WO2021204800A1

WO2021204800A1 - Difluorocyclohexyl derivatives as il-17 modulators

Info

Publication number: WO2021204800A1
Application number: PCT/EP2021/058937
Authority: WO
Inventors: Prafulkumar Tulshibhai CHOVATIA; Gregory William HASLETT; Fabien Claude LECOMTE; James Madden; Nathaniel Julius Thomas Monck; Timothy John Norman; Konstantinos RAMPALAKOS; Adam Peter SMALLEY; Robert Straker; Selvaratnam SUGANTHAN; Mengyang XUAN; Zeshan YOUSUF
Original assignee: UCB Biopharma SRL
Priority date: 2020-04-07
Filing date: 2021-04-06
Publication date: 2021-10-14

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 ofIL-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), 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), and co-pending international patent applications PCT/EP2021/054519 and PCT/EP2021/054523 (claiming earliest priority from United Kingdom patent applications 2002635.7 and 2002636.5 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 N-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

A represents C-R¹ or N;

5 E represents C-R² or N;

Y represents -0-, -N(R³)-, -C(R^4a)(R^4b), -S-, -S(0)-, -S(0>2- or -S(OXN-R⁵>;

Z represents heteroaryl, which group may be optionally substituted by one or more substituents;

R¹ represents hydrogen or fluoro;

R² represents hydrogen or fluoro;

R³ represents -COR^3a, -CO₂R^3a or -SCkR^3®; or R³ represents hydrogen; or R³ represents C_1-6 alkyl or C_3-9 cycloalkyl, either of which groups may be optionally substituted by one or more fluorine atoms;

R^3a represents C_1-6 alkyl, optionally substituted by one or more fluorine atoms; R^4a represents hydrogen, fluoro or hydroxy; or R^4® represents C_1-6 alkyl, which group may be optionally substituted by one or more substituents; and R^4b represents hydrogen, fluoro or C_1-6 alkyl; or

R^4a and R^4b, when taken together with the carbon atom to which they are both attached, represent C_3-9 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents;

R⁵ represents C_1-6 alkyl;

R⁶ represents -OR^6a or -NR^6bR^6c; or R⁶ represents C_1-6 alkyl, C_3-9 cycloalkyl, C_3-9 cycloalkyl(C i-6)alkyl, aryl, aryl(Ci-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci-6)alkyl, heteroaryl or heteroaryl (C i-6)alkyl, any of which groups may be optionally substituted by one or more substituents; R^6a represents C_1-6 alkyl; or R^6a represents C_3-9 cycloalkyl, which group may be optionally substituted by one or more substituents;

R^6b represents hydrogen or C_1-6 alkyl; and R⁶⁰ represents hydrogen or C_1-6 alkyl; or

R^6b and R⁶⁰, when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents.

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 C_1-6 alkyl groups, for example C_1-6 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, w-propyl, isopropyl, w-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as “C_1-6 alkoxy”, “C_1-6 alkylthio”, “C_1-6 alkylsulphonyl” and “C_1-6 alkylamino” are to be construed accordingly.

The term “C_3-9 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 C_3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononanyl.

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

The term “C_3-7 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 “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[3,4-6]-

[1.4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pynolo[3,2-c]- pyridinyl, pyrrolo[3,4-6]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, 4, 5,6,7- tetrahydropyrazolo[l,5-a]pyridinyl, pyrazolo[3 ,4-if]pyrimidinyl, pyrazolo[l,5-a]- pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,l-6]- thiazolyl, imidazo[l,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyridinyl, imidazo- [4,5-6]pyridinyl, imidazo[l,2-6]pyridazinyl, purinyl, imidazo[l,2-a]pyrimidinyl, imidazo- [l,2-c]pyrimidinyl, imidazo[l,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl,

[1.2.4]triazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, 5,6,7,8-tetrahydro-

[ 1 ,2,4]triazolo[4,3 -a]pyridinyl, [ 1 ,2,4]triazolo[ 1 ,5-a]pyrimidinyl, [ 1 ,2,4]triazolo[4,3 -a]- pyrazinyl, 6, 8-dihydro- 57f-[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

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 ¾ ²H (deuterium) or ¾ (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. In one aspect of that embodiment, A represents C-R¹; and E represents C-R².

Suitably, the present invention provides a compound of formula (1-1) or (1-2) or an TV-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein Y, Z, R¹, R² and R⁶ are as defined above.

Suitably, Y represents -0-, -N(R³>, -C(R^4aXR^4b> or -S-, wherein R³, R⁴⁸ and R^4b are as defined above.

Typically, Y represents -C(R^4a)(R^4b)-.

In a first embodiment, Y represents -0-. In a second embodiment, Y represents -N(R³)-. In a third embodiment, Y represents -C(R^4a)(R^4b)-. In a fourth embodiment, Y represents -S-. In a fifth embodiment, Y represents -S(0)-. In a sixth embodiment, Y represents -S(0)2-. In a seventh embodiment, Y represents -S(0)(N-R⁵)-.

Typically, Z represents furyl, benzoftiryl, dibenzofiuyl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,4-6][l,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3 ,4-6]pyridinyl, pyrazolyl, pyrazolo[ 1 , 5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-d]- pyrimidinyl, pyrazolo[ 1 , 5-a]pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2, 1 -6]thiazolyl, imidazo[ 1 ,2-a]pyridinyl, 5,6,7,8-tetrahydro- imidazo[ 1 ,2-a]pyridinyl, imidazo[4, 5-6]pyridinyl, imidazo[ 1 ,2-6]pyridazinyl, purinyl, imidazo[ 1 ,2-a]pyrimidinyl, imidazo[ 1 ,2-c]pyrimidinyl, imidazo[ 1 ,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [l,2,4]triazolo[l,5-a]pyridinyl, [ 1 ,2,4]triazolo[4,3 -a]- pyridinyl, 5,6,7,8-tetrahydro[ 1 ,2,4]triazolo[4,3-a]pyridinyl, [1 ,2,4]triazolo[ 1,5-a]- pyrimidinyl, 6, 8-dihydro- 57f-[l, 2, 4]triazolo[4,3-<z]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl or chromenyl, any of which groups may be optionally substituted by one or more substituents. Additionally, Z may represent [l,2,4]triazolo[4,3-a]pyrazinyl, which group may be optionally substituted by one or more substituents.

Appositely, Z represents pyrazolyl, pyrazolo[l,5-a]pyridinyl, isoxazolyl, isothiazolyl, imidazolyl, imidazo[l,2-a]pyridinyl, imidazo[l,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [l,2,4]triazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents. Additionally, Z may represent [l,2,4]triazolo[4,3-a]pyrazinyl, which group may be optionally substituted by one or more substituents.

More particularly, Z represents imidazolyl, imidazo[l,2-a]pyridinyl, triazolyl, [l,2,4]triazolo[4,3-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyrazinyl or tetrazolyl, any of which groups may be optionally substituted by one or more substituents.

Suitably, Z represents imidazolyl, triazolyl, [l,2,4]triazolo[4,3-a]pyridinyl or tetrazolyl, any of which groups may be optionally substituted by one or more substituents.

Typical examples of optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, cyano, nitro, C_1-6 alkyl, difluoromethyl, trifluoro(C_1-6 )alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[l.l.l]pentanyl, cyano- bicyclo[l .1. l]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(C_1-6 )alkyl, oxo, C_1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, Ci-6 alkylthio, Ci-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, C_1-6 alkylamino, di(C i-6)alkylamino, amino(Ci-6)- alkyl, di(C_1-6)alkylamino(Ci-6)alkyl, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl, di(C_1-6)alkyl aminosulfonyl and di(Ci-6)alkylsulfoximino. Additional examples include difluoroethyl.

Apposite examples of optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, C_1-6 alkyl, difluoromethyl, trifluoro(C i-6)alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, cyanobicyclo[l.l.l]pentanyl and C_1-6 alkyl amino. Additional examples include difluoroethyl. Additional examples include cyano.

Illustrative examples of optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, difluoroethyl, trifluoro- (C i-6)alkyl, difluorocyclobutyl, cyclopropylmethyl and cy anobicyclo[ 1.1.1 ]pentanyl .

Additional examples include cyano.

Selected examples of optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, cyano, difluoroethyl, trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl and cyanobicyclo[ 1.1.1 ]pentanyl .

Suitable examples of optional substituents on Z include one, two or (where possible) three substituents independently selected from halogen, trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl and cyanobicyclo[l.l.l]pentanyl.

Typical examples of particular substituents on Z include one, two or (where possible) three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, w-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluoro- cyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluoro- bicyclo[l.l.l]pentanyl, cyanobicyclo[l.l.l]pentanyl, spiro[2.2]pentanyl, methylspiro- [2.2]pentanyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, oxo, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, methylthio, m ethyl sulfmyl, methyl- sulfonyl, amino, methylamino, dimethylamino, aminomethyl, dimethylaminomethyl, acetyl amino, m ethoxy carbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethyl- aminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximino. Additional examples include difluoroethyl.

Apposite examples of particular substituents on Z include one, two or (where possible) three substituents independently selected from fluoro, methyl, difluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluoro- cyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, cyano- bicyclo[l .1. l]pentanyl and methylamino. Additional examples include difluoroethyl. Additional examples include cyano. Illustrative examples of particular substituents on Z include one, two or (where possible) three substituents independently selected from fluoro, difluoroethyl, trifluoro- ethyl, difluorocyclobutyl, cyclopropylmethyl and cyanobicyclo[l.l.l]pentanyl.

Additional examples include cyano.

Selected examples of particular substituents on Z include one, two or (where possible) three substituents independently selected from fluoro, cyano, difluoroethyl, trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl and cyanobicyclo[l.l.l]pentanyl.

Suitable examples of particular substituents on Z include one, two or (where possible) three substituents independently selected from fluoro, trifluoroethyl, difluoro- cyclobutyl, cyclopropylmethyl and cyanobicy clo[ 1.1.1 ]pentanyl .

Typical values of Z include trifluoroethylpyrazolyl, (methylXtrifluoroethyl)- pyrazolyl, pyrazolo[l,5-a]pyridinyl, methylindazolyl, trifluoroethylisoxazolyl, (methyl)- (trifluoroethyl)isoxazolyl, trifluoroethylisothiazolyl, trifluoroethylimidazolyl, cyclopropylmethylimidazolyl, (methylXtrifluoroethyl)imidazolyl, imidazo[ 1 ,2 -a\- pyridinyl, trifluoroethyltriazolyl, difluorocyclopropyltriazolyl, difluorocyclobutyl- triazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[l.l.l]pentanyltriazolyl, (fluoro)- (trifluoroethyl)triazolyl, (methylXtrifluoroethyl)triazolyl, (difluoromethylXtrifluoroethyl)- triazolyl, (cyclopropylmethylXdifluoromethyl)triazolyl, (methylaminoXtrifluoroethyl)- triazolyl, [ 1 ,2,4]triazolo[ 1 ,5-a]pyridinyl, fluoro[ 1 ,2,4]triazolo[4,3-a]pyridinyl, benzotriazolyl, trifluoroethyltetrazolyl, trifluoroethylpyridinyl, trifluoroethylpyridazinyl, trifluoroethylpyrimidinyl and trifluoroethylpyrazinyl. Additional values include difluoroethyltriazolyl. Additional values include fluoroimidazo[l,2-a]pyridinyl, cyano[l,2,4]triazolo[4,3-a]pyridinyl and cyano[l,2,4]triazolo[4,3-a]pyrazinyl.

Selected values of Z include cyclopropylmethylimidazolyl, fluoroimidazo[l,2-a]- pyridinyl, difluoroethyltriazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicy clo[ 1.1.1 ]pentanyltriazolyl, fluoro[ 1 ,2,4]triazolo- [4,3 -a]pyridinyl, cy ano[ 1 ,2,4]triazolo[4,3 -a]pyridinyl, cy ano[ 1 ,2,4]triazolo[4,3 -a]- pyrazinyl and trifluoroethyltetrazolyl.

Illustrative values of Z include cyclopropylmethylimidazolyl, difluoroethyl- triazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[l.l.l]pentanyltriazolyl, fluoro[l,2,4]triazolo[4,3-a]pyridinyl and trifluoroethyltetrazolyl. Suitable values of Z include cyclopropylmethylimidazolyl, trifluoroethyltriazolyl, difluorocyclobutyltriazolyl, cyclopropylmethyltriazolyl, cyanobicyclo[l .1. l]pentanyl- triazolyl, fluoro[l,2,4]triazolo[4,3-a]pyridinyl and trifluoroethyltetrazolyl.

Suitably, Z represents a group of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh), (Zj), (Zk), (Zl), (Zm), (Zn), (Zp), (Zq), (Zr), (Zs), (Zt), (Zu), (Zv), (Zw), (Zx), (Zy),

(Zz) or (Zaa):

wherein the asterisk (*) represents the point of attachment to the remainder of the molecule;

R^lz represents hydrogen, C_1-6 alkyl, difluoromethyl, difluoroethyl, trifluoro(Ci-6)- alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluoro- cyclopropylmethyl, fluorobicy clo[ 1.1.1 ]pentanyl, cyanobicyclo[ 1.1.1 ]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy(C_2-6)alkyl, C_1-6 alkylsulfonyl, amino(C_2-6)alkyl, di(C_1-6)alkylamino(Ci-6)alkyl, C_2-6 alkylcarbonyl, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl or di(C_1-6)alkylaminosulfonyl; and

R^2z represents hydrogen, halogen, cyano, nitro, C_1-6 alkyl, difluoromethyl, trifluoro(Ci-6)alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[l.l.l]pentanyl, cyanobicyclo[l.l.l]- pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxy(Ci-6)alkyl, C_1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, C_1-6 alkylamino, di(C_1-6)alkyl- amino, amino(Ci-6)alkyl, di(C i-6)alkylamino(C i-6)alkyl, C_2-6 alkyl carbonyl amino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(C_1-6)alkyl aminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl, di(Ci-6)alkyl aminosulfonyl or di(C_1-6)alkyl- sulfoximino.

Selected values of Z include the groups of formula (Zk), (Zl), (Zn), (Zp), (Zs),

(Zt), (Zu), (Zv) and (Zaa) as defined above.

Suitable values of Z include the groups of formula (Zk), (Zl), (Zn), (Zp), (Zs),

(Zt), (Zu) and (Zv) as defined above.

Particular values of Z include the groups of formula (Zk), (Zn), (Zp), (Zs), (Zt), (Zu) and (Zv) as defined above.

Generally, R^lz represents hydrogen, C_1-6 alkyl, difluoromethyl, trifluoro(Ci-6)- alkyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicy clo[ 1.1.1 ]pentanyl, cyanobicyclo[ 1.1.1 ]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy(C_2-6)alkyl, C_1-6 alkylsulfonyl, amino(C_2-6)alkyl, di(C_1-6)alkylamino(Ci-6)alkyl, C_2-6 alkylcarbonyl, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(Ci-6)alkyl aminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl or di(C i-e)alkyl aminosulfonyl . Typically, R^lz represents hydrogen, C_1-6 alkyl, trifluoro(C i-6)alkyl, difluoro- cyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl or cyanobicyclo[l .1. l]pentanyl. Additionally, R^lz may represent difluoroethyl.

Apposite values of R^lz include hydrogen, methyl, ethyl, w-propyl, isopropyl, tert- butyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3- trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[ 1.1.1 ]pentanyl, cyanobicyclo[ 1.1.1 ]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxyethyl, hydroxyisopropyl, methyl- sulfonyl, aminoethyl, dimethylaminomethyl, acetyl, methoxycarbonyl, ethoxy carbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methyl- aminosulfonyl and dimethylaminosulfonyl. Additional values include difluoroethyl.

Typical values of R^lz include hydrogen, methyl, ethyl, w-propyl, isopropyl, tert- butyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl and cyanobicyclo- [l.l.l]pentanyl. Additional values include difluoroethyl.

Illustrative values of R^1z include difluoroethyl, trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl and cyanobicyclo[l.l.l]pentanyl.

Suitably, R^lz represents trifluoroethyl, difluorocyclobutyl, cyclopropylmethyl or cyanobicyclo[ 1.1.1 ]pentanyl .

Typically, R^2z represents hydrogen, halogen, C_1-6 alkyl, trifluoro(C i-6)alkyl, cyclopropylmethyl, difluorocyclopropylmethyl or C_1-6 alkyl amino. Additionally, R^2z may represent cyano.

Suitably, R^2z represents hydrogen, halogen or cyano. More particularly, R^2z represents hydrogen or halogen. In a first embodiment, R^2z represents hydrogen. In a second embodiment, R^2z represents halogen, especially fluoro. In a third embodiment,

R^2z represents cyano.

Apposite values of R^2z include hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, w-propyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoropropyl, 2-methyl-3,3,3-trifluoropropyl, cyclopropyl, difluorocyclopropyl, difluorocyclobutyl, cyclopropylmethyl, difluorocyclopropylmethyl, fluorobicyclo[l .1.1]- pentanyl, cyanobicyclo[l.l.l]pentanyl, spiro[2.2]pentanyl, methylspiro[2.2]pentanyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, phenoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, ethylamino, dimethylamino, amino- methyl, dimethylaminomethyl, acetylamino, methoxycarbonylamino, methyl sulfonyl- amino, formyl, acetyl, carboxy, m ethoxy carbonyl, ethoxycaibonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl and dimethylsulfoximino.

Typical values of R^2z include hydrogen, fluoro, methyl, difluoromethyl, trifluoro- ethyl, trifluoropropyl, 2-methyl-3 ,3 ,3 -trifluoropropyl, cyclopropylmethyl, difluoro- cyclopropylmethyl and methylamino. Additional values include cyano.

Selected values of R^2z include hydrogen, fluoro and cyano.

Suitable values of R^2z include hydrogen and fluoro.

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

In a first embodiment, R² represents hydrogen. In a second embodiment, R² represents fluoro.

Suitably, R³ represents -COR^3a, -COaR³⁸ or -SOaR^3®; or R³ represents hydrogen; or R³ represents C_1-6 alkyl, which group may be optionally substituted by one or more fluorine atoms, generally by one, two or three fluorine atoms, typically by three fluorine atoms.

In a first embodiment, R³ represents -COR^3a. In a second embodiment, R³ represents -CO₂R^3a. In a third embodiment, R³ represents - -SO₂R^3a.^. In a fourth embodiment, R³ represents hydrogen. In a fifth embodiment, R³ represents C_1-6 alkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms. In one aspect of that embodiment, R³ represents unsubstituted Ci-6 alkyl, especially methyl or ethyl. In another aspect of that embodiment, R³ represents C_1-6 alkyl substituted by one, two or three fluorine atoms, typically by three fluorine atoms.

Examples of that aspect include trifluoroethyl. In a sixth embodiment, R³ represents C_3-9 cycloalkyl, optionally substituted by one or more fluorine atoms, typically by one, two or three fluorine atoms. In one aspect of that embodiment, R³ represents unsubstituted C_3-9 cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In another aspect of that embodiment, R³ represents C_3-9 cycloalkyl substituted by one, two or three fluorine atoms, typically by two fluorine atoms. Examples of that aspect include difluorocyclobutyl . Typically, R^3a represents C_1-6 alkyl, optionally substituted by one, two or three fluorine atoms.

Suitably, R^3a represents C_1-6 alkyl or trifluoro(C i-e)alkyl .

In a first embodiment, R^3a represents C_1-6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R^3a represents methyl. In a second aspect of that embodiment, R^3a represents ethyl. In a second embodiment, R^3a represents trifluoro(Ci^)- alkyl, especially trifluoroethyl.

Particular values of R^3a include methyl and trifluoroethyl.

Generally, R^4a represents hydrogen or fluoro; or R^4a represents C_1-6 alkyl, which group may be optionally substituted by one or more substituents.

Typically, R^4a represents hydrogen; or R^4a represents C_1-6 alkyl, which group may be optionally substituted by one or more substituents.

Suitably, R^4a represents hydrogen or C_1-6 alkyl.

In a first embodiment, R^4a represents hydrogen. In a second embodiment, R^4a represents fluoro. In a third embodiment, R^4a represents hydroxy. In a fourth embodiment, R^4a represents C_1-6 alkyl, especially methyl or ethyl, which group may be optionally substituted by one or more substituents. In a first aspect of that embodiment, R^4a represents optionally substituted methyl. In a second aspect of that embodiment, R^4a represents optionally substituted ethyl.

Typical examples of optional substituents on R^4a include one, two or three substituents independently selected from halogen, cyano, nitro, hydroxy, C_1-6 alkoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoroethoxy, Ci-6 alkylthio, Ci-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, C_1-6 alkylamino, di(C i-6)alkylamino, C_2-6 alkyl- carbonylamino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonylamino, formyl, C_2-6 alkyl- carbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di- (C i-6)alkylaminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl, di(C i-e)alkylamino- sulfonyl and di(Ci-6)alkylsulfoximino.

Apposite examples of optional substituents on R^4a include one, two or three substituents independently selected from halogen and C_1-6 alkylsulfonyl.

Suitable examples of optional substituents on R^4a include one, two or three substituents independently selected from halogen.

Typical examples of particular substituents on R^4a include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, hydroxy, methoxy, isopropoxy, difluoromethoxy, difluoroethoxy, trifluoromethoxy, trifluoro- ethoxy, methylthio, methylsulfmyl, methylsulfonyl, ethylsulfonyl, amino, methylamino, dimethylamino, acetylamino, m ethoxy carbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxy carbonyl, ethoxy carbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylamino- sulfonyl and dimethylsulfoximino.

Apposite examples of particular substituents on R^4a include one, two or three substituents independently selected from fluoro and ethylsulfonyl.

Suitable examples of particular substituents on R^4a include one, two or three substituents independently selected from fluoro.

Illustrative values of R^4a include hydrogen, fluoro, hydroxy, methyl, difluoroethyl, trifluoroethyl and ethylsulfonylethyl.

Typical values of R^4a include hydrogen, methyl, difluoroethyl, trifluoroethyl and ethylsulfonylethyl .

Particular values of R^4a include hydrogen, methyl, difluoroethyl and trifluoroethyl. Suitable values of R^4a include hydrogen and methyl.

In a first embodiment, R^4b represents hydrogen. In a second embodiment, R* represents fluoro. In a third embodiment, R^4b represents C_1-6 alkyl, especially methyl or ethyl. In a first aspect of that embodiment, R* represents methyl. In a second aspect of that embodiment, R* represents ethyl.

Typical values of R* include hydrogen and fluoro, especially hydrogen.

Alternatively, R^4a and R* may together form an optionally substituted spiro linkage. Thus, R^4a and R⁴⁶, when taken together with the carbon atom to which they are both attached, may represent C_3-7 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

In a first embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent C_3-7 cycloalkyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a general illustration of that embodiment, R^4a and R⁴⁶, when taken together with the carbon atom to which they are both attached, may suitably represent cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a first particular illustration of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent cyclobutyl or cyclohexyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a second particular illustration of that embodiment, R^4a and R⁴⁶, when taken together with the carbon atom to which they are both attached, may suitably represent cyclopropyl or cyclohexyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a first aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent a cyclopropyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a second aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent a cyclobutyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a third aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent a cyclopentyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a fourth aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent a cyclohexyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

In a second embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent C_3-7 heterocycloalkyl, which group may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a general illustration of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. As a particular illustration of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a first aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent an oxetanyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a second aspect of that embodiment, R^4a and R*, when taken together with the carbon atom to which they are both attached, may suitably represent a pyrrolidinyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a third aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent a tetrahydropyranyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents. In a fourth aspect of that embodiment, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may suitably represent a piperidinyl ring, which may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

Typically, R^4a and R⁴⁶, when taken together with the carbon atom to which they are both attached, may represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

Appositely, R^4a and R^4b, when taken together with the carbon atom to which they are both attached, may represent cyclobutyl, cyclohexyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

Suitably, R^4a and R⁴⁶, when taken together with the carbon atom to which they are both attached, may represent cyclopropyl or cyclohexyl, either of which groups may be unsubstituted, or substituted by one or more substituents, typically by one or two substituents.

Typical examples of optional substituents on the spirocycle formed by R^4a and R^4b include C_1-6 alkyl, halogen, cyano, trifluoromethyl, trifluoroethyl, hydroxy, C_1-6 alkoxy, Ci-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_2-6 alkylcarbonyl, C_2-6 alkoxy carbonyl, amino, C_1-6 alkyl amino and di(C i-6)alkylamino.

Apposite examples of optional substituents on the spirocycle formed by R^4a and R^4b include C_1-6 alkyl, halogen, trifluoroethyl and C_2-6 alkoxycarbonyl, especially halogen.

Suitable examples of optional substituents on the spirocycle formed by R^4a and R* include halogen and C_2-6 alkoxycarbonyl. Typical examples of particular substituents on the spirocycle formed by R^4® and R^4b include methyl, fluoro, chloro, bromo, cyano, trifluoromethyl, trifluoroethyl, hydroxy, methoxy, methylthio, methylsulfinyl, methylsulfonyl, acetyl, m ethoxy carbonyl, ethoxy- carbonyl, amino, methylamino and dimethylamino.

Apposite examples of particular substituents on the spirocycle formed by R^4a and R^4b include methyl, fluoro, trifluoroethyl and methoxycarbonyl, especially fluoro.

Suitable examples of particular substituents on the spirocycle formed by R^4a and R^4b include fluoro and methoxycarbonyl.

Typical examples of the spirocycle formed by R^4a and R^4b include cyclopropyl, difluorocyclobutyl, cyclopentyl, difluorocyclohexyl, oxetanyl, methoxycarbonyl- pyrrolidinyl, tetrahydropyranyl and methoxycarbonylpiperidinyl.

Apposite examples of the spirocycle formed by R^4a and R^4b include difluorocyclobutyl, difluorocyclohexyl, methoxycarbonylpyrrolidinyl, tetrahydropyranyl and methoxycarbonylpiperidinyl .

Selected examples of the spirocycle formed by R^4a and R^4b include cyclopropyl and difluorocyclohexyl.

Suitably, R⁵ represents methyl or ethyl. In a first embodiment, R⁵ represents methyl. In a second embodiment, R⁵ represents ethyl.

Typically, R⁶ represents -OR^6® or -NR⁶^.⁶⁶; or R⁶ represents C_1-6 alkyl, C_3-9 cycloalkyl, C_3-9 cycloalkyl(C i-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.

Suitably, R⁶ represents -OR^6®; or R⁶ represents heteroaryl, which group may be optionally substituted by one or more substituents.

In a first embodiment, R⁶ represents optionally substituted C_1-6 alkyl. In a second embodiment, R⁶ represents optionally substituted C_3-9 cycloalkyl. In a third embodiment, R⁶ represents optionally substituted C_3-9 cycloalkyl(C i-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 C_3-7 heterocycloalkyl. In a seventh embodiment, R⁶ represents optionally substituted C_3-7 heterocycloalkyl(Ci-6)alkyl. In an eighth embodiment, R⁶ represents optionally substituted heteroaryl. In a ninth embodiment, R⁶ represents optionally substituted heteroary 1(C i-e)alkyl . In a tenth embodiment, R⁶ represents -OR^6®. In an eleventh embodiment, R⁶ represents -NR^6aR^6b.

Typical values of R⁶ include -OR^6® or -NR^R⁶⁶; 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.

Illustrative values of R⁶ include -OR^6®; 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.

Apposite values of R⁶ include pyrazolyl and oxadiazolyl, either of which groups may be optionally substituted by one or more substituents.

Particular values of R⁶ include oxadiazolyl, which group may be optionally substituted by one or more substituents.

Typical examples of optional substituents on R⁶ include one, two or three substituents independently selected from halogen, cyano, nitro, C_1-6 alkyl, trifluoro- methyl, phenyl, fluorophenyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, C_1-6 alkoxy, difluoro- methoxy, trifluoromethoxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, amino(Ci-6)alkyl, C_1-6 alkylamino, di(C i-6)alkylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, C_2-6 alkylcarbonylamino, C_2-6 alkyl carbonyl amino(Ci-6)alkyl, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(C i-6)alkyl amino- carbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl, di(C_1-6)alkylaminosulfonyl and di- (C i-6)alkyl sulfoximinyl .

Suitable examples of optional substituents on R⁶ include one, two or three substituents independently selected from C_1-6 alkyl.

Typical examples of particular substituents on R⁶ include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, fluorophenyl, hydroxy, hydroxymethyl, oxo, m ethoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methyl- amino, tert-butylamino, dimethylamino, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, acetylamino, acetylaminoethyl, m ethoxy carbonylamino, methylsulfonyl- amino, formyl, acetyl, carboxy, m ethoxy carbonyl, ethoxy carbonyl, fe/7-butoxy carbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethyl aminosulfonyl and dimethylsulfoximinyl.

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, carboxy ethyl, difluoropropyl, 2-methylpropyl, butyl, cyanocyclopropyl, methylcyclopropyl, ethyl- cyclopropyl, dimethylcyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, fluorophenylcyclopropyl, hydroxycyclopropyl, aminocyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, cyclohexyl, cyclohexylmethyl, phenyl, fluorophenyl, chloro- phenyl, cyanophenyl, methylphenyl, hydroxyphenyl, methylsulfonylphenyl, dimethyl- sulfoximinylphenyl, benzyl, fluorobenzyl, difluorobenzyl, chlorobenzyl, (chloro)(fluoro)- benzyl, dichlorobenzyl, (chloro)(difluoro)benzyl, bromobenzyl, cyanobenzyl, methyl- benzyl, dimethylbenzyl, trifluoromethylbenzyl, phenylbenzyl, hydroxybenzyl, hydroxymethylbenzyl, benzoyl, methoxybenzyl, dimethoxybenzyl, trifluoromethoxy- benzyl, methylsulfonylbenzyl, aminomethylbenzyl, aminoethylbenzyl, dimethylamino- benzyl, pyrrolidinylbenzyl, (dimethylXpyrrolidinyl)benzyl, morpholinylbenzyl, (dimethyl)(morpholinyl)benzyl, piperazinylbenzyl, acetylaminoethylbenzyl, phenylethyl, chlorophenylethyl, methylpyrazolyl, ethylpyrazolyl, (methylXtetrahydropyranyl)- pyrazolyl, methylisoxazolyl, ethylisoxazolyl, methyloxadiazolyl, ethyloxadiazolyl, pyridinyl, triazolylmethyl, benzotriazolylmethyl, pyridinylmethyl and aminopyridinyl- methyl.

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

Selected values of R⁶ include methylpyrazolyl, ethylpyrazolyl, methyloxadiazolyl and ethyloxadiazolyl.

Notable values of R⁶ include methylpyrazolyl, methyloxadiazolyl and ethyl- oxadiazolyl.

Particular values of R⁶ include methyloxadiazolyl and ethyloxadiazolyl.

In a first embodiment, R^6® represents C_1-6 alkyl. In a second embodiment, R^6® represents optionally substituted C_3-9 cycloalkyl. Typically, R^6® represents C_1-6 alkyl; or R^6a represents cyclobutyl, which group may be optionally substituted by one or more substituents.

Typical examples of optional substituents on R^6® include one, two or three substituents independently selected from halogen, cyano, nitro, C_1-6 alkyl, trifluoro- methyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, C_1-6 alkoxy, difluoromethoxy, trifluoro- methoxy, C_1-6 alkylthio, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, amino, amino(Ci-6)alkyl, Ci-6 alkylamino, di(C i-6)alkyl amino, C_2-6 alkylcarbonylamino, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonylamino, formyl, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, aminocarbonyl, C_1-6 alkylaminocarbonyl, di(Ci-6)alkylaminocarbonyl, aminosulfonyl, C_1-6 alkylaminosulfonyl and di(C i-6)alkylaminosulfonyl .

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

Typical examples of specific substituents on R^6® include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethylhydroxy, hydroxymethyl, oxo, methoxy, tert- butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, aminomethyl, aminoethyl, methylamino, tert-butylamino, dimethylamino, acetyl amino, m ethoxy carbonylamino, methyl sulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxy carbonyl, tert-butoxy carbonyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethyl- aminosulfonyl.

Suitable examples of specific substituents on R^6® include one, two or three substituents independently selected from fluoro.

Illustrative examples of specific values of R^6® include methyl, ethyl, w-propyl, isopropyl, w-butyl, tert-butyl, cyclobutyl and difluorocyclobutyl.

Typically, R^6® represents cyclobutyl.

Typically, R⁶⁶ represents hydrogen or methyl.

In a first embodiment, R⁶⁶ represents hydrogen. In a second embodiment, R⁶⁶ represents C_1-6 alkyl, especially methyl.

Typically, R⁶⁰ represents hydrogen or methyl.

In a first embodiment, R⁶⁰ represents hydrogen. In a second embodiment, R⁶⁰ represents C_1-6 alkyl, especially methyl. Alternatively, the moiety -NR^R⁶⁰ may suitably represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents.

Selected examples of suitable substituents on the heterocyclic moiety -NR⁶^⁶⁶ include C_1-6 alkyl, C_1-6 alkylsulfonyl, hydroxy, hydroxy(Ci-6)alkyl, amino(Ci-6)alkyl, cyano, oxo, C_2-6 alkylcarbonyl, carboxy, C_2-6 alkoxycarbonyl, amino, C_2-6 alkylcarbonyl- amino, C_2-6 alkyl carbonylamino(C i-6)alkyl, C_2-6 alkoxycarbonylamino, C_1-6 alkylsulfonyl- amino and aminocarbonyl.

Selected examples of specific substituents on the heterocyclic moiety -NR⁶^⁶⁶ include methyl, methylsulfonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxy carbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulfonylamino and aminocarbonyl.

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

wherein

R¹⁶ represents methyl or ethyl; and A, E, Z and R^4a 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 (ΠΒ) and A-oxides thereof, and pharmaceutically acceptable salts thereof:

wherein

A, E, Z, R^4a 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, comeal transplantation, lamellar or partial thickness transplantation, selective endothelial transplantation, comeal neovascularization, keratoprosthesis surgery, comeal ocular surface inflammatory conditions, conjunctival scarring disorders, ocular autoimmune conditions, Pemphigoid syndrome, Stevens-Johnson syndrome, ocular allergy, severe allergic (atopic) eye disease, conjunctivitis and microbial keratitis. 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.

Dlustratively, 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 spondyloarthritis or ankylosing spondylitis.

The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable carriers.

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 coadministered 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

(m):

wherein Α, Ε, Y, Z and R⁶ are as defined above.

The reaction is convenientiy accomplished in the presence of a coupling agent and a base. Suitable coupling agents include 1 -[bis(dimethylamino)methylene]- 1/f- 1,2,3- triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate (HATU); and 2,4,6-tripropyl- l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide. Suitable bases include organic amines, e.g. a trialkylamine such as N,N-diisopropylethylamine, or pyridine. The reaction is conveniently performed at ambient or elevated temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran; or a dipolar aprotic solvent such as N,N-dimethyl- formamide or N,N-dimethylacetamide; or a chlorinated solvent such as dichloromethane; or an organic ester solvent such as ethyl acetate.

Where R⁶ represents C_1-6 alkyl, e.g. methyl, the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula R⁶-COCl, e.g. acetyl chloride, with a compound of formula (ΙΠ) as defined above. The reaction is conveniently accomplished in the presence of a base. Suitable bases include organic amines, e.g. a trialkylamine such as N,N-diisopropylethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

Where R⁶ represents -OR⁶⁸, the compounds of formula (I) above may be prepared by a two-step process which comprises: (i) reacting a compound of formula R^-OH with N,N-disuccinimidyl carbonate, ideally in the presence of a base, e.g. an organic amine such as triethylamine; and (ii) reacting the resulting material with a compound of formula (ΠΙ) as defined above. Steps (i) and (ii) are conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile.

The intermediates of formula (ΙΠ) above may be prepared by removal of the N- protecting group R^p from a compound of formula (TV):

wherein A, E, Y and Z are as defined above, and R^p represents a /V-protecting group.

The A-protecting group R^p will suitably be tert-butoxycarbonyl (BOC), in which case the removal thereof may conveniently be effected by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

Alternatively, the A-protecting group R^p may be benzyloxycarbonyl, in which case the removal thereof may conveniently be effected by catalytic hydrogenation, typically by treatment with hydrogen gas or ammonium formate in the presence of a hydrogenation catalyst, e.g. palladium on charcoal, or palladium hydroxide on charcoal.

The compounds of formula (I) above wherein Y represents -N(R³)-, in which R³ represents -COR^3a, may be prepared by a process which comprises reacting a carboxylic acid of formula R^3a-C02H, wherein R^3a is as defined above, with the appropriate compound of formula (I) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen; under conditions analogous to those described above for the reaction between compound (ΙΠ) and a carboxylic acid of formula R⁶-C02H.

Likewise, the intermediates of formula (TV) above wherein Y represents -N(R³)-, in which R³ represents -COR^3a, may be prepared by reacting a carboxylic acid of formula R^3a-C02H, wherein R^3a is as defined above, with the appropriate compound of formula (TV) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen; under conditions analogous to those described above for the reaction between compound (III) and a carboxylic acid of formula R⁶-C02H.

The compounds of formula (I) above wherein Y represents -N(R³)-, in which R³ represents -COaR³⁸, may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with a compound of formula L^1a-C02R^3a, wherein L^1a represents a suitable leaving group, and R^3a is as defined above.

Likewise, the intermediates of formula (TV) above wherein Y represents -N(R³)-, in which R³ represents -SO₂R^3a, may be prepared by reacting the appropriate compound of formula (TV) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with a compound of formula L^1a-C02R^3a, wherein L^1a and R^3a are as defined above.

The leaving group L^1a is suitably a halogen atom, e.g. chloro. Alternatively, the leaving group L^1a may suitably be 2,5-dioxopyrrolidin-l-yloxy.

The reaction is conveniently accomplished in the presence of a base. Suitable bases include organic amines, e.g. a trialkylamine such as ^A-diisopropylethylamine or triethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

The compounds of formula (I) above wherein Y represents -N(R³)-, in which R³ represents -SO₂R^3a, may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with a compound of formula L^1b-S02R^3a, wherein L^1b represents a suitable leaving group, and R^3a is as defined above.

Likewise, the intermediates of formula (TV) above wherein Y represents -N(R³)-, in which R³ represents -SOaR³⁸, may be prepared by reacting a compound of formula (TV) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with a compound of formula L^1b-S02R^3a, wherein L^1b and R^3a are as defined above.

The leaving group L^1b is suitably a halogen atom, e.g. chloro.

The reaction is conveniently accomplished in the presence of a base. Suitable bases include organic amines, e.g. a trialkylamine such as ^A-diisopropylethylamine or triethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane. The compounds of formula (I) above wherein Y represents -N(R³)-, in which R³ represents C_1-6 alkyl, optionally substituted by one or more fluorine atoms, may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with a compound of formula L²-R^3b, wherein L² represents a suitable leaving group, and R^3b represents C_1-6 alkyl, optionally substituted by one or more fluorine atoms.

Likewise, the intermediates of formula (TV) above wherein Y represents -N(R³)-, in which R³ represents C_1-6 alkyl, optionally substituted by one or more fluorine atoms, may be prepared by reacting the appropriate compound of formula (TV) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with a compound of formula L²-R^3b, wherein L² and R^3b are as defined above.

The leaving group L² may suitably be a sulfonyloxy derivative, e.g. trifluoro- methanesulfonyloxy.

The reaction is conveniently accomplished in the presence of a base. Suitable bases include organic amines, e.g. a trialkylamine such as triethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

The compounds of formula (I) above wherein Y represents -N(R³)-, in which R³ represents C_3-9 cycloalkyl, optionally substituted by one or more fluorine atoms (e.g. 3,3- difluorocyclobutyl), may be prepared by a process which comprises reacting the appropriate compound of formula (I) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with the appropriate cycloalkanone, optionally substituted by one or more fluorine atoms (e.g. 3,3-difluorocyclobutanone), in the presence of a reducing agent.

Likewise, the intermediates of formula (TV) above wherein Y represents -N(R³)-, in which R³ represents C_3-9 cycloalkyl, optionally substituted by one or more fluorine atoms (e.g. 3, 3 -difluorocyclobutyl), may be prepared by reacting the appropriate compound of formula (IV) as defined above wherein Y represents -N(R³)-, in which R³ represents hydrogen, with the appropriate cycloalkanone, optionally substituted by one or more fluorine atoms (e.g. 3,3-difluorocyclobutanone), in the presence of a reducing agent.

The reducing agent is suitably sodium triacetoxyborohydride. The reaction is conveniently performed in the presence of acetic acid. The compounds of formula (I) above wherein Y represents -N(R³)-, in which R³ represents hydrogen, may conveniently be prepared by reacting the corresponding compound of formula (I) wherein Y represents -N(R³)-, in which R³ represents -SO₂R^3a and R^3a represents fert-butyl, with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

Likewise, the intermediates of formula (TV) above wherein Y represents -N(R³)-, in which R³ represents hydrogen, may conveniently be prepared by reacting the corresponding compound of formula (TV) wherein Y represents -N(R³)-, in which R³ represents -SO₂R^3a and R^3a represents tert-butyl, with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

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 A, E, Y, Z and R⁶ are as defined above.

Cyclisation of compound (VA) or (VB) is conveniently effected by heating in the presence of a suitable medium, e.g. an acid such as acetic acid, or trifluoroacetic acid.

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:

wherein A, E, Y, Z and R⁶ are as defined above; under conditions analogous to those described above for the reaction between compound (ΠΙ) 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-CC>2H with a compound of formula (VIII):

wherein Aik¹ represents C_1-6 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-dimethylaminopropyl)-/V^,-ethylcarbodiimide hydrochloride (EDC.HC1) and O- (benzotriazol- 1 -ylJ-V^A^/VV/V-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 C_1-6 alkanol such as methanol.

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

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

wherein R^p is as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (VII); and

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

In the alternative, the intermediates of formula (ΙΠ) above may be prepared by a procedure which comprises the following steps:

(i) reacting a compound of formula (X) with the compound of formula (XI):

wherein A, E, Y and Z are as defined above, and R^q represents a W-protecting group; to provide a compound of formula (ΧΠ):

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

(ii) removal of the tert-butylsulfinyl group and the W-protecting group R^q from compound (XII).

The W-protecting group R^q will suitably be 2-(trimethylsilyl)ethoxymethyl.

Step (i) is suitably effected by treatment of compound (X) with a base, e.g. an organic base such as w-butyllithium, followed by reaction with compound (XI). The reaction is conveniently accomplished in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

Where the W-protecting group R^q is 2-(trimethylsilyl)ethoxymethyl, removal of the tert-butylsulfinyl group and the W-protecting group R^q from compound (ΧΠ) in step (ii) may both be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

Where the W-protecting group R^q is 2-(trimethylsilyl)ethoxymethyl, the intermediates of formula (X) 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 an organic amine such as N,N-diisopropylethylamine.

The intermediate of formula (XI) above may be prepared by reacting 4,4- difluorocyclohexyl carboxaldehyde with 2-methyl-2-propanesulfinamide. The reaction is suitably effected in the presence of pyridinium /7-toluenesulfonate and magnesium sulfate.

The reaction is conveniently carried out at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

In another procedure, the compounds of formula (I) wherein Z represents a group of formula (Zs) as defined above, in which R^2z is hydrogen, may be prepared by a process which comprises reacting a compound of formula R^lz-NI½ and a trialkyl orthoformate HCCO-Alk¹^ with a compound of formula (XIII):

wherein A, E, Y, R⁶, R^lz and Aik¹ are as defined above.

The reaction is conveniently performed at an elevated temperature in the presence of acetic acid. The reaction may typically be carried out in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane.

The intermediates of formula (XIII) above may be prepared by reacting a compound of formula (XIV):

wherein A, E, Y, R⁶ and Aik¹ are as defined above; with hydrazine hydrate.

The reaction is conveniently performed at an elevated temperature in a suitable solvent, e.g. a C_1-6 alkanol such as ethanol.

The intermediates of formula (XTV) above may be prepared by reacting a carboxylic acid of formula R⁶-C02H with compound of formula (XV):

wherein A, E, Y, R⁶ and Aik¹ are as defined above; under conditions analogous to those described above for the reaction between compound (ΠΙ) and a carboxylic acid of formula R⁶-C02H. The intermediates of formula (XV) above may be prepared by removal of the N- protecting group R^p from a compound of formula (XVI):

wherein A, E, Y, R^p and Aik¹ are as defined above; under conditions analogous to those described above for removal of the N-protecting group R^p from a compound of formula

(IV).

The intermediates of formula (XVI) above may be prepared by a two-step 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, Y and Aik¹ are as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (VII); and (ii) cyclisation of the resulting material under conditions analogous to those described above for the cyclisation of compound (VA) or (VB).

The intermediates of formula (TV) above wherein Z represents a group of formula (Zt) as defined above may be prepared by a three-step procedure which comprises the following steps:

(i) saponification of a compound of formula (XVI) as defined above by treatment with a base;

(ii) reaction of the carboxylic acid derivative thereby obtained with a compound of formula (XVIII):

wherein R^2z is as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (VII); and

(iii) cyclisation of the resulting material by treatment with triphenylphosphine in the presence of a base.

Similarly, the compounds of formula (I) above wherein Z represents a group of formula (Zt) as defined above may be prepared by a three-step procedure which comprises the following steps:

(i) saponification of a compound of formula (XTV) as defined above by treatment with a base;

(ii) reaction of the carboxylic acid derivative thereby obtained with a compound of formula (XVIII) as defined above, under conditions analogous to those described above for the reaction between compounds (VI) and (VII); and

The saponification reaction in step (i) will generally be effected by treatment with a base. Suitable bases include inorganic hydroxides, e.g. an alkali metal hydroxide such as lithium hydroxide. Suitable bases of use in step (iii) include organic amines, e.g. a trialkylamine such as triethylamine. The reaction is conveniently performed at ambient temperature in the presence of hexachloroethane and a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.

In a variant of the above procedure, the compounds of formula (I) above wherein Z represents a group of formula (Zaa) as defined above may be prepared by a three-step procedure which comprises the following steps:

(i) saponification of a compound of formula (XTV) as defined above by treatment with a base, under conditions analogous to those described above;

(ii) reaction of the carboxylic acid derivative thereby obtained with a compound of formula (XVIIIA):

(iii) cyclisation of the resulting material by treatment with triphenylphosphine in the presence of a base, under conditions analogous to those described above.

In another procedure, the compounds of formula (I) wherein Z represents a group of formula (Zu) or (Zv) as defined above, in which R^lz is other than hydrogen, may be prepared by a three-step procedure which comprises the following steps:

(i) reacting an alkali metal azide with a compound of formula (XIX):

wherein A, E, Y, R⁶ and R^q are as defined above;

(ii) reacting the resulting material with a compound of formula R^lz-L³, wherein R^lz is as defined above (and is other than hydrogen), and L³ represents a suitable leaving group; and

(iii) removal of the V-protecting group R^q from the resulting material; imder conditions analogous to those described above for the removal of the /V-protecting group R^q from compound (XII).

In step (i), the alkali metal azide is suitably sodium azide. The reaction is conveniently performed at an elevated temperature in the presence of ammonium chloride and a suitable solvent, e.g. a dipolar aprotic solvent such as ^M-dimethylformamide.

The leaving group L³ may suitably be a sulfonyloxy derivative, e.g. trifluoro- methanesulfonyloxy.

Step (ii) will generally be accomplished in the presence of a base. Suitable bases include alkali metal carbonates, e.g. potassium carbonate. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a carbonyl-containing solvent such as acetone.

Where the V-protecting group R^q is 2-(trimethylsilyl)ethoxymethyl, the intermediates of formula (XIX) above may be prepared by a three-step procedure which comprises the following steps:

(i) reacting a compound of formula (XIV) as defined above with 2-(trimethyl- silyl)ethoxymethyl chloride;

(ii) reacting the resulting material with ammonia; and (iii) reacting the material thereby obtained with trifluoroacetic anhydride in the presence of pyridine.

Step (i) is suitably effected by treating the reactants with a base, e.g. an inorganic base such as sodium hydride, or an organic amine such as Af/V-diisopropylethylamine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as Af/V-dimethylformamide.

Step (ii) is conveniently performed at an elevated temperature in a suitable solvent, e.g. a C_1-6 alkanol such as methanol.

Step (iii) is conveniently carried out at ambient temperature in a suitable solvent, e.g. a cyclic ether such as 1,4-dioxane.

The intermediates of formula (TV) above wherein Z represents a group of formula (Zp) as defined above, in which R^2z is hydrogen, may be prepared by reacting an azide derivative of formula R^lz-N3 with a compound of formula (XX):

wherein A, E, Y, R^lz and R^p are as defined above; in the presence of a transition metal catalyst.

Suitable transition metal catalysts of use in the above reaction include chloro- (pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(n).

The reaction is conveniently carried out at an elevated temperature in a suitable solvent or mixture of solvents. Typical solvents include alkyl ethers, e.g. tert-butyl methyl ether, or 1 ,2-dimethoxy ethane; and cyclic ethers, e.g. tetrahydrofuran.

The intermediates of formula (XX) above may be prepared by reacting a compound of formula (XXI):

wherein A, E, Y and R^p are as defined above; with dimethyl (l-diazo-2-oxopropyl)- phosphonate.

The reaction is generally performed in the presence of a base. Suitably, the base may be an alkali metal carbonate, e.g. potassium carbonate. The reaction is conveniently effected at ambient temperature in a suitable solvent or mixture of solvents. Typical solvents include C_1-6 alkanols, e.g. methanol; and chlorinated solvents, e.g. dichloro- methane.

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

(i) removal of the 0-protecting group R^s from a compound of formula (ΧΧΠ):

wherein A, E, Y and R^p are as defined above, and R^s represents an O-protecting group; and

(ii) treatment of the compound thereby obtained with an oxidising agent.

The 0-protecting group R^s will suitably be acetyl.

Where R^s represents acetyl, the removal thereof in step (i) above may conveniently be effected by treatment with a base. Suitably, the base may be an alkali metal carbonate, e.g. potassium carbonate. The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a C_1-6 alkanol such as methanol.

Suitable oxidising agents of use in step (ii) above include l,l,l-tris(acetyloxy)- 1 , 1 -dihydro- 1 ,2-benziodoxol-3 -(l//)-one (Dess-Martin periodinane). The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

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

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

wherein A, E, Y and R^s are as defined above; under conditions analogous to those described above for the reaction between compounds (VI) and (VII); and

In an alternative method, the intermediates of formula (XXI) above may be prepared by a two-step procedure which comprises the following steps:

(i) reduction of the -CChAlk¹ group in a compound of formula (XVI) as defined above; and

(ii) treatment of the compound thereby obtained with an oxidising agent. Reduction of the ester group -CChAlk¹ in step (i) is conveniently effected by treating compound (XVI) with a conventional reducing agent. Suitable reducing agents include lithium borohydride and diisobutylaluminium hydride.

Suitable oxidising agents of use in step (ii) above include l,l,l-tris(acetyloxy)- l,l-dihydro-l,2-benziodoxol-3-(l//)-one (Dess-Martin periodinane). The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane.

Where they are not commercially available, the starting materials of formula (VI), (VIII), (IX), (XVII), (XVni), (XVIIIA) and (XXIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.

It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound comprising a N-BOC moiety (wherein BOC is an abbreviation for tert-butoxy- carbonyl) may be converted into the corresponding compound comprising a N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.

A compound comprising a N-H functionality may be alkylated, e.g. methylated, by treatment with a suitable alkyl halide, e.g. iodomethane, typically in the presence of a base, e.g. an inorganic carbonate such as sodium carbonate.

A compound comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl halide, e.g. acetyl chloride, typically in the presence of a base, e.g. an organic base such as N,N-diisopropylethylamine or triethylamine. Similarly, a compound comprising a N-H functionality may be acylated, e.g. acetylated, by treatment with a suitable acyl anhydride, e.g. acetic anhydride, typically in the presence of a base, e.g. an organic base such as triethylamine.

Simlarly, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a N-S(0)2Alk¹ functionality (wherein Aik¹ is as defined above) by treatment with the appropriate C_1-6 alkylsulfonyl chloride reagent, e.g. methylsulfonyl chloride, typically in the presence of a base, e.g. an organic base such as triethylamine. Simlarly, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a carbamate or urea moiety respectively by treatment with the appropriate chloroformate or carbamoyl chloride reagent, typically in the presence of a base, e.g. an organic base such as triethylamine. Alternatively, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety by treatment with the appropriate amine-substituted (3 -methylimidazol-3 -ium- 1 -yl)methanone iodide derivative, typically in the presence of a base, e.g. an organic base such as triethylamine. Alternatively, a compound comprising a N-H functionality may be converted into the corresponding compound comprising a urea moiety N-C(0)N(H)Alk¹ (wherein Aik¹ is as defined above) by treatment with the appropriate isocyanate derivative Alk^NK^K), typically in the presence of a base, e.g. an organic base such as triethylamine.

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

A compound comprising a C_1-6 alkoxycarbonyl moiety -CChAlk¹ (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 tert-butoxy- carbonyl moiety may be converted into the corresponding compound comprising a carboxylic acid (-CO2H) moiety by treatment with trifluoroacetic acid.

A compound comprising a carboxylic acid (-CO2H) moiety may be converted into the corresponding compound comprising an amide moiety by treatment with the appropriate amine, under conditions analogous to those described above for the reaction between compound (ΙΠ) and a carboxylic acid of formula R⁶-C02H.

A compound comprising a C_1-6 alkoxycarbonyl moiety -CChAlk¹ (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 C_1-6 alkylcarbonyloxy moiety -OC^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 [1,1 '-bis(diphenylphosphino)fenOcene]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)fenOcene]- dichloropalladium(n), and potassium acetate. Step (ii) is conveniently effected in the presence of a transition metal catalyst such as [l,l'-bis(diphenylphosphino)fenOcene]- dichloropalladium(n), 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 -ami noethyl moiety by a two-step process which comprises: (i) reaction with methylmagnesium chloride, ideally in the presence of titanium(TV) isopropoxide; and (ii) treatment of the resulting material with a reducing agent such as sodium borohydride. If an excess of methylmagnesium chloride is employed in step (i), the corresponding compound comprising a 1 -amino- 1 -methylethyl moiety may be obtained.

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 at least one C=C double bond may be converted into the corresponding compound comprising at least one 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 A-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 IL-17 induced IL-6 release from human dermal fibroblasts. Indeed, when tested in the HDF cell line assay described below, compounds of the present invention exhibit an ICso value of 1500 nM or less, generally of 500 nM or less, usually of 100 nM or less, typically of 50 nM or less, suitably of 25 nM or less, ideally of 20 nM or less, and preferably of 15 nM or less (the skilled person will appreciate that a lower ICso figure denotes a more active compound).

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 TNFo, 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 μL per well. The cells were left for a minimum of three hours, at 37°C/5% CO2, to adhere to the plate.

Compounds were serially diluted in DMSO before receiving an aqueous dilution into a 384 well dilution plate (Greiner #781281), where 5 μL from the titration plate was transferred to 45μL 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 μL of the solution was added to a 384 well reagent plate (Greiner #781281).

10μL from the aqueous dilution plate was transferred to the reagent plate containing 30μL 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, 10μL was transferred to the assay plate, to give a 0.5% DMSO solution, then incubated for 18-20 h at 37°C/5% CO2.

From the Cisbio IL-6 FRET kit (Cisbio #62IL6PEB) europium cryptate and Alexa 665 were diluted in reconstitution buffer and mixed 1 : 1, as per kit insert. To a white low volume 384 well plate (Greiner #784075) were added FRET reagents (10 μL), then supernatant (10μL) 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 IC50 values.

The following Examples illustrate the preparation of compounds according to the invention.

EXAMPLES

Tebbe reagent: p-chloro[di(cyclopenta-2,4-dien- 1 -yl)]dimethyl(p-methylene)titanium- aluminium

HATU: l-[bis(dimethylamino)methylene]-l/f-l,2,3-triazolo[4,5-6]pyridinium 3-oxid hexafluorophosphate XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0) h: hour r.t: room temperature M: mass RT: retention time

HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry SFC: Supercritical Fluid Chromatography

Analytical Conditions

LCMS methods Method 1

X-Bridge CIS 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:

Method 2

X-Bridge CIS 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:

Method 3

Phenomenex Kinetix-XB C18 Part No. 00D-4498-AN (2.1 x 100 mm, 1.7 pm column) Column Temperature: 40°C

Mobile Phase A: water + 0.1% formic acid

Mobile Phase B: acetonitrile + 0.1% formic acid

Flow rate: 0.6 mL/minute

Gradient program:

Method 4

Gemini NX-C18 (2.1 x 20 mm, 3 pm column)

Column Temperature: 40°C 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: 1.0 mL/minute

Gradient program:

Method 5

Acquity UPLC BEH C18 (2.1 x 50 mm, 1.7 pm column)

Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution

Flow rate: 1.5 mL/minute

Gradient program:

Method 6

Phenomenex Gemini NX-C18 (2 x 20 mm, 3 pm column)

Column Temperature: 40°C

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:

Method 7

Waters UPLC® BEH™ C18, Part No. 186002352, 2.1 x 100 mm, 1.7 pm Column Temperature: 40°C Mobile Phase A: 2 mM ammonium bicarbonate, buffered to pH 10

Mobile Phase B: acetonitrile Flow rate: 0.6 mL/minute

Gradient program:

Method 8

Kinetex Core-Shell CIS, Part No. 00B-4601-AN, 2.1 x 50 mm, 5 pm Column Temperature: 40°C Mobile Phase A: water + 0.1% formic acid

Mobile Phase B: acetonitrile + 0.1% formic acid Injection volume: 3μL

Detection signal : UV 215

PDA spectrum: range: 210-420 nm; step: 1 nm

Flow rate: 1.2 mL/minute

Gradient program:

Method 9

Waters UPLC® BEH™ CIS, 2.1 x 50 mm, 1.7 pm Column Temperature: 40°C Mobile Phase A: water + 0.1% formic acid Mobile Phase B: acetonitrile + 0.1% formic acid

Injection volume: 1 μL

Detection signal : UV 215

PDA spectrum: range: 200-400 nm; step: 1 nm Flow rate: 0.9 mL/minute

Gradient program:

Separation Method 1

Chiralpak AD-H (4.6 x 250 mm, 5 pm column) Column Temperature: 40°C Flow rate: 1.0 mL/minute

Mobile phase: 90:10 heptane:ethanol

Separation Method 2

Waters Xbridge Prep C18 (30 x 150 mm, 10 pm column)

Column Temperature: 40°C

Mobile Phase A: 10 mM ammonium bicarbonate in water + 0.1% ammonia solution Mobile Phase B: acetonitrile + 5% water + 0.1% ammonia solution

Flow rate: 40.0 mL/minute

Gradient program:

Separation Method 3 Waters Sunfire C18 (30 x 100 mm, 10 pm column) Column Temperature: room temperature Mobile Phase A: water + 0.1% formic acid

Mobile Phase B: acetonitrile + 0.1% formic acid Flow rate: 40.0 mL/minute

Chiral cel OD-H (4.6 x 250 mm, 5 pm column)

Mobile Phase: 85:15 heptane:ethanol

Flow rate: 18.0 mL/minute

INTERMEDIATE 1

tert-Butyl 2-bromoacetate (45.0 mL, 0.31 mol) was added dropwise over 1 h to a slurry of activated zinc (30.2 g, 0.46 mol) in THF (400 mL) at 60°C. An exotherm was observed. The reaction mixture was stirred at 65°C for 1 h, then allowed to cool to room temperature, with settling of the excess zinc. Conversion was assumed to be 100%, and the resulting yellow solution was assumed to be a 0.77M solution in THF.

INTERMEDIATE 2

To a stirred solution of

-tetrabenzyM-bromo-S-fluorobenzene- 1,2- diamine (5.0 g, 8.84 mmol), XPhos (253 mg, 0.53 mmol) and bis[chloro(prop-2-en-l-yl)- palladium] (97 mg, 0.265 mmol) in THF (50 mL) under nitrogen was added Intermediate 1 in THF (0.7M, 25 mL, 17.7 mmol). The mixture was stirred at 50°C for 1.5 h, then cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (2 x 25 mL). The organic layers were combined, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 10-60% DCM in heptanes, to afford the title compound (5.1 g, 91%) as an off-white solid. δH (400 MHz, CDCb) 7.25-7.16 (m, 16H), 7.09-7.01 (m, 4H), 6.81 (t, 78.2 Hz, 1H), 6.51 (dd, 78.3, 1.0 Hz, 1H), 4.37 (s, 4H), 4.24 (s, 4H), 3.46 (d, J 1.3 Hz, 2H), 1.46 (s, 9H). LCMS (Method 1): [M+H]⁺ m/z 601, RT 2.64 minutes.

INTERMEDIATE 3

To a stirred solution of Intermediate 2 (2.07 g, 3.45 mmol) in THF (18 mL) at room temperature was added LiHMDS solution in THF (1M, 4.1 mL, 4.13 mmol) under a nitrogen atmosphere. The suspension was stirred at room temperature for 2 minutes, then a solution of iodomethane (236 μL, 3.79 mmol) in THF (2 mL) was added. The reaction mixture was stirred for 4 h at room temperature, then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x 30 mL). The combined organic fractions were washed with 0.5M hydrochloric acid (10 mL) and brine (15 mL), then dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 5-20% ethyl acetate in heptanes, to afford the title compound (1.79 g, 80%) as a yellow gum. δH (400 MHz, DMSO-de) 7.25- 7.14 (m, 12H), 7.14-7.03 (m, 8H), 6.79 (t, 78.3 Hz, 1H), 6.61 (d, 78.5 Hz, 1H), 4.28 (s,

4H), 4.23 (s, 4H), 3.63 (q, 77.2 Hz, 1H), 1.33 (s, 9H), 1.22 (d, 77.2 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 615, RT 2.68 minutes.

INTERMEDIATE 4

To a stirred solution of Intermediate 3 (1.69 g, 2.47 mmol) in THF (17 mL) was added lithium aluminium hydride in THF (2.4M, 2.6 mL, 6.19 mmol) drop wise at -5°C. The mixture was stirred at room temperature for 2 h. Water (2.5 mL) was added, then 15% aqueous sodium hydroxide solution (2.5 mL), followed by water (5 mL). The mixture was dried over magnesium sulfate, then concentrated, to give the title compound (1.45 g, 96%) as a pale yellow oil. δH (400 MHz, DMSO-de) 7.26-7.06 (m, 20H), 6.80 (t, J 8.2 Hz, 1H), 6.65 (d, 78.4 Hz, 1H), 4.61 (t, J5.4 Hz, 1H), 4.28 (s, 4H), 4.23 (s, 4H), 3.47-3.39 (m, 1H), 3.30-3.22 (m, 1H), 2.91-2.81 (m, 1H), 1.08 (d, 76.9 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 545, RT 2.34 minutes.

INTERMEDIATE 5

2-r3.4-Bis(dibenzvlaminoV2-fluorophenvl1propanal

To a stirred solution of Intermediate 4 (1.35 g, 2.21 mmol) in DCM (24 mL) was added Dess-Martin periodinane (1.12 g, 2.65 mmol). The mixture was stirred at room temperature for 2 h, then quenched with aqueous potassium iodide: sodium thiosulphate: sodium bicarbonate solution (2:2: 1) (20 mL). The organic layer was separated. The aqueous layer was extracted with DCM (15 mL). The organic fractions were combined, passed through a phase separator and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-20% ethyl acetate in heptanes, to afford the title compound (1.23 g, 95%) as a yellow oil. δH (500 MHz, DMSO-de) 9.44 (d, J 1.7 Hz, 1H), 7.27-7.13 (m, 16H), 7.09-7.04 (m, 4H), 6.80 (t, 78.2 Hz, 1H), 6.73 (d, J

8.5 Hz, 1H), 4.29 (s, 8H), 3.65 (q, 77.1 Hz, 1H), 1.18 (d, 77.1 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 543, RT 2.44 minutes.

INTERMEDIATE 6 Tetrabenzvl-S -fluoro-4-( 1 -methvlDroD-2-vnvnbenzene- 1.2-diamine

To a stirred suspension of Intermediate 5 (550 mg, 0.93 mmol) in methanol (14 mL) at 0°C was added a solution of dimethyl (l-diazo-2-oxopropyl)phosphonate (358 mg, 1.86 mmol) in methanol (2 mL), followed by potassium carbonate (322 mg, 2.33 mmol). The mixture was stirred at 0°C for 10 minutes, then at room temperature for 3 h. The mixture was concentrated, then diluted with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic fractions were washed with brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-3% ethyl acetate in heptanes, to afford the title compound (437 mg, 78%) as a colourless gum. δH (500 MHz, DMSO-de) 7.26-7.15 (m, 12H), 7.15-7.06 (m, 8H), 7.00 (t, 78.4 Hz, 1H), 6.69 (d, 78.4 Hz, 1H), 4.38-4.19 (m, 8H), 3.80-3.73 (m, 1H), 3.10 (d, J2.5 Hz, 1H), 1.24 (t, J 6.8 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 539, RT 2.52 minutes. INTERMEDIATE 7

A suspension of 2-azido- 1,1,1 -trifluoroethane (0.5M, 2.6 mL, 1.28 mmol), copper(II) sulfate pentahydrate (16 mg, 0.064 mmol), sodium L-ascorbate (25 mg, 0.13 mmol) and Intermediate 6 (230 mg, 0.43 mmol) in water (3 mL) and tert-butanol (15 mL) was stirred at room temperature for 2 h, then at 45°C for 2 h. The reaction mixture was heated for a further 38 h at 45°C, during which time additional portions of copper(II) sulfate pentahydrate (48 mg), sodium L-ascorbate (75 mg) and 2-azido- 1,1,1 -trifluoroethane (0.5M, 5.6 mL) were added in five batches. The mixture was concentrated, diluted with water (10 mL) and extracted with ethyl acetate (20 mL). The combined organic fractions were washed with brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-

30% ethyl acetate in heptanes, to afford the title compound (182 mg, 59%) as a colourless gum. δH (400 MHz, CDCb) 7.25-7.20 (m, 6H), 7.20-7.12 (m, 11H), 7.12-7.07 (m, 4H), 6.79 (t, 78.3 Hz, 1H), 6.58 (d, 78.4 Hz, 1H), 4.92 (q, 78.3 Hz, 2H), 4.43-4.32 (m, 5H), 4.28 (s, 4H), 1.63 (d, 77.2 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 664, RT 2.39 minutes.

INTERMEDIATE 8

Palladium on charcoal (50% wet with water, 5.0% w/w loading, 39 mg) was added to a stirred solution of Intermediate 7 (160 mg, 0.22 mmol) and hydrochloric acid (2M, 0.25 mL, 0.5 mmol) in ethanol (4 mL). The reaction mixture was purged and stirred under a hydrogen atmosphere at room temperature for 2 h. The reaction mixture was adjusted to pH 9 using saturated aqueous sodium carbonate solution, then filtered. The organic layer was separated and washed with brine (10 mL), then dried over sodium sulfate and concentrated. The residue was diluted with DCM (10 mL) and washed with water (10 mL). The aqueous fractions were combined, then extracted with DCM (2 x 10 mL). The combined organic layers were dried over sodium sulfate, then concentrated, to give the title compound (65 mg, 96%) as a pale brown oil. δH (400 MHz, DMSO-de) 7.82 (s, 1H), 6.29 (d, JSA Hz, 1H), 6.22 (t, J 8.0 Hz, 1H), 5.41 (q, J92 Hz, 2H), 4.65 (s, 2H), 4.36-4.25 (m, 3H), 1.51 (d, 77.2 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 304, RT 1.39 minutes.

INTERMEDIATE 9

hydrochloride (1.61 g, 6.66 mmol) and triethylamine (3.25 mL, 23.3 mmol) in DCM

(26.6 mL) at 0°C was added A-(benzyloxycarbonyloxy)succinimide (1.61 g, 6.33 mmol). The reaction mixture was warmed to room temperature and stirred for 4 h, then diluted with dichloromethane (25 mL) and washed with 5% hydrochloric acid (50 mL) and water (50 mL). The organic extracts were combined, passed through a phase separator and concentrated. Trituration with hexane (50 mL) afforded the title compound (1.99 g, 91%) as a white solid, δH (300 MHz, DMSO-de) 12.70 (s, 1H), 7.09 (d, J8.7 Hz, 1H), 7.43- 7.26 (m, 5H), 5.04 (s, 2H), 4.00 (dd, 78.7, 6.0 Hz, 1H), 2.12-1.55 (m, 7H), 1.52-1.19 (m,

2H).

INTERMEDIATE 10

HATU (98 mg, 0.26 mmol) was added to a stirred solution of Intermediate 9 (74 mg, 0.23 mmol), Intermediate 8 (65 mg, 0.21 mmol) and DIPEA (75 μL, 0.43 mmol) in DCM (2 mL) at room temperature. The suspension was stirred at room temperature for 16 h. The reaction mixture was washed with water (5 mL), and the aqueous fraction was extracted with ethyl acetate (5 mL). The organic fractions were combined, passed through a phase separator and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 45-60% ethyl acetate in heptanes, to afford the title compound (124 mg, 94%) as a beige solid. LCMS (Method 1): [M+H]⁺ m/z 613, RT 1.93 minutes. INTERMEDIATE 11

Intermediate 10 (124 mg, 0.20 mmol) was stirred in acetic acid (2 mL) at 60°C for 4 h, then at 50°C for 16 h. The solution was concentrated to afford the title compound (128 mg, 100%) as a brown solid. LCMS (Method 2): [M+H]⁺ m/z 595, RT 3.04 minutes.

INTERMEDIATE 12

To a stirred solution of Intermediate 11 (120 mg, 0.20 mmol) in ethanol (3 mL) was added palladium on charcoal (50% wet with water, 5.0% w/w loading, 21 mg). The reaction mixture was purged, and stirred under a hydrogen atmosphere at r.t. for 4 h. The mixture was retreated with palladium on charcoal (50% wet with water, 5.0% w/w loading, 21 mg) and stirred at r.t. under hydrogen for 16 h. The reaction mixture was filtered through a pad of Celite®, then concentrated, to give the title compound (89 mg, 81%) as a colourless solid. LCMS (Method 1): [M+H]⁺ m/z 461, RT 1.55 minutes.

INTERMEDIATE 13

To a stirred suspension of l-bromo-2,3-difluoro-4-nitrobenzene (23.0 g, 96.6 mmol) and potassium carbonate (16.0 g, 116 mmol) in acetonitrile (250 mL) was added TV-benzyl- 1-phenylmethanamine (20.0 mL, 106 mmol). The suspension was stirred at 80°C for 16 h, then re-treated with TV-benzyl- 1 -phenylmethanamine (2.0 mL, 10.4 mmol) and stirred at 80°C for 1 h. The mixture was filtered, then concentrated. The residue was purified by flash column chromatography, eluting with a gradient of ethyl acetate in heptanes, to afford the title compound (40.9 g, 85%) as an orange solid, δH (400 MHz, DMSO-de) 7.64 (dd, 78.8, 6.5 Hz, 1H), 7.54 (dd, 78.8, 1.6 Hz, 1H), 7.33-7.18 (m, 10H), 4.15 (s, 4H). LCMS (Method 1) [M+H]⁺ m/z 415, 417, RT 2.25 minutes. INTERMEDIATE 14

A mixture of Intermediate 13 (7.00 g, 16.2 mmol), XPhos (2.31 g, 4.85 mmol) and Pd2(dba)3 (2.22 g, 2.43 mmol) in dry THF (150 mL) was degassed under nitrogen for 2 minutes at room temperature. A solution of bromo(2-tert-butoxy- 1 -methyl-2-oxoethyl)- zinc in THF (0.5M, 97 mL, 48.5 mmol) was added. The reaction mixture was stirred at 50°C for 1 h, then cooled to room temperature, quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (3 x 30 mL). The organic fractions were combined, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-10% ethyl acetate in heptanes, followed by acidic reverse phase column chromatography, eluting with a gradient of 70-85% acetonitrile in water (with 0.1% formic acid), to afford the title compound (7.24 g, 96%) as an orange oil. δH (500 MHz, CDCh) 7.31 (dd, 78.5, 1.5 Hz, 1H), 7.28-7.25 (m, 8H), 7.25-7.20 (m, 2H), 7.07 (dd, 78.5, 6.7 Hz, 1H), 4.22-4.17

(m, 4H), 3.89 (q, 77.2 Hz, 1H), 1.45-1.39 (m, 12H). LCMS (Method 1): [M+H]⁺ m/z 465, RT 2.32 minutes.

INTERMEDIATE 15

Intermediate 14 (7.20 g, 15.5 mmol) was stirred in DCM (30 mL) and TFA (30 mL) for 18 h. The reaction mixture was concentrated in vacuo to afford the title compound (12.4 g, 100% at 51% purity) as a brown oil. δH (400 MHz, CD3OD) 7.32 (dd, 78.5, 1.5 Hz, 1H), 7.28-7.15 (m, 11H), 4.16 (d, J 1.2 Hz, 4H), 3.95 (q, 77.2 Hz, 1H),

1.44 (d, 77.3 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 409, RT 2.04 minutes.

INTERMEDIATE 16

HATU (1.10 g, 2.8 mmol) was added to a solution of hydrazine in THF (1M, 4.9 mL, 4.9 mmol), Intermediate 15 (1.00 g, 2.4 mmol) and triethylamine (0.51 mL, 3.7 mmol) in DCM (24 mL). The mixture was stirred at room temperature for 15 minutes, then DCM (24 mL) was added. The mixture was stirred at room temperature for 18 h, then washed with water (20 mL). The organic fractions were combined, passed through a phase separator and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexane, to afford the title compound (727 mg, 70%) as an orange solid. LCMS (Method 4): [M+H]⁺ m/z 423, RT 1.39 minutes.

INTERMEDIATE 17

A solution of Intermediate 16 (200 mg, 0.474 mmol), 2,2,2-trifluoroethylamine hydrochloride (131 mg, 0.947 mmol), trimethyl orthoformate (0.08 mL, 0.70 mmol) and acetic acid (0.5 mL, 9.0 mmol) in 1,4-dioxane (5 mL) was heated at 80°C under nitrogen for 1 h, then at 130°C for 1 h. 2,2,2-Trifluoroethylamine hydrochloride (196 mg, 1.42 mmol) was added and the mixture was heated at 130°C for 2 h, then cooled to room temperature. The mixture was concentrated and purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexane, to afford the title compound (59 mg, 17%) as a yellow oil. LCMS (Method 4): [M+H]⁺ m/z 514, RT 1.53 minutes.

INTERMEDIATE 18

Palladium on charcoal (10% w/w, 40 mg) was added to a stirred solution of Intermediate 17 (60 mg, 0.082 mmol) in ethanol (3 mL). The reaction mixture was purged and stirred vigorously under a hydrogen atmosphere at room temperature for 18 h. Palladium on charcoal (10% w/w, 40 mg) was added, and the mixture was stirred for an additional hour. The reaction mixture was filtered through a pad of Celite®, washed with ethanol (2x 10 mL) and concentrated. The crude material was re-dissolved in methanol, loaded onto an SCX cartridge and flushed with methanol, followed by 4M ammonia in methanol. The eluent was concentrated to afford the title compound (30.0 mg, 72%, 60% purity). LCMS (Method 4): [M+H]⁺ m/z 304, RT 0.81 minutes. INTERMEDIATE 19

To a stirred solution of (2S)-2-amino-2-(4,4-difluorocyclohexyl)acetic acid hydrochloride (2.0 g, 8.71 mmol) in DCM (10 mL) were added triethylamine (4.3 mL, 30.5 mmol) and.N-(tert-butoxycarbonyloxy)succinimide (1.72 g, 7.83 mmol). The resulting mixture was stirred at room temperature for 24 h, then diluted with DCM (200 mL), 5% hydrochloric acid (2 x 100 mL) and water (100 mL). The organic extracts were combined, passed through a phase separator and concentrated. Trituration with hexane (100 mL) afforded the title compound (2.0 g, 78%) as a white solid, δH (300 MHz, DMSO-de) 12.60 (s, 1H), 7.09 (d, 78.7 Hz, 1H), 3.91 (dd, 78.5, 6.2 Hz, 1H), 2.08-1.92 (m, 2H), 1.92-1.54 (m, 5H), 1.51-1.16 (m, 11H).

INTERMEDIATE 20

Intermediate 19 (35 mg, 0.12 mmol) and Intermediate 18 (30 mg, 0.10 mmol) were dissolved in DCM (3 mL), then DIPEA (0.026 mL, 0.15 mmol) and HATU (51 mg, 0.13 mmol) were added. The mixture was stirred at room temperature for 1 h, then extracted with ethyl acetate (2 x 10 mL) and washed with brine (10 mL). The organic fractions were combined, passed through a phase separator and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexanes, then 0-10% methanol in DCM, to afford the title compound (37 mg, 49%) as a yellow oil. LCMS (Method 4): [M+H]⁺ m/z 579, RT 1.80 minutes.

INTERMEDIATE 21 0

To a stirred solution of Intermediate 20 (37.0 mg, 0.064 mmol) in DCM (1.3 mL) at 40°C was added TFA (0.015 mL, 0.19 mmol). The mixture was stirred for 16 h under nitrogen. TFA (1 mL) was added, and the mixture was stirred at room temperature for 1 h. The crude material was re-dissolved in methanol, loaded onto an SCX cartridge and flushed with methanol, followed by 4M ammonia in methanol. The eluent was concentrated to afford the title compound (37.0 mg, 89%). LCMS (Method 4): [M+H]⁺ m/z 461, RT 1.23 minutes.

INTERMEDIATE 22

Methyl 2-Γ3 -( dibenzvlaminoV2-fluoro-4-nitroDhenvl1acetate

To a solution of Intermediate 68 (15.0 g, 42.3 mmol) and dimethyl malonate (7.4 mL, 63 mmol) in DMF (85 mL) was added potassium carbonate (14.6 g, 106 mmol). The mixture was heated at 60°C for 24 h, then diluted with tert-butyl methyl ether (450 mL) and water (300 mL). The pH was adjusted to ~7 with 10% aqueous hydrochloric acid. The organic layer was washed with water (2 x 300 mL), then separated and concentrated. The residue was dissolved in a mixture ofDMSO (170 mL) and water (17 mL). Lithium chloride (5.4 g, 130 mmol) was added to the solution, and the mixture was heated at 115°C for20 h. Water (400 mL) was added to the mixture. The resulting yellow suspension was extracted with tert-butyl methyl ether (2 x 300 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), then dried over sodium sulfate and concentrated. The residue was recrystallised from tert-butyl methyl ether and isohexane to give the title compound (11.26 g, 65%). LCMS (Method 5): [M+H]⁺ m/z 409, RT 2.95 minutes.

INTERMEDIATE 23

2-Γ3 -(DibenzvlaminoV2-fluoro-4-nitro_Dhenvl1acetohvdrazi de

To a suspension of Intermediate 22 (2.31 g, 5.66 mmol) in methanol (30 mL) was added hydrazine in THF (1M, 30 mL, 30 mmol). The solution was heated at 60°C and stirred for 16 h. Additional hydrazine in THF (1M, 8 mL, 8 mmol) was added. The reaction mixture was concentrated and suspended in DCM (30 mL). The suspension was filtered, and the filter cake was dried, to give the title compound (725 mg, 31%) as a yellow solid. The filtrate was concentrated and purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexanes, to give a second crop of the title compound (525 mg, 23%) as a yellow solid. LCMS (Method 4): [M+H]⁺ m/z 409, RT 1.29 minutes.

INTERMEDIATE 24

To a suspension of Intermediate 23 (725 mg, 1.78 mmol) in methanol (7 mL) was added triethyl orthoformate (390 μL, 3.6 mmol). The mixture was heated at 70°C in a sealed tube for 6 h, then 1,4-dioxane (2 mL) and toluene (2 mL) were added. Another portion of triethyl orthoformate (200 μL, 1.85 mmol) was added. The reaction mixture was heated at 90°C for 5 h, then divided into two equal halves. To one half (the first portion) was added 2,2,2-trifluoroethylamine hydrochloride (600 mg, 4.34 mmol), and the reaction mixture was maintained at 90°C for 12 h. To the other half (the second portion) were added triethyl orthoformate (200 μL, 1.85 mmol) and 2,2,2-trifluoroethylamine hydrochloride (600 mg, 4.34 mmol), and the reaction mixture was maintained at 90°C for 6 h. The two reaction mixtures were combined and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexanes, then 0-20% methanol in ethyl acetate, to give the title compound (270 mg, 24%) as a yellow solid. LCMS (Method 4): [M+H]⁺ m/z 500, RT 1.43 minutes.

INTERMEDIATE 25

To a solution of Intermediate 24 (265 mg, 0.42 mmol) in ethanol (5 mL) was added palladium on charcoal (10% w/w, 80 mg). The reaction mixture was stirred under an atmosphere of hydrogen gas for 16 h. Palladium on charcoal (10% w/w, 80 mg) was added. The reaction mixture was stirred for 4 h, then filtered through Celite®, washed with methanol (50 mL) and concentrated, to give the title compound (158 mg, 100%) as a brown oil. LCMS (Method 4): [M+H]⁺ m/z 290, RT 0.64 minutes. INTERMEDIATE 26

To a suspension of Intermediate 25 (158 mg, 0.55 mmol) in DCM (6 mL) at room temperature were added Intermediate 9 (180 mg, 0.55 mmol), DIPEA (200 μL, 1.15 mmol) and HATU (260 mg, 0.66 mmol). The reaction mixture was stirred for 1 h, then diluted with water (20 mL) and DCM (30 mL). The organic layer was separated. The aqueous layer was re-extracted with DCM (15 mL). The combined organic layers were dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexanes, to give the title compound (300 mg, 92%) as an orange oil. LCMS (Method 4): [M+H]⁺ m/z 599, RT 1.00 minute.

INTERMEDIATE 27

To a solution of Intermediate 26 (300 mg, 0.50 mmol) in DCM (5 mL) was added TFA (100μL, 1.32 mmol). The reaction mixture was heated at 40°C overnight, then concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in hexanes, and 0-20% methanol in ethyl acetate, to give the title compound (142 mg, 46%) as an orange oil. LCMS (Method 4): [M+H]⁺ m/z 581, RT 1.00 minutes.

INTERMEDIATE 28

To a solution of Intermediate 27 (141.7 mg, 0.23 mmol) in ethanol (5 mL) was added palladium on charcoal (10% w/w, 20 mg). The reaction mixture was stirred under an atmosphere of hydrogen gas for 4 h, then filtered through Celite® and washed with ethanol (80 mL). The filtrate was concentrated to give the title compound (103 mg, 91%) as a yellow foam. LCMS (Method 4): [M+H]⁺ m/z 447, RT 0.78 minutes. INTERMEDIATE 29

Ethvl 2-[3 -( dibenzvlaminoV2-fluoro-4-nitrophenvl1propanoate

To a solution of Intermediate 15 (12.4 g, 0.4 mmol) in ethanol (60.7 mL) was added concentrated sulfuric acid (1.57 g, 15.2 mmol). The resulting solution was stirred at 70°C for 18 h, then concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL). The organic fractions were combined, dried over sodium sulfate and concentrated, to afford the title compound (13.1 g, 99%) as an orange oil. δH (400 MHz, DMSO-de) 7.50 (dd,78.4, 1.3 Hz, 1H), 7.32-7.16 (m, 11H), 4.15-4.06 (m, 6H), 4.06-3.96 (m, 1H), 1.35 (d, 77.2 Hz, 3H), 1.13 (t, 77.1 Hz, 3H). LCMS (Method 4): [M+H]⁺ m/z 437, RT 1.38 minutes.

INTERMEDIATE 30

Ethvl 2-( 3 ,4-diamino-2-fluorophenvDpropanoate

To a solution of Intermediate 29 (13.1 g, 30.0 mmol) in ethanol (150 mL) was added palladium on charcoal (10% w/w, 3.2 g). The reaction mixture was purged and stirred vigorously under a hydrogen atmosphere at room temperature for 18 h, then filtered through a pad of Celite® and washed with ethanol. The solvent was removed to afford the title compound (6.31 g, 84%) as a red oil. δH (300 MHz, DMSO-de) 6.33-6.20 (m, 2H), 4.70 (s, 2H), 4.35 (s, 2H), 4.10-3.95 (m, 2H), 3.73 (q, 77.2 Hz, 1H), 1.30 (d, J 7.2 Hz, 3H), 1.12 (t, 77.1 Hz, 3H). LCMS (Method 4): [M+H]⁺ m/z 227, RT 0.91 minutes.

INTERMEDIATE 31

To a solution of Intermediate 30 (6.30 g, 25 mmol) and Intermediate 9 (7.80 g, 24 mmol) in DCM (240 mL) at room temperature were added DIPEA (8.3 mL, 48 mmol) and HATU (11.0 g, 29 mmol). The mixture was stirred at room temperature for 1.5 h, then washed with water (SO mL). The organic fractions were combined, passed through a phase separator and concentrated. The resulting crude pink solid was suspended in DCM (150 mL) and treated with TFA (3.6 mL, 48 mmol). The mixture was stirred at 45°C for 16 h, then washed with water (75 mL) and saturated aqueous sodium bicarbonate solution (2 x 75 mL). The combined aqueous washings were extracted with DCM (100 mL). The organic fractions were combined, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in isohexane, to afford the title compound (11.5 g, 84%) as a pink solid, δH (300 MHz, DMSO-de) 12.93-12.47 (m, 1H), 8.04-7.79 (m, 1H), 7.39-7.24 (m, 6H), 7.11- 7.04 (m, 1H), 5.10-4.94 (m, 2H), 4.71 (t, 78.2 Hz, 1H), 4.16-3.96 (m, 4H), 2.20-1.61 (m,

4H), 1.54-1.27 (m, 5H), 1.27-1.08 (m, 5H). LCMS (Method 4): [M+H]⁺ m/z 518, RT 2.47 minutes.

INTERMEDIATE 32

To a stirred solution of Intermediate 31 (10.0 g, 19.3 mmol) in ethanol (193 mL) was added palladium on charcoal (10% w/w, 1.77 g). The reaction mixture was purged and stirred vigorously under a hydrogen atmosphere at room temperature for 4 h, then filtered through a pad of Celite® and washed with ethanol (100 mL). The solvent was removed to give the title compound (7.06 g, 86%) as a purple oil. δH (300 MHz, DMSO- de) 12.41 (s, 1H), 7.26 (d, 78.3 Hz, 1H), 7.03 (dd, 78.3, 6.6 Hz, 1H), 4.14-3.99 (m, 3H), 3.87 (d, 76.1 Hz, 1H), 2.09-1.46 (m, 7H), 1.42 (d, 77.2 Hz, 3H), 1.38-1.24 (m, 2H), 1.17- 1.07 (m, 3H). Two proton signals not observed. LCMS (Method 4): [M+H]⁺ m/z 384,

RT 0.91 minutes.

INTERMEDIATE 33

To a stirred solution of 2-methylpyrazole-3 -carboxylic acid (1.4 g, 11 mmol) in DMF (42 mL) were added DIPEA (3.8 mL, 42 mmol) and HATU (4.5 g, 11 mmol), followed by a solution of Intermediate 32 (4.0 g, 10 mmol) in DCM (42 mL). The reaction mixture was stirred at room temperature for 16 h, then washed with water (75 mL). The organic layer was separated and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 40-100% ethyl acetate in isohexane, to afford the title compound (6.4 g, 100%). δH (300 MHz, DMSO-de) 12.84

(d, .776.8 Hz, 1H), 8.93 (dd, .731.3, 8.5 Hz, 1H), 7.47 (d, .72.1 Hz, 1H), 7.27 (d, .78.3 Hz, 2H), 7.12-7.02 (m, 2H), 5.13 (t, .78.5 Hz, 1H), 4.17-3.95 (m, 6H), 2.39-2.16 (m, 1H), 2.15-1.48 (m, 6H), 1.42 (d, .77.2 Hz, 3H), 1.38-1.21 (m, 1H), 1.17 (t, J7.1 Hz, 3H). LCMS (Method 4): [M+H]⁺ m/z 492, RT 1.23 minutes.

INTERMEDIATE 34

To a stirred solution of Intermediate 33 (0.5 g, 0.8 mmol) in ethanol (2.4 mL) was added hydrazine hydrate (1.0 mL, 10 mmol). The mixture was stirred at 70°C for 16 h, then concentrated, to give the title compound (400 mg, 100%). LCMS (Method 4): [M+H]⁺ m/z 478, RT 0.92 minutes.

INTERMEDIATE 35

n-Butyllithium (1.3M, 7.5 mL, 9.8 mmol) was added dropwise to a solution of -tetrabenzy1-4-bromo-3 -fluorobenzene- 1 ,2-diamine (5.0 g, 8.8 mmol) in

tetrahydrofuran (88 mL) at -78°C under nitrogen. After stirring at -78°C for 40 minutes, a solution of DMF (1.4 mL, 18 mmol) in THF (18 mL) was added dropwise over 5 minutes. After stirring for a further 5 minutes, the mixture was quenched with propan-2- ol (5 mL), then allowed to warm to r.t. The mixture was diluted with water (20 mL) and the material was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with brine (3 x 25 mL), then dried (Na2SC>4) and concentrated in vacuo, to give the title compound (4.99 g, 99%) as a pale yellow gum. LCMS (Method 4): [M+H]⁺ m/z 515, RT 1.90 minutes. INTERMEDIATE 36

n-Butyllithium (1.3M, 1.3 mL, 1.7 mmol) was added dropwise to a solution of 1- (cyclopropylmethyl)- 1 //-imidazole (200 mg, 1.6 mmol) in THF (16 mL) at -78°C under nitrogen. After stirring at -78°C for 45 minutes, chlorotriethylsilane (0.53 mL, 3.1 mmol) was added dropwise. After 15 minutes of stirring, the mixture was allowed to warm to r.t, then the solvent was removed in vacuo. The residue was dissolved in THF (16 mL) and cooled to -78°C, then sec-butyllithium (2.4 mL, 3.1 mmol) was added dropwise. The mixture was stirred at -78°C for 30 minutes, then a solution of Intermediate 35 (978 mg,

1.7 mmol) in THF (8 mL) was added dropwise. After 30 minutes, the mixture was warmed to r.t, then the solvents were removed in vacuo. The residue was dissolved in EtOAc (20 mL), then water (20 mL) and cone. HC1 (5 mL) were added. The mixture was stirred vigorously at r.t. for 17 h, then basified with 2M aqueous NaOH solution and extracted with EtOAc (40 mL). The combined organic extracts were washed with brine (30 mL), dried (NaaSCfo) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc in heptanes, to afford the title compound (313 mg, 32%) as a pale yellow gum. LCMS (Method 4): [M+H]⁺ m/z 637, RT 1.77 minutes.

INTERMEDIATE 37

Manganese dioxide (855 mg, 9.8 mmol) was added to a solution of Intermediate 36 (313 mg, 0.49 mmol) in DCM (10 mL). The mixture was stirred at r.t. for 1 h, then filtered through Celite® and concentrated in vacuo, to give the title compound (266 mg, 85%) as a pale yellow solid. LCMS (Method 4): [M+H]⁺ m!z 635, RT 1.87 minutes. INTERMEDIATE 38

Tebbe reagent (1.7 mL, 0.85 mmol) was added to a solution of Intermediate 37 (266 mg, 0.42 mmol) in THF (10 mL) under nitrogen. The mixture was heated at 80°C for 3 h, then allowed to cool to room temperature. The mixture was quenched with saturated aqueous NH4CI solution (10 mL) and diluted with EtOAc (20 mL). The layers were separated. The aqueous layer was further diluted with brine (25 mL) and water (50 mL), and extracted with EtOAc (30 mL). The combined organic extracts were dried (Na2S04) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc in heptanes, then 0-100% EtOAc in MeOH, to give the title compound (236 mg, 89%) as a pale orange solid. LCMS (Method 4): [M+H]⁺ m!z 633, RT 1.92 minutes.

INTERMEDIATE 39

Intermediate 38 (236 mg, 0.37 mmol) was dissolved in ethanol (5 mL), and the solution was placed under N2. Palladium on carbon (198 mg, 0.19 mmol) was added, and the mixture was placed under an atmosphere of H2, then stirred at r.t. for 20 h. Additional palladium on carbon (198 mg, 0.19 mmol) was added. The mixture was stirred for a further 3 h, then filtered through Celite® and concentrated in vacuo, to give the title compound (90 mg, 88%) as a pale orange gum. LCMS (Method 4): [M+H]⁺ m!z 275, RT 0.95 minutes.

INTERMEDIATE 40

Intermediate 9 (129 mg, 0.39 mmol) and Intermediate 39 (90 mg, 0.33 mmol) were dissolved in DMF (6.5 mL), then DIPEA (0.09 mL, 0.5 mmol) and HATU (167 mg, 0.43 mmol) were added. The mixture was stirred at r.t. for 5 h, then diluted with water (20 mL) and brine (10 mL), and extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried (NaaSCfo) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc in heptanes, then 0-100% EtOAc in MeOH, to give the title compound (108 mg, 56%) as a pale orange solid. LCMS (Method 2): [M+H]⁺ m/z 584, RT 1.35 minutes.

INTERMEDIATE 41

Intermediate 40 (108 mg, 0.18 mmol) was dissolved in DCM (2 mL) and treated with TFA (28μL, 0.37 mmol). The reaction mixture was warmed and stirred at 40°C for 5 h, then stirred at room temperature overnight, then stirred for 3 h at 40°C. The mixture was diluted with DCM (2 mL) and toluene (3 mL), then concentrated in vacuo. The residue was stirred in saturated aqueous NaHCCb solution (5 mL) and DCM (5 mL) for 20 minutes. The layers were separated using a phase separator cartridge. The aqueous layer was re-extracted with DCM. The combined organic layers were concentrated in vacuo to yield crude title compound (37 mg) as a brown glass, which was utilised without further purification. LCMS (Method 2): [M+H]⁺ m/z 566, RT 2.37 minutes.

INTERMEDIATE 42

Prepared from Intermediate 41 (37 mg, 0.059 mmol), utilising a procedure analogous to that described for Intermediate 32, to yield the title compound (28 mg), which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m/z 432, RT 1.09 minutes. INTERMEDIATE 43

Intermediate 6 (88% purity, 350 mg, 0.57 mmol), 2-azido- 1,1,1 -trifluoroethane in TBME (0.5M, 1.1 mL, 0.57 mmol) and chloro(l, 2,3,4, 5-pentamethylcyclopenta-2,4-dien- 1 -yl)bis(triphenylphosphine)ruthenium (46 mg, 0.057 mmol) were stirred in THF (3 mL) at 60°C for 2 h, then left to stand at r.t. for 2.5 days. The mixture was retreated with 2- azido- 1,1,1 -trifluoroethane in TBME (0.5M, 0.12 mL, 0.058 mmol) and chloro(l,2,3,4,5- pentamethylcyclopenta-2,4-dien- 1 -yl)bis(triphenylphosphine)ruthenium (5.0 mg, 6.28 pmol), then stirred at 60°C for 30 minutes. The mixture was concentrated, then purified by flash column chromatography, eluting with a gradient of 15-35% EtOAc in heptanes, to afford the title compound (297 mg, 67%, 85% purity) as a dark yellow gum. δH (500 MHz, DMSO-de) 7.71 (s, 1H), 7.30-7.10 (m, 14H), 7.09-7.03 (m, 7H), 6.69-6.58 (m, 2H), 5.38 (dq, J 18.1, 9.1 Hz, 1H), 4.93 (dq, J 17.5, 8.7 Hz, 1H), 4.40-4.21 (m, 8H), 1.44 (d, J

7.1 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 664, RT 2.56 minutes.

INTERMEDIATE 44

Palladium on carbon (50% wet with water, 16.0% w/w loading, 48 mg) was added to a stirred solution of Intermediate 43 (297 mg, 0.45 mmol) in ethanol (3 mL) and 1M HC1 (0.5 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred at r.t. overnight, then filtered and concentrated, to afford the title compound (160 mg, quantitative) as a brown gum. LCMS (Method 1): [M+H]⁺ m/z 304, RT 1.54 minutes.

INTERMEDIATE 45

HATU (205 mg, 0.54 mmol) was added to a stirred solution of Intermediate 9 (154 mg, 0.47 mmol), Intermediate 44 (160 mg, 0.45 mmol) and DIPEA (235 μL, 1.35 mmol) in DCM (4 mL) at r.t. The suspension was stirred at r.t. for 3 h, then diluted with water (5 mL). The organic layer was set aside. The aqueous layer was extracted with DCM (5 mL). The organic fractions were combined, then passed through a hydrophobic frit and concentrated, to afford the title compound as a red gum, which was utilised without further purification. LCMS (Method 1): [M+H]⁺ m/z 613, RT 1.98 minutes.

INTERMEDIATE 46

Intermediate 45 (250 mg, 0.41 mmol) was stirred in acetic acid (2 mL) at 60°C for 4 h, then at 50°C overnight. The mixture was concentrated, then dissolved in EtOAc (5 mL) and washed with saturated aqueous sodium bicarbonate solution (5 mL). The organic fraction was dried over sodium sulfate, then purified by flash column chromatography, eluting with a gradient of 45-70% EtOAc in heptanes, to afford the title compound (179 mg, 63%, 85% purity) as a pale red solid, δH (500 MHz, DMSO-de)

12.76 (d, J 141.5 Hz, 1H), 7.97 (s, 1H), 7.90 (d, J 1.7 Hz, 1H), 7.40-7.23 (m, 6H), 7.00- 6.93 (m, 1H), 5.44 (dq, .718.0, 9.1, 8.3 Hz, 1H), 5.14-4.93 (m, 3H), 4.77-4.59 (m, 2H), 2.14-1.91 (m, 3H), 1.90-1.65 (m, 4H), 1.65-1.54 (m, 3H), 1.51-1.29 (m, 2H). LCMS (Method 1): [M+H]⁺ m/z 595, RT 1.98 minutes.

INTERMEDIATE 47

Palladium on carbon (50% wet with water, 15% w/w loading, 27 mg) was added to a stirred solution of Intermediate 46 (85% purity, 175 mg, 0.25 mmol) in ethanol (3 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred at r.t. for 2 h, then filtered and concentrated, to afford the title compound (122 mg, 91%, 86% purity) as a colourless glass. LCMS (Method 1): [M+H]⁺ m/z 461, RT 1.55 minutes. INTERMEDIATE 48

To a solution of Intermediate 32 (3.14 g, 7.37 mmol, 90% purity) in DMF (36.9 mL) at r.t. were added 4-methyl- 1 ,2,5-oxadiazole-3-carboxylic acid (1.04 g, 8.11 mmol), DIPEA (3.85 mL, 22.1 mmol) and HATU (3.03 g, 7.74 mmol). The mixture was stirred for 1 h, then diluted with water (100 mL) and EtOAc (100 mL). The organic layer was separated. The aqueous layer was re-extracted with EtOAc (2 x 50 mL). The combined organic layers were dried and concentrated. The crude residue was diluted with TBME (100 mL) and washed with water (100 mL; then 2 x 50 mL). The organic layer was dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc in hexanes, then 0-30% MeOH in EtOAc, to give the title compound (3.63 g, 82%, 82% purity) as a sand-coloured solid. LCMS (Method 4): [M+H]⁺ m/z 494, RT 1.34 minutes.

INTERMEDIATES 49 & 50

2-(Trimethylsilyl)ethoxymethyl chloride (0.71 mL, 4.0 mmol) was added to a solution of Intermediate 48 (1.20 g, 1.99 mmol, 82% purity) and DIPEA (0.87 mL, 5.0 mmol) in DMF (10 mL) imder nitrogen. The reaction mixture was stirred for 2.5 h, then diluted with TBME (75 mL) and washed with water (75 mL; then 2 x 50 mL). The organic layer was dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc in hexanes, to give a mixture of the title compounds (1.34 g, quantitative, 94% purity) as a pale orange oil. LCMS (Method 4): [M+H]⁺ m/z 624, RT 1.71 minutes. INTERMEDIATES 51 & 52

A mixture of Intermediate 49 and Intermediate 50 (1.32 g, 1.99 mmol, 94% purity) was dissolved in ammonia in methanol (7 mol/L, 15 mL), and the flask was sealed. The reaction mixture was stirred for 4 days at 60°C, then cooled to r.t. Additional ammonia in methanol (7 mol/L, 15 mL) was added. The reaction mixture was sealed and stirred overnight at 90°C, then at 95°C for a further 3 days, then concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 50-100% EtOAc in hexanes, to give a mixture of the title compounds (0.947 g, 57%, 71% purity) as a pale yellow oil. LCMS (Method 4): [M+H]⁺ m/z 595, RT 1.44 minutes.

INTERMEDIATES 53 & 54 0

Pyridine (0.33 mL, 4.1 mmol), followed by trifluoroacetic anhydride (0.22 mL, 1.5 mmol), were added to a mixture of Intermediate 51 and Intermediate 52 (0.852 g, 1.01 mmol, 71% purity) in 1,4-dioxane (15 mL) trader nitrogen. The reaction mixture was stirred for 20 minutes, then diluted with EtOAc (75 mL) and washed with water (2 x 50 mL). The organic layer was dried and concentrated to give a mixture of the title compounds (0.778 g, quantitative, 75% purity) as a pale yellow oil, which was utilised without further purification. LCMS (Method 4): [M+H]⁺ m/z 577, RT 1.61 minutes. INTERMEDIATES 55 & 56

Ammonium chloride (99.3 mg, 1.86 mmol), followed by sodium azide (122 mg, 1.86 mmol), were added to a mixture of Intermediate 53 and Intermediate 54 (0.357 g,

0.464 mmol, 75% purity) in DMF (9.3 mL) under nitrogen. The reaction mixture was stirred overnight at 100°C, then cooled to room temperature. Additional ammonium chloride (99.3 mg, 1.86 mmol) and sodium azide (122 mg, 1.86 mmol) were added. The reaction mixture was stirred at 100°C for a further 4 days, then diluted with DCM (25 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer was re-extracted with DCM (25 mL). The combined organic layers were dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc in hexanes, to give a mixture of the title compounds (130 mg, 45%) as a pale yellow oil. LCMS (Method 4): [M+H]⁺ m/z 620, RT 1.16 minutes.

INTERMEDIATES 57 TO 60

To a suspension of potassium carbonate (61 mg, 0.44 mmol) in a solution of a mixture of Intermediate 55 and Intermediate 56 (125 mg, 0.20 mmol) in acetone (2.5 mL) was added 2,2,2-triAuoroethyl triAuoromethanesulfonate (59 mg, 0.24 mmol). The reaction mixture was heated at 45°C overnight with stirring, then concentrated in vacuo. The residue was puriAed by column chromatography to afford a mixture of Intermediates 57 & 58 (37 mg, 26%) and a mixture of Intermediates 59 & 60 (59 mg, 41%).

Mixture of Intermediates 57 & 58: LCMS (Method 6): [M+H]⁺ m/z 702, RT 3.07, 3.13 minutes (SEM regioisomers split).

Mixture of Intermediates 59 & 60: LCMS (Method 6): [M+H]⁺ m/z 702, RT 3.29 minutes.

INTERMEDIATE 61

Intermediate 15 (2.44 g, 6.0 mmol) was dissolved in methanol (20 mL) and toluene (40 mL), and (trimethylsilyl)diazomethane (2 mol/L) in hexanes (10 mL) was added dropwise at r.t. The reaction mixture was stirred at r.t. for 12 h, then the volatiles were evaporated. The residue was puriAed using a 50g silica column, eluting with 0- 100% EtOAc in hexanes, to afford the title compound (2.54 g, 100%) as a yellow oil. δH (400 MHz, DMSO-de) 7.51 (dd, 78.5, 1.4 Hz, 1H), 7.37-7.12 (m, 11H), 4.14 (s, 4H), 4.04 (q, 77.1 Hz, 1H), 3.63 (s, 3H), 1.37 (d, 77.2 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 423, RT 1.66 minutes.

INTERMEDIATE 62

To a solution of Intermediate 61 (2.57 g, 6.08 mmol) in ethanol (10 mL) under N2 was added palladium on carbon (300 mg). The reaction mixture was subjected to vacuum and backfilled with N2, then subjected to vacuum and backfilled three times with Hz. The mixture was stirred at r.t. for 3 h, then filtered through Celite®. The filtrate was evaporated to dryness to afford the title compound (1.1 g, 85%) as a brown oil, which was utilied without further purification. δH (400 MHz, DMSO-de) 6.33-6.13 (m, 2H), 4.72 (s, 2H), 4.37 (s, 2H), 3.76 (q, 77.2 Hz, 1H), 3.60 (s, 3H), 1.31 (d, 77.1 Hz, 3H). LCMS (Method 1): [M+H]⁺ m/z 213, RT 0.84 minutes.

INTERMEDIATE 63

Intermediate 62 (1.1 g, 5.2 mmol) was mixed with Intermediate 19 (1.7 g, 5.8 mmol) and HATU (2.2 g, 5.6 mmol), and dissolved completely in DCM (10 mL). DIPEA (2.7 mL, 16 mmol) was added. The solution was stirred at r.t. for 2 h, then diluted with EtOAc and washed with brine (total 300 mL). The organic layers were dried and evaporated. The resulting brown oil was heated in acetic acid (20 mL) at 70°C for 2 h, then the volatiles were evaporated. The residue was purified using a silica gel 50g column, eluting with 0-100% EtOAc in hexanes, to afford the title compound (2.15 g, 88%) as a clear yellow oil. LCMS (Method 1): [M+H]⁺ m/z 470, RT 1.36 minutes. INTERMEDIATE 64

Intermediate 63 (500 mg, 1.1 mmol) was dissolved in THF (5 mL) and water (3 mL). Lithium hydroxide monohydrate (177 mg, 4.0 mmol) was added. The mixture was stirred for 3 h, then the solvent was mostly evaporated. The residue was diluted with EtOAc and washed with water, then the aqueous layer was extracted twice with 1 : 1 chloroform/propan-2-ol . The organic layers were combined, then evaporated, to yield the title compound (326 mg, 67%) as a white solid. LCMS (Method 1): [M+H]⁺ m/z 456, RT 0.95 minutes.

INTERMEDIATE 65

Intermediate 64 (326 mg, 0.71 mmol) was mixed with HATU (308 mg, 0.78 mmol), and the solids were dissolved in DCM (5 mL). DIPEA (0.4 mL, 2.0 mmol) was added, followed by 5-fluoro-2-hydrazinylpyridine (96 mg, 0.71 mmol). The mixture was stirred at r.t. for 30 minutes. The volatiles were evaporated, extracted with EtOAc and washed with brine. The organic layers were dried, filtered and evaporated. The residue was purified by flash silica chromatography, eluting with 0-100% EtOAc in hexanes, to afford the title compound (350 mg, 86%) as a sticky oil. LCMS (Method 1): [M+H]⁺ m/z 565, RT 1.125 minutes.

INTERMEDIATE 66

Intermediate 65 (350 mg, 0.62 mmol) was dissolved in THF (6 mL) and triethylamine (0.35 mL) was added, followed by triphenylphosphine (325 mg, 1.2 mmol) and hexachloroethane (300 mg, 1.25 mmol), at 0°C in an ice bath. The ice bath was removed after the addition, and the reaction mixture was stirred at r.t. for 2 h. The white solids (triphenylphosphine oxide) were removed by filtration through Celite®, then the solvent was removed. The residue was purified by flash silica chromatography, eluting with 0-100% EtOAc in hexanes, then 0-100% MeOH in EtOAc, to afford the title compound (180 mg, 53%) as a yellow oil. LCMS (Method 1): [M+H]⁺ m/z 547, RT 1.22 minutes.

INTERMEDIATE 67

Intermediate 66 (180 mg, 0.32 mmol) was dissolved in DCM (3 mL) and TFA (0.5 mL) was added. The reaction mixture was stirred at r.t. for 1 h, then the volatiles were evaporated. The residue was loaded onto a SCX-2 column and washed with MeOH, then eluted with 4N ammonia in MeOH, to afford the title compound (100 mg, 68%) as a yellow solid. LCMS (Method 1): [M+H]⁺ m/z 447, RT 0.98 minutes.

INTERMEDIATE 68

To a stirred solution of 2,3,4-trifluoronitrobenzene (200 g, 1.13 mol) in acetonitrile (2 L) were added DIPEA (296 g, 2.29 mol) and dibenzylamine (245 g, 1.20 mol). The reaction mixture was stirred at 65°C for 18 h, then TBME (2 L) and water (1 L) were added. The phases were separated, and the organic fractions were washed with water (1 L), 5% HC1 solution (1.6 L), 50% brine (1 L) and brine (600 mL). The organic fraction was dried over Na2SC>4 and concentrated in vacuo. The residue was dissolved in TBME (500 mL) with heating, and isohexane (700 mL) was added. The mixture was allowed to cool to r.t., and crystallisation afforded the title compound (310 g, 77%). δH (300 MHz, DMSO-de) 7.69 (ddd, J9.3, 5.4, 2.2 Hz, 1H), 7.44-7.34 (m, 1H), 7.34-7.19 (m, 10H), 4.20 (s, 4H). INTERMEDIATE 69

To a stirred solution of Intermediate 22 (10.60 g, 26.0 mmol) in THF was added NaH (60%, 1.15 g, 28.6 mmol) in one portion at -10°C. The mixture was stirred for 15 minutes, then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (3.6 mL, 27.2 mmol) was added dropwise. The reaction mixture allowed to warm to r.t. and stirred for 18 h, then quenched with saturated aqueous NHtCl solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (2 x 50 mL) and dried over MgSCh, then filtered and concentrated in vacuo. The resulting crude material was separated by flash column chromatography, eluting with EtO Ac/heptane (0- 100% gradient), to afford the title compound (7.4 g, 59%) as a yellow-orange solid, δH (500 MHz, DMSO-de) 7.53 (dd, 78.4, 0.9 Hz, 1H), 7.38-7.13 (m, 11H), 5.97 (tt, 756.1, 4.4 Hz, 1H), 4.21-4.06 (m, 5H), 3.63 (s, 3H), 2.77-2.55 (m, 1H), 2.23 (dtdd, 719.2, 15.2, 8.2, 4.4 Hz, 1H). LCMS (Method 2): [M+H]⁺ m/z 473, RT 3.66 minutes.

INTERMEDIATE 70

To a solution of Intermediate 69 (3180 mg, 6.73 mmol) in THF (50 mL) and methanol (3 mL) was added sodium tetrahydridoborate (1019 mg, 26.9 mmol). The mixture was slowly heated, then heated at 70°C for 1.5 h. The reaction mixture was cooled in an ice bath, and saturated aqueous ammonium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (2 x 50 mL). The organic fractions were combined and dried (MgSCfo), then the solvent was removed, to give the title compound (3.27 g) as an orange gum. LCMS (Method 1): [M+H]⁺ m/z 445, RT 2.12 minutes.

INTERMEDIATE 71 2 Γ3 (Dib l i V2 fl 4 it h n 44 difl b t l 1 t t

To a solution of Intermediate 70 (2.99 g, 6.73 mmol) in DCM (60 mL) at 0°C were added N,N-dimethylpyridin-4-amine (41 mg, 0.336 mmol), pyridine (0.95 mL, 11.8 mmol) and acetyl chloride (0.72 mL, 10.1 mmol). The reaction mixture was stirred at 0°C for 2 minutes, then at r.t. for 3 h. The reaction mixture was cooled to 0°C and retreated with pyridine (0.95 mL, 11.8 mmol) and acetyl chloride (0.72 mL, 10.1 mmol). The ice bath was removed, and the reaction mixture was stirred for 18 h. The reaction mixture was cooled to 0°C and re-treated with pyridine (0.95 mL, 11.8 mmol) and acetyl chloride (0.72 mL, 10.1 mmol). The ice bath was removed and the reaction mixture was stirred for 2 h, then diluted with saturated aqueous ammonium chloride solution (25 mL). The organic layer was separated and washed with brine (20 mL), then dried (MgSCh).

The solvent was removed. Purification of the resulting orange oil by column chromatography (lOg SNAP-Duo, Isolera, 0-20% EtO Ac/isohexane over 10 column volumes) gave the title compound (3.08 g, 94%) as an orange oil. δH (500 MHz, CDCb) 7.32 (dd, 78.4, 1.5 Hz, 1H), 7.29-7.19 (m, 10H), 6.98 (dd, 78.4, 6.6 Hz, 1H), 5.49 (tdd, J 56.2, 5.7, 3.6 Hz, 1H), 4.21 (d, 73.7 Hz, 4H), 3.47 (dq, 79.4, 6.6 Hz, 1H), 2.31-2.19 (m, 1H), 2.19-2.08 (m, 1H), 2.01 (s, 3H), 1.70-1.59 (m, 1H), 1.34-1.27 (m, 1H). LCMS (Method 1): [M+H]⁺ m/z 487, RT 2.23 minutes.

INTERMEDIATE 72

To a solution of Intermediate 71 (3.07 g, 6.31 mmol) in ethyl acetate (30 mL) under a nitrogen atmosphere was added Pd/C (10%, 672 mg, 0.631 mmol). The flask was evacuated and placed under an atmosphere of hydrogen for 18 h. The solid residues were filtered off through Celite®, and the solvent was removed, to give the title compound (1.75 g, 94%) as a pink gum. δH (400 MHz, DMSO-de) 6.39-6.25 (m, 2H), 5.85 (tt, J 56.7, 5.7, 3.9 Hz, 1H), 4.72 (s, 2H), 4.37 (s, 2H), 4.12 (dd, J 10.7, 7.5 Hz, 1H), 4.07-3.98 (m, 1H), 3.26-3.17 (m, 1H), 2.29-2.02 (m, 2H), 1.97 (s, 3H). LCMS (Method 1):

[M+Na]⁺ m/z 299, RT 1.52 minutes. INTERMEDIATE 73

To a solution of Intermediate 9 (1.94 g, 5.92 mmol) in DCM (20 mL) were added DIPEA (1.7 mL, 9.47 mmol) and HATU (2.70 g, 7.10 mmol). The mixture was stirred for 5 minutes, then Intermediate 72 (94%, 1.74 g, 5.92 mmol) was added. The reaction mixture was stirred for 3 h, then water (30 mL) was added. The organic layer was separated and dried (MgSCfo), then the solvent was removed. Purification of the residue by column chromatography (50g SNAP-Duo, Isolera, 0-30% EtOAc/i sohexane over 10 column volumes) gave the title compound (3.79 g) as an off-white solid. LCMS (Method 1): [M+H]⁺ m/z 586, RT 2.01 minutes.

INTERMEDIATE 74

To a solution of Intermediate 73 (3.42 g, 5.84 mmol) in DCM (30 mL) was added TFA (0.87 mL, 11.7 mmol). The reaction mixture was heated at 50°C for 18 h, then cooled to 0°C and quenched with saturated aqueous NaHCCh solution. The organic layer was separated and dried (MgSCfo), and the solvent was removed. Purification of the resulting oil by column chromatography (50g SNAP-Duo, Isolera, 0-50% EtOAc/iso- hexane over 10 column volumes) gave a first batch of the title compound (100% purity) (1.74 g, 52%) and a second batch of the title compound (84% purity) (1.17g, 35%). LCMS (Method 2): [M+H]⁺ m/z 568, RT 3.20 minutes.

INTERMEDIATE 75

To a solution of Intermediate 74 (1.74 g, 3.07 mmol) in methanol (15.2 mL) was added potassium carbonate (2.12 mmol). The mixture was stirred for 18 h, then water (20 mL) was added, followed by DCM (30 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 x 15 mL). The combined organic layers were dried (MgSCfo), then the solvent was removed, to give the title compound (1.62 g, 100%) as an oil. LCMS (Method 2): [M+H]⁺ m/z 526, RT 2.89 minutes.

INTERMEDIATE 76

To a solution of Intermediate 75 (1.62 g, 3.08 mmol) in DCM (25 mL) at 0°C was added Dess-Martin periodinane (1.57 g, 3.70 mmol). The ice bath was removed and the mixture was stirred for 3 h, then quenched with 50% saturated aqueous sodium thiosulfate solution/saturated NaHCCh solution (25 mL) for 20 minutes. The organic layer was separated and washed with saturated aqueous NaHCCh solution (15 mL). The organic layer was dried (MgSCh), and the solvent was removed. The resulting solid was dissolved in EtOAc (70 mL) and washed with brine (2x 15 mL), then dried (MgS04).

The solvent was removed to give the title compound (1.51 g, 94%) as an off-white solid. LCMS (Method 2): [M+H]⁺ m/z 524, RT 1.97 minutes.

INTERMEDIATE 77

To a suspension of Intermediate 76 (250 mg, 0.478 mmol) in anhydrous MeOH (3 mL) was added DCM (1 mL). The solution was cooled to 0°C, and dimethyl (l-diazo-2- oxopropyl)phosphonate (0.13 mL, 0.860 mmol) and potassium carbonate (165 mg, 1.19 mmol) were added. The mixture was allowed to warm to r.t. and stirred for 18 h, then the solvent was removed. The residue was partitioned between EtOAc (15 mL) and water (15 mL). The organic layer was separated, and the aqueous layer was re-extracted with EtOAc (10 mL). The combined organic layers were dried (MgS04) and the solvent was removed. Purification of the resulting brown solid by column chromatography (lOg SNAP-Duo, Isolera, 0-40% EtOAc/i sohexane over 10 column volumes) gave the title compound (187mg, 75%) as a white solid. LCMS (Method 2): [M+H]⁺ m/z 520, RT 3.30 minutes. INTERMEDIATE 78

To a solution of Intermediate 77 (300 mg, 0.577 mmol) in anhydrous THF (8 mL) were added 2,2,2-trifluoroethyl azide in TBME (0.5M, 1.4 mL, 0.693 mmol) and chloro- (pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II) (22 mg, 0.0577 mmol). The brown mixture was heated at 60°C for 2 h, then the solvent was removed. Purification of the brown residue by column chromatography (lOg SNAP-Duo, Isolera, 0-50% EtOAc/ isohexane over 10 column volumes) gave the title compound (345 mg, 93%) as a brown solid. LCMS (Method 2): [M+H]⁺ m/z 645, RT 3.18 minutes.

INTERMEDIATE 79

To a solution of Intermediate 78 (345 mg, 0.535 mmol) in ethanol (4 mL) under nitrogen was added palladium (50% wet with water) (10%, 57 mg, 0.0535 mmol). The mixture was evacuated and placed under a hydrogen atmosphere for 3 h. The solid residues were filtered off through Celite®, and the solvent was removed, to give the title compound (278 mg) as a brown solid. LCMS (Method 1): [M+H]⁺ m/z 511, RT 1.61 minutes.

INTERMEDIATE 80

A solution of N-diazosulfamoyl fluoride (154 mg, 1.23 mmol) in TBME (4 mL) was diluted with DMF (1.5 mL), then added to solid 2,2-difluoroethanamine (108 mg, 1.34 mmol), followed by aqueous potassium hydrogen carbonate solution (3M, 1.6 mL,

4.92 mmol) at room temperature. The reaction mixture was stirred for 18 h, then diluted with water (3 mL) and extracted with TBME (2x 3 mL). The combined organic layers were washed with water (2 x 5 mL) and brine (10 mL), then dried over sodium sulfate, filtered and partially concentrated under reduced pressure (20°C, 200 mbar), to afford a crude solution containing the title compound in 26% yield (1.7% title compound, 97.6% TBME, 0.7% DMF w/w). δH (400 MHz, DMSO-de) 6.23 (tt, J54.8, 3.3 Hz, 1H), 3.74 (td, J 16.3, 3.2 Hz, 2H).

INTERMEDIATE 81

To a solution of Intermediate 77 (400 mg, 0.770 mmol) in anhydrous THF (10 mL) were added Intermediate 80 (~3%, 99 mg, 0.924 mmol) and chloro(pentamethyl- cyclopentadienyl)(cyclooctadiene)ruthenium(n) (29 mg, 0.077 mmol). The reaction mixture was heated at 60°C for 2 h. Another portion of Intermediate 80 (~3%, 50 mg, 0.46 mmol) was added, and the reaction mixture was heated for a further 1 h. Another portion of Intermediate 80 (~3%, 25 mg, 0.23 mmol) was added, and the reaction mixture was heated for a further 1 h, then the solvent was removed. Purification of the resulting brown gum by column chromatography (lOg SNAP-Duo, Isolera, 0-70 % EtOAc/iso- hexane over 10 column volumes) gave the title compound (351 mg, 75%) as a brown solid. LCMS (Method 2): [M+H]⁺ m/z 627, RT 3.06 minutes.

INTERMEDIATE 82

To a solution of Intermediate 81 (351 mg, 0.560 mmol) in ethanol (4 mL) under nitrogen was added 10% palladium on carbon (50% wet with water) (60 mg, 0.0560 mmol). The mixture was evacuated and placed under a hydrogen atmosphere for 3 h.

The solid residues were filtered off through Celite®, and the solvent was removed, to give the title compound (398 mg) as a brown solid. LCMS (Method 1): [M+H]⁺ m/z 493, RT 1.55 minutes. INTERMEDIATE 83

A three-neck flask was charged with Intermediate 68 (33 g, 93.1283 mmol), potassium carbonate (64.4 g, 466 mmol) and a solution of 1,3 -diethyl 2-(2,2,2-trifluoro- ethyl)propanedioate (56.1 g, 232 mmol) in DMF (200 mL). The resulting mixture was stirred and heated at 90°C (heating block; 80-82°C internal temperature) for 19 h, then cooled to r.t, poured into water and extracted with TBME (2 L). The aqueous washings were re-extracted with TBME (1L), then the combined organic extracts were dried over Na2SC>4, filtered and concentrated in vacuo. Purification by flash chromatography (SNAP 750 g, 0-10% EtOAc in hexane) afforded the title compound (57.6 g) as an orange oil. δH (300 MHz, CDCb) 7.57 (dd, 78.8, 7.1 Hz, 1H), 7.39 (dd, 78.9, 1.7 Hz, 1H), 7.34-7.20 (m, 10H), 4.41-4.23 (m, 4H), 4.16 (t, 71.6 Hz, 4H), 3.22 (q, 710.4 Hz, 2H), 1.30 (t, 77.1 Hz, 6H).

INTERMEDIATE 84

To a solution of Intermediate 83 (57.6 g, 95.8 mmol) in THF (383 mL) were added water (38.3 mL) and lithium hydroxide monohydrate (16.1 g, 384 mmol). The resulting mixture was stirred at 45°C (heating block; internal temperature 40°C) for 17 h, then cooled to room temperature, diluted with water (2 L) and extracted with EtOAc (2 x 1 L). The organic extracts were dried over Na2S04, filtered and concentrated in vacuo. The residue was taken up in ethanol (192 mL), and sulfuric acid (10.7 mL, 191 mmol) was added. The mixture was heated to a gentle reflux (heating block at 100°C; internal temperature 78-80°C) for 4.5 h, then cooled to r.t. and concentrated in vacuo. The residue was taken up in EtOAc (1 L) and washed with water (1 L). The aqueous washings were re-extracted with EtOAc (500 mL). The combined organic extracts were dried over Na2S04, filtered and concentrated in vacuo. Purification by flash chromatography (SNAP

750 g, 5% EtOAc in hexane, then 5-15% EtOAc in hexane) afforded the title compound (41 g, 79.9%) as an orange oil. δH (300 MHz, CDCb) 7.36 (dd, 78.5, 1.6 Hz, 1H), 7.33- 7.21 (m, 10H), 7.07 (dd, 78.5, 6.7 Hz, 1H), 4.31-4.08 (m, 7H), 3.07 (dqd, 715.2, 10.6, 6.0 Hz, 1H), 2.45 (dqd, J 15.2, 10.1, 8.0 Hz, 1H), 1.24 (t, 77.1 Hz, 3H).

INTERMEDIATE 85 2-Γ3 -(DibenzvlaminoV2-fluoro-4-nitroDhenvn-4.4.4-trifluorobutan- 1 -ol

To a stirred solution of Intermediate 84 (7.50 g, 14.9 mmol) and sodium tetrahydridoborate (2.25 g, 59.5 mmol) in anhydrous THF (150 mL) at 70°C was added methanol (7.5 mL) in three portions. The reaction mixture was heated for 1 h, then cooled in an ice bath. Half-saturated aqueous ammonium chloride solution (50 mL) was added, then the mixture was extracted with ethyl acetate (2 x 40 mL). The organic fractions were combined, then dried over sodium sulfate and concentrated under reduced pressure, to give the title compound (6.865 g, 88%) as an orange gum, which was utilised without further purification. LCMS (Method 1): [M+H]⁺ m/z 463, RT 2.1 minutes.

INTERMEDIATE 86

12-Γ3 -(DibenzvlaminoV2-fluoro-4-nitroDhenvn-4.4.4-trifluorobutvl 1 acetate

To an externally cooled (~0°C) stirred solution of Intermediate 85 (88%, 6.87 g, 13.1 mmol) and N,N-dimethylpyridin-4-amine (80 mg, 0.653 mmol) in anhydrous DCM (120 mL) were added pyridine (1.8 mL, 22.9 mmol), then acetyl chloride (1.4 mL, 19.6 mmol), dropwise. After 1 minute, the external cooling was removed. The reaction mixture was stirred for 5 h, then re-treated with pyridine (1.8 mL, 22.9 mmol) and acetyl chloride (1.4 mL, 19.6 mmol) and stirred over the weekend. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL), then water (20 mL) was added. The organic layer was separated, and the aqueous layer was re-extracted with DCM (2x 15 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0-20% EtOAc in heptanes, to give the title compound (6.37 g, 97%) as an orange oil. LCMS (Method 1): [M+H]⁺ m/z 505, RT 2.26 minutes. INTERMEDIATE 87

Palladium on carbon (50% wet with water) (10%, 1343 mg, 1.26 mmol) was added to a stirred solution of Intermediate 86 (6.37 g, 12.6 mmol) in ethyl acetate (80 mL) and 1M aqueous HC1 (118 μL, 0.118 mmol). The reaction mixture was placed under a hydrogen atmosphere and stirred at r.t. overnight. The mixture was filtered and concentrated under reduced pressure to give the title compound (81% purity) (3.84 g, 84%) as a brown oil. LCMS (Method 1): [M-AcOH+H]⁺ m/z 235, RT 1.64 minutes.

INTERMEDIATE 88

To a stirred suspension of Intermediate 9 (4.28 g, 13.1 mmol) in DCM (45 mL) was added DIPEA (3.7 mL, 20.9 mmol) at r.t, followed by HATU (5.96 g, 15.7 mmol). After 5 minutes, a solution of Intermediate 87 (3.84 g, 13.1 mmol) in DCM (10 mL) was added. The reaction mixture was stirred overnight, then water (50 mL) was added. The organic layer was separated, and the aqueous layer was re-extracted with DCM (10 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated in vacuo. The residue was dry-loaded onto a 350 g, Sfar Duo column, eluting with 10-35% EtOAc in heptanes, to give the title compound (72% purity) (7.98 g, 73%) as a brown solid. LCMS (Method 1): [M+H]⁺ m/z 604, RT 2.04 minutes.

INTERMEDIATE 89

To a stirred solution of Intermediate 88 (72%, 7.98 g, 9.52 mmol) in DCM (60 mL) was added TFA (1.4 mL, 19.3 mmol). The reaction mixture was heated at 40°C for 5 h. To the cooled reaction mixture was added saturated aqueous NaHCCh solution (50 mL), then the organic layer was separated off. The aqueous layer was re-extracted with DCM (2x 15 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated in vacuo. The crude solid was purified using column chromatography (350 g Sfar Duo column), eluting with a gradient of EtOAc in heptane (0-100%), to afford the title compound (86% purity) (3.80 g, 59%) as a pink solid, δH (500 MHz, DMSO-de) 12.91-12.54 (m, 1H), 8.03-7.87 (m, 1H), 7.37-7.21 (m, 7H), 5.10-4.97 (m, 2H), 4.77-4.66 (m, 1H), 4.33-4.26 (m, 1H), 4.21-4.12 (m, 1H), 3.73-3.64 (m, 1H), 2.86-2.72 (m, 2H),

2.17-1.93 (m, 6H), 1.92-1.65 (m, 3H), 1.54-1.26 (m, 3H). LCMS (Method 1): [M+H]⁺ m/z 586, RT 2.03 minutes.

INTERMEDIATE 90

To a stirred suspension of Intermediate 89 (86%, 3.80 g, 5.58 mmol) in anhydrous methanol (30 mL) was added potassium carbonate (532 mg, 3.85 mmol) at r.t. After 18 h, the volatiles were concentrated in vacuo, then EtOAc (50 mL), water (20 mL) and brine (20 mL) were added. The organic layer was separated, and the aqueous layer was reextracted with EtOAc (2 x 25 mL). The organic layers were combined, washed with brine (10 mL) and dried over magnesium sulfate, then filtered and concentrated in vacuo, to afford the title compound (87% purity) (3.77 g, 108%) as a pink solid. LCMS (Method 1): [M+H]⁺ m/z 544, RT 1.93 minutes.

INTERMEDIATE 91

To a stirred suspension of Intermediate 90 (87%, 3.77 g, 6.03 mmol) in DCM (65 mL) was added Dess-Martin periodinane (3.07 g, 7.25 mmol). The mixture was stirred for 2.5 h, then saturated aqueous NaHCCh solution (50 mL) was added. The organic layer was separated off, and the aqueous layer was re-extracted with DCM (2 x 20 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated in vacuo. The crude residue was suspended in ethyl acetate, and filtered. The filtrate was dry-loaded onto a 100 g Sfar Duo column. The material was purified, eluting with a gradient ofEtOAc in heptane (30-60%), to afford the title compound (79% purity) (2.96 g, 72%) as a pink solid. LCMS (Method 1): [M+H]⁺ m/z 542, RT 2.01 minutes.

INTERMEDIATE 92

To a stirred suspension of Intermediate 91 (79%, 2.96 g, 4.32 mmol) in anhydrous methanol (30 mL) and DCM (10 mL) at 0°C was added dimethyl (l-diazo-2-oxopropyl)- phosphonate (1.49 g, 7.77 mmol), followed by potassium carbonate (1.49 g, 10.8 mmol). The mixture was stirred at 0°C for 10 minutes, then at r.t. overnight. The mixture was retreated with dimethyl (l-diazo-2-oxopropyl)phosphonate (0.30 g, 1.56 mmol) and potassium carbonate (0.30 g, 2.17 mmol), and stirred at r.t. for another 3 h, then concentrated under vacuum, diluted with water (60 mL) and extracted with DCM (2 x 40 mL). The organic fractions were combined and concentrated. The residue was dry- loaded onto a 100 g Sfar Duo column, eluting with 25-45% EtOAc in heptane, to afford the title compound (90% purity) (1.98 g, 77%) as a white solid, δH (400 MHz, DMSO-de) 13.05-12.50 (m, 1H), 8.03-7.82 (m, 1H), 7.44-6.93 (m, 7H), 5.03 (q, J 12.6 Hz, 2H), 4.72 (t, 78.0 Hz, 1H), 4.41-4.30 (m, 1H), 3.29 (s, 1H), 3.02-2.70 (m, 2H), 2.18-1.54 (m, 7H), 1.54-1.30 (m, 2H). LCMS (Method 1): [M+H]⁺ m/z 538, RT 2.06 minutes.

INTERMEDIATE 93

To a solution of Intermediate 92 (100 mg, 0.186 mmol) and 2,2,2-trifluoroethyl azide in TBME (0.5M, 0.45 mL, 0.223 mmol) in THF (2 mL) was added chloro- (pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(n) (7.1 mg, 0.0186 mmol). The reaction mixture was heated at 60°C under microwave irradiation for 2 h, then the solvent was removed. The crude material was purified by column chromatography, eluting with 0-75% EtOAc in heptanes, to give the title compound (111 mg, 90%) as an off-white solid. LCMS (Method 1): [M+H]⁺ m/z 663, RT 2.01 minutes. INTERMEDIATE 94

Palladium (50% wet with water) (5.0%, 35 mg, 0.0166 mmol) was added to a stirred solution of Intermediate 93 (110 mg, 0.166 mmol) in ethanol (3 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred at r.t. for 5 h. The mixture was filtered through Celite®, and concentrated under reduced pressure, to give the title compound (77 mg, 88%) as a brown solid. LCMS (Method 1): [M+H]⁺ m/z 529, RT 1.64 minutes.

INTERMEDIATE 95

A solution of Intermediate 92 (145 mg, 0.270 mmol), Intermediate 80 in TBME (1.7%, 2014 mg, 0.320 mmol) and chloro(pentamethylcyclopentadienylXcyclooctadiene)- ruthenium(n) (10 mg, 0.027 mmol) in anhydrous THF (5 mL) was heated at 60°C for 1.5 h. Separately, a solution of Intermediate 92 (470 mg, 0.874 mmol), Intermediate 80 in TBME (2.7%, 7128 mg, 1.80 mmol) and chloro(pentamethylcyclopentadienyl)-

(cyclooctadiene)ruthenium(II) (50 mg, 0.131 mmol) in anhydrous THF (15 mL) was heated at 60°C for 2 h. The two reaction mixtures were combined, then dry-loaded onto a 50 g, Sfar duo column and eluted with 45-70% EtOAc in heptanes, to give the title compound (94% purity) (594 mg, 99%) as a brown gum. δH (400 MHz, DMSO-de) 13.02-12.62 (m, 1H), 8.14-8.09 (m, 1H), 8.00-7.86 (m, 1H), 7.39-7.24 (m, 5H), 7.13-7.04

(m, 1H), 6.48-6.16 (m, 1H), 5.11-4.66 (m, 5H), 4.60-4.43 (m, 1H), 3.29-3.15 (m, 2H), 2.18-1.61 (m, 7H), 1.55-1.21 (m, 3H). LCMS (Method 1): [M+H f m/z 645, RT 1.97 minutes. INTERMEDIATE 96

Palladium on carbon (50% wet with water) (5.0%, 92 mg, 0.0433 mmol) was added to a stirred solution of Intermediate 95 (94%, 594 mg, 0.866 mmol) in ethanol (8 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred at r.t. for 3 h. The mixture was filtered, and concentrated under reduced pressure, to give the title compound (82% purity) (422 mg, 78%) as a brown gum. LCMS (Method 1): [M+H]⁺ m/z 511, RT 1.58 minutes.

INTERMEDIATE 97

To a stirred solution of Intermediate 84 (10.00 g, 19.8 mmol) in ethanol (200 mL) was added 10% palladium on charcoal (50% wet) (5.0%, 3.00 g, 1.41 mmol). The reaction mixture was evacuated with nitrogen gas three times, then placed under an atmosphere of hydrogen gas and stirred at ambient temperature for 16 h. The reaction mixture was filtered through celite, and the solvent was removed in vacuo, to afford the title compound (5.85 g, 95% yield corrected for estimated 95% purity) as a brown oil. LCMS (Method 1): [M+H]⁺ m/z 295, RT 1.73 minutes.

INTERMEDIATE 98

To a stirred solution of Intermediate 97 (95%, 5.85 g, 18.9 mmol), Intermediate 9 (6.49 g, 19.8 mmol) and pyridine (6.1 mL, 75.5 mmol) in ethyl acetate (70 mL), cooled in an ice bath, was added T3P® (50% in EtOAc) (50%, 28 mL, 47.2 mmol) dropwise, maintaining the temperature below 10°C. The reaction mixture was stirred at ambient temperature for 2 h, then diluted with ethyl acetate (150 mL), cooled to 0°C and quenched with 1M hydrochloric acid (75 mL). The aqueous phase was removed and the organic phase was washed with water (100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo. The residue was purified by silica column chromatography, eluting with a gradient of ethyl acetate in heptane (5-50%), to afford the title compound (7.79 g, 53% yield corrected for estimated 77% purity) as a pink solid. LCMS (Method 1): [M+H]⁺ m/z 604, RT 2.04 minutes.

INTERMEDIATE 99

To a stirred solution of Intermediate 98 (75%, 7.80 g, 9.69 mmol) in DCM (150 mL) was added TFA (1.4 mL, 19.4 mmol) dropwise. The reaction mixture was stirred at 40°C for 20 h. The reaction mixture was diluted with DCM (100 mL) and washed with 1M aqueous sodium hydroxide solution (50 mL) and water (50 mL), then dried over anhydrous sodium sulfate and filtered. The solvent was concentrated in vacuo. The residue was purified by silica column chromatography, eluting with a gradient of ethyl acetate in heptane (5-50%), to afford the title compound (4.90 g, 86%) as a beige solid. LCMS (Method 1): [M+H]⁺ m/z 586, RT 2.05 minutes.

INTERMEDIATE 100

To a solution of Intermediate 99 (4.75 g, 8.11 mmol) in ethanol (100 mL) and THF (8 mL) under nitrogen was added palladium on carbon (10 mass %, 850 mg, 0.799 mmol). The reaction mixture was stirred under a hydrogen balloon overnight at r.t, then filtered through celite and concentrated. The residue was purified on a KP-H column (“Amino-D”), eluting with 0-100% EtOAc in hexane, followed by 0-100% MeOH in EtOAc, to afford the title compound (2.7 g, 74%) as a yellow oil. LCMS (Method 4): [M+H]⁺ m/z 452, RT 1.28 minutes. INTERMEDIATE 101

To a solution of 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (680 mg, 5.31 mmol) and DIPEA (2.32 mL, 13.3 mmol) in DCM (50 mL) was added HATU (2 g, 5.10 mmol). The reaction mixture was stirred at ambient temperature for 10 minutes, then a solution of Intermediate 100 (100 mass %, 2.00 g, 4.43 mmol) in DMF (5 mL) was added. After stirring at ambient temperature overnight, the volatiles were evaporated. The resulting material was dissolved in EtOAc, then washed with water and brine, and concentrated. The residues was purified by silica column chromatography, eluting with a 0-100% gradient of EtOAc in isohexane, followed by 0-100% MeOH in EtOAc, to afford the title compound (1.8 g). LCMS (Method 4): [M+H]⁺ m/z 562, RT 1.41 minutes.

INTERMEDIATE 102

Intermediate 101 (1.50 g, 2.67 mmol) was dissolved in THF (13 mL) and water (2 mL). Lithium hydroxide monohydrate (354 mg, 8.01 mmol) was added at r.t. and stirred overnight. Additional lithium hydroxide monohydrate (354 mg, 8.01 mmol) was added, and the reaction mixture was heated at 60°C for 3 h, then for 3 days at r.t. The THF was evaporated, and the aqueous layer was acidified with 2N HC1 until solids precipitated out. The mixture was diluted with water and extracted with EtOAc, then dried over sodium sulfate, filtered and concentrated, to afford the title compound (1.4 g, 98%) as a white solid. LCMS (Method 4): [M+H]⁺ m/z 534, RT 0.96 minutes. INTERMEDIATE 103

Intermediate 102 (150 mg, 0.281 mmol) was mixed with HATU (120 mg, 0.306 mmol), and the solids were dissolved in DCM (4 mL). DIPEA (0.15 mL, 0.86 mmol) was added, followed by 6-hy drazinopyridine-3 -carbonitrile (42 mg, 0.313 mmol). The reaction mixture was stirred at r.t. overnight, then the solvent was removed. The residue was purified by silica column chromatography, eluting with 0-100% EtOAc in isohexane, to afford the title compound (130 mg, 71%) as a colourless oil. LCMS (Method 4): [M+H]⁺ m/z 650, RT 1.29 minutes.

INTERMEDIATE 104

To a stirred, nitrogen degassed suspension of Intermediate 69 (97%, 12.57 g, 25.8 mmol) in EtOH (250 mL) was added palladium on carbon (50% wet) (10%, 2.69 g, 2.53 mmol). The reaction mixture was placed under hydrogen gas and stirred for approximately 18 h, then filtered through Celite®, rinsing through with EtOAc (3 x 25 mL). The filtrate was concentrated in vacuo and purified by silica column chromatography, eluting with ethyl acetate in heptane (0-100%), to afford the title compound (6.31 g, 89%) as a dark red oil. δH (500 MHz, DMSO-de) 6.35-6.25 (m, 2H), 6.10-5.81 (m, 1H), 4.80 (s, 2H), 4.43 (s, 2H), 3.87 (t, 77.4 Hz, 1H), 3.58 (s, 3H), 2.65- 2.51 (m, 1H), 2.22-2.07 (m, 1H). LCMS (Method 2): [M+H]⁺ m/z 263, RT 1.77 minutes.

INTERMEDIATE 105

To an externally cooled (approximately 0°C) suspension of Intermediate 9 (6.15 g, 18.8 mmol) in DCM (90 mL) was added DIPEA (8.5 mL, 48.7 mmol) dropwise over 2 minutes, then HATU (9.91 g, 26.1 mmol) was added. The reaction mixture was stirred for 15 minutes, then a solution of Intermediate 104 (97%, 5.25 g, 19.4 mmol) in DCM (30 mL) was added over 5 minutes. After stirring for a further 5 minutes, the external cooling was removed. After stirring for 18 h at r.t, a 1:1 mixture of water and brine (200 mL) was added. The mixture was left for 10-15 minutes, then filtered. The organic layer was separated, and the aqueous layer was extracted with DCM (4 x 25 mL). The organic layers were combined and washed with brine (50 mL), then dried over magnesium sulphate, filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography, eluting with a gradient of ethyl acetate in heptane (0-100%), to afford the title compound (11.77 g, 90% yield corrected for 85% purity) as an off-white solid. δH (500 MHz, DMSO-de) 9.50 (s, 1H), 7.70 (d, J 8.0 Hz, 1H), 7.42-7.27 (m, 5H), 7.06 (d, 78.4 Hz, 1H), 6.51 (t, 78.0 Hz, 1H), 6.18-5.87 (m, 1H), 5.05 (s, 2H), 4.95 (s,

2H), 4.13 (t, 77.9 Hz, 1H), 4.08-3.99 (m, 1H), 3.61 (s, 3H), 2.72-2.56 (m, 1H), 2.31-2.15 (m, 1H), 2.10-1.96 (m, 2H), 1.91-1.63 (m, 5H), 1.48-1.27 (m, 2H). LCMS (Method 2): [M+H]⁺ m/z 572, RT 3.22 minutes.

INTERMEDIATE 106

Methvl 2-i2- -benzvloxvcarbonvlaminof4.4-difluorocvclohexvDmethvll-4-fluoro-l/f-

benzimidazol-5-vl 1 -4.4-difluorobutanoate

To a stirred solution of Intermediate 105 (11.77 g, 20.6 mmol) in DCM (200 mL) was added TFA (3.0 mL, 40.4 mmol). The reaction mixture was heated at 40°C for 18 h. To the cooled reaction mixture was added saturated aqueous NaHCCb solution (4 x 25 mL), and the mixture was left for 5-10 minutes. The organic layer was separated, and the aqueous layer was extracted with DCM (3 x 25 mL). The organic layers were combined and washed with brine (50 mL), then dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica column chromatography, eluting with a gradient of ethyl acetate in heptane (0-100%). The material was further purified by sonicating in a mixture of diethyl ether (10 mL) and heptane (60 mL). The solid was filtered off, then washed with heptane (30 mL) and dried, to afford the title compound (7.48 g, 58% yield corrected for a purity of 88%) as a white solid. δH (500 MHz, CD3OD) 7.43-6.83 (m, 7H), 6.01-5.70 (m, 1H), 5.18-5.00 (m, 2H), 4.78 (d, 78.0 Hz, 1H), 4.28 (t, 77.4 Hz, 1H), 3.67 (s, 3H), 2.84-2.65 (m, 1H), 2.39-2.22 (m, 1H), 2.19- 1.88 (m, 4H), 1.87-1.64 (m, 2H), 1.57-1.26 (m, 3H). LCMS (Method 2): [M+H]⁺ m/z 554, RT 3.20 minutes.

INTERMEDIATE 107

Intermediate 106 (100 mg, 0.181 mmol) was dissolved in 1,4-dioxane (8 mL), and the reaction mixture was cycled between vacuum and nitrogen three times. Palladium on carbon (10% loading, 50% water) (77 mg, 0.0361 mmol) was added and the reaction mixture was cycled between vacuum and hydrogen three times, then stirred under a hydrogen atmosphere for 16 h at r.t. The resulting material was filtered through Celite®, and the solids were washed with EtOH (3 x 30 mL). The combined filtrates were concentrated, then azeotroped with toluene (3 x 3 mL) under vacuum, to afford the title compound (crude) (91 mg) as a pale tan gum containing trace solvent. LCMS (Method

1): [M+H]⁺ m/z 420, RT 1.58 minutes.

INTERMEDIATE 108

HATU (1.24 g, 3.26 mmol) was added to a solution of 4-methyl- 1 ,2,5-oxadiazole- 3-carboxylic acid (0.42 g, 3.26 mmol) and DIPEA (1.4 mL, 8.15 mmol) in DCM (50 mL) at r.t. The resulting materialwas sonicated for 5 minutes and stirred for 10 minutes at r.t, then a solution of Intermediate 107 (95%, 1.20 g, 2.72 mmol) in DCM (10 mL) was added. The reaction mixture was stirred at r.t. for 3 days, then diluted with DCM (50 mL), washed with saturated aqueous NaHCCh solution (50 mL), dried over sodium sulfate and filtered. The solvent was removed. The residue was purified by silica column chromatography, eluting with 0-100% EtOAc in heptane, to afford the title compound (1.10 g, 76%) as a tan gum. δH (400 MHz, CD₃OD) 7.35 (d, J8.4 Hz, 1H), 7.18 (dd, J

8.3, 6.5 Hz, 1H), 5.85 (tt, 74.6 Hz, 1H), 5.25 (d, 78.7 Hz, 1H), 4.28 (t, 77.5 Hz, 1H),

3.67 (s, 3H), 2.80-2.66 (m, 1H), 2.52 (s, 3H), 2.48-2.21 (m, 3H), 2.17-1.98 (m, 3H), 1.95- 1.71 (m, 2H), 1.58-1.40 (m, 2H). LCMS (Method 1): [M+H f m/z 530, RT 1.90 minutes. INTERMEDIATE 109

A mixture of lithium hydroxide monohydrate (268 mg, 6.23 mmol) and Intermediate 108 (1.10 g, 2.08 mmol) in THF (24 mL), water (4 mL) and methanol (7 mL) was stirred at 40°C for 8 h. The reaction mixture was concentrated to low volume in vacuo. The residue was diluted with EtOAc (50 mL), and 2M aqueous HC1 was added until pH 2 was achieved. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic extracts were washed with brine and dried over sodium sulfate, then filtered and concentrated to dryness in vacuo, to afford the title compound (1070 mg, 96%) as a yellow solid. LCMS (Method 1): [M+H]⁺ m/z 516, RT 1.81 minutes.

INTERMEDIATE 110

To a stirred suspension of Intermediate 109 (170 mg, 0.330 mmol) and 5- hydrazinopyrazine-2-carbonitrile (49 mg, 0.363 mmol) in ethyl acetate (4.25 mL) were added pyridine (0.12 mL, 1.48 mmol) and T3P® (0.24 mL, 0.825 mmol). The mixture was stirred at r.t. for 90 minutes, then the solvent was removed. The residue was purified by reverse-phase column chromatography, eluting with 0-60% acetonitrile in water, to afford the title compound (102 mg, 49%) as a yellow gum. LCMS (Method 7): [M+H]⁺ m/z 633, RT 2.91 minutes.

INTERMEDIATE 111

To 6-bromopyridine-2, 3-diamine (100 g, 521.1 mmol) was added a solution of di- tert-butyl dicarbonate (126.5 g, 573.8 mmol) in ethanol (550 mL), followed by guanidine hydrochloride (5.6 g, 58 mmol). The mixture was heated at 50°C for 21 h, then cooled to ambient temperature. The precipitate was filtered off, then washed with ethanol (100 mL) and isohexane (300 mL) and dried, to afford the title compound (125.6g, 84%) as a crystalline tan powder. δH (300 MHz, DMSO-de) 8.45 (s, 1H), 7.55 (d, 78.0 Hz, 1H), 6.69 (d, 78.0 Hz, 1H), 6.24 (s, 2H), 1.46 (s, 9H).

INTERMEDIATE 112

To a mixture of Intermediate 111 (25.00 g, 86.76 mmol) and Intermediate 9 (30.5 g, 93.2 mmol) in ethyl acetate (200 mL) and pyridine (28 mL, 346 mmol) in an ice bath was added T3P® (130 mL, 220.6 mmol) dropwise over 20 minutes. After 15 minutes, the material was removed from the ice bath and stirred at r.t. for 2 h. The reaction mixture was cooled in an ice bath and diluted with IN HC1 (100 mL), then the phases were separated. The organic phase was washed with brine (100 mL) and water (100 mL), then dried in a phase separator. The solvent was removed. The crude solid was suspended in TBME (300 mL) and heated at reflux with stirring for 1 h, then cooled to r.t. with stirring. The solids were filtered off, then washed with TBME (60 mL) and isohexane (20 mL) and dried under vacuum, to give the title compound (26.56 g, 50.2%) as a white solid, δH (300 MHz, DMSO-de) 10.87 (s, 1H), 8.15-7.90 (m, 2H), 7.79 (d, 77.6 Hz, 1H), 7.56 (d, 7 8.5 Hz, 1H), 7.45-7.28 (m, 5H), 5.07 (d, 71.5 Hz, 2H), 4.27 (t, 77.4 Hz, 1H), 2.28-1.63 (m, 9H), 1.43 (s, 9H).

INTERMEDIATE 113

To a stirred solution of Intermediate 112 (8.00 g, 12.7 mmol) in DCM (40 mL) were added TFA (10 mL, 132.3 mmol) and water (0.5 mL). The reaction mixture was heated at reflux for 6 h, then cooled to r.t. and poured into ice-cold saturated NaHCCh solution (120 mL). Solid NaHCCh was added until effervescence subsided. Water (50 mL) was added, and the phases were separated. The organic phase was dried (phase separator) and concentrated in vacuo. The resulting crude solid was dissolved in TBME by heating at 55°C for 45 minutes. The solution was cooled to r.t. with stirring, then cooled in an ice bath for 1 h to initiate precipitation, and left at r.t. overnight. The solids were filtered off, then washed with isohexane, to afford the title compound (5.63 g, 88%) as a dull white solid. LCMS (Method 4): [M+H]⁺ m/z 479/481, RT 1.08 minutes.

INTERMEDIATE 114

Intermediate 113 (1.00 g, 2.09 mmol) was dissolved in DMF (15 mL) and cooled to 0°C. Sodium hydride (209 mg, 5.22 mmol) was added. The reaction mixture was stirred at 0°C for 10 minutes, then [2-(chloromethoxy)ethyl]trimethylsilane (923μL , 5.22 mmol) was added dropwise. The mixture was stirred at r.t. for 1.5 h, then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x 15 mL). The organic fractions were combined and washed with saturated brine (2 x 15 mL), then dried (Na2S04) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-20% ethyl acetate in heptane, to afford the title compounds (1.5 g, 92%) as a colourless oil. LCMS (Method 1): [M+H]⁺ m/z 739, 741, RT 2.50, 2.62 minutes.

INTERMEDIATE 115

Zinc (493 mg, 7.54 mmol) was stirred in THF (8 mL) at r.t., and bromine (52 μL, 1.01 mmol) was added as a solution in THF (0.5 mL). Methyl 1-bromocyclopropane- carboxylate (0.90 g, 5.03 mmol) was added as a solution in THF (0.5 mL). The mixture was stirred at 55°C for 2 h, then cooled to r.t., to give the title compound as a colourless solution (with some zinc settled at the bottom), which was utilised without further purification. INTERMEDIATE 116

To a stirred solution of Intermediate 114 (1.50 g, 2.02 mmol) in THF (10 mL) at r.t. were added ( 1 ,2,3 ,4, 5-pentaphenylcyclopenta-2,4-dien- 1 -yl)[ 1 -(2,2,4,4-tetramethyl- pentan-3 -yl)cyclopenta-2,4-dien- 1 -yl]iron (56 mg, 0.081 mmol) and (1E,4E)-1,5- diphenylpenta- 1 ,4-dien-3 -one palladium (2:1) (47 mg, 0.081 mmol), followed by Intermediate 115 in THF (8.0 mL, 4.40 mmol). The mixture was stirred at r.t. for 20 minutes, then diluted with saturated aqueous ammonium chloride solution (25 mL) and extracted with ethyl acetate (15 mL). The organic fraction was washed with saturated brine (15 mL), then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 5-25% ethyl acetate in heptane, to give the title compounds (1.4 g, 84%) as a pink gum. LCMS (Method 1): [M+H]⁺ m/z 759, RT 2.43, 2.51 minutes.

INTERMEDIATE 117

Intermediate 116 (1.07 g, 1.34 mmol) and 4M lithium tetrahydroborate in THF (937μL , 3.75 mmol) were stirred in THF (20 mL) at r.t. overnight. The mixture was retreated with 4M lithium tetrahydroborate in THF (335 μL, 1.34 mmol) and stirred at r.t. for another 4.5 h. The mixture was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2 x 20 mL). The organic fractions were combined and washed with saturated brine (20 mL), then dried (Na2SC>4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 5-35% ethyl acetate in heptane, to give the title compounds (748 mg, 76%) as a colourless oil. LCMS (Method 1): [M+H]⁺ m/z 731, RT 2.37, 2.43 minutes.

INTERMEDIATE 118

To a solution of Intermediate 117 (725 mg, 0.99 mmol) in DCM (15 mL) was added Dess-Martin periodinane (547 mg, 1.29 mmol) and the mixture was stirred for 30 minutes at r.t. The suspension was diluted with half-saturated aqueous sodium hydrogen carbonate solution (20 mL), and the organic layer was separated and saved. The aqueous layer was extracted with DCM (15 mL). The organic fractions were combined and passed through a hydrophobic frit, then concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-30% ethyl acetate in heptane, to give the title compounds (635 mg, 87%) as a colourless oil. LCMS (Method 1): [M+H]⁺ m/z 729, RT 2.41, 2.49 minutes.

INTERMEDIATE 119

To a stirred suspension of Intermediate 118 (585 mg, 0.80 mmol) in methanol (15 mL) was added potassium carbonate (277 mg, 2.01 mmol), followed by dimethyl (1- diazo-2-oxopropyl)phosphonate (277 mg, 1.44 mmol). The mixture was stirred at r.t. overnight, then concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-20% ethyl acetate in heptane, to give the title compounds (542 mg, 86%) as a colourless oil. LCMS (Method 1): [M+H]⁺ m/z 725, RT 2.56, 2.69 minutes.

INTERMEDIATE 120

To a solution of Intermediate 119 (325 mg, 0.45 mmol) in THF (6 mL) were added chloro( 1 ,2,3 ,4, 5-pentamethylcyclopenta-2,4-dien- 1 -y l)ruthenium;( 1 {Z},5{Z})- cycloocta- 1 ,5-diene (26 mg, 0.067 mmol) and a 0.5M solution of 2,2,2-trifluoroethyl azide in TBME (1.26 mL, 0.63 mmol). The mixture was stirred at 60°C for 1 h, then cooled to r.t. The solution was diluted with half-saturated brine (15 mL) and extracted with ethyl acetate (2 x 15 mL). The organic fractions were combined, dried (Na2SC>4) and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 5-40% ethyl acetate in heptane, to give the title compounds (330 mg, 74%) as a brown oil. LCMS (Method 1): [M+H]⁺ m/z 850, RT 2.43, 2.49 minutes.

INTERMEDIATE 121

Aqueous HC1 (2M, 4.0 mL) was added to a stirred solution of Intermediate 120 (270 mg, 0.32 mmol) in ethanol (8 mL). The reaction mixture was stirred at 65°C for 5 h, then additional 2M aqueous HC1 (1 mL) was added. The resulting solution was stirred at 65°C overnight, then concentrated, diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 x 10 mL). The organic fractions were combined, then purified by flash column chromatography, eluting with a gradient of 50-75% ethyl acetate in heptane, to give the title compound (129 mg, 69%) as a cream solid. LCMS (Method 1): [M+H]⁺ m/z 590, RT 1.91 minutes. INTERMEDIATE 122

Palladium on carbon (50% wet with water) (5.0%, 35 mg, 0.033 mmol) was added to a stirred solution of Intermediate 121 (129 mg, 0.219 mmol) in ethyl acetate (6 mL). The reaction mixture was placed under a hydrogen atmosphere and stirred at r.t. for 6.5 h. The mixture was left standing under nitrogen overnight, then stirred under a hydrogen atmosphere for 3.5 h. The mixture was filtered, then concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 60-100% ethyl acetate in heptane, followed by 0-15% methanol in ethyl acetate, to afford the title compound (46 mg, 41%) as a colourless gum. LCMS (Method 1): [M+H]⁺ m/z 456, RT 1.52 minutes.

INTERMEDIATE 123

Intermediate 35 (378 mg, 0.735 mmol), 6-fluoroimidazo[l,2-a]pyridine (100 mg,

0.735 mmol), 2, 2-dimethyl- 1, 3 -dioxane-4,6-di one (106 mg, 0.735 mmol) and proline (4.2 mg, 0.0367 mmol) were suspended in dry acetonitrile (3 mL). The reaction mixture was heated in a sealed tube with stirring at 50°C for 16 h, then cooled to r.t. The resulting solid was filtered off, then washed with diethyl ether and dried, to afford the title compound (507 mg, 88%) as a white solid. LCMS (Method 1): [M+H]⁺ m/z 777.0, RT

2.06 minutes.

INTERMEDIATE 124

Intermediate 123 (507 mg, 0.653 mmol) was dissolved in pyridine:EtOH (1.35 mL:0.15 mL), and copper (2.0 mg, 0.0315 mmol) was added to the mixture. The solution was stirred under reflux at 120°C for 2 h then solvent was removed under reduced pressure. Ethanol was added, and the resulting material was evaporated to dryness. The residue was diluted with EtOAc (25 mL) and washed with water (20 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness in vacuum. The crude material was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, to afford the title compound (450 mg, 96%) as a white solid. LCMS (Method 1): [M+H]⁺ m/z 721, RT 2.35 minutes.

INTERMEDIATE 125

To a solution of Intermediate 124 (220 mg, 0.305 mmol) in DCM (6 mL) was added 1M diisobutylaluminium hydride (0.92 mL, 0.916 mmol) dropwise at -78°C. The reaction mixture was warmed to r.t. and stirred for 16 h, then carefully quenched by adding saturated aqueous NaHCCh solution dropwise to the reaction mixture at 0°C. The resulting solid was filtered off and washed with DCM. The filtrate was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness in vacuum. The crude residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, to afford the title compound (183 mg, 88%) as an off-white solid. LCMS (Method 1): [M+H]⁺ m/z 679, RT 2.14 minutes.

INTERMEDIATE 126

A mixture of Intermediate 125 (183 mg, 0.270 mmol) and DMSO (0.096 mL, 1.35 mmol) in DCM (4.5 mL) was cooled to 0°C. DIPEA (0.14 mL, 0.809 mmol) was added, followed by sulfur trioxide pyridine complex (1 : 1) (86 mg, 0.539 mmol) portionwise.

The reaction mixture was stirred at r.t. over 1 h, then diluted with DCM (20 mL) and washed with water (20 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness in vacuum. The crude residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, to afford the title compound (153 mg, 84%) as a pale yellow solid. LCMS (Method 1): [M+H]⁺ m/z 677.5, RT 2.27 minutes.

INTERMEDIATE 127

To a solution of Intermediate 126 (153 mg, 0.226 mmol) in DCM (4 mL) at 0°C was added bis(2-methoxyethyl)aminosulfur trifluoride in toluene (2.7M, 0.18 mL, 0.497 mmol) dropwise, then a catalytic amount of EtOH (1 drop) was added. The resulting mixture was warmed to r.t. and stirred for 2 h, then quenched with saturated aqueous NaHCCh solution (5 mL). The layers were separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The organic phases were combined and dried over magnesium sulfate, then filtered and concentrated to dryness in vacuum. The crude residue was purified by flash column chromatography, eluting with a gradient of 0-70% ethyl acetate in heptane, to afford the title compound (71 mg, 45%) as a yellow solid. LCMS (Method 1): [M+H]⁺ m/z 699, RT 2.37 minutes.

INTERMEDIATE 128

Intermediate 127 (71 mg, 0.102 mmol) in trifluoromethanesulfonic acid (2.0 mL, 22.3 mmol) and toluene (2 mL) was heated under microwave irradiation at 120°C for 3 h.

The reaction mixture was poured into water, then basified with saturated aqueous NaHCCh solution and extracted with DCM (2 x 20 mL). The organic phases were dried over magnesium sulfate, filtered and concentrated to dryness in vacuum. The crude residue was purified by flash column chromatography, eluting with a gradient of 0-10% methanol in DCM, to afford the title compound (36 mg, 89%) as a pale yellow solid. LCMS (Method 1): [M+H]⁺ m/z 339, RT 0.72 minutes. INTERMEDIATE 129 -

Intermediate 19 (33 mg, 0.114 mmol) was added to a stirred suspension ofHATU (43 mg, 0.114 mmol) and DIPEA (45 μL, 0.259 mmol) in DCM (4 mL). The reaction mixture was stirred at r.t. under nitrogen for 20 minutes, then Intermediate 128 (35 mg, 0.103 mmol) was added as a solution in DCM (1 mL). The reaction mixture was stirred at r.t. for 16 h, then diluted with DCM (5 mL) and quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 x 10 mL). The organic phases were combined and dried over magnesium sulfate, then filtered and concentrated to dryness in vacuum. The crude residue was purified by flash column chromatography, eluting with a gradient of 10-100% ethyl acetate in heptane, to afford the title compound (51 mg, 80%) as an off- white solid. LCMS (Method 9): [M+H]⁺ m/z 614.3, RT 0.78 minutes.

INTERMEDIATE 130

A solution of Intermediate 129 (51 mg, 0.0831 mmol) in acetic acid (20 mL) was heated at 60°C for 10 h. The reaction mixture was concentrated in vacuum. The residue was dissolved in DCM (15 mL) and cautiously quenched with saturated aqueous sodium hydrogen carbonate solution (10 mL). The layers were separated. The aqueous layer was extracted with DCM (2x 15 mL). The organic phases were dried over magnesium sulfate, filtered and concentrated to dryness in vacuum. The crude residue was purified by flash column chromatography, eluting with a gradient of 0-100% ethyl acetate in heptane, to afford the title compound (45 mg, 89%) as a white solid. LCMS (Method 8): [M+H]⁺ m/z 596.2, RT 1.11 minutes. INTERMEDIATE 131

TFA (110μL, 1.48 mmol) was added dropwise to a stirred solution of Intermediate 130 (44 mg, 0.0739 mmol) in DCM (3 mL) at r.t. The reaction mixture was stirred at r.t. for 16 h, then concentrated in vacuum. The resulting viscous brown oil was re-dissolved in DCM (10 mL) and cautiously quenched with saturated aqueous sodium hydrogen carbonate solution (5 mL). The layers were separated. The aqueous layer was extracted with DCM (2 x 10 mL). The organic phases were dried over magnesium sulfate, then filtered and concentrated to dryness in vacuum, to afford the title compound (51 mg, 80%) as an off-white solid. LCMS (Method 8): [M+H]⁺ m/z 496.15, RT 0.91 minutes.

INTERMEDIATE 132

To a solution of dicyclohexylamine (150 mL, 747 mmol) in toluene (1.00 L) at 0°C was added w-butyllithium (2.5 M in hexanes, 300 mL, 750 mmol) dropwise, maintaining the internal temperature below 5°C (exothermic). After 35 minutes, the suspension was warmed to 20°C and stirred for 60 minutes, then cooled to 0°C. Ethyl 4,4-difluorocyclohexanecarboxylate (152 mL, 826 mmol) was added dropwise, maintaining the internal temperature below 3°C (exothermic). The mixture was maintained at 0°C for 25 minutes, then warmed to 20°C and held at 20°C for 10 minutes. To the suspension was added Intermediate 113 (53.0 g, 110 mmol) in one portion, followed by chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)] palladium(II) (5.7 g,

11 mmol) in one portion. The mixture was stirred for 18 h. To the brown solution was added 2.5M aq citric acid (600 mL), followed by water (600 mL) and ethyl acetate (1.00 L). The mixture was filtered through Celite®, and the filtrate was separated. The organic phase was washed with water (2 x 900 mL), dried over sodium sulfate and concentrated m vacuo. The resulting crude viscous syrup was purified by flash chromatography, eluting with a gradient of 0-50% EtOAc in isohexane, to give the title compound (55.9 g, 79%) as a yellow solid. LCMS (Method 5): [M+H]⁺ m!z 591, RT 2.25 minutes.

INTERMEDIATE 133

To a solution of Intermediate 132 (1.63 g, 2.76 mmol) in DCM (27.6 mL) was added DIPEA (0.96 mL, 5.52 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.77 mL, 4.14 mmol). The mixture was stirred at r.t. for 30 minutes, then diluted with water (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-60% EtOAc in isohexane, to give the title compounds (1.66 g, 83%) as a colourless amorphous solid. LCMS (Method 4): [M+H]⁺ m/z 721, RT 1.60, 1.66 minutes.

INTERMEDIATE 134

To a solution of Intermediate 133 (1.89 g, 2.62 mmol) in THF (26.2 mL) at 0°C was added diisobutylaluminium hydride (0.50M in hexanes, 15.7 mL, 7.86 mmol) dropwise over 30 minutes. After 2.5 h, the reaction mixture was quenched with saturated aqueous Rochelle salt solution (50 mL), then warmed to r.t. and left to stir overnight. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over sodium sulfate, passed through a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in isohexane, to give the title compounds (1.64 g, 92%) as a colourless amorphous solid. LCMS (Method 4): [M+H]⁺ m/z 679, RT 1.45, 1.49 minutes.

INTERMEDIATE 135

To a solution of Intermediate 134 (1.64 g, 2.42 mmol) in DCM (24.2 mL) at 0°C was added Dess-Martin periodinane (1.30 g, 2.91 mmol). The reaction mixture was allowed to warm to r.t. and stirred for 30 minutes, then quenched with saturated aqueous sodium bicarbonate solution (50 mL). The aqueous layer was extracted with DCM (3 x 50 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-80% EtOAc in isohexane, to give the title compounds (1.37 g, 84%) as a pale yellow amorphous solid. LCMS (Method 4): [M+H]⁺ m/z 677, RT 1.53, 1.58 minutes.

INTERMEDIATE 136

To a solution of Intermediate 135 (1.37 g, 2.02 mmol) and dimethyl (l-diazo-2- oxopropyl)phosphonate (0.54 mL, 3.03 mmol) in methanol (20.2 mL) at 0°C was added potassium carbonate (0.84 g, 6.07 mmol). The solution was stirred for 1 h, then quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, passed through a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-60% EtOAc in isohexane, to give the title compounds (1.30 g, 96%) as a colourless, amorphous solid. LCMS (Method 4): [M+H]⁺ m/z 673, RT 1.60, 1.65 minutes.

INTERMEDIATE 137

To a solution of Intermediate 136 (1.00 g, 1.49 mmol) and 2-azido- 1,1,1 -trifluoro- ethane (0.5M in DME, 4.5 mL, 2.23 mmol) in THF (3.72 mL) was added chloro(l,5- cyclooctadieneXpentamethylcyclopentadienyl)ruthenium(n) (57 mg, 0.15 mmol). The reaction mixture was stirred at 60°C for 2 h, then allowed to cool to r.t. and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in isohexane, to give the title compounds (981 mg, 82%) as a brown, amorphous solid. LCMS (Method 4): [M+H]⁺ m!z 798, RT 1.49, 1.54 minutes.

INTERMEDIATE 138

To a vial containing Intermediate 137 (981 mg, 1.23 mmol) was added HC1 (4.0M in 1,4-dioxane, 12.3 mL). The reaction mixture was stirred at r.t. overnight, then concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in isohexane, followed by 0-10% methanol in EtOAc, to give the title compound (560 mg, 68%) as an off-white amorphous solid. LCMS (Method 4): [M+H]⁺ m!z 668, RT 1.19 minutes. INTERMEDIATE 139

To a solution of Intermediate 138 (560 mg, 0.84 mmol) in ethanol (8.4 mL) under an atmosphere of N2 was added 10% palladium on carbon (56 mg, 0.053 mmol), and the reaction flask was placed under an atmosphere of Hz. The reaction mixture was stirred at r.t. for 7.5 h, then passed through a pad of Celite® and concentrated in vacuo, to give the title compound (429 mg, 96%) as an orange amorphous solid. LCMS (Method 4): [M+H]⁺ m!z 534, RT 0.95 minutes.

EXAMPLES 1 & 2

HATU (36 mg, 0.094 mmol) was added to a stirred solution of DIPEA (82μL , 0.47 mmol), Intermediate 12 (36 mg, 0.078 mmol) and 1 -methyl- l//-pyrazole-5- carboxylic acid (11 mg, 0.086 mmol) in DCM (1.5 mL) at room temperature. The mixture was stirred for 1 h, then diluted with water (3 mL) and extracted with DCM (5 mL). The organic fraction was passed through a phase separator and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 50-100% ethyl acetate in heptanes. The diastereomers of the resulting colourless glass (21 mg) were separated using acidic, reverse-phase HPLC (Separation Method 1) to afford distomer Example 1 (RT 17.79 minutes) (6.9 mg, 16%) and eutomer Example 2 (RT 23.36 minutes) (6.4 mg, 14%) as colourless gums.

Example 1: δH (500 MHz, CD₃OD) 7.89 (s, 1H), 7.48 (d, J2.1 Hz, 1H), 7.42-7.23 (m,

1H), 7.16-7.09 (m, 1H), 6.94 (d, J2.\ Hz, 1H), 5.28-5.17 (m, 3H), 4.73 (q, 77.2 Hz, 1H), 4.08 (s, 3H), 2.32-2.22 (m, 1H), 2.16-1.98 (m, 3H), 1.90-1.75 (m, 2H), 1.73 (d, J 7.3 Hz, 3H), 1.59-1.35 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z 569, RT 2.93 minutes.

Example 2: δH (500 MHz, CD₃OD) 7.89 (s, 1H), 7.48 (d, J 2.1 Hz, 1H), 7.44-7.22 (m, 1H), 7.16-7.09 (m, 1H), 6.93 (d, J2.\ Hz, 1H), 5.28-5.15 (m, 3H), 4.73 (q, 77.2 Hz, 1H), 4.08 (s, 3H), 2.33-2.22 (m, 1H), 2.16-1.98 (m, 3H), 1.90-1.75 (m, 2H), 1.73 (d, 77.3 Hz,

3H), 1.58-1.35 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z 569, RT 2.92 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 1 and 2.

EXAMPLE 3

HATU (31 mg, 0.079 mmol) was added to a stirred solution of DIPEA (16 μL, 0.092 mmol), Intermediate 21 (28 mg, 0.061 mmol) and l-methyl-l//-pyrazole-5- carboxylic acid (10 mg, 0.079 mmol) in DCM (2 mL) at room temperature. The mixture was stirred for 2 h, then concentrated and dissolved in DMSO (1 mL). The solution was purified via acidic, reverse-phase HPLC (Separation Method 2) to afford the title compound (8 mg, 18%) as a white powder, δH (400 MHz, DMSO-de) 13.05-12.63 (m, 1H), 9.03-8.85 (m, 1H), 8.55 (s, 1H), 7.48 (m, 1H), 7.26 (d, 78.4 Hz, 1H), 7.07 (dd, 73.8,

2.1 Hz, 1H), 6.95-7.04 (m, 1H), 5.13 (m, 1H), 4.71 (m, 1H), 4.02 (s, 3H), 2.29 (m, 2H), 2.18-1.90 (m, 3H), 1.91-1.70 (m, 3H), 1.67 (m, 2H), 1.60-1.45 (m, 1H), 1.46-1.19 (m, 3H). LCMS (Method 5): [M+H]⁺ m/z 569, RT 1.47 minutes. EXAMPLE 4

To a solution of Intermediate 28 (34 mg, 0.076 mmol) in DCM (2 mL) at room temperature were added 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (55 mg, 0.086 mmol), DIPEA (30 μL, 0.172 mmol) and HATU (36 mg, 0.0918 mmol). The mixture was stirred for 1 h, then diluted with saturated aqueous sodium bicarbonate solution (30 mL), water (30 mL) and DCM (30 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-10% methanol in DCM, to give the title compound (20 mg, 47%) as a colourless solid, δH (400 MHz, DMSO-de) 12.71 (s, 1H), 9.68 (d, 78.4 Hz, 1H), 8.56 (s, 1H), 7.28 (d, 78.3 Hz, 1H), 7.07 (t, 77.5 Hz, 1H), 5.23-5.11 (m, 3H), 4.25 (s, 2H), 2.47 (s, 3H), 2.31-2.25 (m, 1H), 2.12-1.91 (m, 3H), 1.91-1.70 (m, 2H), 1.55 (d, 713.5 Hz, 1H),

1.49-1.22 (m, 2H). LCMS (Method 4): [M+H]⁺ m/z 557, RT 0.91 minutes.

EXAMPLE 5

To a solution of Intermediate 28 (34 mg, 0.076 mmol) in DCM (2 mL) at room temperature were added 4-ethyl- 1 ,2, 5-oxadiazole-3 -carboxylic acid (60 mg, 0.084 mmol), DIPEA (30μL, 0.172 mmol) and HATU (36 mg, 0.0918 mmol). The mixture was stirred for 1 h, then diluted with saturated aqueous sodium bicarbonate solution (30 mL), water (30 mL) and DCM (30 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-10% methanol in DCM, to give the title compound (20 mg, 46%) as a colourless solid, δH (400 MHz, DMSO-de) 12.97 (s, 0.25H), 12.72 (s, 0.75H), 9.71 (d, J 8.5 Hz, 0.75H), 9.66-9.54 (m, 0.25H), 8.56 (d, 73.0 Hz, 1H), 7.39 (d, 78.2 Hz, 0.75H), 7.28 (d, 78.3 Hz, 0.25H), 7.07 (dd, 78.2, 6.7 Hz, 1H), 5.27-5.10 (m, 3H), 4.31-4.25 (m, 2H), 2.90 (qd, 77.5, 0.9 Hz, 2H), 2.33-2.20 (m, 1H), 2.14-1.91 (m, 3H), 1.91-1.68 (m, 2H), 1.55 (d, 713.4 Hz, 1H), 1.47-1.27 (m, 2H), 1.25-1.18 (m, 3H). NMR reveals tautomers. LCMS (Method 4): [M+H]⁺ m/z 571, RT 0.91 minutes.

EXAMPLE 6

To a solution of Intermediate 28 (34 mg, 0.076 mmol) in DCM (2 mL) and DMF (0.5 mL) at room temperature were added 1 -methyl- l/f-pyrazole-5-carboxylic acid (11 mg, 0.083 mmol), DIPEA (30 μL, 0.17 mmol) and HATU (36 mg, 0.0918 mmol). The mixture was stirred for 2 h, then diluted with saturated aqueous sodium bicarbonate solution (30 mL), water (30 mL) and DCM (30 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2 x 30 mL). The combined organic layers were dried and concentrated. The residue was purified by flash column chromatography, eluting with a gradient of 0-10% methanol in DCM, to give the title compound (25 mg, 60%) as a colourless solid, δH (400 MHz, DMSO-de) 12.97 (s, 0.25H), 12.72 (s, 0.75H), 8.99 (d, 78.6 Hz, 0.75H), 8.91 (s, 0.25H), 8.55 (s, 1H), 7.47 (d, 72.1 Hz, 1H), 7.26 (d, 7

8.2 Hz, 1H), 7.11-6.98 (m, 2H), 5.15 (q, 78.9 Hz, 3H), 4.25 (s, 2H), 4.02 (s, 3H), 2.32- 2.24 (m, 1H), 2.12-1.92 (m, 3H), 1.90-1.66 (m, 2H), 1.53 (d, 713.3 Hz, 1H), 1.45-1.22 (m, 2H). LCMS (Method 4): [M+H]⁺ m/z 555, RT 0.88 minutes. EXAMPLE 7

A mixture of Intermediate 34 (100 mg, 0.21 mmol), triethyl orthoformate (53.4 pL, 0.31 mmol), acetic acid (0.24 mL, 4.2 mmol) and cyclopropylmethylamine (29.8 mg, 0.42 mmol) in 1,4-dioxane (2.1 mL) was stirred at 130°C for 2 h in a sealed vial. The reaction mixture was concentrated, and purified by Separation Method 2, to afford the title compound (5.0 mg, 3%) as a colourless powder, δH (400 MHz, DMSO-de) 13.18- 12.16 (m, 1H), 9.02-8.84 (m, 1H), 8.49 (s, 1H), 7.47 (d, 72.1 Hz, 1H), 7.22 (d, 78.3 Hz,

1H), 7.07 (dd, 75.4, 2.1 Hz, 1H), 6.86-6.71 (m, 1H), 5.13 (t, 78.5 Hz, 1H), 4.71 (q, 77.0 Hz, 1H), 4.02 (s, 3H), 3.55 (t, 76.7 Hz, 2H), 2.29 (s, 1H), 2.18-1.90 (m, 2H), 1.91-1.70 (m, 2H), 1.67 (d, 77.7 Hz, 3H), 1.60-1.45 (m, 1H), 1.46-1.19 (m, 2H), 0.91-0.78 (m, 1H), 0.49-0.30 (m, 2H), 0.30-0.21 (m, 1H), 0.19-0.08 (m, 1H). One proton signal not observed; COSY suggests obscured by HOD signal. LCMS (Method 5): [M+H]⁺ m/z 541, RT 1.91 minutes.

EXAMPLE S

A mixture of Intermediate 34 (100 mg, 0.21 mmol), triethyl orthoformate (53.4 pL, 0.31 mmol), acetic acid (0.24 mL, 4.2 mmol) and 3 ,3 -difluorocyclobutanamine (67.3 mg, 0.42 mmol) in 1,4-dioxane (2.1 mL) was stirred at 130°C for 2 h in a sealed vial. The reaction mixture was concentrated, and purified by Separation Method 2, to afford the title compound (14.0 mg, 8%) as a colourless powder. δH (400 MHz, DMSO-de) 13.10- 12.54 (m, 1H), 9.02-8.87 (m, 1H), 8.77 (d, J0.9 Hz, 1H), 7.47 (dd, 72.1, 1.3 Hz, 1H), 7.37-7.17 (m, 1H), 7.07 (t, J2.\ Hz, 1H), 6.73 (q, 76.8 Hz, 1H), 5.15 (t, 78.5 Hz, 1H), 4.69 (q, 76.9 Hz, 1H), 4.43-4.29 (m, 1H), 4.06-3.97 (m, 3H), 3.30-3.07 (m, 2H), 2.68- 2.60 (m, 1H), 2.47-2.24 (m, 2H), 2.13-1.90 (m, 3H), 1.90-1.70 (m, 2H), 1.66 (d, J 6.9 Hz,

3H), 1.61-1.46 (m, 1H), 1.45-1.20 (m, 2H). LCMS (Method 5): [M+H f m/z 577, RT 1.73 minutes.

EXAMPLE 9

A mixture of Intermediate 34 (100 mg, 0.21 mmol), triethyl orthoformate (53.4μL , 0.31 mmol), acetic acid (0.24 mL, 4.2 mmol) and l-aminobicyclo[ 1.1.1 ]pentane-3- carbonitrile (68.0 mg, 0.42 mmol) in 1,4-dioxane (2.1 mL) was stirred at 130°C for 2 h in a sealed vial. The reaction mixture was concentrated, and purified by Separation Method 2, to afford the title compound (47.0 mg, 23%) as a colourless powder, δH (400 MHz, DMSO-de) 13.10-12.63 (m, 1H), 8.97 (t, ./11.2 Hz, 1H), 8.54 (s, 1H), 7.54-7.44 (m, 1H), 7.42-7.18 (m, 1H), 7.12-7.02 (m, 1H), 6.60 (q, 78.0 Hz, 1H), 5.26-5.10 (m, 1H), 4.69 (q, 76.9 Hz, 1H), 4.03 (s, 3H), 2.64-2.55 (m, 3H), 2.49-2.44 (m, 3H), 2.40-2.24 (m, 1H),

2.12-1.70 (m, 5H), 1.68-1.51 (m, 4H), 1.48-1.22 (m, 2H). LCMS (Method 5): [M+H]⁺ m/z 578, RT 1.67 minutes. EXAMPLE 10

Intermediate 42 (28 mg, 0.065 mmol) was dissolved in DCM (2 mL) at r.t. and treated with 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (10 mg, 0.078 mmol), DIPEA (24μL , 0.138 mmol) and HATU (31 mg, 0.0791 mmol). The reaction mixture was stirred at r.t. for 3 h, then diluted with saturated aqueous NaHCCh solution (4 mL), water (2 mL) and DCM (8 mL). The layers were shaken and separated, and the aqueous layer was re- extracted with DCM (10 mL). The combined organic layers were dried through a phase separating cartridge and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 0-100% EtOAc/i sohexane, then 0-15% MeOHZEtOAc. The combined material was loaded onto an SCX-2 cartridge (lg) as a solution in DCM/MeOH (1:1). The SCX-2 cartridge was rinsed with MeOH (4 mL total), then washed with ammonia (3N). The ammonia washes were concentrated in vacuo. The residue was purified by flash column chromatography on KPNH silica, eluting with a gradient of 0-100% EtOAc, then 0-10% MeOHZEtOAc, to yield the title compound (4.3 mg, 12%). δH (400 MHz, DMSO-de) 12.64 (d, J 15.0 Hz, 1H), 9.65 (t, 78.8 Hz, 1H),

7.62 (s, 1H), 7.21 (d, 78.3 Hz, 1H), 6.93 (s, 1H), 6.73 (ddd, 78.9, 6.8, 2.4 Hz, 1H), 5.15 (td, 78.5, 2.3 Hz, 1H), 4.53 (q, 77.0 Hz, 1H), 3.43 (dd, 77.0, 4.8 Hz, 2H), 2.46 (d, 70.7 Hz, 3H), 2.28 (s, 1H), 1.97 (s, 3H), 1.80 (d, 718.4 Hz, 2H), 1.59-1.47 (m, 4H), 1.45-1.17 (m, 2H), 0.91-0.76 (m, 1H), 0.40 (dd, 76.9, 2.8 Hz, 1H), 0.37-0.27 (m, 1H), 0.21 (qd, 7 8.2, 7.1, 3.6 Hz, 1H), 0.11 (dd, 79.3, 4.8 Hz, 1H). LCMS (Method 5): [M+H]⁺ m/z 542, RT 1.85 minutes. EXAMPLES 11 & 12

HATU (51 mg, 0.13 mmol) was added to a stirred solution of DIPEA (117μL , 0.67 mmol), Intermediate 47 (86% purity, 60 mg, 0.11 mmol) and 4-methyl-l,2,5- oxadiazole-3 -carboxylic acid (16 mg, 0.12 mmol) in DCM (1.5 mL) at r.t. The mixture was stirred for 2 h, then washed with water (5 mL). The organic fraction was passed through a phase separator, then concentrated. The residue was dissolved in 1:1 DMSO: MeOH (2 mL) and purified via acidic, reverse-phase HPLC (Separation Method 3), then freeze-dried, to afford a white powder (31.5 mg). Chiral separation of the diastereomers

(Separation Method 4) gave two gums, which were freeze-dried to afford eutomer Example 11 (RT 8.87 minutes) (8 mg, 13%) and distomer Example 12 (RT 13.51 minutes) (10 mg, 16%) as white powders.

Example 11. δH (400 MHz, CD₃OD) 7.90 (s, 1H), 7.37 (d, 78.1 Hz, 1H), 7.03 (dd, 78.4, 6.6 Hz, 1H), 5.28 (d, 78.7 Hz, 1H), 5.25-5.16 (m, 1H), 4.84-4.74 (m, 2H), 2.55 (s, 3H),

2.42-2.28 (m, 1H), 2.20-2.00 (m, 3H), 1.97-1.71 (m, 5H), 1.65-1.38 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z 571, RT 3.36 minutes.

Example 12: δH (400 MHz, CD3OD) 7.90 (s, 1H), 7.37 (d, 78.4 Hz, 1H), 7.03 (dd, 78.4, 6.6 Hz, 1H), 5.30-5.16 (m, 2H), 4.83-4.76 (m, 2H), 2.55 (s, 3H), 2.42-2.28 (m, 1H), 2.20- 2.00 (m, 3H), 1.97-1.70 (m, 5H), 1.65-1.37 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z

571, RT 3.35 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 11 and 12. EXAMPLE 13

To a solution of a mixture of Intermediates 57 & 58 (37 mg, 0.053 mmol) in DCM (85 |JL) was added TFA (40μL). The resulting mixture was stirred at r.t. overnight, then concentrated in vacuo. The crude residue was purified by basic preparative HPLC to afford the title compound (9 mg, 29%) as a colourless solid, δH (400 MHz, DMSO-de) 13.28-12.24 (m, 1H), 9.71-9.53 (m, 1H), 7.50-7.26 (m, 1H), 7.19-7.10 (m, 1H), 5.75-5.42 (m, 2H), 5.17 (t, 78.3 Hz, 1H), 5.05 (q, 76.9 Hz, 1H), 2.48-2.45 (m, 3H), 2.32-2.23 (m,

1H), 2.12-1.67 (m, 8H), 1.59-1.50 (m, 1H), 1.47-1.20 (m, 2H). LCMS (Method 5): [M+H]⁺ m/z 572, RT 1.89 minutes.

EXAMPLE 14

To a solution of a mixture of Intermediates 59 & 60 (59 mg, 0.084 mmol) in DCM (160μL ) was added TFA (80μL). The resulting mixture was stirred at r.t. overnight, then concentrated in vacuo. The crude residue was purified by basic preparative HPLC to afford the title compound (19 mg, 39%) as a colourless solid, δH (400 MHz, DMSO-de) 13.04-12.61 (m, 1H), 9.73-9.50 (m, 1H), 7.45-7.26 (m, 1H), 7.13-7.01 (m, 1H), 5.92 (q, 7 8.8 Hz, 2H), 5.16 (t, 78.3 Hz, 1H), 4.85 (q, 77.0 Hz, 1H), 2.47 (s, 3H), 2.32-2.21 (m, 1H), 2.13-1.66 (m, 8H), 1.61-1.48 (m, 1H), 1.46-1.20 (m, 2H). LCMS (Method 5): [M+H]⁺ m/z 572, RT 2.03 minutes.

EXAMPLES 15 & 16

Intermediate 67 (80 mg, 0.17 mmol) was mixed with 4-methyl-l,2,5-oxadiazole- 3-carboxylic acid (28 mg, 0.21 mmol) and HATU (77 mg, 0.19 mmol), and the solids were dissolved in DCM (2 mL). DIPEA (0.1 mL, 0.6 mmol) was added and the mixture was stirred at r.t. overnight, then the volatiles were evaporated. The residue was purified by silica column chromatography, eluting with 0 to 100% EtOAc in hexanes. The isomers were separated by chiral LC (3-40% MeOH (+0.1% NH4OH); Column: Chiralpak IH-3 150 x 4.6 mm, 3 pm; Column Temperature: 35°C; Flow Rate: 3 mL/ minute) to give Example 15 (chiral LC RT 3.36 minutes) (5 mg, 5%) and Example 16 (chiral LC RT 4.08 minutes) (5 mg, 5%) as white solids.

Example 15: δH (400 MHz, DMSO-de) 12.78 (s, 1H), 9.61 (s, 1H), 8.22 (s, 1H), 7.88 (ddd, J 10.1, 5.0, 0.9 Hz, 1H), 7.45 (ddd, J 10.1, 8.0, 2.3 Hz, 1H), 7.23 (s, 1H), 6.80 (s, 1H), 5.23-4.97 (m, 2H), 2.48 (s, 3H), 2.28 (d, J 11.2 Hz, 1H), 2.00 (d, .730.6 Hz, 3H), 1.84 (d, .77.0 Hz, 4H), 1.77 (d, J 16.6 Hz, 1H), 1.56 (d, J 13.4 Hz, 1H), 1.49-1.21 (m, 1H). LCMS (Method 5): [M+H]⁺ m/z 557, [M-H]⁺ m/z 555, RT 1.65 minutes.

Example 16: δH (400 MHz, DMSO-de) 8.08 (s, 1H), 7.86 (dd, J 10.0, 5.1 Hz, 1H), 7.43 (ddd, J 10.1, 7.9, 2.2 Hz, 1H), 7.12 (s, 1H), 6.59 (s, 1H), 5.06 (dd, .734.9, 7.5 Hz, 2H), 2.49 (s, 3H), 2.20 (s, 1H), 2.10-1.92 (m, 2H), 1.83 (d, .77.0 Hz, 5H), 1.45 (d, J 13.3 Hz, 1H), 1.25 (d, 78.0 Hz, 2H). LCMS (Method 5): [M+H]⁺ m/z 557, [M-H]⁺ m/z 555, RT 1.64 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 15 and 16.

EXAMPLES 17 & 18

To a solution of Intermediate 79 (283 mg, 0.554 mmol) in DCM (4 mL) was added 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (78 mg, 0.610 mmol), followed by DIPEA (0.15 mL, 0.887 mmol) and HATU (0.25 g, 0.665 mmol). The reaction mixture was stirred for 18 h, then water (15 mL) was added. The organic layer was separated and passed through a hydrophobic frit. The solvent was removed. The resulting oil was purified by chromatography (lOg SNAP-Duo, 0-50% EtO Ac/i sohexane, then up to 70% EtOAc/heptane), followed by reverse-phase (30g, C18), to give a white solid (210 mg). The mixture was separated by chiral SFC (Chiralcel OD-H, 20 x 250 mm, 5 pm, 70:30 heptane:IPA) to give Example 17 (Chiral LC: RT 9.07 minutes) (68.7 mg) and Example 18 (Chiral LC: RT 15.6 minutes) (81.9 mg) as white solids.

Example 17\ δH (400 MHz, DMSO-de) 12.77 (s, 1H), 9.64 (s, 1H), 8.14 (s, 1H), 7.31 (s, 1H), 7.19-7.03 (m, 1H), 6.15-5.76 (m, 1H), 5.45 (dt, J 18.3, 9.1 Hz, 1H), 5.24-4.96 (m,

2H), 4.84 (t, J 7.6 Hz, 1H), 2.82-2.65 (m, 2H), 2.47 (s, 3H), 2.33-2.23 (m, 1H), 2.13-1.90 (m, 3H), 1.90-1.64 (m, 2H), 1.64-1.45 (m, 1H), 1.45-1.18 (m, 2H). LCMS (Method 3): [M+H]⁺ m/z 621, RT 3.41 minutes. Example 18: δH (400 MHz, DMSO-de) 12.77 (s, 1H), 9.65 (s, 1H), 8.14 (s, 1H), 7.30 (s, 1H), 7.18-7.03 (m, 1H), 6.15-5.76 (m, 1H), 5.46 (dq, J 17.8, 8.9 Hz, 1H), 5.26-4.97 (m, 2H), 4.84 (t, Jin Hz, 1H), 2.84-2.64 (m, 2H), 2.47 (s, 3H), 2.35-2.24 (m, 1H), 2.02 (d, J 39.7 Hz, 3H), 1.91-1.68 (m, 2H), 1.61-1.47 (m, 1H), 1.43-1.16 (m, 2H). LCMS (Method 3): [M+H]⁺ m/z 621, RT 3.41 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 17 and 18.

EXAMPLES 19 & 20

To a solution of Intermediate 82 (265 mg, 0.538 mmol) in DCM (4 mL) were added 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (76 mg, 0.592 mmol), DIPEA (0.15 mL, 0.861 mmol) and HATU (0.25 g, 0.646 mmol). The reaction mixture was stirred for 18 h, then water (15 mL) was added. The organic layer was separated and passed through a hydrophobic frit. The solvent was removed. The resulting oil was purified by chromatography (lOg SNAP-Duo, 0-70% EtO Ac/isohexane, then up to 70% EtOAc/ heptane), followed by reverse-phase (30g, C18), to give a white solid (178 mg). The mixture was separated by chiral SFC (Chiralcel OD-H, 20 x 250 mm, 5 pm, 70:30 heptane:EtOH) to give Example 19 (Chiral LC: RT 10.0 minutes) (48.8 mg) and Example 20 (Chiral LC: RT 15.4 minutes) (49.0 mg) as white solids.

Example 19: δH (400 MHz, CD₃OD) 7.99 (s, 1H), 7.36 (d, J8.4 Hz, 1H), 7.08 (dd, J8.4, 6.6 Hz, 1H), 6.26-5.94 (m, 1H), 5.94-5.62 (m, 1H), 5.24 (d, 78.7 Hz, 1H), 4.95-4.88 (m, 1H), 4.77-4.62 (m, 1H), 4.59-4.42 (m, 1H), 2.83-2.63 (m, 2H), 2.51 (s, 3H), 2.40-2.24 (m, 1H), 2.16-1.96 (m, 3H), 1.96-1.66 (m, 2H), 1.61-1.35 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z 603, RT 3.25 minutes.

Example 20: δH (400 MHz, CD₃OD) 7.99 (s, 1H), 7.36 (d, J8.0 Hz, 1H), 7.08 (dd, J8.4, 6.6 Hz, 1H), 6.27-5.94 (m, 1H), 5.94-5.62 (m, 1H), 5.25 (d, 78.7 Hz, 1H), 4.95-4.88 (m, 1H), 4.71 (td, J 15.2, 3.1 Hz, 1H), 4.51 (qd, J 13.6, 4.1 Hz, 1H), 2.83-2.63 (m, 2H), 2.51

(s, 3H), 2.38-2.26 (m, 1H), 2.15-1.95 (m, 3H), 1.93-1.66 (m, 2H), 1.63-1.27 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z 603, RT 3.24 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 19 and 20.

EXAMPLES 21 & 22

HATU (65 mg, 0.170 mmol) was added portionwise to a stirred solution of 4- methyl-1, 2, 5-oxadiazole-3-carboxylic acid (22 mg, 0.170 mmol), Intermediate 94 (75 mg,

0.142 mmol) and DIPEA (74μL , 0.426 mmol) in DCM (8 mL). The reaction mixture was stirred at r.t. for 8 h, then diluted with DCM (10 mL) and washed with saturated aqueous ammonium chloride solution (10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The resulting crude material was purified by silica column chromatography, eluting with 075% EtOAc in heptane, to give an off-white solid (51 mg). A sample of the mixture (45.0 mg) was separated using chiral SFC (Chiralpak IC, 10 x 250 mm, 5 pm, 10% MeOH, 90% CO2, 15 mL/minute) to give Example 21 (Chiral LC: RT [M+H]⁺ m/z 639, 4.05 minutes) (15 mg) and Example 22 (Chiral LC: [M+H]⁺ m/z 639, RT 2.37 minutes) (16 mg) as white solids.

Example 21. δH (500 MHz, CD₃0D) 8.10 (s, 1H), 7.37 (d, 78.4 Hz, 1H), 7.13 (dd, 78.5, 6.6 Hz, 1H), 5.31-5.19 (m, 2H), 5.09-5.00 (m, 1H), 4.85-4.79 (m, 1H), 3.29-3.07 (m, 2H), 2.53 (s, 3H), 2.39-2.27 (m, 1H), 2.18-1.99 (m, 3H), 1.94-1.71 (m, 2H), 1.64-1.37 (m, 3H).

LCMS (Method 3): [M+H]⁺ m/z 639, RT 3.54 minutes.

Example 22: δH (500 MHz, CD3OD) 8.08 (s, 1H), 7.36 (d, 78.5 Hz, 1H), 7.11 (dd, 78.4, 6.6 Hz, 1H), 5.32-5.19 (m, 2H), 5.02 (t, 77.3 Hz, 1H), 4.91-4.87 (m, 1H), 3.28-3.04 (m, 2H), 2.51 (s, 3H), 2.37-2.25 (m, 1H), 2.15-1.99 (m, 3H), 1.92-1.70 (m, 2H), 1.63-1.35 (m, 3H). LCMS (Method 3): [M+H]⁺ m/z 639, RT 3.53 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 21 and 22.

EXAMPLES 23 & 24

To a stirred suspension of Intermediate 96 (250 mg, 0.40 mmol) in DCM (2.5 mL) was added DIPEA (0.11 mL, 0.643 mmol) at r.t, followed by 4-methyl- 1 ,2, 5-oxadiazole- 3 -carboxylic acid (57 mg, 0.442 mmol) and HATU (0.18 g, 0.482 mmol). The reaction mixture was stirred overnight, then water (10 mL) was added. The organic layer was separated, and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined, passed through a hydrophobic frit and concentrated in vacuo. The residue was dry-loaded on to a 10 g, Sfar Duo column, eluting with 35-70% EtOAc in heptanes, to give an off-white powder (196 mg). The mixture was separated by chiral chromatography (Chiralcel OD-H, 20 x 250 mm, 5 pm, 70:30 heptane: IP A, 18 mL/minute), followed by reverse-phase chromatography (Sfar HC Duo, Cl 8, acetonitrile/water + 0.1% ammonium hydroxide) for each sample, to give Example 23 (53 mg, 21%) and Example 24 (55 mg, 22%). Example 23: δH (500 MHz, DMSO-de) 12.78 (s, 1H), 9.78-9.52 (m, 1H), 8.12 (s, 1H), 7.46-7.26 (m, 1H), 7.10 (dd, 78.3, 6.7 Hz, 1H), 6.44-6.18 (m, 1H), 5.24-5.12 (m, 1H), 4.93 (t, 77.4 Hz, 1H), 4.91-4.77 (m, 1H), 4.60-4.44 (m, 1H), 3.30-3.17 (m, 2H), 2.47 (s, 3H), 2.35-2.23 (m, 1H), 2.10-1.91 (m, 3H), 1.88-1.71 (m, 2H), 1.59-1.51 (m, 1H), 1.46- 1.22 (m, 2H). LCMS (Method 3): [M+H]⁺ m/z 621, RT 3.36 minutes. Analytical chiral LC (Chiralcel OD-H, 4.6 x 250 mm, 5 pm, 70:30 heptane:IPA, 1 mL/minute): RT 8.46 minutes.

Example 23: δH (500 MHz, DMSO-de) 13.19-12.67 (m, 1H), 9.76-9.49 (m, 1H), 8.12 (s, 1H), 7.46-7.26 (m, 1H), 7.10 (dd, 78.3, 6.7 Hz, 1H), 6.32 (tt, 754.2, 3.2 Hz, 1H), 5.18 (t, 77.7 Hz, 1H), 4.93 (t, 77.4 Hz, 1H), 4.85 (qd, 715.9, 2.7 Hz, 1H), 4.59-4.45 (m, 1H), 3.24 (dd, 718.4, 10.8 Hz, 2H), 2.47 (s, 3H), 2.35-2.25 (m, 1H), 2.10-1.91 (m, 3H), 1.90-

1.70 (m, 2H), 1.55 (d, 711.7 Hz, 1H), 1.45-1.21 (m, 2H). LCMS (Method 3): [M+H]⁺ m/z 621, RT 3.35 minutes. Analytical chiral LC (Chiralcel OD-H, 4.6 x 250 mm, 5 pm, 70:30 heptane:IPA, 1 mL/minute): RT 12.85 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 23 and 24.

EXAMPLE 25

To a solution of Intermediate 139 (30 mg, 0.056 mmol), HATU (26 mg, 0.067 mmol) and 4-methyl-l,2,5-oxadiazole-3-carboxylic acid (8 mg, 0.062 mmol) in DMF (0.56 mL) was added DIPEA (0.03 mL). The reaction mixture was stirred at r.t. for 5 minutes, then diluted with water (5 mL). The aqueous layer was extracted with DCM (3 x 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by flash chromatography, eluting with a gradient of 0-100% EtOAc in isohexane, followed by reverse-phase chromatography, eluting with a gradient of 40-55% acetonitrile in water (+ 0.1%

NH4OH), to afford the title compound (9 mg, 24%) as a colourless amorphous solid. δH (400 MHz, DMSO-d₆) 12.44 (1H, br), 9.55 (1H, s), 8.07 (1H, s), 7.93 (1H, s), 7.18 (1H, d, 77.0 Hz), 5.24 (1H, t, 77.0 Hz), 5.10 (2H, q, 78.5 Hz), 2.87-2.84 (2H, m), 2.49 (3H, s), 2.39-2.23 (3H, m), 2.09-1.74 (9H, m), 1.66-1.63 (1H, m), 1.51-1.24 (2H, m). LCMS (Method 5): [M+H]⁺ m/z 644, RT 2.10 minutes.

EXAMPLES 26 & 27

Intermediate 103 (130 mg, 0.200 mmol) was dissolved in THF (2 mL) and triethylamine (0.1 mL, 0.7 mmol) was added, followed by triphenylphosphine (105 mg, 0.400 mmol) and hexachloroethane (96 mg, 0.402 mmol), at 0°C in an ice bath. The ice bath was removed, and the reaction mixture was stirred at r.t. for 2 h. White solid was filtered off through Celite®, and the filtrate was concentrated. The residue was purified by silica column chromatography, eluting with 0-100% EtOAc in hexanes, then 0-100% MeOH in EtOAc. The resulting impure yellow oil (200 mg) was purified by basic Cl 8 reverse-phase HPLC, followed by chiral SFC (Chiralpak IH, 10% methanol + 0.1% NH4OH) to afford Example 26 (3.7 mg, 2.9%) and Example 27 (5.0 mg, 4.0%). Example 26: LCMS (Method 2): [M+H]⁺ m/z 632, RT 1.86 minutes. LCMS (Method 6): [M+H]⁺ m/z 632, RT 1.85 minutes. Analytical chiral LC (Chiralpak IH, 4.6 x 150 mm, 35°C, 15% MeOH (+ 0.1% NH₄OH), 3 mL/minute) RT 1.92 minutes.

Example 27: δH (400 MHz, DMSO-de) 12.79 (s, 1H), 9.66 (d, 1H), 9.15 (s, 1H), 7.95 (dd, 1H), 7.58 (dd, 1H), 7.29 (d, 1H), 7.17 (d, 1H), 5.47 (dd, 1H), 5.17 (t, 1H), 3.56 (m, 1H),

3.40 (m, 1H), 2.47 (s, 3H), 2.25 (m, 1H), 2.20-1.60 (m, 4H), 1.54 (d, 1H), 1.50-1.20 (m, 3H). LCMS (Method 2): [M+H]⁺ m/z 632, RT 1.85 minutes. LCMS (Method 6): [M+H]⁺ m/z 632, RT 1.83 minutes. Analytical chiral LC (Chiralpak IH, 4.6 x 150 mm, 35°C, 15% MeOH (+ 0.1% NHtOH), 3 mL/minute) RT 2.85 minutes.

The absolute stereochemistry of the chiral centre adjacent to the triazole ring has been arbitrarily assigned for Examples 26 and 27.

EXAMPLE 28

HATU (13 mg, 0.034 mmol) was added to a mixture of Intermediate 122 (87% purity, 15 mg, 0.029 mmol), DIPEA (12 μL, 0.072 mmol) and 4-ethyl- 1,2, 5-oxadiazole-3- carboxylic acid (4.9 mg, 0.034 mmol) in DMF (0.5 mL). The mixture was stirred at r.t. for 3 h, then re-treated with DIPEA (6.2 μL, 0.036 mmol), 4-ethyl-l,2,5-oxadiazole-3- carboxylic acid (2.4 mg, 0.017 mmol) and HATU (6.5 mg, 0.017 mmol). The mixture was stirred at r.t. for another 30 minutes, then diluted with half-saturated brine (10 mL) and extracted with ethyl acetate (2 x 5 mL). The organic fractions were combined and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 35-65% ethyl acetate in heptane. The resulting material was further purified by reverse-phase column chromatography, eluting with a gradient of 40- 55% acetonitrile in water (+ 0.1% formic acid) to afford the title compound (2.5 mg,

15%) as a white powder. δH (400 MHz, CD₃OD) 7.83 (s, 2H), 6.91 (d, 78.4 Hz, IH), 5.24 (d, 78.5 Hz, 1H), 5.11 (q, 78.6 Hz, 2H), 3.01-2.91 (m, 2H), 2.39-2.24 (m, 1H), 2.17- 1.97 (m, 3H), 1.93-1.69 (m, 4H), 1.64-1.34 (m, 5H), 1.29 (t, 77.5 Hz, 3H). LCMS (Method 3): [M+H]⁺ m/z 580, RT 3.41 minutes.

EXAMPLE 29

To a stirred solution of Intermediate 110 (101 mg, 0.160 mmol) in IHF (2.5 mL) were added triethylamine (0.089 mL, 0.639 mmol), hexachloroethane (76 mg, 0.319 mmol) and triphenylphosphine (84 mg, 0.319 mmol). The reaction vessel was sealed and the mixture was stirred for 18 h. The solids were filtered through Celite®, washing with EtOAc (3 mL), then the solvent was removed. The residue was purified by reverse-phase column chromatography, eluting with 0-60% acetonitrile in water, to afford the title compound (18 mg, 18%) as a white solid. δH (400 MHz, DMSO-d₆) 12.81 (s, 1H), 9.69 (s, 1H), 9.49 (d, 71.5 Hz, 1H), 9.35 (s, 1H), 7.45-7.22 (m, 1H), 7.13 (dd, 712.0, 7.5 Hz, 1H), 5.95-6.29 (m, 1H), 5.29 (t, 77.5 Hz, 1H), 5.16 (d, 77.8 Hz, 1H), 3.01-3.20 (m, 1H), 2.75-2.93 (m, 1H), 2.46 (s, 3H), 2.18-2.33 (m, 1H), 1.90-2.14 (m, 3H), 1.66-1.90 (m, 2H), 1.45-1.60 (m, 1H), 1.34-1.45 (m, 1H), 1.15-1.34 (m, 1H). LCMS (Method 7): [M+H]⁺ m/z 615, RT 3.22 minutes. EXAMPLE 30

To a solution of Intermediate 109 (100 mg, 0.194 mmol) in ethyl acetate (5.0 mL) were added pyridine (138 mg, 1.746 mmol) and T3P® (50 wt % solution in ethyl acetate, 0.91 mL, 1.23 mmol). The solution was stirred for 5 minutes at r.t, then 5-fluoro-2- hydrazinylpyridine (27 mg, 0.21 mmol) was added. The reaction mixture was heated in a pressure tube at 120°C for 33 h, then at 130°C for a further 24 h. The resulting material was concentrated in vacuo, and the residual syrup was added to saturated aqueous sodium bicarbonate solution (8 mL) with vigorous stirring for 5 minutes. The aqueous solution was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with a 10-100% gradient of ethyl acetate:ethanol (98:2) in heptane. Chiral separation of the resulting material (mixture of four stereoisomers) (supercritical fluid chromatography, isocratic 80:20 carbon dioxide:ethanol, Chiralpak AD-H, 10 x 250 mm, 5 pm, 15 mL/minute) afforded the title compound (second eluting isomer) (6.1 mg, 5%) as a colourless solid, δH (400 MHz, CD3OD) 8.04-8.00 (m, 1H), 7.79 (dd, J 10.1, 4.8 Hz, 1H), 7.42 (ddd, J 10.0, 7.9, 2.2 Hz, 1H), 7.32 (d, 78.4 Hz, 1H),

7.04 (dd, 78.4, 6.6 Hz, 1H), 6.02 (tt, 756.4, 4.7 Hz, 1H), 5.28-5.19 (m, 2H), 3.27-3.10 (m, 1H), 2.93-2.75 (m, 1H), 2.47 (s, 3H), 2.39-2.25 (m, 1H), 2.18-1.97 (m, 3H), 1.94-1.67 (m, 2H), 1.62-1.47 (m, 2H), 1.47-1.35 (m, 1H). LCMS (Method 7): [M+H]⁺ m!z 607, RT 3.18 minutes. Chiral analysis (Chiralpak AD-H, 4.6 x 250 mm, 5 pm, 4 mL/minute, isocratic 80:20 carbon dioxide:ethanol) RT 4.15 minutes.

The absolute stereochemistry at both chiral centres has been arbitrarily assigned. EXAMPLES 31 & 32

HATU (28 mg, 0.0727 mmol) was added portionwise to a stirred solution of 4- methyl- 1 ,2,5-oxadiazole-3-carboxylic acid (9.3 mg, 0.0727 mmol), DIPEA (32μL , 0.182 mmol) and Intermediate 131 (30 mg, 0.0605 mmol) in DCM (7 mL) at r.t. The mixture was stirred at r.t. for 16 h, then diluted with DCM (10 mL) and washed with aqueous NH4CI solution (10 mL). The organic layers were dried with sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography, eluting with a gradient of 00100% ethyl acetate in heptane. The resulting material was repurified by SCX column, eluting with MeOH, then with 2M NH3 in MeOH. The resulting off-white solid mixture (22 mg) was separated by chiral chromatography (Chiralpak IC, 10 x 250 mm, 5 μm, 25:75 methanol :CC>2, 15 mL/minute) to give Example 31 (10.1 mg) and Example 32 (8.1 mg). Example 31: δH (400 MHz, CD3OD) 8.01-7.93 (m, 1H), 7.83 (s, 1H), 7.58 (dd, 79.8, 5.0 Hz, 1H), 7.34-7.20 (m, 2H), 7.09-7.01 (m, 1H), 6.09-5.69 (m, 1H), 5.24 (d, 78.7 Hz, 1H), 5.06-4.95 (m, 1H), 3.01-2.71 (m, 2H), 2.51 (s, 3H), 2.38-2.25 (m, 1H), 2.17-1.97 (m, 3H), 1.93-1.68 (m, 2H), 1.65-1.35 (m, 3H). LCMS (Method 7): [M+H]⁺ m/z 606.3, RT 3.40 minutes. Analytical chiral SFC (Chiralpak IC, 4.6 x 250 mm, 5 pm, 30:70 methanol :CC>2, 4 mL/minute) RT 1.65 minutes.

Example 32: δH (400 MHz, CD3OD) 8.02-7.98 (m, 1H), 7.85 (s, 1H), 7.61 (dd, 79.9, 4.8 Hz, 1H), 7.37-7.23 (m, 2H), 7.12-7.03 (m, 1H), 6.13-5.65 (m, 1H), 5.26 (d, 78.7 Hz, 1H), 5.08-4.97 (m, 1H), 3.01-2.71 (m, 2H), 2.52 (s, 3H), 2.41-2.26 (m, 1H), 2.20-1.99 (m, 3H), 1.94-1.71 (m, 2H), 1.66-1.39 (m, 3H). LCMS (Method 7): [M+H]⁺ m/z 606.4, RT 3.41 minutes. Analytical chiral SFC (Chiralpak IC, 4.6 x 250 mm, 5 pm, 30:70 methanol :CCh, 4 mL/minute) RT 3.31 minutes.

The absolute stereochemistry of the chiral centre adjacent to the imidazopyridine ring system has been arbitrarily assigned for Examples 31 and 32.

Claims

Claims:

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

wherein

A represents C-R¹ or N;

10 E represents C-R² or N;

Y represents -

R¹ represents hydrogen or fluoro;

R² represents hydrogen or fluoro;

R³ represents -COR^3a, -CChR³⁸ or -SCkR^3®; or R³ represents hydrogen; or R³ represents C_1-6 alkyl or C_3-9 cycloalkyl, either of which groups may be optionally substituted by one or more fluorine atoms;

R^3a represents Cw alkyl, optionally substituted by one or more fluorine atoms; R^4a represents hydrogen, fluoro or hydroxy; or R^4® represents C_1-6 alkyl, which group may be optionally substituted by one or more substituents; and R^4b represents hydrogen, fluoro or C_1-6 alkyl; or

R^4a and R^4b, when taken together with the carbon atom to which they are both attached, represent C_3-9 cycloalkyl or C_3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents; R⁵ represents C_1-6 alkyl;

R⁶ represents -OR^6® or -NR^6b.⁶⁶; or R⁶ represents C_1-6 alkyl, C_3-9 cycloalkyl, C_3-9 cycloalkyl(C i-6)alkyl, aryl, aryl(Ci-6)alkyl, C_3-7 heterocycloalkyl, C_3-7 heterocycloalkyl- (Ci-6)alkyl, heteroaryl or heteroaryl (C i-6)alkyl, any of which groups may be optionally substituted by one or more substituents;

R^6® represents C_1-6 alkyl; or R^6® represents C_3-9 cycloalkyl, which group may be optionally substituted by one or more substituents;

R⁶⁶ represents hydrogen or C_1-6 alkyl; and R⁶⁰ represents hydrogen or C_1-6 alkyl; or

R⁶⁶ and R⁶⁰, when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents.

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

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

3. A compound as claimed in claim 1 or claim 2 wherein Y represents -C(R^4a)(R^4b)-, in which R^4® and R* are as defined in claim 1.

4. A compound as claimed in any one of the preceding claims wherein R⁶ represents 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 A-oxide thereof, or a pharmaceutically acceptable salt thereof:

wherein

R¹⁶ represents methyl or ethyl; and A, E, Z and R^4a are as defined in claim 1.

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

wherein

A, E, Z and R^4a 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 R^4a represents hydrogen; or R^4® represents C_1-6 alkyl, which group may be optionally substituted by one, two or three substituents independently selected from halogen and C_1-6 alkylsulfonyl.

8. A compound as claimed in any one of claims 1 to 4 wherein R^4a and R^4b, when taken together with the carbon atom to which they are both attached, represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl or piperidinyl, any of which groups may be unsubstituted, or substituted by one or more substituents.

9. A compound as claimed in any one of the preceding claims wherein Z represents furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3 ,4-6] [ 1 ,4]dioxinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-6]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3 ,4-6]pyridinyl, pyrazolyl, pyrazolo[ 1 , 5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[ l,5-a]pyridinyl, pyrazolo[3,4-if]pyrimidinyl, pyrazolo[ 1,5-a]- pyrazinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,l-6]- thiazolyl, imidazo[ 1 ,2-a]pyridinyl, 5,6,7,8-tetrahydroimidazo[ 1 ,2-a]pyridinyl, imidazo- [4,5-6]pyridinyl, imidazo[l,2-6]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]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, [l,2,4]triazolo[4,3-a]- pyrazinyl, 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyridinyl, [l,2,4]triazolo[l,5-a]- pyrimidinyl, 6, 8-dihydro- 5//-[l, 2, 4]triazolo[4,3-a]pyrazinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl or chromenyl, any of which groups may be optionally substituted by one or more substituents.

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

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

12. A compound of formula (I) as defined in claim 1 or an A-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.

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

14. 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.

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

16. 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.

17. The use of a compound of formula (I) as defined in claim 1 or an /V-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.

18. 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 A-oxide thereof, or a pharmaceutically acceptable salt thereof.

19. 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.