ANTIMALARIAL HEXAHYDROPYRIMIDINE ANALOGUES The present invention relates to a class of heterocyclic compounds, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted hexahydropyrimidine derivatives, and analogues thereof. These compounds are potent inhibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of malaria. Malaria is a mosquito-borne infectious disease, caused by a parasite of the genus Plasmodium, which has devastating consequences. In 2010, an estimated 225 million cases were reported, with 610,000 to 971,000 deaths, approximately 80% of which occurred in sub-Saharan Africa, mostly in young children (aged 5 years or less). The compounds in accordance with the present invention, being potent inhibitors of the growth and propagation of the P. falciparum parasite in human blood, are therefore beneficial in the treatment of malaria. In addition, 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 2019/192992, co-pending international patent application PCT/EP2020/063083 (published on 19 November 2020 as WO 2020/229427), and co-pending international patent application PCT/EP2020/073011 (published on 25 February 2021 as WO 2021/032687, and claiming priority from United Kingdom patent applications 1911865.2 and 1913759.5), describe certain classes of heterocyclic compounds which are stated to be potent inhibitors of the growth and propagation of the P. falciparum parasite in human blood, and therefore to be beneficial in the treatment of malaria. WO 2017/142825 describes a family of heterocyclic compounds which are stated to be potent inhibitors of P. falciparum growth in vitro that may be useful for the treatment of malaria. WO 2017/089453 and WO 2017/144517 describe heterocyclic compounds which are stated to be potent and selective inhibitors of plasmepsin V activity that are beneficial in the treatment of malaria. WO 2016/172255, WO 2016/118404 and WO 2011/044181 describe certain classes of heterocyclic compounds which are stated to be BACE inhibitors that may be useful for treating Aβ-related pathologies including Alzheimer’s disease. WO 2012/019966 describes 1,4,5,6-tetrahydropyrimidin-2-ylamine derivatives which are stated to have BACE2 inhibitory properties that may be useful in the treatment of metabolic disorders (including type 2 diabetes), and cardiovascular disorders. WO 2008/103351, WO 2006/065277 and WO 2005/058311 describe a family of heterocyclic compounds that are stated to be aspartyl protease inhibitors. The compounds described in those publications are also stated to be effective in a method of inhibiting inter alia plasmepsins (specifically plasmepsins I and II) for treatment of malaria. WO 2006/041404 describes a family of heterocyclic compounds that are stated to be inhibitors of Beta site APP (amyloid precursor protein) Cleaving Enzyme (BACE). The compounds described in that publication are also stated to be effective in a method of modulating BACE activity; and in methods of treating or preventing an amyloid-β- protein-related (Aβ-related) pathology, including Downs syndrome and Alzheimer disease. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein Z represents C _1-6 alkyl, C _3-9 cycloalkyl, C _3-9 cycloalkyl(C _1-6 )alkyl, C _4-9 cycloalkenyl, C _4-12 bicycloalkyl, C _5-9 spirocycloalkyl, C _5-9 spirocycloalkyl(C _1-6 )alkyl, C _8-11 tricycloalkyl, C _8-11 tricycloalkyl(C _1-6 )alkyl, C _7-13 dispirocycloalkyl, C _7-13 dispirocycloalkyl(C _1-6 )alkyl, aryl(C _1-6 )alkyl, C-linked C _3-7 heterocycloalkyl, C _3-7 heterocycloalkyl(C _1-6 )alkyl, C-linked C _4-9 heterobicycloalkyl, C-linked C _4-9 spiroheterocycloalkyl or heteroaryl(C _1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; R ¹ represents C _3-7 cycloalkyl, aryl(C _1-6 )alkyl, C _3-7 heterocycloalkyl, C _3-7 heterocycloalkyl(C _1-6 )alkyl, C _4-9 heterobicycloalkyl, C _4-9 spiroheterocycloalkyl or heteroaryl(C _1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents; R ² represents methyl, fluoromethyl or ethyl; and R ³ represents hydrogen, halogen, methyl, ethyl, difluoromethyl, trifluoromethyl, cyclopropyl, methoxy, difluoromethoxy or trifluoromethoxy. The compounds in accordance with the present invention overlap with the broadest generic scope of WO 2016/172255, WO 2008/103351, WO 2006/065277, WO 2005/058311 and WO 2006/041404. There is, however, no specific disclosure in any of those publications of 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 a pharmaceutically acceptable salt thereof, for use in therapy. The present invention also provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of malaria. The present invention also provides a method for the treatment and/or prevention of malaria which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof. The present invention also provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of malaria. 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. Typically, such groups will be unsubstituted, or substituted by one, two or three substituents, generally 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 use in the invention 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 alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched C _1-6 alkyl groups, for example C _1-4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as “C _1-6 alkoxy”, “C _1-6 alkylthio”, “C _1-6 alkylsulfonyl” 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. SuitableC _3-9 cycloalkyl groups include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononanyl. The term “C _4-9 cycloalkenyl” as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from an unsaturated monocyclic hydrocarbon, and may comprise benzo-fused analogues thereof. Suitable C _4-9 cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The term “C _4-12 bicycloalkyl” as used herein refers to monovalent groups of 4 to 12 carbon atoms derived from a saturated bicyclic hydrocarbon. Typical bicycloalkyl groups include bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[4.1.0]heptanyl and bicyclo[2.2.2]octanyl. Additional bicycloalkyl groups include bicyclo[2.1.1]hexanyl. The term “C _5-9 spirocycloalkyl” as used herein refers to saturated bicyclic ring systems containing 5 to 9 carbon atoms, in which the two rings are linked by a common atom. Suitable spirocycloalkyl groups include spiro[2.3]hexanyl, spiro[2.4]heptanyl, spiro[3.3]heptanyl, spiro[3.4]octanyl, spiro[3.5]nonanyl and spiro[4.4]nonanyl. The term “C _8-11 tricycloalkyl” as used herein refers to monovalent groups of 8 to 11 carbon atoms derived from a saturated tricyclic hydrocarbon. Typical tricycloalkyl groups include adamantanyl. Additional tricycloalkyl groups include cubanyl and tricyclo[3.3.1.0 ^3,7 ]nonanyl. The term “C _7-13 dispirocycloalkyl” as used herein refers to saturated tricyclic ring systems containing 7 to 13 carbon atoms, in which the three rings incorporate two spiro linkages. Suitable dispirocycloalkyl groups include dispiro[2.0.24.13]heptanyl. 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(C _1-6 )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 analogues thereof fused to an aryl or heteroaryl ring. Suitable heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, 2,3- dihydropyrrolo[2,3-b]pyridinyl, 2,3-dihydropyrrolo[3,2-b]pyridinyl, 1,3-dihydropyrrolo- [3,4-b]pyridinyl, 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, dioxanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydro- isoquinolinyl, 7,8-dihydro-5H-1,6-naphthyridinyl, piperazinyl, 1,2,3,4-tetrahydro- quinoxalinyl, hexahydro-[1,2,5]thiadiazolo[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, 2,3-dihydro-1,4-benzoxazinyl, thiomorpholinyl, azepanyl, oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl. The expression “C-linked” denotes that the heterocycloalkyl moiety is linked to the remainder of the molecule via a carbon atom comprised within the heterocycloalkyl ring. The term “C _4-9 heterobicycloalkyl” as used herein refers to monovalent groups of 4 to 9 carbon atoms derived from a saturated bicyclic hydrocarbon, comprising one or more heteroatoms selected from oxygen, sulphur and nitrogen. Typical heterobicyclo- alkyl groups include 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 2-aza- bicyclo[2.2.1]heptanyl, 7-oxabicyclo[2.2.1]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-oxa- 5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.2.0]- heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 2-oxabicyclo- [4.1.0]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 6-azabicyclo[3.2.1]octanyl, 8-oxabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, 3-oxabicyclo[3.3.0]octanyl, 3,6-diazabicyclo[3.2.2]- nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 3,7-dioxa-9-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo[4.2.1]nonanyl. Additional heterobicycloalkyl groups include 2-oxa- bicyclo[2.1.1]hexanyl. The expression “C-linked” denotes that the heterobicycloalkyl moiety is linked to the remainder of the molecule via a carbon atom comprised within the heterobicycloalkyl ring system. The term “C _4-9 spiroheterocycloalkyl” as used herein refers to saturated bicyclic ring systems containing 4 to 9 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom. Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]- heptanyl, 2-oxaspiro[3.3]heptanyl, 1-azaspiro[3.3]heptanyl, 2-azaspiro[3.3]heptanyl, 2- oxa-6-azaspiro[3.3]-heptanyl, 3-oxa-6-azaspiro[3.3]heptanyl, 6-thia-2-azaspiro[3.3]- heptanyl, 5-azaspiro[2.5]octanyl, 6-oxaspiro[2.5]octanyl, 6-azaspiro[3.4]octanyl, 2-oxa-6- azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa- 7-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl and 2,4,8-triazaspiro[4.5]decanyl. The expression “C-linked” denotes that the spiroheterocycloalkyl moiety is linked to the remainder of the molecule via a carbon atom comprised within the spiroheterocycloalkyl ring system. The term “heteroaryl” as used herein refers to monovalent aromatic groups containing at least five 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, sulfur and nitrogen. Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,2-c]- pyridinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]- pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-b]- pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]- pyridinyl, imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]- pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl. The term “halogen” as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine. The absolute stereochemical configuration of the chiral carbon atom in the imino- tetrahydropyrimidinone nucleus of the compounds according to the invention is as depicted in formula (I) above. Generally, the compounds in accordance with the invention are at least 51% enantiomerically pure (by which it is meant that a sample thereof comprises a mixture of enantiomers containing 51% or more of the enantiomer depicted in formula (I) and 49% or less of the opposite antipode). Typically, the compounds in accordance with the invention are at least 60% enantiomerically pure. Appositely, the compounds in accordance with the invention are at least 75% enantiomerically pure. Suitably, the compounds in accordance with the invention are at least 80% enantiomerically pure. More suitably, the compounds in accordance with the invention are at least 85% enantiomerically pure. Still more suitably, the compounds in accordance with the invention are at least 90% enantiomerically pure. Even more suitably, the compounds in accordance with the invention are at least 95% enantiomerically pure. Preferably, the compounds in accordance with the invention are at least 99% enantiomerically pure. Ideally, the compounds in accordance with the invention are at least 99.9% enantiomerically pure. Where the compounds of formula (I) have one or more additional asymmetric centres, they may accordingly exist as enantiomers. Where the compounds in accordance with the invention possess one or more additional asymmetric centres, they may also 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 (CH ₂ C=O)↔enol (CH=CHOH) tautomers or amide (NHC=O)↔hydroxyimine (N=COH) tautomers or imide (NHC=NH)↔aminoimine (N=CNH ₂ ) 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. In addition, under certain circumstances, e.g. where R ³ represents halogen, compounds of formula (I) may exist as atropisomers. Formula (I) and the formulae depicted hereinafter are intended to represent all individual atropisomers 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 ¹ H, ² H (deuterium; D) or ³ H (tritium; T) atom, preferably ¹ H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a ¹² C, ¹³ C or ¹⁴ C atom, preferably ¹² C. Suitably, Z represents C _1-6 alkyl, C _3-9 cycloalkyl, C _3-9 cycloalkyl(C _1-6 )alkyl, C _4-9 cycloalkenyl, C4-12 bicycloalkyl, C _8-11 tricycloalkyl, C _8-11 tricycloalkyl(C _1-6 )alkyl, aryl- (C _1-6 )alkyl, C-linkedC _3-7 heterocycloalkyl, C-linked C _4-9 heterobicycloalkyl, C-linked C _4-9 spiroheterocycloalkyl or heteroaryl(C _1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents. In a first embodiment, Z represents optionally substituted C _1-6 alkyl. In a second embodiment, Z represents optionally substituted C _3-9 cycloalkyl. In a third embodiment, Z represents optionally substituted C _3-9 cycloalkyl(C _1-6 )alkyl. In a fourth embodiment, Z represents optionally substituted C _4-9 cycloalkenyl. In a fifth embodiment, Z represents optionally substituted C _4-12 bicycloalkyl. In a sixth embodiment, Z represents optionally substituted C _5-9 spirocycloalkyl. In a seventh embodiment, Z represents optionally substituted C _5-9 spirocycloalkyl(C _1-6 )alkyl. In an eighth embodiment, Z represents optionally substituted C _8-11 tricycloalkyl. In a ninth embodiment, Z represents optionally substituted C _8-11 tricycloalkyl(C _1-6 )alkyl. In a tenth embodiment, Z represents optionally substituted C _7-13 dispirocycloalkyl. In an eleventh embodiment, Z represents optionally substituted C _7-13 dispirocycloalkyl(C _1-6 )alkyl. In a twelfth embodiment, Z represents optionally substituted aryl(C _1-6 )alkyl. In a thirteenth embodiment, Z represents optionally substituted C-linked C _3-7 heterocycloalkyl. In a fourteenth embodiment, Z represents optionally substituted C _3-7 heterocycloalkyl(C _1-6 )alkyl. In a fifteenth embodiment, Z represents optionally substituted C-linked C _4-9 heterobicycloalkyl. In a sixteenth embodiment, Z represents optionally substituted C-linked C _4-9 spiroheterocycloalkyl. In a seventeenth embodiment, Z represents optionally substituted heteroaryl(C _1-6 )alkyl. Selected examples of Z include ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]- heptanyl, cubanyl, tricyclo[3.3.1.0 ^3,7 ]nonanyl, adamantanyl, adamantanylmethyl, benzyl, tetrahydrofuranyl, dihydrobenzofuranyl, tetrahydropyranyl, 2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxabicyclo[4.1.0]heptanyl, 3-oxabicyclo[3.3.0]octanyl, 6- oxaspiro[2.5]octanyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents. Suitable examples of Z include ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, indanyl, cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo[2.2.1]heptanyl, adamantanyl, adamantanylmethyl, benzyl, tetrahydrofuranyl, dihydrobenzofuranyl, 3-oxabicyclo- [3.1.0]hexanyl, 2-oxabicyclo[4.1.0]heptanyl, 3-oxabicyclo[3.3.0]octanyl, 6-oxaspiro[2.5]- octanyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents. Typical examples of optional substituents on Z include one, two or three substituents independently selected from halogen, cyano, nitro, C _1-6 alkyl, trifluoro- methyl, phenyl, pyrazolyl, hydroxy, oxo, C _1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, amino, C _1-6 alkylamino, di(C _1-6 )alkyl- amino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C _1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, C _1-6 alkyl- aminocarbonyl, di(C _1-6 )alkylaminocarbonyl, aminosulfonyl, C _1-6 alkylaminosulfonyl and di(C _1-6 )alkylaminosulfonyl. Selected examples of optional substituents on Z include one, two or three substituents independently selected from halogen, cyano, C _1-6 alkyl, trifluoromethyl, phenyl, pyrazolyl, hydroxy, oxo, C _1-6 alkoxy and di(C _1-6 )alkylamino. Suitable examples of optional substituents on Z include one, two or three substituents independently selected from halogen, cyano, C _1-6 alkyl, trifluoromethyl, phenyl, pyrazolyl, oxo, C _1-6 alkoxy and di(C _1-6 )alkylamino. Typical examples of particular substituents on Z include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, phenyl, pyrazolyl, hydroxy, oxo, methoxy, tert-butoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methyl- sulfonyl, amino, methylamino, tert-butylamino, dimethylamino, acetylamino, methoxy- carbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxy- carbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylamino- carbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl. Selected examples of particular substituents on Z include one, two or three substituents independently selected from fluoro, chloro, cyano, methyl, tert-butyl, trifluoromethyl, phenyl, pyrazolyl, hydroxy, oxo, methoxy and dimethylamino. Suitable examples of particular substituents on Z include one, two or three substituents independently selected from fluoro, cyano, methyl, trifluoromethyl, phenyl, pyrazolyl, oxo, methoxy and dimethylamino. Selected values of Z include cyanoethyl, dimethylaminopropyl, cyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, (difluoro)(methyl)- cyclopropyl, tetramethylcyclopropyl, cyclobutyl, dimethylcyclobutyl, pyrazolyl- cyclobutyl, (difluoro)(methyl)cyclobutyl, cyclopentyl, indanyl, difluorocyclohexyl, methoxycyclohexyl, (difluoro)(methyl)cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, fluorobicyclo[1.1.1]pentanyl, chlorobicyclo[1.1.1]- pentanyl, tert-butylbicyclo[1.1.1]pentanyl, trifluoromethylbicyclo[1.1.1]pentanyl, methoxybicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, bicyclo- [2.2.1]heptanyl, (dimethyl)(oxo)bicyclo[2.2.1]heptanyl, cubanyl, tricyclo[3.3.1.0 ^3,7 ]- nonanyl, adamantanyl, cyanoadamantanyl, trifluoromethyladamantanyl, hydroxy- adamantanyl, methoxyadamantanyl, difluoroadamantanyl, trifluoroadamantanyl, adamantanylmethyl, benzyl, tetrahydrofuranyl, (dimethyl)(oxo)tetrahydrofuranyl, dihydrobenzofuranyl, dimethyltetrahydropyranyl, (difluoro)(methyl)tetrahydropyranyl, trifluoromethyl-2-oxabicyclo[2.1.1]hexanyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxabicyclo- [4.1.0]heptanyl, 3-oxabicyclo[3.3.0]octanyl, 6-oxaspiro[2.5]octanyl and furylmethyl. Suitable values of Z include cyanoethyl, dimethylaminopropyl, cyclopropyl, cyanocyclopropyl, trifluoromethylcyclopropyl, phenylcyclopropyl, (difluoro)(methyl)- cyclopropyl, cyclobutyl, dimethylcyclobutyl, pyrazolylcyclobutyl, cyclopentyl, indanyl, difluorocyclohexyl, methoxycyclohexyl, (difluoro)(methyl)cyclohexyl, indanylmethyl, cycloheptylmethyl, cyclohexenyl, bicyclo[1.1.1]pentanyl, bicyclo[3.1.0]hexanyl, bicyclo- [2.2.1]heptanyl, (dimethyl)(oxo)bicyclo[2.2.1]heptanyl, adamantanyl, cyanoadamantanyl, trifluoroadamantanyl, adamantanylmethyl, benzyl, tetrahydrofuranyl, (dimethyl)(oxo)- tetrahydrofuranyl, dihydrobenzofuranyl, 3-oxabicyclo[3.1.0]hexanyl, 2-oxabicyclo- [4.1.0]heptanyl, 3-oxabicyclo[3.3.0]octanyl, 6-oxaspiro[2.5]octanyl and furylmethyl. Typically, R ¹ represents C _3-7 cycloalkyl, aryl(C _1-6 )alkyl, C _3-7 heterocycloalkyl, C _3-7 heterocycloalkyl(C _1-6 )alkyl or heteroaryl(C _1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents. Suitably, R ¹ represents C _3-7 cycloalkyl, C _3-7 heterocycloalkyl or C _3-7 heterocycloalkyl(C _1-6 )alkyl, any of which groups may be optionally substituted by one or more substituents. More particularly, R ¹ represents C _3-7 cycloalkyl or C _3-7 heterocycloalkyl, either of which groups may be optionally substituted by one or more substituents. Appositely, R ¹ represents C _3-7 heterocycloalkyl, which group may be optionally substituted by one or more substituents. Suitable examples of R ¹ include cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanylmethyl, tetrahydropyranylmethyl, 7-oxabicyclo[2.2.1]- heptanyl, 8-oxabicyclo[3.2.1]octanyl and 2-oxaspiro[3.3]heptanyl, any of which groups may be optionally substituted by one or more substituents. Additional examples include chromanyl, which group may be optionally substituted by one or more substituents. Typical examples of R ¹ include cyclobutyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydropyranylmethyl, any of which groups may be optionally substituted by one or more substituents. Additional examples include chromanyl, which group may be optionally substituted by one or more substituents. Selected examples of R ¹ include cyclohexyl, tetrahydropyranyl and chromanyl, any of which groups may be optionally substituted by one or more substituents. Illustrative examples of R ¹ include cyclohexyl and tetrahydropyranyl, either of which groups may be optionally substituted by one or more substituents. A particular value of R ¹ is tetrahydropyranyl, which group may be optionally substituted by one or more substituents. Typical examples of optional substituents on R ¹ include one, two or three substituents independently selected from halogen, cyano, nitro, C _1-6 alkyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxy(C _1-6 )alkyl, oxo, C _1-6 alkoxy, difluoromethoxy, trifluoromethoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, amino, C _1-6 alkylamino, di(C _1-6 )alkylamino, amino(C _1-6 )alkyl, di(C _1-6 )alkylamino(C _1-6 )alkyl, C _2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C _1-6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C _2-6 alkoxycarbonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, di(C _1-6 )alkylaminocarbonyl, aminosulfonyl, C _1-6 alkylaminosulfonyl and di(C _1-6 )alkyl- aminosulfonyl. Selected examples of optional substituents on R ¹ include one, two or three substituents independently selected from halogen, C _1-6 alkyl and trifluoromethyl. Apposite examples of optional substituents on R ¹ include one, two or three substituents independently selected from halogen and C _1-6 alkyl. Suitable examples of optional substituents on R ¹ include one, two or three substituents independently selected from C _1-6 alkyl. Typical examples of particular substituents on R ¹ include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, aminomethyl, dimethylaminomethyl, acetylamino, methoxycarbonylamino, methylsulfonylamino, formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methyl- aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl. Selected examples of particular substituents on R ¹ include one, two or three substituents independently selected from fluoro, methyl and trifluoromethyl. Apposite examples of particular substituents on R ¹ include one, two or three substituents independently selected from fluoro and methyl. Suitable examples of particular substituents on R ¹ include one, two or three substituents independently selected from methyl. Typical values of R ¹ include difluorocyclohexyl, (difluoro)(methyl)cyclohexyl, tetrahydropyranyl and methyltetrahydropyranyl. Additional values include cyclohexyl, trifluoromethyltetrahydropyranyl, chromanyl and difluorochromanyl. Selected values of R ¹ include cyclohexyl, difluorocyclohexyl, (difluoro)- (methyl)cyclohexyl, tetrahydropyranyl, methyltetrahydropyranyl, trifluoromethyl- tetrahydropyranyl, chromanyl and difluorochromanyl. Suitable values of R ¹ include difluorocyclohexyl and methyltetrahydropyranyl. In a first embodiment, R ¹ represents difluorocyclohexyl, especially 4,4-difluoro- cyclohexyl. In a second embodiment, R ¹ represents (difluoro)(methyl)cyclohexyl, especially 4,4-difluoro-3-methylcyclohexyl. In a third embodiment, R ¹ represents tetrahydropyranyl. In a fourth embodiment, R ¹ represents methyltetrahydropyranyl, especially 2-methyltetrahydropyran-4-yl. In a fifth embodiment, R ¹ represents cyclohexyl. In a sixth embodiment, R ¹ represents trifluoromethyltetrahydropyranyl, especially 2-(trifluoromethyl)tetrahydropyran-4-yl. In a seventh embodiment, R ¹ represents chromanyl, especially chroman-4-yl. In an eighth embodiment, R ¹ represents difluorochromanyl, especially 5,7-difluorochroman-4-yl. In a first embodiment, R ² represents methyl. In a second embodiment, R ² represents fluoromethyl. In a third embodiment, R ² represents ethyl. Generally, R ³ represents hydrogen or halogen. In a first embodiment, R ³ represents hydrogen. In a second embodiment, R ³ represents halogen, especially fluoro or chloro. In one aspect of that embodiment, R ³ represents fluoro. In another aspect of that embodiment, R ³ represents chloro. In a third embodiment, R ³ represents methyl. In a fourth embodiment, R ³ represents ethyl. In a fifth embodiment, R ³ represents difluoromethyl. In a sixth embodiment, R ³ represents trifluoromethyl. In a seventh embodiment, R ³ represents cyclopropyl. In an eighth embodiment, R ³ represents methoxy. In a ninth embodiment, R ³ represents difluoro- methoxy. In a tenth embodiment, R ³ represents trifluoromethoxy. Illustrative values of R ³ include hydrogen, fluoro and chloro. Suitably, R ³ represents chloro. One sub-class of compounds according to the invention is represented by the compounds of formula (IIA), and pharmaceutically acceptable salts thereof: wherein R ¹¹ represents hydrogen, methyl or trifluoromethyl; R ¹² represents hydrogen or methyl; and Z and R ³ are as defined above. In a first embodiment, R ¹¹ represents hydrogen. In a second embodiment, R ¹¹ represents methyl. In a third embodiment, R ¹¹ represents trifluoromethyl. In a first embodiment, R ¹² represents hydrogen. In a second embodiment, R ¹² represents methyl. In a first embodiment, R ¹¹ and R ¹² both represent hydrogen. In a second embodiment, R ¹¹ represents hydrogen and R ¹² represents methyl. In a third embodiment, R ¹¹ and R ¹² both represent methyl. In a fourth embodiment, R ¹¹ represents trifluoro- methyl and R ¹² represents hydrogen. Another sub-class of compounds according to the invention is represented by the compounds of formula (IIB), and pharmaceutically acceptable salts thereof: wherein Z, R ³ and R ¹¹ 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 thereof. 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 sulfate). 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 of formula (I) 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 of formula (I) 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 of use in 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 of use in 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 of use in 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 compounds may be formulated in an ointment such as petrolatum. For rectal administration the compounds of use in 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 of use in the 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. General methods for the preparation of the compounds of formula (I) as defined above are described in WO 2016/172255, WO 2011/044181, WO 2008/103351 and WO 2006/041404. The compounds in accordance with the invention may be prepared by a process which comprises reacting a compound of formula Z-COCl with a compound of formula (III): wherein Z, R ¹ , R ² and R ³ are as defined above, and R ^p represents hydrogen or an N- protecting group; followed, as necessary, by removal of the N-protecting group R ^p . The reaction between the compound of formula Z-COCl and compound (III) is conveniently accomplished at ambient temperature in the presence of pyridine. Suitably, the N-protecting group R ^p is tert-butoxycarbonyl (BOC). Where the N-protecting group R ^p is BOC, subsequent removal of the BOC group may suitably be accomplished by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid. The reaction will typically be effected at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or a cyclic ether such as 1,4-dioxane. In an alternative procedure, the compounds in accordance with the invention may be prepared by a two-step process which comprises: (i) treating a compound of formula Z-CO ₂ H with oxalyl chloride and N,N-dimethylformamide; and (ii) reacting the material thereby obtained with a compound of formula (III) as defined above; followed, as necessary, by removal of the N-protecting group R ^p . Step (i) is conveniently accomplished at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane. Step (ii) is conveniently carried out in the presence of a base, e.g. an organic base such as triethylamine. The reaction is typically performed at a temperature in the region of 0°C in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane. In another procedure, the compounds in accordance with the invention may be prepared by a process which comprises reacting a carboxylic acid of formula Z-CO ₂ H with a compound of formula (III) as defined above; in the presence of a coupling agent; followed, as necessary, by removal of the N-protecting group R ^p . Suitably, the coupling agent may be chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, in which case the reaction may generally be carried out in the presence of 1-methylimidazole. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a nitrile solvent such as acetonitrile. Alternatively, the coupling agent may be 2,4,6-tripropyl-1,3,5,2,4,6-trioxa- triphosphorinane 2,4,6-trioxide, in which case the reaction may generally be carried out in the presence of a base which may suitably include organic amines, e.g. a trialkylamine such as N,N-diisopropylethylamine, or an aromatic base such as pyridine. The reaction is conveniently performed at ambient temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane. Alternatively, the coupling agent may be 2-chloro-1-methylpyridinium iodide, in which case the reaction may generally be carried out in the presence of a base, e.g. a trialkylamine such as N,N-diisopropylethylamine. The reaction is conveniently performed at ambient or elevated temperature in a suitable solvent, e.g. a chlorinated solvent such as dichloromethane, or an organic nitrile solvent such as acetonitrile. The intermediates of formula (III) above may be prepared by treating a compound of formula (IV): wherein R ¹ , R ² , R ³ and R ^p are as defined above, R ^q represents an N-protecting group, and R ^w represents C _1-4 alkyl, especially methyl; with a base; followed by removal of the N- protecting group R ^q . Suitably, the base of use in the above reaction is a C _1-4 alkoxide salt, typically an alkali metal alkoxide such as potassium tert-butoxide. The reaction is conveniently accomplished at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran. Suitably, the N-protecting group R ^q is benzyloxycarbonyl. Where the N-protecting group R ^q is benzyloxycarbonyl, subsequent removal of the benzyloxycarbonyl group may suitably be accomplished by catalytic hydrogenation. Typically, this will involve treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as palladium on charcoal. The intermediates of formula (IV) above may be prepared by reacting a compound of formula (V) with a compound of formula (VI): wherein R ¹ , R ² , R ³ , R ^p , R ^q and R ^w are as defined above. Generally, the reaction between compounds (V) and (VI) is performed in the presence of a coupling agent. A suitable coupling agent is N-(3-dimethylaminopropyl)- Nʹ-ethylcarbodiimide hydrochloride (EDC.HCl). Suitably, the reaction is performed in the presence of a base, typically an organic base such as N,N-diisopropylethylamine. The reaction between compounds (V) and (VI) is conveniently accomplished at ambient temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N- dimethylformamide. Under certain circumstances, the reaction between compounds (V) and (VI) will proceed directly to the corresponding compound of formula (III). In an alternative procedure, the intermediates of formula (III) above may be prepared by treating a compound of formula (VII):

wherein R ¹ , R ² , R ³ and R ^p are as defined above; with a reducing agent. Suitably, the reducing agent of use in the above reaction may be a mixture of zinc and ammonium formate, in which case the reaction may conveniently be accomplished at ambient temperature in a suitable solvent, e.g. a C _1-4 alkanol such as methanol. Alternatively, the reducing agent may be tin(II) chloride, in which case the reaction may conveniently be accomplished at an elevated temperature in a suitable solvent, e.g. a C _1-4 alkanol such as ethanol. Alternatively, the compound of formula (VII) may be reduced by conventional catalytic hydrogenation, in which case the reaction may conveniently be accomplished by treating compound (VII) with hydrogen gas in the presence of a hydrogenation catalyst, e.g. palladium on charcoal. The reaction will typically be performed at ambient temperature in a suitable solvent, e.g. a C _1-4 alkanol such as methanol. The intermediates of formula (VII) above may be prepared by treating a compound of formula (VIII): wherein R ¹ , R ² , R ³ , R ^p and R ^w are as defined above; with a base; in a manner analogous to that described above for compound (IV). The intermediates of formula (VIII) above may be prepared by reacting a compound of formula (VI) as defined above with a compound of formula (IX): wherein R ² , R ³ and R ^w are as defined above; employing conditions analogous to those described above for the reaction between compounds (V) and (VI). Where they are not commercially available, the starting materials of formula (V), (VI) and (IX) 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. 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 following Examples illustrate the preparation of compounds according to the invention. The compounds of the present invention are potent inhibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood. As such, they are active in a P. falciparum 3D7 asexual blood stage assay, exhibiting IC50 values of 50 μM or less, generally of 20 μM or less, usually of 5 μM or less, typically of 1 μM or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC ₅₀ figure denotes a more active compound). Asexual Blood Stage Assay The assay used to measure the effect of test compounds on a bloodstream stage of Plasmodium falciparum 3D7 strain employs SYBR green as the readout. This is a dye that binds to double stranded deoxyribonucleic acid (DNA) with a resulting increase in fluorescence, allowing detection of P. falciparum DNA in infected erythrocytes, and thereby providing a measure of parasite growth and propagation. P. falciparum culture maintenance Erythrocytes (A+ blood) were prepared for both parasite culture and assay by washing 4 times with incomplete media (15.9 g RPMI 1640 (25 mM HEPES, L- glutamine), 1 g NaHCO ₃ , 2 g glucose, 400 µL gentacin (500 mg/mL), 2 mL hypoxanthine solution (13.6 g/L in 0.1M NaOH pH 7.3) in 1 litre of media). The cells were centrifuged at 1800g for 5 minutes, before decanting the supernatant and re-suspending in fresh incomplete media. On the final wash, the cells were re-suspended in complete media (incomplete media with 5 g/L AlbumaxII), and centrifuged at 1800g for 3 minutes. This cell sediment was treated as 100% haematocrit. P. falciparum 3D7 was cultured in erythrocytes at 5% haematocrit in complete media at 37°C (1% O ₂ , 3%CO ₂ , balance N ₂ ). Cultures were split on a weekly basis to achieve a 1% parasitaemia in erythrocites at 5% haematocrit in fresh media. Culture media is replaced by fresh media every other day (2 times during the week). Assay Procedure On day 1, test compounds were added to assay plates using Echo dispensing technology (1.5 fold dilution and 20 points titration). 50 nL of each compound dilution was added to 50 µL of culture (5% haematocrit, 0.5% parasitaemia) and incubated for 72 h at 37°C (1% O ₂ , 3% CO ₂ , balance N ₂ ). Final concentrations of test compounds ranged from 50,000 nM to 15 nM, in 0.5% DMSO. On day 4, 10 µL SYBR green (Invitrogen S7563 supplied as 10,000 x concentrate in DMSO) pre-diluted to 3 x concentrate with Lysis buffer (20 mM Tris pH 7.9, 5% EDTA, 0.16% w/v, 1.6% TX100 v/v) was added to the cultures and incubated in the dark, overnight, at room temperature. On day 5, fluorescent signal was measured using a BioTek plate reader (excitation 485 nm, emission 528 nm). All data were processed using IDBS ActivityBase. Raw data were converted into per cent inhibition through linear regression by setting the high inhibition control (mefloquine) as 100% and the no inhibition control (DMSO) as 0%. Quality control criteria for passing plates were as follows: Zʹ > 0.5, S:B > 3, %CV _{(no inhibition control)} < 15. The formula used to calculate Zʹ is: where μ denotes the mean; σ denotes the standard deviation; p denotes the positive control; and n denotes the negative control. All EC ₅₀ curve fitting was undertaken using the following bi-phasic two site dose response using XLfit model 300 (IDBS): where A = 100 minus the top of the upper curve 1 and the bottom of lower curve; B = Hill slope; log(C) = IC ₅₀ concentration at lower site; log(D) = IC ₅₀ concentration at upper site; x = inhibitor concentration; and y = % inhibition. When tested in the P. falciparum 3D7 asexual blood stage assay as described above, the compounds of the accompanying Examples were found to exhibit the following IC ₅₀ values.

EXAMPLES Abbreviations DCM: dichloromethane EtOAc: ethyl acetate DMSO: dimethyl sulfoxide THF: tetrahydrofuran MeOH: methanol DMF: N,N-dimethylformamide DIPEA: N,N-diisopropylethylamine TFA: trifluoroacetic acid TFAA: trifluoroacetic anhydride TBME: tert-butyl methyl ether DCE: 1,2-dichloroethane CAN: ceric ammonium nitrate DAST: diethylaminosulfur trifluoride DEA: diethylamine DPPA: diphenylphosphoryl azide DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene LiHMDS: lithium bis(trimethylsilyl)amide EDC.HCl: N-(3-dimethylaminopropyl)-Nʹ-ethylcarbodiimide hydrochloride T3P®: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-tri oxide solution TCFH: chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate h: hour M: mass r.t.: room temperature RT: retention time DAD: Diode Array Detector HPLC: High Performance Liquid Chromatography LCMS: Liquid Chromatography Mass Spectrometry ESI: Electrospray Ionisation VCD: Vibrational Circular Dichroism Nomenclature Compounds were named in accordance with IUPAC guidelines with the aid of Biovia Draw version 19.1. The asterisk (*) – for example, in compounds designated (2R*,4R*) – indicates compounds of known relative stereochemistry but unknown absolute stereochemistry. Analytical Conditions Method 1 Column: Waters X Bridge C18, 2.1 x 30 mm, 2.5 μm Injection Volume 5.0 μL Flow Rate 1.00 mL/minute Detection: MS – ESI+ m/z 150 to 800 UV – DAD 220-400 nm Solvent A 5 mM ammonium formate in water + 0.1% ammonia Solvent B acetonitrile + 5% Solvent A + 0.1% ammonia Gradient program: 5% B to 95% B in 4.0 minutes; hold until 5.00 minutes; at 5.10 minutes concentration of B is 5%; hold up to 6.5 minutes Method 2 Column: Waters UPLC X Bridge BEH (C18, 2.1 x 50 mm, 2.5 µm) Temperature: 45°C Injection volume: 1.0 μL Flow rate: 1.00 mL/minute Detection: Mass spectrometry – +/- detection in the same run PDA: 210 to 400 nm Solvent A: 10 mM ammonium formate in water + 0.1% formic acid Solvent B: 95% acetonitrile + 5% H ₂ O + 0.1% formic acid Time % A % B 0 95 5 0.10 95 5 2.10 5 95 2.35 5 95 2.80 95 5 INTERMEDIATE 1 rac-(2S,4S)-2-Methyltetrahydropyran-4-amine To a stirred solution of 2-methyltetrahydropyran-4-one (10.0 g, 87.6 mmol) in MeOH (100 mL) were added benzylamine (14.3 mL, 131.4 mmol) and acetic acid (0.25 mL, 4.38 mmol) under a nitrogen atmosphere. The mixture was stirred for 4 h at room temperature, then sodium cyanoborohydride (8.27 g, 131.4 mmol) was added at r.t. The reaction mixture was stirred for 16 h, then concentrated under reduced pressure. The crude residue was purified by column chromatography (100-200 mesh silica gel, eluting with 30-100% EtOAc/hexane). The resulting pale brown liquid was dissolved in MeOH (100 mL), and 10% Pd/C (10.0 g) was added in a Parr shaker vessel. The reaction mixture was stirred at r.t. for 16 h, then passed through a celite pad and washed with 10% MeOH in DCM. The filtrate was concentrated under reduced pressure to obtain the title compound (4.0 g, 71%) as a brown liquid. δ _H (400 MHz, DMSO-d ₆ ) 3.81-3.77 (m, 1H), 3.32-3.23 (m, 2H), 2.71-2.63 (m, 1H), 2.32-1.86 (br s, 2H), 1.71-1.58 (m, 2H), 1.14-1.05 (m, 4H), 0.86 (q, J 12.3 Hz, 1H). INTERMEDIATE 2 tert-Butyl N-{[rac-(2S,4S)-2-methyltetrahydropyran-4-yl]carbamothioyl}c arbamate To a solution of N,Nʹ-bis-tert-butoxycarbonylthiourea (12.3 g, 44.5 mmol) in THF (100 mL) under nitrogen was added 60% NaH (5 g, 124.5 mmol) portionwise over a period of 10 minutes at 0°C. The mixture was stirred for 1 h, then TFAA (11.2 mL, 80.1 mmol) was added dropwise at 0°C. The mixture was stirred for 1 h, then a solution of Intermediate 1 (3.16 g, 11.46 mmol) in THF (20 mL) was added. The reaction mixture was stirred at r.t. for 2 h, then quenched with ice-cold water and extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over sodium sulfate, then the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 100-200 mesh, 3% ethyl acetate/hexane) to afford the title compound (2.1 g, 60%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 10.61 (s, 1H), 9.69 (d, J 7.5 Hz, 1H), 4.34-4.30 (m, 1H), 3.86 (dd, J 1.9, 10.8 Hz, 1H), 3.43-3.35 (m, 2H), 2.01 (d, J 10.6 Hz, 1H), 1.93 (d, J 12.2 Hz, 1H), 1.47 (s, 9H), 1.44-1.37 (m, 2H), 1.18-1.13 (m, 1H), 1.10 (d, J 6.12 Hz, 3H). INTERMEDIATE 3 N-[1-(2-Chloro-3-nitrophenyl)ethylidene]-(R)-2-methylpropane -2-sulfinamide To a solution of 1-(2-chloro-3-nitrophenyl)ethanone (10.5 g, 5.1 mmol) and (R)-2- methyl-2-propanesulfinamide (11.2 g, 5.1 mmol) in dry THF (100 mL) was added titanium(IV) ethoxide (23.2 g, 10.5 mmol). The reaction mixture was heated at 75°C for 12 h, then quenched with H ₂ O (500 mL), stirred at room temperature for 1 h and filtered through a pad of Celite®. The aqueous layer was extracted with EtOAc (2 x 150 mL). The organic layer was separated and dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 30% EtOAc in hexanes) to afford the title compound (10.0 g, 63%) as a red liquid. LCMS (Method 1, ESI) 303.00 [MH] ⁺ , RT 3.02 minutes. INTERMEDIATE 4 N-[1-(3-Amino-2-chlorophenyl)ethylidene]-2-(R)-methylpropane -2-sulfinamide To a solution of Intermediate 3 (10.0 g, 33.2 mmol) in MeOH (100 mL) was added Raney Ni (10.0 g) at room temperature. The reaction mixture was stirred at room temperature for 6 h under hydrogen pressure, then filtered through a pad of Celite® and washed with MeOH (150 mL). The filtrate was concentrated in vacuo to afford the title compound (8.80 g, 98%) as a colourless liquid, which was utilised without further purification. LCMS (Method 1, ESI) 273.00 [MH] ⁺ , RT 2.58 minutes. INTERMEDIATE 5 Benzyl N-(3-{N-[(R)-tert-butylsulfinyl]-C-methylcarbonimidoyl}-2-ch lorophenyl)- carbamate To a solution of Intermediate 4 (10.0 g, 36.7 mmol) in THF (100 mL) were added DIPEA (32.5 mL, 183.0 mmol) and benzyl chloroformate (12.5 g, 73.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 h, then quenched with H ₂ O (500 mL) and extracted with EtOAc (3 x 250 mL). The organic layer was separated and dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 30% EtOAc in n-hexanes) to afford the title compound (12.5 g, 84%) as a yellow liquid. LCMS (Method 1, ESI) 407.00 [MH] ⁺ , RT 3.43 minutes. INTERMEDIATE 6 Methyl (3S)-3-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-3-{[(R)-t ert-butylsulfinyl]- amino}butanoate A suspension of CuCl (4.37 g, 44.2 mmol) and Zn (14.4 g, 221.0 mmol) in THF (90 mL) was heated at 50°C for 30 minutes. Methyl bromoacetate (11.0 g, 66.0 mmol) was added dropwise at 80°C, then the reaction mixture was heated at 50°C for 1 h. Intermediate 5 (9.00 g, 22.0 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 16 h, then filtered through a pad of Celite®. The filtrate was washed with brine (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate, then concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 40% EtOAc in hexanes) to afford the title compound (7.50 g, 70%) as a yellow liquid. δ _H (400 MHz, DMSO-d ₆ ) 9.09 (s, 1H), 7.54 (d, J 8.0 Hz, 1H), 7.29-7.43 (m, 7H), 5.39 (s, 1H), 5.14 (s, 2H), 3.47 (s, 3H), 3.31 (s, 2H), 1.86 (s, 3H) 1.13 (s, 9H). LCMS (Method 1, ESI) 481.00 [MH] ⁺ , RT 3.43 minutes. INTERMEDIATE 7 Methyl (3S)-3-amino-3-[3-(benzyloxycarbonylamino)-2-chlorophenyl]bu tanoate To a solution of Intermediate 6 (7.50 g, 15.6 mmol) in MeOH (80 mL) was added 4M HCl in 1,4-dioxane (15.6 mL, 62.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 6 h, then concentrated in vacuo. The residue was basified with saturated aqueous NaHCO ₃ solution (200 mL) and extracted with EtOAc (2 x 250 mL). The organic layer was separated and dried over anhydrous sodium sulfate, then concentrated in vacuo, to afford the title compound (5.18 g, 90%) as a yellow liquid, which was utilised without further purification. INTERMEDIATE 8 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-4 -methyl-1- [(2S,4S)-2-methyltetrahydropyran-4-yl]-6-oxohexahydropyrimid in-2-ylidene}carbamate To a solution of Intermediate 2 (4.85 g, 13.6 mmol), Intermediate 7 (3.94 g, 9.53 mmol) and EDC.HCl (3.90 g, 20.4 mmol) in DMF (15 mL) at 0°C was added DIPEA (4.75 mL, 27.2 mmol). The reaction mixture was stirred at r.t. for 4 h, then diluted with ice-cold water (50 mL) and extracted with EtOAc (2 x 20 mL). The organic layer was separated and washed with brine (20 mL), then dried over Na ₂ SO ₄ and concentrated in vacuo to afford a dark oil (7.2 g crude). A portion of the oil (6.0 g) was dissolved in THF (100 mL), and potassium tert-butoxide (1M in THF, 10.4 mL, 10.4 mmol) was added at 0°C. The reaction mixture was stirred at r.t. for 2 h, then quenched with H ₂ O (300 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 25-45% EtOAc in hexanes). The material was further purified by chiral preparative HPLC (Mobile Phase A: CO ₂ ; Mobile Phase B: MeOH + TBME (60:40) + 0.1% isopropylamine, isocratic: 20% B; Column: Diacel Chiralpak-IG (250 x 4.6 mm, 5 μ); Wavelength: 240 nm; Flow: 3 mL/minute) to afford the title compound (RT 8.45 minutes) (1.60 g, 52%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 0.99 (d, J 5.87 Hz, 3H), 1.07 (d, J 11.74 Hz, 1H), 1.32 (d, J 11.74 Hz, 1H), 1.45 (s, 9H), 1.73 (s, 3H).1.94-2.05 (m, 1H).2.31-2.38 (m, 1H), 3.11 (d, J 16.14 Hz, 1H), 3.22-3.26 (m, 2H), 3.48-3.54 (m, 1H), 3.84 (dd, J 11.25, 3.91 Hz, 1H), 4.63-4.64 (m, 1H), 5.14 (s, 2H), 7.65 (d, J 11 Hz, 1H), 7.34-7.40 (m, 6H), 7.57 (d, J 11 Hz, 1H), 9.26 (br s, 1H), 10.52 (s, 1H). LCMS (Method 1, ESI) 585.1 [MH] ⁺ , RT 2.25 minutes. INTERMEDIATE 9 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-4-methyl-1-[(2S,4S)- 2-methyl- tetrahydropyran-4-yl]-6-oxohexahydropyrimidin-2-ylidene}carb amate To a solution of Intermediate 8 (0.83 g, 1.40 mmol) in MeOH (30 mL) was added 20% Pd/C (0.03 g, 0.28 mmol). The reaction mixture was stirred at r.t. for 3 h under 145 psi hydrogen pressure, then filtered through a pad of Celite®. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 10-40% EtOAc in hexanes) to afford the title compound (0.41 g, 60%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 0.90-0.98 (m, 1H), 1.06 (d, J 5.87 Hz, 3H), 1.45 (s, 9H), 1.73 (s, 3H), 2.07 (d, J 11.25 Hz, 1H), 2.23-2.33 (m, 1H), 3.11 (d, J 16.14 Hz, 1H), 3.22 (d, J 11.74 Hz, 1H), 3.50 (d, J 16.14 Hz, 1H), 3.76 (dd, J 11.00, 4.16 Hz, 1H), 4.66 (t, J 11.98 Hz, 1H), 5.52 (s, 2H), 6.47 (d, J 7.83 Hz, 1H), 6.78 (d, J 8.31 Hz, 1H), 7.00 (t, J 7.83 Hz, 1H), 10.47 (s, 1H) (two H signals merged in solvent peak). LCMS (Method 1, ESI) 451.0 [MH] ⁺ , RT 2.04 minutes. The absolute stereochemical configuration of the title compound was confirmed by applying VCD analysis with a confidence level of 99%. INTERMEDIATE 10 Methyl 3-cyanoadamantane-1-carboxylate To a stirred solution of methyl adamantane-1-carboxylate (2 g, 10.30 mmol) in dry DCE (10 mL) were added p-toluenesulfonyl cyanide (3.73 g, 20.61 mmol), CAN (5.65 g, 10.30 mmol), Li ₂ CO ₃ (0.76 g, 10.30 mmol) and N-hydroxyphthalimide (0.34 g, 2.06 mmol). The reaction mixture was stirred at 75°C for 16 h, then allowed to cool to r.t., filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (100-200 mesh), eluting with 30% EtOAc in hexane, to afford the title compound (510 mg, 22%) as an off-white solid. δ _H (400 MHz, CDCl ₃ ) 3.67 (s, 3H), 2.17-2.13 (m, 4H), 2.03-1.97 (m, 4H), 1.92-1.82 (m, 4H), 1.70 (s, 2H). INTERMEDIATE 11 3-Cyanoadamantane-1-carboxylic acid To a stirred solution of Intermediate 10 (600 mg, 2.74 mmol) in THF (36 mL) was added LiOH (287.67 mg, 6.84 mmol) in water (12 mL). The resulting mixture was stirred at ambient temperature for 16 h, then the THF was removed under reduced pressure. The aqueous layer was diluted with more water and washed with ether, then acidified with aqueous citric acid and extracted with EtOAc. The organic layer was concentrated under vacuum, then the crude residue was triturated with hexanes, to afford the title compound (410 mg, 73%) as a colourless sticky gum. δ _H (400 MHz, DMSO-d ₆ ) 12.33 (s, 1H), 2.04 (br s, 4H), 1.97-1.94 (m, 4H), 1.79-1.72 (m, 4H), 1.67-1.59 (m, 2H). INTERMEDIATE 12 tert-Butyl N-[(4,4-difluorocyclohexyl)carbamothioyl]carbamate Prepared from 4,4-difluorocyclohexanamine (4.09 g, 14.8 mmol) in accordance with the procedure described for Intermediate 2 to afford the title compound (1.9 g, 44%) as a yellow solid. δ _H (400 MHz, CDCl ₃ ) 9.74 (d, J 3.91 Hz, 1H), 7.87 (br s, 1H), 4.30- 4.44 (m, 1H), 2.05-2.24 (m, 4H), 1.84-2.01 (m, 2H), 1.62-1.81 (m, 2H), 1.50 (s, 9H). INTERMEDIATE 13 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -(4,4- difluorocyclohexyl)-4-methyl-6-oxohexahydropyrimidin-2-ylide ne}carbamate Prepared from Intermediate 12 (3.10 g, 4.25 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (1.9 g, 58%) as an off-white solid. δ _H (400 MHz, CDCl ₃ ) 10.60 (br s, 1H), 8.21 (d, J 7.83 Hz, 1H), 7.40- 7.46 (m, 4H), 7.36-7.40 (m, 2H), 7.04 (dd, J 7.83, 1.47 Hz, 1H), 5.24 (s, 2H), 4.60-4.70 (m, 1H), 3.65 (d, J 16.63 Hz, 1H), 2.84 (d, J 16.14 Hz, 1H), 2.56-2.66 (m, 1H), 2.43-2.54 (m, 1H), 1.98-2.14 (m, 2H), 1.83 (s, 3H), 1.72-1.79 (m, 1H), 1.65-1.70 (m, 3H), 1.55 (s, 9H), 1.14 (d, J 12.72 Hz, 1H). LCMS (Method 1, ESI) 606 [MH] ⁺ , RT 2.35 minutes. INTERMEDIATE 14 tert-Butyl (S,E)-[4-(3-amino-2-chlorophenyl)-1-(4,4-difluorocyclohexyl) -4-methyl-6-oxo- tetrahydropyrimidin-2(1H)-ylidene]carbamate Prepared from Intermediate 13 (1.9 g, 3.03 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (1.18 g, 82%) as an off-white solid. δ _H (400 MHz, CDCl3) 10.55 (br s, 1H), 7.00-7.07 (m, 1H), 6.76 (dd, J 8.07, 1.22 Hz, 1H), 6.68 (dd, J 7.82, 1.47 Hz, 1H), 4.61-4.70 (m, 1H), 3.66 (d, J 16.63 Hz, 1H), 2.78-2.85 (m, 1H), 2.57-2.67 (m, 1H), 2.45-2.55 (m, 1H), 2.08-2.11 (m, 1H), 2.00-2.02 (m, 1H), 1.84 (s, 3H), 1.74-1.80 (m, 1H), 1.62-1.70 (m, 2H), 1.55 (s, 9H), 1.15- 1.21 (m, 1H) (two exchangeable proton signals of -NH ₂ not seen due to moisture in the solvent). LCMS (Method 1, ESI) 471.20 [MH] ⁺ , RT 2.12 minutes. INTERMEDIATE 15 tert-Butyl N-[(1R*,3R*)-3-methyl-4-oxocyclohexyl]carbamate To a stirred solution of tert-butyl N-(4-oxocyclohexyl)carbamate (25 g, 117.37 mmol) in dry THF (250 mL) was added LiHMDS (1M in THF, 246.7 mL) at -78°C. The reaction mixture was stirred at -78°C for 1 h, then triethylborane (1M in THF, 176.1 mL) was added. The reaction mixture was stirred at -78°C for 1 h, then iodomethane (14.94 mL, 234.74 mmol) solution in THF (30 mL) was added at -78°C. The reaction mixture was stirred at r.t. for 12 h, then quenched with 1N aqueous NaOH solution, stirred for 2 h, diluted with H ₂ O and extracted with EtOAc. The organic layer was separated and washed with brine, then dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The crude residue was purified by column chromatography on silica gel (100-200 mesh size), eluting with using 20% ethyl acetate in hexane. The resulting material was re-purified by combi-flash chromatography (15% EtOAc in hexanes) to afford the title compound (5 g, 19%) (contaminated with ~15% of the opposite isomer) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 6.82 (br s, 1H), 3.78-3.93 (m, 1H), 2.53-2.62 (m, 1H), 2.02-2.15 (m, 3H), 0.84-0.87 (m, 3H), 1.83-1.87 (m, 1H), 1.54-1.56 (m, 1H), 1.38 (s, 9H), 1.20-1.30 (m, 1H). INTERMEDIATE 16 tert-Butyl N-[(1R*,3R*)-4,4-difluoro-3-methylcyclohexyl]carbamate To a stirred solution of Intermediate 15 (20 g, 88.1 mmol) in DCM (200 mL) was added DAST (23.25 mL, 176.21 mmol) at 0°C. The reaction mixture was stirred at r.t. for 12 h, then diluted with ice-water and extracted with DCM. The organic layer was separated and washed with brine, then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuum. The crude residue was purified by column chromatography (silica, 100-200 mesh, 10-20% EtOAc in hexanes) to afford the title compound (15 g, 68%) (contaminated with ~15% of the opposite isomer) as a light yellow solid. δ _H (400 MHz, DMSO-d ₆ ) 6.77-6.90 (m, 1H), 3.44-3.56 (m, 1H), 2.09-2.29 (m, 1H), 1.86-2.03 (m, 2H), 1.57-1.80 (m, 2H), 1.40-1.50 (br s, 1H), 1.38 (s, 9H), 0.87-0.97 (m, 3H) (one proton signal merged in solvent peak). INTERMEDIATE 17 (1R*,3R*)-4,4-Difluoro-3-methylcyclohexanamine hydrochloride To a stirred solution of Intermediate 16 (15 g, 66.1 mmol) in MeOH (75 mL) was added 4M HCl in 1,4-dioxane (33 mL, 132.2 mmol) at 0°C. The reaction mixture was stirred at r.t. for 12 h, then concentrated under vacuum. The crude residue was washed with diethyl ether and pentane to afford the title compound (9.7 g, 98%) (contaminated with ~10% of the opposite isomer) as a light yellow solid. δ _H (400 MHz, DMSO-d ₆ ) 8.31 (br s, 3H).3.19-3.38 (m, 1H), 2.31-2.40 (m, 1H), 1.89-2.19 (m, 4H), 1.52-1.69 (m, 2H), 1.02-1.13 (m, 3H). INTERMEDIATES 18 & 19 tert-Butyl N-{[(1R,3R)-4,4-difluoro-3-methylcyclohexyl]carbamothioyl}ca rbamate (Intermediate 18) tert-Butyl N-{[(1S,3S)-4,4-difluoro-3-methylcyclohexyl]carbamothioyl}ca rbamate (Intermediate 19) Prepared from Intermediate 17 (2.70 mmol) in accordance with the procedure described for Intermediate 2. The resulting material (1.60 g) was subjected to chiral preparative HPLC (Column: AD; Mobile Phase: EtOH 10%/heptane 90%/DEA 0.1%; Temperature: 30°C; Wavelength: 240 nm, Flow: 1.5 mL/minute) to afford the title compounds (Example 18, RT 2.94 minutes; and Example 19, RT 3.70 minutes) as off- white solids. δ _H (400 MHz, DMSO-d ₆ ) 10.63-10.62 (br s, 1H), 9.69-9.68 (br s, 1H), 4.28- 4.26 (m, 1H), 2.06-2.02 (m, 4H), 1.94-1.83 (m, 1H), 1.52-1.69 (m, 1H), 1.43 (s, 9H), 1.34-1.25 (m, 1H), 0.96 (d, 3H). The absolute stereochemical configuration of the title compounds was confirmed by applying VCD analysis with a confidence level of 98%. INTERMEDIATE 20 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -[(1R,3R)-4,4- difluoro-3-methylcyclohexyl]-4-methyl-6-oxohexahydropyrimidi n-2-ylidene}carbamate Prepared from Intermediate 18 (2.50 g, 2.99 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (2.40 g, 88%) as an off-white solid. LCMS (Method 1, ESI) 619.40 [MH] ⁺ , RT 1.68 minutes. INTERMEDIATE 21 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-1-[(1R,3R)-4,4-diflu oro-3-methyl- cyclohexyl]-4-methyl-6-oxohexahydropyrimidin-2-ylidene}carba mate Prepared from Intermediate 20 (2.40 g, 2.60 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (0.84 g, 57%) as an off-white solid. LCMS (Method 1, ESI) 485.25 [MH] ⁺ , RT 2.35 minutes. INTERMEDIATE 22 2-(Trifluoromethyl)pyran-4-one To a stirred solution of potassium tert-butoxide (29.17 g, 260 mmol) in diethyl ether (300 mL) at -15°C were added methyl 2,2,2-trifluoroacetate (24.19 mL, 240 mmol), followed by (E)-4-methoxybut-3-en-2-one (20 g, 200 mmol), dropwise. The reaction mixture was stirred at r.t. for 3 h, then quenched with 30% aqueous acetic acid. The organic portion was extracted with diethyl ether (2 x 100 mL). The organic layers were combined and dried over Na ₂ SO ₄ , then filtered and concentrated. The residue was dissolved in isopropanol (20 mL) and hydrochloric acid (35% aqueous solution), and heated under reflux for 45 minutes. The reaction mixture was concentrated to remove solvent, then purified via column chromatography, to afford the title compound (9.84 g, 30%) as a colourless oil. δ _H (400 MHz, CDCl3) 7.80-7.78 (d, J 5.84 Hz, 1H), 6.72 (s, 1H), 6.42-6.44 (dd, J 2.28, 5.8 Hz, 1H). INTERMEDIATE 23 (2R*,4S*)-2-(Trifluoromethyl)tetrahydropyran-4-ol To a stirred solution of Intermediate 22 (5.0 g, 30.47 mmol) in ethanol (100 mL) was added 10% Pd/C (5 g) under inert conditions. The mixture was hydrogenated overnight at 50°C under a H2 atmosphere (180 psi), then the Pd/C was filtered off. The filtrate was evaporated, then the resulting material was further purified by column chromatography to afford the title compound (1.8 g, 35%). δ _H (400 MHz, CDCl3) 4.17- 4.07 (m, 1H), 3.87-3.81 (m, 1H), 3.72-3.67 (m, 1H), 3.47 (dt, J 12.36, 1.48 Hz, 1H), 2.14- 2.11 (m, 1H), 2.03 (s, 1H), 1.95-1.91 (m,1H), 1.24 (t, J 7.16, 2H). INTERMEDIATE 24 [(2R*,4R*)-2-(Trifluoromethyl)tetrahydropyran-4-yl] 4-nitrobenzoate Intermediate 23 (2.5 g, 14.7 mmol) was dissolved in dry THF (35 mL) under an inert atmosphere at 0°C. p-Nitrobenzoic acid (4.9 g, 29.38 mmol) and triphenylphosphine (7.7 g, 29.38 mmol) were added at 0°C, then diisopropyl azodicarboxylate (5.94 g, 29.3 mmol) was added slowly over 5 minutes. The reaction mixture was stirred at r.t. for 18 h, then the solvent was evaporated under reduced pressure. The crude residue was purified by flash chromatography to afford the title compound (2.25 g, 48%). δ _H (400 MHz, CDCl3) 8.32 (d, J 8.64 Hz, 2H), 8.21 (d, J 8.64 Hz, 2H), 5.56 (s, 1H), 4.18-4.15 (m, 2H), 3.93 (t, J 12.24 Hz, 1H), 2.14-1.91 (m, 4H). INTERMEDIATE 25 (2R*,4R*)-2-(Trifluoromethyl)tetrahydropyran-4-ol To a stirred solution of Intermediate 24 (3.4 g, 10.6 mmol) in THF (36 mL) was added an aqueous solution of LiOH.H ₂ O (2.2 g, 53.25 mmol). The resulting mixture was stirred at ambient temperature for 16 h, then the solvent was removed under reduced pressure. The aqueous layer was acidified with 1N HCl, then the organic layer was extracted with EtOAc (3 x 30 mL). The organic layers were combined and dried over MgSO4 , then concentrated under vacuum. The crude residue was triturated with hexanes to afford the title compound (1.32 g, 73%). δ _H (400 MHz, CDCl ₃ ) 4.35 (s, 1H), 4.23-4.15 (m, 1H), 3.99-3.88 (m, 2H), 1.96-1.94 (m, 1H) 1.93-1.62 (m, 2H), 1.62-1.87 (m, 1H) (one proton signal absent as a consequence of overlapping peaks). INTERMEDIATE 26 [(2R*,4R*)-2-(Trifluoromethyl)tetrahydropyran-4-yl] 4-methylbenzenesulfonate Intermediate 25 (2.0 g, 11.7 mmol) was dissolved in DCM (20 mL), then p-tosyl chloride (4.48 g, 23.5 mmol) and triethylamine (3.3 mL, 23.5 mmol) were added at r.t. The reaction mixture was heated at 50°C for 16 h, then quenched with water and extracted with DCM (2 x 30 mL). The combined organic layers were dried over MgSO ₄ and concentrated under vacuum. The crude material was purified by column chromatography, eluting with hexane and EtOAc, to afford the title compound (1.98 g, 52%). δ _H (400 MHz, CDCl ₃ ) 7.79 (d, J 8 Hz, 2H), 7.35 (d, J 8 Hz, 2H), 5.28 (s, 1H), 4.08-4.03 (m, 1H), 3.95-3.87 (m, 1H), 3.84-3.80 (m, 1H), 2.45 (s, 3H), 2.43 (s, 1H), 1.94- 1.90 (m, 1H), 1.86-1.50 (m, 2H). INTERMEDIATE 27 (2R*,4S*)-4-Azido-2-(trifluoromethyl)tetrahydropyran To a stirred solution of Intermediate 26 (1.2 g, 3.7 mmol) in DMF (4 mL) was added sodium azide (721 mg, 11.1 mmol). The reaction mixture was heated at 60°C for 16 h, then allowed to cool and diluted with diethyl ether. The organic layer was washed with ice-cold water and separated, then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure, to afford the title compound (570 mg, 79%) as a yellow liquid. δ _H (400 MHz, CDCl ₃ ) 4.18 (dd, J 11.56, 4.08 Hz, 1H), 3.96-3.90 (m, 1H), 3.75-3.70 (m, 1H), 2.14-2.10 (m, 1H), 1.96-1.91 (m, 1H), 1.82-1.79 (m, 1H), 1.56 (t, J 12.16 Hz, 1H), 1.19 (t, J 7.00 Hz, 1H). INTERMEDIATE 28 (2R*,4S*)-2-(Trifluoromethyl)tetrahydropyran-4-amine Intermediate 27 (500 mg, 2.5 mmol) was dissolved in ethanol (2 mL), and 10% w/w Pd/C (50 mg) was added. The reaction mixture was stirred at r.t. under H ₂ (1 atmosphere) for 16 h, then passed through a celite pad and washed with 10% MeOH/ DCM solution. The residue was concentrated under reduced pressure to afford the title compound (312 mg, 72%) as a yellow liquid, which was utilised without further purification. δ _H (400 MHz, CDCl3) 4.20-4.11 (m, 1H), 3.96-3.91 (m, 1H), 3.72-3.68 (m, 1H), 3.51-3.45 (m, 1H), 2.94-2.87 (m, 1H), 1.98 (d, J 12.24 Hz, 1H), 1.82-1.78 (m, 2H), 1.47-1.29 (m, 2H). INTERMEDIATE 29 tert-Butyl N-{[(2S*,4R*)-2-(trifluoromethyl)tetrahydropyran-4-yl]carbam othioyl}- carbamate Prepared from Intermediate 28 (746 mg, 2.7 mmol) in accordance with the procedure described for Intermediate 2 to afford the title compound (270 mg, 40%). δ _H (400 MHz, DMSO-d ₆ ) 10.68 (s, 1H), 9.74 (d, J 7.52 Hz, 1H), 4.50-4.46 (m, 1H), 4.19- 4.15 (m, 1H), 4.05-4.01 (m,1H), 3.58 (t, J 10.84 Hz, 1H), 2.17 (d, J 12.44 Hz, 1H), 1.96 (t, J 9.24 Hz, 1H), 1.64-1.60 (m, 1H), 1.52 (d, J 11.76, 1H), 1.44 (m, 9H). INTERMEDIATES 30 & 31 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-4 -methyl-6- oxo-1-[(2S*,4R*)-2-(trifluoromethyl)tetrahydropyran-4-yl]hex ahydropyrimidin-2- ylidene}carbamate (Intermediate 30) tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-4 -methyl-6- oxo-1-[(2R*,4S*)-2-(trifluoromethyl)tetrahydropyran-4-yl]hex ahydropyrimidin-2- ylidene}carbamate (Intermediate 31) Prepared from Intermediate 29 (650 mg, 0.968 mmol) in accordance with the procedure described for Intermediate 8 to afford, after separation by column chromatography, eluting with 30% ethyl acetate:hexane, the title compounds (Intermediate 30, 200 mg, 40%; and Intermediate 31, 200 mg, 40%). Intermediate 30: δ _H (400 MHz, DMSO-d ₆ ) 9.25 (s, 1H), 7.58 (d, J 7.6 Hz, 1H), 7.39-7.38 (m, 5H), 7.35-7.33 (m, 1H), 7.17 (d, J 7.56Hz, 1H), 5.75 (s, 1H), 5.13 (s, 2H), 4.80-4.74 (m, 1H), 4.09 (br s, 1H), 3.90 (d, J 6.88 Hz, 1H), 3.60 (d, J 16.64 Hz, 1H), 3.39 (t, J 11.36 Hz, 1H), 3.21 (d, J 16.28 Hz, 1H), 2.44-2.38 (m, 1H), 2.32-2.26 (m, 1H), 1.76 (s, 3H), 1.60 (d, J 9.84 Hz, 1H), 1.45 (s, 9H), 0.85 (s, 1H). Intermediate 31: δ _H (400 MHz, DMSO-d ₆ ) 9.24 (s, 1H), 7.57 (d, J 7.32 Hz, 1H), 7.39- 7.38 (m, 5H), 7.36-7.34 (m, 1H), 7.18 (d, J 7.56 Hz, 1H), 5.13 (s, 2H), 4.76-4.71 (m, 1H), 4.05-3.98 (m, 2H), 3.60 (d, J 16.24 Hz, 1H), 3.45 (t, J 12.96 Hz, 1H), 3.23 (d, J 16.32 Hz, 1H), 2.41-2.28 (m, 2H), 1.98 (s, 1H), 1.76 (s, 3H), 1.43 (s, 9H), 1.18-1.13 (m, 2H). INTERMEDIATE 32 tert-Butyl (NE)-N-{(4S)-4-(3-Amino-2-chlorophenyl)-4-methyl-6-oxo-1-[(2 S*,4R*)-2- (trifluoromethyl)tetrahydropyran-4-yl]hexahydropyrimidin-2-y lidene}carbamate Prepared from Intermediate 30 (250 mg, 0.39 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (124 mg, 63%). δ _H (400 MHz, DMSO-d ₆ ) 7.00 (t, J 7.88 Hz, 1H), 6.78 (d, J 7.92 Hz, 1H), 6.47 (d, J 7.56 Hz, 1H), 5.53 (s, 2H), 4.75 (br s, 1H), 4.06-3.98 (m, 2H), 3.54-3.42 (m, 2H), 3.16-3.11 (m, 1H), 2.42-2.33 (m, 2H), 1.73 (s, 3H), 1.44 (s, 9H), 1.28-1.17 (m, 2H), 0.85 (t, J 6.6 Hz, 1H). INTERMEDIATE 33 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-4-methyl-6-oxo-1-[(2 R*,4S*)-2- (trifluoromethyl)tetrahydropyran-4-yl]hexahydropyrimidin-2-y lidene}carbamate Prepared from Intermediate 31 (250 mg, 0.39 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (118 mg, 60%). δ _H (400 MHz, DMSO-d ₆ ) 7.00 (t, J 8.08 Hz, 1H), 6.78 (d, J 8.08 Hz, 1H), 6.47 (d, J 7.72 Hz, 1H), 5.53 (s, 2H), 4.77 (br s, 1H), 4.10-3.91 (m, 2H), 3.54-3.35 (m, 2H), 3.13 (d, J 10.68 Hz, 1H), 2.42-2.33 (m, 2H), 1.73 (s, 3H), 1.44 (s, 9H), 1.23-1.10 (m, 1H), 1.08-1.04 (m, 2H). INTERMEDIATE 34 5,7-Difluorochroman-4-ol To a solution of 5,7-difluorochroman-4-one (4.0 g, 21.7 mmol) in MeOH (70 mL) was added NaBH4 (0.99 g, 26.1 mmol) at 0°C. The reaction mixture was stirred for 30 minutes, then concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 30% EtOAc in hexanes) to afford the title compound (3.90 g, 94%) as an off-white solid. δ _H (400 MHz, CDCl3) 6.50-6.33 (m, 2H), 5.07-4.95 (m, 1H), 4.36-4.18 (m, 2H), 2.16-1.94 (m, 2H) (hydroxy proton signal was not observed). INTERMEDIATE 35 4-Azido-5,7-difluorochromane To a solution of Intermediate 34 (3.90 g, 20.3 mmol) in THF (50 mL) were added DPPA (5.28 g, 24.4 mmol) and DBU (3.98 mL, 26.4 mmol) at 0°C. The reaction mixture was stirred at r.t. for 2 h, then diluted with H ₂ O (150 mL) and extracted with EtOAc (2 x 150 mL). The organic layer was separated and washed with brine (150 mL), then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 5% EtOAc in hexanes) to afford the title compound (3.50 g, 81%) as a colourless oil. δ _H (400 MHz, CDCl ₃ ) 6.39-6.54 (m, 2H), 4.86-4.94 (m, 1H), 4.28-4.40 (m, 1H), 4.13-4.26 (m, 1H) 1.94-2.09 (m, 2H). INTERMEDIATE 36 5,7-Difluorochroman-4-amine To a solution of Intermediate 35 (3.50 g, 16.5 mmol) in MeOH (75 mL) was added 10% Pd/C (0.88 g, 0.82 mmol) at 0°C. The reaction mixture was stirred at r.t. for 5 h under hydrogen pressure (1 atmosphere), then filtered through a pad of Celite® and washed with MeOH (150 mL). The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 60% EtOAc in hexanes) to afford the title compound (2.50 g, 79%) as a pale yellow oil. δ _H (400 MHz, CDCl ₃ ) 6.30-6.47 (m, 2H), 4.28 (dd, J 7.09, 2.69 Hz, 3H), 2.03-2.15 (m, 1H), 1.99 (br s, 2H), 1.78-1.91 (m, 1H). INTERMEDIATE 37 tert-Butyl N-[(5,7-difluorochroman-4-yl)carbamothioyl]carbamate Prepared from Intermediate 36 (2.50 g, 13.0 mmol) in accordance with the procedure described for Intermediate 2 to afford the title compound (3.50 g, 78%). δ _H (400 MHz, DMSO-d ₆ ) 10.83 (s, 1H), 9.98 (d, J 7.34 Hz, 1H), 6.74-6.88 (m, 1H), 6.59- 6.69 (m, 1H), 4.26-4.41 (m, 2H), 3.99 (t, J 11.74 Hz, 1H), 2.18-2.32 (m, 1H), 1.87-2.10 (m, 1H), 1.40 (s, 9H).

INTERMEDIATES 38 & 39 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -[(4S*)-5,7- difluorochroman-4-yl]-4-methyl-6-oxohexahydropyrimidin-2-yli dene}carbamate (Intermediate 38) tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -[(4R*)-5,7- difluorochroman-4-yl]-4-methyl-6-oxohexahydropyrimidin-2-yli dene}carbamate (Intermediate 39) Prepared from Intermediate 37 (4.00 g, 5.67 mmol) in accordance with the procedure described for Intermediate 8 to afford, after purification by column chromatography (hexane:EtOAc), the title compounds (Intermediate 38, 1.70 g, 46%; and Intermediate 39, 1.70 g, 46%) as off-white solids. Intermediate 38: δ _H (400 MHz, DMSO-d ₆ ) 10.58 (br s, 1H), 9.27 (s, 1H), 7.60 (d, J 7.82 Hz, 1H), 7.27-7.43 (m, 5H), 7.21 (d, J 7.82 Hz, 1H), 6.58-6.59 (m, 1H), 6.51 (d, J 8.80 Hz, 1H), 6.02-6.18 (m, 1H), 5.15 (s, 2H), 4.08-4.18 (m, 1H), 3.97-4.07 (m, 1H), 3.49-3.61 (m, 1H), 3.10 (d, J 15.16 Hz, 1H), 1.97 (d, J 17.61 Hz, 2H), 1.59-1.73 (m, 1H), 1.78 (s, 3H), 1.43 (s, 9H). LCMS (Method 1, ESI) 655.25 [MH] ⁺ , RT 2.44 minutes. Intermediate 39: δ _H (400 MHz, DMSO-d ₆ ) 10.72 (br s, 1H), 9.24 (s, 1H), 7.61 (d, J 7.82 Hz, 1H), 7.28-7.46 (m, 5H), 7.13-7.26 (m, 1H), 6.95-7.07 (m, 1H), 6.40-6.52 (m, 1H), 6.00-6.15 (m, 1H), 5.72-5.86 (m, 1H), 5.15 (s, 2H), 4.26-4.40 (m, 1H), 3.98-4.14 (m, 1H), 3.39-3.56 (m, 1H), 3.10-3.24 (m, 1H), 2.27-2.39 (m, 1H), 2.02-2.14 (m, 1H), 1.75 (s, 3H), 1.44 (s, 9H). LCMS (Method 1, ESI) 655.15 [MH] ⁺ , RT 2.42 minutes. INTERMEDIATE 40 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-1-[(4S*)-5,7-difluor ochroman-4-yl]- 4-methyl-6-oxohexahydropyrimidin-2-ylidene}carbamate Prepared from Intermediate 38 (1.70 g, 2.6 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (1.20 g, 89%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 10.53 (br s, 1H), 7.03 (t, J 7.82 Hz, 1H), 6.82 (d, J 7.82 Hz, 1H), 6.56-6.69 (m, 1H), 6.51 (d, J 7.82 Hz, 2H), 6.02-6.21 (m, 1H), 5.55 (br s, 2H), 4.11-4.22 (m, 1H), 3.99-4.10 (m, 1H), 3.49 (d, J 15.65 Hz, 1H), 3.01 (d, J 15.65 Hz, 1H), 1.89-2.15 (m, 1H), 1.38 (s, 9H), 1.79-1.85 (m, 1H), 1.76 (s, 3H). LCMS (Method 1, ESI) 521.05 [MH] ⁺ , RT 2.34 minutes. INTERMEDIATE 41 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -[(1S,3S)-4,4- difluoro-3-methylcyclohexyl]-4-methyl-6-oxohexahydropyrimidi n-2-ylidene}carbamate Prepared from Intermediate 19 (4.0 g, 13 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (4.20 g, 97%) as an off-white solid. LCMS (Method 1, ESI) 619.55 [MH] ⁺ , RT 2.79 minutes. INTERMEDIATE 42 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-1-[(1S,3S)-4,4-diflu oro-3-methyl- cyclohexyl]-4-methyl-6-oxohexahydropyrimidin-2-ylidene}carba mate Prepared from Intermediate 41 (4.20 g, 6.64 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (3.1 g, 95%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 0.92 (d, J 2.45 Hz, 3H), 1.05 (d, J 6.85 Hz, 1H), 1.45 (s, 9H), 1.47-1.55 (m, 1H), 1.73 (s, 3H), 10.47 (br s, 1H), 6.94-7.07 (m, 1H), 6.71-6.84 (m, 1H), 6.47 (d, J 5.38 Hz, 1H), 5.51 (br s, 2H), 4.50-4.67 (m, 1H), 3.50 (d, J 15.65 Hz, 1H), 2.99-3.17 (m, 1H), 2.26-2.38 (m, 1H), 2.22 (d, J 10.76 Hz, 1H), 1.84-2.05 (m, 2H), 1.75-1.85 (m, 1H). LCMS (Method 1, ESI) 485.10 [MH] ⁺ , RT 2.32 minutes. INTERMEDIATE 43 tert-Butyl N-{[(4R)-chroman-4-yl]carbamothioyl}carbamate Prepared from (4R)-chroman-4-amine (300 mg, 2.01 mmol) in accordance with the procedure described for Intermediate 2 to afford the title compound (103 mg, 16%). δ _H (400 MHz, DMSO-d ₆ ) 10.84 (s, 1H), 10.05 (s, 1H), 7.18-7.24 (m, 2H), 6.91 (d, 1H), 6.82 (d, 1H), 5.57 (m, 1H), 4.09-4.22 (m, 2H), 2.14-2.18 (m, 2H), 1.43 (s, 9H). INTERMEDIATE 44 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -[(4R)- chroman-4-yl]-4-methyl-6-oxohexahydropyrimidin-2-ylidene}car bamate Prepared from Intermediate 43 (500 mg, 1.62 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (110 mg, 12%). δ _H (400 MHz, DMSO-d ₆ ) 10.65 (s, 1H), 9.29 (s, 1H), 7.68 (d, 1H), 7.32-7.41 (m, 5H), 7.19 (d, 1H), 6.87-6.91 (m, 1H), 6.26 (m, 1H), 6.62 (d, 1H), 5.78-5.81 (m, 1H), 5.14 (m, 2H), 4.27 (m, 1H), 4.01-4.05 (m, 2H), 4.00 (m, 1H), 3.55-3.59 (m, 1H), 3.21-3.25 (m, 1H), 1.98 (m, 2H), 1.40-1.44 (s, 9H), 1.77 (s, 3H). INTERMEDIATE 45 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-1-[(4R)-chroman-4-yl ]-4-methyl-6- oxohexahydropyrimidin-2-ylidene}carbamate Prepared from Intermediate 44 (250 mg, 0.41 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (147 mg, 76%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 10.59 (s, 1H), 7.03 (m, 1H), 6.91 (m, 2H), 6.64 (m, 1H), 6.51 (m, 1H), 6.30 (m, 1H), 5.82-5.86 (m, 1H), 5.76 (m, 1H), 5.58 (m, 2H), 4.29 (m, 1H), 4.02-4.07 (m, 1H), 3.46-3.51 (m, 1H), 3.35-3.40 (m, 1H), 3.13-3.17 (m, 2H), 1.75 (s, 3H), 1.42 (s, 9H). INTERMEDIATE 46 tert-Butyl N-(cyclohexylcarbamothioyl)carbamate Prepared from cyclohexanamine (4.3 g, 42.39 mmol) in accordance with the procedure described for Intermediate 2 to afford the title compound (3.9 g, 64%). LCMS (Method 1, ESI) 289.2 [MH] ⁺ , RT 1.94 minutes. INTERMEDIATE 47 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -cyclohexyl- 4-methyl-6-oxohexahydropyrimidin-2-ylidene]carbamate Prepared from Intermediate 46 (3.3 g, 12.4 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (2.1g, 35%). δ _H (400 MHz, DMSO-d ₆ ) 10.51 (s, 1H), 9.24 (s, 1H), 7.58-7.56 (d , J 7.52 Hz, 1H), 7.39-7.33 (m, 6H), 7.16-7.14 (d, J 7.32 Hz, 1H), 5.14 (s, 2H), 4.36-4.33 (m, 1H), 3.57-3.53(d, J 16.2 Hz, 1H), 3.19-3.15(d, J 16.2 Hz, 1H), 2.15-2.00 (m, 2H), 1.74-1.44 (m, 16H), 1.16-0.97 (m, 4H). LCMS (Method 1, ESI) 569.2 [MH] ⁺ , RT 4.30 minutes. INTERMEDIATE 48 tert-Butyl (NE)-N-[(4S)-4-(3-amino-2-chlorophenyl)-1-cyclohexyl-4-methy l-6-oxo- hexahydropyrimidin-2-ylidene]carbamate Prepared from Intermediate 47 (2 g, 3.602 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (1.4 g, 89%) as an off-white solid. LCMS (Method 1, ESI) 434.9 [MH] ⁺ , RT 3.80 minutes. INTERMEDIATE 49 tert-Butyl N-{[(4S)-chroman-4-yl]carbamothioyl}carbamate Prepared from (4S)-chroman-4-amine (250 mg, 1.67 mmol) in accordance with the procedure described for Intermediate 2 to afford the title compound (100 mg, 19%). δ _H (400 MHz, DMSO-d ₆ ) 10.85 (s, 1H), 10.05 (s, 1H), 7.18-7.24 (m, 2H), 6.91 (d, 1H), 6.82 (d, 1H), 5.57 (m, 1H), 4.07-4.27 (m, 2H), 2.14-2.22 (m, 2H), 1.43 (s, 9H). INTERMEDIATE 50 tert-Butyl (NE)-N-{(4S)-4-[3-(benzyloxycarbonylamino)-2-chlorophenyl]-1 -[(4S)- chroman-4-yl]-4-methyl-6-oxohexahydropyrimidin-2-ylidene]car bamate Prepared from Intermediate 49 (900 mg, 2.92 mmol) in accordance with the procedure described for Intermediate 8 to afford the title compound (280 mg, 59%). δ _H (400 MHz, DMSO-d ₆ ) 1.42 (s, 9H), 1.81 (s, 3H), 2.23-2.25 (m, 2H), 3.25-3.31 (m, 1H), 3.55-3.57 (s, 1H), 3.95-3.98 (m, 1H), 4.01 (m, 2H), 4.19 (m, 1H), 5.14 (m, 2H), 5.91 (m, 2H), 6.67 (d, 1H), 6.87-6.91 (m, 1H), 7.21 (d, 1H), 7.31-7.40 (m, 5H), 7.61 (d, 1H), 9.25 (s, 1H), 10.58 (s, 1H). INTERMEDIATE 51 tert-Butyl (NE)-N-{(4S)-4-(3-amino-2-chlorophenyl)-1-[(4S)-chroman-4-yl ]-4-methyl-6- oxohexahydropyrimidin-2-ylidene}carbamate Prepared from Intermediate 50 (350 mg, 0.57 mmol) in accordance with the procedure described for Intermediate 9 to afford the title compound (200 mg, 73%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 10.54 (s, 1H), 7.03 (t, 3H), 6.67-6.82 (m, 3H), 6.51 (d, 1H), 5.92 (br s, 1H), 5.53 (m, 2H), 4.20 (br s, 1H), 3.97-4.03 (m, 1H), 3.46-3.50 (m, 1H), 3.18-3.31 (m, 1H), 2.23-2.31 (m, 2H), 1.78 (s, 3H), 1.42 (s, 9H). INTERMEDIATE 52 Methyl 3-methoxyadamantane-1-carboxylate To a solution of 3-hydroxyadamantane-1-carboxylic acid (0.40 g, 2.04 mmol) in DMF (10 mL) was added NaH (0.25 g, 6.11 mmol) portionwise at 0°C. The reaction mixture was stirred at 0°C for 30 minutes, then iodomethane (0.19 mL, 3.06 mmol) was added dropwise at 0°C. The reaction mixture was stirred at r.t. for 16 h, then poured into ice (100 mL) and extracted with EtOAc (3 x 50 mL). The organic layer was separated and washed with brine (2 x 50 mL), then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by combi-flash chromatography (12% EtOAc in hexanes) to afford the title compound (0.31 g, 68%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 3.59 (s, 3H), 3.11 (s, 3H), 2.13-2.23 (m, 2H), 1.71 (d, J 10.68 Hz, 6H), 1.63 (d, J 2.80 Hz, 4H), 1.53 (d, J 1.53 Hz, 2H). INTERMEDIATE 53 3-Methoxyadamantane-1-carboxylic acid To a solution of Intermediate 52 (0.30 g, 1.34 mmol) in THF:MeOH (1:1, 10 mL) was added LiOH (0.05 g, 2.01 mmol) in H ₂ O (2 mL) at 0°C. The reaction mixture was stirred at r.t. for 16 h, then poured into ice (80 mL), acidified with 1N HCl to pH 3, and extracted with EtOAc (3 x 40 mL). The organic layer was separated and washed with brine (2 x 30 mL), then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo, to afford the title compound (0.175 g, 42%) as an off-white solid. δ _H (400 MHz, DMSO-d ₆ ) 12.12 (br s, 1H), 3.11 (s, 3H), 2.18 (s, 2H), 1.62 (d, J 2.54 Hz, 4H), 1.53 (s, 2H), 1.65-1.74 (m, 6H). LCMS (Method 1, ESI) 209.1 [MH] ⁺ , RT 1.3 minutes. EXAMPLES 1 TO 69 General Method 1 The appropriate carboxylic acid derivative (1.05 equivalents) and 2-chloro-1- methylpyridinium iodide (2 equivalents) were added to the appropriate aniline derivative (1.0 equivalent) in DCM (1 mL). DIPEA (3.0 equivalents) was added, and the reaction mixture was stirred at r.t. for 16 h. If the reaction had not gone to completion, the mixture was warmed to 50°C and stirred until no further reaction occurred (with monitoring by LCMS). The solvent was removed, then redissolved in acetonitrile/H ₂ O (7:3) and purified using reverse-phase HPLC-MS. The resulting solid was treated with TFA/DCM (1:1) (1 mL) and stirred for 1 h at r.t. The solvent was removed under reduced pressure, and the solid was redissolved in acetonitrile/H ₂ O (7:3) and purified by reverse-phase HPLC-MS in acidic mode, to afford the title compound (TFA salt). General Method 2 To a solution of the appropriate aniline derivative in DCM were added the appropriate carboxylic acid derivative (1.5 equivalents), DIPEA (2 equivalents) and T3P® (2 equivalents) at r.t. The reaction mixture was stirred at r.t. for 4-12 h, then quenched with H ₂ O and extracted with DCM. The organic layer was separated, washed with H ₂ O and brine, then dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by Combi flash column chromatography. The resulting material was treated with TFA/DCM (1:1) (1 mL) and stirred for 1 h at rt. The solvent was removed under reduced pressure, and the solid was redissolved in acetonitrile/H ₂ O (7:3) and purified by reverse phase HPLC-MS in acidic mode, to afford the title compound (TFA salt). General Method 3 The appropriate TFA salt was dissolved in EtOAc and washed with saturated aqueous NaHCO ₃ solution. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by preparative HPLC where required, then redissolved in dry DCM (8 mL). HCl in 1,4-dioxane (4M, 6 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 30 minutes, then concentrated in vacuo and triturated with diethyl ether or DCM/n- pentane, to afford the title compound (HCl salt). General Method 4 To a solution of the appropriate carboxylic acid derivative in DCM was added DMF (1 drop), followed by the addition of oxalyl chloride (2.0 equivalents) at 0°C. The reaction mixture was stirred at room temperature for 3 h, then concentrated in vacuo. The residue was redissolved in DCM (3 mL), then triethylamine (6.0 equivalents) and the appropriate aniline derivative (1.05 equivalents) were added sequentially at 0°C. After completion, the reaction mixture was quenched with H ₂ O and extracted with DCM. The organic layer was separated, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 30% EtOAc in hexanes). The resulting material was redissolved in DCM, and TFA (20 equivalents) was added at 0°C. The reaction mixture was stirred at room temperature for 6 h, then concentrated in vacuo. The crude residue was purified by washing with diethyl ether (5 mL) and hexane (10 mL), then lyophilized with acetonitrile/H ₂ O (5 mL), to afford the title compound (TFA salt). General Method 5 The appropriate carboxylic acid derivative (2.4 equivalents) and 2-chloro-1- methylpyridinium iodide (2 equivalents) were added to the appropriate aniline derivative (1.0 equivalent) in acetonitrile, then DIPEA (3.0 to 4.0 equivalents) was added. The reaction mixture was heated at 60°C for 24-36 h, then quenched with H ₂ O and extracted with EtOAc. The organic layer was separated and concentrated in vacuo. The crude residue was purified by column chromatography (silica, 100-200 mesh, 70% EtOAc in hexanes). The resulting solid was treated with TFA/DCM (1:1) (1 mL) and stirred for 1 h at r.t. The solvent was removed under reduced pressure, then the solid was redissolved in acetonitrile/H ₂ O (7:3) and purified by reverse-phase HPLC, to afford the title compound (TFA salt). General Method 6 The appropriate aniline derivative (0.166 mmol) and the appropriate carboxylic acid derivative (0.176 mmol) were dissolved in anhydrous acetonitrile (2 mL) and 1- methylimidazole (0.376 mmol) was added, followed by TCFH (0.321 mmol). The reaction mixture was stirred under nitrogen overnight, then concentrated to 0.5 mL under a stream of nitrogen, diluted with water (2 mL) and extracted with EtOAc (2 x 2 mL). The combined organic extracts were washed with brine (2 mL), then dried and concentrated to dryness under vacuum. The residue was purified by preparative HPLC (Standard Method) (Column: XBridge ^TM Prep. C1810 μm OBDTM, 30 x 100 mm; Mobile Phase: 30-95% acetonitrile (0.2% ammonium hydroxide) in water (0.2% ammonium hydroxide) over 10 minutes; Flow Rate: 40 mL/minute; UV: 215 and 254 nm), and the product fractions were concentrated to dryness under vacuum. The resulting solid was treated with TFA/DCM (1:1) (1 mL) and stirred for 1 h at r.t. The solvent was removed under reduced pressure, then the solid was redissolved in acetonitrile/H ₂ O (7:3) and purified by reverse-phase HPLC, to afford the title compound (TFA salt). Examples 1 to 69 Example 1 was prepared from Intermediate 9 and 4-(dimethylamino)butyric acid hydrochloride in accordance with General Method 1. Example 2 was prepared from Intermediate 9 and 4,4-difluorocyclohexane- carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 3 was prepared from Intermediate 9 and adamantane-1-carboxylic acid in accordance with General Method 4 followed by General Method 3. Example 4 was prepared from Intermediate 9 and 3,5,7-trifluoroadamantane-1- carboxylic acid in accordance with General Method 4 followed by General Method 3. Example 5 was prepared from Intermediate 9 and 2-(1-adamantyl)acetic acid in accordance with General Method 4 followed by General Method 3. Example 6 was prepared from Intermediate 9 and bicyclo[1.1.1]pentane-1- carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 7 was prepared from Intermediate 9 and 3,3-dimethylcyclobutane- carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 8 was prepared from Intermediate 9 and phenylacetic acid in accordance with General Method 2. Example 9 was prepared from Intermediate 9 and cycloheptylacetic acid in accordance with General Method 1. Example 10 was prepared from Intermediate 9 and (2R)-tetrahydrofuran-2- carboxylic acid in accordance with General Method 2. Example 11 was prepared from Intermediate 9 and indane-2-carboxylic acid in accordance with General Method 2. Example 12 was prepared from Intermediate 9 and 2-indan-1-ylacetic acid in accordance with General Method 1. Example 13 was prepared from Intermediate 9 and rac-(1S,2S)-2-(trifluoro- methyl)cyclopropanecarboxylic acid in accordance with General Method 2. Example 14 was prepared from Intermediate 9 and bicyclo[3.1.0]hexane-6- carboxylic acid in accordance with General Method 1. Example 15 was prepared from Intermediate 9 and 2-phenylcyclopropane- carboxylic acid in accordance with General Method 2. Example 16 was prepared from Intermediate 9 and 2,3-dihydrobenzofuran-2- carboxylic acid in accordance with General Method 2. Example 17 was prepared from Intermediate 9 and (3R,3aS,6aR)-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]furan-3-carboxylic acid in accordance with General Method 2. Example 18 was prepared from Intermediate 9 and cyclobutanecarboxylic acid in accordance with General Method 2. Example 19 was prepared from Intermediate 9 and 2-(pyrazol-1-yl)cyclobutane- carboxylic acid in accordance with General Method 2. Example 20 was prepared from Intermediate 9 and cyclopentanecarboxylic acid in accordance with General Method 2. Example 21 was prepared from Intermediate 9 and (2S)-tetrahydrofuran-2- carboxylic acid in accordance with General Method 1. Example 22 was prepared from Intermediate 9 and cyclopropanecarboxylic acid in accordance with General Method 1. Example 23 was prepared from Intermediate 9 and 3-cyanopropanoic acid in accordance with General Method 1. Example 24 was prepared from Intermediate 9 and norbornane-1-carboxylic acid in accordance with General Method 1. Example 25 was prepared from Intermediate 9 and 6-oxaspiro[2.5]octane-2- carboxylic acid in accordance with General Method 1. Example 26 was prepared from Intermediate 9 and rac-(1R,6R,7R)-2-oxabicyclo- [4.1.0]heptane-7-carboxylic acid in accordance with General Method 1. Example 27 was prepared from Intermediate 9 and 1-cyanocyclopropane- carboxylic acid in accordance with General Method 1. Example 28 was prepared from Intermediate 9 and 2,2-dimethyl-5-oxo- tetrahydrofuran-3-carboxylic acid in accordance with General Method 1. Example 29 was prepared from Intermediate 9 and 4-methoxycyclohexane- carboxylic acid in accordance with General Method 1. Example 30 was prepared from Intermediate 9 and 2,2-difluoro-1-methyl- cyclopropanecarboxylic acid in accordance with General Method 1. Example 31 was prepared from Intermediate 9 and cyclohex-3-ene-1-carboxylic acid in accordance with General Method 1. Example 32 was prepared from Intermediate 9 and 7,7-dimethyl-2-oxo- norbornane-1-carboxylic acid in accordance with General Method 1. Example 33 was prepared from Intermediate 9 and 2-(3-furyl)acetic acid in accordance with General Method 1. Example 34 was prepared from Intermediate 9 and rac-(1R,5R)-3-oxabicyclo- [3.1.0]hexane-1-carboxylic acid in accordance with General Method 1. Example 35 was prepared from Intermediate 9 and 4,4-difluoro-1-methyl- cyclohexanecarboxylic acid in accordance with General Method 4 followed by General Method 3. Example 36 was prepared from Intermediate 9 and Intermediate 11 in accordance with General Method 2. Example 37 was prepared from Intermediate 40 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 38 was prepared from Intermediate 48 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 39 was prepared from Intermediate 42 and 3-(trifluoromethyl)bicyclo- [1.1.1]pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 40 was prepared from Intermediate 42 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 41 was prepared from Intermediate 42 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 42 was prepared from Intermediate 33 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3. Example 43 was prepared from Intermediate 33 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 44 was prepared from Intermediate 32 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 45 was prepared from Intermediate 21 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 46 was prepared from Intermediate 9 and Intermediate 53 in accordance with General Method 1 followed by General Method 3. Example 47 was prepared from Intermediate 45 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 48 was prepared from Intermediate 51 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 49 was prepared from Intermediate 14 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3. Example 50 was prepared from Intermediate 14 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 51 was prepared from Intermediate 9 and 3-(trifluoromethyl)- adamantane-1-carboxylic acid in accordance with General Method 1 followed by General Method 3. Example 52 was prepared from Intermediate 9 and tricyclo[3.3.1.0 ^3,7 ]nonane-3- carboxylic acid in accordance with General Method 1 followed by General Method 3. Example 53 was prepared from Intermediate 9 and 2,2-dimethyltetrahydropyran- 4-carboxylic acid in accordance with General Method 1 followed by General Method 3. Example 54 was prepared from Intermediate 9 and 3-tert-butylbicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 6. Example 55 was prepared from Intermediate 9 and 3-methoxybicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 6. Example 56 was prepared from Intermediate 9 and 3,3-difluoro-1-methyl- cyclobutanecarboxylic acid in accordance with General Method 6. Example 57 was prepared from Intermediate 9 and 2,2,3,3-tetramethyl- cyclopropanecarboxylic acid in accordance with General Method 2 followed by General Method 3. Example 58 was prepared from Intermediate 9 and cubane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 59 was prepared from Intermediate 14 and 3,5,7-trifluoroadamantane-1- carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 60 was prepared from Intermediate 9 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3. Example 61 was prepared from Intermediate 9 and 5,5-difluoro-2-methyl- tetrahydropyran-2-carboxylic acid in accordance with General Method 1. Example 62 was prepared from Intermediate 9 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 63 was prepared from Intermediate 9 and 4,4-difluoroadamantane-1- carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 64 was prepared from Intermediate 9 and 3-chlorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 6. Example 65 was prepared from Intermediate 9 and 3-(trifluoromethyl)bicyclo- [1.1.1]pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 66 was prepared from Intermediate 32 and 3-hydroxyadamantane-1- carboxylic acid in accordance with General Method 5 followed by General Method 3. Example 67 was prepared from Intermediate 14 and 3-fluorobicyclo[1.1.1]- pentane-1-carboxylic acid in accordance with General Method 2 followed by General Method 3. Example 68 was prepared from Intermediate 9 and bicyclo[2.1.1]hexane-1- carboxylic acid in accordance with General Method 1. Example 69 was prepared from Intermediate 9 and 4-(trifluoromethyl)-2-oxa- bicyclo[2.1.1]hexane-1-carboxylic acid in accordance with General Method 1.