or (Zd).

Preferably, Z represents a group of formula (Zc).

In a first embodiment, Y represents O. In a second embodiment, Y represents N-R⁴. In a third embodiment, Y represents CR^5aR^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-R⁷).

Typically, Y represents O, N-R⁴, CR^5aR^5b or S(0)2, wherein R⁴, R^5a and R^5b are as defined above.

Suitably, Y represents O, N-R⁴ or S(0)2, wherein R⁴ is as defined above.

In a first embodiment, R¹ represents hydrogen. In a second embodiment, R¹ represents fluoro.

In a favoured embodiment, R² represents hydrogen. In another embodiment, R² represents fluoro.

Generally, R³ 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.

Particularly, R³ represents -OR^3a; or R³ represents C3-9 cycloalkyl, C4-12 bicycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

Suitably, R³ represents C3-9 cycloalkyl, C4-12 bicycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

Typically, R³ 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, R³ may represent -OR^3a.

Aptly, R³ represents -OR^3a; orR³ represents cyclobutyl, bicyclo[l.l.l]pentanyl, pyrrolidinyl or tetrahydropyranyl, any of which groups may be optionally substituted by one or more substituents. Appositely, R³ 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 R³ include one, two, three or four substituents independently selected from halogen.

Typical examples of particular substituents on R³ include one, two, three or four substituents independently selected from fluoro.

Typical values of R³ include difluorocyclobutyl, fluorobicyclo[l.l.l]pentanyl, difluoroazetidinyl, difluoropyrrolidinyl, tetrafluoropyrrolidinyl, difluorotetrahydropyranyl and tetrafluoromorpholinyl. Additional values of R³ include -OR^3a.

Selected values ofR³ include -OR^3a, difluorocyclobutyl, fluorobicyclo[ 1.1.1 ]- pentanyl, difluoropyrrolidinyl and difluorotetrahydropyranyl.

Suitable values of R³ include difluorocyclobutyl, fluorobicyclo[l.l.l]pentanyl, difluoropyrrolidinyl and difluorotetrahydropyranyl. In a first embodiment, R^3a represents Ci-₆ alkyl. In a second embodiment, R^3a represents optionally substituted C3-9 cycloalkyl.

Typically, 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.

Suitably, 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)alkylaminocarbonyl, aminosulfonyl, Ci-₆ alkylaminosulfonyl and di(Ci-₆)alkylaminosulfonyl.

Suitable examples of optional substituents on R^3a include one, two or three substituents independently selected from halogen.

Typical examples of specific 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, aminosulfonyl, methylaminosulfonyl and dimethyl- aminosulfonyl.

Suitable examples of specific substituents on R^3a include one, two or three substituents independently selected from fluoro.

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.

Generally, R⁴ represents -COR^4a, -CCER⁴³ or -S02R^4b; or R⁴ represents hydrogen; or R⁴ 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.

Suitably, R⁴ represents -CCER⁴³

In a first embodiment, R⁴ represents -COR^4a. In a second embodiment, R⁴ represents -CCER⁴³ In a third embodiment, R⁴ represents -CCER⁴³ In a fourth embodiment, R⁴ represents hydrogen. In a fifth embodiment, R⁴ represents Ci-₆ alkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms. In one aspect of that embodiment, R⁴ represents unsubstituted Ci-₆ alkyl, especially methyl or ethyl. In another aspect of that embodiment, R⁴ represents Ci-₆ alkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms. Examples of that aspect include difluoroethyl. In a sixth embodiment, R⁴ represents C3-9 cycloalkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms. In one aspect of that embodiment, R⁴ represents unsubstituted C3-9 cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another aspect of that embodiment, R⁴ represents C3-9 cycloalkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms. Examples of that aspect include difluorocyclobutyl .

Typically, R^4a represents Ci-₆ alkyl, optionally substituted by one, two or three fluorine atoms. Suitably, R^4a represents Ci-₆ alkyl or difluoro(Ci-₆)alkyl.

In a first embodiment, 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.

Particular values of R^4a include methyl and difluoroethyl.

Suitably, R^4b represents methyl or ethyl. In a first embodiment, R^4b represents methyl. In a second embodiment, R^4b represents ethyl.

Generally, 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.

Suitably, R^5a represents fluoro, methyl, difluorom ethyl or trifluorom ethyl.

Typically, R^5a represents fluoro or methyl. Generally, R^5b represents hydrogen, fluoro or methyl.

More generally, R^5b represents hydrogen or fluoro.

In a first embodiment, 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.

Typically, R^5b represents fluoro or methyl, especially fluoro.

Alternatively, R^5a and R^5b may together form a spiro linkage. Thus, R^5a and R^5b, when taken together with the carbon atom to which they are both attached, may represent cyclopropyl. Typically, R⁶ represents -OR^6a or -NR^6bR^6c; or R⁶ 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.

Appositely, R⁶ represents -OR^6a; or R⁶ represents C3-9 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.

Suitably, R⁶ represents -OR^6a; or R⁶ represents heteroaryl, which group may be optionally substituted by one or more substituents. In a first embodiment, R⁶ represents optionally substituted Ci-₆ alkyl. In a second embodiment, R⁶ represents optionally substituted C3-9 cycloalkyl. In a third embodiment, R⁶ represents optionally substituted C3-9 cycloalkyl(Ci-₆)alkyl. In a fourth embodiment, R⁶ represents optionally substituted aryl. In a fifth embodiment, R⁶ represents optionally substituted aryl(Ci-₆)alkyl. In a sixth embodiment, R⁶ represents optionally substituted C3-7 heterocycloalkyl. In a seventh embodiment, R⁶ represents optionally substituted C3-7 heterocycloalkyl(Ci-₆)alkyl. In an eighth embodiment, R⁶ represents optionally substituted heteroaryl. In a ninth embodiment, R⁶ represents optionally substituted heteroaryl(Ci-₆)alkyl. In a tenth embodiment, R⁶ represents -OR^6a. In an eleventh embodiment, R⁶ represents -NR^6aR^6b.

Typical values of R⁶ include -OR^6a or -NR^6aR^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.

Apposite examples of R⁶ include -OR^6a; and cyclopropyl, phenyl, pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of R⁶ include -OR^6a; and cyclopropyl, phenyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.

Illustrative values of R⁶ include -OR^6a; and pyrazolyl, isoxazolyl or oxadiazolyl, any of which groups may be optionally substituted by one or more substituents.

Suitable values of R⁶ include pyrazolyl, isoxazolyl and oxadiazolyl, any of which groups may be optionally substituted by one or more substituents. Particular values of R⁶ include oxadiazolyl, which group may be optionally substituted by one or more substituents.

Typical examples of optional substituents on R⁶ include one, two or three substituents independently selected from halogen, cyano, nitro, 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-₆ alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-₆ alkoxycarbonyl, aminocarbonyl, Ci-₆ alkylaminocarbonyl, di(Ci-₆)alkylamino- carbonyl, aminosulfonyl, Ci-₆ alkylaminosulfonyl, di(Ci-₆)alkylaminosulfonyl and di- (C i-₆)alkyl sulfoximinyl .

Apposite examples of optional substituents on R⁶ include one, two or three substituents independently selected from halogen, Ci-₆ alkyl and trifluorom ethyl.

Suitable examples of optional substituents on R⁶ include one, two or three substituents independently selected from Ci-₆ alkyl.

Typical examples of particular substituents on R⁶ include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, 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, carboxy, methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximinyl.

Apposite examples of particular substituents on R⁶ include one, two or three substituents independently selected from fluoro, methyl, ethyl and trifluoromethyl.

Suitable examples of particular substituents on R⁶ include one, two or three substituents independently selected from methyl and ethyl.

Illustrative examples of particular values of R⁶ include methyl, difluoromethyl, methylsulfonylmethyl, aminomethyl, methylaminomethyl, difluoroethyl, carboxyethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl- cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chloro- phenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethyl- sulfoximinylphenyl, benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)- benzyl, di chlorobenzyl, (chloro)(difluoro)benzyl, bromobenzyl, cyanobenzyl, methyl- benzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxy- benzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylamino- benzyl, pyrrolidinylbenzyl, (dimethyl)(pyrrolidinyl)benzyl, morpholinylbenzyl, (dimethyl)(morpholinyl)benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, ethylpyrazolyl, (methyl)(tetrahydropyranyl)- pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl and aminopyridinyl- methyl. Additionally, R⁶ may represent -OR^6a. Additionally, R⁶ may represent fluoro- cyclopropyl.

Selected values of R⁶ include -OR^6a, fluorocyclopropyl, trifluorom ethyl- cyclopropyl, fluorophenyl, methyloxadiazolyl and ethyloxadiazolyl.

Apposite values of R⁶ include -OR^6a, trifluorom ethylcyclopropyl, fluorophenyl, methyloxadiazolyl and ethyloxadiazolyl.

Favoured values of R⁶ include methylpyrazolyl, ethylpyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl and ethyloxadiazolyl.

Particular values of R⁶ include methyloxadiazolyl and ethyloxadiazolyl.

In a first embodiment, R^6a represents Ci-6 alkyl. In a second embodiment, R^6a represents optionally substituted C3-9 cycloalkyl.

Typically, 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, aminosulfonyl, Ci-6 alkylaminosulfonyl and di(Ci-6)alkylaminosulfonyl.

Suitable examples of optional substituents on R^6a include one, two or three substituents independently selected from halogen.

Typical examples of specific substituents on R^6a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, 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, aminosulfonyl, methylaminosulfonyl and dimethyl- aminosulfonyl. Suitable examples of specific substituents on R^6a include one, two or three substituents independently selected from fluoro.

Illustrative examples of specific values of R^6a include methyl, ethyl, «-propyl, isopropyl, «-butyl, /er/-butyl, cyclobutyl and difluorocyclobutyl.

Suitably, R^6a represents isopropyl. Typically, R^6a represents cyclobutyl.

Typically, R^6b represents hydrogen or methyl.

In a first embodiment, R^6b represents hydrogen. In a second embodiment, R^6b represents Ci-₆ alkyl, especially methyl.

Typically, 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.

Suitably, R⁷ represents methyl or ethyl. In a first embodiment, R⁷ represents methyl. In a second embodiment, R⁷ represents ethyl.

One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and L -ox ides thereof, and pharmaceutically acceptable salts thereof:

wherein

R¹⁶ represents methyl or ethyl; and

A, Y and R³ are as defined above. In a first embodiment, R¹⁶ represents methyl. In a second embodiment, R¹⁶ represents ethyl.

Another sub-class of compounds according to the invention is represented by the compounds of formula (IIB) and L -oxides thereof, and pharmaceutically acceptable salts thereof:

wherein

A, Y, R³ and R¹⁶ 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. Generally, the pathological condition is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, arthritis, rheumatoid arthritis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airways disease (COAD), chronic obstructive pulmonary disease (COPD), acute lung injury, pelvic inflammatory disease, Alzheimer’s Disease, Crohn’s disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, Castleman’s disease, axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, dermatomyositis, myocarditis, uveitis, exophthalmos, autoimmune thyroiditis, Peyronie’s Disease, coeliac disease, gall bladder disease, Pilonidal disease, peritonitis, psoriasis, atopic dermatitis, hidradenitis suppurativa, vasculitis, surgical adhesions, stroke, autoimmune diabetes, Type I Diabetes, lyme arthritis, meningoencephalitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis and Guillain-Barr syndrome, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, fibrosing disorders including pulmonary fibrosis, liver fibrosis, renal fibrosis, scleroderma or systemic sclerosis, cancer (both solid tumours such as melanomas, hepatoblastomas, sarcomas, squamous cell carcinomas, transitional cell cancers, ovarian cancers and hematologic malignancies and in particular acute myelogenous leukaemia, chronic myelogenous leukemia, chronic lymphatic leukemia, gastric cancer and colon cancer), heart disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, periodontitis, hypochlorhydia and pain (particularly pain associated with inflammation).

WO 2009/089036 reveals that modulators of IL-17 activity may be administered to inhibit or reduce the severity of ocular inflammatory disorders, in particular ocular surface inflammatory disorders including Dry Eye Syndrome (DES). Consequently, the compounds in accordance with the present invention are useful in the treatment and/or prevention of an IL-17-mediated ocular inflammatory disorder, in particular an IL-17- mediated ocular surface inflammatory disorder including Dry Eye Syndrome. Ocular surface inflammatory disorders include Dry Eye Syndrome, penetrating keratoplasty, corneal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, corneal neovascularization, keratoprosthesis surgery, corneal ocular surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, Pemphigoid syndrome, Stevens- Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis. Particular categories of Dry Eye Syndrome include keratoconjunctivitis sicca (KCS), 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.

Illustratively, the compounds of the present invention may be useful in the treatment and/or prophylaxis of a pathological disorder selected from the group consisting of arthritis, rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic onset juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE), asthma, chronic obstructive airway disease, chronic obstructive pulmonary disease, atopic dermatitis, hidradenitis suppurativa, scleroderma, systemic sclerosis, lung fibrosis, inflammatory bowel diseases (including Crohn’s disease and ulcerative colitis), axial spondyloarthritis, ankylosing spondylitis and other spondyloarthropathies, cancer and pain (particularly pain associated with inflammation).

Suitably, the compounds of the present invention are useful in the treatment and/or prophylaxis of psoriasis, psoriatic arthritis, hidradenitis suppurativa, axial spondylo arthritis or ankylosing spondylitis. The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.

Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.

Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

The compounds according to the present invention may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. In addition to the formulations described above, the compounds according to the present invention may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.

For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.

For topical administration the compounds according to the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds according to the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2- octyldodecanol and water.

For ophthalmic administration the compounds according to the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate. Alternatively, for ophthalmic administration the compounds according to the present invention may be formulated in an ointment such as petrolatum.

For rectal administration the compounds according to the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.

The quantity of a compound according to the present invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.

If desired, a compound in accordance with the present invention may be co administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule. The compounds of formula (I) above may be prepared by a process which comprises reacting a carboxylic acid of formula R⁶-C02H with a compound of formula (III): wherein Z, A, E and R⁶ are as defined above.

The reaction is conveniently accomplished in the presence of a coupling agent and a base. Suitable coupling agents include 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.

Alternatively, the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula R⁶-COCl, e.g. acetyl chloride, 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.

Where R⁶ represents -OR^6a, the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R^6a-OH with A^f, A^f '-di sued ni m i dyl carbonate, ideally in the presence of a base, e.g. an organic amine such as triethylamine; and (ii) reacting the resulting material with a compound of formula (III) as defined above. Steps (i) and (ii) are conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.

In an alternative procedure, the compounds of formula (I) above may be prepared by a process which comprises reacting a carboxylic acid of formula R³-C02H with a compound of formula (IV):

wherein

Z¹ 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, R³ and R⁶ are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R⁶-C02H.

In an alternative procedure, 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 R⁶ 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.

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 R⁶ are as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R⁶-C0₂H.

The intermediates of formula (VII) may be prepared by a two-step procedure which comprises: (i) reacting a carboxylic acid of formula R⁶-C0₂H with a compound of formula (VIII):

wherein Aik¹ represents Ci-4 alkyl, e.g. methyl or ethyl, and R⁶ is as defined above; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R⁶-C0₂H; and (ii) saponification of the resulting material by treatment with a base.

Alternative coupling agents that may usefully be employed in step (i) include N- (3 -dimethyl ami nopropyl )-A"-ethylcarbodii mi de hydrochloride (EDC.HC1) and ()- (benzotriazol-1 -yl)-A^f,A^f,A^f',A"-tetramethyluronium hexafluorophosphate (HBTU).

The saponification reaction in step (ii) will generally be effected by treatment with a base. Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide. Where lithium hydroxide is employed in step (ii) of the above procedure, the product may be the lithium salt of the carboxylic acid of formula (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.

The intermediates of formula (III) above may be prepared by a three-step procedure which comprises the following steps:

(i) reacting a compound of formula (VI) as defined above with a compound of formula (IX):

wherein R^p represents a L -protecting group; under conditions analogous to those described above for the reaction between compounds (VI) and (VII); (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VA) or (VB); and

(iii) removal of the L -protecting group R^p.

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.

Alternatively, 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.

The intermediates of formula (IV) above may be prepared by removal of the N- protecting group R^z from a compound of formula (X):

wherein

Z² represents a group of formula (Za-2), (Zb-2), (Zc-2), (Zd-2), (Ze-2) or (Zf-2):

(Zd-2) (Ze-2) (Zf-2) in which the asterisk (*) represents the point of attachment to the remainder of the molecule;

R^z represents a L -protecting group; and A, E, Y and R⁶ 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 intermediates of formula (X) above may be prepared by a four-step procedure which comprises the following steps:

(i) reacting a compound of formula (IX) as defined above with a compound of formula (XI):

wherein Z², A and E are as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (IX);

(ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VA) or (VB); (iii) removal of the L -protecting group R^p under conditions analogous to those described above; and

(iv) reaction of the material thereby obtained with a carboxylic acid of formula R⁶-C02H, under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R⁶-C02H. In the alternative, the intermediates of formula (III) above may be prepared by a procedure which comprises the following steps:

(i) reacting a compound of formula (XII) with the compound of formula (XIII): wherein Z, A and E are as defined above, and R^q represents a A-protecting group; to provide a compound of formula (XIV):

wherein Z, A, E and R^q are as defined above; and

(ii) removal of the /er/-butylsulfmyl group and the L -protecting group R^q from compound (XIV).

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). The reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

Where the A-protecting group R^q is 2-(trimethylsilyl)ethoxymethyl, 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. Where 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:

(i) reaction of a compound of formula (VI) as defined above with formic acid; and (ii) reaction of the material thereby obtained with 2-(trimethylsilyl)ethoxymethyl chloride.

Step (i) is conveniently carried out at an elevated temperature.

Step (ii) is suitably effected by treating the reactants with a base, e.g. an inorganic base such as sodium hydride or 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. Alternatively, the intermediates of formula (IV) above may be prepared by a procedure which comprises the following steps:

(i) removal of the L -protecting group R^p from a compound of formula (XV):

wherein

Z², 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 R⁶-C02H, under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R⁶-C02H; and

(iii) removal of the L -protecting groups R^q and R^z from the material thereby obtained.

Where the A-protecting group R^p is BOC, and the A -protecting group R^q is 2- (trimethylsilyl)ethoxymethyl, removal of the A-protecting groups R^p and R^q in step (iii) may both be accomplished by treatment with an acid, e.g. an organic acid such as trifluoroacetic acid. Alternatively, the intermediates of formula (III) above may be prepared by a procedure which comprises the following steps:

(i) removal of the A-protecting groups R^q and R^z from a compound of formula (XV) as defined above;

(ii) reacting the material thereby obtained with a carboxylic acid of formula R³-C02H, under conditions analogous to those described above for the reaction between compound (IV) and a carboxylic acid of formula R³-C02H; and

(iii) removal of the A-protecting group R^p from the material thereby obtained, under conditions analogous to those described above.

Where the A-protecting group R^p is BOC, and the A-protecting group R^q is 2- (trimethylsilyl)ethoxymethyl, 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.

In a variant of the above method, the intermediates of formula (III) above wherein R³ represents -OR^3a may be prepared by a procedure which comprises the following steps:

(i) removal of the A-protecting groups R^q and R^z from a compound of formula (XV) as defined above, under conditions analogous to those described above;

(ii) reacting the material thereby obtained with R^3a (2,5-dioxopyrrolidin-l-yl) carbonate; and (iii) removal of the A-protecting group R^p from the material thereby obtained, under conditions analogous to those described above.

Step (ii) is conveniently performed at ambient temperature in 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.

The intermediates of formula (XV) above may be prepared by reacting a compound of formula Z²-C02H with a compound of formula (XVI):

wherein

Z², A, E, R^p and R^q are as defined above, and L¹ represents a suitable leaving group; in the presence of a transition metal catalyst.

The leaving group L¹ 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. an organic base such as l,8-diazabicyclo[5.4.0]undec-7-ene; and the reactants will typically be exposed to a bright light source. 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.

Where the A -protecting group R^q is 2-(trimethylsilyl)ethoxymethyl, 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 L¹ are as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (IX);

(ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VA) or (VB); and (iii) reaction of the material thereby obtained with 2-(trimethylsilyl)ethoxymethyl chloride.

Step (iii) is suitably effected by treating the reactants with a base, e.g. an inorganic base such as sodium hydride or potassium carbonate.

In an alternative method, the intermediates of formula (III) 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 (XI) as defined above, under conditions analogous to those described above for the reaction between compounds (VI) and (IX);

(ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VA) or (VB);

(iii) removal of the L -protecting group R^z under conditions analogous to those described above;

(iv) reacting the material thereby obtained with a carboxylic acid of formula RVCCEH, under conditions analogous to those described above for the reaction between compound (IV) and a carboxylic acid of formula RVCCEH; and

(v) removal of the L -protecting group R^p from the material thereby obtained, under conditions analogous to those described above. In a variant of the above method, the intermediates of formula (III) above wherein R³ represents -OR^3a may be prepared by a procedure which comprises the following steps:

(iv) reacting the material thereby obtained with R^3a (2,5-dioxopyrrolidin-l-yl) carbonate, under conditions analogous to those described above; and

(v) removal of the L -protecting group R^p from the material thereby obtained, under conditions analogous to those described above. Where they are not commercially available, the starting materials of formula (VI),

(VIII), (IX), (XI) and (XVII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound comprising 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. Similarly, a compound comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl anhydride, e.g. acetic anhydride, typically in the presence of a base, e.g. an organic base such as triethylamine. Simlarly, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-S(0)2Alk¹ functionality (wherein Aik¹ 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.

Simlarly, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a carbamate or urea moiety respectively by treatment with the appropriate chloroformate or carbamoyl chloride reagent, typically in the presence of a base, e.g. an organic base such as triethylamine. Alternatively, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety by treatment with the appropriate amine-substituted (3-methyl-imidazol-3-ium-l-yl)methanone iodide derivative, typically in the presence of a base, e.g. an organic base such as triethylamine. Alternatively, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety N-C(0)N(H)Alk¹ (wherein Aik¹ is as defined above) by treatment with the appropriate isocyanate derivative Alk¹-N=C=0, typically in the presence of a base, e.g. an organic base such as triethylamine.

A compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-C(H) functionality by treatment with the appropriate aldehyde or ketone in the presence of a reducing agent such as sodium tri ac etoxy b orohy dri de .

A compound comprising a Ci-4 alkoxycarbonyl moiety -CCbAlk¹ (wherein Aik¹ is as defined above) may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as lithium hydroxide. Alternatively, a compound comprising a /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 R⁶-C02H.

A compound comprising a Ci-4 alkoxycarbonyl moiety -CCkAlk¹ (wherein Aik¹ is as defined above) may be converted into the corresponding compound comprising a hydroxymethyl (-CH2OH) moiety by treatment with a reducing agent such as lithium aluminium hydride.

A compound comprising a Ci-4 alkylcarbonyloxy moiety -0C(0)Alk¹ (wherein Aik¹ is as defined above), e.g. acetoxy, may be converted into the corresponding compound comprising a hydroxy (-OH) moiety by treatment with a base, e.g. an alkali metal hydroxide salt such as sodium hydroxide.

A compound comprising a halogen atom, e.g. bromo, may be converted into the corresponding compound comprising an optionally substituted aryl, heterocycloalkenyl or heteroaryl moiety by treatment with the appropriately substituted aryl, heterocycloalkenyl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1,3 -propanediol or neopentyl glycol. The reaction is typically effected in the presence of a transition metal catalyst, and a base. The transition metal catalyst may be [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In the alternative, the transition metal catalyst may be tris(dibenzylideneacetone)dipalladium(0), which may advantageously be employed in conjunction with 2-dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl (XPhos). Suitably, the base may be an inorganic base such as sodium carbonate or potassium carbonate.

A compound comprising a halogen atom, e.g. bromo, may be converted into the corresponding compound comprising an optionally substituted aryl or heteroaryl moiety via a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately substituted bromoaryl or bromoheteroaryl derivative. Step (i) is conveniently effected in the presence of a transition metal catalyst such as [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 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 compound comprising a C=C double bond may be converted into the corresponding compound comprising a CH-CH single bond by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst, e.g. palladium on charcoal.

A compound comprising an aromatic nitrogen atom may be converted into the corresponding compound comprising an L -oxide moiety by treatment with a suitable oxidising agent, e.g. 3-chloroperbenzoic acid.

Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.

Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode. Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Greene ’s Protective Groups in Organic Synthesis , ed. P.G.M. Wuts, John Wiley & Sons, 5^th edition, 2014. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.

The compounds in accordance with this invention potently inhibit the ability of IL-17A to bind to IL-17RA. Thus, when tested in the IL-17 FRET assay described below, compounds of the present invention exhibit a pICso value of 5.0 or more, generally of 6.0 or more, usually of 7.0 or more, typically of 7.2 or more, suitably of 7.5 or more, ideally of 7.8 or more, and preferably of 8.0 or more (pICso equals -logiofICso], in which IC5₀ is expressed as a molar concentration, so the skilled person will appreciate that a higher pICso figure denotes a more active compound).

Moreover, certain compounds in accordance with this invention potently inhibit IL-17 induced IL-6 release from human dermal fibroblasts. Indeed, when tested in the HDF cell line assay described below, compounds of the present invention exhibit 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).

IL-17 FRET Assay

The purpose of 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 åL-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).

In assay buffer [Dulbecco’s PBS (Sigma #14190-094), 0.05% P20 (Thermo Scientific #28320), 1 mg/mL BSA (Sigma #A2153-500G)] the following solutions were prepared:

For IL-17A assay

• IL-17A-FC-AF647 at 5 nM

• IL-17RA-HKH-Tb at 5 nM

Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), to give a 25% DMSO solution.

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.

When tested in the IL-17 FRET assay as described above, the compounds of the accompanying Examples were found to exhibit the following pICso values.

# not determined Inhibition of IL-17 A induced IL-6 release from Dermal Fibroblast Cell Line

The purpose of this assay is to test the neutralising ability to IL-17 proteins, in a human primary cell system. Stimulation of normal human dermal fibroblasts (HDF) with IL-17 alone produces only a very weak signal but in combination with certain other cytokines, such as TNFa, a synergistic effect can be seen in the production of inflammatory cytokines, i.e. IL-6.

HDFs were stimulated with IL-17A (50 pM) in combination with TNF-a (25 pM). The resultant IL-6 response was then measured using a homogenous time-resolved FRET kit from Cisbio. The kit utilises two monoclonal antibodies, one labelled with Eu- Cryptate (Donor) and the second with d2 or XL665 (Acceptor). The intensity of the signal is proportional to the concentration of IL-6 present in the sample (Ratio is calculated by 665/620 x 104).

The ability of a compound to inhibit IL-17 induced IL-6 release from human dermal fibroblasts is measured in this assay. HDF cells (Sigma #106-05n) were cultured in complete media (DMEM + 10%

FCS + 2 mM L-glutamine) and maintained in a tissue culture flask using standard techniques. Cells were harvested from the tissue culture flask on the morning of the assay using TrypLE (Invitrogen #12605036). The TrypLE was neutralised using complete medium (45 mL) and the cells were centrifuged at 300 x g for 3 minutes. The cells were re-suspended in complete media (5 mL) counted and adjusted to a concentration of 3.125 x 10⁴ 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.

Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 pL from the titration plate was transferred to 45 pL of complete media and mixed to give a solution containing 10% DMSO.

Mixtures of 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.

From the Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1 : 1, as per kit insert. To a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 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). When tested in the HDF cell line assay as described above, 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.

EXAMPLES

Abbreviations

DCM: dichloromethane EtOAc: ethyl acetate MeOH: methanol THF : tetrahydrofuran DMSO: dimethyl sulfoxide DIPEA: A^f, A -di isopropyl ethyl amine AcOH: acetic acid EtOH: ethanol DMF : A^f,A^f-di methyl form amide TFA: trifluoroacetic acid DMAP: 4-(dimethylamino)pyridine mCPBA: 3-chloroperbenzoic acid DAST: diethylaminosulfur trifluoride DBU: l,8-diazabicyclo[5.4.0]undec-7-ene TBAF: tetra-«-butylammonium fluoride DEA: diethylamine IPA: isopropyl alcohol

TMED A : A^f,A^f,A", A^f-tetramethyl _e^y| enedi amine 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)}PF₆: [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

M: mass RT: retention time HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry SFC: Supercritical Fluid Chromatography Analytical Conditions

Method 1

LCMS pH 10 Stationary phase: Waters XBridge MS Cl 8 column (5 mih, 150 x 4.6 mm) Mobile Phase A: water Mobile Phase B: acetonitrile Mobile Phase C: ammonium formate in water 630 mg/L + 500 pL/L NH4OH 30% Flow rate: 1.9 mL/minute to 2.4 mL/minute

Gradient program: Time (min) A% B% C% Flow (mL/min) 0 90 0 10 1.9

1.5 90 0 10 1.9 7.15 2 88 10 2.4

10.5 2 88 10 2.4

10.6 90 0 10 1.9

13 90 0 10 1.9

Method 2

Agilent HPLC 1200 with UV detection at 254 nm Stationary Phase: Chiralcel OJ-3 from Daicel

Mobile Phase: EtOH 50% / heptane 50% / diethylamine 0.1%

Temperature: 30°C

FI ow rate : 1.5 mL/ minute Method 3

LCMS pH 10 Stationary Phase: Phenomenex Gemini NX-C18 (2 x 20 mm, 3 pm) Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1 mL/minute

Gradient program:

Time A% B% 0.00 95.00 5.00 4.00 5.00 95.00

5.00 5.00 95.00

5.10 95.00 5.00 Method 4 pH 10

Stationary Phase: Phenomenex Gemini NX-C18 (2 x 20 mm, 3 pm) Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: 1 mL/minute

Gradient program: Time A% B% 0.00 95.00 5.00

1.50 5.00 95.00

2.25 5.00 95.00

2.50 95.00 5.00

Method 5

MET/CR/1412 Hydrophobic Shimadzu method UV detection (210-420 nm) Column: Kinetex Core-Shell C8 Part No. 00B-4608-AN 2.1 x 50mm, 5pm

Column Temperature: 40°C Mobile Phase A: water + 0.1% formic acid

Mobile Phase B: acetonitrile + 0.1% formic acid

FI ow rate : 1.2 mL/ minute Gradient:

Time (min) B%

0.00 5

1.83 100

2.25 100 2.26 5

Method 6 pH 10 Stationary phase: X-Bridge C18 Waters (2.1 x 20 mm, 2.5 mih column) Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution Flow rate: Pump 1: 1 mL/minute; Pump 2: 0.5 mL/minute Gradient program:

Pump 1 Pump 2 Time A% B% Time A% B% 0.00 95.10 4.90 0.10 5.00 95.00

4.00 5.00 95.00 1.00 5.00 95.00

5.00 5.00 95.00 1.10 95.00 5.00

5.10 95.10 4.90

Method 7

Agilent, pH 3, 3-minute run, X-Bridge C18 Waters (2.1 x 20 mm, 2.5 pm column) Column Temperature: 40°C

Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid

Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid

Flow rate: 1 mL/minute

Gradient program: Time A% B%

0.00 95.00 5.00

1.50 5.00 95.00

2.25 5.00 95.00

2.50 95.00 5.00

Method 8

MSQ1/MSQ2 low pH uPLC - MET-uHPLC-AB-101 7 min Column: Phenomenex Kinetix-XB Cl 8 (2.1 x 100 mm, 1.7 pm)

Column Temperature: 40°C Mobile Phase A: water + 0.1% formic acid

Mobile Phase B: acetonitrile + 0.1% formic acid Flow rate: 1 mL/minute Gradient program: Time A% B% 0.00 95.00 5.00

5.30 0.00 100.00 5.80 0.00 100.00

5.82 95.00 5.00

Method 9

Waters UPC2 - QDa system. Purity and/or enantiomeric purity determined by UV (210- 400 nm) and identity confirmed by MS.

Column: Lux Cellulose-4 (150 x 4.6 mm, 3 pm)

Column Temperature: 35°C Flow Rate: 3 mL/min

Gradient: 10-25% MeOH (+ 0.1% NFLOH) over 6 minutes

Method 10

Column: Lux Cellulose-1 (150 x 4.6 mm, 3 pm) Column Temperature: 35°C

Flow Rate: 3 mL/minute

Gradient: 3-40% MeOH (+0.1% NH4OH) over 6 minutes

Method 11 Chiral analysis Column: Chiralcel OD-H (4.6 x 250 mm, 5 pm)

Flow Rate: 4 mL/minute Mobile Phase: 15% isopropanol, 85% CO2 Method 12

Chiral analysis Column: Chiralcel OD-H (4.6 x 250 mm, 5 pm)

Flow Rate: 1 mL/minute Mobile Phase: 90:10 heptane:EtOH

Method 13

Agilent, pH 3, 6 min run, X-Bridge C18 Waters (2.1 x 20 mm, 2.5 pm column)

Column Temperature: 40°C

Mobile Phase A: 10 mM ammonium formate in water + 0.1% formic acid

Mobile Phase B: acetonitrile + 5% water + 0.1% formic acid

Flow rate: 1 mL/minute

Gradient program:

Time A% B%

0.00 95.00 5.00

4.00 5.00 95.00

5.00 5.00 95.00

5.10 95.00 5.00

Method 14

Purification using a Chiralpak IC 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% MLOH) method (ABPR 60 bar), using a 13 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.

Method 15

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 UPC² Acquity system, in tandem with a Waters QDa mass spectrometer.

Method 16

Purification using a Chiralpak IC 250 x 20 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with a gradient of 3-20% MeOH (+ 0.1% NH4OH) method with a hold gradient embedded in the method from 8% MeOH (+ 0.1% NH4OH) at 2 minutes to 10% at 12 minutes (ABPR 60 bar), using a 13 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer. Method 17

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 UPC² Acquity system, in tandem with a Waters QDa mass spectrometer.

Method 18

Purification using a Chiralpak IC 250 x 20 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with an isocratic 10% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 12 minute run time on a Waters Prep 100 fractionlynx system, in tandem with a Waters SQD2 mass spectrometer.

Method 19

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 UPC² Acquity system, in tandem with a Waters QDa mass spectrometer.

Method 20

Purification using Waters Prep SFC80 with a gradient of 30% MeOH, 70% CO2, on a Pirkle (R,R) Whelk-01 5 pm, 250 x 21.1 mm column with a flow rate of 50 mL/minute.

Method 21

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 22

Purification using a using a Chiralpak IC 250 x 20 mm, 5 pm column, flow rate 100 mL/minute, column temperature 40°C, eluting with a gradient of 10-25% MeOH (+ 0.1% NFLOH) 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 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 UPC² Acquity system, in tandem with a Waters QDa mass spectrometer. Method 24

Chiral separation was performed using the following conditions:

Column: Chiralpak I A 50 x 266 mm, 20 pm

Column Temperature: 30°C

Flow Rate: 360 mL/minute Method: Isocratic, 65% CO2 + 35% ethanol over 13 minutes

Method 25

Chiral analysis was performed using the following conditions:

Column: Chiralpak I A 150 x 4.6 mm, 3 pm Column Temperature: 30°C

Flow Rate: 1.5 mL/minute

Method: Isocratic, 50% EtOH + 50% heptane + 0.1% DEA over 8 minutes

Method 26 Purification was undertaken on a reverse-phase Waters Fractionlynx system, with a 2996 PDA, in tandem with a Waters 3100 MS.

Column: XB ridge Prep Phenyl 5 pm OBD, 19 x 150 mm

Column Temperature: ambient Flow: 19 mL/minute Solvent A: 10 mM ammonium bicarbonate in water + 0.1% ammonia solution

Solvent B: acetonitrile + 5% water + 0.% ammonia aolution Gradient:

Time A% B%

0.00 55.00 45.00

2.50 55.00 45.00 11.00 40.00 60.00

11.50 5.00 95.00

13.00 55.00 45.00

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

Chiral analysis was performed using a Lux Cellulose- 1, 150 x 4.6 mm, 3 pm column, flow rate 3 mL/minute, column temperature 35°C, eluting with a gradient 3-40% MeOH (+ 0.1% NH4OH) method (ABPR 120 bar), using a 6.5 minute run time on a Waters UPC² Acquity system, in tandem with a Waters QDa mass spectrometer.

Method 29

MSDXT, pHlO. Stationary phase: Waters Acquity UPLC BEH C18 2.1 x 50 mm, 1.7 pm column Mobile Phase A: 10 mM ammonium formate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia aolution Flow rate: 1.5 mL/minute

Gradient program:

Time A% B% 0.00 95.00 5.00

0.10 95.00 5.00

3.50 5.00 95.00

4.00 5.00 95.00

4.05 95.00 5.00 Method 30

Analysis was carried out on Waters UPC2-QDa system. Purity and/or diastereomeric purity was determined by UV (210-400 nm) and identity confirmed by MS.

Software: Empower 3

Column: Lux Cellulose-1, 150 x 4.6 mm, 5 pm

Column Temperature: 35 °C Flow Rate: 3 mL/minute

Method: 3-40% MeOH (+ 0.1% NFLOH) over 6.5 minutes

Method 31 RC Chiral Prep.

SFC Prep using Waters Prep SFC80 using a gradient of 15% EtOH:85% CO2, with a Chiralpak AD-H, 10 x 250 mm, 5 pm column and a flow rate of 15 mL/minute.

Method 32 RC Chiral Analysis.

SFC chiral analysis using a gradient of 15% EtOH:85% CO2, with a Chiralpak AD-H, 4.6 x 250 mm, 5pm column and a flow rate of 4 mL/minute.

Method 33

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.

Method 34

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.

Method 35

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

Mobile Phase A: water + 0.1% formic acid Mobile Phase B: acetonitrile + 0.1% formic acid

Flow rate: 40 mL/minute

Gradient program:

Time A% B%

0.00 90.00 10.00

0.55 90.00 10.00

14.44 5.00 95.00

16.55 5.00 95.00

Method 36

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. Method 37

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 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 UPC² Acquity system, in tandem with a Waters QDa mass spectrometer.

Method 40

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 UPC² Acquity system, in tandem with a Waters SQD2 mass spectrometer. Method 42

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.

Method 43

Chiral analysis was performed using a Regis (R,R)-Whelk-1, 250 x 4.6 mm, 5 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 UPC² Acquity system, in tandem with a Waters QDa mass spectrometer.

Method 44

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.

Method 45

Chiral analysis was performed using a 100% MeOH gradient on a Cellulose-4, 4.6 x 250 mm, 5 pm column with a flow rate of 0.5 mL/minute. INTERMEDIATE 1 tert- Butyl 3- diamino-2-f1uorophenyl )morpholine-4-carboxylate

In a Parr reactor, diacetato[(i?)-(+)-5,5'-bis(diphenylphosphino)-4,4'-bi-l,3- benzodioxole]ruthenium(II) (1.11 g, 1.32 mmol) was added to a solution of tert- butyl 5- (3 ,4-diamino-2-fluorophenyl)-2,3 -dihydro- 1 ,4-oxazine-4-carboxylate (WO 2019/138017) (13.6 g, 44.1 mmol) in 2,2,2-trifluoroethanol (273 mL, 20 mL/g) under nitrogen. 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. After a 42% conversion, 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 reaction mixture was filtered through diatomaceous earth, washing with MeOH, then concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/heptane (0.5-70% gradient), gave the title compound (8.30 g, 55%) as a yellow-brown solid in 90% ee. 5H (400 MHz, DMSO-de) 6.43 (t, 78.1 Hz, 1H), 6.30 (d, 78.4 Hz, 1H), 5.00 (d, 73.8 Hz,

1H), 4.74 (s, 2H), 4.37 (s, 2H), 3.99 (d, 711.7 Hz, 1H), 3.84 (dd, 711.3, 3.6 Hz, 1H), 3.69 (td, 711.9, 3.4 Hz, 2H), 3.44 (dd, 711.8, 3.3 Hz, 1H), 3.19 (td, 712.8, 3.9 Hz, 1H), 1.35 (s, 9H). LCMS (Method 1): [M+H]⁺ m/z 312, RT 5.26 minutes. Chiral Analysis (Method 2): Peak 1, RT 7.73 minutes (95%); Peak 2, RT 6.01 minutes (5%).

INTERMEDIATE 2 fc/V-Butyl (3//)-3-!2-rfV)-benzyloxycarbonyla ino(4.4-difluorocvclohexyl )methyll-4- fluoro- benzimidazol-5- 4-carboxylate

To a solution of Intermediate 1 (879 mg, 2.82 mmol) and (A)-4,4-difluoro-a- {[(phenylmethoxy)carbonyl]amino}cyclohexaneacetic acid (880 mg, 2.69 mmol) in DCM (5 mL) were added DIPEA (0.94 mL, 5.40 mmol) and HATU (1.25 g, 3.29 mmol). The reaction mixture was stirred at r.t. for 35 minutes, then diluted with DCM (100 mL) and washed with water (100 mL). The organic layer was separated and dried over Na2SC>4, then filtered and concentrated in vacuo. The crude residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then taken up in AcOH (5 mL) and heated at 70°C. After 4.5 h at 70°C, the reaction mixture was cooled to r.t. and poured into water (150 mL). The resulting suspension was stirred for 15 minutes, after which time the solids were filtered off and dried under a stream of air to give the title compound (0.99 g, 63%) as a pink solid. Two tautomers were observed, in 3.8:1 ratio. 5H (300 MHz, DMSO-de) 12.87 (s, 1H, minor tautomer), 12.61 (s, 1H, major tautomer), 8.01 (d, 78.6 Hz, 1H, major tautomer), 7.88 (d, 78.7 Hz, 1H, minor tautomer), 7.42-7.24 (m, 7H), 5.29 (app s, 1H), 5.10-4.98 (m, 2H), 4.72 (t, 78.1 Hz, 1H), 4.16-4.03 (m, 1H), 3.96-3.88 (m, 1H), 3.84 (dd, 711.9, 4.0 Hz, 1H), 3.75 (d, 712.8 Hz, 1H), 3.53 (td, 711.4, 2.8 Hz, 1H), 3.36-3.27 (obscured m, 1H), 2.20-1.12 (m, 9H), 1.34 (s, 9H). LCMS (Method 3): [M+H]⁺ m!z 603, RT 2.52 minutes.

INTERMEDIATE 3 tert- Butyl ('3//)-3- amino('4.4-difluorocvclohexyl )m ethyl 1-4-fluoro-

benzimidazol-5-yl|morpholine-4-carboxylate

To a solution of Intermediate 2 (5.20 g, 8.60 mmol) in EtOH (83 mL) at r.t. in an EasyMax reactor was added 10% Pd/C (880 mg). The vessel was evacuated and purged with hydrogen, then left to stir at r.t. for 4 h. The mixture was filtered through a pad of Celite® (10 g) under suction, eluting with EtOH (100 mL) and DCM (100 mL), then concentrated in vacuo to give the title compound (4.30 g, 99%) as a grey foam. 5H (300 MHz, DMSO-de) 12.41 (br s, 1H), 7.31-7.21 (m, 2H), 5.28 (unresolved d, 73.6 Hz, 1H), 4.51-4.21 (br s, 1H), 4.08 (d, 711.8 Hz, 1H), 3.96-3.79 (m, 3H), 3.74 (d, J 13.3 Hz, 1H), 3.53 (td, J 11.6, 3.0 Hz, 1H), 3.37-3.23 (obscured m, 2H), 2.09-1.92 (m, 2H), 1.91-1.78 (m, 3H), 1.78-1.61 (m, 1H), 1.58-1.45 (m, 1H), 1.43-1.23 (obscured m, 2H), 1.34 (s, 9H).

LCMS (Method 4): [M+H]⁺ m!z 469, RT 1.68 minutes.

INTERMEDIATE 4 fc/V-Butyl (3R)-3-(2- i fV)-(4.4-difluorocvclohexyl )IY4-ethyl-l .2.5-oxadi azole-3 -carbonyl )- aminolmethyl ί-4-fluoro- benzimidazol-5-yl )morpholine-4-carboxylate

To an EasyMax 100 mL reactor were added Intermediate 3 (4.25 g, 8.30 mmol) and a solution of 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (1.40 g, 9.90 mmol) in DMF (28 mL). Next, a solution of HATU (3.90 g, 9.90 mmol) in DMF (12 mL) and DIPEA (1.20 mL, 6.90 mmol) were added sequentially. The reaction mixture was stirred at r.t. for 2 h, after which time it was poured onto ice/water (150 mL). The resulting suspension was stirred for 10 minutes and the precipitate was isolated by vacuum filtration, washing with water. Purification by flash chromatography, eluting with EtOAc/DCM (0-50% gradient), gave the title compound (4.20 g, 81%) as an off-white solid in 90% ee. Two tautomers were observed, in a 3.7:1 ratio. 5H (300 MHz, DMSO-de) 12.97 (s, 1H, minor tautomer), 12.73 (s, 1H, major tautomer), 9.74 (d, J8.4 Hz, 1H, major tautomer), 9.59 (d, J 8.5 Hz, 1H, minor tautomer), 7.42 (d, J 8.5 Hz, 1H, minor tautomer), 7.36-7.24 (m, 3H, major and minor tautomers), 5.28 (unresolved d, J2.1 Hz, 1H), 5.19 (t, J 8.4 Hz, 1H), 4.14-4.03 (m, 1H), 3.97-3.88 (m, 1H), 3.84 (dd, J 12.0, 4.1 Hz, 1H), 3.74 (app d, J 13.5 Hz, 1H), 3.53 (td, J 11.4, 3.2 Hz, 1H), 3.37-3.24 (obscured m, 1H), 2.91 (q, Jl.l Hz, 2H), 2.39-2.21 (m, 1H), 2.15-1.66 (m, 5H), 1.62-1.49 (m, 1H), 1.48-1.17 (m, 2H), 1.33 (s, 9H), 1.23 (t, J1A Hz, 3H). LCMS (Method 3): [M+H fm/z 593, RT 2.58 minutes.

-rOSy(4.4-DifluorocvclohexyO(4-fluoro-5-r(3i?Vmorpholin-3-yll-li7-benzimidazol-2- yl imethyll-4-ethyl- l oxadiazole-3-carboxamide. trifluoroacetate salt

To a solution of Intermediate 4 (3.00 g, 5.06 mmol) in DCM (40 mL) at r.t. was added TFA (12.4 mL). The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was passed through an SCX column, eluting initially with MeOH, then with 4N ammonia in MeOH. The MeOH/ammonia washings were concentrated in vacuo. The resulting colourless gum was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0-10% gradient), to give the title compound (3.02 g, 98%) as a white solid. 5H (400 MHz, DMSO-de) 12.98 (br s, 1H),

9.76 (br s, 1H), 9.50 (br s, 1H), 9.17 (br s, 1H), 7.52-7.44 (m, 1H), 7.40 (dd, J8.4, 6.1 Hz, 1H), 5.19 (t, J8.2 Hz, 1H), 4.88-4.76 (m, 1H), 4.10-3.99 (m, 3H), 3.92-3.77 (m, 2H), 3.52-3.26 (obscured m, 1H), 2.91 (qd, J7.5, 1.6 Hz, 2H), 2.36-2.23 (m, 1H), 2.13-1.92 (m, 1H), 1.90-1.69 (m, 2H), 1.58-1.48 (m, 1H), 1.47-1.35 (m, 1H), 1.34-1.21 (obscured m, 1H), 1.23 (t, J1.5 Hz, 3H). ¹⁹F {¾} NMR (282 MHz, DMSO-de) d -73.5 (s, 3F),

-90.3 (d, J 233 Hz, IF), -99.7 (d, J 233.0 Hz, IF), -131.4 (s, IF). LCMS (Method 4): [M+H]⁺ m!z 493, RT 1.20 minutes. INTERMEDIATE 6 tert- Butyl dif1uorocvclohexyl )G(4-hi ethyl - 1.2.5-oxadi azole-3 -

carbonyl iaminolmethyl ί-4-fluoro- benzimidazol-5-yl)morpholine-4-carboxylate

Intermediate 3 (2.30 g, 4.05 mmol) in DCM (100 mL) was treated with 4-methyl- l,2,5-oxadiazole-3-carboxylic acid (600 mg, 4.45 mmol), DIPEA (1.75 mL, 10.0 mmol) and HATU (1.74 g, 4.45 mmol). After 16 h, the reaction mixture was diluted with brine and passed through a phase separator. The organic layers were removed in vacuo. The crude material was purified by flash chromatography, eluting with EtO Ac/isohexane (30- 60% gradient), to give the title compound (2.03 g, 83%) as an off-white solid. Two tautomers were observed, in a 3.5:1 ratio. 5H (400 MHz, DMSO-de) 12.95 (s, 1H, minor tautomer), 12.72 (s, 1H, major tautomer), 9.70 (d, J8.5 Hz, 1H, major tautomer), 9.56 (d, J 8.5 Hz, 1H, minor tautomer), 7.43 (d, J 8.5 Hz, 1H, minor tautomer), 7.38-7.22 (m, 3H, major and minor tautomers), 5.28 (unresolved d, J 2.2 Hz, 1H), 5.19 (t, J 8.4 Hz, 1H), 4.12-4.04 (m, 1H), 3.92 (dd, J 11.2, 3.0 Hz, 1H), 3.84 (dd, J 11.9, 4.1 Hz, 1H), 3.74 (d, J 13.3 Hz, 1H), 3.53 (td, J 11.5, 3.3 Hz, 1H), 3.31-3.24 (obscured m, 1H), 2.48 (s, 3H), 2.36-2.23 (m, 1H), 2.13-1.92 (m, 3H), 1.91-1.70 (m, 2H), 1.61-1.50 (m, 1H), 1.45-1.23 (m, 11H). LCMS (Method 4): [M+H]⁺ m/z 579, RT 1.42 minutes.

INTERMEDIATE 7 jV-KA)- Difluorocvclohexyn(4-fluoro-5-r(3i?)-morpholin-3-yll-liT-benzimidazol-2- vHmethyll-4-methyl-E2.5-oxadiazole-3-carboxamide Intermediate 6 (2.03 g, 3.51 mmol) was treated with TFA (8.5 mL) in DCM (25 mL). After 16 h, the reaction mixture was concentrated in vacuo and partitioned between 1M aqueous NaOH solution and EtO Ac. The organic layer was dried over Na2S04, then filtered and concentrated in vacuo , to yield the title compound (1.42 g, 82%). 5H (400 MHz, DMSO-de) 12.69 (br s, 1H), 9.65 (br s, 1H), 7.44-7.14 (m, 2H), 5.17 (unresolved d, J 6.1 Hz, 1H), 4.19 (dd, J 10.1, 3.2 Hz, 1H), 3.76 (d, J 10.6 Hz, 1H), 3.69 (dd, J 10.8, 3.1 Hz, 1H), 3.48 (td, J 10.7, 3.3 Hz, 1H), 3.22 (t, J 10.4 Hz, 1H), 2.98-2.85 (m, 2H), 2.71 (br s, 1H), 2.48 (s, 3H), 2.34-2.23 (m, 1H), 2.13-1.91 (m, 3H), 1.91-1.69 (m, 2H), 1.60-1.50 (m, 1H), 1.47-1.34 (m, 1H), 1.33-1.22 (m, 1H). LCMS (Method 4): [M+H]⁺ m/z 479, RT 1.14 minutes.

INTERMEDIATE 8 Dibenzyl-6-fluoro-3-nitropyridin-2-amine

To a stirred suspension of 2,6-difluoro-3-nitropyridine (2.00 g, 12.5 mmol) and potassium carbonate (2.24 g, 16.2 mmol) in acetonitrile (28 mL) was added A-benzyl-1 - phenylmethanamine (2.5 mL, 13.1 mmol). The reaction mixture became warm, and was stirred at room temperature for 2 h. The mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc in heptane (0-100%), to give the title compound (4.27 g, 96%). 5H (500 MHz, CDCb) 8.16 (dd, 78.6, 7.2 Hz, 1H), 7.25-7.16 (m, 6H), 7.09-7.04 (m, 4H), 6.24 (dd, 78.6, 3.8 Hz, 1H), 4.51 (s, 4H). LCMS (Method 7): [M+H]⁺ m/z 338.0, RT 2.08 minutes.

INTERMEDIATE 9

Ethyl 2-(benzhvdrylideneamino)-2-r6-(dibenzylamino)-5-nitropyridin-2-yllacetate To a solution of Intermediate 8 (2.50 g, 7.41 mmol) and ethyl A-(diphenyl- methylidene)glycinate (1.98 g, 7.41 mmol) in DMF (25 mL) at 0°C was added sodium hydride (60%, 593 mg, 14.8 mmol). The dark purple mixture was allowed to reach room temperature and stirred for 1 h. Further sodium hydride (60%, 59 mg, 1.48 mmol) was added, and the mixture was stirred for 30 minutes. The mixture was quenched with water (10 mL) and diluted with EtOAc (150 mL). Water (150 mL) was added, and the layers were separated. The aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with water (2 x 100 mL), followed by brine (50 mL). The residue was dried over MgS04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (3.35 g, 73%). 5H (400 MHz, CDCb) 8.13 (d, 78.3 Hz, 1H), 7.75-7.69 (m, 2H), 7.47-7.33 (m, 6H), 7.27-7.25 (m, 6H), 7.15-7.08 (m, 7H), 5.24 (s, 1H), 4.59-4.49 (m, 4H), 4.16-4.07 (m, 2H), 1.16 (t, 77.1 Hz, 3H). LCMS (Method 7): [M+H]⁺ m/z 584.9, RT 2.31 minutes. INTERMEDIATE 10

Ethyl 2-amino-2-r5-amino-6-(dibenzylamino)pyri din-2 -yllacetate Intermediate 9 (3.17 g, 5.15 mmol) was dissolved in ethanol (25 mL), and tin(II) chloride dihydrate (4.69 g, 20.6 mmol) was added. The solution was stirred at room temperature for 1 h, then the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (50 mL), and 1M aqueous HC1 (50 mL) was added. The mixture was shaken and separated. 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%). 5H (500 MHz, CDCh) 7.21-7.16 (m, 8H), 7.16-7.08 (m, 2H), 6.82 (d, 77.8 Hz, 1H), 6.77 (d, 77.8 Hz, 1H), 4.35 (s, 1H), 4.23-4.14 (m, 4H), 4.07-4.01 (m, 1H), 3.98-3.87 (m, 1H), 3.80 (s, 2H), 1.71 (s, 2H, obs. by water), 1.07 (t, 77.1 Hz, 3H). LCMS (Method 7): [M+H]⁺ m/z 391.0, RT 1.67 minutes.

INTERMEDIATE 11

2-Amino-2-r5-amino-6-(dibenzylamino)pyridin-2-yllethanol

Intermediate 10 (2.06 g, 4.38 mmol) was dissolved in ethanol (50 mL) and sodium borohydride (600 mg, 15.9 mmol) was added portionwise. The mixture was stirred at room temperature for 1 h. Further sodium borohydride (1.20 g, 31.7 mmol) was added portionwise, and stirring was continued for 2 h. Further sodium borohydride (1.20 g, 31.7 mmol) was added portionwise, and stirring was continued for 16 h. The reaction mixture was quenched with water (20 mL), and the solvent volume was decreased under reduced pressure. The residue was extracted with EtOAc (2 x 50 mL), and the combined organic extracts were washed with saturated aqueous NaHC0₃ solution (25 mL) and brine (25 mL). the resulting material was dried over MgS04, then filtered and concentrated under reduced pressure, to give the title compound (1.79 g, 90%). 5H (500 MHz, CDCh) 7.32- 7.18 (m, 10H), 6.92 (d, J7.8 Hz, 1H), 6.76 (d, J7.8 Hz, 1H), 4.31-4.23 (m, 4H), 3.91 (s, 2H), 3.78-3.72 (m, 1H), 3.62 (dd, J 10.8, 4.8 Hz, 1H), 3.57 (dd, J 10.7, 5.8 Hz, 1H). Three exchangeable protons not observed. LCMS (Method 7): [M+H]⁺ m/z 349.0, RT 1.56 minutes.

INTERMEDIATE 12

/V- 1 -r5-Amino-6-(dibenzylamino)pyri din-2-yll-2-hydroxy ethyl l-2-chloroacetamide

Intermediate 77 (1.79 g, 3.96 mmol) was dissolved in DCM (100 mL) and DIPEA (2.1 mL, 11.9 mmol) was added, followed by 2-chloroacetyl chloride (315 pL, 3.96 mmol) in DCM (5 mL). The mixture was stirred for 1 h at room temperature. Further 2- chloroacetyl chloride (157 pL, 1.98 mmol) in DCM (2.5 mL) was added, and stirring was continued for 15 minutes at room temperature. The solution was concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (1.97 g, 59%). Estimated purity 50% (contains 30% w/w of a double addition product). 5H (500 MHz, CDCb) 7.62 (d, JT.2 Hz, 1H), 7.26-7.06 (m, 10H), 6.89 (d, J1.9 Hz, 1H), 6.77 (d, J1.9 Hz, 1H), 4.88-4.76 (m, 1H), 4.22 (s, 4H), 3.98 (d, J 15.1 Hz, 1H), 3.92 (s, 2H), 3.89 (d, J 15.1 Hz, 1H), 3.77-3.69 (m, 1H), 3.69-3.59 (m, 1H), 3.50-3.36 (m, 1H). LCMS (Method 7): [M+H]⁺ m/z 425/427, RT 1.86 minutes.

INTERMEDIATE 13

5-r5-Amino-6-(dibenzylamino)pyridin-2-yllmorpholin-3-one To a solution of Intermediate 12 (50%, 1.97 g, 2.32 mmol) in /tvV-butanol (35 mL) was added potassium /er/-butoxide (1.48 g, 13.2 mmol) in one portion. The mixture was stirred at room temperature for 30 minutes, then diluted with MeOH (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane, followed by dissolution in MeOH and loading onto a 20 g SCX-2 cartridge. The resulting material was washed with copious MeOH (-100 mL) and eluted with 3.5N Mb/MeOH. The residue was concentrated under reduced pressure to give the title compound (650 mg, 65%). 5H (500 MHz, CDCb) 7.20 (t, J .Ί Hz, 8H), 7.17-7.10 (m, 2H), 6.85 (d, J1.9 Hz, 1H), 6.67 (d, J 7.9 Hz, 1H), 6.19 (s, 1H), 4.52 (dd, 77.1, 4.2 Hz, 1H), 4.24-4.18 (m, 4H), 4.16 (d, 715.9 Hz, 1H), 4.07 (d, 716.7 Hz, 1H), 3.91-3.85 (m, 3H), 3.38 (dd, 711.6, 8.0 Hz, 1H). LCMS (Method 13): [M+H]⁺ m/z 389.0, RT 2.76 minutes.

INTERMEDIATE 14 Dibenzyl-6-(morpholin-3-vnpyridine-2.3-diamine

To a solution of Intermediate 13 (90%, 500 mg, 1.16 mmol) in THF (15 mL) was added a solution of LiAlHi in THF (2.4M, 1.9 mL, 4.63 mmol). The solution was stirred at room temperature for 16 h. A further aliquot of the solution of L1AIH4 in THF (2.4M, 1.9 mL, 4.63 mmol) was added, and the mixture was stirred at room temperature for 4 h (evidence of a delayed exotherm was detected). The mixture was cooled to 0°C and carefully quenched with water (0.4 mL), then 15% aqueous NaOH solution (0.4 mL) was added. The mixture was diluted with diethyl ether (10 mL), and water (1 mL) was added. The mixture was stirred at room temperature for 15 minutes, then MgSCh was added and the mixture was filtered through Celite®, washing with THF. Concentration under reduced pressure gave the title compound (483 mg, 90%). 5H (400 MHz, CDCh) 7.28- 7.21 (m, 8H), 7.21-7.15 (m, 2H), 6.86 (d, 77.8 Hz, 1H), 6.77 (d, 77.8 Hz, 1H), 4.27 (s, 4H), 3.85-3.76 (m, 5H), 3.51-3.40 (m, 1H), 3.31-3.18 (m, 1H), 3.07-2.97 (m, 1H), 2.95- 2.85 (m, 1H). One exchangeable proton not observed. LCMS (Method 7): [M+H]⁺ m/z

375.0, RT 1.63 minutes.

INTERMEDIATE 15 fc/V-Butyl 3-r5-amino-6-(dibenzylamino)pyridin-2-yllmorpholine-4-carboxylate

Intermediate 14 (483 mg, 1.04 mmol) was dissolved in DCM (10 mL) and di -tert- butyl dicarbonate (228 mg, 1.04 mmol) was added. The solution was stirred at room temperature for 2 h, then passed through a 5 g SCX-2 cartridge, washed with MeOH and eluted with 3.5N ML/MeOH. Concentration under reduced pressure and purification by column chromatography, eluting with a gradient of EtOAc in heptane (0-100%), gave the title compound (500 mg, 84%). 5H (500 MHz, CDCh) 7.20-7.17 (m, 8H), 7.15-7.09 (m, 2H), 6.84 (d, 77.9 Hz, 1H), 6.61 (d, 77.9 Hz, 1H), 4.81 (s, 1H), 4.45 (d, 711.2 Hz, 1H), 4.26-4.14 (m, 4H), 3.75 (s, 2H), 3.71-3.59 (m, 3H), 3.50-3.37 (m, 1H), 3.08-2.97 (m, 1H), 1.36 (s, 9H). LCMS (Method 7): [M+H]⁺ m/z 475.0, RT 2.12 minutes.

INTERMEDIATE 16 tert- Butyl 3- diaminopyridin-2-vOmorpholine-4-carboxylate

Intermediate 15 (500 mg, 1.05 mmol) was dissolved in MeOH (10 mL). Aqueous hydrochloric acid (1M, 1.1 mL, 1.05 mmol) was added, followed by 10% palladium on carbon, 50% wet (5.0%, 224 mg, 0.105 mmol). The reaction mixture was stirred vigorously under a hydrogen atmosphere for 7 h, then filtered through Celite® under nitrogen, washing with MeOH. The residue was loaded onto a 5 g SCX-2 cartridge and washed with MeOH, eluting with 3.5N Mb/MeOH. Concentration under reduced pressure gave the title compound (260 mg, 79%). 5H (400 MHz, CDCb) 6.87 (d, J 1.1 Hz, 1H), 6.47 (d, 77.7 Hz, 1H), 4.92-4.85 (m, 1H), 4.71 (d, J 11.4 Hz, 1H), 4.19 (s, 2H), 3.87-3.78 (m, 2H), 3.72 (dd, 711.4, 3.7 Hz, 1H), 3.54 (td, 711.9, 3.1 Hz, 1H), 3.32-3.17 (m, 3H), 1.44 (s, 9H). LCMS (Method 7): [M+H]⁺ m/z 295.0, RT 1.21 minutes.

INTERMEDIATE 17 fc/V-Butyl 3-r6-amino-5-(9//-fluoren-9-ylmethoxycarbonyla ino)pyridin-2-yll- morpholine-4-carboxylate

Intermediate 16 (260 mg, 0.839 mmol) was dissolved in DCM (5 mL) and Fmoc- OSu (311 mg, 0.923 mmol) was added. The solution was stirred at room temperature for 24 h. Additional Fmoc-OSu (75 mg, 0.222 mmol) was added, and stirring was continued at room temperature for 20 h. The mixture was concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc in heptane (0- 100%), to give the title compound (300 mg, 62%). 5H (500 MHz, CDCb) 7.78 (d, 77.4 Hz, 2H), 7.67-7.38 (m, 5H), 7.36-7.29 (m, 2H), 6.57 (d, 78.0 Hz, 1H), 6.13 (s, 1H), 4.90 (s, 1H), 4.70 (d, 711.2 Hz, 1H), 4.58 (d, 76.1 Hz, 2H), 4.45 (s, 2H), 4.29-4.20 (m, 1H), 3.90-3.78 (m, 2H), 3.74 (dd, 711.5, 3.7 Hz, 1H), 3.54 (td, 711.8, 2.9 Hz, 1H), 3.29-3.19 (m, 1H), 1.44 (s, 9H). LCMS (Method 7): [M+H]⁺ m/z 517.0, RT 1.96 minutes. INTERMEDIATE 18 -2-(benzyloxycarbonylamino)-2- dif1uorocvclohexyl )-

pholine-4-carboxylate

Intermediate 17 (209 mg, 0.639 mmol) was dissolved in EtOAc (5 mL). Pyridine

(211 pL, 2.61 mmol) was added, followed by T3P® in EtOAc (50%, 855 pL, 1.45 mmol) and fV)-4,4-difluoro-a-i [(phenylmethoxy)carbonyl]amino}cyclohexaneacetic acid (212 mg, 0.65 mmol). The mixture was stirred at room temperature for 3 h, then quenched with water (20 mL) and diluted with EtOAc (20 mL). The layers were separated and the organic layer was washed with saturated aqueous NaHC03 solution (20 mL), then dried over MgS04, filtered and concentrated under reduced pressure. The residue was dissolved in acetonitrile (5 mL), and diethylamine (1.0 mL, 9.67 mmol) was added. The solution was stirred at room temperature for 1 h, then concentrated under reduced pressure. Purification by column chromatography, eluting with a gradient of EtOAc in heptane, gave the title compound (308 mg, 76%). 5H (500 MHz, CDCb) 8.36-8.22 (m, 1H), 7.40-7.29 (m, 5H), 7.09 (dd, 78.1, 1.4 Hz, 1H), 6.93 (dd, 78.1, 4.5 Hz, 1H), 5.48- 5.38 (m, 1H), 5.18-5.09 (m, 2H), 4.94 (s, 1H), 4.62 (t, 712.6 Hz, 1H), 4.38 (s, 1H), 4.25 (s, 2H), 3.87-3.78 (m, 2H), 3.74 (dt, J 11.4, 3.9 Hz, 1H), 3.54 (td, J 11.8, 2.9 Hz, 1H), 3.21-3.10 (m, 1H), 2.20-2.08 (m, 2H), 2.03-1.95 (m, 1H), 1.94-1.80 (m, 2H), 1.80-1.66 (m, 2H), 1.57-1.37 (m, 11H). LCMS (Method 7): [M+H]⁺ m/z 604.0, RT 1.94 minutes.

INTERMEDIATE 19 fc/V-Butyl 3- ! 2-K^',.V)-benzyloxycarbonylamino(^'4.4-difluorocvclohexyl )methyll- l H- imidazor4.5-/>lpyridin-5-yllmorpholine-4-carboxylate

A solution of Intermediate 18 (308 mg, 0.510 mmol) in acetic acid (2.5 mL) was heated at 50°C for 5 h. The mixture was diluted with MeOH (5 mL) and passed through a 5 g SCX-2 cartridge, then washed with MeOH and eluted with 3.5N Mb/MeOH. The residue was concentrated under reduced pressure. The resulting crude material (240 mg, 24% loss of BOC protecting group) was dissolved in DCM (2.5 mL) and di-fe/7-butyl dicarbonate (28 mg, 0.128 mmol) was added. The solution was left to stand at r.t. for 16 h, then concentrated under reduced pressure, to give the title compound (280 mg, 94%). LCMS (Method 7): [M+H]⁺ m/z 586.0, RT 1.93 minutes. INTERMEDIATE 20 tert- Butyl 3-(2-r SVamino difluorocvclohexyDrnethvH- ridin-5-

4-carboxylate

Intermediate 19 (280 mg, 0.478 mmol) was dissolved in EtOH (2.5 mL) and EtOAc (2.5 mL), then 10% palladium on carbon, 50% wet (5.0%, 102 mg, 0.0478 mmol) was added. The reaction mixture was stirred vigorously under a hydrogen atmosphere for 3 h. The mixture was filtered through Celite® under nitrogen, washing with EtOAc. The residue was loaded onto a 5 g SCX-2 cartridge and washed with MeOH, then eluted with 3.5N ME/MeOH. The resulting material was concentrated under reduced pressure to give the title compound (188 mg, 80%). 5H (400 MHz, CDCb) 10.07 (s, 1H), 8.04-7.82 (m, 1H), 7.12 (dd, 78.3, 2.8 Hz, 1H), 5.28-5.15 (m, 1H), 4.89-4.74 (m, 1H), 4.27-4.18 (m, 1H), 3.95-3.80 (m, 3H), 3.67-3.55 (m, 1H), 3.42-3.23 (m, 1H), 2.21-2.06 (m, 3H), 1.88- 1.58 (m, 7H), 1.46 (s, 9H). LCMS (Method 7): [M+H]⁺ m/z 452.0, RT 1.56 minutes.

INTERMEDIATE 21 fc/V-Butyl 3-(2-!fV)-(4.4-difluorocvclohexyl iKA-ethyl- 1.2.5-oxadiazole-3-carbonyl )- aminolmethyl i- l//-imidazor4.5-/ripyridin-5-yl )morpholine-4-carboxylate

To a solution of 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (71 mg, 0.498 mmol) and DIPEA (0.13 mL, 0.766 mmol) in DCM (3 mL) was added HATU (204 mg, 0.536 mmol). The mixture was stirred at room temperature for 15 minutes, then added to a solution of Intermediate 20 (92%, 188 mg) in DCM (2 mL). The solution was stirred at r.t. for 2 h, then purified by column chromatography, eluting with a gradient of EtOAc in heptane (0-100%), to give the title compound (220 mg, 95%). 5H (400 MHz, CDCb) 13.14-12.43 (m, 1H), 9.76-9.42 (m, 1H), 8.07-7.87 (m, 1H), 7.08 (d, 78.2 Hz, 1H), 5.20 (t, 78.2 Hz, 1H), 5.10-4.98 (m, 1H), 4.60-4.42 (m, 1H), 3.82-3.68 (m, 3H), 3.51-3.41 (m, 2H), 2.94-2.87 (m, 1H), 2.34-2.23 (m, 1H), 2.12-1.90 (m, 3H), 1.90-1.69 (m, 2H), 1.68- 1.54 (m, 2H), 1.48-1.20 (m, 13H). One CH signal obscured by water. LCMS (Method

7): [M+H]⁺ m/z 576.0, RT 1.94 minutes. INTERMEDIATE 22 iV-((5^,)-(4.4-Difluorocvclohexynr5-(morpholin-3-vn-li7-imidazor4.5-/>1pyridin-2- yl1methyl|-4-ethyl-1.2.5-oxadiazole-3-carboxamide Intermediate 21 (220 mg, 0.382 mmol) was dissolved in DCM (10 mL) and TFA

(1 mL) was added. The solution was stirred at room temperature for 4 h, then concentrated under reduced pressure and dissolved in MeOH. The resulting material was passed through a 2 g SCX-2 cartridge, then washed with MeOH and eluted with 7N ML/ MeOH. The residue was concentrated under reduced pressure to give the title compound (145 mg, 76%). 5H (500 MHz, DMSO-de) 12.93 (s, 1H), 9.61 (s, 1H), 8.05-7.76 (m, 1H),

7.34 (d, 78.3 Hz, 1H), 5.29-5.15 (m, 1H), 3.95 (dd, 79.8, 3.3 Hz, 1H), 3.89 (dd, 710.7, 3.3 Hz, 1H), 3.79-3.68 (m, 1H), 3.47-3.39 (m, 1H), 3.30-3.27 (m, 1H), 2.95-2.71 (m, 5H), 2.34-2.23 (m, 1H), 2.14-1.90 (m, 3H), 1.89-1.72 (m, 2H), 1.59 (d, J 11.7 Hz, 1H), 1.49- 1.26 (m, 2H), 1.23 (t, 77.5 Hz, 3H). LCMS (Method 7): [M+H]⁺ m/z 476.0, RT 1.54 minutes.

INTERMEDIATE 23 Tetrabenzyl-4-bromo-3-fluorobenzene-l .2-diamine

4-Bromo-3-fluorobenzene- 1,2-diamine (6.00 g, 29.3 mmol) was added portion- wise to a stirred suspension of NaH (60%, 14.05 g, 0.351 mol) in dry DMF (120 mL) at r.t. and stirred for 45 minutes. The reaction mixture was cooled to 5°C (ice bath), then benzyl bromide (30 mL, 0.253 mol) was added dropwise over 1 h. The reaction mixture was allowed to warm to room temperature. After stirring for 18 h, the mixture was added dropwise onto ice and allowed to warm to room temperature, then extracted with tert- butyl methyl ether (3 x 100 mL). The combined organic layers were washed with water (4 x 100 mL) and brine (100 mL), then dried over Na2SC>4, filtered and evaporated to dryness. The crude material was purified by column chromatography (340 g Ultra KP- Sil, Biotage), eluting with 1:1 toluenedsohexane in isohexane (0-100% gradient), to afford the title compound (11.50 g, 66%) as a colourless oil that solidified on standing. 5H (500 MHz, CDCb) 7.25-7.16 (m, 16H), 7.09 (dd, 78.8, 7.5 Hz, 1H), 7.05-7.01 (m, 4H), 6.43 (dd, 78.8, 1.6 Hz, 1H), 4.38 (s, 4H), 4.25 (s, 4H). INTERMEDIATE 24

3.4-Bis(dibenzylamino)-2-f1uorobenzaldehyde

«-Butyllithium (2.5M in toluene, 2.2 mL, 5.51 mmol) was added dropwise to a stirred solution of Intermediate 23 (3.00 g, 5.04 mmol) in dry THF (40 mL) at -78°C. After stirring for 30 minutes, DMF (780 pL, 10.1 mmol) was added dropwise and the mixture was stirred at -78°C for 1 h. The reaction mixture was carefully quenched with saturated aqueous NFLCl solution (20 mL), followed by water (50 mL), at -78°C. The residue was warmed to room temperature and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (25 mL), then dried over Na2SC>4, filtered and evaporated to dryness. The crude material was purified by column chromatography (100 g KP-Sil, Biotage), eluting with 0-30% EtOAc in heptane, to afford the title compound (2.48 g, 96%) as an off-white solid. 5H (500 MHz, CDCh) 10.12 (s, 1H), 7.50-7.44 (m, 1H), 7.26-7.20 (m, 12H), 7.19-7.14 (m, 4H), 7.03-6.96 (m, 4H), 6.64 (d, 78.7 Hz, 1H), 4.52 (s, 4H), 4.35 (br s, 4H).

INTERMEDIATE 25

Mixture of fer/-butyl 3-r3.4-bis(dibenzylamino)-2-fluorophenyl1piperazine-l-carboxylate and fc/ -butyl 3-r4-(benzylamino)-3-(dibenzylamino)-2-fluorophenyl1piperazine-l- carboxylate

To a solution of /cvV-butyl A^f-(2-aminoethyl)-A-[(tributylstannyl)methyl]carbamate (900 mg, 1.94 mmol) in anhydrous DCM (10 mL) were added Intermediate 24 (1 g, 1.94 mmol) and molecular sieves (190 mg). The resulting mixture was stirred at r.t. for 2 h, then filtered through Celite®. The cake was washed with DCM, and the filtrate was concentrated in vacuo to provide an imine intermediate. In a separate round-bottomed flask, a mixture of dry copper(II) trifluoromethanesulfonate (703 mg, 1.94 mmol) and 2,6-dimethylpyridine (225 pL, 1.94 mmol) in l,l,l,3,3,3-hexafluoro-2-propanol (8 mL) was stirred for 2 h. The previously prepared imine intermediate in DCM (8 mL) was added, and the resulting mixture was stirred at r.t. for 16 h. To the reaction mixture was added 10% aqueous ammonia solution (20 mL), and the resulting mixture was stirred at r.t. for 15 minutes. The layers were separated, and the aqueous layer was extracted with DCM (3 x 25 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over MgS04, filtered and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography (100 g), eluting with 5:95 triethylamine:EtOAc in heptane (20-40% gradient), to afford the title compounds (~1:1 mixture, 750 mg, 61%). LCMS (Method 8): [M+H]⁺ m/z 671 and 581, RT 3.41 minutes.

INTERMEDIATE 26

Mixture of fer/-butyl 3-r3.4-bis(dibenzylamino)-2-fluorophenyll-4-(3.3-difluoro- cvclobutanecarbonyl jpiperazine- 1 -carboxyl ate an butyl 3-r4-(benzylamino)-3-

(dibenzylamino)-2-fluorophenyll-4-(3.3-difluorocvclobutanecarbonyl jpiperazine- 1 - carboxyl ate

To a solution of 3,3-difluorocyclobutanecarboxylic acid (180 mg, 1.32 mmol) in DMF (7.5 mL) was added DIPEA (293 pL, 1.67 mmol), followed by HATU (510 mg, 1.34 mmol). The resulting mixture was stirred at r.t. for 15 minutes. Intermediate 25 (750 mg) was added. The reaction mixture was stirred at r.t. for 1.5 h, then concentrated in vacuo. EtOAc (90 mL) was added. The resulting material was washed with 0.1M hydrochloric acid (3 x 10 mL), water (3 x 20 mL) and brine (10 mL), then dried over Na2SC>4, filtered and concentrated in vacuo. The resulting yellow oil was purified by flash column chromatography (25 g), eluting with EtOAc in heptane (15-35% gradient), to afford the title compounds (~1 : 1 mixture, 880 mg, quantitative) as a colourless oil. LCMS (Method 5): [M+H]⁺ m/z 789 and 699, RT 2.11 minutes.

INTERMEDIATE 27 Mixture of ! 2- bis(dibenzylamino)-2-f1uorophenyl1piperazin- l -yl i difluoro-

cvclobutvnmethanone and 2-r4-(benzylamino)-3-(dibenzylamino)-2-fluorophenyll-

piperazin-1 -yl iO -difluorocvclobutyl imethanone. trifluoroacetate salts

TFA (1 mL, 13.1 mmol) was added to a stirred solution of Intermediate 26 (880 mg) in DCM (10 mL). The resulting mixture was stirred under air at r.t. for 24 h, then concentrated in vacuo , to afford the title compounds (~1 : 1 mixture, 1.06 g, 95%) as an orange oil. LCMS (Method 5): [M+H]⁺ m/z 689 and 599, RT 1.58 minutes. INTERMEDIATE 28

Mixture of methyl 3- bis(dibenzylamino)-2-f1uorophenyl1-4- dif1uoro-

cvclobutanecarbonvnpiperazine-l-carboxylate and methyl 3-r4-(benzylamino)-3- (dibenzylamino)-2-f1uorophenyl1-4- dif1uorocvclobutanecarbonyl )piperazine-l -

carboxyl ate

To a solution of Intermediate 27 (1.06 g) in DCM (10 mL) was added DIPEA (770 pL, 4.41 mmol). To this mixture at 0°C was added methyl chloroformate (95 pL, 1.23 mmol). The resulting mixture was stirred under air at 0°C for 3 h, then concentrated in vacuo and taken up in EtOAc (100 mL). The resulting solution was washed with water (3 x 10 mL) and brine (10 mL), then dried over sodium sulfate, filtered and concentrated in vacuo , to afford the title compounds (~1 : 1 mixture, 750 mg, 92%) as a white foam. LCMS (Method 5): [M+H]⁺ m/z 747 and 657, RT 2.03 minutes. INTERMEDIATE 29

Methyl 3 -(3.4-diamino-2-fluorophenvD-4-( 3.3 -difluorocvclobutanecarbonvDpiperazine- 1 - carboxyl ate

To a purged flask of Intermediate 28 (750 mg) in EtOH (10 mL) and concentrated hydrochloric acid (200 pL, 2.60 mmol) was added palladium (10%, 60 mg, 0.06 mmol). The resulting mixture was purged and stirred under hydrogen for 16 h. To the reaction mixture were added palladium (10%, 60 mg, 0.06 mmol) and concentrated hydrochloric acid (200 pL, 2.60 mmol). The reaction mixture was stirred under hydrogen for 4 h, then filtered through Celite® and concentrated in vacuo , to afford the title compound (498 mg, 88%) as an orange foam. LCMS (Method 5): [M+H]⁺ m/z 387, RT 1.01 minutes.

INTERMEDIATE 30

Methyl 3-(3-amino-4-(r(2Sy2-(^'fer/-butoxycarbonylamino)-2-(4.4-difluorocvclohexyO- acetyllamino i-2-fluorophenyl )-4-(3.3-dilluorocvclobutanecarbonyl )piperazine-l- carboxylate

To a solution of (2k)-2-(/ty7-butoxycarbonyl a i no)-2-(4, 4-dill uorocyclohexyl )- acetic acid (226 mg, 0.77 mmol) in DMF (1 mL) was added DIPEA (185 pL, 1.06 mmol), followed by HATU (320 mg, 0.84 mmol). The resulting mixture was stirred at r.t. for 15 minutes. Intermediate 29 (270 mg, 0.70 mmol) in DCM (10 mL) was added. After stirring for 16 h, the reaction mixture was washed with 0.5M HC1 (2 x 2 mL) and water (2 x 2 mL), then dried over MgSCri, filtered and concentrated in vacuo. The resulting orange oil was purified by flash column chromatography (25 g), eluting with EtOAc in heptane (60-80% gradient), to afford the title compound (416 mg, 90%) as a white gum. LCMS (Method 5): [M+Na]⁺ m/z 684, RT 1.47 minutes.

INTERMEDIATE 31

Methyl 3-(2-KA)-(fer/-butoxycarbonylamino)(4.4-difluorocvclohexynmethyll-4-fluoro- benzimidazol-5-yl 1-4-13.3 -difluorocvclobutanecarbonvDpiperazine-l-carboxylate A solution of Intermediate 30 (416 mg, 0.63 mmol) in AcOH (5 mL) was stirred at 60°C for 9 h. The reaction mixture was concentrated in vacuo , azeotroping from a mixture of EtOAc and heptane, to afford the title compound (405 mg, 53%). LCMS (Method 5): [M+H]⁺ m/z 644, RT 1.44 minutes.

INTERMEDIATE 32

Methyl 3- amino(^'4.4-difluorocvclohexyl )methyll-4-fluoro- benzimidazol-5-

yl !-4-(3.3-difluorocvclobutanecarbonyl jpiperazine- 1 -carboxyl ate trifluoroacetate salt

TFA (480 pL, 6.27 mmol) was added to a stirred solution of Intermediate 31 (405 mg, 0.63 mmol) in DCM (8 mL). The resulting mixture was stirred under air at r.t. for 2 h, then concentrated in vacuo , to afford the title compound (318 mg, 77%) as a yellow oil. LCMS (Method 5): [M+H]⁺ m/z 544, RT 1.06 minutes.

INTERMEDIATE 33 fc/V-Butyl 5-diphenoxyphosphoryloxy-2.3-dihvdro-L4-thiazine-4-carboxylate

To a solution of /tvV-butyl 3-oxothiomorpholine-4-carboxylate (2.54 g, 11.7 mmol) in THF (23 mL), cooled to -78°C, was added lithium bis(trimethylsilyl)amide (1M solution in THF, 12.9 mL, 12.9 mmol) dropwise over 15 minutes. The reaction mixture was stirred for 1 h at -78°C, then diphenyl chlorophosphate (2.57 mL, 12.3 mmol) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to r.t. and stirred for 16 h. The mixture was poured onto saturated aqueous MLCl solution (20 mL) and extracted with EtOAc. The organic layers were washed with saturated aqueous NaHCCh solution and brine, then dried (NaiSCri) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-35% gradient), gave the title compound (4.78 g, 91%) as a colourless oil. 5H (400 MHz, CDCb) 7.41-7.34 (m, 4H), 7.30-7.20 (m, 6H), 5.70 (d, 73.2 Hz, 1H), 3.82-3.75 (m, 2H), 2.99-2.91 (m, 2H), 1.45 (s, 9H). LCMS (Method 4): [M+H-BOC]⁺ m!z 350, RT 1.53 minutes.

INTERMEDIATE 34

Benzyl /V-r(T5y2-(2-amino-4-bromo-3-fluoroanilino)-l- difluorocvclohexyO-2-oxo-

ethyllcarbamate

To a mixture of 4-bromo-3-fluorobenzene- 1,2-diamine (76.0 g, 371 mmol), (25)- 2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (127.0 g, 389 mmol) and HATU (144.0 g, 371 mmol) in a 5 L ReactorReady process reactor was added DCM (1520 mL), followed by dropwise addition of DIPEA (95.8 g, 741 mmol, 129 mL) at such a rate that the internal temperature did not exceed 21°C. The reaction mixture solidified overnight in the reactor. Water (1 L) was added, and the mixture was stirred vigorously. DCM was removed by distillation directly from the reactor. After DCM removal was complete, additional water (500 mL) was added and the mixture was heated at 80°C (internal temperature) for 30 minutes. The solid was removed from the reactor whilst hot, then filtered and washed with cold water (-200 mL). The residue was suspended in water (1 L), and heated at 80°C for 30 minutes, then filtered. The procedure was repeated, then the resulting material was filtered and dried on a sinter overnight, to give the title compound (193.0 g, quantitative) as small dark balls. 5H (400 MHz, DMSO-dr,) 9.53 (s, 1H), 7.72 (d, 77.9 Hz, 1H), 7.37 (s, 2H), 7.42-7.29 (m, 3H), 7.06 (dd, 78.7, 1.7 Hz, 1H), 6.81 (dd, 78.7, 7.2 Hz, 1H), 5.20 (s, 1H), 5.06 (s, 2H), 4.13 (t, 77.9 Hz, 1H), 2.04 (br s, 2H), 1.85 (br s, 3H), 1.70 (d, 713.3 Hz, 2H), 1.39 (m, 3H). LCMS (Method 4): [M+H]⁺ m/z 514/516 (Br isotope), RT 2.15 minutes. INTERMEDIATE 35

Benzyl A^f-r(_>V)-(5-bromo-4-f1uoro- l//-benzimidazol-2-yl )(4.4-dif1uorocvclohexyl )- methyllcarbamate Intermediate 34 (190.0 g, 369.4 mmol) and DCM (200 mL) were introduced into a

5 L process reactor, followed by TFA (56 mL), over 10 minutes. The resulting mixture was heated at 36-37°C (internal temperature) for approximately 20 h, then TFA (5 mL) was added. Stirring was continued for 3 h, then further TFA (1 mL) was added. After 3 h, the mixture was cooled and allowed to stand at r.t. overnight. To the mixture was added saturated aqueous NaFICCb solution (1.2 L), over 20 minutes with stirring, to give a final pH ~10. Water (0.6 L) was added, and the DCM was removed by distillation over approximately 4 h. The resulting solid was removed from the reactor and filtered, then washed on the sinter with water (3 x 500 mL) and sucked dry over 48 h, to yield the title compound (175 g, 95.4%) as a beige solid. 5H (400 MHz, DMSO-de) 12.90 (s, 1H), 8.00 (d, J8.5 Hz, 1H), 7.50-6.93 (m, 6H), 5.35-4.86 (m, 2H), 4.75 (t, J8.1 Hz, 1H), 2.22-1.60

(m, 6H), 1.60-0.88 (m, 3H). LCMS (Method 6): [M+H]⁺ m/z 496/498 (Br isotope), RT 2.09 minutes.

INTERMEDIATE 36

Benzyl A^f- 4.4-difluorocvclohexyl )14-fluoro-5-(4.4.5.5-tetramethyl- l 3.2-dioxa-

borolan-2-yl )- l//-benzi mi dazol-2-nPih ethyl i carbarn ate

To a solution of Intermediate 35 (2.10 g, 4.20 mmol), bis(pinacolato)diboron (1.20 g, 4.70 mmol) and potassium acetate (1.00 g, 10.1 mmol) in 1,4-dioxane (14 mL) were added Pd2(dba)3 (120 mg, 3 mol %) and 2-(dicyclohexylphosphino)-2',4',6'- triisopropylbiphenyl (120 mg, 6 mol %) sequentially. The mixture was purged with N2 for 10 minutes, then heated at 105°C for 1 h. The reaction mixture was cooled to r.t., then EtOAc (50 mL) and H2O (25 mL) were added. The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (2.27 g, 99%) as an orange foam. Two tautomers were observed, in a 4.2: 1 ratio. 5H (400 MHz, DMSO-de) 13.00 (s, 1H, minor tautomer), 12.72 (s, 1H, major tautomer), 8.04 (d, J 8.6 Hz, 1H, major tautomer), 7.93 (d, J8.2 Hz, 1H, minor tautomer), 7.46-7.25 (m, 7H), 5.07 (d, J 12.6 Hz, 1H), 5.01 (d, J 12.5 Hz, 1H), 4.75 (t, J8.1 Hz, 1H), 2.20-1.13 (m, 9H), 1.32 (s, 12H). LCMS (Method 4): [M+H]⁺ m!z 544, RT 1.45 minutes.

INTERMEDIATE 37 tert- Butyl 5-!2- -benzyloxycarbonylamino dif1uorocvclohexyl )m ethyl 1-4-fluoro-

benzimidazol-5-yl !-2.3-dihydro- l .4-thiazine-4-carboxylate

To a solution of Intermediate 36 (1.00 g, 1.84 mmol), Intermediate 33 (993 mg, 2.21 mmol), Pd(dppf)Cl2.DCM (151 mg, 10 mol %) and 1,4-dioxane (3.2 mL) was added aqueous Na2CCh solution (2M, 5.5 mL, 11.0 mmol). The mixture was purged with N2 for 10 minutes, then heated at 105°C. The reaction mixture was cooled to r.t. and filtered through Celite® (1 g), eluting with EtOAc (100 mL). The filtrate was concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (957 mg, 65%) as a white solid. Two tautomers were observed, in a 3:1 ratio. 5H (400 MHz, DMSO-de) 12.85 (s, 1H, minor tautomer), 12.56 (s, 1H, major tautomer), 8.01 (d, J8.6 Hz, 1H, major tautomer), 7.90 (d, .78 8 Hz, 1H, minor tautomer), 7.44-7.27 (m, 5H), 7.23 (d, J8.3 Hz, 1H), 7.12-6.97 (app t, J7.3 Hz, 1H), 6.04 (s, 1H, minor tautomer), 5.97 (s, 1H, major tautomer), 5.07 (d, J 12.6 Hz, 1H), 5.02 (d, J 12.6 Hz, 1H), 4.75 (t, J8.2 Hz, 1H), 3.94-3.80 (m, 2H), 3.11 (unresolved t, J

5.0 Hz, 2H), 2.20-1.90 (m, 3H), 1.89-1.63 (m, 3H), 1.54-1.27 (m, 2H), 1.27-1.13 (obscured m, 1H), 0.93 (s, 9H). LCMS (Method 4): [M+H]⁺ m!z 617, RT 1.52 minutes.

INTERMEDIATE 38

Benzyl A^f- 4.4-difluorocvclohexyl )r4-f1uoro-5-(thiomorpholin-3-yl )-\H-

benzimidazol-2-yllmethyl carbamate

To a solution of Intermediate 37 (903 mg, 1.46 mmol) in DCM (19 mL) at 0°C was added TFA (3.3 mL) dropwise. The ice-bath was removed immediately, and the reaction mixture was warmed to r.t. and stirred for 130 minutes, then concentrated in vacuo. The residue was dissolved in MeOH (20 mL) and cooled to 0°C, then NaB¾

(231 mg, 5.86 mmol) was added portionwise over 5 minutes. The ice-bath was removed immediately, and the reaction mixture was warmed to r.t. and stirred for 40 minutes. The mixture was quenched by the careful dropwise addition of H2O (20 mL), then EtOAc (30 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/isohexane (0-100% gradient), followed by MeOH/DCM (10%), gave the title compound (mixture of diastereomers assumed to be 1:1, indistinguishable by 'H NMR, 655 mg, 86% over two steps) as a white solid. 5H (400 MHz, DMSO-de) 12.92 (s, 1H, minor tautomer), 12.63 (s, 1H, major tautomer), 8.00 (unresolved dd, 78.6, 4.5 Hz, 1H, major tautomer), 7.94-7.85 (m, 1H, minor tautomer), 7.45-7.23 (m, 7H), 5.07 (d, 712.6 Hz, 1H), 5.01 (d, 712.6 Hz, 1H), 4.73 (t, 78.2 Hz, 1H), 4.34 (br s, 1H), 3.49-3.37 (m, 1H), 3.16-3.00 (m, 1H), 2.93-

2.71 (m, 2H), 2.62-2.37 (m, 3H), 2.18-1.91 (m, 2H), 1.91-1.63 (m, 3H), 1.54-1.14 (m, 3H). The NH signal was not observed. LCMS (Method 4): [M+H]⁺ m!z 519, RT 1.32 minutes.

INTERMEDIATE 39

Benzyl A-r(M-(4A-difhiorocvclohexyr)(4-fluoro-5-r4-(3-fluorobicvclori.l.llpentane-l- carbonyl )thiomorpholin-3-yll- benzimidazol-2-yl !methyllcarbamate

Intermediate 38 (200 mg, 0.39 mmol) in DMF (2.5 mL) was treated with 1- fluorobicyclo[l.l.l]pentane-3 -carboxylic acid (53 mg, 0.41 mmol) and DIPEA (0.27 mL,

1.60 mmol), followed by HATU (181 mg, 0.46 mmol). After stirring overnight, water was added, and the mixture was extracted with EtOAc. The organic layers were washed with brine, dried over NaiSCri and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), furnished the title compound (153 mg, 63%) as a white solid. 5H (400 MHz, 373K, DMSO-de) 12.29 (s,

1H), 7.48-7.24 (m, 6H), 7.22-7.16 (m, 1H), 5.81 (t, 76.0 Hz, 1H), 5.10 (d, J 12.6 Hz, 1H), 5.05 (d, J 12.6 Hz, 1H), 4.80 (t, 78.3 Hz, 1H), 4.40-4.28 (m, 1H), 3.45 (unresolved t, 1H), 3.19 (dd, 714.3, 6.6 Hz, 1H), 3.08 (dd, 714.3, 5.1 Hz, 1H), 2.87-2.71 (m, 2H), 2.44-2.32 (m, 6H), 2.20-2.09 (m, 1H), 2.08-1.95 (m, 2H), 1.94-1.86 (m, 1H), 1.85-1.66 (m, 2H), 1.64-1.54 (m, 1H), 1.50-1.26 (m, 2H). The amide NH signal was not observed. ¹⁹F {¾}

NMR (282 MHz, DMSO-de) d -90.1 (d, 7232.5 Hz, IF), -99.7 (d, 7231.7 Hz, IF), -133.0 (s, IF), -147.0 (s, IF). LCMS (Method 4): [M+H]⁺ m!z 631, RT 1.41 minutes. INTERMEDIATE 40

Benzyl A-r(M-(4A-difhiorocvclohexyr)(4-fluoro-5-r4-(3-fluorobicvclori.l.l1pentane-l- carbonyl)- 1.1 -dioxo- 1 4-thiazinan-3 -yll- benzimidazol-2-yl !methyllcarbamate

To a solution of Intermediate 39 (153 mg, 0.24 mmol) in THF (5 mL) at r.t. were added di-/er/-butyl dicarbonate (0.07 mL, 0.30 mmol) and DMAP (3.0 mg, 0.024 mmol). The reaction mixture was stirred for 110 minutes, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-60% gradient). The resulting white foam (the intermediate BOC-protected benzimidazole, 161 mg) was dissolved in DCM (10 mL) and cooled to 0°C. mCPBA (70%, 103 mg, 0.42 mmol) was added in one portion, and the mixture immediately warmed to r.t. After 75 minutes, the mixture was washed with saturated aqueous NaHCCh solution (twice) and brine, then dried (NaiSCri) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). The resulting white foam (176 mg) was dissolved in DCM (10 mL), and TFA (0.57 mL, 7.40 mmol) was added dropwise at r.t. After 80 minutes, the mixture was concentrated to dryness and the residue was passed through an SCX column (10 g), eluting with MeOH, then 4N methanolic ammonia. The methanolic ammonia filtrate was concentrated in vacuo to give the title compound (~1 : 1 mixture of diastereomers indistinguishable by 'H and ¹⁹F NMR, 134 mg, 82% over three steps) as a white foam. 5H (400 MHz, 373K, DMSO-de) 12.34

(s, 1H), 7.58-7.22 (m, 6H), 7.08 (t, Jl.l Hz, 1H), 6.05 (t, J 6.6 Hz, 1H), 5.10 (d, J 12.7 Hz, 1H), 5.05 (d, J 12.7 Hz, 1H), 4.80 (t, 78.2 Hz, 1H), 4.64-4.53 (m, 1H), 4.00-3.85 (m, 2H), 3.67 (dd, J 14.9, 6.0 Hz, 1H), 3.41-3.25 (m, 2H), 2.46-2.34 (m, 6H), 2.23-2.09 (m, 1H), 2.09-1.95 (m, 2H), 1.95-1.86 (m, 1H), 1.86-1.66 (m, 2H), 1.65-1.53 (m, 1H), 1.51- 1.25 (m, 2H). The amide NH signal was not observed. ¹⁹F {¾} NMR (282 MHz,

DMSO-de) d -90.1 (d, 7232.5 Hz, IF), -99.7 (d, 7232.7 Hz, IF), -132.0 (br s, IF),

-147.21 (s, IF). LCMS (Method 4): [M+H]⁺ m!z 663, RT 1.32 minutes. INTERMEDIATE 41

(3- difluorocvclohexyOmethvn-4-fluoro-li7-benzimidazol-5-yl|-El-

dioxo- 1 4-thiazinan-4-yl )(3-fluoro-l -bicvclor 1.1. 1 Ipentanyl )methanone To a solution of Intermediate 40 (134 mg, 0.20 mmol) in EtOAc (10 mL) at r.t. was added Pd(OH)2/C (15 mg) in one portion. The reaction mixture was stirred under an atmosphere of hydrogen for 16 h, then filtered through Celite® (1 g), washing the plug with EtOAc. The filtrate was concentrated in vacuo. The residue was redissolved in EtOAc (10 mL) and re-charged with Pd(OH)2/C (30 mg). The mixture was stirred under an atmosphere of hydrogen at r.t. for a further 3.25 h, then filtered through Celite® (1 g), washing the plug with EtOAc. The residue was concentrated in vacuo. Purification by flash chromatography (KP-NH column), eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (10%), gave the title compound (~1 : 1 mixture of diastereomers, indistinguishable by ¾ and ¹⁹F NMR, 109 mg, quantitative) as a white solid. 5H (400 MHz, 373K, DMSO-de) 7.30 (d, 78.4 Hz, 1H), 7.04 (app t, 77.6 Hz, 1H), 6.04 (t, 76.6 Hz, 1H), 4.64-4.54 (m, 1H), 4.00-3.86 (m, 3H), 3.67 (dd, 14.8, 6.0 Hz, 1H), 3.41-3.25 (m, 2H), 2.46-2.33 (m, 6H), 2.11-1.95 (m, 2H), 1.95-1.86 (m, 1H), 1.86- 1.67 (m, 2H), 1.65-1.56 (m, 1H), 1.54-1.27 (m, 3H). The amine and benzimidazole NH signals were not observed. ¹⁹F {¾} NMR (282 MHz, DMSO-de) d -89.5 (d, 7232.2 Hz, IF), -99.8 (d, 7232.0 Hz, IF), -132.3 (br s, IF), -147.2 (s, IF). LCMS (Method 4): [M+H]⁺ m!z 529, RT 1.04 minutes.

INTERMEDIATE 42 morpholin-3-yll-l //-benzimidazol-2-

vHmethyl1-4-ethyl-E2.5-oxadiazole-3-carboxamide. free base

To a solution of Intermediate 4 (4.20 g, 6.70 mmol) in DCM (70 mL) at 0°C was added TFA (7.0 mL). The reaction mixture was warmed to r.t. and stirred for 5.5 h, then carefully neutralised with saturated aqueous NaHC03 solution. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 120 mL). The combined organic layers were washed with saturated aqueous NaHC03 solution (150 mL), then passed through a phase separator and concentrated in vacuo , to afford the title compound (3.70 g, 100%) as an off-white solid. 5H (300 MHz, DMSO-de) 12.71 (s, 1H), 9.70 (s, 1H), 7.44-7.24 (m, 2H), 5.18 (t, 78.2 Hz, 1H), 4.24-4.13 (m, 1H), 3.81-3.64 (m, 2H), 3.48 (td, 710.6, 3.7 Hz, 1H), 3.22 (t, 710.4 Hz, 1H), 3.02-2.82 (m, 4H), 2.75 (br s, 1H), 2.38- 2.19 (m, 1H), 2.14-1.65 (m, 5H), 1.61-1.48 (m, 1H), 1.48-1.24 (m, 2H), 1.23 (t, 77.4 Hz, 3H). LCMS (Method 6): [M+H]⁺ m/z 493, RT 1.63 minutes.

INTERMEDIATE 43 fc/V-Butyl ZV-(2-amino-6-bromopyri din-3 -vDcarbamate

To a solution of 6-bromopyridine-2, 3 -diamine (100 g, 521 mmol) and di-/er/-butyl dicarbonate (126.5 g, 574 mmol) in EtOH (550 mL) at r.t. was added guanidine hydrochloride (5.60 g, 58.0 mmol). The mixture was heated to 50°C, resulting in effervescence (which subsided after approximately 4 h). The mixture was stirred at 50°C for 21 h, then cooled to r.t. The precipitate was filtered, washed sequentially with EtOH (100 mL) and isohexane (300 mL), then dried, to give the title compound (140.6 g, 94%) as a tan-coloured powder. 5H (300 MHz, DMSO-de) 8.45 (s, 1H), 7.55 (d, 78.1 Hz, 1H), 6.69 (d, 78.0 Hz, 1H), 6.24 (s, 2H), 1.46 (s, 9H).

INTERMEDIATE 44 fc/V-Butyl A^f-(2-i r(2.V)-2-(benzyloxycarbonylamino)-2-(4.4-difluorocvclohexyl iacetyll- 6-bromopyridin-3-vDcarbamate

To a solution of (27)-2-(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)- acetic acid (8.70 g, 27.0 mmol), Intermediate 43 (6.90 g, 24.0 mmol) and pyridine (8.70 mL, 110 mmol) in EtOAc (69 mL) at 0°C was added T3P® (50% in EtOAc, 35 mL, 59.4 mmol) dropwise. The reaction mixture was allowed to warm to r.t. and stirred for 16 h, then quenched with H2O (50 mL) and further diluted with EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with saturated aqueous NaHC03 solution (100 mL), dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (13.86 g, 97%) as a white solid. 5H (400 MHz, 373K, DMSO-de) 10.43 (s, 1H), 8.05 (d, 78.5 Hz, 1H), 7.93 (s, 1H), 7.51 (d, 78.4 Hz, 1H), 7.41-7.22 (m, 6H), 5.11 (d, 712.7 Hz, 1H), 5.08 (d, 7 12.7 Hz, 1H), 4.32 (dd, 77.8, 7.3 Hz, 1H), 2.14-1.91 (m, 3H), 1.91-1.69 (m, 4H), 1.56- 1.37 (m, 2H), 1.46 (s, 9H). ¹⁹F NMR (282 MHz, DMSO-de) d -89.82 (d, 7232.7 Hz, IF), -99.72 (d, 7232.8 Hz, IF). LCMS (Method 4): [M+H]⁺ m/z 597, 599, RT 1.56 minutes.

INTERMEDIATE 45

Benzyl A^f-r6V)-(5-bromo- l//-imidazor4.5-/ripyridin-2-yl )(4.4-difluorocvclohexyl jmethyll- carbamate

To a solution of Intermediate 44 (13.86 g, 23.2 mmol) in DCM (70 mL) at r.t. was added TFA (17.5 mL, 231 mmol) dropwise. The mixture was stirred at 40°C for 4 h, then cooled to r.t., neutralised with saturated aqueous NaHCCb solution (-250 mL), passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (single tautomer) (10.04 g, 90%) as a white solid. 5H (400 MHz, 373K, DMSO-de) 7.87 (d, 78.3 Hz, 1H), 7.47 (br d, 78.5 Hz, 1H), 7.37 (d, J 8.3 Hz, 1H), 7.35- 7.27 (m, 5H), 5.10 (d, 712.7 Hz, 1H), 5.05 (d, J 12.7 Hz, 1H), 4.81 (dd, 78.6, 7.6 Hz,

1H), 2.21-2.09 (m, 1H), 2.09-1.94 (m, 2H), 1.94-1.84 (m, 1H), 1.84-1.66 (m, 2H), 1.64- 1.54 (m, 1H), 1.45 (tdd, J 12.9, 8.3, 3.6 Hz, 1H), 1.32 (qd, J 12.7, 4.2 Hz, 1H). The imidazole NH signal was not observed. ¹⁹F {¾} NMR (282 MHz, DMSO-de) d -90.03 (d, J 232.5 Hz, IF), -99.69 (d, 7232.7 Hz, IF). LCMS (Method 4): [M+H]⁺ m/z 479, 481, RT 1.30 minutes.

INTERMEDIATE 46

Mixture of benzyl iV 5-bromo-l-(2-trimethylsilylethoxymethyl)imidazor4.5-61-

pyridin-2- and benzyl 5-bromo-3-

(2-trimethylsilylethoxymethvnimidazor4.5-Mpyri din-2 -yll(4.4-difluorocv cl ohexyl)- methyllcarbamate

To a solution of Intermediate 45 (10.04 g, 20.95 mmol) in DMF (200 mL) at r.t. were added 2-(trimethylsilyl)ethoxymethyl chloride (8.90 mL, 50.0 mmol) and K2CO3 (7.02 g, 50.3 mmol) sequentially. The reaction mixture was stirred at r.t. for 90 minutes, then treated with additional 2-(trimethylsilyl)ethoxymethyl chloride (1.85 mL, 10.5 mmol) and K2CO3 (1.45 g, 10.5 mmol). The resulting mixture was stirred for 15 minutes at r.t., then water (100 mL), brine (100 mL) and EtOAc (200 mL) were added. The layers were separated, and the aqueous layer was re-extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-50% gradient), gave the title compounds (mixture of two isomers in approximately 2.1:1 ratio; identity of major and minor isomers not determined) (11.88 g, 93%) as a white solid. 5H (400 MHz, 373K, DMSO-d6) 8.04 (d, 78.5 Hz, 1H, minor isomer), 8.01 (d, 78.3 Hz, 1H, major isomer), 7.69 (d, J 8.0 Hz, 1H, minor isomer), 7.62 (d, J 8.3 Hz, 1H, major isomer), 7.48 (d, J 8.3 Hz, 1H, major isomer), 7.47 (d, 78.4 Hz, 1H, minor isomer), 7.36-7.26 (m, 5H), 5.80- 5.63 (m, 2H), 5.08 (d, J 12.7 Hz, 1H, minor isomer), 5.07 (d, J 12.7 Hz, 1H, major isomer), 5.02 (d, J 12.7 Hz, 1H, major isomer), 5.01 (d, J 12.7 Hz, 1H, minor isomer), 4.92 (app t, 78.7 Hz, 1H), 3.67-3.50 (m, 2H), 2.38-2.26 (m, 1H), 2.14-2.00 (m, 2H), 2.00- 1.90 (m, 1H), 1.90-1.65 (m, 2H), 1.57-1.26 (m, 3H), 0.99-0.79 (m, 2H), -0.04 (s, 9H). ¹⁹F {¾} NMR (282 MHz, 373K, DMSO-de) d -90.43 (d, J 233.5 Hz, IF, minor isomer), -90.52 (d, J 233.6 Hz, IF, major isomer), -99.42 (d, J 233.9 Hz, IF, major isomer), -99.53 (d, 7233.8 Hz, IF, minor isomer). LCMS (Method 4): [M+H]⁺ m/z 609, 611, RT 1.69 minutes (minor isomer) and 1.77 minutes (major isomer).

INTERMEDIATE 47

Mixture of tert- butyl 2-!2 benzyloxycarbonyla ino(4.4-difluorocvclohexyl jmethyll-

1 -(2-tri methyl si lylethoxymethyl )imidazor4.5-/lpyridin-5-yl !-5.5-difluoropiperidine- l - carboxylate and fer/-butyl 2-!2 benzyloxycarbonyla ino-(4.4-difluorocvclohexyl)-

methvn-3-(2-trimethylsilylethoxymethvDimidazor4.5- >1pyridin-5-yl|-5.5-difluoro- piperidine- 1 -carboxylate

A screw-cap vial was charged with Intermediate 46 (mixture of two isomers in approximately 2.1:1 ratio) (500 mg, 0.82 mmol), l-(ter/-butoxycarbonyl)-5,5-difluoro- piperidine-2-carboxylic acid (435 mg, 1.64 mmol), 4,4'-di-/er/-butyl-2,2'-dipyridyl (34.0 mg, 0.12 mmol), (Ir[dF(CF3)ppy]2(dtbpy)}PF6 (9.2 mg, 0.0082 mmol), NiCh glyme (28.0 mg, 0.12 mmol), DMF (11.7 mL) and DBU (0.19 mL, 1.20 mmol) sequentially. 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. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-60% gradient), gave the title compounds (mixture of four isomers, the ratio of which could not be accurately determined; identity of major and minor isomers not determined) (469 mg, 76%) as a white foam. 5H (400 MHz, 373K, DMSO-de) 8.06 (d, J 8.2 Hz, 1H), 7.67-7.61 (br s, 1H, minor isomer), 7.61-7.53 (br s, 1H, major isomer), 7.36-7.21 (m, 6H), 5.78-5.61 (m, 2H), 5.49-5.40 (br s, 1H), 5.08 (d, J 12.6 Hz, 1H), 5.02 (d, J 12.6 Hz, 1H), 4.97-4.89 (m, 1H), 4.24 (app t, J 13.6 Hz, 1H), 3.66-3.51 (m, 2H), 3.51-3.27 (m, 1H), 2.41-2.26 (m, 1H), 2.20-2.02 (m, 5H), 2.02-1.90 (m, 1H), 1.89-1.66 (m, 2H), 1.58-1.47 (m, 1H), 1.47-1.30 (m, 3H), 1.42 (s, 9H), 0.97-0.78 (m, 2H), -0.05 (s, 9H). Only the NH (amide) signal corresponding to the major and minor isomers could be identified, with compounds diastereomeric at the benzylic centre indistinguishable at both r.t. and 373K. LCMS (Method 4): [M+H]⁺ m/z 750, RT 1.83 minutes (minor isomer) and 1.88 minutes (major isomer).

INTERMEDIATE 48

Mixture of tert- butyl 2-!2 amino(4.4-difluorocvclohexyl )methyll-l -(2-trimethylsilyl-

ethoxymethvDimidazor4 5.5-difluoropiperidine-l-carboxylate and tert-

butyl 2-!2 amino(4.4-difluorocvclohexyl )methyll-3-(2-trimethylsilylethoxymethyl )-

imidazor4 5.5-difluoropiperidine-l-carboxylate

To a solution of Intermediate 47 (mixture of four isomers) (469 mg, 0.63 mmol) in EtOH (10 mL) at r.t. was added 10% Pd/C (47 mg). The vessel was evacuated and purged with H2. The reaction mixture was stirred at r.t. for 30 minutes, then filtered through a pad of Celite® (10 g) under suction, washing through with EtOH (50 mL). The resulting material was concentrated in vacuo to give the title compound (mixture of four isomers) (389 mg, quantitative) as a grey foam, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m/z 616, RT 1.65 minutes (minor isomer) and 1.70 minutes (major isomer). INTERMEDIATE 49

Mixture of tert- butyl 2-G2-! 0V)-(^'4.4-difluorocvclohexyl ) KA-m ethyl -1 2.5-oxadiazole-3- carbonvDaminolmethyl !-l -(2-tri methyl si lylethoxymethyl )imidazor4.5-/ripyridin-5-yll- 5.5-difluoropiperidine- l -carboxyl ate and fer/-butyl 2-r2-i dif1uorocvclohexyl )-

KA-methyl- oxadiazole-3-carbonyl iaminolmethyl !-3-(2-trimethylsilylethoxy-

methvnimidazor4.5-/>1pyridin-5-yl1-5.5-difluoropiperidine-l-carboxylate

To a solution of Intermediate 48 (mixture of four isomers) (385 mg, 0.62 mmol), 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (81 mg, 0.63 mmol) and DIPEA (0.44 mL, 2.50 mmol) in DMF (10 mL) at r.t. was added HATU (295 mg, 0.75 mmol) in one portion. The mixture was stirred for 20 minutes, then water (10 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), then dried (NaiSCri) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compounds (mixture of four isomers in approx. 3.3:3.3:1:1 ratio; identity of major and minor isomers not determined) (415 mg, 90% over two steps) as a pale yellow foam. 5H (400 MHz, 373K, DMSO-de) 9.35 (d, 78.5 Hz, 1H, minor isomer), 9.28 (d, 78.4 Hz, major isomer), 8.11 (d, 78.2 Hz, 1H, minor isomer), 8.10 (d, 78.2 Hz, 1H, major isomer), 7.31-7.25 (m, 1H, major and minor isomers), 5.84-5.69 (m, 2H), 5.49-5.38 (m, 2H), 4.24 (app t, 714.1 Hz, 1H), 3.68-3.52 (m, 2H), 3.52-3.28 (m, 1H), 2.59-2.46 (obscured m, 2H), 2.48 (2 x s, 3H, 2 x major isomers), 2.47 (2 x s, 3H, 2 x minor isomers), 2.21-2.04 (m, 5H), 2.04-1.96 (m, 1H), 1.94-1.70 (m, 2H), 1.69-1.58 (m, 1H), 1.57-1.37 (m, 2H), 1.42 (2 x s, 9H, 2 x major isomers), 0.93-0.76 (m, 2H), -0.06 (2 x s, 9H, 2 x major isomers). LCMS (Method 4): [M+H]⁺ m/z 726, RT 1.79 minutes (minor isomer) and 1.84 minutes (major isomer).

INTERMEDIATE 50

pyridin-2-yllmethyl i -4-methyl -1.2.5-oxadi azole-3 -carboxamide

Intermediate 49 (mixture of four isomers in approximately 3.3:3.3:1:1 ratio) (415 mg, 0.57 mmol) was dissolved in DCM (11 mL) and TFA (2.2 mL, 28.0 mmol) was added. The solution was stirred at r.t. for 22 h, then concentrated in vacuo. The residue was re-dissolved in MeOH. The resulting material was passed through a 10 g SCX-2 cartridge, then washed with MeOH and eluted with 7N ML/MeOH. The eluate was concentrated in vacuo to give the title compound (mixture of two isomers) (309 mg, quantitative) as a pale yellow solid, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m!z 496, RT 1.19 minutes.

INTERMEDIATE 51

Mixture of tert- butyl 2-i2-rOV)-benzyloxycarbonylamino(^'4.4-difluorocvclohexyl jmethyll- 1 -(2-tri methyl si lylethoxymethyl )imidazor4.5-/ripyridin-5-yl !-4.4-difluoropiperidine- l - carboxylate and fer/-butyl 2-i2-IT.V)-benzyloxycarbonylamino(^'4.4-difluorocvclohexyl )- methvn-3-(2-trimethylsilylethoxymethvDimidazor4 4.4-difluoro-

piperidine- 1 -carboxylate

(2f?)-l-(fer/-Butoxycarbonyl)-4,4-difluoropiperidine-2-carboxylic acid (1.96 g, 7.38 mmol), NiCh glyme (109 mg, 0.492 mmol), 4,4'-di-/er/-butyl-2,2'-dipyridyl (132 mg, 0.492 mmol), (Ir[dF(CF3)ppy]2(dtbpy)}PF₆ (55 mg, 0.0492 mmol) and Intermediate 46 (3.00 g, 4.92 mmol) were divided equally between two 40 mL vials and dissolved in anhydrous DMF (2 x 25 mL). After complete dissolution of the reagents, 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 combined aqueous washes were extracted with EtOAc (50 mL). The combined organic extracts were washed with brine (20 mL), then dried (MgS04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/ heptane (0-100% gradient), gave the title compounds (mixture of regioisomers) (3.27 g, 87%). 5H (500 MHz, CDCb) 8.02-7.74 (m, 1H), 7.37-7.27 (m, 5H), 7.20-7.07 (m, 1H),

5.97-5.64 (m, 3H), 5.16-4.90 (m, 3H), 4.41-4.23 (m, 1H), 3.69-3.09 (m, 4H), 2.42-1.89 (m, 6H), 1.82-1.41 (m, 15H), 1.07-0.89 (m, 2H), -0.01 to -0.09 (m, 9H). One exchangeable proton signal not observed. LCMS (Method 13): [M+H]⁺ m!z 750.0, RT 4.02 minutes (minor isomer) and 4.14 minutes (major isomer).

INTERMEDIATE 52

Mixture of tert- butyl 2-!2 amino(4.4-difluorocvclohexyl )methyll- l -(2-trimethylsilyl-

ethoxymethyl)imidazor4.5-/ripyridin-5-yl !-4.4-difluoropiperidine- l -carboxyl ate and tert- butyl 2-!2 amino(4.4-difluorocvclohexyl )methyll-3-(2-trimethylsilylethoxymethyl )-

imidazor4.5-/>lpyridin-5- 4.4-difluoropiperidine-l-carboxylate

To a solution of Intermediate 51 (99%, 800mg, 1.06mmol) in EtOH (35mL) was added 10% Pd/C (50% wet, 198 mg, 0.093 mmol). The mixture was stirred under an atmosphere of ¾ for 16 h, then evacuated and backfilled with nitrogen. The mixture was filtered through Celite®, washing with EtOH, then concentrated in vacuo , to give the title compounds (mixture of regioisomers) (750 mg, 96%). 5H (400 MHz, CDCb) 8.04-7.73 (m, 1H), 7.17-7.07 (m, 1H), 5.92-5.38 (m, 3H), 4.51-4.12 (m, 2H), 3.65-3.45 (m, 2H), 3.44-3.09 (m, 2H), 2.51-1.83 (m, 8H), 1.82-1.33 (m, 13H), 1.03-0.77 (m, 2H), -0.01 to -0.13 (m, 9H). Two exchangeable proton signals not observed. LCMS (Method 7): [M+H]⁺ m!z 616.0, RT 1.93 minutes.

INTERMEDIATE 53

Mixture of tert- butyl 2-G2-! (V)-(4.4-dif1uorocvclohexyl ) KA-m ethyl -1 2.5-oxadiazole-3- carbonvDaminolmethyl !-l -(2-tri methyl si lylethoxymethyl )imidazor4.5-/ripyridin-5-yll-

4.4-difluoropiperidine- l -carboxyl ate and fer/-butyl 2-r2-i dif1uorocvclohexyl )-

KA-methyl- 1.2.5-oxadiazole-3-carbonyl iaminolmethyl !-3-(2-trimethylsilylethoxy- methvnimidazor4.5-/>1pyridin-5-yl1-4.4-difluoropiperidine-l-carboxylate

A solution of DIPEA (391 pL, 2.24 mmol) and 4-methyl-l,2,5-oxadiazole-3- carboxylic acid (158 mg, 1.23 mmol) in DCM (8 mL) was treated with HATU (511 mg, 1.34 mmol) and stirred at r.t. for 15 minutes. The mixture was added to a solution of Intermediate 52 (690 mg, 1.12 mmol) in DCM (2 mL). Stirring was continued at r.t. for 2 h, then the mixture was concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/heptane (0-100% gradient), gave the title compounds (mixture of regioisomers) (850 mg, 94%). 5H (500 MHz, CDCb) 8.04-7.58 (m, 2H), 7.20-7.09 (m, 1H), 5.94-5.78 (m, 2H), 5.77-5.65 (m, 1H), 5.54-5.38 (m, 1H), 4.39-4.24 (m, 1H), 3.74- 3.46 (m, 2H), 3.44-3.08 (m, 2H), 2.61-2.56 (m, 3H), 2.49-1.90 (m, 6H), 1.86-1.41 (m, 15H), 0.93-0.80 (m, 2H), 0.01 to -0.08 (m, 9H). LCMS (Method 7): [M+H]⁺ mlz 726.0, RT 2.24 minutes (minor isomer) and 2.30 minutes (major isomer).

INTERMEDIATE 54

Pyridin-2-yllmethvn-4-methyl-1.2.5-oxadiazole-3-carboxamide Intermediate 53 (90%, 850 mg, 1.05 mmol) was dissolved in DCM (15 mL) and

TFA (3 mL) was added. The solution was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was dissolved in MeOH and passed through a 10 g SCX-2 cartridge, washing with MeOH and eluting with 3.5N ammonia in MeOH. The eluate was concentrated in vacuo to give the title compound (550 mg, 92%). 5H (400 MHz, DMSO- de) 13.28-12.48 (m, 1H), 9.81-9.53 (m, 1H), 8.14-7.89 (m, 1H), 7.44 (d, J8.2 Hz, 1H), 5.30 (t, J1.9 Hz, 1H), 4.07-3.91 (m, 1H), 3.31-3.20 (m, 1H), 2.94-2.78 (m, 1H), 2.57-2.48 (m, 4H), 2.45-2.30 (m, 2H), 2.27-1.78 (m, 7H), 1.77-1.62 (m, 1H), 1.59-1.34 (m, 2H).

One exchangeable proton signal not observed. LCMS (Method 7): [M+H]⁺ mlz 496.0,

RT 1.55 minutes.

INTERMEDIATE 55 fc/V-Butyl 4-hvdroxy-4-methylpiperidine-l-carboxylate

To a solution of /cvV-butyl 4-oxopiperidine-l-carboxylate (5.00 g, 25.1 mmol) in THF (50 mL) at -40°C was added methylmagnesium chloride (3M in THF, 33.5 mL, 101 mmol) dropwise via syringe. The resulting mixture was warmed to r.t. and stirred for 3 h, then re-cooled to 0°C, carefully quenched with saturated aqueous MLCl solution (until the effervescence subsided). Water (50 mL) was added to the mixture, followed by EtOAc (100 mL). The layers were separated. The aqueous layer was further extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), then dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-60% gradient), gave the title compound (3.61 g, 67%) as a thick colourless oil. 5H (400 MHz, CDCb) 3.70 (dt, J 13.5, 4.1 Hz, 2H), 3.28-3.19 (m, 2H), 1.58-1.51 (m, 4H), 1.46 (s, 9H), 1.26 (s, 3H). Exchangeable OH proton signal not observed.

INTERMEDIATE 56 fc/V-Butyl 4-fluoro-4-methylpiperidine- 1 -carboxylate

To a solution of Intermediate 55 (3.04 g, 14.1 mmol) in DCM (180 mL) at -78°C was added DAST (2.8 mL, 21.0 mmol) dropwise over 5 minutes. The resulting mixture was warmed to r.t. slowly over the course of 16 h, then quenched by the addition of saturated aqueous NaHC03 solution (60 mL). The mixture was stirred vigorously for 10 minutes, then passed through a hydrophobic frit and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-15% gradient), gave the title compound (1.59 g, 52%) as a colourless oil. 5H (300 MHz, CDCh) 3.87 (dt, J 13.4, 3.2 Hz, 2H), 3.10 (ddd, J 13.5, 12.0, 3.1 Hz, 2H), 1.86-1.73 (m, 2H), 1.69-1.48 (m, 2H), 1.45 (s, 9H), 1.37 (d, J2\A Hz, 3H). ¹⁹F {¾} NMR (282 MHz, CDCh) d -153.74 (s, IF).

INTERMEDIATE 57

1 Butoxycarbonyl )-4-fluoro-4-methylpiperidine-2-carboxylic acid To a solution of Intermediate 56 (1.00 g, 4.60 mmol) and TMEDA (1.25 mL, 8.30 mmol) in diethyl ether (45 mL) at -78°C was added sec-butyllithium (1.3M, 6.40 mL, 87.30 mmol) dropwise over 5 minutes. The mixture was stirred at -78°C for 10 minutes, then warmed to -40°C and stirred for 30 minutes. The mixture was re-cooled to -78°C, and CO2 was bubbled through the reaction mixture for 30 minutes. The reaction mixture was warmed to r.t. and stirred for 1 h, then quenched by the addition of saturated aqueous NH4CI solution (30 mL) and H2O (5 mL). The layers were separated. The aqueous layer was washed with diethyl ether (2 x 20 mL) and the combined organic layers were set to one side. The aqueous layer was acidified to pH 3-4 using 0.5N HC1, and the mixture was extracted with EtOAc (3 x 50 mL). The combined EtOAc layers were dried (Na2SC>4) and concentrated in vacuo. Purification by flash chromatography, eluting with

EtO Ac/isohexane (0-100% gradient), then 100% EtOAc, gave the title compound (mixture of two diastereomers in approximately 1:1 ratio) (956 mg, 79%) as a white solid. 5H (400 MHz, DMSO-de) 12.13 (br s, 2H), 4.53 (ddd, 77.0, 4.8, 0.9 Hz, 1H), 3.80 (dtt, J 13.6, 4.9, 0.9 Hz, 1H), 3.61 (ddd, 711.1, 9.5, 5.4 Hz, 1H), 3.25 (ddd, 711.1, 8.7, 6.7 Hz, 1H), 3.14 (ddd, J 13.7, 9.0, 6.1 Hz, 1H), 2.25-2.02 (m, 3H), 2.02-1.92 (m, 1H), 1.86-1.72 (m, 2H), 1.52 (dd, 75.1, 1.2 Hz, 1H), 1.45-1.39 (obscured m, 1H), 1.42 (s, 9H), 1.40 (s, 9H), 1.35 (d, 722.7 Hz, 3H), 1.21 (s, 3H), 1.06 (d, 75.1 Hz, 1H). ¹⁹F { 1H} NMR (282 MHz, 373K, DMSO-de) d -127.45 (s, 2F). The two diastereomers were not distinguishable by ¹⁹F {¾} NMR at 373K.

INTERMEDIATE 58 Mixture of tert- butyl 2- benzyloxycarbonylamino(^'4.4-difluorocvclohexyl jmethyll-

l-(2-trimethylsilylethoxymethyl )imidazor4.5-/ripyridin-5-yl i-4-fluoro-4-m ethyl - piperidine-l-carboxylate and fer/-butyl 2- i 2-rOV)-benzyloxycarbonylamino- difluoro-

cvclohexyDmethvn-3-(2-trimethylsilylethoxymethvDimidazor4 4-

fluoro-4-methylpiperidine-l-carboxylate A screw-cap vial was charged with Intermediate 46 (mixture of two diastereomers in approximately 2.1:1 ratio) (500 mg, 0.82 mmol), Intermediate 57 (mixture of two diastereomers in approximately 1:1 ratio) (429 mg, 1.644 mmol), 4,4'-di-fer/-butyl-2,2'- dipyridyl (34.0 mg, 0.12 mmol), (Ir[dF(CF3)ppy]2(dtbpy)}PF6 (9.2 mg, 0.0082 mmol), NiCh glyme (28.0 mg, 0.12 mmol), DMF (11.7 mL) and DBU (0.19 mL, 1.20 mmol) sequentially. 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. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-60% gradient), gave the title compounds (mixture of eight isomers, the ratio of which could not be accurately determined; identity of major and minor isomers not determined) (73% purity) (494 mg, 59%) as a white foam. LCMS (Method 4): [M+H]⁺ m/z 746, RT 1.79 minutes (minor isomer) and 1.85 minutes (major isomer). INTERMEDIATE 59

Mixture of tert- butyl 2-!2-r(V)-amino(4.4-dif1uorocvclohexyl )methyll-l -(2-tri methyl - silylethoxymethv0imidazor4.5-/>1pyridin-5-yl|-4-fluoro-4-methylpiperidine-l- carboxylate and fer/-butyl 2-i2-r(V)-amino(4.4-dif1uorocvclohexyl )methyl1-3-(2- trimethylsilylethoxymethv0imidazor4.5-/>1pyridin-5- 4-fluoro-4-methylpiperidine-l-

carboxylate

To a solution of Intermediate 58 (mixture of eight isomers) (494 mg, 0.66 mmol) in EtOH (10 mL) at r.t. was added 10% Pd/C (50 mg). The vessel was evacuated and purged with Eh. The reaction mixture was stirred at r.t. for 20 minutes, then filtered through a pad of Celite® (10 g) under suction, washing through with EtOH (50 mL). The resulting material was concentrated in vacuo to give the title compound (mixture of eight isomers, the ratio of which could not be accurately determined) (418 mg, quantitative) as a white foam. LCMS (Method 4): [M+H]⁺ m/z 612, RT 1.62 minutes (minor isomer) and 1.68 minutes (major isomer).

INTERMEDIATE 60

Mixture of fer/-butyl 2-G2-! fV)-(4.4-dif1uorocvclohexyl )G(4-hi ethyl -1.2.5-oxadiazole-3- carbonyl iaminolmethyl i-1 -(2-tri methyl si lylethoxymethyl )imidazor4.5-/ripyridin-5-yll-4- fluoro-4-methylpiperidine-l -carboxylate and tert- butyl 2- difluoro-

cvclohexyl )G(4-Gh ethyl -1.2.5-oxadi azole-3 -carbonyl iaminolmethyl i -3 -(2-tri methyl si lyl- ethoxymethvDimidazor4.5-Z>1pyridin-5-vn-4-fluoro-4-methylpiperidine-l -carboxylate

To a solution of Intermediate 59 (mixture of eight isomers) (405 mg, 0.66 mmol), 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (85 mg, 0.66 mmol) and DIPEA (0.46 mL, 2.60 mmol) in DMF (20 mL) at r.t. was added HATU (311 mg, 0.079 mmol) in one portion. The mixture was stirred for 25 minutes, then water (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried (NaiSCri) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compounds (mixture of eight isomers, the ratio of which could not be accurately determined; identity of major and minor isomers not determined) (71% purity) (416 mg, 62%) as a white foam. LCMS (Method 4): [M+H]⁺ m!z 722, RT 1.76 minutes (minor isomer) and 1.84 minutes (major isomer).

INTERMEDIATE 61 A^f-! Dif1uorocvclohexyl )r5-(4-f1uoro-4-methylpiperidin-2-yl )-

pyridin-2-yllmethvH-4-methyl-L2.5-oxadiazole-3-carboxamide

Intermediate 60 (mixture of eight isomers) (416 mg, 0.41 mmol) was dissolved in DCM (7.9 mL) and TFA (1.6 mL, 21.0 mmol) was added. The solution was stirred at r.t. for 20 h, then concentrated in vacuo. The residue was re-dissolved in MeOH. The resulting material was passed through a 10 g SCX-2 cartridge, then washed with MeOH and eluted with 7N ME/MeOH. The eluate was concentrated in vacuo. Initial purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0-10% gradient), resulted in the elution of all impurities. The column was flushed by eluting with 7N ME/MeOH. The eluate was concentrated in vacuo , then re-dissolved in MeOH. The resulting material was passed through a 10 g SCX-2 cartridge, washed with MeOH, and eluted with 7N ME/MeOH. The eluate was concentrated in vacuo to give the title compound (mixture of four isomers) (179 mg, 89%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 492, RT 1.19 minutes. INTERMEDIATE 62

Benzyl /V-((X)-(4.4-difluorocvclohexy0r5-(4.4-difluoropiperidin-2-v0-li7-imidazor4.5-

/ripyri din-2 -yllmethyllcarbamate

Intermediate 51 (98%, 3.27 g, 4.27 mmol) was dissolved in DCM (40 mL), and TFA (15 mL) was added. The solution was stirred at r.t. for 16 h, then concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g SCX-2 cartridge. The cartridge was washed with MeOH and eluted with 3.5N ME/MeOH. The eluate was concentrated in vacuo to give the title compound (80% purity) (2.13 g, 77%). LCMS (Method 7): [M+H]⁺ m/z 520, RT 1.62 minutes. INTERMEDIATE 63

Benzyl A-r(M-(4A-difluorocvclohexyO(5-r4.4-difluoro-l-(3-fluorobicvclori.l.llpentane-

1 -carbonyl )piperidin-2-yll- imidazor4.5-/lpyridin-2-yl !methyllcarbamate

To a solution of DIPEA (1.1 mL, 6.56 mmol), 3-fluorobicyclo[l.l.l]pentane-l- carboxylic acid (469 mg, 3.61 mmol) and Intermediate 62 (80%, 2.13 g, 3.28 mmol) in DMF (30 mL) was added HATU (1.50 g, 3.94 mmol). The solution was stirred at r.t. for 4 h. Additional 3 -fluorobicyclo[l.l.l]pentane-l -carboxylic acid (220 mg, 1.69 mmol), DIPEA (0.54 mL, 3.08 mmol) and HATU (0.70 g, 1.85 mmol) were added. The mixture was stirred at r.t. for a further 1 h, then diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (25 mL) and brine (25 mL), then dried (MgS04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/heptane (0-100% gradient), gave the title compound (90% purity) (1.61 g, 70%). 5H (400 MHz, CDCb) 8.00-7.78 (m, 1H), 7.40-7.30 (m, 5H), 7.17-6.96 (m, 1H), 6.63- 5.46 (m, 2H), 5.22-5.05 (m, 2H), 5.00-3.98 (m, 2H), 3.74-2.97 (m, 2H), 2.69-2.18 (m,

8H), 2.17-1.87 (m, 5H), 1.83-1.34 (m, 5H). One exchangeable proton signal not observed. LCMS (Method 7): [M+H]⁺ m/z 632, RT 1.94 minutes. INTERMEDIATE 64

(2-(2-KA)-Amino(4.4-difluorocvclohexynmethyll-liT-imidazor4.5-Mpyridin-5-yl|-4.4- difluoropiperidin-l-vD(3-fluorobicvclor 1.1. Upentan-l-vDmethanone

To a solution of Intermediate 63 (90%, 1.61 g, 2.29 mmol) in MeOH (22.5 mL) was added 10% Pd/C (50% wet) (5.0%, 488 mg, 0.229 mmol). The mixture was stirred at r.t. under a balloon of N2 gas whilst triethylsilane (1.8 mL, 11.5 mmol) was added slowly with caution (hydrogen gas release). After complete addition, the mixture was stirred for 30 minutes at r.t. The flask was flushed with N2 for 10 minutes, then the mixture was filtered through Celite® under N2 and concentrated in vacuo. The resulting sticky white gum (1.3 g) was transferred to another vessel in DCM and concentrated in vacuo. The residue was dissolved in MeOH and passed through a 20 g SCX-2 cartridge. The cartridge was washed with MeOH (200 mL) and eluted with 3.5N Mb/MeOH. The eluate was concentrated in vacuo to give the title compound (1.08 g, 90%). LCMS (Method 7): [M+H]⁺ m/z 498, RT 1.57 minutes.

INTERMEDIATE 65

Mixture of fer/-butyl 7- benzyloxycarbonylamino(^'4.4-difluorocvclohexyl jmethyll-

l-(2-trimethylsilylethoxymethvOimidazor4.5-/>1pyridin-5-vH-6-azaspiror2.51octane-6- carboxylate and fert-butyl 7-i2-IT.V)-benzyloxycarbonylamino(^'4.4-difluorocvclohexyl )- methyl1-3-(2-trimethylsilylethoxymethvnimidazor4.5-/>1pyridin-5-yl|-6-azaspiror2.51- octane-6-carboxylate

A screw-cap vial was charged with Intermediate 46 (551 mg, 0.90 mmol), 6 -(tert- butoxycarbonyl)-6-azaspiro[2.5]octane-5-carboxylic acid (462 mg, 1.81 mmol), 4,4'-di- tert- butyl-2, 2 '-dipyridyl (37.0 mg, 0.14 mmol), (Ir[dF(CF3)ppy]2(dtbpy)}PF₆ (11.0 mg, 0.0098 mmol), NiCh glyme (31.0 mg, 0.14 mmol), DMF (12.9 mL) and DBU (0.21 mL, 1.40 mmol) sequentially. 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 90 minutes. The mixture was diluted with EtOAc (30 mL) and washed with FLO (2 x 20 mL). The combined organic layers were dried (Na2SC>4) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/ isohexane (0-50% gradient), gave the title compounds (mixture of isomers) (86% purity) (589 mg, 75%) as a white foam, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m/z 740, RT 1.85 minutes (minor isomer) and 1.94 minutes (major isomer).

INTERMEDIATE 66

Mixture of tert- butyl 7-!2 amino(4.4-difluorocvclohexyl )methyll- l -(2-trimethylsilyl-

ethoxymethvDimidazor4.5-Z>1pyridin-5-yl|-6-azaspiror2.51octane-6-carboxylate and tert- butyl 7-!2 amino(4.4-difluorocvclohexyl )methyll-3-(2-trimethylsilylethoxymethyl )-

imidazor4.5-Z>1pyridin-5-yl|-6-azaspiror2.51octane-6-carboxylate

To a solution of Intermediate 65 (589 mg, 0.68 mmol) in EtOH (15 mL) at r.t. was added 10% Pd/C (60 mg). The vessel was evacuated and purged with EL, then left to stir at r.t. for 30 minutes. The mixture was filtered through a pad of Celite® (10 g) under suction, washing through with EtOH (50 mL), then concentrated in vacuo , to give the title compounds (86% purity) (493 mg, quantitative) as a white foam, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m/z 606, RT 1.67 minutes (minor isomer) and 1.77 minutes (major isomer).

INTERMEDIATE 67

Mixture of fer/-butyl 7-r2- ethyl -1.2.5-oxadiazole-3-

carbonyl iaminolmethyl i-1 -(2-tri methyl si lylethoxymethyl )imidazor4.5-/dpyridin-5-yll-6- azaspiror2.51octane-6-carboxylate and tert- butyl 7-r2- 4.4-dif1uorocvclohexyl )K4-

methyl-1.2.5-oxadiazole-3-carbonyl iaminolmethyl !-3-(2-trimethylsilylethoxymethyl )- imidazor4.5-/>1pyridin-5-yl1-6-azaspiror2.51octane-6-carboxylate

To a solution of Intermediate 66 (482 mg, 0.68 mmol), 4-methyl-l,2,5- oxadiazole-3 -carboxylic acid (88 mg, 0.69 mmol) and DIPEA (0.48 mL, 2.80 mmol) in DMF (20 mL) at r.t. was added HATU (323 mg, 0.82 mmol) in one portion. The mixture was stirred for 10 minutes, then water (20 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), then dried (NaiSCL) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compounds (86% purity) (311 mg, 55%,) as a white foam, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m/z 716, RT 1.82 minutes (minor isomer) and 1.91 minutes (major isomer). INTERMEDIATE 68 difluoro-

cvclohexyl jmethyl i-4-methyl-l.2.5-oxadi azole-3 -carboxamide

Intermediate 67 ( 311 mg, 0.43 mmol) was dissolved in DCM (8.8 mL), and TFA (1.8 mL, 23.0 mmol) was added. The solution was stirred at r.t. for 24 h, then concentrated in vacuo. The residue was re-dissolved in MeOH. The resulting material was passed through a 10 g SCX-2 cartridge, then washed with MeOH and eluted with 7N ML/MeOH. The eluate was concentrated in vacuo. Initial purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0- 10% gradient), resulted in the elution of all impurities. The column was flushed by eluting with 7N NFL/MeOFl. The eluate was concentrated in vacuo , then re-dissolved in MeOH. The resulting material was passed through a 10 g SCX-2 cartridge, washed with MeOH, and eluted with 7N ML/MeOH. The eluate was concentrated in vacuo to give the title compound (164 mg, 78%) as a white solid. LCMS (Method 4): [M+H]⁺ mtz 486, RT 1.24 minutes.

INTERMEDIATE 69

Mixture of tert- butyl 2-!2-rOV)-benzyloxycarbonylamino difluorocvclohexyl jmethyll-

1 -(2-tri methyl si lylethoxymethyl )imidazor4.5-/ripyridin-5-yl !-4-(trifluoromethyl )- piperidine- 1-carboxylate and fer/-butyl 2-i2- -benzyloxycarbonylamino difluoro-

cvclohexyDmethvn-3-(2-trimethylsilylethoxymethvDimidazor4.5-Z>1pyridin-5-vn-4- (trifluoromethyOpiperidine- 1 -carboxylate

A screw-cap vial was charged with Intermediate 46 (975 mg, 1.60 mmol), 1 -(tert- butoxycarbonyl)-4-(trifluoromethyl)piperidine-2-carboxylic acid (1.00 g, 3.20 mmol), 4,4'-di-/er/-butyl-2,2'-dipyridyl (66 mg, 0.24 mmol), (Ir[dF(CF3)ppy]2(dtbpy)}PF₆ (18.0 mg, 0.016 mmol), NiCh glyme (54 mg, 0.24 mmol), DMF (21.3 mL) and DBU (0.37 mL, 2.40 mmol) sequentially. 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, 3000 rpm;

Stir, 400 rpm; LED, 100%) for 18 h. The mixture was diluted with EtOAc (100 mL) and washed with brine (100 mL). The layers were separated, and the aqueous layer was back- extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine (100 mL) and dried (NaS04), then filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-50% gradient), gave the title compounds (mixture of eight stereoisomers) (1.24 g, 99%) as a yellow gummy foam, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m!z 782, RT 3.46 minutes, 3.57 minutes, 3.64 minutes and 3.77 minutes. INTERMEDIATE 70

Benzyl dif1uorocvclohexyl )! 5-r4-(trif1uoromethyl )piperidin-2-yl1-

imidazor4.5-/ lpyridin-2-yl !methyllcarbamate Intermediate 69 (1.24 g, 1.59 mmol) was dissolved in DCM (24 mL) and TFA (6 mL, 79.4 mmol) was added. The solution was stirred at r.t. for 18 h, then diluted with EtOAc and washed with water and 2M aqueous NaOH solution. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with water and concentrated in vacuo. Purification by flash chromatography, eluting with MeOH in EtOAc (0-15% gradient), gave the title compound (mixture of four stereoisomers) (799 mg, 81%) as a yellow oil. LCMS (Method 4): [M+H]⁺ m/z 552, RT 2.11 minutes.

INTERMEDIATE 71 Benzyl 4.4-dif1uorocvclohexyl)! 5-G1 -13-fluorobicvclor 1 1. 1 lpentane- 1 -carbonyl )-

4-(trifluoromethyl )piperidin-2-yll- imidazor4.5-/dpyridin-2-yl jmethyllcarbamate

To a solution of Intermediate 70 (799 mg, 1.45 mmol), 3-fluorobicyclo[l.l.l]- pentane-1 -carboxylic acid (219 mg, 1.60 mmol) and DIPEA (0.64 mL, 3.6 mmol) in DMF (22 mL) was added HATU (624 mg, 1.59 mmol) in one portion. The mixture was stirred for 1.5 h, then partitioned between EtOAc (100 mL) and brine (100 mL). The layers were separated, and the aqueous layer was back-extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried (NaS04), filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (mixture of four stereoisomers) (92% purity) (1.00 g, quantitative) as an orange oily gum. LCMS (Method 4): [M+H]⁺ m/z 664, RT 2.39 minutes (minor diastereomer) and RT 2.49 minutes (major diastereomer).

INTERMEDIATE 72 r2-(2-KA)-Amino(4.4-difluorocvclohexynmethyl1-liT-imidazor4.5-Mpyridin-5-yl|-4-

(^'trifluoromethvDpiperidin-l- fluorobicvclor 1.1. llpentan-l-vDmethanone

To a stirred solution of Intermediate 71 (mixture of four stereoisomers) (973 mg, 1.47 mmol) in EtOH (21 mL) at r.t. was added 10% Pd/C (100 mg). The vessel was evacuated and purged with H2. The reaction mixture was stirred at r.t for 1.5 h, then re treated with 10% Pd/C (75 mg). The resulting mixture was stirred for a further 2.25 h, then re-treated with 10% Pd/C (75 mg). The mixture was stirred for 1.5 h, then filtered through a pad of Celite® (10 g) under suction, washing through with EtOH. The resulting material was concentrated in vacuo to give the title compound (mixture of four stereoisomers) (900 mg, quantitative). LCMS (Method 4): [M+H]⁺ m/z 530, RT 1.84 minutes (minor diastereomer) and RT 1.95 minutes (major diastereomer).

INTERMEDIATE 73 l-fer/-Butoxycarbonyl-4-(difluoromethv0piperidine-2-carboxylic acid

To a solution of /cvV-butyl 4-(difluoromethyl)piperidine-l-carboxylate (2.00 g,

8.50 mmol) in diethyl ether (70 mL) at -78°C under an atmosphere of N2 was added TMEDA (2.3 mL, 15.3 mmol), followed by sec-butyllithium (1.4M solution in hexanes, 11 mL, 15.3 mmol) added over 10 minutes. The resulting solution was stirred for 10 minutes at -78°C, then warmed to -40°C (by quickly replacing the CCh/acetone bath with a CCh/acetonitrile bath). The solution was stirred at -40°C for 30 minutes, then re-cooled to -78°C. CO2 was bubbled into the reaction mixture for 20 minutes via a needle connected to a Dreschel bottle containing dry ice, which passed through a tube containing CaCb for drying. The mixture was allowed to warm to r.t. and stirred for 3 h. The reaction mixture was quenched with saturated aqueous NEECl solution (25 mL) and water (25 mL), then diluted with EtOAc (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were discarded and the pH of the aqueous portion was adjusted to pH 1-2 with 1M aqueous HC1. The aqueous solution was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over MgS04, filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with a gradient of EtOAc in heptane, gave the title compound (1.14 g, 46%). 5H (400 MHz, DMSO-de) 12.60 (s, 1H), 5.96 (td, 756.6, 4.7 Hz, 1H), 4.13 (dd, 78.4, 6.2 Hz, 1H), 3.57-3.40 (m, 1H), 3.39-3.20 (m, 1H), 2.23-2.05 (m, 1H), 2.05-1.92 (m, 1H), 1.82-1.64 (m, 2H), 1.58-1.44 (m, 1H), 1.37 (s, 9H). ¹⁹F

NMR (376 MHz, DMSO-de) d -122.36. INTERMEDIATE 74

Mixture of tert- butyl 2- benzyloxycarbonylamino('4.4-difluorocvclohexyl jmethyll-

l-(2-trimethylsilylethoxymethyl )imidazor4.5-/ripyridin-5-yl !-4-(dif1uorom ethyl )- piperidine- 1-carboxylate and fer/-butyl 2-(2-r(M-benzyloxycarbonylamino(4.4-difluoro- cvclohexynmethyl1-3-(2-trimethylsilylethoxymethvnimidazor4.5-/>1pyridin-5-yl|-4-

(difluoromethvDpiperi dine- 1-carboxylate

A vessel was charged with Intermediate 73 (95%, 1.14 g, 3.88 mmol), Intermediate 46 (1.65 g, 2.71 mmol), (Ir[dF(CF3)ppy]2(dtbpy)}PF6 (30 mg, 0.027 mmol), NiCh glyme (60 mg, 0.27 mmol) and 4,4'-di-ter/-butyl-2,2'-dipyridyl (73 mg, 0.27 mmol) in dry DMF (27 mL). After complete dissolution of the reagents, DBU (607 pL, 4.06 mmol) was added. The solution was divided between two 30 mL vials and purged by bubbling through N2 with sonication for 10 minutes. 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%). 5H (400 MHz, CDCb) 8.54-7.71 (m, 1H), 7.40-7.22 (m, 6H), 6.04-5.27 (m, 4H), 5.27-4.87 (m, 3H), 4.37-3.94 (m, 1H), 3.75-3.28 (m, 2H), 2.91-2.72

(m, 1H), 2.54-1.88 (m, 5H), 1.87-1.39 (m, 18H), 1.10-0.88 (m, 2H), 0.02 to -0.09 (m,

9H). One exchangeable proton signal not observed. LCMS (Method 13): [M+H]⁺ 764.3, RT 4.29 minutes.

INTERMEDIATE 75

Benzyl 4.4-difluorocvclohexyl )! 5-r4-(difluoromethyl )piperidin-2-yll-

imidazor4.5-/ripyridin-2-yl imethyllcarbamate

To a solution of Intermediate 74 (83%, 1.48 g, 1.61 mmol) in DCM (23 mL) was added TFA (11.5 mL). The solution was stirred at room temperature for 20 h, then concentrated under reduced pressure. The residue was dissolved in MeOH and passed through a 10 g SCX-2 cartridge, then washed with MeOH and eluted with 3.5N ammonia in MeOH. The resulting material was concentrated under reduced pressure to give the title compound (990 mg, 95%). LCMS (Method 7): [M+H]⁺ 534.2, RT 1.70 minutes.

INTERMEDIATE 76

Benzyl A-r(M-(4.4-difhaorocvclohexyD(5-r4-(difhaoromethvD-l-(3-fluorobicvclori.l.H- pentane-l-carbonvnpiperidin-2-yll-liT-imidazor4.5-/>lpyridin-2-yl|methyllcarbamate To a solution of 3 -fluorobicyclo[ 1.1.1 ]pentane-l -carboxylic acid (119 mg, 0.91 mmol), DIPEA (0.29 mL, 1.66 mmol) and Intermediate 75 (82%, 540 mg, 0.83 mmol) in DMF (8.5 mL) was added HATU (379 mg, 1.0 mmol). The solution was stirred at r.t. for 4 h, then diluted with EtOAc (20 mL) and washed with water (2 x 20 mL) and brine (10 mL). The organic layer was dried over MgSCL, filtered and concentrated under reduced pressure. Purification by column chromatography, eluting with a gradient of EtOAc in heptane, gave the title compound (480 mg, 87%). 5H (400 MHz, CDCh) 7.96-7.64 (m, 1H), 7.32-7.19 (m, 5H), 7.12-6.98 (m, 1H), 6.37-5.34 (m, 3H), 5.14-4.96 (m, 2H), 4.86-

4.71 (m, 1H), 4.67-3.79 (m, 1H), 3.23-2.79 (m, 1H), 2.72-2.54 (m, 1H), 2.49-2.34 (m,

4H), 2.35-2.15 (m, 4H), 2.12-1.80 (m, 4H), 1.79-1.44 (m, 5H), 1.44-1.25 (m, 2H). One exchangeable proton signal not observed. LCMS (Method 7): [M+H]⁺ 646.2, RT 2.00 minutes.

INTERMEDIATE 77 r2-(2 difluorocvclohexyDmethvH- ridin-5-yl|-4-

(difluoromethvDpiperidin-l-yl1(3-fluorc>bicvclor 1.1. Hpentan-l-vDmethanone To a solution of Intermediate 76 (97%, 480 mg, 0.72 mmol) in MeOH (15 mL) was added 10% Pd/C (50% wet) (5.0%, 153 mg, 0.072 mmol). The mixture was stirred at r.t. under a balloon of N2 whilst triethylsilane (288 pL, 1.80 mmol) was added slowly to minimise bubbling (caution: H2 gas release). The resulting mixture was stirred at r.t. for 2 h, then the flask was flushed with N2 for five minutes and the mixture was filtered through Celite® under N2. The resulting material was concentrated under reduced pressure to give the title compound (300 mg, 73%). LCMS (Method 7): [M+H]⁺ 512.3, RT 1.63 minutes. INTERMEDIATE 78

Cvclopropyl 2- i 2-K^',.V)-benzyloxycarbonylamino(^'4.4-difluorocvclohexyl )m ethyl!- 1 H- imidazor4.5-/>1pyridin-5-yl|-4-(difluoromethvOpiperidine-l-carboxylate To a solution of cyclopropanol (100 mg, 1.72 mmol) in acetonitrile (17.2 mL) at r.t. were added bis(2,5-dioxopyrrolidin-l-yl) carbonate (485 mg, 1.89 mmol) and triethyl- amine (0.36 mL, 2.60 mmol) sequentially. The mixture was stirred for 2.5 h, then DCM (20 mL) and saturated aqueous NaHCCh solution (20 mL) were added. The layers were separated, then the organic layers were dried (NaiSCri) and concentrated under a stream of nitrogen, to give cyclopropyl (2,5-dioxopyrrolidin-l-yl) carbonate (178 mg, 52%) as a colourless oil. 5H (400 MHz, CDCb) 4.37-4.31 (m, 1H), 2.87 (s, 4H), 0.99-0.94 (m, 2H), 0.87-0.81 (m, 2H).

To a solution of Intermediate 75 (82%, 400 mg, 0.62 mmol) in DCM (6 mL) was added cyclopropyl (2,5-dioxopyrrolidin-l-yl) carbonate (147 mg, 0.74 mmol). The solution was stirred at r.t. for 4 h. Additional cyclopropyl (2,5-dioxopyrrolidin-l-yl) carbonate (147 mg, 0.74 mmol) was added, and the solution was stirred at r.t. for 20 h. The resulting material was concentrated under a stream of N2 and purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (402 mg, 88%). LCMS (Method 7): [M+H]⁺ 618.2, RT 2.01 minutes.

INTERMEDIATE 79

Cvclopropyl 2-(2-KA)-amino(4.4-difluorocvclohexynmethyl1- imidazor4.5-Mpyridin-

5-yl -4-(difluoromethvDpiperidine- 1 -carboxylate To a solution of Intermediate 78 (83%, 402 mg, 0.54 mmol) in MeOH (10 mL) was added 10% Pd/C (50% wet) (5.0%, 115 mg, 0.054 mmol). The mixture was stirred at r.t. under a balloon of N2 whilst triethylsilane (216 pL, 1.35 mmol) was added slowly to minimise bubbling (caution: H2 gas release). The resulting mixture was stirred at r.t. for 2 h, then the flask was flushed with N2 for five minutes and the mixture was filtered through Celite® under N2. The resulting material was concentrated under reduced pressure to give the title compound (270 mg, 85%). LCMS (Method 7): [M+H]⁺ 484.2, RT 1.63 minutes. INTERMEDIATES 80 & 81

Benzyl imidazo-

/ lpyridin-2-yl ! methyllcarbamate ( Intermediate 80) Benzyl -4.4-difluoropiperidin-2-yll- imidazo-

/ lpyridin-2-yl ! methyllcarbamate ( Intermediate 81)

Intermediate 62 (59%, 2.00 g, 2.38 mmol) was subject to chiral SFC (Method 24) to yield the title compounds (Peak 1, 531 mg, 43% yield, 92.7% e.e.; and Peak 2, 571 mg, 46% yield, 98.5% e.e.). Chiral analysis (Method 25): Peak 1, RT 2.82 minutes; Peak 2, RT 6.14 minutes.

INTERMEDIATE 82

Benzyl - 1 -(5.5-dif1uorotetrahvdropyran-2-

carbonyl )-4.4-difluoropiperidin-2-yll- imidazor4.5-/dpyridin-2-yl i methyllcarbamate

To a solution of DIPEA (84 pL, 0.481 mmol), 5,5-difluorooxane-2-carboxylic acid (40 mg, 0.231 mmol) and Intermediate 81 (100 mg, 0.192 mmol) in DMF (3 mL) was added HATU (91 mg, 0.231 mmol). The solution was stirred at r.t. overnight, then partitioned between EtOAc and brine. The layers were separated. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (50-100% gradient), to afford the title compound (100 mg, 77%) as a yellow glass. LCMS (Method 4): [M+H]⁺ m/z 668, RT 1.38 minutes.

INTERMEDIATE 83 r(2M-2-f2-r(M-Amino

4.4-difluoropiperidin-l -yll(5.5-difluorotetrahvdropyran-2-yl imethanone

Intermediate 82 (100 mg, 0.15 mmol) was dissolved in EtOAc (5 mL), and palladium hydroxide on carbon (20 wt %, 10 mg) was added. The reaction mixture was stirred vigorously under a hydrogen atmosphere for 16 h, then filtered through Celite® under nitrogen, washing with EtOAc. The residue was concentrated under reduced pressure and purified by flash chromatography, eluting with MeOH/DCM (0-20% gradient), to afford the title compound (80 mg, 95%) as an off-white solid. LCMS (Method 4): [M+H]⁺ m/z 534, RT 1.15 minutes.

INTERMEDIATE 84 Tetrabenzyl-6-bromopyridine-2.3 -diamine

To a solution of 6-bromopyridine-2, 3 -diamine (4.0 g, 21.27 mmol) in DMF (80 mL) at r.t. was added NaH (10.2 g, 255 mmol) portionwise. The mixture was stirred for 30 minutes at r.t., then placed in an an ice bath. Benzyl bromide (23.2 mL, 191 mmol) was cautiously added dropwise via syringe over a period of 25 minutes. The reaction mixture was left to stir at r.t. overnight, then thoroughly agitated whilst water (100 mL) was added dropwise, very slowly. The reaction mixture was further diluted with EtOAc (200 mL), and the layers were separated. The organic phase washed twice with water.

The combined organic phases were dried, filtered and concentrated in vacuo. Purification by flash column chromatography on silica (Biotage SNAP 340 g, Isolera), eluting with 0- 60% toluene/isohexane, yielded the title compound (8.21 g, 70%) as a transparent, pale yellow semi-solid. LCMS (Method 4): [M+H]⁺ m/z 548.0, 550.0, RT 1.97 minutes.

INTERMEDIATE 85 fc/V-Butyl 2-r5.6-bis(dibenzyla ino)pyridin-2-yll-4-oxopiperidine- l -carboxyl ate

To a solution of Intermediate 84 (8.30 g, 15.0 mmol) in THF (80 mL) at -78°C was added //-butyllithium (7.20 mL, 18.0 mmol) dropwise over 10 minutes. The orange material was stirred at -78°C for 20 minutes, then Cul (1.40 g, 7.30 mmol) was added in three portions at -78°C. The reaction mixture was immediately warmed to 0°C and stirred for 20 minutes, then re-cooled to -78°C. A mixture of tert- butyl 4-oxo-2,3- dihydropyridine-l-carboxylate (1.10 g, 5.60 mmol) and chlorotrimethylsilane (5.80 mL, 45.0 mmol) in THF (28 mL) (pre-stirred at r.t. for 5 minutes) was added via cannula over 10 minutes, and rinsed with THF (2 x 5 mL). The resulting brown mixture was allowed to warm gradually to r.t. After 4 h, the mixture was quenched with TBAF (1M in THF, 20 mL) at r.t, then stirred for 5 minutes and diluted with water (20 mL). The mixture was extracted with EtOAc (3 x 100 mL), and the combined organic layers were dried over MgS04 and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (3.60 g, 97%) as a beige solid. 5H (400 MHz, 373K, DMSO-de) 7.24-7.15 (m, 12H), 7.12 (d, 78.0 Hz, 1H), 7.11- 7.05 (m, 8H), 6.70 (d, 77.9 Hz, 1H), 5.41 (unresolved dd, 75.3, 4.3 Hz, 1H), 4.79 (d, 7 15.0 Hz, 2H), 4.63 (d, 715.0 Hz, 2H), 4.37 (d, 714.3 Hz, 2H), 4.31 (d, 714.3 Hz, 2H),

3.88 (dddd, 713.4, 6.7, 4.4, 1.1 Hz, 1H), 3.11 (ddd, 713.2, 9.8, 4.7 Hz, 1H), 2.74-2.63 (m, 2H), 2.35 (ddd, 716.4, 9.8, 6.7 Hz, 1H), 2.15 (dt, 716.4, 4.5 Hz, 1H), 1.40 (s, 9H). LCMS (Method 4): [M+H]⁺ m!z 667, RT 1.94 minutes.

INTERMEDIATES 86 & 87 s_\m-( rac )-/c/V-Butyl 2-r5.6-bis(dibenzylamino)pyridin-2-yl1-4-hvdroxy-4-(trif1uoro- methvnpiperidine-l-carboxylate ( Intermediate 86) anti-( rac )-/er/-B utyl 2- bis(dibenzylamino)pyridin-2-yl1-4-hvdroxy-4-(trif1uoro-

methyl (piperidine- 1 -carboxyl ate ( Intermediate 87)

To a solution of Intermediate 85 (10.0 g, 15.0 mmol) in THF (30 mL) at -5°C was added (trifluoromethyl)trimethylsilane (9.53 mL, 60.0 mmol) dropwise via syringe.

TBAF (1M in THF, 60.0 mL, 60.0 mmol) was subsequently added via syringe over 15 minutes. The mixture was warmed to r.t. over 60 h, then quenched by the addition of saturated aqueous NaHCCh solution (75 mL) and diluted with EtOAc (200 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2S04) and concentrated in vacuo.

Purification by flash chromatography, eluting with EtO Ac/isohexane (0-30% gradient), gave Intermediate 86 (6.67 g, 60%) and Intermediate 87 (2.80 g, 25%) as yellow foams. Intermediate 86: 5H (400 MHz, 373K, DMSO-de) 7.25-7.16 (m, 12H), 7.15-7.10 (m, 5H), 7.08-6.96 (m, 4H), 6.68 (d, 78.0 Hz, 1H), 5.83 (s, 1H, OH), 5.23 (d, J 6.9 Hz, 1H), 4.81 (d, J 14.8 Hz, 2H), 4.71 (d, J 14.9 Hz, 2H), 4.35 (d, J 14.3 Hz, 2H), 4.28 (d, J 14.3 Hz, 2H), 3.95 (dt, J 13.5, 3.8 Hz, 1H), 3.21-3.08 (m, 1H), 2.56-2.45 (obscured m, 1H), 2.02 (dd, J 14.2, 7.3 Hz, 1H), 1.72-1.66 (m, 2H), 1.37 (s, 9H). LCMS (Method 4): [M+H]⁺ m/z 737, RT 2.03 minutes.

Intermediate 87: 5H (400 MHz, 373K, DMSO-de) 7.22-7.11 (m, 16H), 7.06 (m, 5H), 6.60 (d, 78.0 Hz, 1H), 5.70 (br s, 1H, OH), 4.84 (t, 78.3 Hz, 1H), 4.79 (d, 714.7 Hz, 2H), 4.73 (d, 714.7 Hz, 2H), 4.33 (d, 714.3 Hz, 2H), 4.31 (d, 714.3 Hz, 2H), 3.89 (ddd, 713.6, 6.6, 3.9 Hz, 1H), 3.23 (ddd, 713.6, 10.2, 5.4 Hz, 1H), 2.56-2.47 (obscured m, 1H), 2.00 (br s, 1H), 1.89 (ddd, 714.4, 5.4, 3.9 Hz, 1H), 1.82-1.61 (m, 1H), 1.24 (s, 9H). LCMS (Method 4): [M+H]⁺ m!z 737, RT 1.94 minutes.

INTERMEDIATE 88

.si /-(rac)-/i^,/7-Butyl-2-(5.6-diaminopyridin-2-yl )-4-hvdroxy-4-(trif1uoromethyl )- piperidine- 1 -carboxylate

To a solution of Intermediate 86 (6.58 g, 8.93 mmol) in MeOH (150 mL) at r.t. was added 12N aqueous HC1 (1.64 mL, 19.7 mmol), followed by 10% Pd/C (1.65 g), portionwise. The vessel was evacuated and purged with Th, then left to stir at r.t. for 3 days. The mixture was filtered through a pad of Celite® under suction, washing through with EtOH, then concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (10% gradient), gave the title compound (7.3:1 ratio of debenzylated and mono-benzylated material) (2.00 g, 60%) as a brown foam. 5H (400 MHz, 373K, DMSO-de) 6.80 (d, 77.6 Hz, 1H), 6.50 (d, 77.6 Hz, 1H), 5.43 (br s, 2H), 5.34 (app d, 77.5 Hz, 1H), 4.65 (br s, 2H), 3.92 (dt, 713.6, 3.3 Hz, 1H), 3.09 (ddd, 713.7, 10.0, 5.5 Hz, 1H), 2.16 (d, 714.2 Hz, 1H), 2.06 (dd, 714.3, 7.5 Hz, 1H), 1.70-1.62 (m, 2H), 1.44 (s, 9H). The OH proton signal was not observed. LCMS (Method 4): [M+H]⁺ m!z 377, RT 1.25 minutes.

INTERMEDIATE 89

.si7/-(rac)-/7/7-Butyl-2-r6-amino-5-(fe/7-butoxycarbonyla ino)pyridin-2-yll-4-hvdroxy-4- (trifluoromethyOpiperidine- 1 -carboxylate

To a solution of Intermediate 88 (2.00 g, 5.31 mmol) in EtOH (20 mL) was added di-/tv7-butyl dicarbonate (1.40 mL. 6.00 mmol), followed by guanidine hydrochloride (77 mg, 0.80 mmol) in one portion. A reflux condenser was fitted, and the mixture was stirred at 50°C for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (934 mg, 37%) as a pale yellow foam. 5H (400 MHz, 373K, DMSO-de) 8.16 (s, 1H), 7.63 (d, 77.9 Hz, 1H), 7.52 (s, 1H), 6.59 (dd, 77.8, 0.6 Hz, 1H), 5.70 (s, 2H), 5.34 (d, 77.4 Hz, 1H), 3.97 (dt, 713.5, 3.3 Hz, 1H), 3.14 (ddd, 713.7, 9.2, 6.3 Hz, 1H), 2.36-2.29 (m, 1H), 2.06 (dd, J 14.3, 7.6 Hz, 1H), 1.73-1.66 (m, 2H), 1.49 (s, 9H), 1.44 (s, 9H). LCMS (Method 4): [M+H]⁺ m!z 477 , RT 1.46 minutes.

INTERMEDIATE 90 syn-( rac HcvV-Butyl 2-G6-! r(2V)-2-(benzyloxycarbonylamino)-2-(4.4-dif1uorocvclohexyl )- acetyl1amino|-5-(fer/-butoxycarbonylamino)pyri din-2 -yl1-4-hvdroxy-4-(trifluoromethvn- piperidine- 1 -carboxylate

To a solution of Intermediate 89 (1.31 g, 2.75 mmol), (2ri)-2-(benzyloxycarbonyl- amino)-2-(4,4-difluorocyclohexyl)acetic acid (990 mg, 3.03 mmol) and pyridine (1.00 mL, 12.4 mmol) in EtOAc (8.0 mL) at 0°C was added T3P® (50 wt % in EtOAc, 4.05 mL, 6.87 mmol) dropwise over 2 minutes. The ice/water bath was removed, and the mixture was allowed to warm to r.t. and stirred for 2 h, then quenched by the addition of EhO (20 mL) and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (3 x 25 mL). The combined organic extracts were washed with saturated aqueous NaHC03 solution (25 mL), dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/ isohexane (0-50% gradient), gave the title compound (mixture of two stereoisomers) (1.71 g, 72%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 786.2, RT 1.71 minutes.

INTERMEDIATE 91 _Si7/-(rac)-Benzyl A^f-rfV)-(4.4-difluorocvclohexyl )! 5-r4-hvdroxy-4-(trifluoromethyl )- piperidin-2-vn-liT-imidazor4.5-/>lpyridin-2-yl|methyllcarbamate trifluoroacetic acid salt Intermediate 90 (mixture of two stereoisomers) (1.71 g, 1.98 mmol) was dissolved in DCM (5.9 mL) and TFA (2.25 mL, 29.8 mmol) was added. The mixture was heated and stirred at 40°C for 5 h, then cooled to r.t., neutralised with saturated aqueous NaHC03 solution and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0-10% gradient), gave the title compound (mixture of two stereoisomers) (1.40 g, quantitative) as a white solid. LCMS (Method 4): [M+H]⁺ m!z 568.2, RT 1.24 minutes. INTERMEDIATE 92

.vy/i-lrac 1-Benzyl yV-r0V)-(4.4-difluorocvclohexyl ) ( 5-G 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonyl )-4-hvdroxy-4-(trif1uorom ethyl )piperidin-2-yl1- imidazor4.5-/ 1pyridin-2-yl !-

methyllcarbamate

To a solution of Intermediate 91 (mixture of two stereoisomers) (1.40 g, 2.05 mmol), 3 -fluorobicyclo[l.l.l]pentane-l -carboxylic acid (294 mg, 2.26 mmol) and DIPEA (1.43 mL, 8.22 mmol) in DMF (30 mL) at r.t. was added HATU (966 mg, 2.46 mmol) in one portion. The mixture was stirred for 16 h, then H2O (50 mL) was added. The resulting material was extracted with EtOAc (2 x 30 mL) and the combined organic extracts were washed with brine (50 mL), then dried (NaiSCL) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (mixture of two stereoisomers) (1.02 g, 73%) as a white foam. LCMS (Method 4): [M+H]⁺ m/z 680.2, RT 1.42 minutes.

INTERMEDIATE 93 -Amino(4.4-difluorocvclohexynmethyll- imidazor4.5-Mpyridin-5-

vH-4-hvdroxy-4-(trifluoromethvnpiperidin-l-yll(3-fluorobicvclor 1.1. llpentan-1-nP- methanone

To a solution of Intermediate 92 (mixture of two diastereomers) (1.02 g, 1.50 mmol) in EtOH (20 mL) at r.t. was added 10% Pd/C (100 mg). The vessel was evacuated and purged with Eh, then left to stir at r.t. for 1 h. The mixture was filtered through a pad of Celite® (10 g) under suction using EtOH (50 mL), then concentrated in vacuo.

Purification by flash chromatography (KP-NH column), eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0-10%), gave the title compound (mixture of two stereoisomers) (778 mg, 95%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 546.2, RT 1.20 minutes. INTERMEDIATE 94 anli-( rac )-/c/V-Butyl 2- diaminopyridin-2-yl )-4-hvdroxy-4-(trif1uoromethyl )-

piperidine- 1 -carboxylate To a solution of Intermediate 87 (1.23 g, 1.67 mmol) in MeOH (33 mL) at r.t. was added 12N aqueous HC1 (0.31 mL, 3.70 mmol), followed by 10% Pd/C (308 mg) portionwise. The vessel was evacuated and purged with Th, then left to stir at r.t. overnight. The mixture was filtered through a pad of Celite® under suction using MeOH, then concentrated in vacuo , to give the crude title compound (917 mg) as a pale yellow solid, which was utilised without further purification. 5H (400 MHz, 373K, DMSO-dr,) 6.71 (d, 77.6 Hz, 1H), 6.30 (d, 77.7 Hz, 1H), 5.05 (br s, 2H), 4.77 (dd, 710.2, 6.4 Hz, 1H), 4.32 (br s, 2H), 3.88 (ddd, 713.7, 6.5, 3.8 Hz, 1H), 3.83-3.56 (br s, 1H), 3.38-3.26 (m, 1H), 2.16 (dd, 714.0, 10.2 Hz, 1H), 2.05 (ddd, 714.0, 6.4, 1.4 Hz, 1H), 1.96-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.31 (s, 9H). LCMS (Method 4): [M+H]⁺ m/z 377.2, RT 1.01 minutes.

INTERMEDIATE 95 anli-( rac )-tert-B utyl 2-r6-amino-5-(fer/-butoxycarbonylamino)pyridin-2-yl1-4-hvdroxy-4- (trifluoromethyOpiperidine- 1 -carboxylate

To a solution of Intermediate 94 (917 mg) in EtOH (12.5 mL) was added di- ter t- butyl dicarbonate (0.43 mL, 1.90 mmol), followed by guanidine hydrochloride (24 mg, 0.25 mmol) in one portion. A reflux condenser was fitted, and the mixture was heated and stirred at 50°C for 16 h, then cooled to r.t. and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (481 mg, 61% over two steps) as a white solid. 5H (400 MHz, 373K, DMSO- de) 8.05 (s, 1H), 7.51 (d, 77.9 Hz, 1H), 6.46 (d, 77.9 Hz, 1H), 5.74 (s, 1H), 5.41 (s, 2H), 4.81 (t, 78.3 Hz, 1H), 3.90 (ddd, 713.8, 6.4, 4.1 Hz, 1H), 3.35 (ddd, 713.7, 10.0, 5.4 Hz, 1H), 2.11 (d, 78.4 Hz, 2H), 1.93 (dt, 714.3, 4.7 Hz, 1H), 1.80 (ddd, 714.9, 9.9, 6.4 Hz, 1H), 1.48 (s, 9H), 1.31 (s, 9H). LCMS (Method 4): [M+H]⁺ m!z 477.2, RT 1.29 minutes. INTERMEDIATE 96 ant/-( rac )-/_<3/V-B utyl 2-G6-! r(2V)-2-(benzyloxycarbonylamino)-2-(4.4-dif1uorocvclohexyl )- acetyl1amino|-5-(fer/-butoxycarbonylamino)pyri din-2 -yl1-4-hvdroxy-4-(trifluoromethvn- piperidine- 1 -carboxylate

To a solution of Intermediate 95 (481 mg, 1.01 mmol), (2ri)-2-(benzyloxy- carbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (364 mg, 1.11 mmol) and pyridine (0.37 mL, 4.60 mmol) in EtOAc (6.0 mL) at 0°C was added T3P® (50 wt % in EtOAc, 1.50 mL, 2.50 mmol) dropwise over 2 minutes. The ice/water bath was removed, and the mixture was allowed to warm to r.t. and stirred for 16 h, then additional ( 2S)-2 -

(benzyloxycarbonylamino)-2-(4,4-difluorocyclohexyl)acetic acid (132 mg, 0.40 mmol), pyridine (0.13 mL, 1.64 mmol) and T3P® (50 wt % in EtOAc, 0.60 mL, 1.01 mmol) were added sequentially. The mixture was stirred for an additional 16 h, then quenched by the addition of LEO (50 mL) and diluted with EtOAc (50 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with saturated aqueous NaHC03 solution (100 mL), dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/ isohexane (0-100% gradient), gave the title compound (mixture of two stereoisomers)

(682 mg, 86%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 786.2, RT 1.62 minutes.

INTERMEDIATE 97 r/////-(rac)-Benzyl A^f-r6V)-(4.4-difluorocvclohexyl )! 5-r4-hvdroxy-4-(trifluoromethyl )- piperidin-2-vn-liT-imidazor4.5-/>lpyridin-2-yl|methyllcarbamate trifluoroacetic acid salt Intermediate 96 (mixture of two stereoisomers) (682 mg, 0.87 mmol) was dissolved in DCM (2.6 mL) and TFA (1.00 mL, 13.2 mmol) was added. The mixture was heated and stirred at 40°C for 6 h, then cooled to r.t., neutralised with saturated aqueous NaHCCh solution and diluted with EtOAc (20 mL). The layers were separated, and the aqueous layer was re-extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried (Na2S04) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0-10% gradient), gave the title compound (mixture of two stereoisomers) (478 mg, 81%) as a white solid. LCMS (Method 4): [M+H]⁺ m!z 568.2, RT 1.23 minutes. INTERMEDIATE 98 anti-( racVBenzyl AHfVi-iAA-difluorocvclohexyl )i 5-ri-(3-fluorobicvclor 1.1. Hpentane-1- carbonyl )-4-hvdroxy-4-(trif1uorom ethyl )piperidin-2-yl1- imidazor4.5-/1pyridin-2-yl !-

methyllcarbamate

To a solution of Intermediate 97 (mixture of two stereoisomers) (478 mg, 0.70 mmol), 3 -fluorobicyclo[l.l.l]pentane-l -carboxylic acid (101 mg, 0.78 mmol) and DIPEA (0.49 mL, 2.80 mmol) in DMF (10 mL) at r.t. was added HATU (330 mg, 0.84 mmol) in one portion. The mixture was stirred for 16 h, then H2O (50 mL) was added. The resulting material was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (50 mL), then dried (NaiSCri) and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (mixture of two stereoisomers) (470 mg, 98%) as a white foam. LCMS (Method 4): [M+H]⁺ m/z 680.2, RT 1.35 minutes.

INTERMEDIATE 99 -r2-(2-r(A)-Amino(4.4-difluorocvclohexynmethyll- imidazor4.5-Mpyridin-5-

To a solution of Intermediate 98 (mixture of two diastereomers) (470 mg, 0.69 mmol) in EtOH (10 mL) at r.t. was added 10% Pd/C (50 mg). The vessel was evacuated and purged with Eh, then left to stir at r.t. for 2.5 h. The mixture was filtered through a pad of Celite® (10 g) under suction using EtOH (50 mL), then concentrated in vacuo. Purification by flash chromatography (KP-NH column), eluting with EtO Ac/isohexane (0-100% gradient), then MeOH/DCM (0-10%), gave the title compound (mixture of two stereoisomers) (301 mg, 80%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 546.2, RT 1.12 minutes. INTERMEDIATE 100

.si /-(rac)-Cvclopropyl 2-i2-rfV)-benzyloxycarbonylamino('4.4-difluorocvclohexyl )- methyl 1- 1 //-i mi dazor4.5-/ 1pyridin-5-yl !-4-hvdroxy-4-(trif1uoromethyl )pi peri dine- 1 - carboxyl ate

To a solution of Intermediate 91 (150 mg, 0.26 mmol) in DCM (2.6 mL) at r.t. were added cyclopropyl (2,5-dioxopyrrolidin-yl) carbonate (prepared as described in Intermediate 78) (64 mg, 0.32 mmol) and DIPEA (0.19 mL, 1.10 mmol) sequentially. The solution was stirred for 50 minutes, then 7N ME/MeOH (2 mL) was added. The mixture was stirred for 5 minutes, then concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient), gave the title compound (mixture of two stereoisomers) (131 mg, 76%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 652.2, RT 1.45 minutes. INTERMEDIATE 101

.si7/-(rac)-Cvclopropyl 2-!2-rfV)-amino(4.4-difluorocvclohexyl )methyl1- imidazor4.5-

Z>1pyridin-5- 4-hvdroxy-4-(trifluoromethvnpiperidine-l-carboxylate

To a solution of Intermediate 100 (mixture of two diastereomers) (131 mg, 0.20 mmol) in EtOH (20 mL) at r.t. was added 10% Pd/C (13 mg). The vessel was evacuated and purged with Eh, then left to stir at r.t. for 3 h. The mixture was filtered through a pad of Celite® (10 g) under suction using EtOH (50 mL), then concentrated in vacuo , to give the title compound (mixture of two stereoisomers) (100 mg, 96%) as a grey foam. LCMS (Method 4): [M+H]⁺ m/z 518.2, RT 1.23 minutes.

INTERMEDIATE 102

3-Fluoro-5-(4.4.5.5-tetramethyl- l .3.2-dioxaborolan-2-yl )benzene- l .2-diamine

To a suspension of 5-bromo-3-fluorobenzene-l, 2-diamine (1.00 g, 4.88 mmol) in 1,4-dioxane (10 mL) were added pinacolborane (1.49 g, 5.85 mmol), potassium acetate (1.45 g, 14.6 mmol) and Pd(dppf)Cl2 (0.23 g, 0.32 mmol). The mixture was stirred at 105°C in a sealed tube for 16 h. After cooling to r.t., the mixture was diluted with ethyl acetate and filtered through Celite®. The filtrate was concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of ethyl acetate in heptane, to give the title compound (estimated purity 63%) (1.75 g, 90%), accompanied by boron-containing and pinacol by-products. 5H (500 MHz, DMSO-de) 6.73 (s, 1H),

6.56 (dd, J 10.9, 1.1 Hz, 1H), 4.80-4.73 (m, 4H), 1.24 (s, 12H). LCMS (Method 7): [M+H]⁺ 253.0, RT 1.62 minutes.

INTERMEDIATE 103 fc/V-Butyl 5-(3.4-diamino-5-fluorophenvO-2.3-dihvdro-E4-oxazine-4-carboxylate To a mixture of Intermediate 102 (63%, 0.70 g, 1.75 mmol), /c/V-butyl 5- diphenoxyphosphoryloxy-2,3-dihydro-l,4-oxazine-4-carboxylate (1.00 g, 2.31 mmol) and 2M aqueous potassium carbonate solution (3.5 mL, 7.00 mmol) in 1,4-dioxane (10 mL) was added Pd(dppf)Cl2 (80 mg, 0.11 mmol). The resulting mixture was stirred at 100°C in a sealed tube for 16 h. After cooling to r.t., the mixture was diluted with EtOAc and filtered through Celite®. The filtrate was concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (estimated purity 71%) (477 mg, 63%), accompanied by some pinacol by-product. 5H (500 MHz, DMSO-de) 6.24-6.22 (m, 1H), 6.18-6.14 (m, 2H), 4.74 (s,

2H), 4.28 (s, 2H), 4.04-4.01 (m, 2H), 3.63-3.58 (m, 2H), 1.11 (s, 9H). LCMS (Method 7): [M-¾u+H]⁺ 254.0, RT 1.63 minutes.

INTERMEDIATE 104 tert- Butyl 5-(4-amino-3- ! r -2-(benzyloxycarbonylamino)-2- dif1uorocvclohexyl )-

acetyl 1 ami no ! -5-fluorophenyl )-2.3-dihydro- l .4-oxazine-4-carboxylate

To a solution of DIPEA (382 mE, 2.19 mmol) and (2ri)-2-(benzyloxycarbonyl- amino)-2-(4,4-difluorocyclohexyl)acetic acid (430 mg, 1.31 mmol) in DCM (6 mL) was added HATU (541 mg, 1.42 mmol). After stirring at r.t. for 15 minutes, the mixture was added to a solution of Intermediate 103 (71%, All mg, 1.09 mmol) in DCM (4 mL). The resulting material was stirred at r.t. for 2 h, then concentrated under a stream of nitrogen. Purification by column chromatography, eluting with a gradient of EtOAc in heptane, gave the title compound (688 mg, 79%). 5H (500 MHz, CDCb) 7.81 (s, 1H), 7.39-7.31 (m, 5H), 6.99 (s, 1H), 6.81 (dd, 711.3, 1.9 Hz, 1H), 6.17 (s, 1H), 5.34 (d, Jl.l Hz, 1H), 5.13 (s, 2H), 4.17-4.09 (m, 3H), 3.84-3.66 (m, 4H), 2.15 (s, 2H), 2.03-1.96 (m, 1H), 1.95- 1.63 (m, 4H), 1.54-1.37 (m, 2H), 1.19 (s, 9H). LCMS (Method 7): [M-¾u+H]⁺ 563.0,

RT 2.01 minutes.

INTERMEDIATE 105 tert- Butyl 5-!2- -benzyloxycarbonylamino dif1uorocvclohexyl )m ethyl 1-7-fluoro-

benzimidazol-5-yl !-2.3-dihydro- l .4-oxazine-4-carboxylate

A solution of Intermediate 104 (488 mg, 0.79 mmol) in AcOH (10 mL) was stirred at 50°C for 16 h. Excess solvent was removed under reduced pressure, then the residue was diluted with saturated aqueous NaHCCb solution (10 mL) and extracted with DCM (2 x 10 mL). The combined organic extracts were passed through a hydrophobic frit (washing with DCM) and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (140 mg, 30%). LCMS (Method 7): [M+H]⁺ 601.0, RT 2.01 minutes.

INTERMEDIATE 106 fc/V-Butyl 5-!2-rfV)-amino(4.4-dif1uorocvclohexyl )methyll-7-fluoro- benzimidazol-5-

vH -2.3 -dihydro- 1.4-oxazine-4-carboxylate

To a solution of Intermediate 105 (140 mg, 0.23 mmol) in a mixture of EtOH (2 mL) and EtOAc (4 mL) was added 10% palladium on carbon (50% wet) (5.0%, 50 mg, 0.023 mmol). The reaction mixture was stirred vigorously under a hydrogen atmosphere for 4 h. Additional 10% palladium on carbon (50% wet) (5.0%, 50 mg, 0.023 mmol) was added, and the reaction mixture was stirred vigorously under a hydrogen atmosphere for 16 h. The resulting material was filtered through Celite® under nitrogen, washing with EtOAc. The filtrate was concentrated under reduced pressure to give the title compound (100 mg, 86%). LCMS (Method 7): [M+H]⁺ 467.0, RT 1.66 minutes. INTERMEDIATE 107 tert- Butyl 5-(2-!(V)-(4.4-dif1uorocvclohexyl iKA-ethyl- 1.2.5-oxadiazole-3-carbonyl )- aminolmethyl ί-7-fluoro- benzimidazol-5-yl )-2.3-dihydro- l .4-oxazine-4-carboxylate

To a solution of 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (37 mg, 0.26 mmol) and DIPEA (70 pL, 0.40 mmol) in DCM (2 mL) was added HATU (106 mg, 0.28 mmol). After stirring at r.t. for 15 minutes, the mixture was added to a solution of Intermediate 106 (93%, 100 mg, 0.20 mmol) in DCM (1 mL). The resulting material was stirred at r.t. for 3 h, then purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (3:1 rotameric mixture) (100 mg, 76%). 5H (500 MHz, CDCb) 9.92-9.75 (m, 1H), 7.72 (d, 78.5 Hz, 1H), 7.41-7.37 (m, 1H, rotamer B), 7.13-7.08 (m, 1H, rotamer A), 6.95-6.87 (m, 1H), 6.30-6.24 (m, 1H), 5.13-5.01 (m, 1H), 4.23-4.12 (m, 2H), 3.89-3.71 (m, 2H), 3.11-3.00 (m, 2H), 2.53-2.32 (m, 1H), 2.24-1.92 (m, 3H), 1.85-1.63 (m, 3H), 1.54-1.47 (m, 2H), 1.40-1.34 (m, 3H), 1.14 (s, 9H). LCMS (Method 7): [M+H]⁺ 591.0, RT 2.10 minutes.

INTERMEDIATE 108

A-((A)-(4.4-Difluorocvclohexynr7-fluoro-5-(morpholin-3-v benzimidazol-2-

yllmethyl ! -4-ethyl - 1.2.5-oxadiazole-3-carboxamide

To a solution of Intermediate 107 (90%, 100 mg, 0.15 mmol) in DCM (2 mL) was added TFA (0.20 mL, 2.69 mmol). The solution was stirred at r.t. for 5 h, then concentrated under reduced pressure. The residue was dissolved in MeOH (4 mL) and cooled to 0°C in an ice/water bath, then treated with sodium borohydride (23 mg, 0.61 mmol) (immediate gas release). The cooling bath was removed, and the solution was allowed to warm to room temperature. The reaction mixture was stirred for 1 h, then quenched with water (1 mL). The majority of the MeOH was removed under reduced pressure, then DCM (20 mL) and saturated aqueous NaHC03 solution (20 mL) were added. The mixture was shaken, then passed through a hydrophobic frit, washing with DCM. The resulting material was concentrated under reduced pressure and purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (45 mg, 60%). LCMS (Method 7): [M+H]⁺ 493.0, RT 1.61 minutes. EXAMPLE 1

morpholin-3-yl|-4-fluoro-li7-benzimidazol-2-vnmethyl1-4-ethyl-1.2.5-oxadiazole-3- carboxamide

To a solution of Intermediate 42 (3.70 g, 7.50 mmol) and (7)-l -(/c/V-butoxy- carbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (2.00 g, 8.00 mmol) in DMF (35 mL) were added DIPEA (2.4 mL, 14.0 mmol) and HATU (3.20 g, 8.20 mmol). The reaction mixture was stirred at r.t. for 15 h, then poured onto ice/water (200 mL). The resulting suspension was stirred for 10 minutes, after which time the precipitate was isolated by vacuum filtration, washing with water. The residue was purified by flash chromatography, eluting with EtO Ac/hexanes (0-100% gradient). The resulting off-white solid (4.44 g, 5.70 mmol) was dissolved in DCM (60 mL), and TFA (6.0 mL, 80.0 mmol) was added dropwise at 0°C. The mixture was warmed to r.t. and stirred for 3 h, then carefully neutralised with saturated aqueous NaHCCh solution. The layers were separated, and the aqueous layer was extracted with EtO Ac (twice). The combined organic layers were washed with saturated aqueous NaHC03 solution (100 mL), then passed through a phase separator and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). The resulting white foam was dissolved in hot EtO Ac (20 mL), and isohexane was added until a solid precipitated. The precipitate was isolated by vacuum filtration and washed with isohexane, then dried in a drying pistol under vacuum at 50°C overnight, to give the title compound (3.16 g, 71% over two steps) as a white solid in 90% ee. Two tautomers were observed, in a 3.3:1 ratio. 5H (400 MHz, DMSO-de) 12.99 (s, 1H, minor tautomer), 12.74 (s, 1H, major tautomer), 9.72 (d, J 8.4 Hz, 1H, major tautomer), 9.62 (d, J 8.5 Hz, 1H, minor tautomer), 7.51-7.20 (m, 2H), 5.69 (s, 1H), 5.18 (t, 78.3 Hz, 1H), 4.36-4.15 (m, 2H), 3.96-3.72 (m, 3H), 3.63-3.41 (m, 2H), 3.20-3.96 (m, 2H), 2.91 (q, 77.4 Hz, 2H), 2.60-2.37 (m, 2H), 2.37-2.21 (m, 1H), 2.14-1.90 (m, 3H), 1.90-1.69 (m, 2H), 1.61-1.49 (m, 1H), 1.47-1.19 (m, 2H), 1.23 (t, 77.5 Hz, 3H). The pyrrolidine NH signal was not observed. LCMS (Method 6): [M+H]⁺ m/z 626, RT 1.79 minutes.

EXAMPLE 2

A-r(M-(4.4-DifluorocvclohexyD(4-fluoro-5-r(3i?)-4-(3-fluorobicvclo|T.l.Hpentane-l- carbonyl )morpholin-3-yll- benzimidazol-2-yl imethyll-4-ethyl- l 2.5-oxadiazole-3-

carboxamide

A solution of Intermediate 5 (100 mg, 0.16 mmol) in DMF (5 mL) was added to l-fluorobicyclo[l.l.l]pentane-3 -carboxylic acid (24 mg, 0.18 mmol) and DIPEA (0.11 mL, 0.63 mmol), and treated with HATU (78.0 mg, 0.20 mmol). After 1 h, water was added, and the mixture was extracted with EtOAc. The organic layers were washed with brine, then dried over Na2SC>4 and concentrated in vacuo. The resulting crude material was purified by column chromatography, eluting with EtO Ac/hexanes (0-100% gradient), followed by preparative HPLC and lyophilisation, to furnish the title compound (16 mg, 16%) as a white solid. 5H (400 MHz, 373K, DMSO-de) 12.36 (br s, 1H), 9.10 (s, 1H),

7.32 (d, 78.4 Hz, 1H), 7.19 (t, 77.6 Hz, 1H), 5.56 (s, 1H), 5.25 (d, 77.8 Hz, 1H), 4.24 (d, 711.3 Hz, 1H), 4.00 (d, J 13.6 Hz, 1H), 3.92 (dd, 711.4, 3.8 Hz, 1H), 3.87 (dd, 712.0,

4.1 Hz, 1H), 3.57 (td, 711.4, 3.3 Hz, 1H), 3.44-3.33 (m, 1H), 2.94 (q, 77.5 Hz, 2H), 2.39- 2.31 (m, 7H), 2.13-1.92 (m, 3H), 1.91-1.72 (m, 2H), 1.71-1.62 (m, 1H), 1.55-1.32 (m,

2H), 1.27 (t, 77.5 Hz, 3H). LCMS (Method 6): [M+H]⁺ m!z 605, RT 1.90 minutes.

EXAMPLES 3 & 4

5-difluorotetrahvdropyran-2-

carbonyl1morpholin-3-yl|-4-fluoro-li7-benzimidazol-2-vnmethyl1-4-ethyl-1.2.5- oxadiazole-3 -carboxamide ( Example 3)

A^f-rbV)- 5.5-difluorotetrahvdropyran-2-

carbonyl1morpholin-3-yl|-4-fluoro-li7-benzimidazol-2-vnmethyl1-4-ethyl-1.2.5- oxadiazole-3 -carboxamide ( Example 4)

Intermediate 5 (250 mg, 0.37 mmol), 5,5-difluorooxane-2-carboxylic acid (85 mg, 0.49 mmol), DIPEA (0.20 mL, 1.14 mmol) and HATU (175 mg, 0.45 mmol) in DMF (5 mL) were stirred for 16 h. The mixture was partitioned between EtOAc and brine, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04 and concentrated in vacuo.

The residue was purified by flash chromatography, eluting with EtOAc/DCM (30-80% gradient). The resulting white solid was subject to chiral SFC (Waters Prep 100-SQD2 equipped with a Chiralpak IC 250 x 20 mm, 5 pm column), flow rate 100 mL/minute, column temperature 35°C, eluting with MeOH (+ 0.1% NEEOH) in food fresh grade liquid CO2 (3-40% gradient), to yield, after lyophilisation, the title compounds (Peak 1, 21 mg, 9%; and Peak 2, 20 mg, 8%). 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). The benzimidazole NH signal was not observed at 373K. LCMS (Method 6): [M+H]⁺ m!z 641, RT 1.95 minutes. Chiral analysis (Method 10): RT 3.36 minutes.

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). The benzimidazole NH signal was not observed at 373K. LCMS (Method 6): [M+H]⁺ mlz 641, RT 1.90 minutes. Chiral analysis (Method 10): RT 3.72 minutes.

EXAMPLE 5

A-r(M-(4.4-DifluorocvclohexyD(4-fluoro-5-IY3i?)-4-(3-fluorobicvclori.l.Hpentane-l- carbonyl )morpholin-3-yll- benzimidazol-2-yl i methyl 1-4-methyl- l .2.5-oxadiazole-3-

carboxamide

A solution of Intermediate 7 (200 mg, 0.42 mmol) in DMF (5 mL) was added to 3 -fluorobicyclo[l.l.l]pentane-l -carboxylic acid (58 mg, 0.44 mmol) and DIPEA (0.22 mL, 1.26 mmol), and treated with HATU (180 mg, 0.46 mmol). After 16 h, the solvent was removed in vacuo and the residue was partitioned between DCM and brine, then passed through a phase separator. The organic phase was removed in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (50-100% gradient), followed by preparative HPLC and lyophilisation, to give the title compound (165 mg, 67%) as a white solid. 5H (400 MHz, 373K, DMSO-de) 12.44 (br s, 1H), 9.14 (br s, 1H), 7.33 (br s, 1H), 7.24 (t, 77.6 Hz, 1H), 5.56 (s, 1H), 5.26 (t, 78.3 Hz, 1H), 4.23 (d, 711.8 Hz, 1H), 3.99 (d, 712.9 Hz, 1H), 3.92 (dd, 711.4, 3.5 Hz, 1H), 3.87 (dd, 712.0,

4.1 Hz, 1H), 3.56 (td, 711.5, 3.3 Hz, 1H), 3.38 (br t, 711.0 Hz, 1H), 2.49 (s, 3H), 2.41- 2.25 (m, 7H), 2.15-1.92 (m, 3H), 1.92-1.70 (m, 2H), 1.70-1.61 (m, 1H), 1.53-1.42 (m,

1H), 1.43-1.31 (m, 1H). LCMS (Method 6): [M+H]⁺ m!z 591, RT 1.77 minutes. EXAMPLE 6

N- G OSV (4.4-DifluorocvclohexyO( 5-G4-13 -fluorobicvclor 1.1.1 Ipentane- 1 -carbonvO- morpholin-3-yl1-li7-imidazor4.5-/>1pyridin-2-yl|methyl1-4-ethyl-1.2.5-oxadiazole-3- carboxamide

To a solution of 3 -fluorobicyclo[ 1.1.1 ]pentane-l -carboxylic acid (24 mg, 0.182 mmol) and DIPEA (49 pL, 0.280 mmol) in DCM (1 mL) was added HATU (74 mg,

0.196 mmol). After stirring at room temperature for 15 minutes, the reaction mixture was added to a solution of Intermediate 22 (95%, 70 mg, 0.140 mmol) in DCM (1 mL). The mixture was stirred at room temperature for 16 h, then purified by column chromatography, eluting with a gradient of EtOAc in heptane. The residue was dissolved in MeOH and passed through a 2 g SCX-2 cartridge, eluting with 7N NEE/MeOH, then concentrated under reduced pressure, to give the title compound (~1 : 1 mixture of diastereomers A & B and rotamers by ¾ NMR, 52 mg, 60%). 5H (500 MHz, DMSO-de) 12.81 (br s, 1H), 9.83-9.50 (m, 1H), 8.08-7.86 (m, 1H), 7.20 (d, J7.8 Hz, 1H, isomer A),

7.06 (d, J8.3 Hz, 1H, isomer B), 5.51-5.40 (m, 1H, isomer B), 5.25-5.12 (m, 2H, contains 1 x isomer A), 4.67-4.53 (m, 1H), 4.15 (d, J 13.3 Hz, 1H, isomer A), 3.90-3.41 (m, 4H), 3.12-3.02 (m, 1H, isomer B), 2.91 (q, J7.4 Hz, 2H), 2.48-2.46 (m, 2H, obscured by DMSO), 2.34-2.14 (m, 5H), 2.11-1.90 (m, 3H), 1.90-1.72 (m, 2H), 1.66-1.55 (m, 1H), 1.50-1.27 (m, 2H), 1.23 (t, J1.5 Hz, 3H). LCMS (Method 8): [M+H]⁺ m/z 588.3, RT

3.16 minutes.

EXAMPLES 7 & 8

N- G OSV (4.4-DifluorocvclohexyO( 5-IY3i?)-4-(3 -fluorobicvclor 1.1.1 Ipentane- 1 -carbonvD- morpholin-3-yl1- imidazor4.5-/>1pyridin-2-yl|methyl1-4-ethyl-1.2.5-oxadiazole-3-

carboxamide ( Example 7)

A-r(X)-(4.4-Difluorocvclohexyn(5-r -4-(3-fluorobicvclor 1.1.llpentane-l-carbonvD-

morpholin-3-v 4-ethyl-1.2.5-oxadiazole-3-

carboxamide ( Example 8)

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-

3.04 (m, 1H, rotamer B), 2.91 (q, 77.3 Hz, 2H), 2.48-2.42 (m, 2H), 2.35-2.13 (m, 5H), 2.11-1.88 (m, 3H), 1.89-1.70 (m, 2H), 1.67-1.53 (m, 1H), 1.47-1.27 (m, 2H), 1.23 (t, 77.5 Hz, 3H). Approximately 1:1 mixture of observable rotamers A & B. LCMS (Method 8): [M+H]⁺ m/z 588.3, RT 3.17 minutes. Chiral analysis (Method 11): RT 16.08 minutes. 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 1:1 mixture of observable rotamers A & B. LCMS (Method 8):

[M+H]⁺ m!z 588.3, RT 3.18 minutes. Chiral analysis (Method 11): RT 16.08 minutes. EXAMPLE 9

Methyl 4- dif1uorocvclohexyl )-

IY4-ethyl- oxadiazole-3-carbonyl iaminolmethyl !- benzimidazol-5-yl )piperazine-

1 -carboxyl ate

To a solution of 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (78 mg, 0.55 mmol) in DMF (0.5 mL) was added DIPEA (260 pL, 1.49 mmol), followed by HATU (226 mg, 0.60 mmol). The resulting mixture was stirred at r.t. for 15 minutes, then Intermediate 32 (163 mg, 0.25 mmol) in DCM (5 mL) was added. The reaction mixture was stirred at r.t. for 15 h, then diluted with DCM (5 mL). The residue was washed with 0.5M HC1 (2 x 2 mL) and water (2 x 2 mL), then dried over MgSCri, filtered and concentrated in vacuo.

The resulting orange oil was purified by flash column chromatography (25 g), eluting with EtOAc in heptane (60-80% gradient). The resulting yellow film (145 mg) was purified by preparative HPLC to afford, after freeze-drying, the title compound (33 mg, 19%) as a white powder. 5H (400 MHz, DMSO-de) 12.58 (s, 1H), 9.26 (s, 1H), 7.31 (d, J

8.4 Hz, 1H), 7.06 (dd, 78.3, 7.0 Hz, 1H), 5.60 (s, 1H), 5.25 (d, 78.1 Hz, 1H), 4.02 (dd, 7 13.8, 5.2 Hz, 2H), 3.75-3.72 (m, 1H), 3.72-3.69 (m, 1H), 3.55 (d, 71.2 Hz, 4H), 3.40-3.18 (m, 3H), 2.96-2.89 (m, 2H), 2.87-2.69 (m, 3H), 2.30-2.25 (m, 1H), 2.13-1.93 (m, 3H), 1.91-1.70 (m, 2H), 1.64 (d, 713.6 Hz, 1H), 1.54-1.41 (m, 1H), 1.41-1.30 (m, 1H), 1.25 (t, 77.5 Hz, 3H). LCMS (Method 8): [M+H]⁺ m/z 668, RT 3.43 minutes.

EXAMPLES 10 & 11

Methyl (3/^)-4-(3.3-difluorocvclobutanecarbonyl )-3-(4-fluoro-2-!0S')-(4.4-difluoro- cvclohexyOIY4-ethyl- oxadiazole-3- benzimidazol-5-

yl ipiperazine- 1 -carboxyl ate ( Example 10)

Methyl difluorocvclobutanecarbonyl )-3-(4-fluoro-2-!0V)- difluoro-

cvclohexyl )IY4-ethyl- oxadiazole-3-carbonyl iaminolmethyl !- benzimidazol-5-

yl Ipiperazine- 1 -carboxyl ate ( Example 11)

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.

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 (Method 12): RT 16.08 minutes.

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, RT 3.42 minutes. Chiral analysis (Method 12): RT 19.41 minutes. EXAMPLE 12

A-r(X)-(4.4-Difluorocvclohexyn(4-fluoro-5-r4-(3-fluorobicvclori.l.l1pentane-l- carbonvD- 1.1 -dioxo- 1 4-thiazinan-3 -yll- liT-benzimidazol-2-yl lmethvH-4-ethyl- 1.2.5- oxadiazole-3 -carboxamide

Intermediate 41 (109 mg, 0.21 mmol), 4-ethyl-l,2,5-oxadiazole-3-carboxylic acid (31 mg, 0.22 mmol), DIPEA (0.14 mL, 0.81 mmol) and HATU (97 mg, 0.25 mmol) were stirred in DMF (2.5 mL) ar r.t. overnight. Water was added, and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. The crude material was subject to column purification (Isolera: 50g SNAP column), eluting with EtO Ac/isohexane (0-100% gradient), to give the title compound (~1:1 mixture of diastereomers, indistinguishable by ¾ or ¹⁹F NMR, 47 mg, 35%) as a white solid. 5H (400 MHz, 373K, DMSO-de) 9.23 (br s, 1H), 7.34 (br s, 1H), 7.10 (app t, 77.7 Hz, 1H), 6.05 (t, 76.7 Hz, 1H), 5.28 (unresolved t, 76.1 Hz, 1H), 4.63-4.53 (m, 1H), 4.01-3.86 (m, 2H), 3.67 (dd, 714.9, 6.0 Hz, 1H), 3.41-3.25 (m, 2H), 2.94 (q, 77.5 Hz, 2H), 2.46-2.34 (m, 8H), 2.15-1.93 (m, 2H), 1.93- 1.71 (m, 2H), 1.71-1.61 (m, 1H), 1.56-1.32 (m, 2H), 1.27 (t, 77.5 Hz, 3H). The benzimidazole NH signal was not observed. ¹⁹F {¾} NMR (282 MHz, DMSO-de) d -90.3 (d, 7232.6 Hz, IF), -99.7 (d, 7232.7 Hz, IF), -131.8 (s, IF), -147.2 (s, IF). LCMS (Method 6): [M+H]⁺ m!z 653, RT 1.80 minutes.

EXAMPLES 13 & 14

A-r(X)-(4.4-Difluorocvclohexyn(5-r -5.5-difluoro-l-(3-fluorobicvclori.l.l1pentane-l-

carbonvDpiperidin-2-yl1- 4-methyl-1.2.5-

oxadiazole-3 -carboxamide ( Example 13)

A-r(X)-(4.4-Difluorocvclohexyn(5-r(2i?V5.5-difluoro-l-(3-fluorobicvclori.l.l1pentane-l- carbonvnpiperidin-2-yl1-li7-imidazor4.5-/>1pyridin-2-yl|methyl1-4-methyl- 1.2.5- oxadiazole-3 -carboxamide ( Example 14)

To a solution of Intermediate 50 (mixture of two isomers) (283 mg, 0.57 mmol), 3 -fluorobicyclo[l.l.l]pentane-l -carboxylic acid (82 mg, 0.63 mmol) and DIPEA (0.40 mL, 2.30 mmol) in DMF (10 mL) at r.t. was added HATU (269 mg, 0.69 mmol) in one portion. The mixture was stirred for 35 minutes, then additional 3-fluorobicyclo[l .1.1]- pentane-1 -carboxylic acid (82 mg, 0.63 mmol), DIPEA (0.40 mL, 2.30 mmol) and HATU (269 mg, 0.69 mmol) were added. After a further 1 h at r.t., additional 3-fluorobicyclo- [l.l.l]pentane-l -carboxylic acid (82 mg, 0.63 mmol), DIPEA (0.40 mL, 2.30 mmol) and HATU (269 mg, 0.69 mmol) were added. Stirring was continued for a further 3 days, then water (10 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), then dried (NaiSCri) and concentrated in vacuo. Purification by flash chromatography, eluting with EtOAc/ isohexane (0-100% gradient), gave a white foam. Further purification was performed by chiral SFC (Method 14) to afford, after lyophilisation, the title compounds (single tautomers) (Peak 1, 45.0 mg, 13% yield, 100% d.e.; and Peak 2, 42 mg, 12% yield, 96.7% d.e.). 5H (400 MHz, 373K, DMSO-de) 12.70 (br s, 1H), 9.13 (br s, 1H), 7.98 (d, J8.3 Hz, 1H), 7.19 (d, J 8.3 Hz, 1H), 5.84-5.52 (br s, 1H), 5.35-5.23 (br s, 1H), 4.68-4.19 (br s, 1H), 3.66-3.18 (br s, 1H), 2.61 (unresolved d, J93 Hz, 1H), 2.54-2.48 (obscured s, 3H),

2.47-2.28 (m, 7H), 2.18-1.93 (m, 6H), 1.93-1.66 (m, 3H), 1.56-1.34 (m, 2H). ¹⁹F {¾} NMR (282 MHz, 373K, DMSO-de) d -90.43 (d, J234.2-Hz, IF), -97.50 (v br d, J 240.6 Hz, IF), -99.37 (d, d 234.1 Hz, IF), -102.19 (v br d, J241.3 Hz, IF), -147.23 (s, IF). LCMS (Method 6): [M+H]⁺ m!z 608, RT 2.02 minutes. Both diastereomers had identical ¾ and ¹⁹F NMR spectra, and identical LCMS data. Chiral analysis (Method 15): Peak 1, RT 2.59 minutes; Peak 2, RT 2.87 minutes.

EXAMPLES 15 & 16

N- G I^'M- (4.4-DifluorocvclohexyD( 5-G(2M- 4.4-difluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvnpiperidin-2-yl1- 4-methyl- 1.2.5-

oxadiazole-3 -carboxamide ( Example 15)

N-\ hSy (4.4-DifluorocvclohexyD( 5-r(2i?)-4.4-difluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvnpiperidin-2-yl1- 4-methyl- 1.2.5-

oxadiazole-3 -carboxamide ( Example 16)

To a solution of DIPEA (163 pL, 0.931 mmol), 3-fluorobicyclo[l.l.l]pentane-l- carboxylic acid (67 mg, 0.512 mmol) and Intermediate 54 (87%, 265 mg, 0.465 mmol) in DMF (6 mL) was added HATU (212 mg, 0.558 mmol). The solution was stirred at r.t. for 2 h, then diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous phase was extracted with EtOAc (10 mL). The combined organic extracts were washed with water (2 x 20 mL) and brine (10 mL), then dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/heptane (0-100% gradient). Further purification was performed by chiral SFC (Method 16) to afford, after lyophilisation, the title compounds (single tautomers) (Peak 1, 29.5 mg, 18% yield, 100% d.e.; and Peak 2, 31.8 mg, 19% yield, 90% d.e.). 5H (400 MHz, 373K, DMSO-de) 12.91-12.34 (br s, 1H), 9.34-8.81 (br s, 1H), 7.92 (d, J8.3 Hz, 1H), 7.09 (d, J 8.3 Hz, 1H), 5.83-5.71 (m, 1H), 5.28 (d, J7.7 Hz, 1H), 4.44-4.30 (m, 1H), 3.48-3.28 (m, 1H), 3.20-3.07 (m, 1H), 2.51 (obscured s, 3H), 2.46-2.28 (m, 8H), 2.14-1.93 (m, 5H), 1.93-1.67 (m, 3H), 1.57-1.34 (m, 2H). ¹⁹F {¾} NMR (282 MHz, 373K, DMSO-de) d

-86.72 (d, J 236.7 Hz, IF), -90.41 (d, J234.1 Hz, IF), -95.59 (br d, J236.2 Hz, IF),

-99.38 (d, J 234.0 Hz, IF), -147.14 (s, IF). LCMS (Method 6): [M+H]⁺ m/z 608, RT 2.28 minutes. Both diastereomers had identical ¾ and ¹⁹F NMR spectra, and identical LCMS data. Chiral analysis (Method 17): Peak 1, RT 4.06 minutes; Peak 2, 4.63 minutes. EXAMPLES 17 TO 20

N- -4-f1uoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 -

carbonvn-4-methylpiperidin-2-yl1-li7-imidazor4.5-/>1pyri din-2 - 4-methyl-

1.2.5-oxadi azole-3 -carboxamide ( Example 17)

N- G bSV (4.4-DifluorocvclohexyD( 5-r(2i?.4i?)-4-fluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvn-4-methylpiperidin-2-yl1-li7-imidazor4.5-/>1pyri din-2 - 4-methyl-

1.2.5-oxadi azole-3 -carboxamide ( Example 18)

N- G OSV (4.4-DifluorocvclohexyO( 5-r(2i?.4X)-4-fluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvn-4-methylpiperidin-2-yll-li7-imidazor4.5-/>lpyri din-2 -yllmethyll-4-methyl-

1.2.5-oxadi azole-3 -carboxamide ( Example 19)

N- G OSV (4.4-DifluorocvclohexyO( 5-r(2,5^,.4X)-4-fluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvn-4-methylpiperidin-2-yll-li7-imidazor4.5-/>lpyri din-2 -yllmethyll-4-methyl-

1.2.5-oxadi azole-3 -carboxamide ( Example 20)

To a solution of Intermediate 61 (mixture of four isomers) (179 mg, 0.36 mmol),

3 -fluorobicyclo[l.l.l]pentane-l -carboxylic acid (52 mg, 0.40 mmol) and DIPEA (0.25 mL, 1.40 mmol) in DMF (10 mL) at r.t. was added HATU (171 mg, 0.44 mmol) in one portion. The mixture was stirred for 16 h, then water (10 mL) was added. The mixture was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), then dried (Na2SC>4) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). Further purification of the resulting white foam was performed by chiral SFC (Method 18) to afford, after lyophilisation, the title compounds (single tautomers) (Peak 1, 8 mg, 3.6% yield, 100% d.e.; Peak 2, 22 mg, 10% yield, 98.6% d.e.; Peak 3, 7 mg, 3.2% yield, 93.1% d.e.; Peak 4, 18 mg, 8.2% yield, 94.7% d.e.). Peaks 1 and 3 had identical ¾ and ¹⁹F NMR spectra, and identical LCMS data. Similarly, Peaks 2 and 4 had identical 'H and ¹⁹F NMR spectra, and identical LCMS data. 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,

4H), 1.92-1.60 (m, 5H), 1.57-1.26 (m, 2H), 1.35 (d, 721.1 Hz, 3H). ¹⁹F NMR (282 MHz, 373K, DMSO-7e) d -90.39 (d, 7234.4 Hz, IF), -99.35 (d, 7233.9 Hz, IF), -147.03 (s, IF). The 3-fluorobicyclo[l .1. ljpentane fluorine signal broadened significantly and was not observed. LCMS (Method 6): [M+H]⁺ mlz 604, RT 1.96 minutes. Chiral analysis (Method 19): Peak 1, RT 4.95 minutes; Peak 3: 8.74 minutes.

Peaks 2 and 4: 5H (400 MHz, 373K, DMSO-de) 12.59 (s, 1H), 9.11 (s, 1H), 7.91 (d, 78.2 Hz, 1H), 7.11 (d, 78.2 Hz, 1H), 5.54 (t, 76.5 Hz, 1H), 5.28 (d, 77.7 Hz, 1H), 4.23-4.13 (m, 1H), 3.46-3.33 (m, 1H), 2.69-2.47 (m, 1H), 2.54-2.47 (obscured s, 3H), 2.40-2.26 (m,

8H), 2.14-1.66 (m, 8H), 1.57-1.33 (m, 2H), 1.16 (d, 722.3 Hz, 3H). ¹⁹F NMR (282 MHz, 373K, DMSO-7e) 5 -90.39 (d, 7234.2 Hz, IF), -99.36 (d, 7234.1 Hz, IF), -127.36 (s, IF), -147.01 (s, IF). LCMS (Method 6): [M+H mlz 604, RT 1.98 minutes. Chiral analysis (Method 19): Peak 2, 6.21 minutes; Peak 4, 9.50 minutes.

EXAMPLES 21 & 22

N- G OSV (4.4-DifluorocvclohexyO( 5-G(2M- 4.4-difluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvDpiperidin-2-yl1-liZ-imidazor4.5-Z>1pyridin-2-yl|methyl1-2-fluorc>benzamide ( Example 21)

N-\ OSV (4.4-DifluorocvclohexyO( 5-r(2i?)-4.4-difluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvDpiperidin-2-yl1- 2-fluorc>benzamide

( Example 22)

To a solution of Intermediate 64 (200 mg, 0.382 mmol) and DIPEA (0.13 mL, 0.764 mmol) in DCM (9.5 mL) was added 2-fluorobenzoyl chloride (50 pL, 0.420 mmol).

The mixture was stirred at r.t. for 2 h, then 7N ME/MeOH was added. The resulting fine white precipitate was stirred at r.t. for a further 2 h. The mixture was concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/heptane (0-100% gradient). The resulting material (215 mg) was purified by chiral SFC (Method 20) to give the title compounds (Peak 1, 43 mg, 100% d.e.; and Peak 2, 45 mg, 100% d.e.).

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). LCMS (Method 8): [M+H]⁺ m/z 620, RT 3.32 minutes.

Chiral analysis (Method 21): RT 4.30 minutes.

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

(obscured m, 3H), 2.44-2.11 (m, 5H), 2.11-1.89 (m, 5H), 1.90-1.68 (m, 2H), 1.68-1.52 (m, 1H), 1.52-1.27 (m, 2H). LCMS (Method 8): [M+H]⁺ m/z 620, RT 3.32 minutes.

Chiral analysis (Method 21): RT 7.23 minutes. EXAMPLES 23 & 24

A-r(X)-(4.4-Difluorocvclohexyn(5-r -4.4-difluoro-l-(3-fluorobicvclori.l.l1pentane-l-

carbonyl )piperidin-2-yll- methyl 1-1 -(trifluoromethyl )-

cvclopropanecarboxamide ( Example 23)

N-\ OSV (4.4-DifluorocvclohexyO( 5-r(2i?)-4.4-difluoro- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonyl )piperidin-2-yll- methyl 1- -(trifluoromethyl )-

cvclopropanecarboxamide ( Example 24)

To a solution of DIPEA (0.13 mL, 0.764 mmol), l-(trifluoromethyl)cyclopropane- carboxylic acid (65 mg, 0.420 mmol) and Intermediate 64 (200 mg, 0.382 mmol) in DMF (5 mL) was added HATU (0.17 g, 0.458 mmol). The solution was stirred at r.t. for 2 h, then diluted with EtOAc (20 mL) and washed with water (20 mL). The aqueous phase was extracted with EtOAc (20 mL). The combined organic extracts were washed with water (2 x 20 mL) and brine (10 mL), then dried over MgS04, filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/heptane (0-100% gradient). The resulting material (181 mg) was purified by chiral SFC (Method 20) to give the title compounds (Peak 1, 54 mg, 100% d.e.; and Peak 2, 33 mg, 100% d.e.).

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),

3.59-2.90 (m, 2H), 2.58-2.51 (obscured m, 3H), 2.39-2.12 (m, 5H), 2.11-1.91 (m, 4H), 1.91-1.65 (m, 3H), 1.57-1.45 (m, 1H), 1.43-1.34 (m, 2H), 1.33-1.17 (m, 4H). LCMS (Method 8): [M+H]⁺ m!z 634, RT 3.43 minutes. Chiral analysis (Method 21): RT 2.63 minutes. Peak 2: 5H (400 MHz, DMSO-de) 13.29-12.44 (m, 1H), 8.41-8.06 (m, 1H), 8.06-7.79 (m, 1H), 7.24-6.92 (m, 1H), 6.08-5.50 (m, 1H), 5.04 (t, 78.2 Hz, 1H), 4.73-4.05 (m, 1H), 3.57-2.91 (m, 2H), 2.62-2.51 (obscured m, 3H), 2.45-2.12 (m, 5H), 2.09-1.91 (m, 4H), 1.90-1.63 (m, 3H), 1.57-1.47 (m, 1H), 1.44-1.33 (m, 2H), 1.33-1.16 (m, 4H). LCMS (Method 8): [M+H]⁺ mlz 634, RT 3.43 minutes. Chiral analysis (Method 21): RT 4.01 minutes.

EXAMPLES 25 & 26

Isopropyl /V-r(X)-(4.4-difluorocvclohexyn(5-r(2X)-4.4-difluoro-l-(3-fluorobicvclori.l.ll- pentane-l-carbonvnpiperidin-2-yll-li7-imidazor4.5-/>lpyridin-2-

( Example 25)

Isopropyl /V-IYM- (4.4-difluorocvclohexyO ( 5-G (2i?)-4.4-difluoro- 1 -(3 -fluorobicvclor 1.1.11- pentane-l-carbonv0piperidin-2-yll-

( Example 26)

A solution of Intermediate 64 (200 mg, 0.382 mmol) and DIPEA (0.13 mL, 0.764 mmol) in DCM (10 mL) was treated with propan-2-yl carbonochloridate in toluene (1M, 420 pL, 0.420 mmol). The mixture was stirred at r.t. for 8 h, then additional propan-2-yl carbonochloridate in toluene (1M, 200 pL, 0.200 mmol) was added. The solution was stirred at r.t. for 16 h, then 7N NEb/MeOH (0.5 mL) was added. The resulting fine white precipitate was stirred at r.t. for 30 minutes, then the mixture was concentrated in vacuo and 7N NEE/MeOH (2 mL) was added. The solution was stirred at r.t. for 1 h, then concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/heptane (0-100% gradient). The resulting material (160 mg) was purified by chiral SFC (Method 20) to give the title compounds (Peak 1, 53 mg, 100% d.e.; and Peak 2, 39 mg, 100% d.e.).

Peak 1: 5H (400 MHz, DMSO-de) 13.30-12.30 (m, 1H), 8.03-7.79 (m, 1H), 7.71-7.18 (m, 1H), 7.18-6.92 (m, 1H), 6.02-5.49 (m, 1H), 4.80-4.66 (m, 2H), 4.66-4.11 (m, 1H), 3.57- 2.93 (m, 2H), 2.62-2.51 (obscured m, 3H), 2.42-1.90 (m, 9H), 1.90-1.62 (m, 3H), 1.59- 1.43 (m, 1H), 1.43-1.21 (m, 2H), 1.17 (dd, J 14.7, 6.2 Hz, 6H). LCMS (Method 8): [M+H]⁺ mlz 584, RT 3.21 minutes. Chiral analysis (Method 21): RT 2.90 minutes.

Peak 2: 5H (400 MHz, DMSO-de) 13.25-12.25 (m, 1H), 8.08-7.79 (m, 1H), 7.74-7.17 (m, 1H), 7.17-6.94 (m, 1H), 6.05-5.52 (m, 1H), 4.82-4.66 (m, 2H), 4.66-4.07 (m, 1H), 3.61- 2.97 (m, 2H), 2.64-2.51 (obscured m, 3H), 2.43-1.90 (m, 9H), 1.90-1.62 (m, 3H), 1.56- 1.45 (m, 1H), 1.43-1.20 (m, 2H), 1.17 (dd, J 14.7, 6.2 Hz, 6H). LCMS (Method 8): [M+H]⁺ m!z 584, RT 3.21 minutes. Chiral analysis (Method 21): RT 4.55 minutes. EXAMPLES 27 & 28

N-\ (A)- (4.4-DifluorocvclohexyD( 5-IY7M- 6-(3 -fluorobicvclor 1.1.1 lpentane- 1 -carbonvD-6- azaspiror2.51octan-7-yll-H7-imidazor4.5-/>lpyridin-2- 4-methyl-1.2.5-

oxadiazole-3 -carboxamide ( Example 27) N-\ OS^*)- (4.4-DifluorocvclohexyD( 5-IY77?)- 6-(3 -fluorobicvclor 1.1.1 lpentane- 1 -carbonvD-6- azaspiror2.51octan-7-yll-H7-imidazor4.5-/>lpyridin-2- 4-methyl-1.2.5-

oxadiazole-3 -carboxamide ( Example 28)

To a solution of Intermediate 68 (164 mg, 0.34 mmol), 3-fluorobicyclo[l.l.l]- pentane-1 -carboxylic acid (50 mg, 0.38 mmol) and DIPEA (0.24 mL, 1.40 mmol) in DMF (10 mL) at r.t. was added HATU (162 mg, 0.41 mmol) in one portion. The mixture was stirred for 50 minutes, then water (15 mL) was added. The mixture was extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with brine (30 mL), then dried (NaiSCL) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). The resulting white foam (175 mg) was further purified by chiral SFC (Method 22) to afford, after lyophilisation, the title compounds (single tautomers) (Peak 1, 29 mg, 14% yield, 100% d.e.; and Peak 2, 36 mg, 18% yield, 93.8% d.e.). 5H (400 MHz, 373K, DMSO-de) 12.62 (s, 1H), 9.09 (s, 1H), 7.92 (unresolved d, J8.1 Hz, 1H), 7.08 (d, J8.3 Hz, 1H), 5.69-5.53 (m, 1H), 5.29 (d, J7.7 Hz, 1H), 4.36-4.12 (m, 1H), 3.41-3.21 (m, 1H), 2.59-2.43 (obscured s, 3H), 2.44-2.27 (m, 7H), 2.27-2.17 (m, 1H), 2.17-1.92 (m, 4H), 1.92-1.66 (m, 4H), 1.56-1.34 (m, 2H), 1.04-0.94 (m, 1H), 0.33-0.27 (m, 1H), 0.27-0.20 (m, 1H), 0.09- 0.00 (m, 2H). LCMS (Method 6): [M+H]⁺ m!z 598, RT 2.01 minutes. Both diastereomers had identical 'H NMR spectra, and identical LCMS data. Chiral analysis (Method 23): RT 3.46 minutes (Peak 1) and 3.74 minutes (Peak 2). EXAMPLES 29 TO 32

N- G OSV (4.4-DifluorocvclohexyO( 5-G(2£4^)- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvn-4-(trifluoromethvnpiperidin-2-yl1-li7-imidazor4.5-/>1pyridin-2- 4-

methyl-L2.5-oxadiazole-3-carboxamide

N- G OSV (4.4-DifluorocvclohexyO( 5-G(2 ?.4C)- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvD-4-(trifluorc>methvDpiperidin-2-yl1- 4-

methyl-L2.5-oxadiazole-3-carboxamide

N- G OSV (4.4-DifluorocvclohexyO( 5-IY2&4X)- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvD-4-(trifluorc>methvDpiperidin-2-yl1- 4-

methyl-1.2.5-oxadiazole-3-carboxamide

N- G (X)-(4.4-Difluorocvclohexyn( 5-r(2i?.4i?)- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvD-4-(trifluorc>methvDpiperidin-2-yl1- 4-

methyl-1.2.5-oxadiazole-3-carboxamide

To a solution of Intermediate 72 (434 mg, 0.82 mmol), 4-methyl-l,2,5- oxadiazole-3 -carboxylic acid (122 mg, 0.90 mmol) and DIPEA (0.36 mL, 2.1 mmol) in DMF (12 mL) was added HATU (354 mg, 0.90 mmol) in one portion. The mixture was stirred for 18 h, then partitioned between EtOAc (100 mL) and brine (100 mL). The layers were separated, and the aqueous layer was back-extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried (NaS04), filtered and concentrated in vacuo. Purification by flash chromatography, eluting with EtO Ac/isohexane (20-80% gradient), and reverse phase HPLC (Method 26) separated the major and minor diastereisomers. The minor diastereoisomers were purified by chiral SFC (Method 27) to afford, after lyophilisation, Example 29 (arbitrarily assigned as syn isomer 27,47) (2.4 mg, 0.46%) and Example 30 (arbitrarily assigned as syn isomer 27,47) (2.2 mg, 0.42%). The major diastereomers were purified by chiral SFC (Method 28) to afford, after lyophilisation, 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%).

The 'H NMR and LCMS retention times were identical for Examples 29 and 30.

5H (400 MHz, 373K, DMSO-de) 7.78 (d, 78.1 Hz, 1H), 6.98 (d, 78.1 Hz, 1H), 5.32 (dd, 7 9.7, 7.3 Hz, 1H), 5.22 (d, 77.1 Hz, 1H), 4.16-4.03 (m, 1H), 3.62-3.49 (m, 1H), 3.24-2.81 (obscured m, 3H), 2.56-2.47 (obscured m, 3H), 2.38-2.25 (m, 8H), 2.24-2.12 (m, 1H), 2.11-1.97 (m, 2H), 1.96-1.79 (m, 1H), 1.79-1.65 (m, 2H), 1.59-1.46 (m, 1H), 1.45-1.33 (m, 1H), 1.28 (s, 1H). LCMS (Method 29): [M+H]⁺ m/z 640, RT 2.03 minutes. Chiral analysis (Method 30): Example 29 , 2.53 minutes; Example 30, 2.72 minutes.

The ¹HNMR and LCMS retention times were identical for Examples 31 and 32.

5H (400 MHz, 373K, DMSO-de) 12.69 (s, 1H), 9.35-8.66 (m, 1H), 7.96 (d, 78.3 Hz, 1H), 7.08 (d, 78.3 Hz, 1H), 6.12-5.46 (m, 1H), 5.28 (d, 77.7 Hz, 1H), 4.58-3.86 (m, 1H), 2.92- 2.76 (m, 8H), 2.54-2.49 (obscured s, 3H), 2.49-2.37 (m, 5H), 2.37-2.26 (m, 1H), 2.15- 1.65 (m, 4H), 1.46 (dddt, 738.1, 21.0, 12.7, 6.2 Hz, 3H). LCMS (Method 29): [M+H]⁺ m/z 640, RT 2.12 minutes. Chiral analysis (Method 30): Example 31, 2.49 minutes; Example 32, 2.61 minutes.

EXAMPLE 33

A-r Sy(4.4-DifluorocvclohexyD(5-r4-(difluoromethvD-l-(3-fluorcbicvclc>ri.l.Hpentane- l-carbonvDpiperidin-2-yl1- ridin-2-vnmethyl1-4-methyl-1.2.5-

oxadiazole-3 -carboxamide

To a solution of Intermediate 77 (150 mg, 0.3 mmol), 4-methyl- 1,2, 5-oxadiazole- 3-carboxylic acid (37 mg, 0.29 mmol) and DIPEA (92 pL, 0.53 mmol) in dry DMF (2.5 mL) was added HATU (120 mg, 0.32 mmol). The solution was stirred at r.t. for 16 h, then diluted with EtOAc (50 mL) and washed with water (2 x 25 mL). The combined aqueous washes were extracted with EtOAc (25 mL). The combined organic extracts were washed with brine (10 mL) and dried over MgS04, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (100 mg, 61%). 5H (400 MHz, DMSO-de) 13.30-12.59 (m, 1H), 9.81-9.42 (m, 1H), 8.12-7.85 (m, 1H), 7.18-6.97 (m, 1H), 6.14-5.45 (m, 2H), 5.29-5.11 (m, 1H), 4.56-3.91 (m, 1H), 3.15-2.56 (m, 2H), 2.49-2.41 (m, 6H), 2.40-2.22 (m, 4H), 2.15-1.53 (m, 9H), 1.50-1.16 (m, 3H). LCMS (Method 8): [M+H]⁺ 622.3, RT 3.48 minutes.

EXAMPLES 34 & 35

N-\ 0Sy(4.4-DifluorocvclohexyD( 5-IY2£4A)-4-(difluorom ethyl)- 1 -(3 -fluorobicvclo- ri.l.llpentane-l-carbonvnpiperidin-2-yll- imidazor4.5-Mpyridin-2- 4-

methyl-L2.5-oxadiazole-3-carboxamide

A^f-rfV)-(4.4-Ditluorocvclohexyl )i 5-r(2/ri4/ -4-(difluoromethyl )- 1 -(3-fluorobicvclo- ri.l.llpentane-l-carbonvnpiperidin-2-yll- imidazor4.5-Mpyridin-2- 4-

methyl-L2.5-oxadiazole-3-carboxamide 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

(m, 5H), 1.49-1.20 (m, 3H). ¹⁹F NMR (376 MHz, DMSO-de) d -90.14 (d, J 233.2 Hz), -99.69 (d, J 233.4 Hz), -122.58 to -124.03 (m), -146.57 to -147.05 (m). LCMS (Method 8): [M+H]⁺ 622.3, RT 3.48 minutes. Chiral analysis (Method 32): RT 3.80 minutes. 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). ¹⁹F NMR (376 MHz, DMSO-de) d -90.14 (d, J 229.1 Hz), -99.71 (d, J 235.0 Hz), -122.52 to -125.58 (m), -145.68 to -148.30 (m). LCMS (Method

8): [M+H]⁺ 622.3, RT 3.48 minutes. Chiral analysis (Method 32): RT 9.29 minutes.

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

To a solution of Intermediate 77 (150 mg, 0.3 mmol), 1-fluorocyclopropane-l- carboxylic acid (30 mg, 0.29 mmol) and DIPEA (92 pL, 0.53 mmol) in DCM (2.5 mL) was added HATU (120 mg, 0.32 mmol). The solution was stirred at r.t. for 2 h, then concentrated under a stream of N2. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (130 mg, 77%). d_H (400 MHz, DMSO-de) 13.44-12.37 (m, 1H), 8.83-8.48 (m, 1H), 8.07-7.85 (m, 1H), 7.15-6.98 (m, 1H), 6.10-5.47 (m, 2H), 5.15-5.00 (m, 1H), 4.49-3.94 (m, 1H), 3.16-2.73 (m, 1H), 2.73-2.61 (m, 1H), 2.48-2.26 (m, 7H), 2.25-2.15 (m, 1H), 2.11-1.88 (m, 3H),

1.87-1.44 (m, 5H), 1.42-1.09 (m, 7H). LCMS (Method 8): [M+H]⁺ 598.3, RT 3.28 minutes. N- -4-(dif1uoromethyl )- 1 -(3 -fluorobicvclo-

ri.l.l1pentane-l-carbonvDpiperidin-2-yl1- l-

fluorocvclopropanecarboxamide

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). ¹⁹F NMR (376 MHz, DMSO-de) d -90.30 (d, J233.7 Hz), -99.56

(d, J 230.3 Hz), -122.59 to -124.15 (m), -146.28 to -147.51 (m), -195.90 to -196.60 (m). LCMS [M+H]⁺ 598.3, RT 3.29 minutes. Chiral analysis (Method 34): RT 8.79 minutes. 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,

7H). LCMS (Method 8): [M+H]⁺ 598.3, RT 3.28 minutes. Chiral analysis (Method 34): RT 13.65 minutes. EXAMPLE 39

dif1uorocvclohexyl ) KA-m ethyl - oxadiazole-3-carbonyl )-

r4.5-/>1pyridin-5-v0-4-(difluoromethyr)piperidine-l-

carboxyl ate

To a solution of Intermediate 79 (130 mg, 0.25 mmol), 4-methyl-l,2,5- oxadiazole-3 -carboxylic acid (32 mg, 0.25 mmol) and DIPEA (80 pL, 0.46 mmol) in dry DMF (2 mL) was added HATU (104 mg, 0.28 mmol). The solution was stirred at r.t. for 2 h, then diluted with EtOAc (10 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over MgSCri, filtered and concentrated under reduced pressure. The residue was purified by column chromatography, eluting with a gradient of EtOAc in heptane, followed by reverse phase HPLC (Method 35), to give the title compound (27 mg, 19%). 5H (400 MHz, DMSO-de) 13.37-12.43 (m, 1H), 9.86-9.31 (m, 1H), 8.06-7.88 (m, 1H), 7.17-7.01 (m, 1H), 6.09-5.73 (m, 1H), 5.62-5.32 (m, 1H), 5.26- 5.16 (m, 1H), 4.14-3.84 (m, 2H), 3.07-2.91 (m, 1H), 2.63-2.54 (m, 1H), 2.48 (s, 3H),

2.32-1.90 (m, 5H), 1.90-1.56 (m, 5H), 1.50-1.25 (m, 3H), 0.74-0.39 (m, 4H). LCMS (Method 8): [M+H]⁺ 594.3, RT 3.57 minutes.

Cvclopropyl (2V.4/^)-2-(2-!(V)-(4.4-dif1uorocvclohexyl)r(4-methyl- l 2.5-oxadiazole-3- carbonv0aminolmethyl|-li7-imidazor4.5- >1pyridin-5-v0-4-(difluoromethv0piperidine-l- carboxyl ate

Cvclopropyl ^i^M^-^-IOS ^^-difluorocvclohexyOr^-methyl- oxadiazole-S-

carbonv0aminolmethyl|-li7-imidazor4.5- >1pyridin-5-v0-4-(difluoromethv0piperidine-l- carboxyl ate

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. LCMS (Method 8): [M+H]⁺ 594.3, RT 3.57 minutes. 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). LCMS (Method 8): [M+H]⁺

594.3, RT 3.57 minutes. Chiral analysis (Method 37): RT 35.43 minutes. EXAMPLES 42 TO 45

-5.5-difluorotetrahvdropyran-2-

carbonyl1-4.4-difluoropiperidin-2-yl|-li7-imidazor4.5-/>1pyridin-2-vnmethyl1-4-methyl- oxadiazole-3-carboxamide

A^f-rbV)- -5.5-difluorotetrahvdropyran-2-

carbonyl1-4.4-difluoropiperi din-2 -vH-li7-imidazor4.5-/>1pyri din-2 -vnmethyll-4-methyl- 1.2.5-oxadiazole-3-carboxamide

To a solution of DIPEA (240 pL, 1.393 mmol), 5,5-difluorooxane-2-carboxylic acid (117 mg, 0.668 mmol) and Intermediate 54 (80%, 345 mg, 0.557 mmol) in DMF (8 mL) was added HATU (262 mg, 0.668 mmol). The solution was stirred at r.t. for 2.5 h, then partitioned between EtOAc and brine. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-80% gradient). Further purification was performed by chiral SFC (Method 38) to afford, after lyophilisation, the title compounds (Peak 1, 1.2 mg, 0.3% yield, 100.0% d.e.; Peak 2, 1.5 mg, 0.4% yield, 80.8% d.e.; Peak 3, 5.5 mg, 1.5% yield, 86.8% d.e.; and Peak 4, 5 mg, 1.4% yield, 99.0% d.e.). Example 42 (arbitrarily assigned R,S ): LCMS (Method 29): [M+H]⁺ m/z 644, RT 1.91 minutes. Chiral analysis (Method 39): RT 11.03 minutes. Example 43 (arbitrarily assigned S,S): LCMS (Method 29): [M+H]⁺ m/z 644, RT 1.91 minutes. Chiral analysis (Method 39): RT 12.68 minutes.

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,

2H), 1.76-1.67 (m, 1H), 1.56-1.45 (m, 1H), 1.47-1.33 (m, 1H). LCMS (Method 29): [M+H]⁺ m/z 644, RT 1.89 minutes. Chiral analysis (Method 39): RT 14.19 minutes. Example 45 (arbitrarily assigned S,R): 5H (400 MHz, 373K, DMSO-dr,) 12.61 (br s, 1H), 9.10 (br s, 1H), 7.91 (d, J8.2 Hz, 1H), 7.13 (d, J 8.3 Hz, 1H), 5.85 (s, 1H), 5.28 (d, J7.7 Hz, 1H), 4.71-4.63 (m, 1H), 4.33 (br s, 1H), 3.95-3.64 (m, 2H), 3.43 (s, 1H), 3.24-3.11 (m, 1H), 2.53-2.49 (obscured s, 3H), 2.48-2.21 (m, 3H), 2.17-1.94 (m, 8H), 1.93-1.73 (m, 2H), 1.76-1.66 (m, 1H), 1.56-1.46 (m, 1H), 1.44-1.33 (m, 1H). LCMS (Method 29): [M+H]⁺ m/z 644, RT 1.89 minutes. Chiral analysis (Method 39): RT 19.06 minutes.

EXAMPLES 46 & 47

A^f-r0V)- -5.5-difluorotetrahvdropyran-2-

carbonyll-4.4-difluoropiperidin-2- imidazor4.5-/>l_Pyridin-2-v0methyll-l-fluoro-

cvclopropanecarboxamide

A^f- -5.5-difluorotetrahvdropyran-2-

carbonyll-4.4-difluoropiperidin-2- imidazor4.5-/>lpyridin-2-v0methyll-l-fluoro-

cvclopropanecarboxamide

To a solution of DIPEA (84 pL, 0.481 mmol), 1-fluorocyclopropylcarboxylic acid (24 mg, 0.231 mmol) and Intermediate 83 (100 mg, 0.192 mmol) in DMF (3 mL) was added HATU (91 mg, 0.231 mmol). The solution was stirred at r.t. for 2 h, then partitioned between EtOAc and brine. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). Further purification of the resulting white solid was performed by chiral SFC (Method 40) to afford, after lyophilisation, the title compounds (Peak 1, 13 mg, 15% yield, 100.0% d.e.; and Peak 2, 30 mg, 35% yield, 94.8% d.e.).

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). LCMS (Method 29): [M+H]⁺ m!z 620, RT 1.80 minutes. Chiral analysis (Method 41): RT 2.21 minutes. Example 47 (arbitrarily assigned S,R ): 5H (400 MHz, 373K, DMSO-de) 8.05 (br s, 1H), 7.49 (d, J8.0 Hz, 1H), 6.61 (d, J7.9 Hz, 1H), 5.73 (s, 1H), 4.95 (d, J5.7 Hz, 1H), 4.66- 4.58 (m, 1H), 4.25 (br s, 1H), 3.94-3.82 (m, 1H), 3.76-3.68 (m, 1H), 3.58 (br s, 1H), 3.38- 3.25 (m, 1H), 2.39-1.91 (m, 10H), 1.80-1.69 (m, 3H), 1.69-1.50 (m, 2H), 1.43-1.13 (m, 5H). One NH signal was not observed. LCMS (Method 29): [M+H]⁺ m/z 620, RT 1.78 minutes. Chiral analysis (Method 41): RT 2.44 minutes.

EXAMPLES 48 & 49

N-\ (A)- (4.4-DifluorocvclohexyD( 5-G(2£47?)- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvO-4-hy droxy-d-ftrifluorom ethyQpiperi din-2 -vn-liT-imidazor4.5-/>lPyri din-2- vnmethyl1-4-methyl-1.2.5-oxadiazole-3-carboxamide

N-\ OSV (4.4-DifluorocvclohexyO( 5-G(27?.4M- 1 -(3 -fluorobicvclor 1.1.1 Ipentane- 1 - carbonvn-4-hvdroxy-4-(trifluoromethvnpiperi din-2 -vH- imidazor4.5-/>1pyridin-2-

vHmethvn-4-methyl-L2.5-oxadiazole-3-carboxamide

To a solution of Intermediate 93 (mixture of two stereoisomers) (200 mg, 0.37 mmol), 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (47 mg, 0.37 mmol) and DIPEA (0.26 mL, 1.50 mmol) in DMF (10 mL) at r.t. was added HATU (173 mg, 0.44 mmol) in one portion. The mixture was stirred for 16 h, then H2O (10 mL) was added. The resulting material was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), then dried (NaiSCL) and concentrated in vacuo. Purification was performed using flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). Further purification of the resulting white foam (mixture of two isomers) (238 mg) was performed by chiral HPLC (Method 42) to afford, after lyophilisation, the title compounds (Peak 1, 39 mg, 16% yield, 100.0% d.e.; and Peak 2, 60 mg, 25% yield, 99.5% d.e.).

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,

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). The OH proton signal was not observed. ¹⁹F NMR (282 MHz, 373K, DMSO-de) d -82.87 (s, 3F), -90.42 (d, J 234.3 Hz, IF), -99.36 (d, J 234.1 Hz, IF), -147.00 (s, IF). LCMS (Method 29): [M+H]⁺ m/z 656.2, RT 2.01 minutes. Chiral analysis (Method 43): RT 5.22 minutes.

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). The OH proton signal was not observed. ¹⁹F NMR (282 MHz, 373K, DMSO-de) d -82.87 (s, 3F), -90.43 (d, J 234.1 Hz, IF), -99.39 (d, J 234.4 Hz, IF), -147.02 (s, IF). LCMS (Method 29): [M+H]⁺ m/z 656.2, RT 2.02 minutes. Chiral analysis (Method 43): RT 5.72 minutes.

EXAMPLES 50 & 51

N-\ (A)- (4.4-DifluorocvclohexyD( 5-G(2£4M- 1 -(3 -fluorobicvclor 1.1.1 lpentane- 1 - carbonvn-4-hvdroxy-4-(trifluoromethvnpiperi din-2 -yll- imidazor4.5-/>lpyridin-2-

vnmethyll-4-methyl-L2.5-oxadiazole-3-carboxamide

N-\ (A)- (4.4-DifluorocvclohexyD( 5-IY2i?.4iO- 1 -(3 -fluorobicvclor 1.1.1 lpentane- 1 - carbonvn-4-hvdroxy-4-(trifluoromethvnpiperi din-2 -yll- imidazor4.5-/>lpyridin-2-

vnmethyll-4-methyl-L2.5-oxadiazole-3-carboxamide To a solution of Intermediate 99 (mixture of two stereoisomers) (150 mg, 0.28 mmol), 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (36 mg, 0.28 mmol) and DIPEA (0.19 mL, 1.10 mmol) in DMF (10 mL) at r.t. was added HATU (130 mg, 0.33 mmol) in one portion. The mixture was stirred for 16 h, then H2O (10 mL) was added. The resulting material was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), then dried (NaiSCri) and concentrated in vacuo. Purification was performed using flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). Further purification of the resulting white foam (mixture of two isomers) (152 mg) was performed by chiral HPLC (Method 42) to afford, after lyophilisation, the title compounds (Peak 1, 41 mg, 22.7% yield, 100.0% d.e.; and Peak 2, 41 mg, 22.7% yield, 97% d.e.).

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

Hz, 1H), 2.55-2.47 (obscured s, 3H), 2.39-2.25 (m, 9H), 2.15-1.93 (m, 4H), 1.92-1.65 (m, 4H), 1.57-1.34 (m, 2H). One NH proton signal was not observed. ¹⁹F NMR (282 MHz, DMSO-de) d -82.41 (s, 3F), -90.10 (d, J 232.9 Hz, IF), -99.72 (d, 7232.6 Hz, IF),

-146.91 (s, IF). LCMS (Method 29): [M+H]⁺ m/z 656.2, RT 1.81 minutes. Chiral analysis (Method 43): RT 4.91 minutes.

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). ¹⁹F NMR (282 MHz, DMSO-de) d -82.40 (s, 3F), -90.11 (dd, 7233.1, 16.0 Hz, IF),

-99.74 (d, 7231.9 Hz, IF), -146.92 (d, 73.0 Hz, IF). LCMS (Method 29): [M+H]⁺ m/z 656.2, RT 1.82 minutes. Chiral analysis (Method 43): RT 5.57 minutes.

EXAMPLES 52 & 53

Cvclopropyl (2V.4/ -2-(2-i0V)-(4.4-difluorocvclohexyl)r(4-methyl- l .2.5-oxadiazole-3- carbonyl iaminolmethyl l_Pyridin-5-yl)-4-hvdroxy-4-(^'trifluoromethyl )-

piperidine- 1 -carboxylate

Cvclopropyl 4.4-difluorocvclohexyl)r(4-methyl- l .2.5-oxadiazole-3-

carbonyl iaminolmethyl lpyridin-5-yl)-4-hvdroxy-4-(^'trifluoromethyl )-

piperidine- 1 -carboxylate

To a solution of Intermediate 101 (mixture of two stereoisomers) (100 mg, 0.19 mmol), 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (25 mg, 0.20 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (5 mL) at r.t. was added HATU (91 mg, 0.23 mmol) in one portion. The mixture was stirred for 70 minutes, then H2O (10 mL) was added. The resulting material was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), then dried (NaiSCL) and concentrated in vacuo. Purification was performed using flash chromatography, eluting with EtO Ac/isohexane (0-100% gradient). Further purification of the resulting white foam (mixture of two isomers) (86.5 mg) was performed by chiral HPLC (Method 42) to afford, after lyophilisation, the title compounds (Peak 1, 26 mg, 21.4% yield, 100.0% d.e.; and Peak 2, 24 mg, 19.8% yield, 100% d.e.).

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,

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 (Method 29): [M+H]⁺ m/z 628.2, RT 2.08 minutes. Chiral analysis (Method 43): RT 4.98 minutes.

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 (Method 29): [M+H]⁺ m/z 628.2, RT 2.09 minutes. Chiral analysis (Method 43): RT 5.38 minutes.

EXAMPLE 54

A-r(X)-(4.4-Difluorocvclohexyn(7-fluoro-5-r4-(3-fluorobicvclori.l.l1pentane-l- carbonyl )morpholin-3-yll- benzimidazol-2-yl imethyll-4-ethyl-l oxadiazole-3-

carboxamide

To a solution of 3 -fluorobicyclo[ 1.1.1 ]pentane-l -carboxylic acid (15 mg, 0.12 mmol) and DIPEA (32 pL, 0.18 mmol) in DCM (1 mL) was added HATU (49 mg, 0.13 mmol). After stirring at r.t. for 15 minutes, the mixture was added to a solution of Intermediate 108 (45 mg, 0.091 mmol) in DCM (1 mL). The resulting mixture was stirred at r.t. for 4 h, then purified by column chromatography, eluting with a gradient of EtOAc in heptane, to give the title compound (36 mg, 64%). 5H (500 MHz, DMSO-dr,) 13.12-12.55 (m, 1H), 9.80-9.45 (m, 1H), 7.49-7.08 (m, 1H), 7.08-6.80 (m, 1H), 5.57-5.05 (m, 2H), 4.51-4.32 (m, 1H), 4.24-3.64 (m, 3H), 3.57-3.39 (m, 1H), 3.29-3.18 (m, 1H), 2.97-2.83 (m, 2H), 2.47-2.38 (m, 4H), 2.35-2.21 (m, 3H), 2.12-1.91 (m, 3H), 1.90-1.70 (m, 2H), 1.65-1.51 (m, 1H), 1.47-1.26 (m, 2H), 1.26-1.20 (m, 3H). LCMS (Method 8):

[M+H]⁺ 605.3, RT 3.44 minutes.

EXAMPLES 55 & 56

A-r(X)-(4.4-Difluorocvclohexyn(7-fluoro-5-r(3i?)-4-(3-fluorobicvclori.l.l1pentane-l- carbonyl )morpholin-3-v benzimidazol-2-yl imethyll-4-ethyl- l 2.5-oxadiazole-3-

carboxamide rV-r(X)-(4.4-Difluorocvclohexyn(7-fluoro-5-r -4-(3-fluorobicvclori.l.Hpentane-l-

carbonyl )morpholin-3-yll- benzimidazol-2-yl imethyll-4-ethyl- l 2.5-oxadiazole-3-

carboxamide

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)

(10 mg, 98% d.e.).

Example 55: 5H (500 MHz, DMSO-de) 13.21-12.60 (m, 1H), 9.85-9.53 (m, 1H), 7.53-7.08 (m, 1H), 7.08-6.80 (m, 1H), 5.61-5.03 (m, 2H), 4.53-4.32 (m, 1H), 4.22-3.68 (m, 3H), 3.57-3.39 (m, 1H), 3.29-3.16 (m, 1H), 2.99-2.84 (m, 2H), 2.47-2.39 (m, 4H), 2.36-2.20 (m, 3H), 2.10-1.92 (m, 3H), 1.89-1.70 (m, 2H), 1.63-1.49 (m, 1H), 1.45-1.26 (m, 2H),

1.23 (t, 77.5 Hz, 3H). LCMS (Method 8): [M+H]⁺ 605.3, RT 3.48 minutes. Chiral analysis (Method 45): RT 7.70 minutes.

Example 56: 5H (500 MHz, DMSO-de) 13.16-12.54 (m, 1H), 9.85-9.53 (m, 1H), 7.51-7.08 (m, 1H), 7.06-6.80 (m, 1H), 5.58-5.05 (m, 2H), 4.53-4.30 (m, 1H), 4.25-3.64 (m, 3H), 3.57-3.39 (m, 1H), 3.28-3.18 (m, 1H), 2.98-2.83 (m, 2H), 2.47-2.39 (m, 4H), 2.35-2.21

(m, 3H), 2.11-1.91 (m, 3H), 1.89-1.69 (m, 2H), 1.65-1.49 (m, 1H), 1.47-1.27 (m, 2H),

1.23 (t, 77.5 Hz, 3H). LCMS (Method 8): [M+H]⁺ 605.3, RT 3.48 minutes. Chiral analysis (Method 45): RT 9.19 minutes.

Claims

Claims:

1. A compound of formula (I) or an A-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

A represents C-R¹ or N;

E represents C-R² or N;

Z represents a group of formula (Za), (Zb), (Zc), (Zd), (Ze) or (Zf):

(Za) (Zb) (Zc) in which the asterisk (*) represents the point of attachment to the remainder of the molecule;

Y represents O, N-R⁴, CR^5aR^5b, S, S(0), S(0)₂ or S(0)(N-R⁷);

R¹ represents hydrogen or fluoro;

R² represents hydrogen or fluoro;

R⁴ represents -COR^4a, -C0₂R^4a or -S0₂R^4b; or R⁴ represents hydrogen; or R⁴ represents Ci-₆ alkyl or C3-9 cycloalkyl, either of which groups may be optionally substituted by one or more fluorine atoms;

R^4b represents Ci-₆ alkyl;

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^6a 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; and R⁷ represents Ci-6 alkyl.

2. A compound as claimed in claim 1 represented by formula (1-1) or (1-2) or an L -oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein Z, R¹, R² and R⁶ are as defined in claim 1.

3. A compound as claimed in claim 1 or claim 2 wherein Z represents a group of formula (Zc) or (Zd) as defined in claim 1.

4. A compound as claimed in any one of the preceding claims wherein R⁶ represents -OR^6a, in which R^6a is as defined in claim 1; or R⁶ represents C3-9 cycloalkyl, aryl or heteroaryl, which group may be optionally substituted by one or more substituents.

5. A compound as claimed in claim 1 represented by formula (IIA) or an L -oxide thereof, or a pharmaceutically acceptable salt thereof: wherein

R¹⁶ represents methyl or ethyl; and A, Y and R³ are as defined in claim 1.

6. A compound as claimed in claim 1 represented by formula (IIB) or an A-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

A, Y and R³ are as defined in claim 1; and R¹⁶ is as defined in claim 5.

7. A compound as claimed in any one of the preceding claims wherein Y represents O, N-R⁴, CR^5aR^5b or S(0)2, in which R⁴, R^5a and R^5b are as defined in claim 1.

8. A compound as claimed in any one of the preceding claims wherein R³ represents -OR^3a; or R³ represents C3-9 cycloalkyl, C4-12 bicycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.

9. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.

10. A compound of formula (I) as defined in claim 1 or an L -oxide thereof, or a pharmaceutically acceptable salt thereof, for use in therapy.

11. A compound of formula (I) as defined in claim 1 or an L -oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.

12. A compound of formula (I) as defined in claim 1 or an L -oxide thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder.

13. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an A-oxide thereof, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

14. A pharmaceutical composition as claimed in claim 13 further comprising an additional pharmaceutically active ingredient.

15. The use of a compound of formula (I) as defined in claim 1 or an A-oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated.

16. The use of a compound of formula (I) as defined in claim 1 or an N- oxide thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of an inflammatory or autoimmune disorder.

17. A method for the treatment and/or prevention of disorders for which the administration of a modulator of IL-17 function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an N- oxide thereof, or a pharmaceutically acceptable salt thereof.

18. A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined in claim 1 or an N- oxide thereof, or a pharmaceutically acceptable salt thereof.