BICYCLIC HETEROAROMATIC DERIVATIVES AS MODULATORS OF CXCR3 FUNCTION This invention relates to a series of bicyclic heteroaromatic derivatives, to compositions containing them, to processes for their preparation, and to their use in medicine.

Over the last few years it has become increasingly clear that chemokines (chemotactic cytokines) play a key role in the recruitment and activation of a variety of cell types in inflammatory processes, for example recruitment of eosinophils in the tissue eosinophilia that is a feature of a number of pathological conditions including asthma, rhinitis, eczema and parasitic infections. Further, certain chemokines have been implicated in a variety of autoimmune diseases, such as rheumatoid arthritis, irritable bowel disease and multiple sclerosis, as well as playing a critical role in the pathway of viral infection, such as invasion by HIV [Schwarz, M. K. and Wells, T. N. C., Curr. Opin. Chem. Biol., 1999,3, 407-17; Bousquet, J. et al., N. Eng. J. Med., 1990,323, 1033-39; Kay, A. B. and Corrigan, C. J. , Br. Med. Bull., 1992,48, 51-64].

Chemokines are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils [Luster, New Eng. J. Med. , 1998,338, 436-45; Rollins, Blood, 1997,90, 909-28]. To date, almost 40 human chemokines have been well characterised [Schwarz, M. K., ibid ; Wells, T. N.

C. et al., Trends Pharmacol. Sci., 1998,19, 376-380] and they have been classified into two major classes, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). Members of two additional classes, C chemokines (lymphotactin-1 and lymphotactin-2) and a CX3C chemokine (fractalkine) have also been identified. It was initially thought that CXC chemokines, such as IL-8 (a neutrophil attractant), were associated with acute inflammation whilst CC chemokines were associated with chronic inflammatory diseases such as asthma, arthritis and atherosclerosis.

However, it is now known that members of both classes are involved in both chronic and acute inflammation.

In general the CXC chemokines, such as interleukin-8 (IL-8), neutrophil- activating protein-2 (NAP-2) and melanoma growth stimulatory activating protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas CC chemokines such as RANTES (regulation-upon-activation, normal T-cell expressed and secreted), MIP-1a, MIP-1p, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, MCP-5) and, the eotaxins (-1,-2 and-3) are chemotactic for macrophages, T lymphocytes, eosinophils, dendritic cells and basophils.

The chemokines bind to specific cell-surface receptors. Seventeen mammalian receptors have been reported to date [Schwarz, M. K., ibid], all of which are seven-transmembrane-spanning G-protein coupled receptors. The ligand-binding characteristics of these receptors have been identified; for example, the ligands for CCR-1 are RANTES, MIP-1a and MCP-3, whilst those for CCR-2 are MCP-1,2, 3,4 and 5.

Chemokines and their receptors have been implicated as important mediators of inflammatory, infectious and immunoregulatory diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.

The CXCR3 chemokine receptor is expressed primarily in T lymphocytes, and its functional activity can be measured by cytocolic calcium elevation or chemotaxis. The receptor was previously referred to as GPR9 or CKR-L2. Its chromosomal location is unusual among the chemokine receptors in being localised to Xq13. Ligands that have been identified that are selective and are of high affinity are the CXC chemokines, interferon- gamma inducible protein (IP10), monokine induced by interferon-gamma (MIG) and interferon-inducible T-cell alpha chemoattractant (ITAC).

The highly selective expression of CXCR3 makes it an ideal target for the intervention to interrupt inappropriate T-cell trafficking. The clinical indications for such intervention are in T-cell mediated diseases such as multiple sclerosis, rheumatoid arthritis and type I diabetes. Inappropriate T- cell infiltration also occurs in psoriasis and other pathogenic skin inflammation conditions, although the diseases may not be true autoimmune disorders. In this regard, up-regulation of IP-10 expression in keratinocytes is a common feature in cutaneous immunopathologies. Inhibition of CXCR3 can be

beneficial in reducing rejection in organ transplantation. Ectopic expression of CXCR3 in certain tumours, especially subsets of B-cell malignancies, indicate that selective inhibitors of CXCR3 will have value in tumour immunotherapy, particularly attenuation of metastasis [see, for example, Qin S. et al., J. Clin.

Invest., 1998,101, 746-754; Srenson T. L. et al., J. Clin. Invest., 1999,103, 807-815].

Accordingly, in view of the clinical importance of CXCR3 there is a great need for new therapeutic agents that modulate CXCR3 function. We have found a class of bicyclic heteroaromatic derivatives that are potent and selective modulators of the interaction between CXCR3 and its chemokine ligands. Selective modulation of this interaction can be expected to have a beneficial effect and the compounds are thus of use in medicine, for example in the prevention or treatment of conditions involving inappropriate T-cell trafficking such as certain inflammatory, autoimmune and immunoregulatory disorders as described hereinafter.

Thus, according to the first aspect of the invention we provide a compound of formula (1): wherein: q is zero or the integer 1,2 or 3; R, when present, is an atom or group-L2 (Alk2) mL3 (R5) n in which L2 and L3, which may be the same or different, is each a covalent bond or a linker atom or group; m is zero or the integer 1; n is the integer 1,2 or 3; Alk2 is an optionally substituted aliphatic or heteroaliphatic chain; and R5 is a hydrogen or halogen atom or a group selected from alkyl, oR6 [where R6 is a hydrogen atom or an optionally substituted alkyl group],-SR6,-NR6R7 [where R is as just defined for R6 and may be the same or different],-N02,-CN,-C02R6, <BR> <BR> <BR> - R,-OCONR R,-CSNR R,-COR6,-OCOR6,-N (R6) COR, -N(R6)CSR7, -SO2N(R6)(R7), -N(R6)SO2R7, -N(R6)CON(R7)(R8) [where R is a hydrogen atom or an optionally substituted alkyl group], -N (R6) CSN (R (R8),

-N (R6) So2N (R7) (R8) or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group; provided that when m is zero and each of L2 and L3 is a covalent bond then n is the integer 1; X is a N atom or a C (R1) group, wherein R1 is as defined for R; Y is a N atom or a C (R1) group; r is zero or the integer 1; when r is the integer 1, Z is a N atom or a C (R1) group and represents a double bond; provided that when r is the integer 1 at least one of the groups X, Y or Z is a N atom; or when r is zero, Z is an O or S atom or a group N (R2) and represents a single bond, wherein R2 is a hydrogen atom or an optionally substituted alkyl group; L1 is absent or is an O atom or a N (R3) group, wherein R3 is a hydrogen atom or an optionally substituted alkyl group; Cy is an optionally substituted heterocycloaliphatic ring of formula (A) or (B) : in which a indicates the point of attachment of any available ring carbon in the ring Cy to the group L1 ; b indicates the point of attachment to Alk1 ; s and t, which may be the same or different, is each zero or the integer 1 or 2, provided that s + t is the integer 1,2, 3 or 4; R4 is an optionally substituted alkyl group; and W is a pharmaceutically acceptable counterion; Alk1 is a covalent bond or an optionally substituted straight or branched C16 alkylene chain; and E is an optionally substituted C710 cycloalkyl, C710 cycloalkenyl or C710 polycycloaliphatic group; and the salts, solvates, hydrates, tautomers or N-oxides thereof.

It will be appreciated that certain compounds of formula (1) may exist as geometric isomers (E or Z isomers). The compounds may also have one

or more chiral centres, and exist as enantiomers or diastereomers. The invention is to be understood to extend to all such geometric isomers, enantiomers, diastereomers and mixtures thereof, including racemates.

Formula (1) and the formulae hereinafter are intended to represent all individual isomers and mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (1) may exist as tautomers, for example urea tautomers [-NHC (O) NH-] and [-N=C (OH) NH-]. Formula (1) and the formulae hereinafter are intended to represent all individual tautomers and mixtures thereof, unless stated otherwise.

It will also be appreciated that where desired the compounds of the invention may be administered in a pharmaceutical acceptable pro-drug form, for example as a protected carboxylic acid derivative, e. g. as a physiologically acceptable ester. It will be further appreciated that the pro- drugs may be converted in vivo to the active compounds of formula (1), and the invention is intended to extend to such pro-drugs. Such pro-drugs are well known in the literature; see, for example, International Patent Application No.

WO 00/23419; Bodor, N. (Alfred Benzon Symposium, 1982,17, 156-177); Singh, G. et al. (J. Sci. Ind. Res. , 1996,55, 497-510) and Bundgaard, H.

(Design of Prodrugs, 1985, Elsevier, Amsterdam).

In the compounds of the invention and as represented by formula (1) and the more detailed description hereinafter certain of the general terms used in relation to substituents are to be understood to include the following atoms or groups unless specified otherwise.

Thus as used herein the term"alkyl", whether present as a group or part of a group, includes optionally substituted straight or branched C1 10alkyl groups, for example C1 6alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or neo-pentyl groups. Optional substituents when present on these groups include those optional substituents mentioned hereinafter.

The term"aliphatic chain"is intended to include optionally substituted straight or branched Cl-loalkylene, e. g. C1 6alkylene, C210alkenylene, e. g.

C26alkenylene, or ! kynyfene, e. g. C2-6alkynylene, groups.

Examples of aliphatic chains include optionally substituted straight or branched C16alkylene chains such as-CH2-,-CH2CH2-,-CH (CH3) CH2-, -(CH2)2CH2-, -(CH2)3CH2-, -CH(CH3) (CH2) 2CH2-, -CH2CH (CH3) CH2-,-C (CH3) 2-, -C (CH3) 2CH2-,-CH2C (CH3) 2CH2-, -(CH2)2CH (CH3) CH2-, -CH (CH3) CH2CH2-, - CH (CH3) CH2CH (CH3) CH2-, -CH2CH (CH3) CH2CH2-,- (CH2) 2C (CH3) 2CH2-, -(CH2)4CH2- or -(CH2) 5CH2; C26alkenylene chains such as-CH=CH-, <BR> <BR> <BR> <BR> - CH=CHCH2-,-CH2CH=CH-,-CH=CHCH2CH2-,-CH2CH=CHCH2-or - (CH2) 2CH=CH- ; and C26alkynylene chains such as-C=-C-,-C=-CCH2, -CH2C#C-, -C#CCH2CH2-, -CH2C#CCH2- or -(CH2)2C#C- chains. More particular examples include optionally substituted C13alkylene chains selected from-CH2-,-CH2CH2-,-CH2CH2CH2-,-CH (CH3) CH2-, -C (CH3) 2- and - CH2CH (CH3)- chains.

The term"heteroaliphatic chain"is intended to include the optionally substituted aliphatic chains just described but with each additionally containing one, two, three or four heteroatoms or heteroatom-containing groups. Particular heteroatoms or groups include atoms or groups L4 where L4 is a linker atom or group. Each L4 atom or group may interrupt the aliphatic group, or may be positioned at its terminal carbon atom to connect the group to an adjoining atom or group. Particular examples include optionally substituted -L4CH2-, -CH2L4-, -L4CH (CH3) -,-CH (CH3) L4-,-CH2L4CH2-,-L4CH2CH2-,-L4CH2CH (CH3) -, - CH (CH3) CH2L4-, -CH2CH2L4-, -CH2L4CH2CH2-, -CH2L4CH2CH2L4-, -(CH2)2L4CH2-, -(CH2)3L4CH2-, -L4 (CH2) 2CH2-, -L4CH2CH=CH-, -CH=CHCH2L4-, -(CH2) 2L4CH2CH2-,-(CH2) 3L4-and-L4CH2L4CH2CH2-chains.

When L4 is present in heteroaliphatic chains as a linker atom or group it may be any divalent linking atom or group. Particular examples include-0- or-S-atoms and-C (O)-,-C (O) O-, -OC (O)-,-C (S) -,-S (O)-,-S (O) 2-, -N (Ri4)- [where R14 is a hydrogen atom or a C1-6alkyl group], -N (R14) N (R14)-, -N(R14)O-, -ON(R14)-, -CON(R14)-, -OC(O) N (R14)-,-CS N (R14)-,-N (R14) CO-, -N(R14)C(O)O-, -N(R14 CS-,-S (O) 2N (R14)-, -N(R14)S(O)2-, -N(R14 CON (Ri4)-, - N (Ri4) CSN (R14)- or -N(R14)SO2N(R14)- groups. Where L4 contains two R14 groups these may be the same or different.

In general in the compounds of formula (1) the term"cycloaliphatic group"includes optionally substituted non-aromatic cyclic or multicyclic,

saturated or partially saturated 3-10 ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, norbornyl, norbornenyl, bicyclo [2.2. 1] heptanyl or'bicyclo [2.2. 1] heptenyl.

Particular examples include optionally substituted C36cycloalkyl ring systems such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups. Optional substituents present on these groups include those substituents mentioned hereinafter.

The term"heterocycloaliphatic group"refers to an optionally substituted non-aromatic 3-to 10-membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system containing one, two, three or four heteroatoms or heteroatom-containing groups L4 as defined above. Optional substituents present on the heterocycloaliphatic groups include those substituents mentioned hereinafter.

Particular examples of heterocycloaliphatic groups include optionally substituted cyclobutanonyl, cyclopentanonyl, cyclohexanonyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolinyl, e. g. 2-or 3-pyrrolinyl, pyrrolidinyl, pyrrolidinonyl, oxazolidinyl, oxazolidinonyl, dioxolanyl, e. g. 1,3- dioxolanyl, imidazolinyl, e. g. 2-imidazolinyl, imidazolidinyl, pyrazolinyl, e. g. 2- pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, e. g. 2-or 4-pyranyl, pyranonyl, piperidinyl, piperidinonyl, quinuclidinyl, 1, 4-dioxanyl, morpholinyl, morpholinonyl, 1, 4-dithianyl, thiomorpholinyl, piperazinyl, N-C16alkyl- piperazinyl, homopiperazinyl, dihydrofuran-2-onyl, tetrahydropyran-2-onyl, isothiazolidinyl 1,1-dioxide, [1,2] thiazinanyl 1,1-dioxide, tetrahydrothiophenyl, tetrahydrothiopyranyl, pyrazolidin-3-onyl, tetrahydrothiopyranyl 1,1-dioxide, tetrahydrothiophenyl 1,1-dioxide, 1,3, 5-trithianyl, oxazinyl, e. g. 2H-1, 3-, 6H-1,3-, 6H-1,2-, 2H-1, 2- or 4H-1, 4-oxazinyl, 1,2, 5-oxathiazinyl, isoxazinyl, e. g. o-or p-isoxazinyl, oxathiazinyl, e. g. 1,2, 5- or 1,2, 6-oxathiazinyl, and 1,3, 5- oxadiazinyl groups.

The optional substituents which may be present on the alkyl, cycloaliphatic or heterocycloaliphatic groups described above include one, two, three or more substituents, which each may be the same or different, selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH2), substituted amino, optionally substituted

C6-12arylamino,-CN,-C02H,-C02R9 (where R9 is an optionally substituted C1-6alkyl group), -SO3H, -SOR10 (where Rlo is a C1-6alkyl group), -SO2R10, -SO3R10, -OCO2R10, -C(O) H, -C (O) Rio,-OC (O) R10,-C (S) Rio, -C(O) N (R11) (Ri2) (where R11 and R12, which may be the same or different, is each a hydrogen atom or a C1-6alkyl group), -OC (O) N (R11) (R12), -N (R11)C(O)R12, -CSN(R11)(R12), -N(R11)C(S)(R12), -SO2N(R11)(R12), -N(R11)SO2R12, -N(R11) C (O) N (R12) (R13) (where R13 is a hydrogen atom or a C1-6alkyl group), -N (Rii) C (S) N (R12) (R13), -N(R11)SO2N(R12)(R13), or optionally substituted aromatic or heteroaromatic groups, or a C16alkyl group optionally substituted by one, two, three or more of the same or different atoms or groups selected from halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy, thiol, alkylthio, amino, substituted amino, optionally substituted C6-12arylamino, -CN, -CO2H, -CO2R9, -SO3H, -SOR10, -SO2R10, -SO3R10, -OCO2R10, -C (O)H, -C(O)R10, -OC(O)R10, -C(S)R10, -C(O)N(R11)(R12), <BR> <BR> <BR> <BR> <BR> -OC (O)N(R11)(R12), -N(R11)C(O)R12, -CSN(R11)(R12), -N(R11)C(S)(R12),<BR> -SO2N(R11)(R12), -N(R11)SO2R12, -N(R11)C(O)N(R12)(R13), -N (R11)C(S)N(R12)(R13), -N(R11)SO2N(R12)(R13), or optionally substituted aromatic or heteroaromatic groups. Substituted amino groups include -HNR10 and-N (R) (R) groups.

The optional substituents which may be present on aliphatic or heteroaliphatic chains, for example Alk2, include one, two, three or more substituents where each substituent may be the same or different and is selected from halogen atoms, e. g. fluorine, chlorine, bromine or iodine atoms, or -OH, -CN, -CO2H, -CO2R11b [where R11b is an optionally substituted C1-6alkyl group], e. g.-CO2CH3 or-C02C (CH3) 3, -CONHR11b, e. g.-CONHCH3, -CON(R11b) 2, e. g.-CON (CH3) 2, -COR11b, e. g.-COCH3, C1-6alkoxy, e. g. methoxy or ethoxy, haloC16alkoxy, e. g. trifluoromethoxy or difluoromethoxy, -SH, -S(O)R11b, e. g.-S (O) CH3, -S (O) 2R, e. g. -S(O)2CH3, C1-6alkylthio, e. g. methylthio or ethylthio, amino, -NHR11b, e. g.-NHCH3, or-N (R11b)2, e -N(CH3) 2, groups. Where two R11b groups are present in any of the above substituents these may be the same or different.

The optional substituents which may be present on alkylen chains, for example Alk1, include those as just defined for aliphatic or heteroaliphatic chains.

Cycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon atom. Heterocycloaliphatic groups may be linked to the remainder of the compound of formula (1) by any available ring carbon or, where available, ring nitrogen atom.

In the compounds of the invention the cycloalkyl and cycloalkenyl groups represented by E include non-aromatic cyclic or multicyclic, saturated or partially saturated C710cycloalkyl or C710cycloalkenyl ring systems. Where appropriate the cycloalkyl and cycloalkenyl groups may be substituted with one or more substituents as described hereinafter.

The C710polycycloaliphatic groups represented by E include optionally substituted C710bi-or tricycloalkyl or C710bi-or tricycloalkenyl groups.

Examples of groups represented by E include, but are not limited to, optionally substituted cyclooctyl, cyclononyl, cyclodecyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, adamantanonyl, noradamantyl, bicyclo [2.2. 1] heptanyl, bicyclo [2.2. 1] heptenyl, bicyclo [3.1. 1] heptanyl, bicyclo [3.1. 1] heptenyl, bicyclo [2.2. 2] octanyl, bicyclo [2.2. 2] octenyl, bicyclo [3.2. 1] octanyl, bicyclo [3.2. 1] octenyl, bicyclo [3.3. 1] nonanyl, bicyclo [6.2. 0] decanyl, octahydro-4, 7-methanoindenyl or octahydronaphthalenyl.

Optional substituents which may be present on the group E include one, two, three or more substituents, which each may be the same or different, selected from oxo, alkoxy, haloalkyl, e. g.-CF3 or-CF2H, haloalkoxy, e. g. -OCF2H, hydroxy (-OH), thiol (-SH), alkylthio,-CN,-CO2H,-CO2R9a (where R9a is an optionally substituted C16alkyl group),-S03H,-SOR'oa (where Rloa is a C1-6alkyl group), -SO2R10, -SO3R10, -OCO2R10, -C(O) H, -C (O)R10, -OC(O)R10, -C(S)R10, -C(O)N(R11a)(R12a) (where R11a and R which may be the same or different, is each a hydrogen atom or a Ci-eaikyi group),-N -N(R11a)C(O)R12a, -CSN(R11a)(R12a), -N(R11a)C(S)(R12a), -SO2N (R11a)(R12a), -N(R11a)SO2R12a, -N(R11a)C(O)N(R12a)(R13a) (where R13a is a hydrogen atom or a d-eaikyi group), -N (R) C (S) N (R) (R),

- N (R ) S02N (R ) (R ), or an optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group, or a straight or branched Chalky ! or C26alkenyl group optionally substituted by one, two, three or more of the same or different halogen atoms, or alkoxy, haloalkyl, haloalkoxy, hydroxy (-OH), thiol (-SH), alkylthio, amino (-NH2), substituted amino, optionally substituted C6-12arylamino, -CN, -CO2H, -CO2R9a, -SO3H, -SOR10a, -SO2R10, -SO3R10, -OCO2R10, -C(O) H, -C (O) R10,-OC (O) R'O, -C (S)R10, -C(O)N(R11a)(R12a), -N(R11a)C(O)R12a, -CSN(R11a)(R12a), -N (R11a)C(S)(R12a), -SO2N(R11a)(R12a), -N(R11a)SO2N(R12a)(R13a), -N (R11a)C(O)N(R12a)(R13a), -N(R11a)SO2R12a, -N(R11a)C(S)N(R12a)(R13a), or optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic groups.

The term"halogen atom"is intended to include fluorine, chlorine, bromine or iodine atoms.

The term"haloalkyl"is intended to include the alkyl groups just mentioned substituted by one, two or three of the halogen atoms just described. Particular examples of such groups include-CF3,-CC13,-CHF2, -CHCl2, -CH2F and -CH2Cl groups.

The term"alkoxy"as used herein is intended to include straight or branched C1-10alkoxy, for example C16alkoxy such as methoxy, ethoxy, n- propoxy, isopropoxy and tert-butoxy."Haloalkoxy"as used herein includes any of those alkoxy groups substituted by one, two or three halogen atoms as described above. Particular examples include-OCF3,-OCCI3,-OCHF2, -OCHCI2,-OCH2F and-OCH2CI groups.

As used herein the term"alkylthio"is intended to include straight or branched C1-10alkylthio, e. g. C16alkylthio such as methylthio or ethylthio groups.

The terms"aromatic group"and"aryl group"are intended to include for example optionally substituted monocyclic ring C612aromatic groups, such as phenyl, or bicyclic fused ring C6-12 aromatic groups, such as 1-or 2-naphthyl groups.

The terms"heteroaromatic group"and"heteroaryl group"are intended to include for example optionally substituted Cl-gheteroaromatic groups

containing for example one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms (or oxidised versions thereof). In general, the heteroaromatic groups may be for example monocyclic or bicyclic fused ring heteroaromatic groups. Monocyclic heteroaromatic groups include for example five-or six-membered heteroaromatic groups containing one, two, three or four heteroatoms selected from oxygen, sulfur or nitrogen atoms.

Bicyclic heteroaromatic groups include for example eight-to thirteen- membered fused-ring heteroaromatic groups containing one, two or more heteroatoms selected from oxygen, sulphur or nitrogen atoms.

Each of these aromatic or heteroaromatic groups may be optionally substituted by one, two, three or more R16 atoms or groups as defined below.

Particular examples of monocyclic ring heteroaromatic groups of this type include pyrrolyl, furyl, thienyl, imidazolyl, N-Cl-6alkylimidazolyi, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl and triazinyl.

Particular examples of bicyclic ring heteroaromatic groups of this type include benzofuryl, benzothienyl, benzotriazolyl, indolyl, indazolinyl, benzimidazolyl, imidazo [1,2-a] pyridyl, benzothiazolyl, benzoxazolyl, <BR> <BR> <BR> <BR> benzisoxazolyl, benzopyranyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrido [3, 4-b] pyridyl, pyrido [3,2-b] pyridyl, pyrido [4,3-b] pyridyl, quinolinyl, isoquinolinyl and phthalazinyl.

Optional substituents which may be present on the aromatic or heteroaromatic groups include one, two, three or more substituents, each selected from an atom or group R16 in which R16 is-Ri6a or -Alk4(R16a)f, where R16a is a halogen atom, or an amino (-NH2),-NHR17 [where R17 is an optionally substituted heterocycloaliphatic, cycloaliphatic, aryl or heteroaryl group, or -Alk4(R17s)f, where R17a is the same as R17],-N (R17) 2, nitro, cyano, amidino, formyl, hydroxy (OH), carboxyl (-C02H),-C02R, thiol (-SH),-SR - OR17, -COR17, -CSR17, -SO3H, -SOR17, -SO2R17, -SO3R17, -SO2NH2, -SO2NHR17, -SO2N (R17)2, -CONH2, -CSNH2, -COHR17, -CSNHR17, -CON(R17)2, -CSN(R17) 2, -N (R18) SO2R17, [where Ris is a hydrogen atom or a d-eaikyi group],-N (S02Rl7) 2, -N (Ri8) SO2NH2, -N(R18)SO2NHR17, - N(R17)SO2N(R18) 2, -N (Ri8) COR17,-N (R18) CONH2,-N (R18) CONHR13,

-N(R18) CON (R17)2, -N(R18)CSNH2, -N(R18)CSNHR17, -N(R18)CSN(R17)2, -N(R18)CSR17, -N(R18) C (O) OR17, -SO2NHet1 [where -NHet1 is an optionally substituted C37heterocycloaliphatic group optionally containing one or more other-O-or-S-atoms or-N (R18)-,-C (O)- or -C(S)- groups], -CONHet1, -CSNHet1, -N (R18)SO2NHet1, -N(R18)CONHet1, -N(R18)CSNHet1, -SO2N(R18) Het2 [where Het2 is an optionally substituted monocyclic C37 cyclo- aliphatic group optionally containing one or more -O- or -S- atoms or-N (R18)-, -C (O)-or-C (S)-groups],-CON (R18) Het2, -CSN (Ri8) Het2, -N(R18) CON (Ri8) Het2, -N (Ri8) CSN (Ri8) Het2, or optionally substituted aryl, heteroaryl, cycloaliphatic or heterocycloaliphatic group; Alk4 is a straight or branched C1-6alkylene, C26alkenylene or C26 alkynylene chain, optionally interrupted by one, two or three -O- or -S- atoms or-S (O) g- [where g is an integer 1 or 2] or-N (R18)-groups ; and f is zero or an integer 1,2 or 3. It will be appreciated that when two R17 or R18 groups are present in one of the above substituents, the R17 or R18 groups may be the same or different.

When in the group-Alk4 (Rl6a) f or -Alk4(R17a)f f is an integer 1,2 or 3, it is to be understood that the substituent or substituents R16a or R17a may be present on any suitable carbon atom in-Alk4. Where more than one R16a or R17a substituent is present these may be the same or different and may be present on the same or different atom in-Alk4. Clearly, when f is zero and no substituent R16a or R17a is present the alkylen, alkenylene or alkynylene chain represented by-Alk4 becomes an alkyl, alkenyl or alkynyl group.

When-NHet1 or-Het2 forms part of a substituent R16 each may be for example an optionally substituted 2-or 3-pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperazinyl, imidazolinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl, oxazolidinyl or thiazolidinyl group. Additionally, -Het2 may represent, for example, an optionally substituted cyclopentyl or cyclohexyl group. Optional substituents which may be present on -NHet1 or -Het2 include those substituents described above in relation to aromatic groups.

Particularly useful atoms or groups represented by R16 include fluorine, chlorine, bromine, iodine, C1-6alkyl, haloC16alkyl, e. g.-CF3, haloC1-6alkoxy, e. g.-OCF3 or -OCF2H, -NH2, -NHR17, -N(R17)2, -CN, -CO2H, -CO2R17, -SR17,

- OH, -OR17, -COR17, -CSR17, -SO2R17, -SO2NH2, -SO2NHR17, SO2N(R17)2, -CONH2, -CSNH2, -CONHR17, -CSNHR17, -CON (R17)2, -CSN(R17)2, -N (R18)SO2R17, -N(R18)COR17, -N(R18)CONH2, -N(R18)CONHR17, -N(R18)CSR17, -N(R18) C (O) OR17,-S02NHet',-CONHet',-CSNHet',-Alk4NH2, - Alk4NHR17 -Alk4N(R17)2, -Alk4CN, -Alk4CO2H, -Alk4CO2R17, -Alk4SR17, - Alk4OR17, -Alk4COR17, -Alk4CSR17, -Alk4SO2R17, -Alk4SO2NH2, -Alk4SO2NHR17, -Alk4SO2N (R17)2, -Alk4CONH2, -Alk4CSNH2, -Alk4CONHR17, -Alk4CSNHR17, -Alk4CON (R17)2, -Alk4CSN(R17)2, -Alk4N(R18)SO2R17, -Alk4N (R18)COR17, -Alk4N(R18)CONH2, -Alk4N(R18)CONHR17, -Alk4N (R18) CSR17-AIk4N (R18) C (O) OR17, -Alk4SO2NHet1, -Alk4CONHet1, -Alk4CSNHet1, optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic,-Alk4phenyl,-Alk4monocyclic heteroaryl,-Alk4monocyclic heterocycloaliphatic, and-Alk4cycloaliphatic.

Particularly useful R17 groups include-Alk4 (where f is zero), optionally substituted phenyl, monocyclic heteroaryl, monocyclic heterocycloaliphatic, cycloaliphatic,-Alk4phenyl,-Alk4monocyclic heteroaryl,-Alk4monocyclic heterocycloaliphatic, and-Alk4cycloaliphatic. R13 is particularly hydrogen or methyl.

When-Alk4 is present it may be for example a methylene, ethylene, n- propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene, ethynylene, 2- propynylene, 2-butynylene or 3-butynylene chain, optionally interrupted by one, two, or three-O-or-S-atoms or-S (O)-,-S (O) 2- or-N (R18)- groups.

Particular examples of-Alk4 include C16alkylene chains, especially C13alkylene chains, e. g. methylene, ethylene or propylene, or, when f is zero, C16alkyl groups, especially C14alkyl groups, e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.

Particular examples of aryl, heteroaryl, heterocycloaliphatic or cycloaliphatic groups which may be represented by -R16a, -R17 or -R17a include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <BR> <BR> <BR> <BR> azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, imidazolidinyl, thiazolidinyl, piperazinyl, N-Cl-ralkylpiperazinyl, especially N-methylpiperazinyl, N-C16alkyl- pyrrolidinyl, especially N-methylpyrrolidinyl, N-C16alkylpiperidinyl, especially N-

methylpiperidinyl, homopiperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, <BR> <BR> <BR> <BR> tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyrrolyl, furyl, thienyl, imidazolyl, <BR> <BR> <BR> <BR> <BR> <BR> <BR> N-C16alkylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, tetrazolyl, triazinyl, pyridyl-N-oxide, dihydropyrazolonyl and imidazolonyl.

Optional substituents which may in particular be present on the aryl or heteroaryl groups represented by-R16a,-R17 or-R17a include one, two, three or more atoms or groups selected from fluorine, chlorine, methyl,-OCH3, -OCF, -OCF2H, -CF3, -CN, -NHCH3, -N (CH3)2, -CONH2, -CONHCH3, - CON (CH3) 2,-C02CH3,-C02CH2CH3,-C02C (CH3) 3,-COCH3,-NHCOCH3, -N (CH3) COCH3,-SCH3,-S02CH3 or-CO2H.

Optional substituents which may in particular be present on the heterocycloaliphatic or cycloaliphatic groups represented by-R16a,-R17 or -R17a include one, two, three or more atoms or groups selected from-OCH3, -OCF3,-OCF2H,-CF3, C13alkylthio, straight or branched C13alkyl,-CN, -NHCH3, -N (CH3) 2,-CONH2,-CONHCH3,-CON (CH3) 2,-C02CH3, -CO2CH2CH3, -CO2C (CH3) 3, -COCH3,-NHCOCH3,-N (CH3) COCH3 or -CO2H.

Where desired, two adjacent Ris substituents may be linked together to form a cyclic group such as a cyclic ether, e. g. a C16alkylenedioxy group such as methylenedioxy or ethylenedioxy, or a C3-6cycloalkyl or 3-to 10-membered monocylic heterocycloaliphatic group as defined herein.

It will be appreciated that where two or more R16 substituents are present, these need not necessarily be the same atoms and/or groups. In general, the substituent (s) may be present at any available ring position in the aromatic or heteroaromatic group.

Optional substituents which may be present on any available carbon of the ring Cy include one, two or three substituents, RA, where RA is a halogen atom or an alkyl group. Thus, for example, Cy may be substituted by a halogen atom or a straight or branched C110alkyl group as defined herein.

Examples of heterocycloaliphatic rings represented by Cy in compounds of the invention include : where s is the integer 1, t is zero or the integer 1 or 2 (especially the integer 1), and a, b, W and R4 are as described earlier, or

where s is the integer 1 or 2, t is zero or the integer 1 or 2, and a, b, W and R4 are as described earlier.

Linker atoms or groups L2 and L3, when present in the group R, R1 or R2 in compounds of the invention, may be any of the linker atoms or groups as previously defined for L4. Each linker atom or group may be the same or different.

When the groups R6 and R7 or R7 and R8 are both present in the group R, R1 or R2 as alkyl groups these groups may be joined together with the N atom to which they are attached to form a heterocyclic ring. Such heterocyclic rings may be optionally interrupted by a further heteroatom selected from-0-, -S- or -N(R6)-. Particular examples of such heterocyclic rings include piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolidinyl and piperazinyl rings.

Examples of the substituents represented by R, R1 or R2 when present in compounds of the invention include atoms or groups-L2Alk2L3R5,-L2Alk2R5, -L2R5,-R5,-Alk2R5 and-Alk2 (R5) n, wherein L2, Alk2, L3, R5 and n are as defined above. Particular examples of such substituents include-L2CH2L3R5, -L2CH(CH3)L3R5, -L2 (CH2) 2L3R5, -L2CH2R5, -L2CH(CH3)R5, -L2(CH2)2R5, -CH2R5, -CH(CH3)R5, -(CH2)2R5 and -R5 groups.

Particularly useful atoms or groups represented by R, Razor (where relevant) R2 in compounds of the invention include, for example, halogen atoms, e. g. fluorine, chlorine, bromine or iodine atoms, and C16alkyl, e. g. methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl optionally substituted C3-8cycloalkyl, e. g. optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted C37heterocycloalkyl, e. g. optionally substituted pyrrolidinyl,

piperidinyl, imidazolidinyl, morpholinyl or piperazinyl, C1-6hydroxyalkyl, e. g. hydroxymethyl, hydroxyethyl or-C (OH) (CF3) 2, carboxyC16alkyl, e. g. carboxyethyl, C16alkylthio e. g. methylthio or ethylthio, carboxyC16alkylthio, e. g. carboxymethylthio, 2-carboxyethylthio or 3-carboxypropylthio, C1-6alkoxy, e. g. methoxy or ethoxy, hydroxyC16alkoxy, e. g. 2-hydroxyethoxy, haloC16alkyl, e. g.

-CF3, -CHF2 or-CH2F, haloC16alkoxy, e. g.-OCF3,-OCHF2 or-OCH2F, C16alkyl- amino, e. g. methylamino or ethylamino, amino (-NH2), aminoC16alkyl, e. g. aminomethyl or aminoethyl, C1-6alkylamino, e. g. dimethylamino or diethylamino, C1-6alkylaminoC1-6alkyl, e. g. ethylaminoethyl, Cl-rdialkylamino- C16alkyl, e. g. diethylaminoethyl, aminoC16alkoxy, e. g. aminoethoxy, C1-6alkylaminoC1-6alkoxy, e. g. methylaminoethoxy, C1-6dialkylaminoC1-6alkoxy, e. g. dimethylaminoethoxy, diethylaminoethoxy, diisopropylaminoethoxy, or dimethylaminopropoxy, nitro, cyano, amidino, hydroxyl (-OH), formyl [HC (O)-], carboxyl (-CO2H), -CO2Alk5 [where Alk5 is an optionally substituted alkyl group], C1-6 alkanol e. g. acetyl, thiol (-SH), thioC16alkyl, e. g. thiomethyl or thioethyl, sulphonyl (-SO3H), -SO3Alk5, C1-6alkylsulphinyl, C1-6alkylsulphonyl, e. g. methylsulphonyl, aminosulphonyl (-SO2NH2), C1-6 alkylaminosulphonyl, e. g. methylaminosulphonyl or ethylaminosulphonyl, C1-6dialkylaminosulphonyl, e. g. dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl, carboxamido (-CON2), C1-6alkylaminocarbonyl, e. g. methylaminocarbonyl or ethylaminocarbonyl, C16dialkylaminocarbonyl, e. g. dimethylaminocarbonyl or diethylaminocarbonyl, aminoC16alkylaminocarbonyl, e. g. aminoethyl- aminocarbonyl, C1-6dialkylaminoC1-6alkylaminocarbonyl, e. g. diethylaminoethyl- aminocarbonyl, aminocarbonylamino, C16alkylaminocarbonylamino, e. g. methylaminocarbonylamino or ethylaminocarbonylamino, C1-6dialkylamino- carbonylamino, e. g. dimethylaminocarbonylamino or diethylaminocarbonyl- amino, C1-6alkylaminocabonylC1-6alkylamino, e. g. methylaminocarbonyl- methylamino, aminothiocarbonylamino, Cl-6alkylaminothiocarbonylamino, e. g. methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C16dialkyl- aminothiocarbonylamino, e. g. dimethylaminothiocarbonylamino or diethylamino- thiocarbonylamino, C1-6alkylaminothiocarbonylC1-6alkylamino, e. g. ethylamino- thiocarbonylmethylamino, C16alkylsulphonylamino, e. g. methylsulphonylamino or ethylsulphonylamino, C16dialkylsulphonylamino, e. g. dimethylsulphonylamino or diethylsulphonylamino, aminosulphonylamino (-NHSO2NH2), C16alkylamino-

sulphonylamino, e. g. methylaminosulphonylamino or ethylamino- sulphonylamino, C16dialkylaminosulphonylamino, e. g. dimethylaminosulphonyl- amino or diethylaminosulphonylamino, C16alkanoylamino, e. g. acetylamino, aminod-eaikanoyiamino e. g. aminoacetylamino, C1-6dialkylaminoC1-6alkanoyl- amino, e. g. dimethylaminoacetylamino, C1-6alkanoylaminoC1-6alkyl, e. g. acetyl- aminomethyl, C16alkanoylaminoC16alkylamino, e. g. acetamidoethylamino, d-eaikoxycarbonyiamino, e. g. methoxycarbonylamino, ethoxycarbonylamino or teff-butoxycarbonylamino, optionally substituted C6-12aryl, e. g. optionally substituted phenyl, optionally substituted C19heteroaryl, e. g. optionally substituted pyridyl, pyrimidinyl, thiophenyl or furyl, optionally substituted -C1-6alkylC6-12aryl, e. g. optionally substituted benzyl or phenylethyl, optionally substituted -C1-6alkylC1-9heteroaryl, e. g. optionally substituted pyridylmethyl, furanylmethyl or thiophenylmethyl, -C1-6alkoxyC6-12aryl, e. g. optionally substituted benzyloxy or phenylethoxy, and optionally substituted -C1-6alkoxyC1-9heteroaryl, e. g. optionally substituted pyridylmethoxy, furanylmethoxy or thiophenylmethoxy, groups.

Where desired, two R substituents may be linked together to form a cyclic group such as a cyclic ether, e. g. a C16alkylenedioxy group such as methylenedioxy or ethylenedioxy. In addition, when two R substituents are on adjacent carbon atoms of the heteroaromatic ring of formula (1) they may be joined to form, together with the heteroaromatic ring carbon atoms to which they are joined, a heteroaromatic ring-fused optionally substituted cycloaliphatic, heterocycloaliphatic, aromatic or heteroaromatic ring where such rings and optional substituents are as previously defined.

It will be appreciated that where two or more R substituents are present these need not necessarily be the same atoms and/or groups. In general the substituent (s) may be present on any available ring position in the heteroaromatic ring in compounds of formula (1).

When R, R, R, R, R, R12, R12a, R13, R13a, R14 or R18 is present as a d-eaikyi group it may be a straight or branched d-oaikyi group, e. g. a C1-3 alkyl group such as methyl, ethyl or isopropyl.

Examples of optionally substituted alkyl groups present in ester groups of formulae -CO2R9, -CO2R9a, -CO2R11b and -CO2Alk5 include C1-6 alkyl groups

as herein described. Optional substituents, which may be present on these alkyl groups, include optionally substituted cycloaliphatic, aromatic or heteroaromatic groups as herein defined.

R4 when present in compounds of formula (1) as an optionally substituted alkyl group may be any optionally substituted alkyl group as previously defined. Particular examples of such groups include d-eaikyi groups and optionally substituted C612arylC16alkyl groups, especially methyl, ethyl and optionally substituted benzyl groups.

A pharmaceutical acceptable counterion means an ion having a charge opposite to that of the substance with which it is associated and that is pharmaceutical acceptable. Representative examples include, but are not limited to, chloride, bromide, iodide, methanesulfonate, p-tolylsulfonate, trifluoroacetate, acetate, nitrate, sulfate, phosphate, carbonate, propionate, malonate and the like, such as are described in Remington's Pharmaceutical Sciences, 1 7th ed., Mack Publishing Company, Easton, PA, 1985.

The presence of certain substituents in the compounds of formula (1) may enable salts of the compounds to be formed. Suitable salts include pharmaceutical acceptable salts, for example acid addition salts derived from inorganic or organic acids, and salts derived from inorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides, alkylsulphonates, e. g. methanesulphonates, ethanesulphonates, or isothionates, arylsulphonates, e. g. p- toluenesulphonates, besylates or napsylates, phosphates, sulphates, hydrogensulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.

Particularly useful salts of compounds according to the invention include pharmaceutically acceptable salts, especially acid addition pharmaceutical acceptable salts.

In one embodiment, r is the integer 1.

In one embodiment, X is a N atom. In another embodiment, X is a C (R1) group.

In one embodiment, Y is a N atom. In another embodiment, Y is a C (R1) group.

In one embodiment, Z is a N atom. In another embodiment, Z is a C (R1) group.

Suitably, R1 is hydrogen.

In one group of compounds of formula (1), X and Z is each a N atom and Y is a group C (R'). In one particular class of compounds of this type, R is a hydrogen atom.

In another group of compounds of formula (1), X is a N atom, and Y and Z are both C (R). In one particular class of compounds of this type, R1 is a hydrogen atom.

One particular group of compounds of the invention has the formula (2): wherein R, q, X, Z, L', Cy, Alk1 and E are as defined for formula (1).

In general, in compounds of formula (1) or (2), q is preferably zero or the integer 1 or 2.

Suitable values of R include halogen, C16alkyl, trifluoromethyl, C16alkoxy, trifluoromethoxy, nitro and optionally substituted phenyl.

Examples of typical substituents on R include halogen, trifluoromethyl, Cl-6alkoxy and cyano.

Detailed values of R include fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy, nitro, chlorophenyl, dichlorophenyl, trifluoromethyl-phenyl, methoxyphenyl and cyanophenyl.

Representative values of R include halogen, C16alkyl, trifluoromethyl, C16alkoxy, trifluoromethoxy and nitro. Specific values of R include fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy, trifluoromethoxy and nitro.

Particularly useful R or R1 substituents when present in compounds of formula (1) or (2) include halogen atoms, especially fluorine, chlorine or

bromine atoms, or C13alkyl, especially methyl, halomethyl, especially-CF3 or -CHF2, methoxy, halomethoxy, especially -OCF3 or -OCHF2, -CN, -CO2R6, especially-C02CH3,-COR6, especially-COCH3,-N02, amino (-NH2), substituted amino (-NR6R7), especially-NHCH3 or-N (CH3) 2, and-N (R6)COR7, especially-NHCOCH3, groups.

X in one particular group of compounds of formula (2) is a N atom or a C (H) group. In compounds of this class X is most preferably a N atom.

In compounds of formula (2), Z is in particular an O or S atom or a N (R2) group, where R2 is a hydrogen atom or an optionally substituted CI-6 alkyl group. Especially useful NR2 groups include NH, NCH3 and NCH2Ph where Ph is an optionally substituted phenyl ring, most especially NH or NCH3.

In one embodiment of the compounds of formula (2), Z is O. In another embodiment of the compounds of formula (2), Z is S. In a further embodiment of the compounds of formula (2), Z is NH.

In one embodiment of the compounds according to the invention, L1 is absent. In another embodiment of the compounds according to the invention, L1 represents N (R3). In a specific embodiment, L1 is NH.

In the compounds according to the invention, R3 suitably represents hydrogen, C1-6alkyl, C37cycloalkylC16alkyl or C16alkoxyC16alkyl. Particular values of R3 include hydrogen, methyl, cyclopropylmethyl and methoxypropyl.

A specific value of R3 is hydrogen.

L1 in compounds of formula (1) or (2) is preferably an O atom or a N (R3) group. In compounds of this type R3 is in particular a hydrogen atom or an optionally substituted C1-6 alkyl, especially C1-3 alkyl, group. Especially useful NR3 groups include NH, NCH3 and NCH2Ph where Ph is an optionally substituted phenyl ring. In one particular group of compounds of this class L is an O atom or an NH or NCH3 group.

Cy in compounds of formula (1) or (2) is most especially : wherein a, b, R4 and W are as herein defined.

R4 in one particular group of compounds of the invention is a C13 alkyl group, such as a methyl or ethyl group, especially a methyl group.

Alk1 in one group of compounds of formula (1) or (2) is preferably a C13alkylene chain, in particular-CH2-,-CH2CH2-or-CH2CH2CH2-, more particularly-CH2-.

Alternatively, Alk1 in another group of compounds of formula (1) or (2) is a covalent bond.

One group of compounds has the formula (1) or (2) wherein E is selected from optionally substituted cycloheptyl, cyclooctyl, cyclononyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, adamantyl, bicyclo [2.2. 1] heptanyl, bicyclo [2.2. 1] heptenyl, bicyclo [3.1. 1] heptanyl or bicyclo [3.1. 1] heptenyl.

Particular substituents, which may be present on the group E, are one, two, three or more groups selected from hydroxy, optionally substituted phenyl or monocyclic heteroaromatic,-CONH2,-CONHCH3,-CON (CH3) 2,-C02CH3, - C02CH2CH3,-C02H, or optionally substituted straight or branched C16alkyl or C26alkenyl, wherein the optional alkyl or alkenyl substituent is in particular an optionally substituted phenyl or monocyclic heteroaromatic group. Particular examples of the optionally substituted C16alkyl or C26alkenyl groups are-CH3, -CH2CH3,-CH (CH3) 2, (CH2) 2CH3,- (CH2) 3CH3,-CH (CH3) CH2CH3, -CH2CH (CH3) 2, -CH2C (CH3) 3, -C (CH3) 3,-(CH2) 4CH3,-(CH2) 5CH3-CH=CH2, -CH=CHCH3, -CH2CH=CH2, -CH=CHCH2CH3, -CH2CH=CHCH3, - (CH2) 2CH=CH2 or-C (CH3) =CH2.

One preferred group of compounds is where E is substituted with one, two, three or more methyl groups.

E in one particular group of compounds of the invention is a 1- cyclooctenyl, 6, 6-dimethylbicyclo [3.1. 1] hept-2-en-2-yl, adamantyl or cyclooctyl group. In one group of compounds of the invention E is especially a 6,6- dimethylbicyclo [3.1. 1] hept-2-en-2-yl group.

One particular group of optional substituents which may be present on cycloaliphatic or heterocycloaliphatic groups in compounds of formula (1) or (2), in particular on the E group substituents, are one, two or three groups selected from C13 alkoxy,-OCF3,-OCF2H,-CF3, C13alkylthio,-CN,-NHCH3, -N (CH3) 2,-CONH2,-CONHCH3,-CON (CH3) 2,-C02CH3,-C02CH2CH3,

- C02C (CH3) 3,-COCH3,-NHCOCH3,-N (CH3) COCH3,-C02H, or optionally substituted straight or branched C13alkyl, wherein the optional alkyl substituent is in particular-CN, C13alkoxy,-NHCH3,-N (CH3) 2,-CON2, -CONHCH3,-CON (CH3) 2,-C02CH3,-C02CH2CH3,-C02C (CH3) 3,-COCH3, -NHCOCH3,-N (CH3) COCH3 or-CO2H.

Particular aromatic or heteroaromatic substituents, which may be present on compounds of formula (1), in particular on the E group substituents, are one, two or three atoms or groups selected from fluorine, chlorine, bromine, straight or branched C13alkyl, methoxy,-OCF3,-OCF2H,-CF3,-CN, - N02,-NH2,-NHCH3,-N (CH3) 2,-CONH2,-CONHCH3,-CON (CH3) 2,-C02CH3, -C02CH2CH3 or-C02H.

Compounds according to the invention are potent and selective inhibitors of chemokines binding to the CXCR3 receptor as demonstrated by differential inhibition of this receptor when compared to other chemokine receptors, such as CCR3. The ability of the compounds to act in this way may be simply determined by employing tests such as those described in the Examples hereinafter.

The compounds are of use in modulating chemokine-mediated cell signaling and in particular are of use in the prophylaxis and/or treatment of diseases or disorders involving inappropriate T-cell trafficking. The invention extends to such a use and to the use of the compounds of formula (1) or (2) for the manufacture of a medicament for treating such diseases and disorders.

Particular diseases include inflammatory, autoimmune and immunoregulatory disorders.

Particular uses to which the compounds of the invention may be put include: (1) inflammatory or allergic diseases such as systemic anaphylaxis or hypersensitivity responses, drug allergies, insect sting allergies ; inflammatory bowel diseases, such as Crohn's disease, ulcerative colitis, ileitis and enteritis; vaginitis; psoriasis and inflammatory dermatoses such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis ; spondyloarthropathies ; scleroderma ; respiratory allergic diseases such as asthma, allergic rhinitis, hypersensitivity lung diseases and the like ;

(2) autoimmune diseases, such as arthritis (rheumatoid and psoriatic), multiple sclerosis, systemic lupus erythematosus, diabetes, glomerulonephritis and the like ; (3) graft rejection (including allograft rejection and graft-v-host disease); and (4) other diseases in which undesired inflammatory responses are to be inhibited, e. g. atherosclerosis, myositis, neurodegenerative diseases, Alzheimer's disease, encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, conjunctivitis, otitis, chronic obstructive pulmonary disease, sinusitis, Behcet's syndrome, Sjogren's syndrome and glomerulonephritis.

In a particular embodiment, the compounds of the present invention are useful for the treatment of the aforementioned exemplary disorders irrespective of their etiology, for example for the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, allograft rejection and graft-v-host disease.

The compounds of formula (1) or (2) can be used alone or in combination with other compounds having related utilities to prevent and treat inflammatory and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as multiple sclerosis, rheumatoid arthritis and atherosclerosis, and those pathologies as discussed herein.

For the prophylaxis or treatment of disease the compounds according to the invention may be administered as pharmaceutical compositions, and according to a further aspect of the invention we provide a pharmaceutical composition which comprises a compound of formula (1) or (2) together with one or more pharmaceutical acceptable carriers, excipients or diluents.

Alternative compositions of this invention comprise a compound of formula (1) or (2) or a pharmaceutically acceptable salt thereof; an additional agent selected from an immunosuppressant or an anti-inflammatory agent; and any pharmaceutically acceptable carrier, adjuvant or vehicle.

Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, vaginal 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 pharmaceutical acceptable excipients such as binding agents (e. g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (e. g. lactose, microcrystalline cellulose or calcium hydrogenphosphate) ; lubricants (e. g. magnesium stearate, talc or silica) ; disintegrants (e. g. potato starch or sodium glycollate) ; or wetting agents (e. g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutical acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles and preservatives. The preparations may also contain buffer salts, and flavouring, colouring 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 (1) or (2) 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. For particle-mediated administration the compounds of formula (1) or (2) may be coated on particles such as microscopic gold particles.

In addition to the formulations described above, the compounds of formula (1) or (2) 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 for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of suitable propellant, e. g. dichlorodifluoromethane, trichlor- fluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.

For vaginal or rectal administration the compounds of formula (1) or (2) may be formulated as a suppository. These formulations may be prepared by mixing the active ingredient with a suitable non-irritating excipient which is a solid at room temperature but liquid at the body temperature. Such materials include, for example, cocoa butter and polyethylene glycols.

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

The quantity of a compound of 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 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 around 0.05 mg to around 1000 mg, e. g. around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.

The compounds of the invention may be prepared by a number of processes as generally described below and more specifically in the Examples hereinafter. Many of the reactions described are well-known standard synthetic methods which may be applied to a variety of compounds and as such can be used not only to generate compounds of the invention, but also where necessary the intermediates thereto.

In the following process description, the symbols R, X, Y, Z, q, s, t, L', Cy, Alk1, E, R4 and W, when used in the formulae depicted, are to be understood to represent those groups described above in relation to formula

(1) unless otherwise indicated. In the reactions described below, it may be necessary to protect reactive functional groups, for example hydroxy, amino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice [see, for example, Greene, T. W. in"Protective Groups in Organic Synthesis", John Wiley and Sons, (1999) and the examples herein]. In some instances, deprotection may be the final step in the synthesis of a compound of formula (1) and the processes according to the invention described hereinafter are to be understood to extend to such removal of protecting groups.

Thus, according to a further aspect of the invention, a compound of formula (1) or (2), in which L1 is an O atom or a group N (R3), may be prepared as shown in Scheme (A) below : (ici) (i) Scheme A (1) Thus, a compound of formula (1) may be prepared by reaction of an amine or alcohol of formula (ii), wherein L1 is an O atom or a N (R3) group, with a compound of formula (i), wherein V is a leaving group. Examples of suitable leaving groups include halogen atoms, e. g. fluorine, bromine, iodine or chlorine atoms, alkylsulfonyl groups, e. g. methanesulfonyl, or sulfonyloxy groups such as alkylsulfonyloxy, e. g. trifluoromethylsulfonyloxy, or arylsulfonyloxy, e. g. p- toluenesulfonyloxy, groups. The reaction may be performed in the presence of a base. Appropriate bases may include, but are not limited to, silazane, e. g. lithium hexamethyldisilazane (LiHMDS) or sodium hexamethyldisilazane (NaHMDS), carbonates, e. g. potassium carbonate, hydrides, e. g. sodium hydride, or organic amines, e. g. triethylamine or N, N-diisopropylethylamine or cyclic amines such as N-methylmorpholine or pyridine. The reaction may be performed in an organic solvent such as an amide, e. g. a substituted amide such as N, N-dimethylformamide, an ether, e. g. a cyclic ether such as tetrahydrofuran or 1,4-dioxane, or N-methylpyrrolidone or acetonitrile, at a temperature from ambient to the reflux temperature. Where appropriate, the

reaction may be performed at an elevated temperature in the presence of microwave irradiation.

Compounds of formula (ii) wherein L1 is a N (R3) group may be prepared as shown in Scheme B below : E-Alkb N-H/N-Alkl-E E-Alki-T (v) P-N R3 (I) Scheme FF) , HN R3 (ici) Thus, an amine of general formula (iii) where P is a suitable protecting group, e. g. tert-butoxycarbonyl, may be reacted with a compound of formula E-Alk'-T (v), wherein T is a suitable leaving group (e. g. a halogen atom, such as chlorine or bromine, or an arylsulfonyloxy group, such as p-toluene- sulfonyloxy), to give a compound of general formula (vi). The reaction may be performed in the presence of a base such as potassium carbonate in, for example, refluxing acetonitrile or N, N-dimethylformamide at around ambient temperature.

Alternatively, the protected amine of general formula (vi) may be prepared by reductive alkylation of a compound of formula (iii) with a compound of formula E-Alk1b (iv), wherein Alk1b is a suitable precursor to Alk1, for example Alk1b contains a reactive group such as a reactive carbonyl. This reaction may be achieved using methods known to those skilled in the art.

For example, when Alk1b is an aldehyde, appropriate conditions may include the use of a suitable borohydride as reductant, for example sodium triacetoxy- borohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e. g. dichloromethane, or an alcohol, e. g. methanol or ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature. A dehydrating agent such as an orthoformate, e. g. triethyl orthoformate or trimethyl orthoformate, may also be employed in the reaction.

The compounds of formula (v) may be prepared from an alcohol of general formula E-Alk'-OH (vii) using standard methodology known to those skilled in the art. For example, when T is an arylsulfonate ester, e. g. p- toluenesulfonyloxy, this may be prepared by reaction of the alcohol (vii) with p-toluenesulfonyl chloride in the presence of an amine base, e. g. triethylamine, in an appropriate solvent, such as dichloromethane or tetrahydrofuran.

The compounds of formula (vii) may also be used to prepare the compounds of formula (iv) using standard oxidising conditions such as those described herein.

The intermediate compound of formula (vi) may be deprotected using standard methodology, for example by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, to give an amine starting material of general formula (ii).

It will be appreciated by those skilled in the art that alcohols of formula (ii): may also be prepared in a similar manner. The use of protecting groups may not be required, particularly when reductive alkylation is employed.

It will be further appreciated that the order of reactions in which a compound of formula (1) or (2) is prepared may be varied. Thus, for example, a compound of formula (viii) : where U is an O or N (R3) group, and P is as defined above; may be reacted with compound of general formula (i) using the reactions just described to yield a compound of formula (ix):

The resulting compound of formula (ix) may be deprotected using methods known to those skilled in the art and reacted with a compound of general formula (iv) or (v) using standard techniques, such as the methods described herein.

Compounds of formula (1) or (2), in which L1 is absent, may be prepared as shown in Scheme (C) below : () i v () Rq : z 1) "2) Scheme C ) /N-Alk'-E 'UL' r

Thus, a compound of formula (i) may be reacted with an organometallic reagent such as butyllithium in an organic solvent such as diethyl ether or tetrahydrofuran at-78°C, followed by addition of a ketone of formula (x). The resulting intermediate may then be treated with acid, e. g. trifluoroacetic acid, in a halogenated hydrocarbon, e. g. dichloromethane, to give a compound of formula (xi). Compounds of formula (1) or (2) may be prepared by reduction of a compound of formula (xi) using methods known to those skilled in the art, e. g. hydrogenation in the presence of a palladium catalyst. It will be appreciated by the person skilled in the art that a compound of formula (xii), wherein P is a protecting group, may be used as an alternative to compounds of formula (x):

(xii)

The protecting group may be removed using standard methodology at the end of the procedure described in Scheme (C) and the resulting amine manipulated using methods as described above to give. a compound of formula (1) or (2).

The compounds of formula (2) wherein X is N, Z is NH and L1 is absent may be prepared by a process which comprises cyclising a compound of formula (xiii): (xiii) wherein q, R, Cy, Alk1 and E are as defined above.

The cyclisation of compound (xiii) is conveniently effected by heating in phosphorus oxychloride, typically in the presence of pyridine.

The synthesis of compounds of formula (1) or (2) may be amenable to high throughput methods, such as combinatorial or parallel synthesis techniques familiar to those skilled in the art.

Intermediates of formula (i)- (xiii) and any other intermediates required to obtain compounds of formula (1) or (2), if not available commercially, may be prepared by methods known to those skilled in the art following procedures set forth in references such as Rodd's Chemistry of Carbon Compounds, Volumes 1-15 and Supplementals (Elsevier Science Publishers, 1989); Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-19 (John Wiley and Sons, 1999); Comprehensive Heterocyclic Chemistry, ed. Katritzky et al., Volumes 1-8, 1984, and Volumes 1-11,1994 (Pergamon); Comprehensive Organic Functional Group Transformations, ed. Katritzky et al., Volumes 1-7, 1995 (Pergamon); Comprehensive Organic Synthesis, ed. Trost and Fleming, Volumes 1-9 (Pergamon, 1991); Encyclopedia of Reagents for Organic Synthesis, ed. Paquette, Volumes 1-8 (John Wiley and Sons, 1995); Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989); and March's Advanced Organic Chemistry (John Wiley and Sons, 1992).

Thus, for example, compounds of formula (i), wherein V is a halogen atom such as chlorine or bromine, may be prepared from an amine of formula (xiv):

(xiv) Thus, for example, a bromide or chloride of formula (i) may be prepared by treatment of a compound of formula (xiv) with an alkyl nitrite, for example teint-butyl nitrite, or sodium nitrite in the presence of an acid, e. g. sulphuric acid or hydrochloric acid, followed by addition of a copper salt, for example copper (l) or copper (II) bromide or chloride, in the presence of a solvent, for example a nitrile such as acetonitrile or acetic acid, at a temperature from about 0°C to around 65°C.

The intermediates of formula (xiii) may be prepared by reacting a compound of formula Q1-Cy-Aik1-E with a compound of formula (xv): (xv) wherein q, R, Cy, Alk1 and E are as defined above, and Q1 represents an activated carboxylate moiety, e. g. an acid chloride functionality-COCI. The reaction is conveniently carried out in the presence of a base, e. g. diisopropyl- ethylamine, in a solvent such as dichloromethane.

The intermediates of formula Q1-Cy-Alk1-E wherein Q1 is-COCI may suitably be prepared from the corresponding compound wherein Q1 is a carboxylic acid moiety-C02H by treatment with oxalyl chloride. The latter compound may in turn be prepared from a precursor ester derivative, e. g. the methyl or ethyl ester, under standard saponification conditions, for example by treatment with lithium hydroxide.

It will be appreciated that compounds of formula (1) or (2), or any preceding intermediates, may be further derivatised by one or more standard

synthetic methods employing substitution, oxidation, reduction or cleavage reactions. Particular substitution approaches include conventional alkylation, arylation, heteroarylation, acylation, thioacylation, halogenation, sulphonylation, nitration, formylation and coupling procedures. It will be appreciated that these methods may also be used to obtain or modify other compounds of formula (1), where appropriate functional groups exist in these compounds.

Thus, compounds of formula (1) or (2) which contain the group R4 may be prepared from a compound of formula (1) or (2) using the general method as shown in Scheme D: \\/ , N-Alk-E 11-- \ ) Z Scheme (1) Thus, a compound of formula (1) may be reacted with an alkylating agent R4-W such as an alkyl halide, e. g. methyl or ethyl iodide, or a benzyl halide such as benzyl bromide in a solvent such as a halogenated hydrocarbon, e. g. dichloromethane, an alcohol, e. g. methanol or ethanol, an ether, e. g. diethyl ether, or a mixture of such solvents, at, for example, ambient temperature.

For example, ester groups may be converted to the corresponding acid [-CO2H] by acid-or base-catalysed hydrolysis depending on the nature of the ester. Acid-or base-catalysed hydrolysis may be achieved, for example, by treatment with an organic or inorganic acid, e. g. trifluoroacetic acid, in an aqueous solvent or a mineral acid such as hydrochloric acid in a solvent such as 1,4-dioxane or an alkali metal hydroxide, e. g. lithium hydroxide, in an aqueous alcohol, e. g. aqueous methanol. Similarly, an acid [-C02H] may be prepared by hydrolysis of the corresponding nitrile [-CN], using for example a base such as sodium hydroxide in a refluxing alcoholic solvent, such as ethanol.

In another example, -OH groups may be generated from a corresponding ester or aldehyde [-CHO] by reduction, using for example a complex metal hydride such as lithium aluminium hydride or sodium borohydride in a solvent such as methanol. Alternatively an alcohol may be prepared by reduction of the corresponding acid [-C02H], using for example lithium aluminium hydride in a solvent such as tetrahydrofuran.

Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e. g. trifluoromethyl- sulfonyloxy, or arylsulfonyloxy, e. g. p-toluenesulfonyloxy, group, using conditions known to the skilled artisan. For example, an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon, e. g., dichloromethane, to yield the corresponding chloride. A base, e. g. triethylamine, may also be used in the reaction.

Aldehyde [-CHO] groups may be obtained by oxidation of a corresponding alcohol using well-know conditions. For example, using an oxidising agent such as a periodinane, e. g. Dess Martin, in a solvent such as a halogenated hydrocarbon, e. g. dichloromethane. An alternative oxidation procedure may be suitably brought about by activating dimethylsulfoxide using, for example, oxalyl chloride, followed by addition of an alcohol, and subsequent quenching of the reaction by the addition of an amine base, such as triethylamine. Suitable conditions for this reaction may be using an appropriate solvent, for example a halogenated hydrocarbon, e. g. dichloromethane, at -78°C followed by subsequent warming to room temperature. a, (3-Unsaturated aldehydes, for example, of formula OHC-E, where E is cycloalkenyl, may be prepared by hydrolysis of a corresponding allylic nitro compound. This may be achieved, for example, by treatment of the allylic nitro compound with a base, such as sodium methoxide or potassium tert-butoxide, followed by addition of a buffered aqueous titanium trichloride solution. The allylic nitro compound may be prepared by nucleophilic addition of nitromethane to the corresponding ketone, followed by elimination of water. Suitable conditions for this reaction may be refluxing in toluene under Dean-Stark conditions, in the presence of an amine base, such as N, N-dimethylethylene diamine. It will be appreciated that these aldehydes may be used in reductive alkylations to give compounds of formula (1) where Alk1 is-CH2-using the conditions described herein.

In a further example primary amine [-NH2] or secondary amine [-NH-] groups may be alkylated using a reductive alkylation process employing an aldehyde and a borohydride, for example sodium triacetoxyborohyride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, e. g.

dichloromethane, a ketone such as acetone, or an alcohol, e. g. ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.

A compound of formula (1) wherein L1 is NH may be converted into the corresponding compound wherein LJ represents N (R3), in which R3 is other than H, by treatment with an alkyl halide R3-Hal, e. g. iodomethane, cyclopropylmethyl bromide or 1-bromo-3-methoxypropane, in the presence of a base, e. g. sodium hydride, typically in a solvent such as N, N-dimethylformamide.

In a further example, amine [-NH2] groups may be obtained by hydrolysis from a corresponding imide by reaction with hydrazine in a solvent such as an alcohol, e. g. ethanol, at ambient temperature.

In another example, a nitro [-NO2] group may be reduced to an amine [-NH2], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium, on a support such as carbon in a solvent such as an ether, e. g. tetrahydrofuran, or an alcohol, e. g. methanol, or by chemical reduction using for example a metal, e. g. tin or iron, in the presence of an acid such as hydrochloric acid.

In a further example amine [-CH2NH2] groups may be obtained by reduction of nitriles [-CN], for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney@ nickel, in a solvent such as an ether, e. g. a cyclic ether such as tetrahydrofuran, or an alcohol, e. g. methanol or ethanol, optionally in the presence of ammonia solution at a temperature from ambient to the reflux temperature, or by chemical reduction using for example a metal hydride, e. g. lithium aluminium hydride, in a solvent such as an ether, e. g. a cyclic ether such as tetrahydrofuran, at a temperature from 0°C to the reflux temperature.

Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange with a base, for example a lithium base such as n- butyl-or tert-butyllithium, optionally at a low temperature, e. g. around-78°C, in a solvent such as tetrahydrofuran and then quenched with an electrophile to introduce a desired substituent. Thus, for example, a formyl group may be introduced by using N, N-dimethylformamide as the electrophile ; or a thiomethyl group may be introduced by using dimethyidisulphide as the electrophile.

N-Oxides of compounds of formula (1) or (2) may be prepared, for example, by oxidation of the corresponding nitrogen base using an oxidising agent such as hydrogen peroxide in the presence of an acid such as acetic acid, at an elevated temperature, for example around 70°C to 80°C, or alternatively by reaction with a peracid such as peracetic acid in a solvent, e. g. dichloromethane, at ambient temperature.

A compound of formula (1) wherein R is halogen, e. g. bromo, may be converted into the corresponding compound wherein R represents an optionally substituted aryl (e. g. phenyl) or heteroaryl group by treatment with the appropriate aryl or heteroaryl boronic acid in the presence of a transition metal catalyst, e. g. tetrakis (triphenylphosphine) palladium (0). The reaction is conveniently performed at an elevated temperature in a suitable solvent, e. g. aqueous 1,4-dioxane, typically in the presence of a base such as sodium carbonate.

Salts of compounds of formula (1) or (2) may be prepared by reaction of a compound of formula (1) or (2) with an appropriate base or acid in a suitable solvent or mixture of solvents, e. g. an organic solvent such as an ether, e. g. diethyl ether, or an alcohol, e. g. ethanol, or an aqueous solvent, using conventional procedures. Salts of compounds of formula (1) or (2) may be exchanged for other salts by use of conventional ion-exchange chromatography procedures.

Where it is desired to obtain a particular enantiomer of a compound of formula (1) or (2) 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 (1) or (2), 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 (1) or (2) may be separated using chiral High Performance Liquid Chromatography.

Alternatively, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.

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.

The following Examples illustrate the invention. All temperatures are in °C. Where experimental detail is not given for the preparation of a reagent it is either commercially available, or it is known in the literature, for which the CAS number is quoted. The compounds are named with the aid of Beilstein Autonom supplied by MDL Information Systems GmbH, Theodor-Heuss-Allee 108, D-60486 Frankfurt, Germany.

1H NMR spectra were obtained at 300 MHz or 400 MHz unless otherwise indicated.

The following LCMS conditions were used to acquire the retention times as reported herein: LCMS conditions HP1100 (Diode Array) linked to a Finnigan LC-Q Mass Spectrometer, ESI mode with Pos/Neg ionisation.

Column : Luna C18 (2) 100 x 4.6 mm, 5 , m particle size Analytical column Column Temp: 35°C Mobile Phase: A: Water + 0.08% formic acid B: Acetonitrile + 0.08% formic acid Flow rate: 3 ml/min Gradient: Time (min): % Composition B: 0 5 4.4 95 5.30 95 5.32 5 6.5 5 Run time: 6.5 min Typical Injection Vol : 10 n. i Detector Wavelength : DAD 200-400 nm

Preparative HPLC conditions (Method A) Gilson 215 liquid handler setup.

Column : Luna C18 (2) 250 x 21.2 mm, 5 ; j, M partide size prep column Column Temp: Ambient Gradient: Variable-depends on retention time of sample in LC-MS analysis.

Run Time: 20 min Flow rate: 25 ml/min Typical Injection Vol : 0.5-4. Oml at 25mg/mi Detector Wavelength : 210 and 254 nm Mobile Phase: A: Water + 0.08% formic acid B: Acetonitrile + 0.08% formic acid Preparative HPLC conditions (Method B) Gilson 215 liquid handler setup.

Column : Luna C18 (2) 250 x 21.2 mm, 5 llM particle size prep column Column Temp: Ambient Gradient: Variable-depends on retention time of sample in LC-MS analysis.

Run Time: 20 min Flow rate: 25 ml/min Typical Injection Vol : 0.5-4. 0 ml at 25 mg/ml Detector Wavelength : 210 and 254 nm Mobile Phase: A: 10 mM NH40Ac in water B: 10 mM NH40Ac in acetonitrile Abbreviations used AcOH-Acetic acid BOC-tert-Butoxycarbonyl DCM-Dichloromethane DIPEA-Diisopropylethylamine DMF-N, N-Dimethylformamide Et2O-Diethyl ether EtOAc-Ethyl acetate MeCN-Acetonitrile MeOH-Methanol NMP-1-methyl-2-pyrrolidinone RT-Retention time TEA-Triethylamine

TFA-Trifluoroacetic acid THF-Tetrahydrofuran TMOF-Trimethyl orthoformate Intermediate 1 4- (Boc-amino)-1- (cvcloocten-1-vlmethvl) piperidine Piperidin-4-ylcarbamic acid test-butyl ester hydrochloride [CAS No.

73874-95-0] (2 g) was dissolved in DCM (20 ml), and TEA (2 g) and TMOF (5 ml) were added. 1-Cyclooctene carboxaldehyde [CAS No. 6038-12-6] (2 g) was added and the mixture was stirred for 30 min, then sodium triacetoxy- borohydride (4 g) was added and the mixture was stirred overnight at room temperature. The solution was washed with saturated NaHCO3 (20 ml), dried (MgS04) and evaporated to give the title compound as a beige solid (2.6 g).

TLC Rf 0. 25 (5% MeOH/DCM).

Intermediate 2 [1-((1R,5S)-6,6-Dimethylbicyclo[3. 1. llhept-2-en-2-Vimethyl) piperidin-4- vllcarbamic acid tert-butyl ester Prepared in a similar manner to Intermediate 1 from piperidin-4-yl- carbamic acid tert-butyl ester hydrochloride [CAS No. 73874-95-0] (1.63 g) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No. 18486-69- 6] (1.26 ml) to give a light yellow oil (2.91 g). Purification by column chromatography (5% MeOH/DCM) afforded the title compound as a colourless solid (1.75 g). RT 2.25 minutes. M+H 335.

Intermediate 3 4-Amino-1- (cycloocten-1-vimethvl) piperidine TFA (10 ml) was added to a solution of Intermediate 1 (2.6 g) in DCM (30 ml) at room temperature. The solution was stirred for 2 h, and then evaporated in vacuo and the residue dissolved in water (30 ml) and washed with Et2O (20 ml). The aqueous layer was basified with NaOH pellets and extracted with DCM (2 x 20 ml). The solvent was washed with H20 (20 ml) and brine (20 ml), dried (MgS04) and evaporated to give the title compound as a pale yellow oil. TLC Rf 0. 22 (10% MeOH/DCM; 1 % NH40H).

Intermediate 4 1- ( (1 R, 5S)-6, 6-Dimethvlbicvclof3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4- lav mine

Prepared in a similar manner to Intermediate 3 from Intermediate 2 (3 g. ) to give the title compound as an orange oil (2.4 g). TLC Rf 0.30 (10% MeOH/DCM; 1% NH40H).

Intermediate 5 1- ((1S,5R)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-ylmethyl)pipe ridine-4- carboxylic acid methvl ester From methyl isonipecotate [CAS No. 2971-79-1] (7.53 g, 52.58 mmol) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No. 18486-69- 6] (7.98 mi, 52.58 mmol) to give a pale yellow oil (15.2 g). Column chromatography (EtOAc/heptane 1: 8) afforded the title compound as a near- colourless oil (13. 8 g). RT 2. 06 min. M+H 278.

Intermediate 6 1- ((1S,5R)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-ylmethyl)pipe ridine-4- carboxylic acid LiOH. H20 (2.20 g, 52.3 mmol) dissolved in H20 (8 mi) was added to a solution of Intermediate 5 (13.80 g, 49.8 mmol) in THF (50 ml), and the mixture stirred at room temperature overnight. The solution was then concentrated to dryness and dried at 50°C in a vacuum oven to give a solid (12.1 g). The solid was re-dissolved in THF (80 mi) and HCI solution in Et20 (47.2 mi, 47.2 mmol) added. The solvents were then removed in vacuo to afford the title compound as an off-white solid (13.66 g). RT 1.83 min. M+H 264.

Intermediate 7 1- ( ( S, 5R)-6, 6-Dimethylbicvclo (3. 1. 1lhept-2-en-2-vlmethyl) piperidine-4- carboxylic acid (2-amino-5-trifluoromethylphenvl) amide Intermediate 6 (0.86 g, 2.81 mmol) suspended in DCM (18 mi) was treated with oxalyl chloride (0.74 ml, 8.44 mmol) and the mixture stirred for 45 min. The solution was then evaporated and the residue re-dissolved in DCM (20 ml). 3, 4-Diaminobenzotrifluoride [CAS No. 368-71-8] (495 mg, 2.81 mmol) and DIPEA (2 mi, 11.5 mmol) were added, and the solution stirred overnight at room temperature. The solution was washed with saturated NaHCO3 solution (30 ml), dried (MgS04) and evaporated to give a brown foam (1.51 g).

Purification by column chromatography (5% MeOH/DCM) afforded the title compound as a red-orange foam (845 mg). RT 2.69 min. M+H 422.

General method for preparation of 2-chlorobenzothiazoles The appropriate 2-aminobenzothiazole (10 mmol) was dissolved in AcOH (30 ml), H2O (10 ml) and concentrated HCI (20 ml). The solution was cooled in ice and sodium nitrite (15 mmol) added portionwise over 30 min.

When addition was complete, copper (l) chloride (15 mmol) was added and the mixture stirred overnight at room temperature. H20 (200 ml) was added and the products collected by filtration. Intermediates 8 to 11 were prepared using this general methodology.

Intermediate 8 2-Chloro-4, 6-difluorobenzothiazole From 2-amino-4, 6-difluorobenzothiazole [CAS 119256-40-5] (1.9 g, 10.3 mmol). The title compound was obtained as a yellow solid (1.65 g). M+H 206.

TLC Rf (DCM) 0.75.

Intermediate 9 2-Chloro-5|6-dimethvibenzothiazole From 2-amino-5, 6-dimethylbenzothiazole [CAS 29927-08-0] (1.8 g, 10.2 mmol). The title compound was obtained as a beige solid (1.80 g). M+H 198. TLC Rf (DCM) 0.71.

Intermediate 10 4-Bromo-2-chlorobenzothiazole From 2-amino-4-bromobenzothiazole [CAS 20358-02-5] (0.7 g, 3.0 mmol). The title compound was obtained as a yellow solid (530 mg). M+H 248. TLC Rf 0.76 (DCM).

Intermediate 11 5-Bromo-2-chlorobenzothiazole From 2-amino-5-bromobenzothiazole [CAS 20358-03-6] (0.8 g, 3.5 mmol). The title compound was obtained as a yellow solid 9800 mgO. M+H 248. TLC Rf 0 : 81 (DCM).

Intermediate 12 N-(6-Bromobenzothiazol-2-vl)-N-r1-((1 Rb5S)-6|6-dimethyl- bicvclof3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4-yl]amine Prepared in a similar manner to Example 4 from 6-bromo-2- chlorobenzothiazole [CAS No. 80945-86-4] (73 mg) and Intermediate 4 (100 mg). Yield 14. 3 mg. M+H 446. TLC Rf 0. 23 (5% MeOH/DCM).

Intermediate 13 <BR> <BR> 4-rN- (Benzothiazol-2-vl)-N-methvlaminolpiperidine-1-carboxvlic acid tert- butyl ester Prepared in a similar manner to Example 4 from 2-chlorobenzothiazole [CAS No. 615-20-3] (0.61 ml) and 4-(methylamino) piperidine-1-carboxylic acid tert-butyl ester [CAS No. 147539-41-1] (2.0 g). The crude product was purified by column chromatography, eluting with EtOAc/heptane, to give the title compound (900 mg) as a cream-coloured solid. RT 4.03 minutes. M+H 348.

Intermediate 14 4-rN- 1H-Benzimidazol-2-vl)-N-methvlaminolpiperidine-1-carboxvlic acid tert-butvl ester Prepared in a similar manner to Example 4 from 2-chlorobenzimidazole [CAS No. 4857-06-1] (200 mg) and 4-(methylamino) piperidine-1-carboxylic acid teint-butyl ester [CAS No. 147539-41-1] (562 mg) to give the title compound (63 mg) as a yellow solid. RT 1. 95 minutes. M+H 331.

Intermediate 15 <BR> <BR> 4-[N-(4-Ch lorobenzothiazol-2-vl)-N-methelaminolpi peridine-1-carboxvlic acid tert-butvl ester Prepared in a similar manner to Example 4 from 2, 4-dichloro- benzothiazole [CAS No. 3622-30-8] (100 mg) and 4- (methylamino) piperidine- 1-carboxylic acid tert-butyl ester [CAS No. 147539-41-1] (209 mg) to give the title compound (141 mg) as a colourless glass/white solid. RT 4.69 minutes.

M+H 382.

Intermediate 16 4-rN-Methvl-N- (auinoxalin-2-vl) aminolpiperidine-1-carboxvlic acid tert- butvi ester Prepared in a similar manner to Example 4 from 2-chloroquinoxaline [CAS No. 1448-87-9] (200 mg) and 4-(methylamino) piperidine-1-carboxylic acid tert-butyl ester [CAS No. 147539-41-1] (521 mg), adding NMP (0.5 ml) and heating in the microwave at 120°C for 65 min, to give the title compound (227 mg) as a yellow gum. RT 4.00 minutes. M+H 343.

Intermediate 17 N- (Benzothiazol-2-vt)-N-methyl-N- (piperidin-4-vl) amine 2HCl salt

Intermediate 14 (895 mg) was dissolved in MeOH (18 ml) and a solution of HCI in Et20 added (1.0 M, 30 ml). The reaction was left to stir for 18 h then the precipitate produced was filtered off and washed with Et20 (2 x 20 ml) to give the title compound (723 mg) as a white solid. RT 1.52 minutes.

M+H 248.

Intermediate 18 N- (1 H-Benzimidazol-2-vl)-N-methyl-N- (piperidin-4-vl) amine 2HCI salt Prepared in a similar manner to Intermediate 17 from Intermediate 14 (63 mg) to give the title compound (42 mg) as an orange solid. RT 0.50 minutes. M+H 231.

Intermediate 19 <BR> <BR> <BR> <BR> N- (4-Chlorobenzothiazol-2-vl)-N-methvl-N- (piperidin-4-vl) amine 2HCI salt Prepared in a similar manner to Intermediate 17 from Intermediate 15 (141 mg) to give the title compound (63 mg) as a pale green solid. RT 1.85 minutes. M+H 282.

Intermediate 20 N-Methvl-N-(piperidin-4-vl)-N-(quinoxalin-2-vl) amine 2HCI salt Prepared in a similar manner to Intermediate 17 from Intermediate 16 (227 mg) to give the title compound (200 mg) as a pale green solid. RT 1.42 minutes. M+H 243.

Example 1 N-(Benzoxazol-2-vl)-N-91-(cvolooct-1-envlmethvl) piPeridin-4-vllamine A mixture of 2-chlorobenzoxazole [CAS No. 615-18-9] (52.2 mg), Intermediate 3 (75 mg) and DIPEA (0.5 ml) in MeCN (5 ml) was refluxed for 18 hours. The reaction mixture was concentrated and partitioned between DCM (25 ml) and a saturated solution of NaHCO3 in H20 (25 ml). The organic layer was washed with brine (2 x 15 ml), dried (MgS04), concentrated in vacuo and purified by preparative HPLC (Method A) to give the title compound as a beige solid (104 mg). RT 1.94 minutes. M+H 340.

Example 2 N-(Benzoxazol-2-vl)-N-91-((1 R, 5S)-6. 6-dimethvlbicvclor3. 1. 1lhept-2-en-2- vlmethvl) piperidin-4-vllamine Prepared in a similar manner to Example 1 from 2-chlorobenzoxazole [CAS No. 615-18-9] (52 mg) and Intermediate 4 (77 mg). Yield 30 mg. RT 2.21 minutes. M+H 352.

Example 3 N- [1-(Adamantan-1-ylmethyl)piperidin-4-yl]-N-(benzoxazol-2-yl) amine Prepared in a similar manner to Example 1 from 2-chlorobenzoxazole [CAS No. 615-18-9] (52 mg) and 1-(adamantan-1-ylmethyl) piperidin-4-ylamine [CAS No. 64306-80-5] (84 mg). Yield 4 mg. RT 2.17 minutes. M+H 366.

Example 4 N- (Benzothiazol-2-vl)-N- 1- (cvclooct-1-envimethvl) piperidin-4-vilamine A mixture of 2-chlorobenzothiazole [CAS No. 615-20-3] (57.7 mg), Intermediate 3 (75 mg) and DIPEA (1.0 ml) in NMP (10 ml) was refluxed for 65 hours. The reaction mixture was concentrated and partitioned between DCM (25 ml) and a concentrated solution of NaHCO3 in H20 (25 ml). The organic layer was extracted with brine (15 ml), dried and concentrated. The crude product was purified by preparative HPLC to give the title compound (21.5 mg). RT 2.12 minutes. M+H 356.

Example 5 N- (Benzothiazol-2-yl)-N-r1- ( (1 R, 5S)-6, 6-dimethvlbicvclor3. 1. 1lhept-2-en-2- vlmethvl) piperidin-4-vllamine Prepared in a similar manner to Example 4 from 2-chlorobenzothiazole [CAS No. 615-20-3] (58 mg) and Intermediate 4 (77 mg). Yield 17 mg. RT 2.27 minutes. M+H 368.

Example 6 N-r1- (Adamantan-1-vimethvl) piperidin-4-vll-N- (benzothiazol-2-vl) amine Prepared in a similar manner to Example 4 from 2-chlorobenzothiazole [CAS No. 615-20-3] (58 mg) and 1- (adamantan-1-ylmethyl) piperidin-4-ylamine [CAS No. 64306-80-5] (84 mg). Yield 7 mg. RT 2.22 minutes. M+H 382.

Example 7 N-(1H-Benzimidazol-2-yl)-N-[1-((1R,6S)-6,6-dimethylbicyclo[3 . 1. 1lhept-2- en-2-vimethvl) piperidin-4-vllamine

Prepared in a similar manner to Example 4 from 2-chlorobenzimidazole [CAS No. 4857-06-1] (61 mg) and Intermediate 4 (84 mg). Yield 9 mg. RT 1.48 minutes. M+H 351.

Example 8 N-f 1- (Adamantan-1-vlmethvl) piperidin-4-vfl-N- ( H-benzimidazol-2- I) amine Prepared in a similar manner to Example 4 from 2-chlorobenzimidazole [CAS No. 4857-06-1] (55 mg) and 1- (adamantan-1-ylmethyl) piperidin-4- ylamine [CAS No. 64306-80-5] (90 mg). Yield 6 mg. RT 2.35 minutes. M+H 481.

Example 9 N- (5-Chlorobenzothiazol-2-y)-N- 1- ( (1 R, 5S) -6, 6-dimethyl- bicvclof3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4-vllamine Prepared in a similar manner to Example 4 from 5-chloro-2- methanesulfonylbenzothiazole [CAS No. 29203-76-7] (80 mg) and Intermediate 4 (100 mg). Yield 23 mg. M+H 402. TLC Rf 0.26 (5% MeOH/DCM).

Example 10 N- (4, 6-Difluorobenzothiazol-2-yl)-N-[1-((1R,5S)-6,6-dimethyl- bicyclo[3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4-yl]amine Prepared in a similar manner to Example 4 from Intermediate 8 (70 mg) and Intermediate 4 (100 mg). Yield 32 mg. M+H 404. TLC Rf 0.26 (5% MeOH/DCM).

Example 11 <BR> <BR> <BR> <BR> N-n- ( (1R, 5S)-6, 6-Dimethvlbicvclof3. 1. 1lhept-2-en-2-vimethvl) piperidin-4- <BR> <BR> <BR> <BR> <BR> <BR> <BR> ell-N-(6-nitrobenzothiazol-2-yl) amine Prepared in a similar manner to Example 4 from 2-chloro-6- nitrobenzothiazole [CAS No. 2407-11-6] (69 mg) and Intermediate 4 (100 mg).

Yield 21 mg. M+H 413. TLC Rf 0.22 (5% MeOH/DCM).

Example 12 N- (5,6-Dimethylbenzothiazol-2-yl)-N-[1-((1R,5S)-6,6-dimethyl- bicvclof3. 1. 11 hept-2-en-2-vlmethvl) piperidin-4-vllamine

Prepared in a similar manner to Example 4 from Intermediate 9 (63 mg) and Intermediate 4 (100 mg). Yield 17 mg. M+H 396. TLC Rf 0.26 (5% MeOH/DCM).

Example 13 N- [1-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-ylmethyl)p iperidin-4- vll-N- (6-trifluoromethoxvbenzothiazol-2-vl) amine Prepared in a similar manner to Example 4 from 2-chloro-6-trifluoro- methoxybenzothiazole [CAS No. 133840-96-7] (76 mg) and Intermediate 4 (100 mg). Yield 27 mg. M+H 452. TLC Rf 0.21 (5% MeOH/DCM).

Example 14 N- [1-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-ylmethyl)p iperidin-4- vll-N- (6-fluorobenzothiazol-2-vl) amine Prepared in a similar manner to Example 4 from 2-chloro-6- fluorobenzothiazole [CAS No. 399-74-6] (59 mg) and Intermediate 4 (100 mg).

Yield 40 mg. M+H 386. TLC Rf 0. 25 (5% MeOH/DCM).

Example 15 N- (4-Chlorobenzothiazol-2-yi)-N-fl- ( (IR, 5S) -6, 6-dimethyl- b) cvc) or3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4-yl]amine Prepared in a similar manner to Example 4 from 2,4- dichlorobenzothiazole [CAS No. 3622-30-8] (68 mg) and Intermediate 4 (100 mg). Yield 33. 1 mg. M+H 402. TLC Rf 0. 26 (5% MeOH/DCM).

Example 16 N-(4-Bromobenzothiazol-2-yl)-N-[1-((1 R, 5S)-6, 6-dimethvl- bicyclo [3.1.1]hept-2-en-2-ylmethyl)piperidin-4-yl]amine Prepared in a similar manner to Example 4 from Intermediate 10 (500 mg, 2.0 mmol) and Intermediate 4 (600 mg, 1.98 mmol). Yield 51. 0 mg. M+H 446. TLC Rf 0.21 (5% MeOH/DCM).

Example 17 N- (5-Bromobenzothiazol-2-yl)-N-[1-((1R,5S)-6,6-dimethyl- bicvclor3. 1. 11hept-2-en-2-vlmethvl) piperidin-4-vllamine From Intermediate 11 (500 mg, 2.0 mmol) and Intermediate 4 (600 mg, 1. 98 mmol). Yield 37.0 mg. M+H 446. TLC Rf 0.24 (5% MeOH/DCM).

Example 18 N- [1-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-ylmethyl)piperi din-4-yl]-N- (quinoxalin-2-vl) amine 2-Chloroquinoxaline (1.0 mmol, 165 mg) was added to a stirred solution of Intermediate 4 (1.0 mmol, 302 mg) and DIPEA (0.517 g, 4.0 mmol,) in NMP (1 ml) under an inert atmosphere. After heating at reflux overnight the reaction mixture was cooled, concentrated in vacuo and partitioned between DCM (20 ml) and NaHCO3 (20 ml), washed with brine (20 ml), dried (MgS04), and concentrated to yield a dark brown oil. The product was purified by preparative HPLC, to yield the title compound as an amber oil (13.8 mg). RT 2.26 minutes. M+H 406.

Example 19 N-(6-Chlorobenzothiazol-2-vl)-N-f1-((1 S5R)-6, 6-dimethvl- bicyclo [3.1.1]hept-2-en-2-ylmethyl)piperidin-4-yl]amine A mixture of 2, 6-dichlorobenzothiazole [CAS No. 3622-23-9] (200 mg), Intermediate 4 (301 mg) and DIPEA (0.55 ml) in NMP (2 ml) was heated in the microwave at 200°C for 15 min. The reaction mixture was partitioned between Et20 and H20 (30 ml each). The aqueous was extracted with Et20 (10 mi) and the combined organics washed with H20 (30 ml) and brine (30 ml), dried (MgS04) and evaporated. The crude product was purified by column chromatography on silica eluting with 30% EtOAc/heptane to give the title compound as a cream-coloured solid (170 mg). RT 2.50 minutes. M+H 402.

Example 20 N ( ( R, 5S)-6, 6-Dimethvlbicvclof3. 1. 11hept-2-en-2-vlmethVl) piperidin-4- vil-N- (quinolin-2-vl) amine 2-Chloroquinoline (0.611 mmol, 100 mg) was added to a stirred solution of Intermediate 4 (0.611 mmol, 187 mg) and DIPEA (1.833 mmol, 319 mg) in MeCN (2 mt) under an inert atmosphere. After heating at 140°C for 15 minutes by microwave the reaction mixture was cooled, concentrated in vacuo and partitioned between DCM (20 ml) and NaHCO3 (20 ml), washed with brine (20 ml), dried (MgS04), and concentrated, to yield a dark brown oil. The product was purified by chromatography (2.5% MeOH/DCM), to yield the title compound as a yellow oil (155 mg; 70%). RT 1. 54 minutes. M+H 362.

General procedure for the preparation of substituted phenvl-2-T1- ( (1 S, 5R)-6, 6-dimethvlbicvclor3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4- vlaminolbenzothiazoles Tetrakis (triphenylphosphine) palladium (0) [CAS No 14221-01-3] was added to a degassed solution of the appropriate N- (bromobenzothiazol-2-yl)- N-[1-((1R, 5S) -6, 6-dimethylbicyclo [3.1. 1]hept-2-en-2-ylmethyl)piperidin-4-yl]- amine (0.11 mmol), Na2CO3 (0.06 mmol) and the appropriate boronic acid (0.12 mmol) in 1,4-dioxane (10.0 ml) and water (5 ml) and the solution was heated with stirring to 80°C for six hours. The mixture was poured into saturated ammonium chloride solution (30 mi) and extracted with Et20 (3 x 30 ml). The solvent was dried (MgSO4) and evaporated. Crude products were purified by silica chromatography to give the title compounds.

Example 21 6-(2-Chlorophenyl)-2-[1-((1S,5R)-6,6-dimethylbicyclo[3. 1. llhept-2-en-2- vlmethvl) piperidin-4-vlaminolbenzothiazole From intermediate 12 (50 mg, 0.11 mmol) and 2-chlorophenylboronic acid [CAS No. 3900-89-8] (17.5 mg, 0.12 mmol). Yield 2.3 mg. M+H 478.

TLC Rf 0.24 (5% MeOH/DCM).

Example 22 6-(3-Chlorophenyl)-2-[1-((1S,5R)-6,6-dimethylbicyclo[3. 1. 1lhept-2-en-2- vlmethyl) piperidin-4-vlaminolbenzothiazole From Intermediate 12 (50 mg, 0.11 mmol) and 3-chlorophenylboronic acid [CAS No. 63503-60-6] (17.5 mg, 0.12 mmol). Yield 3.8 mg. M+H 478.

TLC Rf 0.22 (5% MeOH/DCM).

Example 23 2-f 1- ( (1 S, 5R)-6, 6-Dimethvlbicvclor3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4- ylamino]-6- (2-methoxyphenyl)benzothiazole From Intermediate 12 (50 mg, 0.11 mmol) and 2-methoxyphenylboronic acid [CAS No. 5720-06-9] (17.0 mg, 0.12 mmol). Yield 4.8 mg. M+H 474.

TLC Rf 0.26 (5% MeOH/DCM).

Example 24 2-[1-((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1lhept-2-en-2-vlmethVl) piperidin-4- vlaminol-6- (3-trifluoromethvlphenvl) benzothiazole

From Intermediate 12 (50 mg, 0.11 mmol) and 3-trifluoromethyl- phenylboronic acid [CAS No. 1423-26-3] (21.3 mg, 0.12 mmol). Yield 5.4 mg.

M+H 512. TLC Rf 0.23 (5% MeOH/DCM).

Example 25 2-roi- ((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4- elami (4-trifluoromethvlphenvl) benzothiazole From Intermediate 12 (50 mg, 0.11 mmol) and 4-trifluoromethyl- phenylboronic acid [CAS No. 128796-39-4] (21.3 mg, 0.12 mmol). Yield 4.8 mg. M+H 512. TLC Rf 0. 26 (5% MeOH/DCM).

Example 26 3-f2-r1- ((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1]hept-2-en-2-ylmethyl)piperidin- 4-ylamino] benzothiazol-6-yl}benzonitrile From Intermediate 12 (50 mg, 0.11 mmol) and 3-cyanophenylboronic acid [CAS No. 150255-96-2] (16.5 mg, 0.12 mmol). Yield 4.8 mg. M+H 512.

TLC Rf 0.28 (5% MeOH/DCM).

Example 27 2-[1-((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4- vlaminol-4- (3-trifluoromethvlphenvl) benzothiazole From Example 16 (50 mg, 0.11 mmol) and 3-trifluoromethyl- phenylboronic acid [CAS No. 1423-26-3] (21.3 mg, 0.12 mmol). Yield 10.0 mg.

M+H 512. TLC Rf 0.22 (5% MeOH/DCM).

Example 28 2-[1-((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4- ylamino]-4- (2-methoxyphenyl)benzothiazole From Example 16 (50 mg, 0.11 mmol) and 2-methoxyphenylboronic acid [CAS No. 5720-06-9] (17 mg, 0.12 mmol). Yield 8.4 mg. M+H 474. TLC Rf 0.26 (5% MeOH/DCM).

Example 29 4-(2-Chlorophenvl)-2-r1-((1 S5R)-66-dimethvlbicvclof3. 1. 1lhept-2-en-2- ylmethyl) piperidin-4-vlaminolbenzothiazole From Example 16 (50 mg, 0.11 mmol) and 2-chlorophenylboronic acid [CAS No. 3900-89-8] (17.5 mg, 0.12 mmol). Yield 12.3 mg. M+H 478. TLC Rf 0.21 (5% MeOH/DCM).

Example 30 4- (2,5-Dichlorophenyl)-2-[1-((1S,5R)-6,6-dimethylbicyclo[3.1.1 ]hept-2-en- 2-vimethvl) piperidin-4-vlaminolbenzothiazole From Example 19 (50 mg, 0.11 mmol) and 2, 5-dichlorophenylboronic acid [CAS No. 135145-90-3] (22.0 mg, 0.12 mmol). Yield 11.4 mg. M+H 512.

TLC Rf 0.22 (5% MeOH/DCM).

Example 31 2-r1-((1 S, 5R)-6, 6-Dimethylbisvclof3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4- vlaminol-5- (3-trifluoromethvlphenvl) benzothiazole From Example 17 (50 mg, 0.11 mmol) and 3-trifluoromethyl- phenylboronic acid [CAS No. 1423-26-3] (21.3 mg, 0.12 mmol). Yield 8.9 mg.

M+H 512. TLC Rf 0.23 (5% MeOH/DCM).

Example 32 2-[1-((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1]hept-2-en-2-ylmethyl)piperidin-4- ylamino]-5- (2-methoxyphenyl)benzothiazole From Example 17 (50 mg, 0.11 mmol) and 2-methoxyphenylboronic acid [CAS No. 5720-06-9] (17.0 mg, 0.12 mmol). Yield 12.0 mg. M+H 474.

TLC Rf 0.24 (5% MeOH/DCM).

Example 33 5-(2-Chlorophenyl)-2-[1-((1S,5R)-6,6-dimethylbicyclo[3. 1. 1lhept-2-en-2- vlmethvl) piperidin-4-vlaminolbenzothiazole From Example 17 (50 mg, 0.11 mmol) and 2-chlorophenylboronic acid [CAS No. 3900-89-8] (17.5 mg, 0.12 mmol). Yield 11.2 mg. M+H 478. TLC Rf 0.21 (5% MeOH/DCM).

Example 34 5-(2,5-Dichlorophenyl)-2-[1-((1S,5R)-6,6-dimethylbicyclo[3. 1. 1lhept-2-en- 2-vlmethvl) piperidin-4-vlaminolbenzothiazole From Example 17 (50 mg, 0.11 mmol) and 2, 5-dichlorophenylboronic acid [CAS No. 135145-90-3] (22.0 mg, 0.12 mmol). Yield 9.6 mg. M+H 512.

TLC Rf 0.20 (5% MeOH/DCM).

Example 35 2-r1-((1 S, 5R) -6, 6-Dimethylbicyclo[3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4- yl] -1H-benzimidazole

Prepared in a similar manner to Intermediate 1 from the hydrochloride salt of 4- (benzimidazol-2-yl) piperidine [CAS No. 38385-95] (257 mg, 0.94 mmol) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No.

18486-69-6] (0.142 ml, 0.94 mmol) to give a cream solid (287 mg).

Purification by column chromatography (5% MeOH/CH2CI2) afforded the title compound as a colourless solid (118 mg). RT 1.61 minutes. M+H 336.

Example 36 N-(Benzothiazol-2-yl)-N-[1-((1S,5R)-6,6-dimethylbicyclo[3. 1. 1lhept-2-en-2- v) Pi peridin-4-vll-N-methylamine Prepared in a similar manner to Intermediate 1 from Intermediate 17 (85 mg) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No.

18486-69-6] (50 lui). The crude product was purified by column chromatography on silica, eluting with EtOAc/heptane, to give the title compound (79 mg) as a colourless gum. RT 2. 38 minutes. M+H 382.

Example 37 N- (1H-Benzimidazol-2-yl)-N-[1-((1S,5R)-6,6-dimethylbicyclo[3.1 .1]hept-2- en-2-vlmethvl) piperidin-4-vll-N-methvlamine Prepared in a similar manner to Intermediate 1 from Intermediate 18 (42 mg) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No.

18486-69-6] (30 Ill) to give the title compound (12 mg) as a pale yellow glass.

RT 1.47 minutes. M+H 365.

Example 38 N- (4-Chlorobenzothiazol-2-yl)-N-[1-((1S,5R)-6,6-dimethyl- bicvclof3. 1. 11hept-2-en-2-vlmethvl) piperidin-4-vll-N-methvlamine Prepared in a similar manner to Intermediate 1 from Intermediate 19 (55 mg) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No.

18486-69-6] (29 J) to give the title compound (18 mg) as a colourless gum after purification by preparative HPLC (Method A). RT 2.66 minutes. M+H 416.

Example 39 N-[1-((1S,5R)-6,6-Dimethylbicyclo[3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4- yl]-N-methyl-N- (quinoxalin-2-yl)amine

Prepared in a similar manner to Intermediate 1 from Intermediate 20 (50 mg) and 6, 6-dimethylbicyclo [3.1. 1] hept-2-ene-2-carbaldehyde [CAS No.

18486-69-6] (27 i) to give the title compound (5.9 mg) as a yellow gum/solid after purification by preparative HPLC (Method B). RT 5.00 minutes. M+H 377.

Example 40 2-[1-((1 S, 5R)-6, 6-Dimethylbicyclor3. 1. 1lhept-2-en-2-vlmethvl) piperidin-4- vl1-5-trifluoromethvl-1 H-benzimidazole Intermediate 7 (845 mg, 2.01 mmol) was dissolved in anhydrous pyridine (3 ml) and the solution treated dropwise with phosphorus oxychloride (0.6 ml, 6.44 mmol). The mixture was heated at 80°C for 30 minutes. The solution was quenched with H20 (20 ml) and extracted with EtOAc (2 x 50 ml).

The organic phase was dried (MgS04), concentrated in vacuo, and the residue purified by column chromatography (EtOAc-heptane 1: 2) to afford the title compound as an orange solid (100 mg). RT 2.35 minutes. M+H 404.

Example 41 N-(Benzoxazol-2-vl)-N-91-((1 S, 5R)-6, 6-dimethvl bisvclof3. 1. 1lhept-2-en-2- ylmethvl) piperidin-4-vll-N-methvlamine Example 2 (101 mg) was dissolved in DMF (2 ml) under a N2 atmosphere and NaH (60% in oil, 11.5 mg) was added. The reaction mixture was left to stir for 30 min, then cooled in an ice bath and iodomethane (18 ul) was added. The mixture was allowed to warm to room temperature and left to stir for 24 hours. The reaction mixture was partitioned between Et2O and water (30 mi each) and the organic layer washed with water (2 x 20 ml) and brine (20 ml), dried (MgS04) and evaporated. The crude product was purified by column chromatography on silica, eluting with EtOAc, to give the title compound as a colourless gum (58 mg). RT 2.24 minutes. M+H 366.

Example 42 N- lorobenzothiazol-2-vl)-N-r1-((1 S, 5R) -6, 6-dimethvl- bicvclor3. 1. 11hept-2-en-2-vimethvl) piperidin-4-vll-N-methylamine Prepared in a similar manner to Example 41 from Example 19 (100 mg) and iodomethane to give, after purification by preparative HPLC (Method A), the title compound as a colourless gum (41 mg). RT 2.62 minutes. M+H 416.

Example 43 N- (Benzothiazol-2-yl)-N-(cyclopropylmethyl)-N-[1-((1S,5R)-6,6- dimethyl- bicvclor3. 1. 1lhept-2-en-2-vimethvl) piperidin-4-vllamine Prepared in a similar manner to Example 41 From Example 5 (24 mg) and cyclopropylmethyl bromide [CAS No. 7051-34-5] (9 mg) to give, after purification by preparative HPLC (Method A), the title compound (9.2 mg). RT 2.77 minutes. M+H 422.

Example 44 N- (Benzothiazol-2-vl)-N-f1- ( (1S, 5R)-6, 6-dimethvlbicvclor3. 1. llhept-2-en-2- vimethvl) piperidin-4-vll-N- (3-methoxvpropvl) amine Prepared in a similar manner to Example 41 from Example 5 (57 mg) and 1-bromo-3-methoxypropane [CAS No. 36865-41-5] (24 mg) to give, after purification by preparative HPLC (Method A), the title compound (16.7 mg).

RT 2.60 minutes. M+H 440.

Example 45 4- (Benzoxazol-2-ylamino)-1- ( (1 R, 5S)-6, 6-dimethvlbicvclor3. 1. 1lhept-2-en- 2-vlmethvl)-1-methvlpiperidinium iodide Example 2 (8 mg) was dissolved in dry Et20 (2 ml) and iodomethane (1 ml) was added. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered off and purified by preparative HPLC (Method A) to give the title compound as a white solid (3 mg). RT 2.19 minutes. M+H 366.

Example 46 4-rN- (Benzoxazol-2-vl)-N-methvlaminol-1- ( (1 R, 5S)-6, 6-dimethvl- bicvclor3. 1. 11hept-2-en-2-ylmethvl)-1-methelpiperidinium iodide Example 2 (8 mg) was dissolved in dry Et2O (2 ml) and iodomethane (1 ml) was added. The reaction mixture was stirred overnight at room temperature. The resulting precipitate was filtered off and purified by preparative HPLC (Method A) to give the title compound as a white solid (3 mg). RT 1.56 minutes. M+H 380.

Biological Assavs The following assays were used to demonstrate the activity and selectivity of compounds according to the invention.

Chemokine calcium assay The following assay may be used to determine the inhibition of binding of a chemokine to its receptor.

CHO cells stably transfected with the human CXCR3 were seeded in a 96-well, black-walled, clear-bottomed tissue culture plate and incubated overnight at 37°C in the presence of 5% C02. The culture medium was gently removed from the well and replaced with wash buffer (Hank's Balanced Salts Solution with 0.2% BSA and 20 mM HEPES pH 7.2) containing 3 wu Fluo-4 and 0. 03% pluronic acid. The plate was incubated at 37°C for 1-2 hours, gently washed and 100 pI wash buffer added per well.

Test compounds were dissolved in DMSO and further diluted in wash buffer to give a DMSO concentration of 0.8% (reduced to 0. 2% when added to the assay plate in the FLIPRw).

The assay was performed using a FLIPR TM (Molecular Devices).

Compound was added to the assay plate after a 10 second baseline. Diluted human recombinant ITAC, IP-10 or MIG was added after a further 2 minutes.

Compound activity was calculated as a percentage inhibition of a DMSO solvent control.

Compounds of the invention, including in particular the compounds of each of the Examples, are able to inhibit the binding of ITAC, IP-10 or MIG to their receptor (CXCR3) with an activity of >50% at 5 I1M. In this assay the most active compounds according to the invention have IC50 values of around 1 M or below.

The above assay can also be used to determine the selectivity of the compounds according to the invention, by replacement of CXCR3 with an alternative chemokine receptor such as CCR3 and the use of a chemokine known to bind to such a receptor, such as eotaxin.

In this way the compounds of the invention can be shown to be selective inhibitors of CXCR3. Thus, for example, the compounds of each of the Examples are at least 5 times more selective with respect to CXCR3 than to other chemokine receptors such as CCR3.